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Risks from Dual Antiplatelet Therapy (DAPT) may be reduced by Genotyping Guidance of Cardiac Patients

Reporter: Aviva Lev-Ari, PhD, RN

 

Genotyping Cardiac Patients May Reduce Risks From DAPT

-STEMI patient study reaches noninferiority mark for adverse cardiac events

In the investigational arm, all 1,242 patients were tested for CYP2C19 loss-of-function alleles *2 or *3. Carriers received ticagrelor or prasugrel, while noncarriers received clopidogrel, considered to be less powerful.

No genetic testing was performed in the standard treatment arm (n=1,246), in which patients largely went on to receive ticagrelor or prasugrel. Nearly all patients in both cohorts received dual antiplatelet therapy (DAPT) with aspirin.

Following primary PCI, patients went on to the P2Y12 inhibitor for at least 12 months, with drug adherence similar between the genotype-guided (84.5%) and standard groups (82.0%).

For patients with CYP2C19 loss-of-function alleles in the genotype-guided arm, 38% received ticagrelor and 1% received prasugrel. The remaining 61% of patients — the noncarriers — received clopidogrel. In the control arm, 91% were treated with ticagrelor, 2% with prasugrel, and 7% with clopidogrel, according to local protocol.

Ten Berg said that prasugrel is not typically used in the Netherlands, where eight of the centers in the trial were located, but that this might change given that the drug lowered rates of ischemic events versus ticagrelor in the head-to-head ISAR REACT 5 trial, which was also presented at ESC.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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UPDATED on 2/25/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02-25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

The FDA approved the first ultrathin strut drug-eluting stent, Orsiro, as well as a shelf-stable, premixed vancomycin injection for infective endocarditis and other indications.

UPDATED on 3/16/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02-25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

Dual antiplatelet therapy with ticagrelor (Brilinta) reduced major adverse cardiovascular events in type 2 diabetes patients with coronary artery disease but no prior heart attack or stroke, Astra Zeneca announced in topline results from the THEMIS trial. However, no numerical data were released.

Coronary Artery Interventions: Balloon, Stent, Drug-eluting Stent and Antiplatelet Demand

Curator: Justin D. Pearlman, MD, PhD, FACC

Italicized text represents the voice of Dr. Pearlman

Coronary Artery Disease (CAD), causing impeded blood supply to the heart, constitutes a major cause of disability and death, amounting to triple all forms of cancer combined. The warning symptoms may include a decline in exertion tolerance, usually accompanied by additional symptoms known as “chest pain.” However, “chest pain” is an inaccurate term because it may not be in the chest and it may not include pain (commonly, “chest pain” may occur in the neck, jaw, anterior chest and/or left arm, and may just felt as a light pressure, squeezing, ache, or sense of doom, sometimes with sweating, nausea and/or palpitations, the sensation of abnormal heart beats).

Dr. Heberden is credited with establishing the diagnostic malady called “angina pectoris.” Angina Pectoris corresponds to obstruction in a coronary artery resulting in  exertion-limiting symptoms related to effort (cardiac demand), typically in the chest, neck, jaw and/or arm. The term “angina pectoris” literally means sore throat in the chest. Classic angina is a pressure in the chest that moves to the left arm, reproducible at a particular degree of exertion, such as climbing 1 flight of stairs, that is relieved withing 5 minutes of rest or sublingual nitroglycerin. Other patterns of pain are called “atypical” either because they represent a different expression of the same disease, or because they are not cardiac in etiology. Many studies report that women with CAD are more often “atypical,” which can lead to missed diagnosis.

The first right heart catheterization in a human was performed by Werner Forssmann on himself in 1929. Diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s. Dr. Palin and others identified focal partial blockages in patients with angina by injecting the aorta with iodinated contrast agents followed by x-ray imaging. Selective coronary angiography was described by Mason Sones in the early 1960s, based on an accidental engagement of a catheter into a coronary origin during aortography. 

The facts that coronary angiography generally leads to intervention, and has some risk of damaging an artery and possibly triggering a heart attack, has promoted widespread use of “stress tests” to screen for risk level prior to consummating a decision to perform angiography for elevated coronary risk findings. Coronary revascularization has proven beneficial for classic “ST elevation” heart attacks or the equivalent presenting as a new left bundle block, within the first 6-12 hours of onset, preferably within 1 hour, and also for blockages with poor “flow reserve” involving all tree coronary territories or the left main coronary artery.  Also, revascularization provides a means to relieve angina as an alternative to medications for patients with lesser disease, even though that has not been shown to be reliable in prevention of future heart attacks. Some patients, particularly those with diffuse coronary disease not suitable for stents or bypass, undergo a repeated challenge of compression to the legs and buttocks called “EECP” (enhanced external couterpulsation) to stimulate natural remodeling of the blood supply to the heart, some, after severe damage substantially weakens the heart, take on the cancer and infection risks of a immunosuppression heart transplant, and some receive a mechanical heart or a left ventricular assist pump.

Whereas some “stress tests” check for “rush hour traffic jams” by checking status at baseline and then when speeding up the heart with an exercise challenge, other forms of “stress testing” use chemicals either to speed up the heart rate, to stimulate higher workload conditions, or just to increase blood flow in the coronary arteries (increase traffic by arterial dilation without stress).  Thus, just as “chest pain” does not have to include chest or pain, stress tests do not have to include stress.

Keywords: In-stent restenosis (ISR), stent thrombosis (ST), bare metal stents (BMS), drug-eluting stent (DES), drug-coated balloon (DCB), paclitaxel-eluting balloon (PEB)

The history of cardiac catheterization. – NCBI

Can J Cardiol. 2005 Oct;21(12):1011-4.

The history of cardiac catheterization.

Abstract

The evolution of cardiac catheterization has occurred over at least four centuries. One of the first major steps was the description of the circulation of the blood by William Harvey in 1628. The next milestone was the measurement of arterial pressure by Stephen Hales, one century later. The 19th century represented the golden age of cardiovascular physiology, highlighted by the achievements of Carl Ludwig (physiology of blood pressure), Etienne-Jules Marey (pulse and blood pressure measurement) and Claude Bernard (vasomotor control of blood supply), among others. Human cardiac catheterization developed during the 20th century. The first right heart catheterization in a human was performed by Werner Forssmann on himself in 1929. Diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s, and selective coronary angiography was described by Mason Sones in the early 1960s. More recently, with the advent of catheter-based interventions, pioneered by Andreas Gruentzig in the late 1970s, there has been considerable progress in the refinement and expansion of these techniques. Currently, the Sones technique (direct cannulation of a coronary artery) substantially replaced the previously indirect aortography coronary angiography. Both selective coronary angiography and percutaneous coronary intervention rely mainly on percutaneous femoral and percutaneous radial artery entry routs.

On the occasion of the 50th anniversary of the Montreal Heart Institute, we will highlight the contributions of that institution on selective coronary angiography and percutaneous coronary interventions.

PMID:
16234881

https://www.uptodate.com/contents/intracoronary-stent-restenosis

 

Etiopathogenesis

Restenosis is a progressive phenomenon that begins in the early hours after the barotrauma from PCI (Table 1).

Table 1

Time-related assessment of in-stent restenosis (ISR)
Early (within days)
   Elastic return (recoil) (ER)
   Relocation of axially transmitted plaque
Late (weeks to months)
   Reorganization of thrombus
   Neointima formation
      Cell proliferation
      Cell migration
      Cell matrix synthesis
   Remodelling
   Resolution of inflammation

ISR, in-stent restenosis; ER, elastic recoil.

The three major pathogenic mechanisms that underlie restenosis are:

  1. Early elastic return (recoil) (ER);
  2. Vascular remodeling;
  3. Neointimal hyperplasia.

The first and the second mechanisms are typical of “old-style” or “plain old balloon” angioplasty (POBA) before the stent era. The presence of metallic struts from stents promotes a new mechanism called neointimal hyperplasia.

Myointimal trauma induced by PCI affects the atherosclerotic process and changes its course from the natural evolution of atherosclerotic plaque to a more aggressive local response to the treatment. Atherosclerosis is characterized by a sequence of processes which induce vasoconstriction and the initial endothelial dysfunction resulting in the mechanism of endoplasmic reticulum (ER and vascular remodelling, enhanced by an inflammatory process triggered by vessel injury, as evidenced by the increase in C-reactive protein or MCP-1 in patients at increased risk of restenosis (20).

SOURCES

 

 

The following articles review the benefits of stents to keep coronary arteries propped open after balloon expansion of a focal area of blockage. These articles establish the motivation for drug-eluting stents to address the problem that stents introduced of stimulating a tissue reaction which causes early in-stent re-stenosis (tissue in-growth obstructing the desired blood channel).

Research findings which support the widespread use of drug-eluting stents and uninterrupted use of strong antiplatelet agents

  • TI In-stent restenosis in the drug-eluting stent era.
  • AU Dangas GD, Claessen BE, Caixeta A, Sanidas EA, Mintz GS, Mehran R
  • SO J Am Coll Cardiol. 2010;56(23):1897.
The introduction of the drug-eluting stent (DES) proved to be an important step forward in reducing rates of restenosis and target lesion revascularization after percutaneous coronary intervention. However, the rapid implementation of DES in standard practice and expansion of the indications for percutaneous coronary intervention to high-risk patients and complex lesions also introduced a new problem: DES in-stent restenosis (ISR), which occurs in 3% to 20% of patients, depending on patient and lesion characteristics and DES type. The clinical presentation of DES ISR is usually recurrent angina, but some patients present with acute coronary syndrome. Mechanisms of DES ISR can be biological, mechanical, and technical, and its pattern is predominantly focal. Intravascular imaging can assist in defining the mechanism and selecting treatment modalities. Based upon the current available evidence, an algorithm for the treatment approaches to DES restenosis is proposed.AD
Cardiovascular Institute, Mount Sinai Medical Center, New York, New York 10029, USA. george.dangas@mssm.eduPMID
This is an early report on advantages of stent placement over the prior “plain old balloon angioplasty” (POBA). 
BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes.
METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.
RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, P = 0.011), a larger immediate increase in the diameter of the lumen (1.72 +/- 0.46 vs. 1.23 +/- 0.48 mm, P<0.001), and a larger luminal diameter immediately after the procedure (2.49 +/- 0.43 vs. 1.99 +/- 0.47 mm, Por = 50 percent) of 22 and 32 percent, respectively (P = 0.02). Peripheral vascular complications necessitating surgery, blood transfusion, or both were more frequent after stenting than after balloon angioplasty (13.5 vs. 3.1 percent, P<0.001). The mean hospital stay was significantly longer in the stent group than in the angioplasty group (8.5 vs. 3.1 days, Por =50% follow-up diameter stenosis [DS]) in 419 of 1,437 (29%) patients undergoing routine angiographic follow-up correlated directly with the likelihood of TLR (73% vs. 26% for>70% DS compared with<60% DS). Smaller pretreatment minimum lumen diameter (MLD), smaller final MLD, longer stent length, diabetes mellitus, unstable angina, and hypertension were independent predictors of TLR. Prior MI and current smoking were negative predictors.
CONCLUSIONS: At one year after stenting, most clinical restenosis reflected TLR, which was predicted by the same variables previously associated with an increased risk of angiographic restenosis. The lower absolute rate of clinical restenosis relative to angiographic restenosis was due to infrequent TLR in lesions with less severe (28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization.
CONCLUSION: Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents.

The following reports clarified the basis for early stent re-stenosis, first by intravascular miniaturized ultrasound imaging of the problem, then by animal models.

BACKGROUND: Studies have suggested that restenosis within Palmaz-Schatz stents results from neointimal hyperplasia or chronic stent recoil and occurs more frequently at the articulation.
METHODS AND RESULTS: Serial intravascular ultrasound (IVUS) was performed after intervention and at follow-up in 142 stents in 115 lesions. IVUS measurements (external elastic membrane [EEM], stent, and lumen cross-sectional areas [CSAs]and diameters) were performed, and plaque CSA (EEM lumen in reference segments and stent lumen in stented segments), late lumen loss (delta lumen), remodeling (delta EEM in reference segments and delta stent in stented segments), and tissue growth (delta plaque) were calculated. After intervention, the lumen tended to be smallest at the articulation because of tissue prolapse. At follow-up, tissue growth was uniformly distributed throughout the stent; the tendency for greater neointimal tissue accumulation at the central articulation reached statistical significance only when normalized for the smaller postintervention lumen CSA. In stented segments, late lumen area loss correlated strongly with tissue growth but only weakly with remodeling. Stents affected adjacent vessel segments; remodelingprogressively increased and tissue growth progressively decreased at distances from the edge of the stent. These findings were similar in native arteries and saphenous vein grafts and in lesions treated with one or two stents. There was no difference in the postintervention or follow-up lumen (at the junction of the two stents) when overlapped were compared with nonoverlapped stents.
CONCLUSIONS: Late lumen loss and in-stent restenosis were the result of neointimal tissue proliferation, which tended to be uniformly distributed over the length of the stent.

Animal modeling as well as human sample histology showed biochemical basis for stent tissue in-growth which lead to effective choices for drug-eluting stents to release chemicals slowly over a long time to counteract that issue. However, the treatment may be too effective, as it also blocks protective endothelial lining of the stents, so blood products in circulation passing through a stent remain exposed to trauma that can promote thrombosis.

OBJECTIVES: We examined the relative contributions of inflammation and arterial injury to neointimal formation in a porcine coronary overstretch restenosis model.
BACKGROUND: Previous studies established that stents cause neointimal proliferation proportional to injury. Although inflammation has been postulated to be a major contributor to restenosis after angioplasty, there is a paucity of data on the relation between inflammation and subsequent neointimal formation.
METHODS: Twenty-one pigs underwent balloon injury followed by implantation of oversized, tubular, slotted stents (stent/artery ratio 1.2:1) in the left anterior descending coronary artery. Morphometric analysis of the extent of injury (graded as injury score 0 to 3) and inflammation (graded as inflammation score 0 to 3) 1 month later was assessed and correlated with neointimal formation.
RESULTS: An inflammatory reaction was observed in 20 of 21 pigs, and significant positive correlations were found between the degree of arterial injury and the extent of the inflammatory reaction (r = 0.80, p<0.01) and between the extent of inflammatory reaction and the neointimal thickness (r = 0.75, p<0.01), neointimal area (r = 0.53, p = 0.01) and percent area stenosis (r = 0.66, p<0.01) within the stents. Importantly, there were areas with inflammation only in the absence of injury, and vice versa, that were also associated with neointimal hyperplasia.
CONCLUSIONS: These data suggest that the inflammatory reaction plays an equally important role as arterial injury in neointimal formation after coronary stenting, and that anti-inflammatory approaches may be of value to reduce in-stent restenosis.

BACKGROUND: Experimental animal studies have shown that coronary stenting induces neointimal proliferation. However, the histopathological events after coronary stenting in humans have not been studied systematically.
METHODS AND RESULTS: We investigated 11 stented coronary arteries (9 Palmaz-Schatz stents, 1 Wiktor stent, and 1 ACS Multi-Link stent) obtained from 11 patients who had died 2 days to 21 months after stenting. We focused on gross, histological, and immunohistochemical aspects of the repair processes. Two patients developed symptoms of restenosis. Serial sections were stained with antibodies against smooth muscle cells (SMCs), macrophages, and endothelial cells. At 9 and 12 days after stenting, the stent sites showed thrombus formation with early formation of neointima composed of abundant macrophages and alpha-actin-negative spindle cells. From 64 days on, all sites with stenting showed a distinct layer of neointima, albeit to varying degrees. In nonrestenotic lesions, neointimal thickening was markedly less than in restenotic lesions but without qualitative differences; the neointima contained macrophages but was composed predominantly of alpha-actin-positive SMCs.
CONCLUSIONS: These observations strongly support the concept that neointimal proliferation in humans is a process of staged redifferentiation of SMCs, which may cause in-stent stenosis. Moreover, the exuberant neointimal proliferation with accumulation of macrophages and extensive neovascularization at sites of stent restenosis suggests a role for organization of mural thrombus.

BACKGROUND: Despite the increasing use of stents, few reports have described human coronary artery morphology early and late after stenting.

METHODS AND RESULTS: Histology was performed on 55 stents in 35 coronary vessels (32 native arteries and 3 vein grafts) from 32 patients. The mean duration of stent placement was 39+/-82 days. Fibrin, platelets, and neutrophils were associated with stent struts</=11 days after deployment. In stents implanted for20 associated inflammatory cells compared with 44% of struts embedded in a lipid core and 36% of struts in contact with damaged media (P<0.001). Neointimal growth determined late histological success, and increased neointimal growth correlated with increased stent size relative to the proximal reference lumen area. Neointimal thickness was greater for struts associated with medial damage than struts in contact with plaque (P<0.0001) or intact media (P<0.0001). When matched for time since treatment, neointimal cell density in stented arteries was similar to that in unstented arteries that had undergone balloon angioplasty and showed similar proteoglycan deposition.

CONCLUSIONS: Morphology after coronary stenting demonstrates early thrombus formation and acute inflammation followed by neointimal growth. Medial injury and lipid core penetration by struts result in increased inflammation. Neointima increases as the ratio of stent area to reference lumen area increases. Deployment strategies that reduce medial damage and avoid stent oversizing may lower the frequency of in-stent restenosis.

OBJECTIVES: The goal of this study was to evaluate the cellular and extracellular composition of human coronary arterial in-stent restenosis after various periods of time following stent deployment.

BACKGROUND: Neointimal in-growth rather than stent recoil is thought to be important for coronary arterial in-stent restenosis. There is only limited data on the cellular and extracellular composition changes with time after stent deployment.

METHODS: We analyzed 29 coronary arterial in-stent restenotic tissue samples (14 left anterior descending coronary artery, 10 right coronary artery, and 5 left circumflex artery) retrieved by using directional coronary atherectomy from 25 patients at 0.5 to 23 (mean, 5.7) months after deployment of Palmaz-Schatz stents employing histochemical and immunocytochemical techniques.

RESULTS: Cell proliferation was low (0% to 4%). Myxoid tissue containing extracellular matrix (ECM) enriched with proteoglycans was found in 69% of cases and decreased over time after stenting. Cell-depleted areas were found in 57% of cases and increased with time after stenting. Versican, biglycan, perlecan, and hyaluronan were present with varying individual distributions in all samples. Positive transforming growth factor-beta1 staining was found in 80% of cases. Immunostaining with alpha-smooth muscle actin identified the majority of cells as smooth muscle cells with occasional macrophages present (<or =12 cells per section).

CONCLUSIONS: These data suggest that enhanced ECM accumulation rather than cell proliferation contribute to later stages of in-stent restenosis. Balloon angioplasty of in-stent restenosis may, therefore, fail due to ECM changes during: 1) additional stent expansion, 2) tissue extrusion out of the stent, or 3) tissue compression.

BACKGROUND: Coronary-artery stents are known to reduce rates of restenosis after coronary angioplasty, but it is uncertain how long this benefit is maintained.

METHODS: We evaluated clinical and angiographic follow-up information for up to three years after the implantation of Palmaz-Schatz metallic coronary-artery stents in 143 patients with 147 lesions of native coronary arteries.

RESULTS: The rate of survival free of myocardial infarction, bypass surgery, and repeated coronary angioplasty for stented lesions was 74.6 percent at three years. After 14 months, revascularization of the stented lesion was necessary in only three patients (2.1 percent). In contrast, coronary angioplasty for a new lesion was required in 11 patients (7.7 percent). Follow-up coronary angiography of 137 lesions at six months, 114 lesions at one year, and 72 lesions at three years revealed a decrease in minimal luminal diameter from 2.54 +/- 0.44 mm immediately after stent implantation to 1.87 +/- 0.56 mm at six months, but no further decrease in diameter at one year (in patients with paired angiograms, 1.95 +/- 0.49 mm at both six months and one year). Significant late improvement in luminal diameter was observed at three years (in patients with paired angiograms, 1.94 +/- 0.48 mm at six months and 2.09 +/- 0.48 mm at three years; P<0.001).

CONCLUSIONS: Clinical and angiographic outcomes up to three years after coronary-artery stenting were favorable, with a low rate of revascularization of the stented lesions. Late improvement in luminal diameter appears to occur between six months and three years.

BACKGROUND: Recently, it has been reported that the luminal diameter shows phasic changes after stenting: the progression of luminal narrowing followed by its regression. To elucidate the mechanisms involved in the phasic changes in luminal diameter after stenting, we examined the changes in neointimal thickness and the appearance of neointima by a series of angiographic and angioscopic observations for 3 years after stent implantation.

METHODS AND RESULTS: In 12 patients who received a Wiktor coronary stent, serial angiographic and angioscopic examinations were performed immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after the stenting without repetition of angioplasty. Neointimal thickness was determined by angiography as the difference between stent and luminal diameters. The angioscopic appearance of neointima over the stent was classified as transparent or nontransparent according to the visibility of the majority of the stent. Neointimal thickness increased significantly at 3 months (0.75+/-0.32 mm) without further changes at 6 months (0.74+/-0.32 mm). Thereafter, however, it decreased significantly over 3 years (0.51+/-0.26 mm). The angioscopic appearance was classified as transparent in 8 patients (100) immediately after stenting, 6 patients (100%) at 2 to 4 weeks, 2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7 patients (58%) at 3 years.

CONCLUSIONS: The neointima became thick and nontransparent until 6 months and then became thin and transparent by 3 years. We conclude that neointimal remodeling exists after stenting and plays a major role in the alteration of coronary luminal diameter after stenting.

Although previous randomized trials 1-2 have demonstrated lower restenosis rates in selected lesions with coronary stents than with conventional balloon angioplasty. in-stent restenosis remains an important clinical problem.(3,4) Previous serial angiographic studies(5,6) showed that lumen loss after stenting occurred within 6 months. On the other hand, improvements in lumen dimensions between 6 months and 2 to 3 years have been demonstrated by angiography.(6-9) Serial (postintervention and at 6-month follow-up) intravascular ultrasound (IVUS) studies(10,11) have demonstrated that coronary stenting eliminates negative arterial remodeling, and thus intimal hyperplasia is solely responsible for in-stent restenosis. However, little has been reported about changes in intimal hyperplasia that occur beyond this 6-month period. This serial IVUS study evaluated the changes in intimal hyperplasia between 6 and 12 months after stent placement.

BACKGROUND: The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR).

METHODS AND RESULTS: We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (10 mm within the stent, pattern III includes ISR>10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively; P=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (P=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (Por =50%, late lumen loss as lumen diameter reduction and target lesion revascularization (TLR) as any repeat PTCA or coronary artery bypass surgery involving the stented lesion.

RESULTS: Multivariate analysis demonstrated that diabetes mellitus, placement of multiple stents and minimal lumen diameter (MLD) immediately after stenting were the strongest predictors of restenosis. Diabetes increased the risk of binary restenosis with an odds ratio (OR) [95% confidence interval]of 1.86 [1.56 to 2.16]and the risk of TLR with an OR of 1.45 [1.11 to 1.80]. Multiple stents increased the risk of binary restenosis with an OR of 1.81 [1.55 to 2.06]and that of TLR with an OR of 1.94 [1.66 to 2.22]. An MLDor = 50% diameter stenosis at follow-up angiography, diffuse restenosis as a follow-up lesion length>or = 10 mm and aggressive restenosis as either an increase in lesion length from the original lesion or a restenotic narrowing tighter than the original. Clinical, anatomic and procedural characteristics were evaluated for lesions associated with these types of restenosis.

RESULTS: Diffuse restenosis was associated with a smaller reference artery diameter, longer lesionlength, female gender, longer stent length and the use of coil stents. Aggressive restenosis was more common in women, with the use of Wallstents and with long stent to lesion length ratios. Aggressive restenosis occurred earlier and was more closely associated with symptoms and myocardial infarctions than nonaggressive restenotic lesions.

CONCLUSIONS: Markers for diffuse restenosis were also important markers for the presence of any restenosis. A long stent to lesion length ratio is an important marker for aggressive restenosis. When severe forms of in-stent restenosis occur, they tend to present earlier and with more symptoms, including myocardial infarction. More careful consideration of the type of in-stent restenosis may aid in identifying when alternative strategies may be useful.

OBJECTIVES: We sought to assess whether coronary stents have modified the predictive value of demographic, clinical and quantitative coronary angiographic (QCA) predictors of coronary restenosis.

BACKGROUND: A systematic analysis in a large cohort of registries and randomized trials of the percutaneous transluminal coronary angioplasty (PTCA) and stent era has never been performed.

METHODS: A total of 9,120 treated lesions in 8,156 patients included in nine randomized trials and 10 registries, with baseline, post-procedural and six-month follow-up QCA analyses, were included in this study. Predictors of restenosis were identified with univariate and multivariate logistic regression analyses. Interaction terms were introduced in the regression equation to evaluate whether the predictors of restenosis were common to both eras or specific for either one of the revascularization techniques.

RESULTS: The restenosis rate was 35% after PTCA and 19% after angioplasty with additional stenting. In the univariate analysis, favorable predictors were previous coronary artery bypass graft surgery (CABG), stent use, stent length and a large pre-procedural minimal lumen diameter (pre-MLD); unfavorable predictors were weight, body mass index, diabetes mellitus, multi-vessel disease, lesion length and a high residual post-procedural diameter stenosis (post-DS). Predictors specific for the PTCA population were a large post-procedural MLD (post-MLD) as favorable and a severe pre-procedural DS (pre-DS) as unfavorable. Favorable predictors specific for the stent population were a large post-MLD and a large pre-procedural reference diameter (pre-RD). In the multivariate analysis, the best model included the following favorable predictors: stent use, a large post-MLD, previous CABG and the interaction term between stent use and a large post-MLD; unfavorable predictors were lesion length and diabetes mellitus.

CONCLUSIONS: There are no major differences in demographic and clinical predictors of coronary restenosis between PTCA and stent populations. In the modern (stent) era, a severe pre-DS is no longer an unfavorable predictor of restenosis. Still important, but more so in the stent population, is a large post-MLD (optimal result). Finally, a larger pre-RD became a favorable predictor with the advent of stenting.

OBJECTIVES: We sought to evaluate the relation between stented segment length and restenosis.

BACKGROUND: Multiple or long coronary stents are now being implanted in long lesions or in tandem lesions. A longer stented segment might result in a higher probability of restenosis. However, there is little information available on the relation between stented segment length and restenosis.

METHODS: Between April 1995 and December 1996, 725 patients with 1,090 lesions underwent stenting. Lesions were divided into three groups according to the length of the stented segment: 1) group I (n = 565): stented segment length20 but35 mm.

RESULTS: There was no significant difference in the incidence of subacute stent thrombosis among the three groups (0.4% in group I, 0.4% in group II, 1.2% in group III; p = NS). The minimal lumen diameter (MLD) after stenting was greater in group I than in group III (3.04 +/- 0.60 mm in group I, 3.01 +/- 0.54 mm in group II, 2.91 +/- 0.58 mm in group III; p<0.05). At follow up, a smaller MLD was observed in group III as compared with group I and group II (2.04 +/- 0.93 mm in group I, 1.92 +/- 1.00 mm in group II, 1.47 +/- 0.97 mm in group III; p<0.01). The restenosis rates were 23.9% in group I, 34.6% in group II and 47.2% in group III (p36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to11.01; P<0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P<0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P=0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P<0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P=0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P<0.01).

CONCLUSIONS: Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

BACKGROUND: The aim of this study was to evaluate the relationship between residual plaque burden after coronary stent implantation and the development of late in-stent neointimal proliferation.

METHODS AND RESULTS: Between January 1996 and May 1997, 50 patients underwent intravascular ultrasound (IVUS) interrogation at 6+/-1.2 months after coronary stent implantation in native coronary arteries. IVUS images were acquired with a motorized pullback, and cross-sectional measurements were performed within the stents at 1-mm intervals. The following measurements were obtained: (1) lumen area (LA), (2) stent area (SA), (3) area delimited by the external elastic membrane (EEMA), (4) percent neointimal area calculated as (SA-LA/SA)x100, and (5) percent residual plaque area calculated as (EEMA-SA)/EEMAx100. Volume measurements within the stented segments were calculated by applying Simpson’s rule. In the pooled data analysis of 876 cross sections, linear regression showed a significant positive correlation between percent residual plaque area and percent neointimal area (r=0.50, y= 45.03+0.29x, P<0.01). There was significant incremental increase in mean percent neointimal area for stepwise increase in percent residual plaque area. Mean percent neointimalarea was 16.3+/-10.3% for lesions with a percent residual plaque area of/=50% (P<0.001). The volumetric analysis showed that the percent residual plaque volume was significantly greater in restenotic lesions compared with nonrestenotic lesions (58.7+/-4.3% versus 51.4+/-5.7%, respectively; Por = 50% diameter stenosis at follow-up, follow-up percent diameter stenosis [DS]and follow-up minimal lumen diameter [MLD]) were determined.

RESULTS: Three variables were the most consistent predictors of the follow-up angiographic findings: ostial lesion location, IVUS preinterventional lesion site plaque burden (plaque/total arterial area) and IVUS assessment of final lumen dimensions (whether final lumen area or final MLD). All three variables predicted both the primary (binary restenosis) and secondary (follow-up MLD and follow-up DS) end points. In addition, a number of variables predicted one or more but not all the end points: 1) restenosis (IVUS preinterventional lumen and arterial area); 2) follow-up DS (QCA lesion length); and 3) follow-up MLD (QCA lesion length and preinterventional MLD and DS and IVUS preinterventional lumen and arterial area).

CONCLUSIONS: Ostial lesion location and IVUS preinterventional plaque burden and postinterventional lumen dimensions were the most consistent predictors of angiographic in-stent restenosis.

OBJECTIVES: We aimed to identify periprocedural quantitative coronary angiographic (QCA) variables that have predictive value on long-term angiographic results and to construct multivariate models using these variables for postprocedural prognosis.

BACKGROUND: Coronary stent implantation has reduced the restenosis rate significantly as compared with balloon angioplasty in short de novo lesions in coronary arteries>3 mm in size. Although the postprocedural minimal luminal diameter (MLD) is known to have significant bearing on long-term angiographic results, no practically useful model exists for prediction of angiographic outcome based on the periprocedural QCA variables.

METHODS: The QCA data from patients who underwent Palmaz-Schatz stent implantation for short (3 mm and completed six months of angiographic follow-up in the four prospective clinical trials (BENESTENT I, BENESTENT II pilot, BENESTENT II and MUSIC) were pooled. Multiple models were constructed using multivariate analysis. The Hosmer-Lemeshow goodness-of-fit test was used to identify the model of best fit, and this model was used to construct a reference chart for prediction of angiographic outcome on the basis of periprocedural QCA variables.

RESULTS: Univariate analysis performed using QCA variables revealed that vessel size, MLD before and after the procedure, reference area before and after the procedure, minimal luminal cross-sectional area before and after the procedure, diameter stenosis after the procedure, area of plaque after the procedure and area stenosis after the procedure were significant predictors of angiographic outcome. Using multivariate analysis, the Hosmer-Lemeshow goodness-of-fit test showed that the model containing percent diameter stenosis after the procedure and vessel size best fit the data. A reference chart was then developed to calculate the expected restenosis rate.

CONCLUSIONS: Restenosis rate after stent implantation for short lesions can be predicted using the variables percent diameter stenosis after the procedure and vessel size. This meta-analysis indicates that the concept of “the bigger the better” holds true for coronary stent implantation. Applicability of the model beyond short lesions should be tested.

BACKGROUND: Restenosis prediction from published studies is hampered by inadequate sample size and incomplete angiographic follow-up. The prediction of restenosis with the existing variables is poor. The aim of the present study was to include the clinical and angiographic variables commonly associated with angiographic restenosis and develop a prediction model for restenosis from the PRESTO database.

METHODS AND RESULTS: This study included 1312 patients with a single lesion enrolled in the angiographic substudy of the PRESTO trial. We constructed 2 risk scores. The first used preprocedural variables (female gender, vessel size [4 mm], lesion length>20 mm, diabetes, smoking status, type C lesion, any previous percutaneous coronary intervention [PCI], and unstable angina) derived from previous studies. Estimated restenosis rates and corresponding variability for each possible level of the resultant risk score were obtained via bootstrapping techniques. The area under the receiver-operator characteristic (ROC) curve was 0.63, indicating modest discriminatory abilityto predict restenosis. The second approach constructed a multiple logistic regression model considering significant univariate clinical and angiographic predictors of restenosis identified from the PRESTO database (treated diabetes mellitus, nonsmoker, vessel size, lesion length, American College of Cardiology/American Heart Association type C lesion, ostial location, and previous PCI). The area under the ROC curve for this risk score was also 0.63.

CONCLUSIONS: The preprocedural clinical and angiographic variables from available studies and from the PRESTO trial have only modest predictive ability for restenosis after PCI.

  • AD Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minn 55905, USA.
  • PMID 15173022
  • TI Effects of stent length and lesion length on coronary restenosis.
  • AU Mauri L, O’Malley AJ, Cutlip DE, Ho KK, Popma JJ, Chauhan MS, Baim DS, Cohen DJ, Kuntz RE
  • SO Am J Cardiol. 2004;93(11):1340.

The choice of drug-eluting versus bare metal stents is based on costs and expectations of restenosis and thrombosis risk. Approaches to stent placement vary from covering just the zone of maximal obstruction to stenting well beyond the lesion boundaries (normal-to-normal vessel). The independent effects of stented lesion length, nonstented lesion length, and excess stent length, on coronary restenosis have not been evaluated for bare metal or drug-eluting stents. We analyzed the angiographic follow-up cohort (1,181 patients) from 6 recent bare metal stent trials of de novo lesions in native coronary arteries. Stent length exceeded lesion length in 87% of lesions (mean lesion length 12.4 +/- 6.3 mm, mean stent length 20.0 +/- 7.9 mm, mean difference 7.6 +/- 7.9 mm). At 6- to 9-month follow-up, the mean percent diameter stenosis was 39.1 +/- 20.1%. In an adjusted multivariable model of percent diameter stenosis, each 10 mm of stented lesion length was associated with an absolute increase in percent diameter stenosis of 7.7% (p<0.0001), whereas each 10 mm of excess stent length independently increased percent diameter stenosis by 4.0% (p<0.0001) and increased target lesion revascularization at 9 months (odds ratio 1.12, 95% confidence interval 1.02 to 1.24). Significant nonstented lesion length was uncommon (12.5% of cases). In summary, stent length exceeded lesion length in most stented lesions, and the amount of excess stent length increased the risk of restenosis independent of the stented lesion length. This analysis supports a conservative approach of matching stent length to lesion length to reduce the risk of restenosis with bare metal stents.

BACKGROUND: Observed rates of restenosis after drug-eluting stenting are low (or =32% relative increase in power,>or =24% absolute increase for late loss between 0.2 and 0.6 mm).

CONCLUSIONS: Late loss is monotonically related to restenosis risk in published stent trials. It is a generalizable and powerful angiographic end point in early or small trials of new drug-eluting stents.

BACKGROUND: Binary angiographic and clinical restenosis rates can vary widely between clinical studies, even for the same stent, influenced heavily by case-mix covariates that differ among observational and randomized trials intended to assess a given stent system. We hypothesized that mean in-stent late loss might be a more stable estimator of restenosis propensity across such studies.

METHODS AND RESULTS: In 46 trials of drug-eluting and bare-metal stenting, increasing mean late loss was associated with higher target lesion revascularization (TLR) rates (P<0.001). When the class of bare-metal stents was compared with the class of effective drug-eluting stents, late loss was more discriminating than TLR as measured by the high intraclass correlation coefficient (rho) (late loss, rho=0.71 versus TLR, rho=0.22; 95% CI of difference=0.33, 0.65). When the individual drug-eluting stents and bare-metal stents were compared, late loss was a better discriminator than TLR (0.68 versus 0.19; 95% CI of difference=0.24, 0.60). Greater adjustments of study covariates are needed to stabilize assessments of TLR compared with late loss because of greater influence of reference vessel diameter on TLR than on in-stent late loss. Optimization of late loss with the use of a novel method ofstandardization according to diabetes prevalence and mean lesion length resulted in minor adjustments in late loss (<0.08 mm for 90% of reported trials) and an ordered array of mean late loss values for the stent systems studied.

CONCLUSIONS: Late loss is more reliable than restenosis rates for discriminating restenosis propensity between new drug-eluting stent platforms across studies and might be the optimum end point for evaluating drug-eluting stents in early, nonrandomized studies.

BACKGROUND: Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization.

METHODS: We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days.

RESULTS: The rate of failure of the target vessel was reduced from 21.0 percent with a standard stentto 8.6 percent with a sirolimus-eluting stent (P<0.001)–a reduction that was driven largely by a decrease in the frequency of the need for revascularization of the target lesion (16.6 percent in the standard-stent group vs. 4.1 percent in the sirolimus-stent group, P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received sirolimus-eluting stents, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target-lesion revascularization in all subgroups examined.

CONCLUSIONS: In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed.

  • AD Cardiovascular Research Foundation and Lenox Hill Heart and Vascular Institute of New York, New York 10021, USA. jmoses@lenoxhill.net
  • PMID 14523139
  • TI A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.
  • AU Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME, TAXUS-IV Investigators
  • SO N Engl J Med. 2004;350(3):221.

BACKGROUND: Restenosis after coronary stenting necessitates repeated percutaneous or surgical revascularization procedures. The delivery of paclitaxel to the site of vascular injury may reduce the incidence of neointimal hyperplasia and restenosis.

METHODS: At 73 U.S. centers, we enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis (vessel diameter, 2.5 to 3.75 mm; lesion length, 10 to 28 mm) in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a bare-metal stent, and 662 to receive an identical-appearing, slow-release, polymer-based, paclitaxel-eluting stent. Angiographic follow-up was prespecified at nine months in 732 patients.

RESULTS: In terms of base-line characteristics, the two groups were well matched. Diabetes mellitus was present in 24.2 percent of patients; the mean reference-vessel diameter was 2.75 mm, and the mean lesion length was 13.4 mm. A mean of 1.08 stents (length, 21.8 mm) were implantedper patient. The rate of ischemia-driven target-vessel revascularization at nine months was reduced from 12.0 percent with the implantation of a bare-metal stent to 4.7 percent with the implantation of a paclitaxel-eluting stent (relative risk, 0.39; 95 percent confidence interval, 0.26 to 0.59; P<0.001). Target-lesion revascularization was required in 3.0 percent of the group that received a paclitaxel-eluting stent, as compared with 11.3 percent of the group that received a bare-metal stent (relative risk, 0.27; 95 percent confidence interval, 0.16 to 0.43; P<0.001). The rate of angiographic restenosis was reduced from 26.6 percent to 7.9 percent with the paclitaxel-eluting stent (relative risk, 0.30; 95 percent confidence interval, 0.19 to 0.46; P<0.001). The nine-month composite rates of death from cardiac causes or myocardial infarction (4.7 percent and 4.3 percent, respectively) and stent thrombosis (0.6 percent and 0.8 percent, respectively) were similar in the group that received a paclitaxel-eluting stent and the group that received a bare-metal stent.

CONCLUSIONS: As compared with bare-metal stents, the slow-release, polymer-based, paclitaxel-eluting stent is safe and markedly reduces the rates of clinical and angiographic restenosis at nine months.

BACKGROUND: Recent studies have suggested that smokers may require less frequent repeated revascularization after percutaneous coronary intervention (PCI) compared with nonsmokers. However, the mechanism of this phenomenon is unknown.

METHODS AND RESULTS: We examined the association between smoking and restenosis using pooled data from 8671 patients treated with PCI in 9 multicenter clinical trials. Clinical restenosis was examined in the cohort of 5682 patients who were assigned to clinical follow-up only. Angiographic restenosis was evaluated in the subset of 2989 patients who were assigned to mandatory angiographic restudy. Among those patients assigned to clinical follow-up only, target lesion revascularization (TLR) occurred in 6.6% of smokers and 10.1% of nonsmokers (P<0.001). After adjustment for baseline clinical and angiographic differences, the rate of TLR remained significantly lower in smokers with an adjusted relative risk of 0.69 (95% CI, 0.54 to 0.88). Among the angiographic cohort, there were no differences in the rates of angiographic restenosis or follow-up diameter stenosis in either univariate or multivariate analyses. This dissociation between clinical and angiographic restenosis was explained in part by reduced sensitivity to restenosis on the part of smokers and by the greater reluctance of smokers to seek medical attention despite recurrent angina.

CONCLUSIONS: In patients undergoing contemporary PCI, cigarette smoking is associated with a lower rate of subsequent TLR without affecting angiographic restenosis. These findings have important implications for the follow-up of smokers after PCI and suggest that cross-study comparisons of rates of clinical restenosis must account for the potential confounding effect of smoking.

  • AU Violaris AG, Thury A, Regar E, Melkert R, Serruys PW
  • SO Heart. 2000;84(3):299.

OBJECTIVES: To assess the influence of smoking on restenosis after coronary angioplasty.

DESIGN AND PATIENTS: The incidence of smoking on restenosis was investigated in 2948 patients. They were prospectively enrolled in four major restenosis trials in which quantitative angiography was used before and immediately after successful angioplasty and again at six months.

RESULTS: Within the study population there were 530 current smokers, 1690 ex-smokers, and 728 non-smokers. Smokers were more likely to be men (85.9% v 87. 5% v 65.3%, current v ex- v non-, p<0.001), to be younger (54.0 (9. 0) v 57.0 (9.1) v 59.9 (9.4) years, p<0.001), to have peripheral vascular disease (7.2% v 5.5% v 2.3%, p<0.001), and have sustained a previous myocardial infarction (42.9% v 43.9% v 37.9%, p = 0.022), but were less likely to be diabetic (9.1% v 9.5% v 12.6%, p = 0.043) or hypertensive (24.9% v 29.3% v 37.2, p50% diameter stenosis) at six months (35.28% v 35.33% v 37.09%, current v ex- v non-), or the absolute loss (0.29 (0.54) v 0.33 (0.52) v 0. 35(0.55) mm, respectively; p = 0.172).

CONCLUSIONS: Although smokers have a lower incidence of known predisposing risk factors for atherosclerosis, they require coronary intervention almost six years earlier than non-smokers and three years earlier than ex-smokers. Once they undergo successful coronary angioplasty, there appears to be no evidence that smoking influences their short term (six month) outcome, but because of the known long term effects of smoking, patients should still be encouraged to discontinue the habit.

  • AU Pache J, Kastrati A, Mehilli J, Schühlen H, Dotzer F, Hausleiter J, Fleckenstein M, Neumann FJ, Sattelberger U, Schmitt C, Müller M, Dirschinger J, Schömig A
  • SO J Am Coll Cardiol. 2003;41(8):1283.

OBJECTIVES: We tested the hypothesis that thinner-strut stents are associated with a reduced rate of restenosis when comparing two stents with different design.

BACKGROUND: We have previously shown that, for two stents with similar design, the risk for restenosis is dependent on the strut thickness. It is unknown whether strut thickness preserves its relevance as a determinant of restenosis even in the presence of different stent designs.

METHODS: A total of 611 patients with symptomatic coronary artery disease were randomly assigned to receive either the thin-strut ACS RX Multilink stent (Guidant, Advanced Cardiovascular Systems, Santa Clara, California) (strut thickness 50 microm, interconnected ring design; n = 309) or the thick-strut BX Velocity stent (Cordis Corp., Miami, Florida) (strut thickness 140 microm, closed cell design; n = 302). The primary end point was angiographic restenosis (>or =50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of target-vessel revascularization (TVR) and the combined rate of death and myocardial infarction (MI) at one year.

RESULTS: The incidence of angiographic restenosis was 17.9% in the thin-strut group and 31.4% in the thick-strut group, relative risk, 0.57 (95% confidence interval, 0.39 to 0.84), p<0.001. A TVR due to restenosis was required in 12.3% of the thin-strut group and 21.9% of the thick-strut group, relative risk, 0.56 (95% confidence interval, 0.38 to 0.84), p = 0.002. No significant difference was observed in the combined incidence of death and MI at one year.

CONCLUSIONS: When two stents with different design are compared, the stent with thinner struts elicits less angiographic and clinical restenosis than the thicker-strut stent.

  • AU Yoshitomi Y, Kojima S, Yano M, Sugi T, Matsumoto Y, Saotome M, Tanaka K, Endo M, Kuramochi M
  • SO Am Heart J. 2001;142(3):445.

BACKGROUND: Experimental studies have revealed that stent configuration influences intimal hyperplasia. The purpose of this study was to evaluate clinical outcomes for 2 stent designs in a randomized trial with quantitative coronary angiography (QCA) and intravascular ultrasonography (IVUS).

METHODS: We randomly assigned 100 patients with 107 lesions and symptomatic coronary artery disease to deployment of a Multilink stent (Advanced Cardiovascular Systems, Guidant, Santa Clara, Calif) or a GFX stent (Applied Vascular Engineering, Santa Rosa, Calif) with IVUS guidance. QCA and IVUS studies were performed before and after intervention and at follow-up (4.2 +/- 1.0 months).

RESULTS: There were no significant differences in baseline characteristics and QCA and IVUS parameters before and after intervention between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger in the Multilink group (2.46 +/- 0.59 vs 2.08 +/- 0.79 mm, P<.05). Maximal in-stent intimal hyperplasia was significantly larger in the GFX group (2.9 +/- 1.7 vs 1.8 +/- 1.2 mm(2), P<.01). The restenosis rate differed between the 2 groups (Multilink 4% vs GFX 26%, P =.003). In multiple stepwise logistic regression analysis, the only predictor that significantly correlated with restenosis was stent type (P<.01). The odds ratio for the GFX stent-treated vessels was 18.65 (95% confidence interval 2.10-165.45).

CONCLUSIONS: With deployment of the GFX stent, a thicker neointima develops within the stent. Stent configuration may affect clinical outcomes.

  • AU Castagna MT, Mintz GS, Leiboff BO, Ahmed JM, Mehran R, Satler LF, Kent KM, Pichard AD, Weissman NJ
  • SO Am Heart J. 2001;142(6):970.

OBJECTIVES: Serial intravascular ultrasonographic (IVUS) studies have shown that in-stent restenosis is the result of intimal hyperplasia (IH). However, routine preintervention IVUS imaging has suggested that many restenotic stents were inadequately deployed. The purpose of this IVUS study was to determine the incidence of mechanical problems contributing to in-stent restenosis (ISR).

METHODS: Between April 1994 and June 2000, 1090 patients with ISR were treated at the Washington Hospital Center. All underwent preintervention IVUS imaging. IVUS measurements included proximal and distal reference lumen areas and diameters; stent, minimum lumen, and IH (stent minus lumen) areas; and IH burden (IH/stent area).

RESULTS: In 49 ISR lesions (4.5%), there were morphologic findings that contributed to the restenosis. These were termed mechanical complications. Examples include (1) missing the lesion (eg, an aorto-ostial stenosis), (2) stent “crush,” and (3) havingthe stent stripped off the balloon during the implantation procedure. Excluding mechanical complications, stent underexpansion was common. In 20% of the ISR cases the stents had a cross-sectional area (CSA) at the site of the lesion<80% of the average reference lumen area. Twenty percent of lesions had a minimum stent area<5.0 mm(2) and an additional 18% had a minimum stent area of 5.0 to 6.0 mm(2). Twenty-four percent of lesions had an IH burden<60%.

CONCLUSION: Mechanical problems related to stent deployment procedures contribute to a significant minority of ISR lesions (approximately 25%).

  • AU Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM
  • SO Circulation. 1990;82(4):1193.

To assess the likelihood of procedural success in patients with multivessel coronary disease undergoing percutaneous coronary angioplasty, 350 consecutive patients (1,100 stenoses) from four clinical sites were evaluated. Eighteen variables characterizing the severity and morphology of each stenosis and 18 patient-related variables were assessed at a core angiographic laboratory and at the clinical sites. Most patients had Canadian Cardiovascular Society class III or IV angina (72%) and two-vessel coronary disease (78%). Left ventricular function was generally well preserved (mean ejection fraction, 58 +/- 12%; range, 18-85%) and 1.9 +/- 1.0 stenoses per patient had attempted percutaneous coronary angioplasty. Procedural success (less than or equal to 50% final diameter stenosis in one or more stenoses and no major ischemic complications) was achieved in 290 patients (82.8%), and an additional nine patients (2.6%) had a reduction in diameter stenosis by 20% or more with a final diameter stenosis 51-60% and were without major complications. Major ischemic complications (death, myocardial infarction, or emergency bypass surgery) occurred in 30 patients (8.6%). In-hospital mortality was 1.1%. Stepwise regression analysis determined that a modified American College of Cardiology/American Heart Association Task Force (ACC/AHA) classification of the primary target stenosis (with type B prospectively divided into type B1 [one type B characteristic]and type B2 [greater than or equal to two type B characteristics]) and the presence of diabetes mellitus were the only variables independently predictive of procedural outcome (target stenosis modified ACC/AHA score; p less than 0.001 for both success and complications; diabetes mellitus: p = 0.003 for success and p = 0.016 for complications). Analysis of success and complications on a per stenosis dilated basis showed, for type A stenoses, a 92% success and a 2% complication rate; for type B1 stenoses, an 84% success and a 4% complication rate; for type B2 stenoses, a 76% success and a 10% complication rate; and for type C stenoses, a 61% success and a 21% complication rate. The subdivision into types B1 and B2 provided significantly more information in this clinically important intermediate risk group than did the standard ACC/AHA scheme. The stenosis characteristics of chronic total occlusion, high grade (80-99% diameter) stenosis, stenosis bend of more than 60 degrees, and excessive tortuosity were particularly predictive of adverse procedural outcome. This improved scheme may improve clinical decision making and provide a framework on which to base meaningful subgroup analysis in randomized trials assessing the efficacy of percutaneous coronary angioplasty.

  • AU Kastrati A, Schömig A, Elezi S, Dirschinger J, Mehilli J, Schühlen H, Blasini R, Neumann FJ
  • SO Circulation. 1999;100(12):1285.

Background-The modified American College of Cardiology/American Heart Association (ACC/AHA) lesion morphology criteria are predictive of early outcome after various coronary catheter interventions. Their potential prognostic value after stent implantation and, in particular, for restenosis and long-term clinical outcome has not been studied. We assessed the prognostic value of the modified ACC/AHA criteria for the long-term angiographic and clinical outcome of patients after coronary stenting. Methods and Results-This study includes 2944 consecutive patients with symptomatic coronary artery disease treated with coronary stent placement. Modified ACC/AHA lesion morphology criteria were used to qualitatively assess the angiograms; type A and B1 lesions were categorized as simple, and type B2 and C lesions were designated complex. Primary end points were angiographic restenosis and 1-year event-free survival. Restenosis rate was 33.2% in complex lesions and 24.9% in simple lesions (P<0.001). It was 21. 7% for type A, 26.3% for type B1, 33.7% for type B2, and 32.6% for type C lesions. One-year event-free survival was 75.6% for patients with complex lesions and 81.1% for patients with simplelesions (P50% by QCA. IVUS predictors were minimum and mean in-stent area, stent length, and in-stent diameter. Multiple models were constructed with multivariate logistic regression analysis. The model containing minimum in-stent area and stent length best fit the Hosmer-Lemeshow goodness-of-fit test. This model was used to construct a reference chart to calculate the expected 6-month restenosis rate.

CONCLUSIONS: The expected 6-month in-stent restenosis rate after stent implantation for short lesions in relatively large vessels can be predicted by use of in-stent minimal area (which is inversely related to restenosis) and stent length (which is directly related to restenosis), both of which can be read from a simple reference chart.

  • AU Kastrati A, Schömig A, Elezi S, Schühlen H, Wilhelm M, Dirschinger J
  • SO Circulation. 1998;97(24):2396.

BACKGROUND: Little is known about the behavior with regard to restenosis of multiple lesions within the same patient treated with intracoronary stenting. Our objective was to test the hypothesis that there is an intrapatient dependence of restenosis between lesions.

METHODS AND RESULTS: Quantitative analysis was carried out on angiograms obtained before, immediately after, and at 6 months after coronary stent placement in 1734 lesions in 1244 patients. We used a specialized logistic regression that not only accounts for intraclass correlation but also quantifies it in the form of odds ratio (OR) as the change in risk of a lesion to develop restenosis if another companion lesion had restenosis. The model was based on 23 patient- and lesion-related variables with binary restenosis (diameter stenosis>or =50%) as end point. The overall restenosis rate was 27.5%: 24.4% for single-lesion, 28.6% for double-lesion, and 33.8% for>or =3-lesion interventions. After adjustment for the influence of significant factors (hypercholesterolemia, systemic arterial hypertension, diabetes mellitus, previous PTCA, ostial lesion, location in left anterior descending coronary artery, number of stents placed, vessel size, stenosis severity, balloon-to-vessel ratio, and final result), the analysis found a significant intrapatient correlation, OR 2.5 (1.8 to 3.6). This means that in patients with multilesion interventions, the risk of a lesion to develop restenosis is 2.5 times higher if a companion lesion has restenosis, independently of the presence or absence of analyzed patient risk factors (eg, diabetes).

CONCLUSIONS: This study demonstrates that there is a dependence of restenosis between coronary lesions in patients who undergo a multilesion intervention. The likelihood of restenosis for a lesion is higher when another companion lesion has also developed restenosis. Other, as yet unidentified patient factors may be the source of this intrapatient correlation of restenosis.

  • AU Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, Berger PB
  • SO J Am Coll Cardiol. 2002;39(7):1113.

OBJECTIVES: We sought to determine the effect of varying degrees of renal insufficiency on death and cardiac events during and after a percutaneous coronary intervention (PCI).

BACKGROUND: Patients with end-stage renal disease have a high mortality from coronary artery disease. Little is known about the impact of mild and moderate renal insufficiency on clinical outcomes after PCI.

METHODS: Cardiac mortality and all-cause mortality were determined for 5,327 patients undergoing PCI from January 1, 1994, to August 31, 1999, at the Mayo Clinic, based on the estimated creatinine clearance or whether the patient was on dialysis.

RESULTS: In-hospital mortality was significantly associated with renal insufficiency (p = 0.001). Even after successful PCI, one-year mortality was 1.5% when the creatinine clearance was>or =70 ml/min (n = 2,558), 3.6% when it was 50 to 69 ml/min (n = 1,458), 7.8% when it was 30 to 49ml/min (n = 828) and 18.3% when it was<30 ml/min (n = 141). The 18.3% mortality rate for the group with<30 ml/min creatinine clearance was similar to the 19.9% mortality rate in patients on dialysis (n = 46). The mortality risk was largely independent of all other factors.

CONCLUSIONS: Renal insufficiency is a strong predictor of death and subsequent cardiac events in a dose-dependent fashion during and after PCI. Patients with renal insufficiency have more baseline cardiovascular risk factors, but renal insufficiency is associated with an increased risk of death and other adverse cardiovascular events, independent of all other measured variables.

Recent studies have shown that patients with mild chronic renal insufficiency (CRI) have a high prevalence of cardiovascular disease and cardiac death. Furthermore, patients with CRI undergoing percutaneous coronary intervention have a higher rate of in-hospital and long-term morbidity and mortality. A recent retrospective subgroup analysis of  patients with CRI undergoing percutaneous intervention suggests that the use of stents may improve their in-hospital and long-term outcomes.

OBJECTIVE: To investigate 4-year outcomes and predictors of repeat revascularization in patients treated with Resolute™zotarolimus-eluting stent (R-ZES) and XIENCE V™everolimus-eluting stent (EES) in the RESOLUTE All Comers trial.

BACKGROUND: Data on long-term outcomes of new generation drug-eluting stents are limited, and predictors of repeat revascularization due to restenosis and/or progression of disease are largely unknown.

METHODS: Patients were randomly assigned to treatment with R-ZES (n=1,140) or EES (n=1,152). We assessed pre-specified safety and efficacy outcomes at 4 years including target-lesion failure (TLF) and stent thrombosis (ST). Predictors of revascularization at 4 years were identified by Cox regression analysis.

RESULTS: At 4 years, rates of TLF (15.2% vs. 14.6%, p=0.68), cardiac death (5.4% vs. 4.7%, p=0.44), target-vessel myocardial infarction (MI) (5.3% vs. 5.4%, p=1.00), clinically-indicated target-lesion revascularization (TLR) (7.0% vs. 6.5%, p=0.62), and definite/probable ST (2.3% vs. 1.6%, p=0.23) were similar with R-ZES and EES. Independent predictors of TLR were: age, insulin-treated diabetes, SYNTAX score, treatment of saphenous vein grafts, ostial lesions, and instent restenosis. Independent predictors of any revascularization were: age, diabetes, previous PCI, ST-elevation MI, smaller reference vessel diameter, SYNTAX score, and treatment of left anterior descending, right coronary artery, saphenous vein grafts, ostial lesions, or instent restenosis.

CONCLUSIONS: R-ZES and EES demonstrated similar safety and efficacy throughout 4 years. TLR represented less than half of all repeat revascularization procedures. Patient and lesion-related factors predicting the risk of TLR and any revascularization showed considerable overlap.

CLINICAL TRIAL INFO: RESOLUTE All Comers; NCT00617084.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) has been thought to present in a stable manner as exertional angina. However, the presentation of in-stent restenosis (ISR) is not well-studied. We hypothesized that a substantial proportion of bare metal ISR presents as acute coronary syndromes. We aimed to characterize the severity of the clinical presentation of ISR.

METHODS: We searched our PCI database for all cases of PCI for bare metal ISR occurring between May 1999 and September 2003. Multivessel interventions were excluded. In-stent restenosis presentation was classified into three categories: (1) myocardial infarction (MI), (2) unstable angina requiring hospitalization before angiography, and (3) exertional angina. Routine angiographic screening after initial stent placement was not performed, so ISR episodes were clinical, rather than angiographic, ISR.

RESULTS: We identified 1186 cases of bare metal ISR in 984 patients. Median age was 63, 72% were male, and 36% had diabetes. Of the ISR episodes, 9.5% presented as acute MI (7.3% as non-ST-segment elevation MI and 2.2% as ST-segment elevation MI), 26.4% as unstable angina requiring hospitalization before angiography, and 64.1% as exertional angina.

CONCLUSIONS: More than one third of bare metal ISR episodes presented as MI or unstable angina requiring hospitalization. The acuity of the clinical presentation of bare metal ISR appears to be more severe than has been previously thought. Aggressive efforts, such as drug-eluting stents to decrease the incidence of unstable angina due to bare metal ISR, are warranted.

 

OBJECTIVES: We sought to evaluate the long-term clinical outcome of patients undergoing successful balloon angioplasty for in-stent restenosis, and to determine correlates of the need for subsequent target lesion revascularization (TLR).

BACKGROUND: In-stent restenosis can be safely treated by repeat percutaneous intervention. Reported subsequent TLR rates have varied from 20% to 80% and seem related to the type of restenotic lesion.

METHODS: The study population comprised 234 patients with follow-up data who were successfully treated with repeat balloon angioplasty for in-stent restenosis in 257 lesions between May 1995 and January 1998 at our institution.

RESULTS: Clinical follow-up was available at 459 (286 to 693) days after the repeat procedure. Event-free survival was 78.5% and 74.6% at 12 and 24 months, respectively. Recurrent events occurred in 58patients (24.8%), including 6 deaths (2.6%), 4 myocardial infarction (1.7%) and repeat target vessel revascularization in 50 patients (21.4%). Independent predictors of repeat TLR were time to in-stent restenosis<90 days (Hazard ratio 4.67, p<0.001), minimal luminal diameter after repeat procedure (Hazard ratio 0.38, p = 0.034) and the angiographic pattern of in-stent restenosis (Hazard ratio 1.65, p = 0.036).

CONCLUSIONS: Balloon angioplasty is an effective means of treating in-stent restenosis. The long-term results are acceptable particularly for focal restenotic lesions. Further restenosis is more common in patients with early initial recurrence, more proliferative lesions and a poorer angiographic result from repeat angioplasty.

 

Coronary stents have been the major advancement in percutaneous coronary intervention in the last decade and are used in 60% to 80% of patients. However, in-stent restenosis continues to be a problem, occurring in 20% to 30% of cases. The clinical presentation of patients who develop restenosis after stenting has not been well characterized. In this study we compared the clinical presentation of in-stent restenosis with that of restenosis without stenting. Of 739 patients who underwent percutaneous coronary intervention and had repeat catheterization between October 1, 1997, and June 30, 2000, 262 consecutive patients with recurrent ischemia and restenosis were identified: 191 patients with (group A) and 71 without (Group B) stenting. Patients who underwent interventions in bypass grafts and those who developed early acute stent thrombosis were excluded from the study. Recurrent clinical ischemia occurred at a mean of 5.5 months in group A and 6.5 months in group B (p = 0.24). Rest angina (Braunwald class II and III) was more frequent in group A (48% vs 32%, p = 0.032). Acute coronary syndromes, the combination of rest angina, and acute myocardial infarction were also more frequent in group A (68% vs 46%, p = 0.03). Patients in group A were more likely to have angiographically visible thrombus than those in group B (9% vs 0%, p = 0.02). Thus, acute coronary syndromes are a common clinical presentation of restenosis among patients whose follow-up angiogram is obtained for clinical reasons, and occur more frequently in patients with in-stent restenosis than in those with restenosis without stenting.

 

OBJECTIVES: The purpose of this study was to examine the outcomes of patients who developed coronary in-stent restenosis (ISR) or stent thrombosis (STH) inside drug-eluting stents (DES).

BACKGROUND: Drug-eluting stents have markedly reduced the incidence of restenosis. However, when restenosis occurs within a DES, its optimal management remains unclear.

METHODS: We retrospectively analyzed clinical and angiographic data from 92 patients who underwent revascularization for ISR (n = 84) or STH (n = 8) within a DES at our institution. Regular follow-ups were available up to 2 years. We recorded the occurrence of major adverse cardiac events (MACE), defined as deaths from all causes, myocardial infarction (MI), or target lesion revascularization (TLR), among patients treated by the “DES sandwich” technique or by other treatment methods.

RESULTS: In-hospital MACE included 1 periprocedural MI and 2 deaths. Over a mean follow-up of 15 +/- 6 months, the overall rates of death, MI, and TLR were 8.7%, 2.2%, and 30.6%, respectively. By actuarial analysis, the 12-month TLR and MACE rates were 28.2% and 42.9%, respectively.

CONCLUSIONS: Current treatments of ISR or STH in DES are associated with a high long-term rate of MACE.

 

BACKGROUND: Limited information is available regarding restenosis after implantation of a sirolimus-eluting stent (SES).

OBJECTIVE: To report on angiographic characteristics, clinical presentation and treatment of this particularly complex type of coronary lesion.

METHODS AND RESULTS: A total of 1424 SES were implanted in 1159 patients (average 1.2 per patient) for chronic or acute coronary syndromes in the University Hospital of Siena (Siena, Italy), which is a tertiary centre. Symptomatic in-SES restenosis was observed in 26 patients (2.2%) at 10+/-5 months (median eight months, range four to 23 months) following the initial intervention. In-SES restenosis was associated with stable angina in 16 patients, acute myocardial infarction in three patients and unstable angina in seven patients. Two patients had restenosis in two separate SES. Conditions often associated with in-SES restenosis included treatment of chronic total occlusion, geographic miss or in-stent restenosis during the index procedure. Among the first 20 patients, those with focal, in-body SES (type Ic) restenosisreceived balloon-only angioplasty, and patients with other patterns received repeat SES implantation. Clinical and angiographic follow-up (average 16+/-7 months) recorded one death (noncardiac) in the balloon-only group and four cases of unstable angina (three due to relapsing in-SES restenosis in the balloon-only group and the fourth due to a de novo lesion). Follow-up quantitative angiography showed a higher incidence of binary restenosis after balloon-only treatment (57% versus 17%; P<0.05), as well as higher lumen loss and loss index (Por =10 mm) inside the stent (71%) or focal (29%). Mean stent length was 16+/-7 mm. Balloon diameter of2.98+/-0.37 mm and maximal inflation pressure of 10+/-3 atm were used for balloon angioplasty. Angiographic success rate was 100% without any complication. Acute gain was lower after balloon angioplasty for in-stent restenosis than after stent implantation: 1.19+/-0.60 mm vs. 1.75+/-0.68 mm (p=0.0002). At 6-month follow-up, 60% of patients were asymptomatic and no patient died. Eighteen patients (35%) had repeat target vessel revascularization. Angiographic restenosis rate was 54%. Recurrent restenosis rate was higher when in-stent restenosis was diffuse: 63% vs. 31% when focal, p=0.046.

CONCLUSIONS: Although balloon angioplasty for in-stent restenosis can be safely and successfully performed, it leads to less immediate stenosis improvement than at time of stent implantation and carries a high recurrent angiographic restenosis rate at 6 months, in particular in diffuse in-stent restenosis lesions.

 

BACKGROUND: In-stent restenosis is an increasing clinical problem. Discordant results have been published regarding the risk of recurrent restenosis after repeat angioplasty for the treatment of in-stent restenosis.

METHODS AND RESULTS: One hundred three consecutive patients (107 vessels) underwent repeat percutaneous intervention for the treatment of in-stent restenosis and were entered in a prospective angiographic follow-up program. Repeat balloon angioplasty was performed at 93 lesions (87%) and additional stenting at 14 lesions (13%). The primary success rate was 98%. Six-month angiographic follow-up was performed in 85% of eligible patients. Restenosis was determined by quantitative angiography. Restenosis defined as a>50% diameter stenosis at follow-up was observed at 22% of lesions. The rate of target-lesion revascularization at 6 months was 17%. Repeat intervention for diffuse in-stent restenosis and severe stenosis before repeat intervention were associated with significantly higher rates of recurrent restenosis.

CONCLUSIONS: The overall restenosis rate after repeat intervention for in-stent restenosis is low. Thesubgroup of patients with diffuse and/or severe in-stent restenosis, however, is at higher risk of recurrent restenosis and may benefit from alternative therapeutic strategies.

 

OBJECTIVES: This randomized trial compared repeat stenting with balloon angioplasty (BA) in patients with in-stent restenosis (ISR).

BACKGROUND: Stent restenosis constitutes a therapeutic challenge. Repeat coronary interventions are currently used in this setting, but the recurrence risk remains high.

METHODS: We randomly assigned 450 patients with ISR to elective stent implantation (224 patients) or conventional BA (226 patients). Primary end point was recurrent restenosis rate at six months. Secondary end points included minimal lumen diameter (MLD), prespecified subgroup analyses, and a composite of major adverse events.

RESULTS: Procedural success was similar in both groups, but in-hospital complications were more frequent in the balloon group. After the procedure MLD was larger in the stent group (2.77 +/- 0.4 vs. 2.25 +/- 0.5 mm, por =3 mm) the restenosis rate (27% vs. 49%, p = 0.007) and the event-free survival (84% vs. 62%, p = 0.002) were better after repeat stenting.

CONCLUSIONS: In patients with ISR, repeat coronary stenting provided better initial angiographic results but failed to improve restenosis rate and clinical outcome when compared with BA. However, in patients with large vessels coronary stenting improved the long-term clinical and angiographic outcome.

 

OBJECTIVES: We sought to analyze the very late outcomes of patients treated for in-stent restenosis (ISR) according to treatment allocation and 10 prespecified variables.

BACKGROUND: Long-term results (>2 years) of patients with ISR undergoing repeat coronary interventions are not well established.

METHODS: The Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study compared these two strategies in 450 patients with ISR. A detailed systematic protocol was used for late clinical follow-up.

RESULTS: At one-year follow-up (100% of patients), the event-free survival was similar in the two groups (77% stent implantation [ST]arm, 71% balloon angioplasty [BA]arm, log-rank p = 0.19). Additional long-term clinical follow-up (median 4.3 years, range 3 to5 years) was obtained in 98.6% of patients. During this time 22 additional patients died (9 ST arm, 13 BA arm), 7 suffered a myocardial infarction (3 ST arm, 4 BA arm), 23 required coronary surgery (11 ST arm, 12 BA arm), and 9 underwent repeat coronary interventions (4 ST arm, 5 BA arm) (nonexclusive events). At four years the event-free survival was 69% in the ST arm and 64% in the BA arm (log-rank p = 0.21). Among the 10 prespecified variables, vessel size>or = 3 mm had a major influence on the clinical outcome at four years, with better results in the ST group (hazard ratio 0.51, 95% confidence interval 0.3 to 0.89, p = 0.016).

CONCLUSIONS: Patients with ISR undergoing repeat interventions have a significant event rate at late follow-up. Continued medical surveillance should be continued after one year. Patients with large vessels have a better outcome after repeat stenting.

 

BACKGROUND: Although both percutaneous transluminal coronary angioplasty (PTCA) and additional stenting can be used for the treatment for focal in-stent restenosis (ISR), no large-scale comparative data on the clinical outcomes after these interventional procedures have been reported.

METHODS: In the current study we compared the in-hospital and long-term clinical results of PTCA alone (n = 266 patients, n = 364 lesions) versus stenting (n = 135 patients, n = 161 lesions) for the treatment of focal ISR, defined as a lesion length less than or equal to 10 mm.

RESULTS: There were significantly more diabetic patients in the PTCA group than in the stent group (36% vs 26%, P =.04), but other baseline characteristics were similar. Lesion length and preprocedure minimal lumen diameter (MLD) were also similar in the two groups, but the stent group had a larger reference vessel diameter (3.40 +/- 0.73 mm vs 2.99 +/- 0.68 mm, P<.001). Stenting achieved a larger postprocedure MLD than PTCA did (2.95 +/- 0.95 mm vs 2.23 +/- 0.60 mm, P5 times normal was more frequent with stent (18.5% vs 9.7%, P =.05). At 1 year the two interventional strategies had similar cumulative mortality (4.6% PTCA vs 5.1% stent, P not significant) and target lesion revascularization rate (24.6% PTCA vs 26.5% stent, P not significant). By multivariate analysis, the sole predictor of target lesion revascularization was diabetes (odds ratio 2.4, 95% confidence intervals 1.2-4.7, P =.01).

CONCLUSION: Repeat stenting for the treatment of focal ISR had a higher postprocedure creatine kinase myocardial band elevation rate and similar long-term clinical results compared with PTCA alone.

 

BACKGROUND: We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis.

METHODS AND RESULTS: Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07+/-0.2 mm in-stent and -0.05+/-0.3 mm in-lesion at 4 months, and 0.36+/-0.46 mm in-stent and 0.16+/-0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92+/-1.9 mm(3) at 4 months and 2.55+/-4.9 mm(3) after 1 year. Percent volume obstruction was 0.81+/-1.7% and 1.76+/-3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations.

CONCLUSION: This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.

 

OBJECTIVES: In this study, we assess the value of sirolimus eluting stent (SES) implantation in patients with complex in-stent restenosis (ISR).

BACKGROUND: The treatment of ISR remains a therapeutic challenge, since many pharmacological and mechanical approaches have shown disappointing results. The SESs have been reported to be effective in de-novo coronary lesions.

METHODS: Sixteen patients with severe, recurrent ISR in a native coronary artery (average lesion length 18.4 mm) and objective evidence of ischemia were included. They received one or more 18 mm Bx VELOCITY SESs (Cordis Waterloo, Belgium). Quantitative angiographic and three-dimensional intravascular ultrasound (IVUS) follow-up was performed at four months, and clinical follow-up at nine months.

RESULTS: The SES implantation (n = 26) was successful in all 16 patients. Four patients had recurrent restenosis following brachytherapy, and three patients had totally occluded vessels preprocedure. At four months follow-up, one patient had died and three patients had angiographic evidence of restenosis (one in-stent and two in-lesion). In-stent late lumen loss averaged 0.21 mm and the volume obstruction of the stent by IVUS was 1.1%. At nine months clinical follow-up, three patients had experienced four major adverse cardiac events (two deaths and one acute myocardial infarction necessitating repeat target vessel angioplasty).

CONCLUSIONS: The SES implantation in patients with severe ISR lesions effectively prevents neointima formation and recurrent restenosis at four months angiographic follow-up.

 

BACKGROUND: The first clinical study of paclitaxel-eluting stent for de novo lesions showed promising results. We performed the TAXUS III trial to evaluate the feasibility and safety of paclitaxel-eluting stent for the treatment of in-stent restenosis (ISR).

METHODS AND RESULTS: The TAXUS III trial was a single-arm, 2-center study that enrolled 28 patients with ISR meeting the criteria of lesion lengthor =50%) at 6-month follow-up angiography based on “in-segment” analysis. Primary analysis was comparison between stent groups and balloon angioplasty groups; a secondary analysis compared sirolimus and paclitaxel stents.

RESULTS: Follow-up angiography was performed in 275 (92%) of 300 patients. The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.

CONCLUSIONS: In patients with in-stent restenosis, a strategy based on sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.

 

OBJECTIVES: We sought to assess the effectiveness of sirolimus-eluting stents (SES) in patients with in-stent restenosis (ISR).

BACKGROUND: Treatment of patients with ISR remains a challenge.

METHODS: The Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) study is a multicenter randomized trial conducted in 150 patients with ISR (76 allocated to SES and 74 to balloon angioplasty [BA]). The primary end point was recurrent restenosis rate at nine months. Secondary end points included prespecified subgroup analysis, lumen volume on intravascular ultrasound (IVUS), and a composite of major clinical events at one year.

RESULTS: Angiographic success was obtained in all patients. At 9-month angiographic follow-up (96% of eligible patients) minimal lumen diameter was larger (2.52 mm [interquartile range (IQR) 2.09 to 2.81]vs. 1.54 mm [IQR 0.91 to 2.05]; p<0.001) and recurrent restenosis rate was lower (11% vs. 39%; p<0.001) in the SES group. Prespecified subgroup analyses were consistent with the main outcome measure. Lumen volume on IVUS at 9 months was also larger (279 mm3 [IQR 227 to 300]vs. 197 mm3 [IQR 177 to 230]; p<0.001) in the SES group. At one-year clinical follow-up (100% of patients), the event-free survival (freedom from death, myocardial infarction, and target vessel revascularization) was significantly improved in the SES group (88% vs. 69%; p<0.004) as the result of a lower requirement for target vessel revascularization (11% vs. 30%; p<0.003).

CONCLUSIONS: In patients with ISR, the use of SES provides superior long-term clinical, angiographic, and IVUS outcome than BA treatment.

 

Few data are available on the effectiveness of sirolimus-eluting stent implantation for the treatment of in-stent restenosis, and no data exist about the predictors of outcome after sirolimus-eluting stent implantation for complex in-stent restenosis (diffuse, proliferative, or total occlusion). From April 2002 to May 2004, 136 patients with 161 complex in-stent restenoses underwent sirolimus-eluting stent implantation. At 9 months, 5 patients had died (3 of cardiac and 2 of noncardiac causes), no reinfarctions had occurred, and 11 target vessel revascularization procedures had been performed. The target vessel revascularization rate was 8%, and the in-segment binary restenosis rate was 17%. The predictors of the risk of recurrence were unstable angina as the clinical presentation of in-stent restenosis, an ostial location of the target lesion, lesion length, and sirolimus-eluting stent diameter<or =2.5 mm.

OBJECTIVES: The aim of this study was to evaluate the long-term clinical outcome of the efficacy and safety of sirolimus-eluting stents (SES) for in-stent restenosis (ISR) in the TRUE (Tuscany Registry of Unselected In-Stent Restenosis) database.

BACKGROUND: The TRUE registry demonstrated that SES in the treatment of bare-metal stent ISR is efficacious (5% of target lesion revascularization [TLR]) and safe (stent thrombosis<1%) at 9 months. Clinical outcome at 4 years is reported.

METHODS: A total of 244 patients with ISR who were treated with SES implantation represent the study population. The incidence of major adverse cardiac events was collected at 4 years.

RESULTS: At 4-year follow-up, overall mortality was 9.8% (24 patients). Cardiac death occurred in 11 (4.5%), nonfatal myocardial infarction in 8 (3.2%), and TLR in 27 (11.1%) patients for a cumulative event-free survival rate of 80.3%. Definite stent thrombosis occurred in 5 (2%) patients and possible stent thrombosis in 2 (0.8%). Diabetes remained an independent negative predictor of freedom from TLR (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.20 to 0.71, p = 0.002) and major adverse cardiac events (OR: 0.38; 95% CI: 0.20 to 0.71, p = 0.002).

CONCLUSIONS: The clinical benefit of SES implantation for bare-metal stent ISR is maintained at 4 years with a low TLR rate and an overall incidence of stent thrombosis of 0.7% per year.

 

In patients with stable CAD, PCI can be considered a valuable initial mode of revascularization in all patients with objective large ischaemia in the presence of almost every lesion subset, with only one exception: chronic total occlusions that cannot be crossed. In early studies, there was a small survival advantage with CABG surgery compared with PCI without stenting. The addition of stents and newer adjunctive medications improved the outcome for PCI. The decision to recommend PCI or CABG surgery will be guided by technical improvements in cardiology or surgery, local expertise, and patients’ preference. However, until proved otherwise, PCI should be used only with reservation in diabetics with multi-vessel disease and in patients with unprotected left main stenosis. The use of drug-eluting stents might change this situation. Patients presenting with NSTE-ACS (UA or NSTEMI) have to be stratified first for their risk of acute thrombotic complications. A clear benefit from early angiography (<48 h) and, when needed, PCI or CABG surgery has been reported only in the high-risk groups. Deferral of intervention does not improve outcome. Routine stenting is recommended on the basis of the predictability of the result and its immediate safety. In patients with STEMI, primary PCI should be the treatment of choice in patients presenting in a hospital with PCI facility and an experienced team. Patients with contra-indications to thrombolysis should be immediately transferred for primary PCI, because this might be their only chance for quickly opening the coronary artery. In cardiogenic shock, emergency PCI for complete revascularization may be life-saving and should be considered at an early stage. Compared with thrombolysis, randomized trials that transferred the patients for primary PCI to a ‘heart attack centre’ observed a better clinical outcome, despite transport times leading to a significantly longer delay between randomization and start of the treatment. The superiority of primary PCI over thrombolysis seems to be especially clinically relevant for the time interval between 3 and 12 h after onset of chest pain or other symptoms on the basis of its superior preservation of myocardium. Furthermore, with increasing time to presentation, major-adverse-cardiac-event rates increase after thrombolysis, but appear to remain relatively stable after primary PCI. Within the first 3 h after onset of chest pain or other symptoms, both reperfusion strategies seem equally effective in reducing infarct size and mortality. Therefore, thrombolysis is still a viable alternative to primary PCI, if it can be delivered within 3 h after onset of chest pain or other symptoms. Primary PCI compared with thrombolysis significantly reduced stroke. Overall, we prefer primary PCI over thrombolysis in the first 3 h of chest pain to prevent stroke, and in patients presenting 3-12 h after the onset of chest pain, to salvage myocardium and also to prevent stroke. At the moment, there is no evidence to recommend facilitated PCI. Rescue PCI is recommended, if thrombolysis failed within 45-60 min after starting the administration. After successful thrombolysis, the use of routine coronary angiography within 24 h and PCI, if applicable, is recommended even in asymptomatic patients without demonstrable ischaemia to improve patients’ outcome. If a PCI centre is not available within 24 h, patients who have received successful thrombolysis with evidence of spontaneous or inducible ischaemia before discharge should be referred to coronary angiography and revascularized accordingly–independent of ‘maximal’ medical therapy.

CONTEXT: Restenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although subsequent recurrence rates are high, with vascular brachytherapy (VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established.

OBJECTIVE: To investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries.

DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5-3.75 mm; lesion length,<or =46 mm).

INTERVENTIONS: Patients were randomly assigned to undergo angioplasty followed by VBT with a beta source (n = 201) or paclitaxel-eluting stent implantation (n = 195). Clinical and angiographic follow-up at 9 months was scheduled in all patients.

MAIN OUTCOME MEASURE: Ischemia-driven target vessel revascularization at 9 months.

RESULTS: Diabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic target lesion revascularization were 27 (13.9%) vs 12 (6.3%) (relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P = .01); for ischemic target vessel revascularization, 34 (17.5%) vs 20 (10.5%) (RR, 0.60; 95% CI, 0.36-1.00; P = .046); and for overall major adverse cardiac events, 39 (20.1%) vs 22 (11.5%) (RR, 0.57; 95% CI, 0.35-0.93; P = .02), with similar rates of cardiac death or myocardial infarction (10 [5.2%]vs 7 [3.7%]; RR, 0.71; 95% CI, 0.28-1.83; P = .48) and target vessel thrombosis (5 [2.6%]vs 3 [1.6%]; RR, 0.61; 95% CI, 0.15-2.50; P = .72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents (RR, 0.47; 95% CI, 0.30-0.71; P<.001).

CONCLUSION: Treatment of bare-metal in-stent restenotic lesions with paclitaxel-eluting stents rather than angioplasty followed by VBT reduces clinical and angiographic restenosis at 9 months and improves event-free survival.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00287573.

 

AIMS: This study sought to investigate the 2-year outcomes of patients treated with the paclitaxel-eluting TAXUS((R)) stent (PES) or vascular brachytherapy (VBT), the previous ‘gold standard therapy’, for bare metal stent in-stent restenosis (ISR).

METHODS AND RESULTS: In the TAXUS V-ISR trial, 396 patients with bare metal stent ISR referred for percutaneous coronary intervention were prospectively randomized to either PES or beta source VBT. The present analysis reports 24-month clinical outcomes from that study. Between 9 and 24 months, ischaemia-driven target lesion revascularization tended to be required less frequently with assignment to PES compared to VBT (5.3 vs. 10.3%, P = .07). As a result, ischaemia-driven target lesion revascularization at 24 months was significantly reduced with PES compared with VBT (10.1 vs. 21.6%, P = 0.003), as was ischaemia-driven target vessel revascularization (18.1 vs. 27.5%, P = .03). There were no significant differences between the two groups with regard to death, myocardial infarction, or target vessel thrombosis either between 12 and 24 months, or cumulative to 24 months.

CONCLUSION: Freedom from clinical restenosis at 2 years is significantly enhanced after PES placement compared with VBT for bare metal stent ISR, with similar rates of death, myocardial infarction, and target vessel thrombosis.

 

CONTEXT: Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited.

OBJECTIVE: To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent.

DESIGN, SETTING, AND PATIENTS: Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005.

INTERVENTIONS: Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259).

MAIN OUTCOME MEASURE: Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure.

RESULTS: Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55]mm vs 17.22 [7.97]mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63]mm vs 1.80 [0.63]mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60]vs 1.0 [0.61]mm; P<.001) due to stenting and no edge restenosis.

CONCLUSION: Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00231257.

 

 

The greatest recent mechanical advance in percutaneous coronary revascularization (PCR) has been the development of bare-metal stents, which compared with traditional balloon angioplasty substantially reduce angiographic restenosis and the need for repeat target vessel revascularization (TVR). Stents provide a larger arterial lumen diameter immediately postprocedure (acute gain), although their drawback is an increased reparative response of neointimal formation (late loss). Fortunately, the net gain remains greatest with stents compared with other PCR devices. In less complex lesions, the rate of TVR with bare-metal stents is approximately 10% to 15%, although this rate has been reported to be 2- to 3-fold higher in more complex lesions and unique patient subsets.1,2 In 2003, at a time when the use of bare-metal stents peaked, approximately 1 million coronary stents were placed in patients hospitalized in the United States.3 Even with a conservative estimate, this means at least 100 000 in-stent restenotic lesions occurred, making this an important clinical problem.

BACKGROUND: We evaluated the clinical and angiographic outcomes of patients presenting with restenosis after sirolimus-eluting stent (SES) implantation treated with repeated percutaneous intervention.

METHODS AND RESULTS: A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, 1 (4%) was re-treated with a bare stent, 3 (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated drug-eluting stent implantation (SES in 12 lesions [44%], paclitaxel-eluting stents in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42.9%. The risk of recurrent restenosis was increased for patients with hypercholesterolemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with drug-eluting stents was 18.2%.

CONCLUSIONS: Even though de novo lesions treated with SES at baseline and re-treated with drug-eluting stents had reasonably better outcomes than other lesion types and strategies, our study shows that the treatment of post-SES restenosis is currently suboptimal and warrants further investigation.

 

Although clinical outcomes after sirolimus-eluting stents (SESs) have been previously described (“primary” success rates), the fate of patients whose SES implantation fail and who require ischemia-driven target lesion revascularization is poorly understood. The SIRIUS trial is a prospective, randomized, clinical trial that includes 533 evaluable patients with SESs. Twenty-two of these patients had adjudicated ischemia-driven target lesion revascularization (4.1%) within the first year of follow-up and comprised the study population of this analysis. Of these patients, 11 (50%) had diabetes, and restenotic lesions were focal and located at the proximal stent edge in 91% and 73% of patients, respectively. Restenosis was treated with bare metal stent implantation, balloon dilatation, or intravascular brachytherapy in 82%, 13.5%, and 4.5% of patients, respectively. At 1-year follow-up after the first recurrence (2-year follow-up after the index procedure), only 5 of these patients (23%) required a second repeat revascularization procedure. Risk factors for a second recurrence after treatment of SES restenosis were female gender, long lesions that required long stents at the index procedure, and an early first recurrence. In conclusion, SES failure treated with traditional percutaneous coronary intervention yielded good outcome at 1-year follow-up (secondary failure rate only 23%), perhaps due to the focal nature of the SES restenotic lesion. Future studies should evaluate other methods, including drug-eluting stents, to further optimize the outcome of treatment of SES failures.

 

  • AD Columbia University Medical Center-New York Presbyterian Hospital and Cardiovascular Research Foundation, New York, New York, USA. imoussa@crf.org
  • PMID 16728218
  • TI Drug-eluting stent restenosis: the pattern predicts the outcome.
  • AU Cosgrave J, Melzi G, Biondi-Zoccai GG, Airoldi F, Chieffo A, Sangiorgi GM, Montorfano M, Michev I, Carlino M, Bonizzoni E, Colombo A
  • SO J Am Coll Cardiol. 2006;47(12):2399.

OBJECTIVES: We sought to determine if the angiographic pattern of in-stent restenosis in drug-eluting stents (DES) maintains its prognostic importance.

BACKGROUND: The pattern of restenosis in the bare-metal stent era had a significant impact on therapeutic outcomes.

METHODS: We identified a total of 250 consecutive restenotic lesions in 203 patients (66.4% sirolimus-eluting stents and 33.6% paclitaxel-eluting stents). We divided these lesions into two groups: focal, defined as<or =10 mm, 163 lesions (65.2%); and nonfocal, which were diffuse, proliferative, or obstructive, 87 lesions (34.8%). The end points analyzed were angiographic restenosis and target lesion revascularization (TLR).

RESULTS: Diabetes was the only clinical variable associated with the pattern of restenosis (28.8% focal compared with 52.9% diffuse; p = 0.0001). Angiographic follow-up of the treatment of restenosis was available in 61.2% of the lesions and was similar between the two groups. The rate of angiographic restenosis was 17.8% in the focal group and 51.1% in the nonfocal group (p = 0.0001). The incidence of TLR also increased with the type of restenosis treated (9.8% and 23%, respectively; p = 0.007). An adjusted multivariate analysis revealed that the pattern of restenosis remained associated with both the occurrence of restenosis and TLR (odds ratio [OR]5.1 [95% confidence interval (CI) 1.1 to 23], p = 0.03; and OR 3.61 [95% CI 1.2 to 10.9], p = 0.02; respectively).

CONCLUSIONS: Similar to bare-metal stent data, the angiographic pattern of restenosis following DES implantation is prognostically important. Diabetes is a significant predictor of the pattern of restenosis in the DES era.

 

OBJECTIVE: The authors aimed to compare the clinical outcomes with repeat drug-eluting stent (DES) implantation utilizing the same type versus an alternate DES type for in-stent restenosis (ISR) of DES.
BACKGROUND: : DES are proven as an effective treatment for bare metal ISR.
METHODS: A cohort of 116 patients previously treated with a sirolimus-eluting stent (SES) or a paclitaxel-eluting stent (PES) who presented with angiographic ISR were treated with repeat DES. Of these, 62 (53.4%) were treated with different DES and 54 (46.6%) were treated with the same DES. This cohort was followed for clinical events at 30 days, 6 months, and 1 year.
RESULTS: Baseline characteristics were similar except for more diabetes among patients receiving the different type of DES. Of the 116, overall 16.4% of the DES were implanted for previous ISR and 2.6% had previously received brachytherapy. At 6 months, the overall target vessel revascularization (TVR) rate was 12.2% for the entire cohort. The TVR-major adverse cardiac event (MACE) rate for the patients treated with different DES was 14.5% and 16.7% for the same DES (P = 0.750). Overall TVR rate at 1 year was 28.8%. The TVR-MACE was 32.6% for different DES and 35.0% for the same DES (P = 0.814).
CONCLUSIONS: Reimplantation of DES for the treatment of DES ISR (same or different) is safe but associated with a high rate of recurrences at 1 year regardless of the initial DES type. Other treatment modalities for ISR of DES should be considered to further improve the overall TVR-MACE.

 

BACKGROUND: Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet.
METHODS AND RESULTS: During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P<0.0001). Among 33 baseline variables evaluated, only hemodialysis was identified to be the independent risk factor for recurrent TLR by a multivariable logistic regression analysis. After adjusting for confounders, repeated SES implantation was associated with a strong treatment effect in preventing recurrent TLR over BA (odds ratio, 0.44; 95% confidence interval, 0.32 to 0.61; P50%) at 6- to 8-month follow-up, target lesion revascularization, the composite of death or myocardial infarction, and definite stent thrombosis at 12 months.
RESULTS: Regarding anti-restenotic efficacy, there were no differences between SES and PES in late loss (0.40 +/- 0.65 mm vs. 0.38 +/- 0.59 mm; p = 0.85), binary restenosis (19.6% vs. 20.6%; p = 0.69), or target lesion revascularization (16.6% vs. 14.6%; p = 0.52). In terms of safety outcomes, the rates of death/myocardial infarction (6.1% vs. 5.8%; p = 0.86) and stent thrombosis (0.4% vs. 0.4%; p>0.99) were also similar.
CONCLUSIONS: In cases of SES restenosis, treatment with either repeat SES or switch to PES was associated with a comparable degree of efficacy and safety. Drug resistance at an individual patient level may play a contributory role to the somewhat higher than expected late loss observed with the SES in the current study. (Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for In-Stent Restenosis 2 [ISAR-DESIRE 2]; NCT00598715).

 

BACKGROUND: Treatment of coronary in-stent restenosis is hampered by a high incidence of recurrent in-stent restenosis. We assessed the efficacy and safety of a paclitaxel-coated balloon in this setting.
METHODS: We enrolled 52 patients with in-stent restenosis in a randomized, double-blind, multicenter trial to compare the effects of a balloon catheter coated with paclitaxel (3 microg per square millimeter of balloon surface area) with those of an uncoated balloon catheter in coronary angioplasty. The primary end point was late luminal loss as seen on angiography. Secondary end points included the rates of restenosis (a binary variable) and major adverse cardiac events.
RESULTS: Multivessel disease was present in 80% of patients in both groups. Quantitative coronary angiography revealed no significant differences in baseline measures. At 6 months, angiography showed that the mean (+/-SD) in-segment late luminal loss was 0.74+/-0.86 mm in the uncoated-balloon group versus 0.03+/-0.48 mm in the coated-balloon group (P=0.002). A total of 10 of 23 patients (43%) in the uncoated-balloon group had restenosis, as compared with 1 of 22 patients (5%) in the coated-balloon group (P=0.002). At 12 months, the rate of major adverse cardiac events was 31% in the uncoated-balloon group and 4% in the coated-balloon group (P=0.01). This difference was primarily due to the need for target-lesion revascularization in six patients in the uncoated-balloon group (P=0.02).
CONCLUSIONS: Treatment of coronary in-stent restenosis with paclitaxel-coated balloon catheters significantly reduced the incidence of restenosis. These data suggest that the inhibition of restenosis by local drug delivery may not require stent implantation and sustained drug release at the site of injury. (ClinicalTrials.gov number, NCT00106587 [ClinicalTrials.gov].).

 

BACKGROUND: Treatment of in-stent restenosis with paclitaxel-coated balloon catheter as compared with plain balloon angioplasty has shown surprisingly low late lumen loss at 6 months and fewer major adverse cardiac events up to 2 years. We compared the efficacy and safety of a paclitaxel-coated balloon with a paclitaxel-eluting stent as the current standard of care.
METHODS AND RESULTS: One hundred thirty-one patients with coronary in-stent restenosis were randomly assigned to treatment by a paclitaxel-coated balloon (3 microg/mm2) or a paclitaxel-eluting stent. The main inclusion criteria encompassed diameter stenosis of>or =70% and<or =22 mm in length, with a vessel diameter of 2.5 to 3.5 mm. The primary end point was angiographic in-segment late lumen loss. Quantitative coronary angiography revealed no differences in baseline parameters. At 6 months follow-up, in-segment late lumen loss was 0.38+/-0.61 mm in the drug-eluting stent group versus 0.17+/-0.42 mm (P=0.03) in the drug-coated balloon group, resulting in a binary restenosis rate of 12 of 59 (20%) versus 4 of 57 (7%; P=0.06). At 12 months, the rate of major adverse cardiac events were 22% and 9%, respectively (P=0.08). This difference was primarily due to the need for target lesion revascularization in 4 patients (6%) in the coated-balloon group, compared with 10 patients (15%) in the stent group (P=0.15).
CONCLUSIONS: Treatment of coronary in-stent restenosis with the paclitaxel-coated balloon was at least as efficacious and as well tolerated as the paclitaxel-eluting stent. For the treatment of in-stent restenosis, inhibition of re-restenosis does not require a second stent implantation.

 

OBJECTIVE: We sought to compare the efficacy of drug-eluting balloons (DEB) and everolimus-eluting stents (EES) in patients with bare-metal stent (BMS) in-stent restenosis (ISR).
BACKGROUND: Treatment of patients with ISR remains a challenge.
METHODS: This was a prospective, multicenter, randomized trial comparing DEB and EES in patients with BMS-ISR. The primary end-point was minimal lumen diameter at 9-month follow-up.
RESULTS: 189 patients with BMS-ISR from 25 Spanish sites were included (95 allocated to DEB and 94 to EES). Procedural success was achieved in all patients. At late angiography (median 249 days, 92% of eligible patients) patients in the EES arm had a significantly larger minimal lumen diameter (2.36+0.6 vs 2.01+0.6 mm, p<0.001; absolute mean difference 0.35 mm 95%CI 0.16-0.53) and a lower % diameter stenosis (13+17% vs 25+20%, p<0.001). However, late loss (0.04+0.5 vs 0.14+0.5 mm, p=0.14) and binary restenosis rate (4.7 vs 9.5%, p=0.22) were very low and similar in both groups. Clinical follow-up (median 365 days) was obtained in all (100%) patients. The occurrence of the combined clinical outcome measure (cardiac death, myocardial infarction and target vessel revascularization) (6 vs 8%; HR:0.76;95%CI:0.26-2.18, p=0.6) and the need for target vessel revascularization (2 vs 6%; HR:0.32:0.07-1.59, p=0.17) were similar in the 2 groups.
CONCLUSIONS: In patients with BMS-ISR both DEB and EES provide excellent clinical results with a very low rate of clinical and angiographic recurrences. However, as compared with DEB, EES provide superior late angiographic findings.
CLINICAL TRIAL INFO: NCT01239953.

BACKGROUND: The best way to manage restenosis in patients who have previously received a drug-eluting stent is unknown. We investigated the efficacy of paclitaxel-eluting balloons (PEB), paclitaxel-eluting stents (PES), and balloon angioplasty in these patients.
METHODS: In this randomised, open-label trial, we enrolled patients older than 18 years with restenosis of at least 50% after implantation of any limus-eluting stent at three centres in Germany between Aug 3, 2009, and Oct 27, 2011. Patients were randomly assigned (1:1:1; stratified according to centre) to receive PEB, PES, or balloon angioplasty alone by means of sealed, opaque envelopes containing a computer-generated sequence. Patients and investigators were not masked to treatment allocation, but events and angiograms were assessed by individuals who were masked. The primary endpoint was diameter stenosis at follow-up angiography at 6-8 months. Primary analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00987324.
FINDINGS: We enrolled 402 patients, of whom 137 (34%) were assigned to PEB, 131 (33%) to PES, and 134 (33%) to balloon angioplasty. Follow-up angiography at 6-8 months was available for 338 (84%) patients. PEB was non-inferior to PES in terms of diameter stenosis (38·0% [SD 21·5]vs 37·4% [21·8]; difference 0·6%, one-sided 95% CI 4·9%; p(non-inferiority)=0·007; non-inferiority margin of 7%). Findings were consistent in per-protocol analysis (p(non-inferiority)=0·011). PEB and PES were superior to balloon angioplasty alone (54·1% [25·0]; p(superiority)<0·0001 for both comparisons). Frequency of death, myocardial infarction, or target lesion thrombosis did not differ between groups.
INTERPRETATION: By obviating the need for additional stent implantation, PEB could be a useful treatment for patients with restenosis after implantation of a drug-eluting stent.
FUNDING: Deutsches Herzzentrum.

 

OBJECTIVE: To evaluate the clinical and angiographic outcome in patients with in-stent restenosis in small coronary arteries and repeat target lesion revascularisation.
DESIGN: Patients with in-stent restenosis in coronary arteries<or = 2.85 mm were eligible for the study and underwent target lesion revascularisation. Clinical and angiographic variables were assessed during a six month follow up period.
RESULTS: 73 patients with 79 lesions were treated by percutaneous transluminal coronary angioplasty (47%), excimer laser angioplasty (25%), or restenting (28%). The mean (SD) reference diameter before target lesion revascularisation was 2.12 (0.5) mm. Procedural success was achieved in all cases, but 57% of the patients had restenosis after six months. The rate of further restenosis was higher with laser angioplasty (78%) than with restenting (47%) or balloon angioplasty alone (49%, p<0.05).
CONCLUSIONS: Treatment for in-stent restenosis in small coronary arteries is feasible and safe, with a second restenosis rate comparable to large coronary artery series. The strategy of target lesion revascularisation influences further in-stent restenosis, with an increased rate with laser angioplasty compared with restenting and repeat dilatation alone.

 

OBJECTIVE: We examined long-term outcomes of patients with in-stent restenosis (ISR) who underwent different percutaneous interventions at the discretion of individual operators: balloon angioplasty (BA), repeat stent or rotational atherectomy (RA). We also examined long-term outcomes of patients with ISR who underwent coronary artery bypass surgery (CABG).
BACKGROUND: In-stent restenosis remains a challenging problem, and its optimal management is still unknown.
METHODS: Symptomatic patients (n = 510) with ISR were identified using cardiac catheterization laboratory data. Management for ISR included BA (169 patients), repeat stenting (117 patients), RA (107 patients) or CABG (117 patients). Clinical outcome events of interest included death, myocardial infarction, target vessel revascularization (TVR) and a combined end point of these major adverse cardiovascular events (MACE). Mean follow-up was 19+/-12 months (range = 6 to 61 months).
RESULTS: Patients with ISR treated with repeat stent had significantly larger average post-procedure minimal lumen diameter compared with BA or RA (3.3+/-0.4 mm vs. 3.0+/-0.4 vs. 2.9+/-0.5, respectively, p<0.05). Incidence of TVR and MACE were similar in the BA, stent and RA groups (39%, 40%, 33% for TVR and 43%, 40%, 33% for MACE, p = NS). Patients with diabetes who underwent RA had similar outcomes as patients without diabetes, while patients with diabetes who underwent BA or stent had worse outcomes than patients without diabetes. Patients who underwent CABG for ISR, mainly because of the presence of multivessel disease, had significantly better outcomes than any percutaneous treatment (8% for TVR and 23% for MACE).
CONCLUSIONS: In this large cohort of patients with ISR and in the subset of patients without diabetes, long-term outcomes were similar in the BA, repeat stent and RA groups. Tissue debulking with RA yielded better results only in diabetic patients. Bypass surgery for patients with multivessel disease and ISR provided the best outcomes.

 

BACKGROUND: In patients who develop in-stent restenosis, successful revascularization can be difficult to achieve using percutaneous methods. This study was designed to verify the surgical results in this setting and to evaluate the potential beneficial role of arterial bypass conduits.
METHODS AND RESULTS: Sixty consecutive coronary artery bypass patients with previous in-stent restenosis and 60 control cases were randomly assigned to receive an arterial conduit (either right internal thoracic or radial artery; study group) or a great saphenous vein graft (control group) on the first obtuse marginal artery to complete the surgical revascularization procedure. At a mean follow-up of 52+/-11 months, patients were reassessed clinically and by angiography. Freedom from clinical and instrumental evidence of ischemia recurrence was found in 19 of 60 subjects in the study group versus 45 of 60 in the control series (P=0.01). The results of the arterial grafts were excellent in both the study and control groups (right internal thoracic artery patency rate, 19 of 20 for both, and radial artery patency rate, 20 of 20 versus 19 of 20; P=0.99). Saphenous vein grafts showed lower patency rate than arterial grafts in both series and had extremely high failure rate in the study group (patency rate, 10 of 20 in the study group versus 18 of 20 in the control group; P=0.001). Use of venous graft was an independent predictor of failure in the study group, whereas hypercholesterolemia was associated with graft failure in both series.
CONCLUSIONS: Venous grafts have an high incidence of failure among cases who previously developed in-stent restenosis, whereas the use of arterial conduits can improve the angiographic and clinical results. Arterial grafts should probably be the first surgical choice in this patient population.

Background It is still unclear if patients treated for ISR may benefit from a long DAPT regimen.

Methods For the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications.

  • AD PMID 24161321
  • TI Prasugrel versus clopidogrel in patients with acute coronary syndromes.
  • AU Wiviott SD1, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators.
  • SO N Engl J Med. 2007 Nov 15;357(20):2001-15. Epub 2007 Nov 4.

BACKGROUND:

Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention.

METHODS:

To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding.

RESULTS:

The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002).

CONCLUSIONS:

In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)

The lumen diameter reduction after percutaneous coronary intervention (PCI) is well known as “restenosis”. This phenomenon is due to vessel remodeling/recoil in case of no-stent strategy or, in case of stent employ, “neointimal proliferation” that consists in an excessive tissue proliferation in the luminal surface of the stent otherwise by a further new-occurring atherosclerotic process called “neoatherosclerosis”. The exact incidence of in-stent restenosis (ISR) is not easy to determine caused by different clinical, angiographic and operative factors. In the pre-stent era the occurrence of restenosis ranged between 32-55% of all angioplasties, and drop to successively 17-41% in the bare metal stents (BMS) era. The advent of drug eluting stent (DES), especially 2nd generation, and drug-coated balloon (DCB) further reduce restenosis rate until <10%. We here review the main characteristics of this common complication of coronary interventions, from its pathogenesis to the most appropriate treatment strategy.

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CABG: a Superior Revascularization Modality to PCI in Patients with poor LVF, Multivessel disease and Diabetes, Similar Risk of Stroke between 31 days and 5 years, post intervention

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/4/2019

SYNTAX at 10 Years: Bypass vs PCI Still a Toss-Up Overall

But CABG beats stenting for important subgroups

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81944?xid=nl_mpt_DHE_2019-09-04&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Daily%20Headlines%202019-09-04&utm_term=NL_Daily_DHE_Active

Lancet Study, 2/2018

Interpretation

CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies.

JACC Study, 7/2018

CONCLUSIONS

This individual patient-data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30-day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization.

European Journal of Cardiothoracic Surgery Study, 6/2018

CONCLUSIONS

Despite a longer length of hospital stay, patients with impaired LVF requiring intervention for coronary artery disease experienced a greater post-procedural survival benefit if they received CABG compared to PCI. We have demonstrated this at 30 days, 90 days, 1 year, 3 years, 5 years and 8 years following revascularization. At present, CABG remains a superior revascularization modality to PCI in patients with poor LVF.

 

New Studies on Clinical Outcomes from two Revascularization Strategies: CABG and PCI

 

J Am Coll Cardiol. 2018 Jul 24;72(4):386-398. doi: 10.1016/j.jacc.2018.04.071.

Stroke Rates Following Surgical Versus Percutaneous Coronary Revascularization.

Abstract

BACKGROUND:

Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are used for coronary revascularization in patients with multivessel and left main coronary artery disease. Stroke is among the most feared complications of revascularization. Due to its infrequency, studies with large numbers of patients are required to detect differences in stroke rates between CABG and PCI.

OBJECTIVES:

This study sought to compare rates of stroke after CABG and PCI and the impact of procedural stroke on long-term mortality.

METHODS:

We performed a collaborative individual patient-data pooled analysis of 11 randomized clinical trials comparing CABG with PCI using stents; ERACI II (Argentine Randomized Study: Coronary Angioplasty With Stenting Versus Coronary Bypass Surgery in Patients With Multiple Vessel Disease) (n = 450), ARTS (Arterial Revascularization Therapy Study) (n = 1,205), MASS II (Medicine, Angioplasty, or Surgery Study) (n = 408), SoS (Stent or Surgery) trial (n = 988), SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial (n = 1,800), PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) trial (n = 600), FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900), VA CARDS (Coronary Artery Revascularization in Diabetes) (n = 198), BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) (n = 880), NOBLE (Percutaneous Coronary Angioplasty Versus Coronary Artery Bypass Grafting in Treatment of Unprotected Left Main Stenosis) trial (n = 1,184), and EXCEL (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial (n = 1,905). The 30-day and 5-year stroke rates were compared between CABG and PCI using a random effects Cox proportional hazards model, stratified by trial. The impact of stroke on 5-year mortality was explored.

RESULTS:

The analysis included 11,518 patients randomly assigned to PCI (n = 5,753) or CABG (n = 5,765) with a mean follow-up of 3.8 ± 1.4 years during which a total of 293 strokes occurred. At 30 days, the rate of stroke was 0.4% after PCI and 1.1% after CABG (hazard ratio [HR]: 0.33; 95% confidence interval [CI]: 0.20 to 0.53; p < 0.001). At 5-year follow-up, stroke remained significantly lower after PCI than after CABG (2.6% vs. 3.2%; HR: 0.77; 95% CI: 0.61 to 0.97; p = 0.027). Rates of stroke between 31 days and 5 years were comparable: 2.2% after PCI versus 2.1% after CABG (HR: 1.05; 95% CI: 0.80 to 1.38; p = 0.72). No significant interactions between treatment and baseline clinical or angiographic variables for the 5-year rate of stroke were present, except for diabetic patients (PCI: 2.6% vs. CABG: 4.9%) and nondiabetic patients (PCI: 2.6% vs. CABG: 2.4%) (p for interaction = 0.004). Patients who experienced a stroke within 30 days of the procedure had significantly higher 5-year mortality versus those without a stroke, both after PCI (45.7% vs. 11.1%, p < 0.001) and CABG (41.5% vs. 8.9%, p < 0.001).

CONCLUSIONS:

This individual patient-data pooled analysis demonstrates that 5-year stroke rates are significantly lower after PCI compared with CABG, driven by a reduced risk of stroke in the 30-day post-procedural period but a similar risk of stroke between 31 days and 5 years. The greater risk of stroke after CABG compared with PCI was confined to patients with multivessel disease and diabetes. Five-year mortality was markedly higher for patients experiencing a stroke within 30 days after revascularization.

KEYWORDS:

coronary artery bypass graft; left main; mortality; multivessel; percutaneous coronary intervention; stenting; stroke

PMID:
30025574
DOI:
10.1016/j.jacc.2018.04.071

 

Lancet Study

Head SJ, Milojevic M, Daemen J, Ahn JM, Boersma E, Christiansen EH, Domanski MJ, Farkouh ME, Flather M, Fuster V, Hlatky MA, Holm NR, Hueb WA, Kamalesh M, Kim YH, Mäkikallio T, Mohr FW, Papageorgiou G, Park SJ, Rodriguez AE, Sabik JF, Stables RH, Stone GW, Serruys PW, Kappetein AP. Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. Lancet. 2018 Feb 22 [Epub ahead of print]. doi: 10.1016/S0140-6736(18)30423-9. PMID: 29478841

Summary

Background

Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies.

Methods

We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all-cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics.

Findings

We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3·8 years (SD 1·4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26·0 (SD 9·5), with 1798 (22·1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11·2% after PCI and 9·2% after CABG (hazard ratio [HR] 1·20, 95% CI 1·06–1·37; p=0·0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11·5% after PCI vs 8·9% after CABG; HR 1·28, 95% CI 1·09–1·49; p=0·0019), including in those with diabetes (15·5% vs 10·0%; 1·48, 1·19–1·84; p=0·0004), but not in those without diabetes (8·7% vs 8·0%; 1·08, 0·86–1·36; p=0·49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10·7% after PCI vs 10·5% after CABG; 1·07, 0·87–1·33; p=0·52), regardless of diabetes status and SYNTAX score.

Interpretation

CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies.

SOURCE

European Journal of Cardiothoracic Surgery Study, 6/2018

 

Eur J Cardiothorac Surg. 2018 Jun 22. doi: 10.1093/ejcts/ezy236. [Epub ahead of print]

Comparison of the survival between coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with poor left ventricular function (ejection fraction <30%): a propensity-matched analysis.

Abstract

OBJECTIVES:

Existing evidence comparing the outcomes of coronary artery bypass graft (CABG) surgery versus percutaneous coronary intervention (PCI) in patients with poor left ventricular function (LVF) is sparse and flawed. This is largely due to patients with poor LVF being underrepresented in major research trials and the outdated nature of some studies that do not consider drug-eluting stent PCI.

METHODS:

Following strict inclusion criteria, 717 patients who underwent revascularization by CABG or PCI between 2002 and 2015 were enrolled. All patients had poor LVF (defined by ejection fraction <30%). By employing a propensity score analysis, 134 suitable matches (67 CABG and 67 PCI) were identified. Several outcomes were evaluated, in the matched population, using data extracted from national registry databases.

RESULTS:

CABG patients required a longer length of hospital stay post-revascularization compared to PCI in the propensity-matched population, 7 days (lower-upper quartile; 6-12) and 2 days (lower-upper quartile; 1-6), respectively (Mood’s median test, P = 0.001). Stratified Cox-regression proportional-hazards analysis of the propensity-matched population found that PCI patients experienced a higher adjusted 8-year mortality rate (hazard ratio 3.291, 95% confidence interval 1.776-6.101; P < 0.001). This trend was consistent amongst urgent cases of revascularization: patients with 3 or more vessels with coronary artery disease and patients where complete revascularization was achieved. Although sub-analyses found no difference between survival distributions of on-pump versus off-pump CABG (log-rank P = 0.726), both modes of CABG were superior to PCI (stratified log-rank P = 0.002).

CONCLUSIONS:

Despite a longer length of hospital stay, patients with impaired LVF requiring intervention for coronary artery disease experienced a greater post-procedural survival benefit if they received CABG compared to PCI. We have demonstrated this at 30 days, 90 days, 1 year, 3 years, 5 years and 8 years following revascularization. At present, CABG remains a superior revascularization modality to PCI in patients with poor LVF.

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Ralph’s Story: An Entertainer at Heart

Patient was diagnosed with heart disease and pulmonary hypertension in January 2016 and had a triple-bypass operation at age 69. Interview was conducted six months post-surgery.

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

 

Evergreen, Colorado, an idyllic, peaceful community with an elevation of 8,000 feet west of Denver, offers its residents and visitors a beautiful place for arts and culture, summer and winter sporting activities, and scenic beauty. In fact, Ralph Nichols has lived in the town for more than 20 years.

“This past September [2015] was, particularly, challenging for me, where winter begins quite early for us. It became increasingly painful and difficult to breathe in the freezing temperatures. It seemed that my lungs were inflamed and I couldn’t even stand the cold weather. I thought it might be the beginning of a bad cold, and I wasn’t overly concerned that there was anything terribly wrong.”

At that time, Ralph went to his family physician who performed the usual routine examination with no significant results.

“Many years ago, I developed a mild case of scleroderma, a chronic connective tissue disease. I thought that perhaps my symptoms were the result of some type of inflammation in my body that could be managed with prescription medications.”

Scleroderma is known as an autoimmune disease, which adds an inappropriate amount of collagen to various parts of the body, such as the joints, skin, and later stages, various organs, such as the lungs, in Ralph’s case. Scleroderma can cause the organs to shut down and, eventually, cause death.

“I never let this condition stop me from doing anything as it is life-long condition. It was always something I had to tolerate and work through.”

http://www.scleroderma.org/site/PageNavigator/patients_whatis.html#.V5Zrm84luKo

 

Image SOURCE: Photographs courtesy of Ralph Nichols and Gabriela Contreras.  Top left: Ralph today. Top right: Ralph recovering one month after surgery. Bottom left and center: Ralph with his medical team. Bottom right: Ralph in rehabilitation center.

Over the brutal Colorado winter, Ralph’s symptoms were getting worse. He had no idea that his life would dramatically change over the next few months. He went to see his family physician again. During this physical examination, Ralph was referred to pulmonary and cardiovascular specialists for a routine electrocardiogram, echocardiogram and stress test in order to further diagnose his symptoms. He had always been relatively healthy and fit and never been seriously ill or hospitalized.

“On the outside, Ralph was the picture of good health,” said his wife, Gabriela. “On the inside, his body was telling him that something was wrong.”

Three months later in December 2015, Ralph met with Dr. Alexandra Smart, a pulmonologist, who ordered a chest x-ray and other diagnostic tests, including a right heart catheterization. At that point, Ralph’s medical team grew. It was then determined that Ralph needed to see other cardiovascular specialists and undergo more tests. In January 2016, he met with Dr. Sameer Mehta, cardiologist at Cardiac & Thoracic Surgery Associates, in Lakewood, Colorado, who reviewed his tests to date, listened to Ralph’s symptoms, and told him he needed both a right and left heart cardiac catheterization.

 “They gave me sedation for the catheterization procedure and went through my neck with a camera to see what was going on with my lungs and heart. We were all singing together on the way to the operating room. During the procedure, my cardiologist found more than he had anticipated.”

The result was not good. Ralph had major blockages in two main arteries that supply blood to his heart muscle compounded by the fact that his lungs were affected by scleroderma.

“The catheterization was alarming. It showed that my arteries were in bad shape. They were both clogged with atherosclerotic plaque; one of them was 99 percent blocked and the other was 85 percent blocked.”

His cardiologist believed that the blockages would not respond to medications quickly or a stent.

“Even though my father had major heart disease and died two years later of cancer at the age of 56, I thought that I would be immune to this particular experience. After all, I was in good health, exercised regularly, lived a reasonable lifestyle and had a great diet.”

 Preparing for Life-Saving and Life-Changing Surgery

Unfortunately, surgery was the next step. Ralph was referred to Dr. Mehta’s colleague, Dr. Patrick D. Rudersdorf, cardiothoracic surgeon at Cardiac & Thoracic Surgery Associates.

“I didn’t leave the hospital that day as expected. Instead, I got a visit from Dr. Rudersdorf and couldn’t believe what he was telling me. My only chance to live was having triple bypass surgery which needed to be done immediately. The doctor met with me that same day to explain the procedure, answer my questions and talk through the details of the rehabilitation period after the surgery.”

Dr. Rudersdorf reassured Ralph that he was doing the right thing and calmed my fears.

“He said that I needed this life-saving surgery because I was at high risk for having a major heart attack. I was shocked, at first, at the thought of the intensity of surgery on my body. It’s a situation that no one likes to be in, but I had to make a decision about alleviating the ongoing pain and pressure in my chest along with shortness of breath due to diseased heart arteries. Coronary bypass surgery was my answer to feeling better — and it essentially gave me my life back.”

Dr. Rudersdorf moved his previously planned morning surgery to another day to accommodate me first thing in the morning. Ralph underwent triple bypass surgery at St. Anthony Hospital in Lakewood, Colorado. The procedure was complex and took eight hours. He was in the hospital for a total of 31 days.

“It was an ordeal that I thought I’d never have to experience. I had no time to call anyone, or time to even contemplate life and death…or even being scared.  My wife Gabriela spent the entire time in the hospital, supported by our dearest friends, Norma Delaney and Garret Annofsky, in addition to keeping family and friends in other parts of the United States and Mexico updated as well. Once the surgery was over, the medical team woke me up and said the procedure was successful, but I was far from being out of the woods.”

Ralph had some complications because of a condition called pulmonary hypertension, a type of high blood pressure that affects the arteries in the lungs and the right side of the heart. According to the Mayo Clinic’s web site, in one form of pulmonary hypertension, tiny arteries in the lungs, called pulmonary arterioles, and capillaries become narrowed, blocked or destroyed. This makes it harder for blood to flow through the lungs, and raises pressure within the lungs’ arteries. As the pressure builds, the heart’s lower right chamber (right ventricle) must work harder to pump blood through the lungs, eventually causing the heart muscle to weaken and fail. http://www.mayoclinic.org/diseases-conditions/pulmonary-hypertension/home/ovc-20197480

“The pulmonary hypertension limited some of the medications that the doctors would have used during my recovery. It was a tough few days for me in intensive care, hooked up to about 18 monitors. The medical team had to stop and re-start my heart four different times because of atrial fibrillation — finally getting both parts of the heart to dance together in the same rhythm.”

Ralph’s heart was beating abnormally fast and irregular and not functioning the way it should. The doctors restore regular rhythm to the heart by sending an electrical shock to the heart, which is called electrical cardioversion or chemically using antiarrhythmia medications, which is called pharmacologic or chemical cardioversion.

“The doctors shocked my heart first chemically with medications when I was awake. This procedure was the scariest. I was sitting up in bed and felt my heart stop, then the medical team flushed the medication out with saline in order to restart my heart. That procedure was not successful, so that is why the doctors had to shock my heart three more times electrically.

“The reason the doctors stopped my heart was to correct the atrial fibrillation and to get my heart into regular sinus rhythm, which is a wave mode of the heart where everything is synchronized. The doctors did not want me to continue to experience atrial fibrillation because if continued, I would not be able to regain my strength.”

Ralph was finally moved from intensive care to intermediate care after five days and the medical team kept him in intermediate care another 12 days until his heart and lungs got stronger.

“From there, I didn’t go home but instead went to Evergreen Life Center for rehabilitation for two weeks to learn how to walk, climb stairs so that I could access my home on my own, and develop my strength again. The rehab team would let me leave only after making sure I had oxygen in my home.”

After that, Ralph started another phase of his rehabilitation at St. Anthony Cardiac Rehabilitation and Wellness Center. For the next three months, he took part in cardiac rehabilitation three days a week. He passed that with flying colors. Now, he is in another phase of rehabilitation, building his lung capacity two days a week.

Ralph didn’t have the means or even the will to communicate with friends during this tumultuous time, except Gabriela and several close friends who were always at the hospital and rehabilitation center who gave him the strength to continue.

“I finally returned home after many weeks with an enormous feeling of gratitude for each and every one of my friends, as well as the St. Anthony’s hospital team of doctors, nurses, and therapists, who supported me and Gabriela during this exceptional adventure that has certainly changed my life.”

Surely, this experience has been a life-changing experience for Ralph.

 Coronary Artery Bypass Facts

 Coronary artery bypass grafting (CABG, often pronounced “cabbage”) is a surgical treatment for blocked coronary arteries. Coronary arteries supply blood to the heart muscle and when blockages in these arteries form, chest pain, shortness of breath and heart attacks can occur. Catheter procedures performed by interventional cardiologists address the blockages themselves with stents. Coronary bypass surgery performed by cardiac surgeons reroutes the blood around the blockages to supply better blood supply to the heart muscle and is a better treatment option, although more invasive, for certain patients and more durable for most patients.

http://ctsurgery.com/conditions-procedures/heart-aorta/cardiac-surgery/coronary-artery-bypass-grafting-cabg/

Life for Ralph Today

Today, Ralph is regaining his strength both in mind and body. He visits the cardiovascular and pulmonary rehabilitation center three times a week for the past few months and walks on their treadmill, lifts weights and pedals the bicycle for one hour, supervised by the therapists. He also sees his medical team for regular check-ups every month, eats healthier with no fat and no salt, and takes a cocktail of medicines daily for his heart and lungs, including amiodarone, furosemide, pitavastatin, and aspirin.

“Almost six months after my surgery, although I am not in the best shape of my life, however, I am in the best spiritual place than ever before. This is a huge milestone for me. I continue to improve my strength, which will make my heart more resilient. There is nothing that I can’t do now, and I am doing everything I can to experience a normal life as far as work and regaining my strength. I find it necessary to move to a warmer climate and lower altitude in order to continue to improve.”

Ralph also is the former lead singer of The Letterman and The Sandpipers, two American easy-listening bands during the 1960-70-80s. He is an entertainer at heart with over 3,000 professional appearances to his credit. He has been performing and recording for over 50 years, traveled the world extensively and performed before members of the Vatican with Pope Pius XII and Royalty with Prince Rainier and Princess Grace Kelly, as well as notables such as Frank and Nancy Sinatra, Tony Bennett, Ronald Reagan, Merv Griffin, Danny Thomas, Shirley Bassey, Rosalind Russell and Bob Hope.

Ralph and his vocal group were dubbed by Billboard Magazine as “the greatest romantic vocal group of all time.” He is also a member of the Vocal Group Hall of Fame, a prestigious honor. He is a true legend as his group has sold more than 20 million recordings, performed live thousands of times, and whose recording of the song “Love” was left by NASA astronauts in a time capsule on the moon.

“I enjoy each and every day and appreciate all that life has to offer.”

Ralph’s next step is to get back to singing and his solo entertainment business, which he holds dear to his heart. That should be a task that he can easily accomplish.

 

Editor’s note:

We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support that she provided in scheduling time to talk with Ralph Nichols.

Ralph Nichols provided his permission to publish this interview on July 30, 2016.

 

REFERENCES/SOURCES

http://www.scleroderma.org/site/PageNavigator/patients_whatis.html#.V5Zrm84luKo

http://www.mayoclinic.org/diseases-conditions/pulmonary-hypertension/home/ovc-20197480

http://ctsurgery.com/conditions-procedures/heart-aorta/cardiac-surgery/coronary-artery-bypass-grafting-cabg/

 

Other related articles:

Retrieved from http://www.sunset.com/travel/rockies/evergreen-colorado-day-trip-travel-planner

Retrieved from http://www.secondscount.org/heart-condition-centers/info-detail-2/benefits-risks-of-coronary-bypass-surgery-2#.V5dkK_krKUk

Other related articles were published in this Open Access Online Scientific Journal include the following: 

2016

People with blood type O have been reported to be protected from coronary heart disease, cancer, and have lower cholesterol levels.

https://pharmaceuticalintelligence.com/2016/01/11/people-with-blood-type-o-have-been-reported-to-be-protected-from-coronary-heart-disease-cancer-and-have-lower-cholesterol-levels/

2015

A Patient’s Perspective: On Open Heart Surgery from Diagnosis and Intervention to Recovery

https://pharmaceuticalintelligence.com/2015/05/10/a-patients-perspective-on-open-heart-surgery-from-diagnosis-and-intervention-to-recovery/

No evidence to change current transfusion practices for adults undergoing complex cardiac surgery: RECESS evaluated 1,098 cardiac surgery patients received red blood cell units stored for short or long periods

https://pharmaceuticalintelligence.com/2015/04/08/no-evidence-to-change-current-transfusion-practices-for-adults-undergoing-complex-cardiac-surgery-recess-evaluated-1098-cardiac-surgery-patients-received-red-blood-cell-units-stored-for-short-or-lon/

2013

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

https://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

On Devices and On Algorithms: Arrhythmia after Cardiac SurgeryPrediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset

https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

 

Editor’s note:

I wish to encourage the e-Reader of this Interview to consider reading and comparing the experiences of other Open Heart Surgery Patients, voicing their private-life episodes in the ER that are included in this volume.

I also wish to encourage the e-Reader to consider, if interested, reviewing additional e-Books on Cardiovascular Diseases from the same Publisher, Leaders in Pharmaceutical Business Intelligence (LPBI) Group, on Amazon.com.

  •  Perspectives on Nitric Oxide in Disease Mechanisms, on Amazon since 6/2/12013

http://www.amazon.com/dp/B00DINFFYC

  • Cardiovascular, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation, on Amazon since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

  • Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases, on Amazon since 12/26/2015

http://www.amazon.com/dp/B019UM909A

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Entire Family of Impella Abiomed Impella® Therapy Left Side Heart Pumps: FDA Approved To Enable Heart Recovery

Reporter: Aviva Lev-Ari, PhD, RN

 

Abiomed Impella® Therapy Receives FDA Approval for Cardiogenic Shock After Heart Attack or Heart Surgery

Entire Family of Impella Left Side Heart Pumps FDA Approved To Enable Heart Recovery

DANVERS, Mass., April 07, 2016 (GLOBE NEWSWIRE) — Abiomed, Inc. (NASDAQ:ABMD), a leading provider of breakthrough heart support technologies, today announced that it has received U.S. Food and Drug Administration (FDA) Pre-Market Approval (PMA) for its Impella 2.5™, Impella CP®, Impella 5.0™ and Impella LD™ heart pumps to provide treatment of ongoing cardiogenic shock. In this setting, the Impella heart pumps stabilize the patient’s hemodynamics, unload the left ventricle, perfuse the end organs and allow for recovery of the native heart.  This latest approval adds to the prior FDA indication of Impella 2.5 for high risk percutaneous coronary intervention (PCI), or Protected PCI™, received in March 2015.

With this approval, these are the first and only percutaneous temporary ventricular support devices that are FDA-approved as safe and effective for the cardiogenic shock indication, as stated below:

The Impella 2.5, Impella CP, Impella 5.0 and Impella LD catheters, in conjunction with the Automated Impella Controller console, are intended for short-term use (<4 days for the Impella 2.5 and Impella CP and <6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (<48 hours) following acute myocardial infarction (AMI) or open heart surgery as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures with or without an intra-aortic balloon pump.  The intent of the Impella system therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.

The product labeling also allows for the clinical decision to leave Impella 2.5, Impella CP, Impella 5.0 and Impella LD in place beyond the intended duration of four to six days due to unforeseen circumstances.

The Impella products offer the unique ability to both stabilize the patient’s hemodynamics before or during a PCI procedure and unload the heart, which allows the muscle to rest and potentially recover its native function. Heart recovery is the ideal option for a patient’s quality of life and as documented in several clinical papers, has the ability to save costs for the healthcare system1,2,3.

Cardiogenic shock is a life-threatening condition in which the heart is suddenly unable to pump enough blood and oxygen to support the body’s vital organs. For this approval, it typically occurs during or after a heart attack or acute myocardial infarction (AMI) or cardiopulmonary bypass surgery as a result of a weakened or damaged heart muscle. Despite advancements in medical technology, critical care guidelines and interventional techniques, AMI cardiogenic shock and post-cardiotomy cardiogenic shock (PCCS) carry a high mortality risk and has shown an incremental but consistent increase in occurrence in recent years in the United States.

“This approval sets a new standard for the entire cardiovascular community as clinicians continue to seek education and new approaches to effectively treat severely ill cardiac patients with limited options and high mortality risk,” said William O’Neill, M.D., medical director of the Center for Structural Heart Disease at Henry Ford Hospital. “The Impella heart pumps offer the ability to provide percutaneous hemodynamic stability to high-risk patients in need of rapid and effective treatment by unloading the heart, perfusing the end organs and ultimately, allowing for the opportunity to recover native heart function.”

“Abiomed would like to recognize our customers, physicians, nurses, scientists, regulators and employees for their last fifteen years of circulatory support research and clinical applications. This FDA approval marks a significant milestone in the treatment of heart disease. The new medical field of heart muscle recovery has begun,” said Michael R. Minogue, President, Chairman and Chief Executive Officer of Abiomed. “Today, Abiomed only treats around 5% of this AMI cardiogenic shock patient population, which suffers one of the highest mortality risks of any patient in the heart hospital. Tomorrow, Abiomed will be able to educate and directly partner with our customers and establish appropriate protocols to improve the patient outcomes focused on native heart recovery.”

Abiomed Data Supporting FDA Approval

The data submitted to the FDA in support of the PMA included an analysis of 415 patients from the RECOVER 1 study and the U.S. Impella registry (cVAD Registry™), as well as an Impella literature review including 692 patients treated with Impella from 17 clinical studies. A safety analysis reviewed over 24,000 Impella treated patients using the FDA medical device reporting (“MDR”) database, which draws from seven years of U.S. experience with Impella.

In addition, the Company also provided a benchmark analysis of Impella patients in the real-world Impella cVAD registry vs. these same patient groups in the Abiomed AB5000/BVS 5000 Registry. The Abiomed BVS 5000 product was the first ventricular assist device (VAD) ever approved by the FDA in 1991 based on 83 patient PMA study. In 2003, the AB5000 Ventricle received FDA approval and this also included a PMA study with 60 patients.

For this approval, the data source for this benchmark analysis was a registry (“AB/BVS Registry”) that contained 2,152 patients that received the AB5000 and BVS 5000 devices, which were originally approved for heart recovery. The analysis examined by the FDA used 204 patients that received the AB5000 device for the same indications. This analysis demonstrated significantly better outcomes with Impella in these patients.

The Company believes this is the most comprehensive review ever submitted to the FDA for circulatory support in the cardiogenic shock population.

  1. Maini B, Gregory D, Scotti DJ, Buyantseva L. Percutaneous cardiac assist devices compared with surgical hemodynamic support alternatives: Cost-Effectiveness in the Emergent Setting.Catheter Cardiovasc Interv. 2014 May 1;83(6):E183-92.
  2. Cheung A, Danter M, Gregory D. TCT-385 Comparative Economic Outcomes in Cardiogenic Shock Patients Managed with the Minimally Invasive Impella or Extracorporeal Life Support. J Am Coll Cardiol. 2012;60(17_S):. doi:10.1016/j.jacc.2012.08.413.
  3. Gregory D, Scotti DJ, de Lissovoy G, Palacios I, Dixon, Maini B, O’Neill W. A value-based analysis of hemodynamic support strategies for high-risk heart failure patients undergoing a percutaneous coronary intervention. Am Health Drug Benefits. 2013 Mar;6(2):88-99


ABOUT IMPELLA

Impella 2.5 received FDA PMA approval for high risk PCI in March 2015, is supported by clinical guidelines, and is reimbursed by the Centers for Medicare & Medicaid Services (CMS) under ICD-9-CM code 37.68 for multiple indications. The Impella RP® device received Humanitarian Device Exemption (HDE) approval in January 2015. The Impella product portfolio, which is comprised of Impella 2.5, Impella CP, Impella 5.0, Impella LD, and Impella RP, has supported over 35,000 patients in the United States.

The ABIOMED logo, ABIOMED, Impella, Impella CP, and Impella RP are registered trademarks of Abiomed, Inc. in the U.S.A. and certain foreign countries.  Impella 2.5, Impella 5.0, Impella LD, and Protected PCI are trademarks of Abiomed, Inc.

ABOUT ABIOMED
Based in Danvers, Massachusetts, Abiomed, Inc. is a leading provider of medical devices that provide circulatory support.  Our products are designed to enable the heart to rest by improving blood flow and/or performing the pumping of the heart.  For additional information, please visit: www.abiomed.com

FORWARD-LOOKING STATEMENTS
This release includes forward-looking statements.  These forward-looking statements generally can be identified by the use of words such as “anticipate,” “expect,” “plan,” “could,” “may,” “will,” “believe,” “estimate,” “forecast,” “goal,” “project,” and other words of similar meaning.  These forward-looking statements address various matters including, the Company’s guidance for fiscal 2016 revenue. Each forward-looking statement contained in this press release is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statement.  Applicable risks and uncertainties include, among others, uncertainties associated with development, testing and related regulatory approvals, including the potential for future losses, complex manufacturing, high quality requirements, dependence on limited sources of supply, competition, technological change, government regulation, litigation matters, future capital needs and uncertainty of additional financing, and the risks identified under the heading “Risk Factors” in the Company’s Annual Report on Form 10-K for the year ended March 31, 2015 and the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015, each filed with the Securities and Exchange Commission, as well as other information the Company files with the SEC.  We caution investors not to place considerable reliance on the forward-looking statements contained in this press release.  You are encouraged to read our filings with the SEC, available at www.sec.gov, for a discussion of these and other risks and uncertainties.  The forward-looking statements in this press release speak only as of the date of this release and the Company undertakes no obligation to update or revise any of these statements.  Our business is subject to substantial risks and uncertainties, including those referenced above.  Investors, potential investors, and others should give careful consideration to these risks and uncertainties.

For more information, please contact: Aimee Genzler Director, Corporate Communications 978-646-1553 agenzler@abiomed.com Ingrid Goldberg Director, Investor Relations igoldberg@abiomed.com

SOURCE
http://investors.abiomed.com/releasedetail.cfm?ReleaseID=964113

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Moderate Ischemic Mitral Regurgitation: Outcomes of Surgical Treatment during CABG vs CABG without Mitral Valve Repair

Curator: Aviva Lev-Ari, PhD, RN

 

Original Article

Michler RE et al. Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med2016 Apr 3; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1602003)

– See more at: http://www.jwatch.org/na40963/2016/04/03/repairing-moderate-mitral-regurgitation-during-cabg-update#sthash.3wfUSvPm.dpuf

 

April 3, 2016

Repairing Moderate Mitral Regurgitation During CABG: An Update

 

Harlan M. Krumholz, MD, SM reviewing Michler RE et al. N Engl J Med 2016 Apr 3.

Two-year findings do not support widespread adoption of the combined procedure.

When the Cardiothoracic Surgical Trials Network randomized 301 patients with moderate mitral regurgitation to undergo coronary artery bypass grafting (CABG) alone or CABG plus mitral valve repair, the two groups had similar postsurgical ventricular dimensions, survival, and major adverse events at 1 year. However, the combined-procedure group had a significantly lower prevalence of moderate-to-severe mitral regurgitation — but longer postsurgical hospital stays and higher incidences of postoperative supraventricular arrhythmias and serious neurologic events (NEJM JW Cardiol Jan 2015 and N Engl J Med 2014; 371:2178).

We now have the 2-year findings.

  • The postsurgical left-ventricular end-systolic volume index was again similar between the two groups.
  • Two-year mortality was slightly, but not significantly, higher with CABG alone than with the combined procedure (10.6% vs. 10.0%)
  • CABG-alone group had a significantly higher incidence of moderate-to-severe mitral regurgitation (32% vs. 11%).
  • The two groups had similar rates of hospital readmission and
  • The two groups had similar major adverse events,
  • Most quality-of-life scores were similar between the two groups.

except that

  • serious neurologic events and supra-ventricular arrhythmias were significantly more common with the combined procedure.

 

SOURCES

Michler RE et al. Two-year outcomes of surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med2016 Apr 3; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1602003)

http://www.jwatch.org/na40963/2016/04/03/repairing-moderate-mitral-regurgitation-during-cabg-update#sthash.3wfUSvPm.dpuf

http://www.jwatch.org/na40963/2016/04/03/repairing-moderate-mitral-regurgitation-during-cabg-update

 

Other related articles published in this Open Access Online Scientific Journal Include the following:

Articles on Heart Failure N=6

https://pharmaceuticalintelligence.com/?s=Heart+Failure

Articles on coronary artery bypass graft CABG N=36

https://pharmaceuticalintelligence.com/?s=CABG

Articles on Pharmacotherapy of Cardiovascular Diseases N=296

https://pharmaceuticalintelligence.com/?s=Pharmacotherapy+of+Cardiovascular+Disease

Articles on Mitral Valve Repair or Replacement N = 47

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Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Poor Outcomes on Medical Therapy alone

Curator: Aviva Lev-Ari, PhD, RN

CABG improves survival for individuals with coronary artery disease and compromised left ventricular function,” said NHLBI Director Gary H. Gibbons, MD

Monday, April 4, 2016

Original article

http://www.nejm.org/doi/full/10.1056/NEJMoa1602001

Study results show bypass surgery extends lives of patients with heart failure

Research may lead to improved outcomes for large number of patients who previously had limited therapeutic options.

Scientists funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health have found that a greater number of patients with coronary artery disease may benefit from coronary artery bypass graft (CABG) surgery than previously thought.

CABG — a surgical procedure to help improve blood flow to the heart by bypassing arteries clogged with cholesterol plaques — was thought to be too risky for patients with the long-term effects of coronary artery disease: left ventricular dysfunction (when the left side of the heart is unable to pump normally) and heart failure. Studies of the safety and effectiveness of CABG in the 1970s excluded most patients with these two conditions. The procedure was typically used to relieve angina, or chest pain.

“With limited data showing any benefit for patients with left ventricular dysfunction and heart failure, physicians and patients were less likely to engage in such an invasive, and thus risky, procedure as CABG for diagnosis and treatment,” said lead author Eric J. Velazquez, MD, FACP, FACC, FASE, FAHA, of Duke University Medical Center. “Patients with these conditions largely received medical therapy alone and had poor outcomes.”

Dr. Velazquez and his team conducted a five-year global, randomized controlled clinical trial, called the Surgical Treatment for Ischemic Heart Failure (STICH) study, and a five-year extension study (STICHES(link is external)), to evaluate whether CABG plus guideline-directed medical therapy had a durable benefit over medical therapy alone for patients with coronary artery disease and left ventricular dysfunction. The researchers found that CABG added to medical therapy led to significantly lower rates of death and hospitalization among patients with coronary artery disease, left ventricular dysfunction, and heart failure.

“Our results usher in a new era in the treatment of coronary artery disease because we now have evidence that with CABG and medical therapy, there is a 16 percent reduction in the risk of death from any cause over 10 years,” Dr. Velazquez said.

He added that there is also a median survival benefit of nearly a year and a half, and that he and his team saw that the addition of CABG to medical therapy prevented a death from any cause for every 14 patients they treated. Their data further suggest that the reduction in the risk of death could be even greater in real-world practice.

“Conducting this trial was critically important to determine in a scientifically rigorous study that CABG improves survival for individuals with coronary artery disease and compromised left ventricular function,” said NHLBI Director Gary H. Gibbons, MD. “The current 10-year follow-up provides new important insights about patient subgroups that are more likely to benefit from CABG as compared to medical therapy alone. As such, we now have a solid evidence base to inform patient care and the future development of clinical practice recommendations.”

Dr. Velazquez noted that the results are particularly important because the prevalence of left ventricular dysfunction and heart failure is expected to increase to approximately 8 million individuals by 2030 in the U.S. alone. The increase in the projected prevalence is a result of advances in the management of cardiovascular disease and its risk factors, increasingly transforming coronary artery disease into a chronic disease with long-term effects such as left ventricular dysfunction and heart failure.

George Sopko, MD, MPH, the program director in NHLBI’s Division of Cardiovascular Sciences who administered the study grant, added that this investigation, published in The New England Journal of Medicine (April 2016), is one of only a few cardiovascular trials with 10 years of follow-up and with approximately 98 percent of the patients followed throughout the study period.

“It is unusual to have this quality of follow-up for so long,” said Dr. Sopko. “It speaks to the rigor of the results.” He added that the results are very generalizable, as the study included a diverse patient population spread across 22 countries and various health systems.

SOURCE

http://www.nih.gov/news-events/news-releases/study-results-show-bypass-surgery-extends-lives-patients-heart-failure

http://www.nejm.org/doi/full/10.1056/NEJMoa1602001

Other related articles published in this Open Access Online Scientific Journal include the following:

Articles on Heart Failure N=6

https://pharmaceuticalintelligence.com/?s=Heart+Failure

Articles on coronary artery bypass graft CABG N=36

https://pharmaceuticalintelligence.com/?s=CABG

Articles on Pharmacotherapy of Cardiovascular Diseases N=296

https://pharmaceuticalintelligence.com/?s=Pharmacotherapy+of+Cardiovascular+Disease

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A Fantastic Vessel-Clearing Innovation on The vessel-clearing device, U.S. Patent No. 8,663,209

This article is a Contribution to this Open Access Online Scientific Journal and to our BioMed e-Series on 2/29/2016 by William Harrison Zurn, member of our Team, holder of multiple US Patents in the Medical Devices field.

 

This article will be REPUBLISHED with permission in a forthcoming e-Book by Leaders in Pharmaceutical Business Intelligence in our BioMed e-Series

https://pharmaceuticalintelligence.com/biomed-e-books/

Series E: Patient-centered Medicine

Content Consultant: Larry H Bernstein, MD, FCAP

Volume 1: 

The VOICES of Patients, HealthCare Providers, Care Givers and Families: Personal Experience with Critical Care and Invasive Medical Procedures – Work-in-Progress

https://pharmaceuticalintelligence.com/biomed-e-books/series-e-titles-in-the-strategic-plan-for-2014-1015/2014-the-patients-voice-personal-experience-with-invasive-medical-procedures/

 

This article first appeared in the February 2016 issue of Inventors Digest magazine. Published by permission.

Permission SOURCE to re-publish

From: Cama McNamara <cama@inventorsdigest.com

Date: 2/26/2016 08:39 (GMT-08:00) 

To: William Zurn <wilzur@msn.com

Subject: Re: Re-Publish Article 

 

Cardiac Patient’s Comment to the article:

Re-published with permission

Permission SOURCE to re-publish

On Feb 28, 2016, at 8:19 PM, William Zurn <wilzur@msn.com> wrote:

 Aviva, the person with the reply gave his permission.

Please removed all his contact information.

 

It’s from a heart patient, who underwent a triple bypass in his 40s, and Dr. Mehmet Oz performed the surgery.

Received on LinkedIn on 02/19/2016: 

“Hello, My name is XXXXX  and I am a cardiovascular disease patient. I am a retired NY police officer and I read about your great work in Inventors Digest. I was 44yrs of age when I suffered a heart attack and had triple bypass surgery at Colunbia Prebyterian Hospital in NYC.Dr.Mehmet Oz was my surgeon. I am very active in a gym and exercise daily.I am now 64 yrs of age and God willing I will continue to be healthy. I was so interested in your work I had to write to you. God Bless you for your brilliant mind and the work you are doing. Please keep me in mind if in the future you get to a stage that heart arteries can actually me cleaned of any arterial plaque. I would be happy to undergo this procedure when you have perfected this.

Thank you….

XXXXX

[Name, Phone Number and e-mail address was omitted to maintain Patient’s Privacy.]

A FANTASTIC VESSEL-CLEARING INNOVATION

How the 1960s-era Science-Fiction Movie Fantastic Voyage Is Becoming a Reality

By Clifford Thornton

 

In 1966, the science-fiction movie Fantastic Voyage was far ahead of its time in special effects, technology and cinematography. What is most remarkable, though, is the foresight of the film’s creators and directors to capture an almost unimaginable concept at the time: nano technology and micro-electro mechanical systems, which are coming very close to reality today.

Previous science-fiction movies focused on intergalactic travel, but Fantastic Voyage delved into another kind of space—“inner space”—space inside the human body. In this case, the body is explored by a successful brain surgeon, scientists and other specialists aboard the customized submarine Proteus, which is designed to navigate through the human vascular system after it is shrunk to microscopic size, placed in a syringe and injected into the bloodstream.

The team’s mission is to save the life of the scientist who holds the secrets of the miniaturization technology. He suffers from a life-threatening blood clot in his brain, which has left him in a coma.

Once miniaturized, the submarine and its crew are inserted into the scientist’s carotid artery, where it begins its arduous journey. The nuclear-powered vessel’s location is tracked through the isotopes it emits, and the vessel’s status is monitored by control-and-command center personnel, who use radio to communicate with the crew.

To determine the shortest route through the scientist’s vessels to the clot, the team uses diagrams of the human anatomy as navigation charts. Once the submarine reaches the clot, the scientists aboard use a laser beam to pry the clot from the blocked vessel. The journey is quite exciting, as the crew can see what no human has previously seen: the wonders and workings of the inner human body at the microscopic level—in close proximity and vivid detail.

 

Lasers and MRIs

What do miniature submarines, a dying scientist and a surgical laser beam have to do with nanotechnology and MEMS? This imagined medical surgical capability, as far-fetched as it seemed at the time, is extremely close to becoming a reality. Inventor William Zurn has exercised his decades-long experience in technology development and engineering to design a now-patented vessel-clearing system that will accomplish, in a very similar fashion, what Proteus and its crew set out to do—eliminate blood clots—but in a more modern and realistic way.

Clotting of the blood, such as when an injury occurs and the bleeding stops, is a normal occurrence in the body. However, clotting can also cause irreparable bodily damage, or even death. Clots that pose a risk or threat to a patient can occur in the heart, veins or arteries.

Zurn was inspired to develop a patentable stent after researching the causes and effects of aneurysms. This led to a system of controlling, guiding and placing medical-implant modules within the principles of nuclear magnetic resonance. The vessel-clearing device is a huge leap in medical technology, transcending present methods of clearing atherosclerotic plaque and clots from human vessels and arteries. The vessel-clearing system will enable complete mapping of the cardiovascular system via magnetic resonance imaging, and precise locating and targeting of the occlusion.

Additionally, computer-assisted surgical methods of clearing clots and atherosclerotic plaque will be employed. The system computes the circulatory system path algorithm, which, in turn, allows for navigation to, around and from the source of the blockage. Finally, an algorithm for removing the blockage, which is programmed into the master computer, directs the motion of a biocompatible module apparatus, constructed by nanotechnology and/or semiconductor material, which then utilizes laser energy to remove the blockage. This is a much more effective, safe and efficient method than a traditional angioplasty procedure, which uses a balloon to compress the blockage or plaque against the artery walls. Recent studies have shown that after a few years, many patients must have an additional angioplasty procedure.

Nanotechnology Is a Giant Step

What exactly is the vessel-clearing system and how does it work? We can compare Proteus and its imagined capabilities to the vessel-clearing system. Within the system, a biocompatible module composed of multiple subsections, referred to as “pods,” are constructed by a combination of nanotechnology and integrated circuit technology. The size of these injectable pods is approximately 100 nanometers by 50 nanometers (a nanometer is equal to one-billionth of a meter). These pods are analogous to Proteus, and just as Proteus was introduced to the scientist’s body through a syringe and needle, the BCMs, or pods, will be inserted into patients in the same fashion.

In the same way that Proteus had radio communication between its crew and the control center, the vessel-clearing system will allow for similar communication between the pods and the control console, which is operated by a surgeon. As such, the pods have a communications unit, a radio frequency receiving and conversion section, and a laser-transmission section. The laser functions as the tool to untether and fragment the clot. The remaining residue is processed by the kidneys. Just as Proteus’ location in the scientist’s body was tracked by the control center via nuclear emissions, the vessel-clearing pods will be transmitted and closely and accurately tracked by nuclear resonance imaging. The collected information will be displayed on the control console.

In the film, Proteus and its crew have a certain time frame—60 minutes—in which the miniaturized state will remain active. Past that time, everyone and everything involved return to normal size. Zurn’s vessel-clearing system will not experience this problem. The vessel-clearing system and related procedure will be carried out in an efficient and timely manner with a focus on patient safety. Once, it is determined that all applicable and dangerous blockages have been cleared, the BCMs will be collected and extracted from the patient’s body in the same way in which they were introduced, via a syringe and needle.

If this sounds like another fantastic voyage, think again. The vessel-clearing device, U.S. Patent No. 8,663, 209, will be making its inaugural journey soon.

 

Clifford M. Thornton is a Certified Cardiovascular Technologist and a registered Diagnostic Cardiac Sonographer. He is also a journalist in the medical device field, particularly in the fields of cardiology and nanotechnology.

 

 

 

 

 

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A Patient’s Perspective: On Open Heart Surgery from Diagnosis and Intervention to Recovery – A New Day, a New Lease and Unfolding Questions!

Guest Author: Ferez S. Nallaseth, Ph.D.

Life Sciences Institute of New Jersey, Belle Mead, NJ 08502; Complex Biological Systems Alliance, Boston, MA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901.

Contact information:

Email Addresses: ferez.nallaseth@cbsaimtt.com

ferez.nallaseth@gmail.com

Tel: 646 283 5163 (M)
908 431 5069 (CBSA)
Skype Address: ferez.nallaseth
Websites:Life Sciences Institute of New Jersey, Belle Mead, NJ.
Member – Complex Biological Systems Alliance
Ferez S. Nallaseth, Ph.D. (Google Scholar)
Ferez S. Nallaseth, Ph.D. (Google Sites)
Ferez’nSquashDocs (website and blog)
LinkedIn:http://www.linkedin.com/pub/ferez-soli-nallaseth/14/2a7/311
Twitter:@fnallase1

This article will be published in 

Series E: Patient-Centered Medicine 

Volume One: The Patient’s Voice: Personal Experience with Invasive Medical Procedures

All subsequent excerpt submissions for publications elsewhere MUST include the following sentence:

START QUOTE

I, Ferez Nallaseth, PhD was commissioned (at no exchange of any financial rewards) by Dr. Aviva Lev-Ari, PhD, RN, the Editor-in-Chief of the Open Access Online Scientific Journal 

http://pharmaceuticalintelligence.com

on 2/14/2015 to write an original article representing “The Voice of the Cardiovascular Diseased Patient who underwent an invasive procedure, i.e. CABG, aka, Open Heart Surgery.”

Date: Sat, Feb 14, 2015 at 5:37 AM

Subject: Invitation to write one article about your experience: From Diagnosis to Recovary

To: Ferez Nallaseth <ferez.nallaseth@gmail.com>

Cc: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

We are publishers of a BioMed e-Books e-Series

Please go to

Http://pharmaceuticalintelligence.com

Click on

BioMed e-Series

1. Please click on Series A: Cardiovascular Diseases

Volume 1,2,3,4,5,6

2. Please Click on Series E: Patient-Centered Medicine

Volume One: The Patient Voice – Experience with Invasive Surgery

HERE, I WISH TO INVITE YOU TO CONTRIBUTE ONE ARTICLE ON YOUR EXPERIENCE WITH OPEN HEART SURGERY.

Please reply if interested.

I am looking forward to your reply.

Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed Series

  • This article was edited by Stephen J Wiiliams, PhD, Senior Editor at Leaders in Pharmaceutical Business Intelligence (LPBI) as part of the publishing process of the article in the Journal.

This article was published in the Journal on May 10, 2015. This article will appear in the forthcoming ebook, Titled, 

 This is Volume One in Series E: Patient-centered Medicine, in the BioMed e-Series will be published by LPBI on Amazon.com

The URL for the original article is listed, below:

https://pharmaceuticalintelligence.com/2015/05/10/a-patients-perspective-on-open-heart-surgery-from-diagnosis-and-intervention-to-recovery/

END QUOTE

  • All References to the article as a Reference source, should cite the link, above

HOWEVER, since this article has been included already in Volume One of Series E AND Volume One is WORK-IN-PROGRESS, not yet on Amazon.com as a published e-Book THEN 

  • for all cases of using an excerpt versus citing the article in its entirety for ANY OTHER PUBLISHER, i.e. Squash Report, it needs to add a footnote with the QUOTE, above

A Patient’s Perspective: On Open Heart Surgery from Diagnosis and Intervention to Recovery – A New Day, a New Lease and Unfolding Questions!

Ferez S. Nallaseth, Ph.D.

Life Sciences Institute of New Jersey, Belle Mead, NJ 08502; Complex Biological Systems Alliance, Boston, MA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901.

ABSTRACT:

A minor cardiac event last Christmas revealed how seriously my life was threatened. It was averted by the amazing efforts of the, Biomedical Community, Family, Friends and Colleagues all pulling together and from around the Globe. The brush with ‘eternity and infinity’ left me aware that the ‘just war’ in which I had been engaged for close to 4 decades had left too much not done and too many, neglected in too many ways and too far removed from the core of my being! At least part of the consequences of that trauma on the 25th of December was the initiation of a thought process (or the lack of it) in filling this void! And yet remaining mindful of history and those in it, even ordinary ones, to whom we owe so much, precisely because they made the right and hard, choices that I am faced with today!

SYNOPSIS:

This is the perspective of a Life Scientist who underwent a Heart Attack and triple Bypass Surgery. Because this is a retrospective experience with little data to support it and I am neither a Cardiologist nor a Cardiac Surgeon, this exercise is of necessity, a largely subjective delivery of the process that saved my life. It is one in which I was merely the beneficiary of the highest form of dedicated professionalism! It is in part an expression of my deepest gratitude to my family, friends, some even emerging from long neglect, and medical professionals who leapt to my rescue! As well as addressing a need for more systematized studies to address the true frequencies of the events that I underwent. A gratitude that usually dawns when one has had a brush with ‘eternity and infinity’ and effectively becomes bedridden – if only transiently so! Considering the technical complexity of the undertaking by (a) Dr. Andrew Shanahan, my Cardiologist, in detecting the block by catheterization and angiography and (b) Dr. George Batsides, my Cardiac Surgeon and (c) their respective teams in intervening with the triple bypass surgery, all with a 98% success rate, it is nothing short of amazing!

However, the scientific and medical literature and my Cardiologist’s and Cardiac Surgeon’s observations also supports the interpretation, although not experimentally verifiable, that competitive Squash and training for it in India delayed Coronary Artery Disease and kept me alive till Dr. Shanahan and Dr. Batsides had time to intervene! It probably saved my life in 3 important ways. Firstly, as 1 of about 20 high intensity sports (METs of 6 -13) it is likely to have significantly lowered the risk of Coronary Disease (22 – 40%), thus secondly, delaying the massive blockage (95% – 99%) of 5 major Coronary Arteries by Coronary Artery Disease (CAD) that was recorded. Lastly Squash, and training for it, likely preconditioned (Ischemic Preconditioning or IPC) my cardiomyocytes, making them resistant to hypoxia and so ensured their predominant survival (96 – 98%) when the inevitable Heart Attack (Myocardial Infarction or MI) predicted by several Risk Factors, occurred. However, the ~2% of cardiomyocytes which did succumb to cell death could not have been resistant to total Oxygen (O2) deprivation (anoxia) as is expected e.g.from observations in Sudden Cardiac Arrest (SCA). Conversely, the hypoxia resistance of my cardiomyocytes may have contributed to the inability to stress them with O2 deprivation in Stress Tests as was revealed by Electrocardiograms, Transthoracic Echocardiography and Electroradiographic monitoring. This may have, despite chest spasms, led to the inability to detect the disease over 10 years. Only catheterization and angiography, justified by the elevation of circulating levels of the biomarker Troponin T and done by Dr. Shanahan could confirm this dire Coronary Artery Disease diagnosis.

Although an attempt has been made to include, (1) useful information recommended by all the Medical Personnel involved who have previewed an outline of this article, (2) select scientific and medical literature relevant to it have been added to each of the contributing dimensions that were considered (but are restricted to Supplementary Information Boxes (SIB)), (3) those lifelong events, activities and habits (including the assault on my professional work and personal life) that either contributed to or ameliorated known Risk Factors for the Heart Attack which on hindsight was inevitable! At the very least the combination of my decades long cardiac and sports experience, the scientific literature and the findings of Dr. Shanahan and Dr. Batsides after I finally had a Heart Attack, as well as the experience of others in the Cardiac Physiotherapy Program that I attend, strongly suggest a need for a systematic screening for these symptoms. Of necessity preceded by a re-evaluation of the methods for detection of all types of silent diseases affecting the Cardiac system.  For example development of various Tomography approaches e.g. Multi Spectral Optoacoustic Tomography (MSOT) (97,98).

I’ve also made an attempt to come to terms with perhaps an insidious process that is still underway – somewhere in the back of my mind. It may mimic the ‘know thyself’ of Delphos, and what I like to think of as the nebulous, amorphous and often contradictory aspects of being human. This includes the many communities in any life – family, friends, medical, professional and social networks. Those who were either at one with me or dropped everything in their own lives to leap to my rescue, and also included onlookers and even outright adversaries who seemed to be genuinely concerned! Possibly transfixed by the specter of mortality?

Work unfinished due to unavoidable circumstances that were alluded to earlier and the transience of life were the compelling, if sub conscious, forces over the past 40 years or so and although now dampened by these events, they have not disappeared. And in some unclear ways may perhaps even have been heightened in my sub-conscious by the potential extent of the waste of my life if things had ended less favorably. Not only of the terminated future, but also of the long span of the past which had been dedicated to the body of unpublished Scientific work, which would have been discarded instead of being in the literature where it serves a more useful purpose!

However, the true nature and impact of the recent events on my life and their effects go beyond the Operating (Surgical) Theater and are still evolving! Included are a revision of the cavalier considerations of activities and habits contributing to cardiac Risk Factors with ‘you only live once’ which have now been tempered by that brush! A temperance into both, a reticence that is almost Pavlovian as well as one of a sense of responsibility to those whose graciousness, generosity, sacrifice and hard work rescued me from near certain death! In addition to those Physicians and Surgeons who played the most active roles in saving my life, all those unbelievably dedicated Biomedical Support Personnel who assiduously contributed to the diagnosis, intervention and recovery of a relative stranger who had undergone a Heart Attack and required Critical Care are included here. They are implicitly or explicitly noted in the acknowledgements (link). This event and the period spanning it will remain a watershed that has unleashed many ongoing developments in my life.

INTRODUCTION:

Last Christmas morning (25th December 2014) would become a Watershed Day in my life! Although I had, what was subsequently confirmed as, only a minor Heart Attack (Myocardial Infarction), it unleashed a progression of events that culminated in Open Heart Surgery. They continue to alter my perspectives radically, and in ways, with which I am still coming to terms. For a start it conclusively resolved the “Will-O’–the-Wisp” of Chest Pains and Diagnoses’ that ‘ruled out’ Cardiac malfunctions over the last 10 years. There were other ways in which it does so but this followed more (bad but good) news that was yet to come. When I was brought in by the Emergency Medical Services the Biomedical teams in the Emergency Room of the University Medical Center of Princeton in Plainfield, led by Chief Emergency Physician Dr. Eileen Daly, the Attending Physician Dr. Ying-Kei Hui and the Cardiologist Dr. Banu Mahalingam immediately concentrated on stabilizing my condition, the seriousness of which I alone was not fully aware! And more on this effort was to follow. I looked on all this as an inconvenience and planned on getting back to my keyboard – sooner than later. It would be nearly a month before I had finally managed to have done so – and likely would not have been writing this if I had been allowed to have my way! Since this is meant to address the concerns of those Patients who will follow in my experience I think it would be useful to define an outline of this article that the Editor of BioMed Online (Cancer, Cardiology, and Cardiology Devices) Dr. Aviva Lev-Ari had asked me to write. First of all the simple question arises as to why, as a Scientist who depends on controlled experiments, I would even agree to write something that is so subjective an experience? The short, if incomplete answer, is gratitude! For those who kept me alive medically and my family members and friends who dropped everything in their lives to either appear by my side or write and some even reappear in my life! And of equal importance these events convey a need that has been identified by others like myself – for a systematic and controlled study to address the gaps in a system that is otherwise remarkably fail safe!

But to address this and other questions meaningfully, it would be useful to deliver this narrative in (1) a chronological order, (2) while making necessary diversions with supplemental information boxes (SIB) included for short informative discussions on the, (a) literature on e.g., Risk Factors and rudimentary Cardiology and Cardiac Surgery, (b) definitions and analyses such as, (c) vital signs that may have made revelations about the process and why cause and effect as scientific and medical conclusions are unknowable in my case, (d) pain from Open Heart Surgery, (e) compassion, warmth, concern and yet skill, dedication and professionalism of all the Biomedical personnel involved, (3) summary of the relevant literature on contemporary methods of (a) establishing Risk Factors, (b) the energetics and physiology behind the cardio-pulmonary system, (c) the molecular, cellular and developmental biology of the cardiac system, its protection from genotoxic shock and disease states, (d) the contribution of specific processes to Risk Factors as well as their amelioration, (e) Sports Physiology and the role of Sports with an emphasis on Squash in the reduction of cardiac Risk Factors, (4) a summary on elements of the literature and the observations of my Cardiologist and Cardiac Surgeon that are consistent with the explanations for the events – first slowing down plaque buildup and then protecting my cardiomyocytes and allowing survival from the Myocardial Infarction (MI) or Heart Attack, (5) acknowledgement of those who either saved or eased my life, (6) reference list, (7) a more detailed review of this article focused on Sports Physiology and Cardiac Risk Factors to be oriented and submitted to a Sports or Clinical Sports Journal (1).

(8) (a) To begin with, it is only appropriate to thank my Cardiologist Dr. Andrew Shanahan and my Cardio -Thoracic Surgeon Dr. George Batsides. Dr. Batsides’ highly encouraging message to my query for permission to publish an event that involved his work, his team as well as his Editorial assistance:


“Ferez, I’m very glad to hear that you are doing well.  Thank you for your very kind words.  Our team would be honored to be included.  We are all very happy that this has not only helped you physically but has also impacted you in such a positive manner.  Cardiovascular disease is still the great killer and one’s experience and perspective throughout the diagnosis, intervention, and recovery can be very valuable to others.  This can save lives by informing others on what to look for, how to seek help, and to not completely fear the process. Thank you for undertaking this project.  Please feel free to contact us for any help.  

All the best,

George B.  “


(8)(b) this article has additional input, (i) from concerned, highly skilled, dedicated, kind and professional, Biomedical Staff, Physicians and Surgeons at both the University Medical Center of Princeton (UMCP) in Plainsboro as well as at the Robert Wood Johnson University Hospital (RWJUH) in New Brunswick, (ii) my Family, and Friends, including my brother Attorney Cyrus Nallaseth who flew in from Bombay, (Mumbai) India on a moment’s notice, family, friends spanning generations such as Dr. Adil Mulla, an Anesthesiologist and his daughter Dr. Simone Mulla, who either appeared by my side or called regularly, at a vanishingly short notice, (iii) a long list of the most warm, kind, supportive and encouraging friends, fellow Squash Players, Scientists, fellow LinkedIn Members, fellow ResearchGate Members, Teachers at Princeton High School and others from around the World who responded via email to my ‘Late New Year’s Greetings’ and postings of the news, with nothing but the most supportive words that were re-invigorating in ways that I could not even have imagined! They are all listed in the acknowledgements link! In addition the article attempts to recognize as many contributors as were identifiable (with apologies included for any inadvertent omissions). This narrative will of necessity require covering the Risk Factors for Cardiac Disease that were both imposed or unavoidable and inevitably led to the cardiac event of the 25th of December 2014. As well as the ones that were those that I had either exacerbated or ameliorated. This will follow after introducing a few events in chronological order.

(A) NARRATIVE: A CHRONOLOGY OF LANDMARK EVENTS:

     1. Pre Heart Attack symptoms.

Over the last 10 years or so, prior to the Heart Attack, I had fleeting spasms in different locations of my chest and even while at rest. Depending on the circumstances e.g. acute stress, I had always had digestive and neurophysiological symptoms that are recognized as stress and environment related. They could either mask or promote cardiac pathologies. Approximately 35% of the US population displays all or some of these and other related symptoms (2). Furthermore, my colleague Peter Shimon of the Darwinian Evolutionary Medicine Group on LinkedIn identified a publication noting that Historians had recorded that these stress related symptoms, although near incapacitating, were overcome by those associated with the creative characteristics common to many artists, scientists and others, including Charles Darwin (3a,b)! In fact Darwin continued working, while having to solely depend on the ineffective therapies of his time, such as cold compresses applied to the spine. He wrote a whole chapter in the ‘Descent of Man’ while immersed in ice water to relieve the grip of nausea and migraine! (3a). It was, what we call, ‘Mind over Biology’ in the World of Sports!

As far as the spasms in my chest went, initially I did not think much of them but from around 2004 onwards, consulted Cardiologists and had gone through several Stress and other tests which were negative for cardiac malfunction that they had administered over that period. So it was hard to diagnose the cause of those chest spasms and my Primary Care Physician Dr. Perry Pong reminded me to remain wary of pulsating pains in the area of the sternum but not to worry too much about the other areas. Advice that was to save my life!

     2. Did Overtraining in my competitive Squash playing days lower the Risk Factors for Heart Disease through Ischemic Preconditioning (IPC)?

I had trained hard (in Sports Physiology this is termed over-training) in India 38 years ago (up to 1976 when I left for the US) for competitive Squash, an intense sport (~ 20 of 100 sports with a near maximal Metabolic Equivalent Task (METs) of 6 to 12). From results in national level tournaments, I was in the top 10 and remained in good shape even after decades of detraining an example of the training regimen I used was posted for the Rutgers University Squash Racquets Club (and this will matter as we will see later) (4). In the United States, after I had lived for 13 years in small University towns, which due to a lack of competition, essentially resulted in detraining, my game had ceased to exist and conditioning had dropped irreversibly to a fraction of the level in India along with my performance on the court. This happens to the best of Racquet Athletes who detrain relatively early in their careers e.g. Wimbledon and multiple (near) Grand Slam Tennis Champion Bjorn Borg! However, I still regained some of this conditioning, on subsequent retraining, with new literature referenced and to be discussed in this article, providing a molecular and cellular mechanistic basis for this observation – one which has always been well known to Athletes.

After moving up to the New York area in 1989 my game was partially recovered and I was nationally ranked in the USA in 1992 as a 40 year old (top 20 in the 5.5 level and higher in other age group divisions, by US Squash). Even in 2006/2007 long after my prime when I was 54/55 the residual game and conditioning retained were still sufficient to secure semi-final and final level performances in Open tournaments in New York (at 5.0 or Ltd A levels – 3 levels down from the highest 6.0 level)! As well as a 3 -2 win over a top ranked (by US Squash) Amateur/Pro (6.0 level) level competitor, Shane Doyle in a tough 90 minute interclub match. I was playing for the Rutgers USRC against Francis Odeh’s Valkyrie Club. Shane was an All American Surf Boarder and one of the toughest players in this semi-contact sport whom I have ever played in the United States! This may mean that 30 years after ceasing high intensity training, I still retained some of the conditioning developed in India. Squash, has been rated as having the highest Exercise Intensity (METs = 6 -12 cals/kg/hr), Health Benefit to Injury Ratios (517 Calories per 30 minutes of a game to Injury Score of 2) and Healthiest Sport with a total score of 22.5 of 10 sports as measured by Sports Physiologists, Athletes and Coaches (5, 6). And so a lifetime of conditioning in Squash, was likely to have contributed to my cardiac conditioning and saved my life (as will be shown later). However, after 2006/2007, I was again professionally pre-occupied and despite perfunctory workouts in the local gym my game and conditioning deteriorated further to low levels. This is dealt with in greater detail in the final segment.

     3. Did I have a Heart Attack in April 2010 long before the one on December 2014 that could not be detected by all the tests for cardiac malfunction that were administered?

At some time in April 2010, while on the court, I had a prolonged (1- 2 minute) chest spasm of medium intensity. Dr. Pong and I decided it was time to have it thoroughly examined by a Cardiologist. The Cardiologist whom we consulted was Dr.Tak Kwan. He was methodical, dedicated, reassuring, skilled and professional! I was subjected to 4 tests that were considered to constitute a thorough analyses of cardiac malfunctions. They were:

  • Electrocardiogram
  • Transthoracic Echocardiography (without 2D, color flow Doppler Echocardiography)
  • Transthoracic Echocardiography (with 2D, color flow Doppler Echocardiography)
  • Exercise Myocardial Perfusion Imaging with Dual Isotopes SPECT (Gated Tomography) or Electroradiographic monitoring for 24 hours

Based on the results of these 4 tests Dr. Kwan excluded cardiac mal-function with a 95% confidence interval. He felt that the Health Insurance Provider would not authorize any further more definitive tests such as catheterization and angiography. And subsequent events on the 25th of December 2014 confirmed the elusive nature of detecting even an ongoing Myocardial infarction (Heart Attack) which supported his conclusion.

As I was not a Cardiologist, there was little more that I could do and since I did not want to become a hypochondriac, I stopped thinking about this problem and did what we are trained to do in our time as athletes! That is work our way through ‘Pain Barriers’ as defined by the Multiple British Open Squash Champion, Jonah Barrington, in the 1970s (7). Although to be honest this level of pain would qualify for discomfort – at best!

That is till about 8.00 am on Christmas morning of 2014. I was on the computer keyboard – probably checking the Online News when things began to happen! The circumstances became reminiscent of my father’s passing from the second and fatal of two Ventricular Fibrillations that he suffered which was far more traumatic than my Heart Attack.

(B) HAVING POSSIBLE SYMPTOMS OF A HEART ATTACK (MYOCARDIAL INFARCTION):

(I) My apartment on Christmas day of 2014:

(i) On holidays I made a conscious effort to try and forget the ‘Elephant in the Room’ (‘EitR’ to be explained). Since one of its latest consequences was a lack of a job and funds for the past 8 (and often in the last 35) years my entertainment was restricted to consumption and TV at home. On that day this included Appetizers, Breads, Liquors, Prime Rib, Vegetables, Mashed Potatoes, and Christmas Plum Pudding with Plum Sauce! It was a good meal and sampling began on Christmas Eve (12/24/2014) although its leftovers were anticipated to last through the holidays – and well past New Year’s day!

The lipids and calories associated with this meal when either consumed in excess or regularly are classified as Risk Factors by the American Heart Association, the National Heart, Lung and Blood Institute of the national Institutes of Health and the Centers for Disease Control (CDC), the New York State Department Of Health and the Mayo Clinic Health System] as representing significant Risk Factors for Coronary Heart Disease (CHD), Coronary Artery Disease (CAD) and Coronary Vein Disease (8 – 26). The multifactorial nature (gene, environment, etc..) of heart disease(s) has always made it difficult for Cardiologists to identify and evaluate the impact of Risk Factors. However, contemporary genetic and statistical methods which are far more comprehensive as well as of higher resolution are accepted as reliably identifying and quantifying the Risk Factors associated with cardiac diseases (SIB-1, 7A to 7D). Included are the Risk Factors that my life style clearly incurred and those that it ameliorated.

The above meal was a Risk Factor! However it was a needed the distraction, could not be afforded often enough for it to amount to a dangerous Risk Factor, there were routinely included counteractive measures (workouts, statins, diet, etc..) and after all one only lived once! As we will see shortly, this led to an enforced leave of absence for 3 weeks in the Hospital, I ended up giving away, returning or discarding all the ‘good stuff’ – and may have not lived long enough to write this article!

(narrative interrupted).


Supplemental Information Box: SIB- 1:

Why do we have Heart Attacks, Cardiac Arrests and Ischemia/Strokes? To appreciate the reasons behind these pathological conditions requires some understanding of the basic biology of the (a) the 2 specialized organs the heart and the brain and their functional cells, called cardiomyocytes and neurons, which function through their generation of an electrical output? Addressed in: (26, 27, 28, 29, 31, 32, and 33), (b) How do they function to produce an electrical discharge/current (depolarization/repolarization) which induces cardiac contraction, in a process that includes the heart generating its own electrical discharge? Addressed in: (20, 23, 25 – 34), (c) What are their requirements for the source of their energy (ATP molecules) synthesized in the cellular power plants of all cells called Mitochondria? Addressed in: (32, 33), (d) Why is O2 critical for their function as well as their survival? Addressed In: (20, 23, 25 – 34), (e) What happens when the blood supply and so the O2 it transports to the heart via red blood cells is reduced or cutoff? Addressed In: (20, 23, 25 – 34), (f) How much work is done and what is the volume of blood pumped by a heart in the lifetime of an individual? Addressed In: (26, 30, 34, 35).

(a) The physiological functions of the heart and brain, are similarly dependent on electrical output, generated by cells carrying out the functions characteristic of these 2 organs called cardiomyocytes and neurons (26 – 34). Although in other ways cardiomyocytes and neurons are distinct, because of their high energetic demands, they are both hypersensitive to O2 deprivation, compared to e.g. muscle cells (myocytes) which can survive anaerobically through glycolysis. Energetic and reducing equivalents (biochemical molecules called ATP and NADH) required for the functions of all cells including cardiomyocytes and neurons are generated in mitochondria (26 – 34). The energy vehicle ATP is a molecule with a high energy chemical bond which when it is cleaved releases the energy necessary for executing most of the biochemical processes in most forms of life (26 – 34).

(b) Cardiomyocytes and neurons depend on ATP and NADH to drive the ion channels and pumps required for creating the electrical gradients across their cell membranes. This gradient is required for their functions of electrical discharge or depolarization (electrical waves) by pumping Na+ and K+ ions out and Cl ions into cardiac cells through special channels and pumps (that require ATP) causing their beating (26 – 34).

(c) ATP and NADH are generated on mitochondrial membranes by a controlled ‘slow burn’ of molecules derived from food, which unlike rapid combustion (flame), allows the harnessing of released energy as high energy chemical bonds of ATP molecules. Food is digested and biochemically degraded (catabolism) by specific biochemical pathways (glycolysis and the TCA cycle) preceding the products being ‘fed’ into the Mitochondrial Electron Transport system. The electrons from the (‘burnt’) molecules of food are sequentially passed down a series of membrane bound complexes, called the electron transport chain which represent increasingly oxidized (‘burnt’) molecules (oxidation states). The passage of electrons is harnessed with the synthesis of ATP by pumping electrons and H+ through another complex known as the F1/F0 complex which traverses the mitochondrial membrane. The process of ATP synthesis is called Oxidative Phosphorylation and is chemically and enzymatically coupled with Electron Transport. The final complex in the electron transport chain donates electrons to O2 as the final (terminal) acceptor molecule of electrons and H+ (protons) producing H2O as a reduction product. When e.g. arteries are either partially or completely blocked, O2 levels drop, electrically specialized and sensitive cells like cardiomyocytes and neurons not only cannot function but also die e.g. usually by a process called programmed cell death or apoptosis, which cleaves the cell while packaging is contents to prevent spillover of immunogenic components (27, 36, 37, 47, 50, 51).

(d) In ischemia/hypoxia-reperfusion studies products of genes such as HIF1, EPAS1, Akt, Bcl2, VEGF, CD-29, p38 Kinase, JAK-STAT, p29, and NOX2 and the hormone Estrogen attenuate injury by ROS to cardiac tissue through a multitude of mechanisms which will be covered in the section on the molecular, cellular and developmental biology of the cardiac system (36 – 51).

(e) the beating (contraction/relaxation) of the cells in the Heart is initiated from 3 electrical centers (called nodes) of cardiomyocytes that discharge coordinated electrical impulses. These impulses are known as depolarization and repolarization waves and basically represent an inversion and restoration of electrical charge and voltage across cell membranes which is known as membrane potential. These nodes are the Sinoatrial (SA) node located in the upper right Atrial chamber which releases the first discharge. The depolarization wave (current) then migrates down to the Atrioventricular (AV) node located at the junction of the 2 chambers causing it to discharge. There is a third system lining the walls of the Ventricle called the His-Prurkinje (H-P) system which therefore also discharges. Illustrating the extreme coordination underlying the contractions of the heart. Contraction is ATP dependent and mechanically mediated by intracellular (cardiomyocyte) filaments of motor molecules of Actin, Myosin and Troponin that are anchored to cell membranes. They have specific structural arrangements similar to anchored fibers and ratchets that facilitate contraction and relaxation of the cardiomyocyte. The electrochemical basis of the discharge is positively charged ions like Ca++, Na+ and K+ and negatively charged ions like Cl which can only cross cell membranes through specific specialized ‘pores’ called ion channels and require ATP to do so. When there is an influx of Ca++ ions into the cardiomyocytes it precipitates the passage of Na+/K+ , depolarization (inversion of electrical gradients across the cell membrane) occurs and there is a generation of an electrical voltage and current. All of which also require energy supplied by ATP. The beating of cardiomyocytes is synchronized in and between the various chambers of the Heart (Auricles (Atrial chambers) and Ventricles) to allow it to pump blood throughout the body – including to all the extremities and over a lifetime. Some indicators of the amount of work done and the volumes pumped by the Heart (29, 30):

  • The average adult heart beats 72 times a minute; 100,000 times a day;3,600,000 times a year; and 2.5 billion times during a lifetime.f
  • Though weighing only 11 ounces on average, a healthy heart pumps 2,000 gallons of blood through 60,000 miles of blood vessels each day.c
  • A kitchen faucet would need to be turned on all the way for at least 45 years to equal the amount of blood pumped by the heart in an average lifetime.a
  • The volume of blood pumped by the heart can vary over a wide range, from five to 30 liters per minute.e
  • Every day, the heart creates enough energy to drive a truck 20 miles. In a lifetime, that is equivalent to driving to the moon and back.a
  • Because the heart has its own electrical impulse, and can continue to beat even when separated from the body, as long as it has an adequate supply of oxygen.c

(See ref: 34, 35 for more data and examples).

Finally there are multiple Risk Factors for Coronary Heart Disease (CHD), Coronary Arterial Disease (CAD), and Sudden Cardiac Arrest or Sudden Death (SCA, SD) that have been established in many different ways by many organizations. Some have counteracting positive behaviors (8 – 27, 34, 35).

(A) Risk factors from the website of the National Heart, Lung and Blood Institutes, National Institutes of Health (NHLB, NIH) (11):

Risk factors are conditions or habits that make a person more likely to develop a disease. They can also increase the chances that an existing disease will get worse. Important risk factors for heart disease that you can do something about are:`

  • High blood pressure
  • High blood cholesterol
  • Diabetes and prediabetes
  • Smoking
  • Being overweight or obese
  • Being physically inactive
  • Having a family history of early heart disease
  • Having a history of preeclampsia during pregnancy
  • Unhealthy diet
  • Age (55 or older for women)

(B) Additional risk factors (National Health Services, UK) (18)

Additional Risk Factors identified by the National Health Services of the United Kingdom are:

  • diabetes
  • ethnic background

Also from the NHS, UK other factors that affect your risk of developing CVD include:

  • sex – men are more likely to develop CVD at an earlier age than women
  • age – your risk of developing CVD increases with age

Results in several new and ongoing areas of research in cardiac molecular, cellular and developmental biology illustrate the unfolding appreciation of the complexity of the Heart in Development and the many points at which its subversion could lead to the accumulation of risk factors! They are discussed in detail in the section (SIB-7C to 7E).

(d) partial interruption of blood flow and thus Oxygen supplies, called hypoxia, which results from plaques of lipid deposits and atherosclerosis causes the milder Heart Attack (Myocardial infarction). While the complete interruption of O2 supplies (anoxia) for 5 minutes due to cardiac electrical malfunction results in the more severe and often lethal Sudden Death (SD) or Sudden Cardiac Arrest (SCA). SCA unrectified for 10 minutes is always lethal. Neurons are irreversibly dead after 4 – 5 minutes of cutoff of O2 in Ischemia/Stroke. However in the case of mammalian (rodent) cardiomyocytes there is such a thing as physiological or ischemic preconditioning (IPC), wherein 20 minutes of hypoxia, elevates the level of resistance of the cardiomyocyte to subsequent challenges of hypoxia administered after even 48 – 72 hours. In the case of Sudden Cardiac Arrest the autonomous electrical supply of the heart initiated by the Sinoatrial Node is no longer coordinated within and between groups of cardiomyocytes in the Auricular and Ventricular chambers leading to their uncoordinated spasmodic contractions or fluttering and Ventricular or Atrial Fibrillation. The O2 supply to both neurons and cardiomyocytes is completely cutoff and the time for a successful resuscitation is a maximum of 5 minutes. It requires restoration of the supply of blood and O2 for rescuing cardiomyocytes with an Automated External Defibrillators (AED) before the patient, as the term suggests goes into irreversible Cardiac Arrest! Atrial Fibrillations (AF) are categorized as those which can (Paroxysmal AF and Persistent AF ) and those which cannot (Permanent AF) be corrected with therapy (23, 24, 25, 27).

(e) diet – a high-fat diet can cause fatty deposits to build up inside your arteries, leading to high blood cholesterol levels and high blood pressure

  • alcohol – excessive alcohol consumption can also increase your cholesterol and blood pressure
  • stress – not taking measures to reduce stress is thought to increase your risk of developing CVD

(C) Other risk factors (WebMD) (19)

Another Risk Factor obesity is now shown to require additional reinforcing factors to manifest their effects in the question: “Could it be genetics, specific dietary intake, physical lifestyle, emotional health or even the microbes that live in the gut? We need more studies to try to understand why obesity causes specific diseases in some people but not in others” (54).

Some risk factors, such as age and family history of early heart disease cannot be changed. Risk factors are multi-factorial and act synergistically.

Although complex the establishment of Risk Factors for CHD, CAD, CVD and Sudden Cardiac Arrest or Sudden Death (SCA, SD) has been made more reliable by contemporary methods such as Genome Wide Association Studies (GWAS) with up to 1,622,114 SNPs, various levels of Metabolic Equivalent Tasks (METs) as indices (METS = 6-16 calories/kilogram body weight/hour), large Cohorts of 6000 to 215,413 individuals, controlled applications of physiological stress (athletics, weights, graded Squash Specific Tests (ST) as opposed to Tread Mill Tests (TT), etc..) alone and strong Personal Record Keeping (high correlation with METs of 0.6.  These methods and Risk Factors will be discussed in detail along with the Risk to Benefit Factor Ratios of exercise e.g. Squash (SIB-7F).


(narrative resumed).

(ii) How many of the Risk Factors identified in SIB-1 were exacerbated and how many were ameliorated by my life style? The answer is mixed. Although as many as 5 of 10 Risk Factors listed by the NHLB, NIH, including moderately high cholesterol, decreased level of physical activity, being a little (20lbs/9kg) overweight, a history of a somewhat unhealthy diet (fast foods for 20 years, but home cooked for the most recent 15 years), and family history of heart disease and even early death from it (all 4 of us in the immediate and others in the extended family) apparently applied but were qualified. However, both family history and physical inactivity were ameliorated by overriding non-genetic factors and somewhat regular workouts. At least 3 more Risk Factors, gender, stress and uncontrolled anger (for good reason) being drawn from the list assembled by the NHS (UK) and WebMD applied to some degree. However determining the Risk Factors contributing to my MI or Heart Attack cannot go far without first addressing the ‘Elephant in the Room,’ (EitR), that had to have contributed heavily to the events under discussion! This is only alluded to once in this article, if for no other reason than to restore attention to those whom it belongs – the Biomedical Community, my family, friends and colleagues from all walks, who in different ways, either set aside all their concerns or preoccupations or focused their occupations, and leapt to save my life!

To understand the magnitude of the pressures from my professional life that had to have been a major contributor to stress as a Risk Factor, events spanning the last 35 years, and still ongoing, require being sketched. To protect something that was well established in Evolutionary Genetics and which led to discoveries of a fundamental Scientific importance and so to the Public Interest, (56, 57), I had to endure a multi-dimensional assault for largely venal reasons! First on our work and then, when an honest editor Dr. Walter Fitch finally published it, on me personally! Our work was first misunderstood by those who should have been more familiar with the literature, then eagerly sought by those at top labs and universities. The assault was coordinated from the highest levels of science by someone at the very pinnacle of scientific authority who was then at a major Research Institution/University in Boston, and had invited me to give a seminar on my work. From hindsight it was clearly with the intent of handing our work over to the designated ‘chosen’ in the field – a long term habit for which all the Principal Investigators involved in this process were infamous! This Investigator was proven to be one of the most unethical and ruthless Scientists in History by a US Congressman, by the National Institute of Health’s Office of Research Integrity (ORI) as well as by the President of an Ivy League University who Chaired a separate Committee Ruling on the events and reported that what had been documented was “only the most visible” of events. All this until a reversal was forced under pressure from the HHS!

In the spectrum of hostile actions taken against us the willing participation, of colleagues and even bystanders from the scientific community, who should have been more trustworthy, was secured! Yes, given the nature of the threat (combined with the prods of incitement and ingratiation!) there were consequences for refusing to participate, but let us just say that the actions of these scientists did not quite amount to upholding the Public Interest. Let alone, amounting to the resistance of, Dr. Robert Oppenheimer to the House Committee on Un-American Activities, or of Dr. Albert Einstein to the Nazis, or of Dr. Andrei Sakharov to the Soviet Politburo and its KGB. And most of all of Dr.Nikolai Vavilov (and his students) who endowed Humankind with Agricultural Biodiversity as well as with their own lives in their resistance to Trofim Lysenko, Lavrenty Beria, Joseph Stalin’s NKVD or the Nazis (during the Siege of Leningrad)!

The only way for me to have protected the Public Interest in our work and yet to have dealt with the ‘EitR’ was to become single minded, developed a thick skin, innovated, resisted attempts at cooption and continued grinding. As can be imagined, that meant losing many things large and small which took a toll finally even including my health! I had obviously concluded that this work was of large enough importance to persevere, if only reluctantly so, and to incur their wrath! However, unfolding results and events clearly supported this conclusion (56, 57)! And so it was always on the back of if my mind including on that morning of the 25th of December 2014.

Although, given its magnitude, prevalence and duration, it is of critical importance, the literature makes it unlikely that this assault on my scientific career and my person was the sole Risk Factor in the Coronary Event of 12/25/2014. As will be clear from the literature these Risk Factors were also likely to have been ameliorated by my having competed and trained hard (overtraining) for the high intensity (METs index of 6 to 12 cals/kg/hr) sport of Squash Rackets. The literature shows that this activity probably resulted in my cardiomyocytes being preconditioned to hypoxia resistance by a process known as ischemic preconditioning (IPC). This IPC can either last or be restored even after long periods of detraining. It also probably lowered the Risk Factors for Coronary Artery Disease (CAD) by 22 – 40% and so slowed down the buildup of plaque from CAD that was underway until the inevitable accumulation of plaques attained 95 – 99% blockage in 5 major coronary arteries as will be documented later. Together with the afore mentioned pressures this CAD inevitably led to the Heart Attack (Myocardial Infarction or MI) on the 25th of December 2014. But again, probably at a much later point in my life, and when it did occur, the MI was minor as ~98% of the (IPC) preconditioned cardiomyocytes survived. Only ~2% of the cardiomyocytes succumbed, as determined by Dr. Andrew Shanahan (using angiography and acoustic methods) and they probably succumbed to anoxia. This preconditioning induced hypoxia tolerance of cardiomyocytes also explains the inability of Cardiologists to detect cardiac malfunctions in Stress Tests over 10 years and so detect the developing CAD probably underlying my chest spasms. It is based on the proven retention of overtraining derived hypoxia tolerance even after a prolonged period of detraining (67). Another factor is the number of new cardiomyocytes born in periods of low or no training calculated from Retrospective Birth Dating (RBD) studies of Dr. Jonas Frisén and his colleagues (58, 59). RBD could have resulted in the maximal replacement of ~4.4% of cardiomyocytes leaving them susceptible hypoxia in the event that IPC was not transferred. However, an alternative explanation is also possible. Those ~2% of cardiomyocytes which succumbed could have done so because they were resident in a cardiac segment that lacked any blood and Oxygen (O2) supply and so were completely anoxic which results in lethality within 5 minutes.

(iii) After my second cup of coffee on Christmas morning, things started going South – but it was still nothing to cause panic! They were all routine digestive and neurophysiological symptoms that were handled before! For example by appropriate titrations of doses of medications and foods – or so I thought!

(iv) I started feeling nauseous, broke out in a cold sweat, vomited, became lightheaded and thought I was passing out, but lay down and recovered. And most differently of all, shortly before 8.00 am, now felt the pulsating beat below the sternum that Dr. Pong had warned me about staying alert. Somewhere along the way I realized that the Emergency Medical Services (EMS) of Princeton might be needed and so dialed: 911. As it turned out this decision ‘not to tough it’ was another one that probably saved my life!

(v) The Princeton EMS personnel were at my apartment in next to no time (about 8.15 – 8.20 am). I had recovered by then, and so could let them in. The Heart Attack, as would be confirmed later, from the time of detection of the Troponin T marker, had probably occurred in this time frame. They checked my vital signs (blood pressure, pulse, heart rate, temperature, etc..) and decided that I had to go into the Emergency Room – they suggested the University Medical Center of Princeton at Plainsboro (UMCP). It turned out to be a very good choice! The EMS personnel kept a close watch, and constantly engaged me in conversation while checking for the vital signs, every 1- 2 miles as we went north up highway US 206 which I knew well! I felt fine – but realized it was time to find a different less destructive distraction to the ‘EitR’!

(A)     THE EMERGENCY ROOM OF THE UNIVERSITY MEDICAL CENTER OF PRINCETON AT PLAINSBORO (UMCP):

(i)     We arrived around 8.50 am and by 9.00 am I was in the Emergency Room! With the Nurses and Dr. Shivani Sharma taking my recent and family History for the Charts, a technologist recorded my Electro Cardio Gram (ECG), and vital signs, a technologist drawing blood for the Pathology Lab for the quantification of Lipid Panels, Enzyme and Troponin T markers testing whether a Heart Attack had occurred. My charts show that I was placed on the usual combinations of Blood Thinners, Nitroglycerin paste, Protonix, Aspirin, Statins, etc.. to stabilize the condition resulting from a Heart Attack.

(ii)     Troponin T is a marker which is accepted as 100% diagnostic for a Heart Attack (Myocardial Infarction). Blood drawn at ~ 9.00 am did not show an elevation of this marker. This is not surprising as it takes 2 – 4 hours after onset of Chest Pains to be elevated to detectable levels in the bloodstream and then can lasts at elevated levels for 7 days (15, 18).

(narrative interrupted).


Supplemental Information Box: SIB – 2.

Reasons for the acceptance of Troponin T as a marker for Heart Attacks (Myocardial Infarctions) with near 100% confidence (15, 18).


(narrative resumed).

(iii)     The Electrocardiogram (ECG) traced at 10.40 am confirmed an irregularity. X-rays were taken. The Attending Physician listed on the charts was Dr. Ying – Kei Hui and the Head Physician of the Emergency Room was Dr. Eileen Daly. I was in good hands and most of my early interactions on the 25th of December were with Dr. Shivani, Dr. Daly and their supporting Nurses and Staff.

(iv)     The cell phone rang – my cousin Carl Engineer from San Francisco and his family, wife Dina, son Jehan, daughter Nisha and Son-in-Law (to be shortly), Chris Johnson, broke out in a Christmas Carol! Most of us are not religious, although I was raised in a Jesuit School and our family includes members from a multitude of religions, persuasions and nations, but we do know, as is obvious, a good time! And Christmas brought it whether we were in Bombay or London or New York or San Francisco! And I was not about to let on and ruin it – gaining the Nurses silence during the call! Particularly since over the last 10 years chest pains and stress tests had all turned out to be negative for cardiac mal-function ! By this point my thoughts had drifted back to the keyboard – TV worked as a distraction for about 10 minutes!

(v)     At 2.00 pm the batteries of Tests were administered again. This would soon become an hourly fixture and if anything multiplied in numbers and varieties over the next 3 weeks. The Troponin T level was now detectable at 0.11 ng/ml! Thus ending the ‘Willo-the-Wisp’ of the last 10 years and confirming that a Heart Attack had occurred! Based on the time of appearance of Troponin T, the MI may have been those pulsating spasms below the Sternum that occurred between 8.00 am and 9.00 am when I was still in the apartment! This result changed my life irreversibly! Dr. Daly came in and exclaimed ‘you see there is a method to our madness’ – obviously referring to the wait showing that the Troponin T finally rose to detectable levels as well as to my question about the period of time I would have to stay in the hospital.

(vi)     I was now moved up to the 3rd Floor in the Telemetry Wing for patients requiring either Cardiac Care or Intensive Care Units, fitted with a mobile Heart Rate Monitor which transmits signals that are recorded in a Central Station. The Monitor of the Central Station reports any loss of signal (e.g. wires coming loose from the patient or worse) and a Nurse corrects the problem immediately. The rigor was impressive!

(vii)     Dr. Daly came back took one look and said ‘look at you – cool as a cucumber’! What she could not have known, was that although I am not known to be slow, when it comes to these large, if not monumental events, I tend not to react, as there is not much to do that can change things! An example of a monumental event was represented by the time when I lived with my brother’s family 2 blocks away from the World Trade Center on 9/11 and we heard the first Plane [via Brooklyn fly over and into the North Tower, then waited, kept watch with those who had loved ones in the North Tower, until it collapsed and we had to run from the rush of debris!]. Also by this point, (and Dr. Daly could not have possibly known), my thoughts had positively drifted back to the keyboard – little did I know what lay ahead!

(viii)     Blood drawn at 9.00 pm showed that the Troponin T level further risen to 0.19 ng/ml which is considered high. On 12/27/2014 it had spiked at 0.47 ng/ml before gradually returning to 0.19 ng/ml and then to basal levels in responding to treatment.

(ix)     The Nurses were all in smart uniforms and I thought this was a Christmas Day informal uniform free day – until told with a smile, that it was a regular uniform! Through the night my vital signs were monitored, blood was drawn, medications administered and electronic records updated – like clockwork!

(x)     The next morning I had the pleasure of meeting Dr. Hui and Dr. Mahalingam who went about their usual responsibilities but were warm and empathetic while remaining professional. However, as soon as I asked Dr. Mahalingam about going home I was read the ‘Riot Act’ seemingly reserved for Coronary Patients – she might have been primed. Basically she explained how quickly even a mild Heart Attack, which is what I seem to have had, can turn into one like that which left a current occupant of the ICU hanging by a thread. And we were soon to find out exactly how right she was!

(xi)     It had been decided that a catheterization and angiography was now justifiable as it would reveal more information about the condition of the Heart and its Coronary blood vessels. Dr. Andrew Shanahan who was Dr. Mahalingam’s colleague at the Hospital and at Cardiology Associates of Princeton was the Cardiologist who would perform them at the facilities available at the Robert Wood Johnson University Hospital (RWJUH) Catheter Lab. I had the pleasure of meeting Dr. Shanahan on Saturday the 27th of December and we decided on being transferred (by Ambulance) to the RWJUH on the 29th of December for the procedure..

(D) THE ROBERT WOOD JOHNSON UNIVERSITY HOSPITAL (RWJUH) (1) CATHETERIZATION, ANGIOGRAPHY and (2) TRIPLE BYPASS (OPEN HEART) SURGERY

At this point we were still thinking in terms of a couple of Stents being inserted to relieve a couple of blocked coronary arteries. On the 29 th of December I had neither informed anyone in the family nor any of my friends of the impending tests. And expected to have the stents inserted, to recuperate at home and to inform them when it was safe to do so – long after recovery! The reasons for this will become clear soon! But things were about to change drastically – and although I am on the mend physically the progression of changes in perceptions, relationships and the future continues to evolve.

  1. Catheterization and angiography reveals a problem that is far more serious than we realized :

(i)     Transfer: I was transferred from the UMC Princeton to the core-2 facility in RWJUH in New Brunswick on the 29th of December 2015. The mobile Heart Rate Monitors were switched on and the transporting EMS personnel and ambulance from South Jersey used ‘Ambulance Humor’ because they thought it was needed, while the vital signs were constantly monitored even though they stayed stable! At the core-2 facility in RWJUH New Brunswick I was met by a very capable team of Nurses who carried out the standard procedures. They made me comfortable in every way, had me repeat my name, medical history, contacts, etc.., (to ensure that I was alert), recorded my vital signs, replaced the Intravenous (IV) connection in my arm with a new one, etc..

(ii)     What is cardiac catheterization followed by coronary angiography? In the cardiac catheterization procedure a catheter is inserted into the groin or arm and guided along the blood vessels of the torso to the heart and into the Coronary Arteries (21, 22). In the subsequent coronary angiography X-ray opaque dye is released from the terminus of the catheter and X-rays of the arteries and the heart are taken. The distribution of the dye reveals where blockages have occurred in the arteries (21, 22). Needless to say this requires expertise – manual skills and knowledge in Cardiology, both of which Dr. Shanahan was to reveal in spades.

(narrative interrupted).


Supplementary information box:(SIB-3) incorporated with (SIB-4)

Reasons for (a) relying on catheterization (angiography) in the diagnosis of the condition of the heart and as a cause of Heart Attacks (Myocardial Infarctions) (b) Angioplasty and (c) choice of ByPass Surgery versus Stent Insertion (Section on ByPass Surgery.


(narrative resumed).

(iii)     Catheterization and angiography: On the same evening, of the 29th of December 2015, I was prepared for catheterization and angiography by Dr. Shanahan’s Colleagues and a team. I was wheeled in on a gurney into a holding room until it was time. After depilation the Electro Cardio Gram (ECG) leads could be attached, sterility ensured and contact made.

(iv)     Catheter Lab: The team was waiting for me in the ‘Catheter Lab’ as it is known. Once again as the two most recent Operating Theaters that I had been in, tended to be packed with equipment, this lab was the opposite of the ones I remembered. Either from the last time I was in one around 40 years ago in Bombay or those from Hollywood. It was brightly lit, but sparse (due to miniaturization of electronics and to ensure sterility concerns?) with a high wattage overhead light and a camera/screen and a computer console next to the operating table. The room was really cold and they covered me with blankets that felt like they had just emerged from an oven (sterility considerations?). The areas for insertion of the catheter were further rinsed and shaved to ensure sterility.

(v)     Shanahan and his team: arrived and I was anesthetized!

(vi)     Shanahan finds a high level of blockage by CAD but a negligible level of cardiomyocyte cell death: I woke up groggily to find Dr. Shanahan pointing to the screen and explaining the extent of the mess! He pointed out that 5 major coronary arteries were massively blocked 95% – 99% with lipid plaque (but only ~2% cardiomyocytes had succumbed to cell death)! I was shocked – not realizing at the time that it could be a number of Risk Factors, rather than my behavior alone, that led to this condition. This was much worse than we had anticipated, with too many arteries involved for the safe insertion of stents. Furthermore, the potential for the deterioration of stents was much higher with greater numbers of stents. The alternative approach of ByPass Surgery was required and he had called the Surgeon for the confirmation of this judgement. It was to be a new Ball Game – called Open Heart Surgery, and I began preparing myself for it! They considered the situation ‘dangerous’ enough as per Dr. Shanahan, to warrant doing the ByPass as soon as the basic information (X-rays, MRIs, Sonograms, Blood work, etc…) could be collected and preparations (for the Operating Theater) completed. All the preparations and preliminary tests were immediately begun.

(vii)     Family notifications? At this point my main concern was whether I should keep this new development from my family. My brother Cyrus Nallaseth who lives in Mumbai, India, has serious health issues of his own, which makes travel hazardous to say the least! He also has primary responsibilities to a young family to consider – his wife and his sons! But should I inform him, I knew all this would not stop him from getting on the first available flight to New York any more than it did from New York to Mumbai when our mother was in the Intensive Care Unit after having had a massive Heart Attack.

(viii)      Dr. Shanahan makes the call: It was finally decided for me when Dr. Shanahan asked whether he could call any family members to let them know. I called my cousin in California (Carl Engineer) and then Cyrus to inform them and still got an earful! Never mind that Cardiologists over the last 10 years, could not have predicted this and until the catheterization and angiography results came in nobody could! And so he was on his way! In fact he had our good friend Mr. Mo Noori immediately drive up from Springfield, Virginia for Moral Support!! Mo, who had been a Radiologist, found me in the corridors while I was waiting to be wheeled into the X-ray suite.

(ix)     Pre Surgery Tests: Throughout the next few days I would go through batteries of tests, procedures and therapies in preparation for Surgery. Blood was drawn for various Pathology Lab Procedures (Lipid Panel, Blood Count, etc…), Doppler Sonograms, ECG, X rays, vital signs repeatedly and regularly taken. There were panels of medications and blood thinners that had to be administered regularly in addition to medications already in use prior to hospitalization and records to be entered. Again as at UMC Princeton, all the Residents, Physicians, Physicians Assistants, Nurses, Nurses Assistants, Technologists and Orderlies were thoroughly empathetic, skilled, dedicated and yet professional at whatever time of day or night that they interacted with me. They are all listed in the acknowledgements at the end of this article.

(x)      Dr. Shanahan met with me: was extremely generous with his time in explaining what was involved in ByPass Surgery and that it had a 98% success rate. We will see why this is an astounding success rate later!

(xi)     Dr. Michael Carlucci the Internal Medicine Practitioner: who assists Dr. George Batsides, the Cardiac Surgeon who would be carrying out the procedure, next stopped by several times to explain his role and procedures and tests that had to be completed before surgery.

2.     Open Heart Surgery – Preparations and Necessary Delays; Being Enveloped with the Healing Support of Care Givers, Family and Friends:

(i)     Dr. George Batsides and his Team stop by: On the 31st of December Dr. George Batsides and his team came to my room to meet me and explain the procedure, and re-confirmed that ByPass Surgery had a 98% success rate. The prediction is that the patient emerges from the Operating Theater, is held in the Intensive Care Unit (ICU) for 1 day and then in the general cardiac unit (core-2) of the wards for 5 days before being discharged. In fact because of variations in the vital signs (which may have been expected) it took a total of 9 days to be discharged on the 10th of January 2015 followed by a return after 1 day as a precautionary measure against significant variations of vital signs!

(ii)     The Handbook by Cardiac Coordinators & Nurses Rhonda Sabel and Jen Gopez (60): was extremely useful and outlined Pre and Post Operative Events, Precautions and Preparations in detail for the patient.

(iii)     Dr, Andrew Shanahan and Dr. George Batsides: Perhaps the most important and tangible source of strength and support came from the calm assured manner and concern of both Dr. Shanahan and Dr. Batsides that endured throughout the turmoil that was to follow. As a professional scientist this worked wonders for me!

(iv)     Warmth – circle of Family and Friends: Perhaps another of those most important if intangible sources of strength and support came from the very ones whom I had taken for granted over the years. It is something that as scientists, at least some of us forget, as it is not quantifiable. The presence of Family and Friends – it emanated a glow of warmth! Now I understood another reason beyond precaution, why Dr. Shanahan had asked to notify them. By this time phone calls, emails, cards and appearances from Family members and Life Long Friends (LLF) and/or Long Lost Friends (LLF) from all over the Planet had started pouring in! I had not had a chance to inform most of my colleagues and did not want any of them to feel excluded – or worse unaware of silent cardiac risks that we had uncovered and something of which they may have to be made aware! Although they were always on my mind there were those who had to persevere with penetrating the shell into which I had been placed by my work! Most were confused and shocked to hear the news! I was a good athlete and so they felt I should not have this happening while still others were consumed with worry about Open Heart Surgery as they may not have known of that 98% success rate that Dr. Batsides and Dr. Shanahan had shared. I’ve listed all of them because they all revived me! I had been transported from necessary isolation (and often outright alienation!) for good reason, into a state of warmth, inclusion and belonging! There were many! They were my (1) Nephews Soli Nallaseth, Zahan Nallaseth and my Sister-In-Law Simi Nallaseth, her Mother Sarla Gulati and (2) my cousin Dr. Zenobia Mehta from Bombay (Mumbai) India and daughter of Dr. Meherji P. Mehta, (3) my cousin Anita Jal from Mahableshwar, India (via Melbourne Australia and London, England), (4) my many Cousins and Aunts from London, including Mayerlene Engineer, who is very ill herself, Jessie Dhondy, Perin Martin and Laila and Martin Simpson, Rohin Jal and my cousins Firoza and Farida Cooper and my Aunt Zarine Cooper (whose husband Dr. Rusi Cooper (passed) and Ambassador/Solicitor Nanabhoy ‘Nani’ Palkhivala successfully challenged an stayed a decision by the Prime Minister thus upholding the Indian Constitution in the Supreme Court), and (5) all the Engineers, my cousin Susan and her husband Scott Sherman from California and (6) my Uncle Sarosh Dhondy and Fanny Lopera from Miami FL, (7) and of course Dr.Tehmi Mulla who along with her husband Dr. Dadi Mulla (who has passed) attended Medical School with my father Dr. Soli P. Nallaseth (the first of 3 generations of our family connections) and was deeply concerned! And her son Dr. Adil Mulla my Anesthesiologist/Medical Expert/Life Long Friend (LLF)/Fierce Competitor on the Courts, in the Pools and on the Velodrome or the Road/School Mate, from Warren and Danbury, Connecticut and his daughter Dr. Simone Mulla (JD) of Rutgers University in Newark along with (8) Professor Charles Heckscher my colleague from Rutgers, Squash partner, Coach of the Rutgers Squash Club and neighbor from Princeton and (9) Dr. Rustam Sethna and who came with his wife Katrin Glode-Sethna from Clinton, NJ and my brother’s LLF and my fast friends Mo Noori and Emma Dudang, from Springfield Virginia, (10) Anil Nayar from Miami, FL, a LLF and Squash Mentor and Partner, (11) Libby Case who with her husband both who are also LLF, Squash Students and team mates from Columbia SC from my student days at the University of South Carolina – Libby actually flew up to “bring a glass of water!”, (12) Professor Nawin Mishra who had served as the Chairman of my Dissertation Committee at the University of South Carolina and his wife Punam, called and spoke several times, (13) Cyrus’s Law firm partners Stanley and Maria Wallenstein (Stanley who is not well himself), Piraan Choga and Anil Jethmalani, whom I had got to know over the decades or years, either came or called, (14 )of course decades long friend Sheroy Ranji drove down from Manhatten, NY (15) and finally, Dr. Jeff Ceci with whom I was in Graduate School at USC, Columbia on the phone.

Many of them had emerged instantly and some emerged to recover relationships that had seen years of neglect! I was nestled in a warm glow for once – and not awaiting the Stiletto or the Whisper – with the impending Open Heart Surgery far removed from my thoughts!! It was tonic! I was already grateful, if not for being out of the woods, then certainly for the communion at which I had arrived with those who meant so much to me, and of whom, I had been able to think or think so little over the decades!

(v)     Scientific colleagues, Squash community, Social groups on LinkedIn, Twitter, ResearchGate, and other circles.: I still had to reach out to them! The thought being that disappearing from the Face of the Earth (although unlikely) without reaching out was impolite to say the least – regardless of the background! I had yet to deal with the thought of how easily a struggle to preserve a lifetime of work (again in the Public Interest), could have ended in the garbage if that minor Heart Attack had turned into an irretrievable one either leaving me incapacitated or worse. I had seen a colleague have a Stroke while – we were speaking – as well as the devastation of the after effects and so considered myself fortunate!

(vi)     Adil who is an Anesthesiologist trained at Yale University: had been through a similar life threatening medical situation a few years ago. Professionally he has seen many Open Heart Surgeries and had already inquired about my frame of mind. When I mentioned, that based on my experience (with the effects of the rubbing of enervated trabeculae between the metatarsal and tarsal of the big toe joint in my foot and resection surgery for a pilonidal sinus) I was steeled for the consequences of a motorized surgical saw splitting my sternum, he pointed out that things had changed! The new mesh/net sutures (and superimposed glue) would hold and immobilize the two halves of the sternum and drop the levels of pain that would otherwise come from the ‘rubbing’ of the edges of the enervated trabeculae. Along with the effect of the pain killers and advice by the Nurse’s to hold a pillow firmly to my chest when the inevitable coughing (from fluid filled lungs) or the retching (possibly due to a hyperactive Vagal Plexus (?) began, this turned out to be invaluable and prescient advice!

(vii)     My brother Cyrus Nallaseth was himself: and made me very glad that he had caught that flight to New York despite my exertions! He made sure that the Management at my apartment complex got things, that had been neglected, finally done, made arrangements for a, wonderful Helper at Home, Iris Amaya Castro whom I have got to depend on, arranged for a Visiting Nurse Service, a Rehab Clinic for me after discharge, worked on Health Insurance Extensions, Social Security and other Disability Benefits and generally waited on me hand and foot before and after surgery. I do not think I was ever so glad to see him as shortly after having emerged from Surgery in the Operating Theater and regained consciousness. I found myself in the Intensive Care Unit (ICU) lying on a low slung Gurney craving for a drink of water but unable to speak due to the effects of the anesthesia (60 – 62). I understand that he sent out Daily Bulletins on my condition to our Global Family and Friends.

(viii)     Libby, a LLF arrived from Columbia, SC: after I was moved to the Cardiac Rehab Clinic Libby arrived at a perfect time and spent a few days easing Cyrus’s load both at my apartment and at the Clinic. Libby was being Libby and also waited on me hand and foot! It was good to catch up! While here she called the Social Security Department, worked on Health and Apartment Benefits and set things up so as soon as I came out of the Rehab I could pick up the thread and fill in all the forms on and offline! As of submission the Wheels of Government and Nature are still turning!

(ix)     Mo Noori and Emma Dudang family friends – and a Nurse: who had also helped with my Aunt Firoza Jacobsen when she was in terminal stages of lung cancer in Miami, must have driven up from Springfield, Virginia after work, at least half a dozen times! They kept my brother and I company – as well as running many errands.

(x)     Surgery: Originally, due to the urgency of the situation, surgery was scheduled for the 31st of December. The exact length of time for the procedure itself would depend on the time taken to complete work on complications and the patient ahead of me in the Operating Theater but the total length of each surgery was estimated at 4 – 5 hours.

(xi)     Unforseen Barriers: However a series of complications in my health arose and surgery had to be postponed several times. It speaks to the professionalism of all the teams involved in leading up to to the Open Heart Surgical procedure that they worked with each other seamlessly! Despite the urgency of the situation, specifically in my thorax, all forward motion to surgery seized when a problem that would complicate the outcome, was detected and only resumed when it was solved! The Cardio-Thoracic Surgical Team stepped back and the appropriate replacement team e.g. Hematologists or Gastroenterologists required to solve the problem stepped up with all the teams working seamlessly with each other. The new team evaluated, quantified, analyzed and solved or classified the problem as non-disruptive, decisions were made and forward progress towards surgery resumed. Although they monitored me closely the urgency for surgery did not induce the slightest panic or rush to action in the Cardiac Team! And although I fully appreciated that the possible consequences of a misstep, might have been my life, this professionalism on their part was not only admirable but also deeply reassuring to me as the patient with a background in science!

(xii)     Problem 1: Enlarged liver and elevated liver enzyme activities. The function of the liver is to de-toxify the bloodstream. To clear persistent toenail fungus I had been on anti-fungizones (Fluconazole, Terbinafine) for around 18 months. These drugs are known to be filtered by the liver which therefore is affected, may have elevated its enzyme activities and size. This enlargement could possibly impede the flow rate of blood through the liver and to the heart creating problems during surgery. The alternative cause for enlargement, of alcohol consumption (less than 1 glass wine/day) was less likely and half a glass of wine per day is actually recommended by the American Heart Association. Half a glass of wine (30 gm) or less actually increases survival of CABG patients by 9% according to the AHA (25). Ultrasound measurements and Doppler Acoustic Sonography of the abdomen showed that the flow rate through the liver was not significantly impeded. We could now move forward. Dr. Pong had known and worried about this problem, we were trying to solve it before the Myocardial Infarction.

(xiii)     Problem 2: I was told that my complexion had become yellowish – did I have jaundice? The bilirubin levels were high. Again this was associated with the malfunctioning liver or gall bladder. However, ultrasound measurements and Doppler Acoustic Sonography of the abdomen showed that the flow rate of blood through the liver was not significantly impeded. It was concluded that a long past infection of Hepatitis B could have spontaneously raised and sustained the levels of bilirubin but it was not an impediment to surgery. We could now move forward.

(xiv)     Problem 3: Hemoglobin and the blood count was low. I was given 2 units of blood, the count was restored and we could now move forward.

(xv)     Problem 4: I had always had routine outbreaks of gout caused by crystals of uric acid deposited in joints, possibly breaking loose spontaneously and causing inflammation. Often, as on that occasion, for no apparent reason. Loose crystals could complicate surgery! A quick determination of uric acid levels showed only ~15% elevation. We could now move ahead.

(xvi)     Problem 5: the vital signs (blood pressure, heart rate and temperature) fluctuated fairly widely. It was decided that this was either a consequence of the Heart Attack or not serious enough to hold an urgent procedure where they would be stabilized manually and we could now move forward.

(xvii)     Still more preparation: involved identifying potential veins in the leg which were mapped for Endoscopy Vein Harvesting for CABG in the Endoscopy Lab (60 – 64).

(xviii)     Finally I was wheeled into the Pre Operating Theater: on the morning of the 2nd of January the Orderly wheeled the Gurney I was on into the Pre surgery Preparation Room. Along the way he lightened up the atmosphere by informing me that I had a high bar to match. Someone had gone through Open Heart Surgery and run a marathon only 10 days later!! Well I am not sure what to say – and neither could Dr. Shanahan! Although the whole ByPass Surgical experience was much less painful, if much more weakening than I anticipated (10 days after surgery I could barely sustain a conversation for 10 minutes without getting winded) I cannot imagine having walked let alone running a marathon 10 days after surgery!

3.     Open Heart Surgery – Pre Operating Theater Preparations and the Operating Theater on 01/02/2015:

(i)     In going through the insurance forms and Hospital charges the broad categories of procedures in the Operating Theater were identified and led to the list presented below (SIB -4). They are listed below in the narrative resumed in the Operating Theater

(There were approximately 25 Pre- and Post- Surgery Pathology Tests for Markers, in addition to Electrocardiographs (ECG), Sonograms, X-rays, Doppler and other tests resulting in the conclusion of “ACUTE MI SUBNNOCARDIAL INFARCT INIT EDC” and “RECOVERY” many of them given/measured multiple times/24 hour period. They reflected the extreme care given to me as the patient).

(ii)     The various types of Heart Surgery are well documented by NIH and by RWJUH (60 – 64). I was to be subjected to Pump Assisted Coronary Artery Bypass Grafting (CABG) pronounced like the vegetable or ‘cabbage’, i.e. the Heart is replaced by an artificial pump. As I would be unconscious during the procedure and so unaware of the steps, this is the description of CABG from NHLBI (NIH) website:

(narrative interrupted).


Supplementary information box (SIB) – 4:

(from the National Heart Lung Blood (National Institutes of Health) NHLB (NIH) website) (11, 60 – 62) :

What Is Coronary Artery Bypass Grafting?

Coronary artery bypass grafting (CABG) is a type of surgery that improves blood flow to the heart. Surgeons use CABG to treat people who have severe coronary heart disease (CHD).

CHD is a disease in which a waxy substance called plaque (plak) builds up inside the coronary arteries. These arteries supply oxygen-rich blood to your heart.

Over time, plaque can harden or rupture (break open). Hardened plaque narrows the coronary arteries and reduces the flow of oxygen-rich blood to the heart. This can cause chest pain or discomfort called angina (an-JI-nuh or AN-juh-nuh).

If the plaque ruptures, a blood clot can form on its surface. A large blood clot can mostly or completely block blood flow through a coronary artery. This is the most common cause of a heart attack. Over time, ruptured plaque also hardens and narrows the coronary arteries.

CABG is one treatment for CHD. During CABG, a healthy artery or vein from the body is connected, or grafted, to the blocked coronary artery. The grafted artery or vein bypasses (that is, goes around) the blocked portion of the coronary artery. This creates a new path for oxygen-rich blood to flow to the heart muscle.

Surgeons can bypass multiple coronary arteries during one surgery.

Coronary Artery Bypass Grafting

cardiacgraftsampleeditedferezfig1

Figure 1. Coronary Artery Bypass Grafting. Figure A shows the location of the heart. Figure B shows how vein and artery bypass grafts are attached to the heart. Note: Arrows in Figure B show the direction of blood flow.

Overview

CABG is the most common type of open-heart surgery in the United States. Doctors called cardiothoracic (KAR-de-o-tho-RAS-ik) surgeons do this surgery.

However, CABG isn’t the only treatment for CHD. Other treatment options include lifestyle changes, medicines, and a procedure called coronary angioplasty (AN-jee-oh-plas-tee).

Angioplasty is a nonsurgical procedure that opens blocked or narrow coronary arteries. During angioplasty, a stent might be placed in a coronary artery to help keep it open. A stent is a small mesh tube that supports the inner artery wall.

CABG or angioplasty may be options if you have severe blockages in your large coronary arteries, especially if your heart’s pumping action has already grown weak.

CABG also may be an option if you have blockages in the heart that can’t be treated with angioplasty. In this situation, CABG may work better than other types of treatment.

The goals of CABG may include:

  • Improving your quality of life and reducing angina and other CHD symptoms
  • Allowing you to resume a more active lifestyle
  • Improving the pumping action of your heart if it has been damaged by a heart attack
  • Lowering the risk of a heart attack (in some patients, such as those who have diabetes)
  • Improving your chance of survival

Outlook

The results of CABG usually are excellent. The surgery improves or completely relieves angina symptoms in most patients. Although symptoms can recur, many people remain symptom-free for as long as 10 to 15 years. CABG also may lower your risk of having a heart attack and help you live longer.

You may need repeat surgery if blockages form in the grafted arteries or veins or in arteries that weren’t blocked before. Taking medicines and making lifestyle changes as your doctor recommends can lower the risk of a graft becoming blocked.


(narrative resumed).

The Operating Theater:

(iii)     The nurses depilated the chest, checked the IV and injected a blood thinner. A local anesthetic was administered and the catheter with sensors inserted through the neck into my heart to monitor its vital signs in real time. The steps to be taken by the Cardiac Surgeon, some, while I was under anesthesia:

(a) Anesthesia CABG with Pump

(b) Insertion catheter, Artery

(c) Insert/Place Heart Catheter

(d) Echo Transeosophageal

(e) Doppler Echo Exam, Heart

(f) Doppler Color Flow Add-On

(iv)     The Operating Theater looked like a more (or better?) equipped version of the catheter/angiography lab. However, compared either to the version in the Movies or the ones I remember in India when I was the patient and operated on by an Uncle, Dr. Meherji P. Mehta, this one was sparse. Possibly to preserve sterility. Dr. Mehta was a pioneering Cardiac Surgeon who performed the 4th Ventricular Septum Reconstruction as well as some of the first Heart Transplants in the History of Cardiac Surgery at the K.E.M. Hospital in Mumbai (65, 66). He was also a contemporary of the renowned Pioneer of Cardiac Surgery Dr. Michael DeBakey with whom he exchanged Surgical visits. Although Dr. Mehta secured his F.R.C.S. degree in the UK his specialized training in Cardiothoracic Surgery was received at the Christian Medical Center in Vellore (C.M.C.V.) directed by Dr. Reeve Betts. This was one of the 3 Major Cardiac Centers established in India by British Surgeons who had mastered their craft in the Theater of the North African Desert in the Second World War (65, 66). Ironically Dr. Mehta, like my father (his step brother) Dr. Soli P. Nallaseth succumbed to Heart Attacks or Ventricular Fibrillations in their mid to late fifties. All of us in our immediate and several others in our more distant family either succumbed to or had Heart Attacks or Fibrillations when relatively young. However, in each case overwhelming additional factors complicated any simple interpretation of family history or a genetic cause (65, 66).

(v)     My brother was designated as the responsible relative to whom reports would be delivered and along with Mo waited outside the Operating Theater over the 4-5 hours of surgery.

(vi)     Dr. Batsides reassured me that his assistants ‘really knew their work’! But I had no doubt especially since everything the Surgical Team had done up till then was convincingly efficient, diligent and professional. I was as relaxed and accepting, as one can be under those circumstances, for the simple reason that I would have liked to live a little longer!

(vii)     I remember feeling some blood trickling down my neck from the ‘In Heart ‘ catheter and their fixing it in short order with a few stiches.

(viii)     Shortly after this the anesthetic was administered, I blacked out and assume that the CABG procedure described in (SIB-4) from the NHLBI (NIH) website began.

(ix)     I awoke on a low slung gurney in a line of gurneys in what presumably was the Intensive Care Unit (ICU). It was painted bright white with Nurses, Assistant Nurses. Technologists in white and urgent, purposeful but unhurried movements. There is a good description in NHLB – NIH outline of CABG in (SIB-4).

(x)     My throat was parched and when I tried speaking, no sound emerged, due to the effect of the anesthetics! So I could not get the drink of water that I desperately needed.

(xi)     My brother Cyrus was allowed into the ICU – I had that water soon. I don’t think I’ve ever been so glad to see him! And soon enough realized it was going to be a tough few days to normalcy.

(xii)     I was re-attached to a mobile Cardiac Monitor and intravenous IV feed and moved to the core-2 facility (Cardiac Wards) the next day.

(xiii)     The impression of the whole CABG process and its aftermath that lingers in my mind is not one of excruciating pain, but certainly one of labored attempts to move, resulting in acute discomfort, even sitting was difficult and conversations led to being easily winded within minutes! This low consequence was probably due to the excellent surgery and the thorough immobilization of the incision along the sternum, the pain killers and nursing all of which were excellent! Food did not seem at all appetizing – partly because of the fear of unleashing a ‘retching’ episode. One attempt, in that first 10 day period, at a Walker Assisted walk around the core-2 ward sent my blood pressure soaring! So walks were suspended!

(xiv)     Here too the Nurses, Nursing Assistants and Technical Staff taught me little tricks like building up my strength by sitting, rather than the more easily done, lying in the bed. One of the pieces of equipment used to ease the congestion in the lungs and keep them functional was the Spirometer – breathing into it to elevate the indicator, maximally without overshooting an easily overshot mark – 10x/day. The Nurses were insistent but in the only resistance I gave them, I found the Spirometer to be a waste of time – needless to say I was wrong!

(xv)     Dr. Amy Tilara, among others from Dr. Batsides group, checked my condition every day before and after surgery, e.g. making notes on the records of the vital signs. Dr. Tilara was also the ‘Enforcer of Spirometer Use’ and fairly dogged in extracting an accounting! She was also the one to deliver the message related to the 2nd discharge after I had been brought back from the Foothill Acres Rehab Center when the vital signs fluctuated again.

(xvi)     I was looked after and monitored closely in core-2, from the recording of vital signs to any of the ablutions and to the slightest need all of which were responded to when the buzzer brought them to my bedside. This besides their doing such things as recording ECGs with portable machines, administering medications at regular intervals at all times of the day and night.

(xvii)     I have never felt so dependent! Something that is anathema to me! Probably because of my professional experience!

(xviii)     The vital signs, particularly my temperature and blood pressure fluctuated sufficiently to cause some concern for the next 2 weeks. But considering the magnitude of the impact that the CABG procedure had to have on the body perhaps this was not entirely surprising.

(narrative interrupted).


Supplementary Information Box (SIB) – 5

What to expect in the ICU, the day after surgery, the second day after surgery, Recovery at home (60 – 62)

http://www.secondscount.org/treatments/treatments-detail?cid=afd902b3-1db7-4f67-

bcc5-985e7c77587e#.VVDybvDe-VN    (copy and paste into your browser)


(narrative resumed).

(E) CARDIAC REHAB AT THE FOOTHILL ACRES REHABILITATION AND NURSING CENTER:

(i) Discharge from RWJUH core-2 on the 10th of January 2015 was administered by Dr. Leonard Lee, who was the Chief of Cardiac Surgery, and stopped by to check the scar and by Nurse Kelly Mayer-Delgado. Nurse Mayer-Delgado had spent time with and shown me several ways of managing the everyday problems that follow Bypass Surgery throughout my stay in the core-2 facility. She got me to stand for Dr. Lee without wobbling too much!

(ii) Dr. Lee caught sight of my Squash Bag (now serving as a garment bag) and that led to an exchange of some pleasantries about our mutual interests in the game, a friend and fellow Coach Geoff Mitchell from a Club (the Chatham Club) at which we had spent many years playing Squash (and I sometimes still do).

(iii) I was then prepared for the ambulance and transported to the Foothill Acres Rehab Clinic (FARC) for cardiac rehabilitation.

(iv) Little did I know that I would be returning to RWJUH the next day. The vital signs (blood pressure, heart rate, pulse and temperature) were high or fluctuated and a vigilant Nurse and Physician wanted the immediate results of a possible infection with microbial assays that were available at RWJUH but not at FARC.

(v) I was returned to the Emergency Room at RWJUH, with the vital signs elevated. Then tested for infections, other sources of problems, and while the vital signs stayed elevated.

(vi)I was kept under observation overnight. After Dr. Batsides’ and his Staff concluded this was normal given the magnitude of the impact that the surgical procedure would have had Dr. Tilara communicated the message and I was returned to the FARC Rehab Center the next day.

(vii)The Foothill Acres Rehab Center as its name implies imposed a regimen of a good diet, monitoring of the vital signs, good regimens for medications, therapies and physiotherapy. Which may explain the rapid recovery of patients.

(viii) One of my Room Mates at Foothills was an Engineer – Vincent Barone. Our conversations were entertaining.

(ix) On the 4th of February 2015 I had a long overdue follow-up visit with Dr. Batside’s Colleague and the Cardiothoracic Surgery Clinical Coordinator Rhonda Sabel RN.C.BSN. and was given permission for Discharge from the Rehab Clinic.

(x)By now I had started using my laptop and learned the sad news that my good friend Princeton Squash Coach Bob Callahan had finally fallen to the glioblastoma that he had resisted for 3 years on the 27th of January 2015! More than twice the mean time that other patients with this dread disease survive!

(xi) Players from the Rutgers Squash Club organized a memorial posting for Bob on the online journal Daily Squash Report and the social medium LinkedIn.

(xii) In thinking of the events of that past month I realized that my colleagues, mentors and friends in Squash at all the courts, in Science, at the New York Academy of Sciences, the Society for Developmental Biology, other Universities, Institutions, on Social Media like LinkedIn and ResearchGate among other places would want to know of the recent events and its strange biomedical contradictions! And so I sent out emails or posted the news on Social Sites and received nearly 300 deeply concerned, warm, supportive and encouraging replies!

(xiii) By the 30th of January 2015 I had been walking without a walker!!

(xiv) By the middle of that week of 4th of February 2015 I was climbing 78 steps on the FARC staircase which was equal to twice the numbers of stairs present at home, in addition to Physiotherapy administered by the expert Therapists of Foothills Acre Rehab Clinic.

(xv )By the end of that week, 6th of February 2015 I thanked the entire staff and personnel who had got me back up on my feet again and left. Iris brought me home.

(xvi) It was clean – Cyrus, Iris and Libby had done all the work!!

(xvii) I was still too unsteady to do much.

(xviii) On the 28th of February I could finally drive and make the overdue follow-up visit with Cardiologist Dr. Shanahan.

(xix) He put me through the necessary Stress Test on the 13th of March 2015.

(xx) I was cleared for cardiac physiotherapy at the University Medical Center of Princeton and made arrangements – but Squash and the Apartment Gym were  excluded for 6 months.

(xxi) I have now been writing regularly since 3.3.2015.

(narrative interrupted).


Supplementary Information Box (SIB) – 6 (62)

Cardiac Rehabilitation

During the recovery period, you may begin participation in a cardiac rehabilitation program, if prescribed by your physician. You may begin cardiac “rehab” while you are still in the hospital and continue it in the months moving forward. Cardiac rehab is, in part, a structured exercise program that can help you increase your physical activity level while under the direct supervision of medical professionals. The program also includes work with dieticians, occupational therapists, psychologists, and other healthcare providers who can help you recover from your surgery and feel confident that you have the skills to adopt a heart-healthy lifestyle. Regaining physical strength and eating a diet of nutrient-rich foods are critical to a successful recovery from coronary bypass surgery and to returning to the lifestyle you want to live. Studies have shown that cardiac rehab is more than just a good idea. It can be a lifesaver. Recent research has found that patients who complete cardiac rehab are more likely to be alive five years after a heart event than those who do not.


(narrative resumed).

(F)  A series of questions and issues related to my heart attack or MI arise that are addressed below.

  • As discussed the two types of traumatic cardiac pathologies resulting from either the deprivation or the complete cutoff of the supplies of blood flow and so O2 by plaques or fibrillation (fluttering heart muscles), respectively cause Myocardial Infarctions (Heart Attacks) and Sudden Cardiac Arrest (SCA) or Sudden Death (SD) (20, 23 – 27, 30). The Risk Factors for these 2 types of pathologies have also been discussed briefly but are dealt with in greater detail in the supplementary information box (SIB-7) and in even greater detail by multiple health agencies (8 – 27). As is clear from the above references cardiac diseases are considered to be multifactorial (genetic, environmental, behavioral, among other factors). It is useful to now specifically focus on the 5 principle elements of the cardiac event of 12.25.2914      (1) Risk Factors and the role of exercise in modifying or ameliorating them,(2) Squash ameliorates the Risk Factors as shown by results from recent studies that are in depth and so subsume contradicting results of older studies,(3) New research results support the interpretation that the intense competitive and exercise routine that I maintained in India, (high level overtraining) delivered conditioning that was at least partially retained in the US until 2006 and 2007,(4) This conditioning likely delayed the ongoing coronary artery disease (CAD) and the ongoing coronary heart disease (CHD), (5) Ameliorated the impact of a Heart Attack by preconditioning (IPC) cardiomyocytes.

The relevant literature, albeit selected, that will be drawn on, is listed in the (SIB-7). However a significantly more detailed version of the discussion of these events and the relevant literature on Sports Physiology and Clinical implications will be submitted to the appropriate Journal (1).

  • Salient and relevant features in the reconstruction of events from diagnosis and intervention to recovery, from: questions, medical reports and extrapolations of the literature:

 To summarize the details, the salient features of the cardiac events in my thorax culminating in the Coronary Artery Bypass Graft (CABG) Surgery and into ongoing recovery, as determined by (i) Cardiologist Dr. Andrew Shanahan, (ii) Cardiac Surgeon Dr. George Batsides, (iii) their teams, (iv) extrapolated from the literature, (v) those factors that remain unknown are enumerated as 1-14 below. The questions raised and possible reasons for survival are also considered.

(1)     Need for Oxygen: As it is indispensable as a terminal terminal e-1 acceptor required for generating molecules of ATP, the high energy vehicle which is required for most cellular functions, Oxygen is of fundamental importance to the survival of the vast majority of living organisms. The importance of Oxygen to the function and survival of cardiomyocytes and the heart has already been established in this article (SIB – 1).

(2)     Sequence of events leading to, and reasons for, the CAD and MI: As mentioned, in the 10 years from around 2005 to 2014, I had multiple chest spasms, underwent multiple tests of increasing rigor, for detecting cardiac malfunction, and in more than one institution. All of which had failed to implicate cardiac malfunction as the cause of my chest pains. Although there are several possible reasons for this interpretation: (a) the accumulated plaque in arteries (due to CAD), known to occur over decades, was likely already present during those Stress Tests but went undetected, (b) detection of cardiac mal-function or blood flow and so O2 supply in these Stress (and other) Tests are revealed by cardiac electrical (Electrocardiographs , ECG) perturbations of the discharge by cardiomyocytes which is caused by exercise dependent hypoxia (O2 deficits) and detected by (ECGs). These cardiomyocytes were not perturbed and so failed to reveal cardiac mal-function, (c) they were probably not perturbed because the cardiomyocytes were hypoxia tolerant, due to their overtraining based ischemic preconditioning (IPC) resulting from training for Squash, (d) this inference was supported by the necessity for having to elevate the Treadmill Settings (stress) 3x above normal settings for Stress Tests before hypoxia driven stress on the ECG, even registered, (e) this despite the likely hypoxia caused by the plaque ridden vessels (CAD) in addition to that caused by the Stress Tests, (f) Stress Tests are among those widely applied as a first line of investigation, but often may fail to detect cardiac malfunctions, as may have been so in my case, (g) however this explanation is the unlikely choice between known effects (IPC, 3x elevation of Treadmill settings) and a hypothetical premise (rate of failure of stress tests), (h) or alternatively significant blockage of coronary arteries (by CAD) and the resultant hypoxia may have set in relatively recently and rapidly (after the 30th of April 2010, which was the date of the most recent comprehensive cardiac tests) and (i) this explanation is also unlikely as an asintotic elevation of CAD is not commonly known.

(3)     Time course for plaque formation: The period of time that the plaque dramatically reduced or blocked, blood flow in 5 major coronary arteries, and so the Oxygen that they delivered to the cardiac tissues to induce hypoxia in cardiomyocytes, cannot be determined. The rate of deposition of plaques to attain a final blockage of 95% – 99% in 5 major coronary arteries is unknown. This level ranged from near complete 95% (hypoxia) and approached complete deprivation 99% (anoxia) of blood flow and oxygen delivery to cardiomyocytes, (personal communication from Dr. Shanahan and his Medical Report) is a condition which is likely to be lethal within 5 minutes.

(4)     How many cardiomyocytes succumbed? Yet only ~2% of cardiomyocytes were irreversibly dead as determined by Acoustic measurements during catheterization and angiography (personal communication by the performing Cardiologist Dr. Andrew J. Shanahan and Nurse Rhonda Sabel). They were presumably lost to apoptosis caused by anoxic conditions.

(5)     Why was there such a large disparity (~ 50x) between blockage of coronary arteries by plaques and cardiomyocyte cell death? Why were only ~2% of cardiomyocytes lost to cell death when the blockage of 5 major coronary (blood) vessels amounted to 95% – 99% with its corresponding reduction of blood, and so Oxygen, supplies? Although based on Retrospective Birth Dating (RBD) of cardiomyocytes, ~95.6% of cardiomyocytes could be expected to be resistant to hypoxia due to overtraining and IPC they would not be resistant to anoxia which is lethal within 5 minutes. This is shown experimentally as well as by the results of Atrial or Ventricular Fibrillations (fluttering heart muscles leading to a cutoff of blood and O2). It is possible that the ~2% of cardiomyocytes that succumbed were located in a cardiac segment that was anoxic.

(6)     What is the window of time between plaque deposition to complete arterial blockage and new blood vessel formation to relieve the pressures of hypoxia but not anoxia? It is known that new coronary blood vessel formation is induced as a compensatory response to hypoxia resulting from the blockage of coronary arteries by plaques through processes called angiogenesis or vasculogenesis (37). Their growth is stimulated by vasculogenesis endothelial growth factor (VEGF) and GATA nucleotide sequence binding protein, binds nucleotides (GATA 1-6), among other factors (37). However, fragments of plaques are broken off walls of blood vessels, either form dangerous and circulating clots or travel to new sites, where they are deposited and form nucleation foci for new deposits at rapid rates (SIB-4, NHLB(NIH). We neither know how quickly the plaque was deposited to block the blood vessels nor how quickly induction and new blood vessel formation occurred. But there must have been a window of time between, plaque deposition upto near complete blockage and the formation of new blood vessels vessel induced by VEGF, in which hypoxia had not yet progressed to anoxia. The length of this window of time that was sufficient to allow cardiomyocytes to survive is unknowable. However ~2% of cardiomyocytes did succumb to cell death and so there is evidence for this window having closed. This cell death (~2% cardiomyocytes) was either due to their location in a cardiac segment that was anoxic or due to an incomplete transfer of hypoxia (apoptosis) resistance from hypoxia resistant nuclei to newly born cardiomyocytes as is shown to occur in myonuclei (67). These new cardiomyocytes were likely born in the ~7 years after 2006/2007 the last 2 years of my low level overtraining for Squash in the US.

(7) (a)  How much hypoxia can cardiomyocytes tolerate and for how long do they do so in order to be able to resist cell death (apoptosis)? (b) How much anoxia can cardiomyocytes tolerate and for how long to be able to resist cell death (apoptosis)? The answer to both is unknowable without experiments. But the answer to (a) is complicated while the answer to (b) is the 5 minute period (maximally) and 10 minutes (survival with irreparable cardiac and neuronal damage) that emerges from Sudden Cardiac Arrest (SCA) or Sudden Cardiac Death (SCD) reports in the literature (SIB- 4, NHLB(NIH).

(8)     How long and how much did ischemic preconditioning (IPC) contributed to the observed disparity between coronary artery blockage (95-99%) and cardiomyocyte cell death (~2%)? A further complication arises from applying interpretations of results from experimental mammalian systems (mouse and rat) to humans. In rodents it has been shown that an initial and transient application of hypoxia (e.g. for 20 minutes) induces a state of tolerance (resistance) to subsequent prolonged challenges of hypoxia even 72 hours after transient exposure. This is known as ischemic pre-conditioning (IPC) and molecules either encoded by genes such as Akt, JAK-STAT, Bcl2, VEGF, GATA 1-6 BF, p38 kinase, HIF1, EPAS1, or hormones Estrogen or the signaling molecule NOX2, and the anti-inflammatory drug Sulindac all contribute to this effect through known pathways and mechanisms (36 – 51). Although overtraining dependent ischemic preconditioning (IPC) pre-conditioning in Squash probably facilitated survival of cardiomyocytes during the Heart Attack (MI) ~ 2% cardiomyocytes succumbed probably to anoxia. Some questions that follow. What was the distribution of blocked and new coronary (blood) vessels over the heart and did it supply the segment of the cardiac tissue spanning those ~2% cardiomyocytes that succumbed? What was the contribution of IPC in the blocked and supplied cardiac segments of cardiomyocytes? How long after this window of time between complete blockage and supply of new vascular vessels to populations of cardiomyocytes closed did they survive? These questions are unanswerable!

(9)     How many Cardiomyocytes were born after low level overtraining had ceased in 2006/2007? And were they resistant to hypoxia and apoptosis? Jonas Frisén, and his colleagues have innovated a method called retrospective birth dating (RBD) which measures the replicative loss of atmospheric residual 14C radioisotope with long half-life of 5,730±40 years, released from surface atomic tests and incorporated into our genomic DNA, by alterrations in 14C:12C ratios of tissues (58, 59). They used RBD to show that approximately 50% of cardiomyocytes were replaced in a human lifetime (58, 59). Based on this estimate and an average Life Span of 80 years the calculated number of newly formed cardiomyocytes in my heart since 2006/2007 (~7 years) is ~4.4% new cells. Can this number be used to calculate the numbers of cardiomyocytes that were ‘born’ after the cessation of low intensity overtraining (strenuous workouts) and hypoxic conditioning? These new cardiomyocytes (~4.4%) were not exposed to low intensity overtraining and despite predictions (67) may not have been equivalent to the ~95.6% of cardiomyocytes that were exposed to low intensity overtraining 7 years ago (in previous workouts) and so may not be preconditioned by IPC to resist hypoxia (67). Alternatively, either the transfer of resistance from the old hypoxia/apoptosis resistant templates was only partially complete in ~2% of cardiomyocytes, or they were resident in a segment of cardiac segment that was only partially vascularized nearly devoid of blood flow and so O2 thus becaming nearly completely anoxic. These questions are unanswerable.

(10)     Could high intensity overtraining for Squash which is a high intensity sport (METs index = 6 – 12 cals/kg/hr) in India 38 years ago (since 1976) have conferred IPC that was retained and so contributed to the survival of my cardiomyocytes in 2014? Could hypoxia resistance result from low intensity overtraining in the US (upto 2006/2007) and have lasted for ~7 years after nearly detraining (2006/2007 to 2014)? From experimental work done in rats it is known that skeletal muscle myocytes following strenuous training (overtraining) gain in numbers and sizes of myonuclei which results in hypoxia (and apoptosis) resistance (67). This increase in numbers and sizes of myonuclei correlates with hypoxia resistance and is retained after at least 3 months of detraining (67). After detraining these trained myonuclei remain resistant to hypoxia and apoptosis, and may serve as templates for the synthesis of new hypoxia and apoptosis resistant nuclei and are likely to extend conditioning into old age (67). This last observation is common knowledge among athletes! Based on several physical and physiological parameters of estimation (4), I had overtrained for Squash at a significantly higher intensity (or high intensity overtraining) more than 38 years ago in India until having arrived in the US in 1976. Based on the calculations in question 9, this would yield 23.8% of newly born cardiomyocytes since 1976 in the US, that were not exposed to the same high intensity overtraining. The intensity of overtraining in the US varied from low level overtraining to detraining (none) for Squash tournaments which would leave at least 23.8% of newly born cardiomyocytes either resistant or sensitive to hypoxia and apoptosis. This depends on whether this level of overtraining in the US was sufficient to induce hypoxia/apoptosis resistance. If sufficient does it explain the retention of hypoxia resistant conditioning over the 7-8 years since 2006/2007 when even the lower (US based) level of overtraining ceased? And are the ~2% cardiomyocytes that were not resistant among the calculated cardiomyocytes (~4.4%) that were ‘born’ in this period? Were these ~2% cardiomyocytes either (i) not exposed to sufficient overtraining and so endowed with low levels of hypoxia resistance or (ii) actually detrained or (iii) had they failed to acquire any resistance from hypoxia and apoptosis resistant nuclear templates or (iv) were they resident in a segment of cardiac tissue that was devoid of blood flow and O2 and so completely anoxic thus so succumbing to cell death? These are unanswerable questions.

(11)     Can cardiomyocytes survive anoxia? How many cardiomyocytes must be lost to apoptotic death to result in Sudden Cardiac Arrest (SCA) or Sudden Death (SD) fatality rather than Myocardial Infarction (MI) or Heart Attack ?

Cardiomyocytes may survive anoxia for more than 5 minutes but the damage is irreparable and after 10 minutes anoxia is invariably lethal. Finally there is a threshold of cardiomyocyte cell death that must be attained for the Myocardial Infarction to become irreversible. Why and What is that number? In Sudden Death (SD) or Sudden Cardiac Arrest (SCA) syndromes it is known that the entire Atrium or Ventricle fibrillates (flutters due to uncoordinated electrical discharges required for contraction) and so blood supply and Oxygen are cut-off. And lethality results in as little as 5 minutes This shows that inactivity of either of these 2 chambers is sufficient to prove fatal.

(narrative interrupted).


Supplementary Information box (sib) # 7:

RISK FACTORS (RF) – METHODS FOR DETECTION , MODIFICATION (AMELIORATION) UNDER HOMEOSTASIS AND EXPERIMENTAL CONDITIONS, PRELIMINARY RESULTS – ONGOING DISCOVERIES, NEW MODIFIERS OF RF, EXERCISE AND SQUASH AS MODIFIERS OF RF:

(SIB-7A) Well established Risk Factors and reporting organizations.

(SIB-7B) Establishing Risk Factors by controlled Genome Wide Association Studies (GWAS).

(SIB-7C) Significant numbers of cardiomyocytes are replaced (~50%) in a lifetime.

(SIB-7D) Known cellular and molecular mechanisms for coping with cardiac stress and protecting hypoxic cardiomyoctes.

(SIB-7E) Preliminary results – Ongoing Discoveries, Identification of Potential New Risk Factors & Modifiers of Risk In Cardiac Disease States.

(SIB-7F) Exercise and Squash – optimal health to injury ratios, modification of Risk Factors for and induction of, Coronary Heart Disease (CHD), Coronary Artery Disease (CAD), Coronary Vein Disease (CVD) and Sudden Cardiac Arrest (SCA).

 

Review of the salient points of the relevant literature in each of the 6 categories listed in the Supplementary Information Box (SIB) -7:

To enable a meaningful discussion of the events of the MI I had, requires a minimal discussion of the last 15 years of methods and analyses that have turned multifactorial traits or pathologies, that were previously intractable to analytical resolution into those that can be resolved. These include Cardiology, Sports Medicine and Physiology, Molecular and Cellular Biology of Cardiac functions, and their interrelated dimensions such as Risk Factors and Intensity/Vigor of Sports Activities. Most have been exhaustively treated in each of the references. These references are restricted to those listed and their links in (SIB – 7A to 7F).

(SIB-7A) Risk Factors: The definition of Risk Factors, their types and numbers for the various Coronary diseases and Sudden Cardiac Arrest have been briefly outlined and are discussed in the links distributed in each of the categories (some with overlapping functions and definitions) in (SIB-7A to 7F). There are those Risk Factors that can be ameliorated by altering life styles, diet, weight, exercise, etc… and those that cannot be ameliorated such as incidences of Arterial Fibrillation, Gender, Age, Family Backgrounds (Genetics?), etc… Those Risk Factors provided by the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) section (11). However several other Risk Factors have been identified by a number of other methods and organizations e.g. (NHS (UK) and WebMD) have been listed (18, 19). Organizations such as those listed on Wikipedia not only include the standard definitions but also their pathophysiology (8 – 27). The Centers for Disease Control (8) classifies Risk Factors into 3 major categories (Conditions, Behavior and Heredity), the National Library of Medicine (9) categorizes 17 distinct Risk Factors into 2 major groups of those that (a) cannot be changed and (b) can be changed. The former group (a) also depends on excluding negative behaviors (smoking, foods raising levels of cholesterol, not exercising, alcohol consumption above moderate levels, etc..) and cultivating positive proactive (controlling diet, eating nuts, vegetables and fruits, lean meats, non-hydrogenated foods) behaviors (9). These are dealt with in detail via the links to these and other websites of other Public Service Organizations (8 – 23).

However, application of genetics (e.g. Genome Wide Association Studies (GWAS) has not only reduced the frequency of errors but also marginalized the uncertainties of the highly multifactorial field of cardiology so as to reinforce its parameters e.g. Risk Factors but has also gone far beyond. It has revealed new and surprising information on sources of Risk Factors and how they may either be exacerbated or ameliorated in ongoing research and unfolding discoveries. GWAS in the analyses of cardiac conditions (e.g. Risk Factors) and the influence of Sports Physiology on these conditions will be discussed in greater detail in a Journal concentrating on Sports Physiology or Sports and Clinical Medicine (1).

(SIB-7B, -7F) Well defined and improved contemporary approaches including combinations, such as Genome Wide Association Studies (GWAS), high numbers of reporter alleles (SNPs), Large Cohort Sizes, ranges of Metabolic Equivalent Task indices (METs), known and controlled quotients of stress and Personal Record Maintenance (PRM) have significantly elevated the reliability of measuring Risk Factors for Cardiac Heart Disease (CHD), Cardiac Arterial Disease (CAD), Cardiac Vein Disease (CVD), Sudden Cardiac Death (SCD) or Sudden Cardiac Arrest (SCA).

The large numbers of environmental, genetic, developmental, behavioral, dietary, emotional and other factors that contribute to Cardiac Heart Disease (CHD), Cardiac Arterial Disease (CAD), Cardiac Vein Disease (CVD), Sudden (Cardiac) Death (SD) or Sudden Cardiac Arrest (SCA), represent the multiple contributing Risk Factors. Making the evaluation of their contributions to these pathological conditions multifactorial and highly error prone, subjective and complicated (SIB-7A to SIB-7F) see references 8 – 96). To firmly establish these Risk Factors or for that matter any other dimensions of these diseases requires the robust analytical methods which have emerged in the last ~15 years. Most significant of these analytical developments are the combinatorial application of: (i) Genome Wide Association Studies (GWAS), (ii) with higher distributions and numbers of small nucleotide polymorphic SNPs/genome equivalent (upto 1.6 x106 SNPs) as reporter sequences, (iii) newer complementary robust statistical and analytical methods such as large Cohort Sizes (6000 to 215,413) elevating resolution of quantified dimensions,(iv) measurements of physiological parameters such as well-established Metabolic Equivalence Task Indices (METs) (a wide range of METs from a low of 2 to a high of 16 cals/kg/hr), (v) a range of known and controlled quotients of stress delivered by sports such as Walking, Racket Sports, Boxing and Marathon and (vi) Personal Record Maintenance (PRM) with high correlation factors to e.g. METs (0.6) which together significantly elevate the resolution and reliability or confidence intervals in measuring Risk Factors for the above pathologies.

What is GWAS? Also known as Whole Genome Analyses (GWA) or Common-Variant Association Study (CVAS) it is an epidemiological method examining large numbers of Variables including genes or short strings of reporter genetic code letter words called Small Nucleotide Polymorphisms (SNPs) and Clinical conditions to establish a clear associative relation between the two parameters (68).

The significance of this GWAS based studies (76 – 79, 81) and 2 studies predating GWAS (80, 82) will become clear in the interpretation of the role of Squash, high intensity overtraining exercise resulting in IPC and the hypoxia tolerance of cardiomyocytes as they relate to 2 variables in my case. They relate to the inability to detect CHD/CAD by stress tests, despite chest spasms for 10 years, as well as the minimal numbers (~2%) of cardiomyocytes that were lost in the Heart Attack despite the magnitude of the blockage of coronary arteries (95% – 99%/CAx5CA).

A point of note, there were 4 Sudden Cardiac Arrest (SCA) or Sudden Deaths (SD) among 215,413 Marathon runners in the US or 0.002% per race over 30 years (81). Although this 0.002% rate is 5x higher than the rate of Sudden Deaths 4 SDs/1000000 athletes or 1:250,000 or 0.0004% among all athletes in the US, it is significantly lower than the death rate recorded for many activities (80, 81, 82). Still other GWAS examine risk factors for CHD that are unique to distinct populations such as African Americans (78) and are strongly linked to their economic circumstances. In other reports such as longitudinal GWAS studies (following the development of a trait over time) of children in Finland whose risks for adult disease of Coronary Vascular Disease (CVD) are predicted during their development into adults and are also examined in detail by another group (79).

Additionally single nucleotide polymorphisms (SNP) based studies have established the role of adaptation of an evolutionarily modified form of Hypoxia Inducible Factor (HIF1) namely, Endothelial PAS (Per Arnt Sim) domain transcriptional factor (42, 43, 44). The gene encoding prolyl hydroxylase 2 which degrades HIF1 has acquired a protective SNP mutation in Tibetan populations that lowers the Km for O2 (42). Thus degrading HIF1 in hypoxic conditions and preempting its induction of polycythemia under hypoxic conditions at high altitude (42). EPAS1 as sensor and regulator of physiologically protective responses to O2 deficits at altitude (42) and in athletes has been previously referenced (43, 44). GWAS with 12 SNPs across EPAS1 and normal controls revealed that specific SNPs were enriched in each of 2 power:time groups and was further reinforced by a 3rd haplotype (43). The authors proposed that the SNPs associated with EPAS1 functions influenced adaptation and the relative contribution of aerobic and anaerobic metabolism and hence the maximum sustainable metabolic power for a given event duration (43). In a final study 5 SNPs associated with EPAS1 which regulates delivery of oxygen to the tissues were surveyed as plausible candidates to influence athletic performance (44). Using innovative statistical methods, the authors found SNPs that were highly predictive of sprint/power athletic performance, while interactions between other SNPs were less likely to contribute to elevated sprint/power athletic performance (44).

(SIB-7C) Significant numbers of cardiomyocytes are replaced (~50%) in a lifetime:

In a seminal body of work done in the laboratory of Dr. Jonas Frisén a method for dating the birth and replacement of cells in a tissue was designed (58, 59). During surface atomic tests of the mid 1960s the release of the radioisotope 14C into the atmosphere led to its incorporation into human genomic DNA at a level that reflected its level in the atmosphere (58). The half-life of 14C is 5,730±40 years but the predominant form of Carbon in nature is 12C. By measuring the ratio of 14C to 12C in a tissue which changes with the DNA replication associated with cell division the loss/replacement the numbers of new cells can be determined (58). This method was termed as Retrospective Birth Dating (RBD) and its application allowed Dr. Frisén and his colleagues to establish that all tissues except the cerebellum underwent cell replacement. This included the Heart with approximately 50% of its cardiomyocytes being replaced in a lifetime (58, 59). The significance of the number for the turnover of cardiomyocytes in the interpretation of numbers of my cardiomyocytes that were lost in the Heart Attack will become clear.

(SIB-7D) Known cellular and molecular mechanisms for coping with cardiac stress and protecting hypoxic cardiomyoctes.

Although it was always known that stress puts a strain on the cardio-pulmonary system the insidious role of chronic stress on all dimensions of health including cardiac disease is now much better appreciated as even being dangerous (53). New genetics and molecular biological approaches are identifying new risk factors beyond traditional targets for Coronary Artery Disease (CAD) (54, 55) such as the cardioprotective effects of IL1 against heart disease which is subverted by anti-inflammatory agents that are inhibitory for this factor (55). Furthermore, additional factors beyond weight gain act together with it to elevate the magnitude of Risk Factors for health problems (54).

As has been pointed out the principal source of cardiac stress is the deprivation of O2 (hypoxia) due to various factors affecting coronary blood flow. Hypoxia is responsible for pathologies such as heart disease, cancer, stroke, and chronic lung disease, which are responsible for 60% of deaths in the United States (38 – 44). Hypoxia Inducible Factor 1 (comprising of HIF1α and its partner HIF1β) is the molecule playing a principal role in ameliorating the consequences of low O2 in all mammalian cell types including cardiomyocytes. HIF1α has evolutionarily diverged into the related to Endothelial PAS (Per Arnt Sim) domain 1 (EPAS1) also interacting with the same partner HIF1β to initiate transcription. In poorly vascularized embryos EPAS1 responds to hypoxia as a developmental signal during embryogenesis and is responsible for vasculogenesis and angiogenesis (38 – 44). HIF1 and EPAS1 belong to the class of molecules known as transcription factors as they regulate the expression of genes necessary for physiological processes that elevate blood and O2 supply (angiogenesis, vasculogenesis, erythropoiesis and hematopoiesis) and are all essential for coping with O2 deficits. [In molecular biology and genetics, a transcription factor (sometimes called a sequence-specific DNA-binding factor) is a protein that binds to specific DNA sequences, thereby controlling the rate of transcription of genetic information from DNA to messenger RNA (46)]. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator regulated by O2 and plays essential roles in mammalian development, physiology and disease pathogenesis. HIF1 was discovered by its ability to bind the enhancer and upregulate the transcription of the gene encoding Erythropoietin (EPO) a hormone required to elevate erythropoiesis (Red Blood Cell production (38 – 44). In the presence of O2 the HIF-1α subunit undergoes ubiquitination and proteasomal degradation – processes that are arrested in the absence O2. Interaction of HIF-1α transactivation domains with coactivators is induced by hypoxia. The signal transduction pathway is unresolved, but does involve generation of reactive oxygen species (ROS), (38 – 44).

HIF1 also plays a direct role in ischemic preconditioning (IPC) which is of critical importance in moderating the effects of CAD, CHD and SCA. Remote ischemic preconditioning (IPC) is induced by 5 minute cycles of limb ischemia and reperfusion, which are induced in mice by cyclical clamping and unclamping of the femoral artery and in human subjects by inflating and deflating a blood pressure cuff. Even after a period of 72 hours IPC results in protection of the heart against a subsequent prolonged induction of ischemia and reperfusion. The mechanisms possibly involve signals generated by the nervous system and by secreted factors, such as the cytokine interleukin-10 (IL-10) The transcriptional activator hypoxia-inducible factor 1 (HIF-1) has been shown to be necessary and sufficient for remote IPC in vivo, reduction of infarct size as well as for the up-regulation of Il10 mRNA in cultured mouse myocytes. Induction of HIF-1 activity may confer cardioprotection on patients undergoing cardiac bypass surgery (40).

Similarly the anti-inflammatory molecule Sulindac an inhibitor of cyclo oxygenase (COX1/COX2) also induces IPC in myocardial tissues via a pathway that includes protein kinase c (PKC), Nitric Oxide Synthase, Hsp27 protect cardiac tissues against ROS and oxidative damage (36 – 51). Similar protective effects against ROS are conferred on Retinal Pegmented Epithelial (RPE) cells (41, 45). Several of the genes listed above also deliver IPC to cardiomyocytes and include Akt, Bcl2, IL1, PPAR-a, CDC29, p38 kinase, and JAK-STAT (36 – 51).

Others have proposed therapeutic options based on in vitro cardiomyocytes and work done on IPC either demonstrating resistance due to IPC under conditions of hypotonic shock documented with cell biological methods or with molecular, cellular and immunological approaches (68, 69).

Other labs have studied additional mechanisms documented for cardiomyocyte cell death (68). These include the overload of Ca ++, perforative permeabilization of mitochondrial membranes and tendency for breakage of cytoskeletal and membrane components induced by protease activation which are also transferred to adjacent cardiomyocytes through gap junctions. Similarly these cell death signals are also received from blood cells and other cardiomyocytes via gap junctions. Most forms of protective treatment against reperfusion injury are in early stages of development, with atrial natriuretic peptide, inhibition of mitochondrial permeabilization and ischemic postconditioning holding some promise. Rescue from Myocardial Infarction by the therapeutic effect of an adjuvant during coronary recanalization presents a new therapeutic option (68).

The adaptive evolutionary response of the genes encoding HIF1 and EPAS1 to low O2 conditions mimicking CAD and CHD are clearly illustrated by Tibetans resident at high altitudes (>15000 meters) and Athletes (42 – 44). Tibetans do not exhibit increased hemoglobin concentration and polycythemia which is hypoxia-induced and HIF1 mediated at the rarefied atmosphere of high altitudes (42). A high-frequency missense mutation c.[12C>G; 380G>C] in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), contributes to this adaptive response. PHD2 causes degradation of HIFs which regulate responses to hypoxia, e.g. erythropoiesis (42). The PHD2 p.[Asp4Glu; Cys127Ser] variant has a lower Km value for oxygen, which correlates with continued binding low density of O2 at high altitude and so increased HIF degradation under hypoxic conditions. Although hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is retarded under hypoxic culture conditions thus decreasing HIF-mediated polycythemia. The c.[12C>G; 380G>C] mutation originated ~8,000 years ago on the same haplotype previously associated with adaptation to high altitude (42).

The adaptive evolutionary relationship between SNPs in EPAS1 and athletic performance was documented in 2 studies (43, 44). In one study of athletes, SNPs and 2 power:time ratios the authors proposed that specific SNPs associated with each power:time ratio (43). EPAS1 functioning as a sensor with its additional ability of integrating cardiovascular function, energetic demand, muscle activity and oxygen therefore influenced adaptation and the relative contribution of aerobic and anaerobic metabolism and hence conferred the maximum sustainable metabolic power for a given event duration (43). In a second study, 2 of 5 SNPs across EPAS1 were found to be highly predictive of sprint/power athletic performance, while interactions between 3 SNPs were less likely to contribute to elevated sprint/power athletic performance (44).

Additionally, beyond established genes and mechanisms (36 – 51) results in several new, divergent and ongoing areas of research in cardiac, molecular, cellular and developmental biology illustrate the unfolding appreciation of the complexity of the Heart in Development. They identify the many new points of subversion leading to potential Risk Factors!

These mechanisms are discussed in detail in the references and in section SIB-7C to 7E. Furthermore, a select and representative sampling of the literature, molecules and mechanisms either inducing or offsetting the lethality of hypoxia-reperfusion or ischemia – reperfusion in neurons and cardiomyocytes by various mechanisms including apoptosis, has been addressed in previous sections. Molecules such as Akt, Bcl2, HIF1, EPAS1, VEGF, GATA binding factor, JAK-STAT, NOX2, Estrogen, p38 Kinase Isoforms, and Sulindac contribute to IPC through well-defined pathways (36 – 45, 47 – 51). HIF1 up-regulates VEGF and GATA nucleotide sequence (GATA 1-6) binding protein to induce angiogenesis and vasculogenesis in response to hypoxia and so retard ischemic cell death by apoptosis (36 – 45, 47 – 51). While other mechanisms also contribute to IPC and the survival of cardiomyocytes (36 – 45, 47 – 51).

However a cautionary qualification is essential at this point! It may be the striking qualification of the above results assembled in lab mice (52). These results which afford the analytical power of mammalian molecular genetics, in lab mice may be qualified by evolutionary genetics of wild populations of another species – teleost fish (52). Thus, although HIF1 and EPAS1 in their cardioprotective responses to hypoxia and ischemia have been covered in detail in model organisms e.g. mice they may not be completely applicable to humans (36 – 44).

Although only 1x-2x differences in levels of expression of genes in Inbred Strains of mice can result in pathologies like cardiac diseases and cancer, in an organism with identical or similar tissue specific expression patterns and levels of the same genes, teleost fish, different results were obtained (52). A wide variation in gene expression among tissues was observed, with only a small fraction (31%) of known tissue-specific differences being conserved between all feral or wild populations of these fish (52). Thus the application of these interpretations from mice to patients may involve a large step, which is complicated by these alternative results. This parallels the disparity in application of therapeutic results obtained from mice to humans that is often noted in cancers. However, each of these approaches brings its own analytical power, and it is likely that eventually they will all be integrated to contribute to enhancing the understanding and therapeutic offsetting of CAD, CHD, CVD and SCA or SD in humans.

(SIB-7E) Preliminary Results – Ongoing Discoveries, Identification of Potential New Risk Factors & Modifiers of Risk In Cardiac Disease States

In contrast, results emerging from research in the molecular, cellular and developmental biology of coronary vessel – myocardial systems is providing an entirely new perspective for determining Risk Factors and therapeutic applications. A select and representative sampling of the literature, molecules and mechanisms either inducing or offsetting the lethality of hypoxia-reperfusion or ischemia – reperfusion in neurons and cardiomyocytes by various mechanisms including apoptosis, has been addressed in previous sections (SIB-1, 7A, 7B, 7C & 7D) and references (36 – 45, 47 – 59, 67 – 69).

The results of these relatively new studies and results, some of which have been touched on before are sketched over here (36 – 45, 47 – 52, 53 – 59, 67 – 74). Studies on detraining of muscle myocytes following strenuous training (overtraining) which show that neither the numbers and sizes of myonuclei nor hypoxia and apoptosis resistance are lost and are retained for at least 3 months if not longer (67). Other mechanisms including the development of the heart and its cardiomyocytes, surprising new findings, molecules and mechanisms that play similar roles or contribute to the development and function of cardiomyocytes in heretofore unknown ways that have also been discussed in previous sections (67 – 74).

Still more sources of environmental and developmental variation potentially contributing cardiac Risk Factors and identifying therapeutic interventions have been reported (67 – 74). These include, results showing the dependence of maximal amplitude of contraction and pumping action of the cardiomyocytes, (and so the heart) on the optimal alignment of subunits of its filaments (of actin, myosin and troponin) as well as the flexibility of filament bundles in cardiomyocytes (70). Another group demonstrated the elevation of the viscosity of cardiomyocytes in response to decreasing flexibility of the collagen framework in the surroundings of the thorax is important for its efficiency and amplitude of contraction (71). Additionally, a range of results from molecular genetics of cardiology provide new therapeutic recourse and have already been discussed (72). In the introduction to the pumping amplitude of the heart, the role of Nup10 molecules regulating ER/NPC as well as the differentiation of muscles has been outlined (SIB-1) and references (67 – 74).

Finally the contributions of various inhibitors and genes of hypoxia induced apoptotic death of cardiomyocytes have also been discussed (ref: ref: 17 – 31, 38, 39, 66 – 74 ).

Three new areas of results illustrate the unfolding appreciation of the complexity of Cardiac Development and the many points at which its subversion could lead to the accumulation of Risk Factors!

To expand on the first set of new and ongoing fields of study and their results show that the synchronized beating of cardiomyoctes caused by their multi filament content organization is dependent on specific events which must have occurred during the early development of the embryonic heart (70). For this coordinated beating to attain maximal amplitude of contraction of the muscle cells the filament subunits and their boundaries must be properly aligned in bundles which are thus dependent on numbers of coordinately contracting bundles. Additionally the appropriate physical environment such as the elasticity of the Extracellular Matrix (ECM) is also a determinant of the amplitude of contraction (70). Other groups have shown that the flexibility of the Heart is optimized for amplitude of contraction by adjusting its myosin concentration in response to stiffening collagen in its surroundings, during development (71)!

Additionally the differentiation of the heart is regulated by a unique mechanism involving gp210/Nup210 a lynchpin nucleoporin regulating muscle and neuronal differentiation. The conserved N terminus of gp210/Nup210 inserts into the perinuclear space and induces muscle cell differentiation (75). This gp210/Nup210 molecule also plays a critical role in the maintenance of homeostasis in its interactions between the Nuclear Envelope and the Endoplasmic Reticulum through its large luminal domain. It does so independently of its binding to the Nuclear Pore Complex (NPC). Molecules of gp210/Nup210 block the stress specific caspase cascade response and retain their muscle cell differentiation capacity despite the absence of the C terminus and the NPC binding domain in the N-terminus (75).

In other work a newly discovered molecule RBFox2 in mice (73) plays a role in the compensatory phase (supports increased work and blood flow) as well as the decompensatory phase (which induces decreased work and blood flow progressing to failure) post Cardiac Heart Disease (CHD). The expression of RBFox2 in the decompensatory phase was the mirror image of developmental ‘remodeling’ (genetic reinforcement) of the heart. This pivotal role of RBFox2 in heart failure has been experimentally verified and could be a Risk Factor (73).

Furthermore, as shown, surprising new perceptions of other Risk Factors for CAD, CHD and SD such as interleukin-1 (IL-1) mediated inflammation are emerging (54). It is now shown that anti-inflammatory mediated suppression of inflammation, via inhibition of IL-1, may actually elevate the risk for Coronary Heart Disease (54).

Finally there are neuroprotective globins such as neuroglobin and cytoglobin that sequester ROS and may bind O2 within hypoxic mammalian brains (74). Their levels range significantly between terrestrial aquatic species (74). Running, swimming and diving elevates levels and modifies these neuroprotecting globins in the mammalian brain (74). They are expressed in all tissues including cardiac tissues, are upregulated by hypoxia and likely to play a cardioprotective role (74).

(SIB-7F) Exercise and Squash – Optimal Health/Injury Ratios, Modification of Risk Factors for, Coronary Heart Disease (CHD), Coronary Artery Disease (CAD), Coronary Vein Disease (CVD) and Sudden Cardiac Arrest (SCA)

The prominent role of exercise in reducing the risk of all Coronary Aretery Diseases (CAD), Coronary Heart Diseases (CHD) including Sudden Cardiac Arrest (SCA) has been well established (76, 77, 80 – 96). The known and hypothetical mechanisms for this protection have been characterized and some of the prominent ones include: (1) raising levels of fitness and physical activity (80 – 90), (2) ischemic pre-conditioning (IPC) of cardiomyocytes, that is protective even from late (up to 72 hour) ischemic challenges (36 – 51, 67 – 69), (3) involvement of a range of mediating molecules and mechanisms (36 – 51, 67 – 69, 80 – 96), (4) retention of overtraining generated hypoxia (and apoptosis) resistant myonuclei for at least 3 months if not longer into old age after detraining (67), (5) retention despite RBD confirming replacement of 50% of cardiomyocytes/lifetime (58, 59) . Having reviewed this literature it is useful to find that it proposes a role for high intensity (METs index of 6 – 12 cals/lg/hr) sports like Squash Rackets in reducing the Risk Factors (4 -22%) of these various cardiac diseases. Squash also represents an activity promoting high Health Benefit to Injury Ratios (5-7, 67 – 69, 80 – 96).

The Risk of Sudden Death or Sudden Cardiac Arrest among all athletes in the USA is 4/106 or 1:250,000 or 0.0004% and in the Republic of Ireland it is 1:600000 or 0.000167% (80, 81). In the last 5 decades of my life Competitive Squash and training for it, at various levels of intensity was the major physical activity. To understand any role that Squash may have played in my surviving the MI, it is worth reviewing studies and analyzing whether and how much it contributes to either elevating or decreasing the risk of all forms of cardiac pathologies (5 – 7, 67 – 69, 80 – 96). Analyses that were drawn on, included 4 groups of studies applying:

(1) older less representative methods which serve a useful purpose as indices (80, 82 – 84, 86),

(2) more contemporary, highly quantitative, statistically robust, defined and representative studies from 2000 – 2013, some based on GWAS/METs, with a Scientific emphasis (81, 85, 90),

(3) studies that are still scientifically systematic, quantitative or statistically robust and yet somewhat more representative of Racket Sports, especially Squash, that embodies arhythmicity, explosivity of basal to peak velocities, upper to lower body coordination, highly developed skills, (hand-eye coordination, racketwork, spatial dimensions, postures, on court moves and footwork). They are based on criteria selected by Players and Coaches in conjunction with Sports Physiologists (who may also be Physicians (MDs) and Research Scientists (PhDs). They are still restricted to a small range of skills, explosivity and relatively rhythmic movements (87 – 90),

(4) studies that are low on scientific and quantitative dimensions and statistical robustness but are significantly more representative of Racket Sports, especially Squash that embodies, arhythmicity, explosivity of basal to peak velocities, upper to lower body coordination, highly developed skills, (hand-eye coordination, racketwork, spatial dimensions, postures, on court moves and footwork). They are based on criteria selected by Players and Coaches in conjunction with Sports Physiologists (who may also be Physicians (MDs) and Research Scientists (PhDs) (5 – 7, 80, 91 – 94).

(1)  Does Squash have a high Metabolic Equivalent Task Index (MET), Work (wattage) or Cardiorespiratory Fitness (CRF) value? And is it higher than that measured in other sports?

Yes! Whether Squash has a higher Metabolic Equivalent Task Index (MET), work wattage or Cardiorespiratory Fitness (CRF) value than other sports depends on how it is measured but in all cases, the complexities of the game make the maximal values far lower than the actual values! This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar METs 6 – 12, work of 120 – 210 watts, are considered to represent high intensity exercise but due to the manner tested (without inclusion of all the variables identified in the above questions) it can only remain a minimal estimate of the true value for Squash (SIB-7B,-7F) and references (5 – 7, 67 – 69, 80 – 96).

An example of this discrepancy in evaluation is provided by the results of 7 studies (82, 85 – 90).This whole section will be covered in a more detailed Sports Physiology and Cardiac Risk Factor to be for oriented and submitted to a Journal dealing with Sports physiology or Clinical Medicine and Sports (1).

Study 1 (82): The study by Jette et al, 1990, (82) is both quantitative and thorough with an older definition of METs Index at (mls of O2/kg/min x 3.5 at rest (sitting).This work does not include e.g. ways of measuring all the variables defining Squash that were identified in questions 3 and 4. Thus, as the authors noted, this study lacks quantification of many of the determinants of rigor/intensity in Squash that distinguish its higher intensity over other sports including Racket Sports. Accepting this limitation, they showed that of 100 physical activities or sports tested, some at multiple intensities/rigors, 7 (Squash, Racquetball, Orienteering, Jogging, Judo, Karate and Boxing) had an intensity of 12 METs/210 watts. Another 13 sports had equal or ~3 had greater maximal intensity with Cross Country Skiing and Rowing at 13 METs/228 watts and running at up to 16 METs/280 watts (92). The relative energetic output, physiological output and thus the intensity of workouts in Squash relative to other sports obtained with contemporary methods have superseded this original ranking and distribution and been based on a Squash Specific quantifications (5 – 7, 85 – 90).

Studies 2 & 3 (5 – 7, 85 – 90): Squash is well known as a highly arrhythmic, explosive and spatially dynamic sport with a high density and wide range of movements, racketwork and skills that introduce variations which are extremely difficult to detect let alone quantify even for the experienced experimental observer! This is confirmed by the clusterings of tournament performance results of similarly ranked professionals in the Professional Squash Association (PSA). It is impossible to adequately cover let alone quantify the density, range and depth of these strokes and movements in the lexicon of current Sports Physiology. Given these limitations some attempts at quantification coupled with more qualitative estimates remain the best and only recourse. The strokes and movements include the whole range of Motor-Sensory-Spatial processes and their various permutations and combinations that are translated into the ‘Read (Stroke)->Get (Ball)->Stroke (Make)’ triad on the Squash Court either determined by, or in response to, a wide range of Sensory Perceptions or cues read in fractions of seconds as time periods (5 -7, 93, 94). These are best communicated in colloquial terms known to Players, Coaches and Exercise or Sports Physiologists rather than in formal scientific terminology (5 – 7, 93, 94, 87 – 90).

The range of Moves and Strokes in Squash although dependent on improvisation are mostly precise, technically demanding and occur in a varied and sequential intermix. Yet in the absence of time and space on the court all of this must be compressed into an improvised response! Adaptability is a core requirement in Squash. This is why Squash Players operate at high skill levels that involve a high density, arhythmicity and range of sudden (explosive) moves and strokes, upper and lower body coordination all producing high torque, intensity, caloric and metabolic expenditure (5 – 7, 93, 94, 87 – 90). The relative energetic (METs) Index, physiological (glycolytic and aerobic) output and the intensity of workouts in Squash relative to other sports have been obtained with contemporary methods based on a method known as Squash Specific Tests (ST) or Field Tests that have superseded its original ranking and distribution based on standard Treadmill Tests (TT) or Laboratory Tests (5 – 7, 93, 94, 87 – 90).

The first Squash Specific Test (ST) or Field Test was a computerized variation on the ‘Ghosting’ (or Star Drills in the USA) invented by Jonah Barrington, the former 6 time British Open (Wimbledon of Squash) Winner and the Coach of the Player currently ranked number 1 in the World – Mohammed El Shorbagy (7). Star Drills involve moves made on the Squash Court without a ball for efficiency, high and sustained pressure (7). Barrington is known to Players and Coaches, for maximizing Physical Conditioning for Squash (7). The computerized commands (introducing arhythimicity and explosivity) in Star Drills consists of 6 points (2 lateral points in addition to the 4 corners) on the court, identified by audio-visual commands leading the players from the strategic T junction (center of the court), to the designated points (displacements) with the swinging of the Racket at an imaginary ball on arrival (87). This sequence has high numbers of repetitions and with occasional breaks at standard intervals. In the Field Test or the Squash Specific Test (ST) players were monitored for physiological, biochemical and physical parameters such as Heart Rate, levels of Blood Lactate (mmol/L), time taken for the last step, VO2 max (mls/min/kg or METs) and Performance at the Anaerobic Threshold (Te) light flashes/hour). The same parameters for the same Players were also monitored in the Treadmill or Laboratory Test (TT) with the exception that final Threshold performance was recorded in km/Hr (87). Players, who were Juniors in German Squash, were assigned rank performances for both methods. It was established that there was a significantly greater correlation (>1.7x with p range >50x) between the Squash Specific or Field Test (ST = 0.90, p<0.001) and the rank established by the various physical, physiological and biochemical parameters than between the Treadmill and Laboratory Test (TT= 0.52, p>0.05) and these 3 performances (87). Of most importance the ST predicted the performance of the players in routine competitive play (tournaments) far better than the TT (87).

In a third study (88, 89), essentially the same methods of Squash Specific or Field Tests (ST), Treadmill or Laboratory Tests (TT) were again compared with some changes introduced. Firstly, the conditioning and performance of the tested players was exponentially elevated by changing the subjects tested to Professional Squash Association (PSA) Players including the top ranked player in the world (World #1) in the years of the study (2004/2005). Secondly the Squash Specific Tests (ST) were graded with distance, directions and times calibrated with PSA tournament level performances by taped audio-visual cues. Thirdly, the computational programs were more sophisticated and could introduce greater arrhythmicity into the graded ST with specific audiovisual cues. Finally the numbers and resolution of physiological, physical and biochemical parameters was elevated and more sophisticated. They included heart rate (HR), VCO2/VO2, time to exhaustion (Te) and VO2 parameters under various conditions in ST and TT (88, 89). In both the graded ST and TT neither the heart rate (HR) nor the %VO2max, at VT and RCP were significantly different for the PSA Pros. However, other indicators such as VO2, VCO2 and breathing frequency values measured at maximal loads were significantly higher levels in ST than in TT. As with the Juniors, results of parameters determined in ST and TT correlated with known performances of the PSA Pros recorded in tournaments (88, 89).

Of most importance differences in the ST and TT results for the Junior Players and PSA Pro Players were revealing (87, 88, and 89). For the Juniors the values obtained in the TT and ST were significantly different (87) while for the PSA Pros they were mostly similar (88, 89) confirming the greater facility of the Pros with the higher rigor of the ST. This confirms a determining factor in the game that is well known to Squash Players. As expected the Pros are physically stronger and faster than the Juniors. But of more importance, the Pros have integrated the critical elements of Squash specific movements, racketwork, footwork and spatial dimensions to a significantly higher level than that of mastered by the Junior Players. This mastery by the Pros brings a significantly greater economy of energetic expenditures to the graded ST that is not required in the TT thus diminishing the rigor of the graded ST and the disparity between the 2 tests (87, 88, 89). Therefore the calculations of intensity for Squash e.g. METs by even graded ST methods is almost certainly an underestimate.

Another reason for this underestimate is drawn from the magnitude, density and range of movements and strokes from the ‘Read-Get-Stroke’ triad in an Amateur match let alone a high level PSA Squash match that would simply overwhelm even the graded ST or Field Test (87, 88, and 89). The energetic requirements of movements on the Squash Court are akin to overcoming the Inertia with all their Activation Energy Barriers (quantities from Formal Physics) that a Sprinter would overcome in (i) launching from the Starting Blocks, then (ii) coming to a hard stop and (iii) finally re-launching from mid track! And all this in Sprinting would be devoid of the many vectors that would present additional Activation Energy Barriers such as switched spatial orientations and directions that Squash Players have to routinely overcome in a match! The density and range of movements in the ‘Get’ segment of the ‘Read-Get-Stroke’ triad of Squash includes Sprint-Walk-Step, Dive, Twist, Turn, Stretch , Bend, Jump, Reach, Upper and Lower Body Coordination, Basal-Peak Velocities either in rapid succession or in overlapping or in a varied and sequential interchanges (87, 88, 89). The depth, range and spectrum of these movements as well as their energetic requirements are not adequately definable let alone measurable by scientific or Sports Physiological methods. This has led to the significant underestimate between the calculations of energetic demands and metabolic intensities for Squash e.g. METs indices by even graded ST methods relative to other sports (1, 4 – 6, 80 – 94).

To assay these factors more realistically requires inclusion of the less, controlled, quantitative, statistically robust and scientific methods designed by Athletes, Players, Coaches, Sports and Exercise Physiologists. It is an analyses more reflective of muscle strength, muscle endurance, cardiorespiratory endurance, flexibility and speed, semi-quantitatively measured and reported by Forbes and (TopTen) ESPN Sports (5 – 7, 87 – 89). These answers to this question requires experimental verification.

(2) Does Squash have a high workout intensity (calories per kilogram per hour (unit time)) as measured by studies done by Players, Coaches in conjunction with Sports Physiologists? Does Squash have a high Health Benefit/Injury ratio as measured by Forbes? And by ESPN(Top10)?

Yes to both questions. Controlled, systematic, physiologically and statistically robust methods for measuring METs indices was addressed in the answer to the above question as well as in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar METs indices (6 – 12) lower Risk Factors for MI, CHD, CAD, and SD or SCA by 22% – 40% (SIB-7B,-7F) and references (5 – 7, 80 – 94).

However, these scientifically robust methods were also shown not to be completely representative of the intensity and energetic requirements of the game. To appreciate the full magnitude of the physiological and physical intensity of the game, Competitors, Personal Trainers, Coaches and Exercise Physiologists quantified 6 parameters in 10 sports with the results being published in ForbesOnline (5, 6).

Parameters that were quantified on a scale of 1 – 5 (direct relationship) with the exception of injury risk on a scale of 3 -1 (inverse relationship) and were tallied for:

  • Cardio-respiratory endurance
  • Muscle strength
  • Muscle endurance
  • Flexibility
  • Calories/30 minutes
  • Injury risk

The highest scores for (1) energy consumption (517 calories/30 minutes), (2) ratio of Injury risk/calories per 30’(is 0.44 when corrected for differential of 1.1 in calories from rock climbing) and (3) total score of 22.5 were all assigned to Squash – making it the healthiest of the 10 sports tested (5, 6). They provide the alternative more realistic combinatorial approach and independent confirmation of Squash being one of the most energy and work intensive sports with the lowest risk of Injury and so the healthiest sport tested.

In contrast there are reports of serious injuries, such as concussion and even Parkinson’s Disease resulting from competition in other sports such as football, boxing and soccer (95, 96). These injuries have neither been included in evaluating, the Risk Factors nor in interrupted, unsustained and diminished training intensities associated with these sports (95, 96).

The above questions were addressed in a different way by ESPN(Top 10) with different results (91). They identified 10 attributes of athleticism, and then asked a group of experts made up of sports scientists, kinesiology academics and sporting journalists to assign a number from 1 to 10 to each of these skills. This analysis was applied to 60 sports from around the world, and the final results are shown in the table here. See also the sports lists for each of the components of athleticism.

The results from this ESPN(Top10) (91) are inconsistent with and even contradict the results from all other studies spanning the last 3 decades (1, 5 – 7, 80 – 94). Some of the reasons for the problems leading to this disparity are addressed elsewhere (1, 5, 6, 91 – 94) and suggest a lack of familiarity of the evaluators with the dynamics of Racket Sports, the relevant literature distinguishing their properties as well as with much of the literature in Sports Physiology in general (91: Table I; 1, 5 – 7, 80 – 94). These include e.g. the non-interchangeable nature of the differences in power generation between, Racket Sports and Boxing (its top rated sport) or Weight Lifting. In the Racket Sports e.g. Badminton power generation is predominantly based on technique and the timing of strokes while in Boxing (its top rated sport) or Weight Lifting it is based more on muscle mass and force than in technique. The qualities acquired in the latter would actually impede power generation in the former. This study contrasts sharply with the others and is cited as an example of the dangers of complexity, subjectivity and ad hoc attempts at quantifications of Sports in general (1, 5 – 7, 80 – 94).

(3) Does Squash cause Sudden Death or Sudden Cardiac Arrest (SCA)?

Only when pre-existing cardiac pathologies such as CHD, CAD, CVD have seriously compromised the cardiac health of the Players! There are 3 older references (83, 84, 86) that claim that Squash “causes Sudden Death” while a fourth paper and the contemporary literature suggest that these data reflect increases of the risk of Sudden Death among those with various pre-existing cardiac pathologies. Unlike either more comprehensive older or more systematized contemporary (GWAS, METs, PRM based) methods the above studies fail to show that Squash and similar activities actually register a decrease (22 – 40%) in the Risk Factors of CVD, CAD and MI ( (80, 82, 85, 87 – 90).

An exhaustive pre-GWAS study by Dr. Fionnuala Quigley (80) clarified some of these results and presciently revealed data that would be consistent with the contemporary studies of a decade later. In an unbiased survey of the population of 3,000,000 in the Republic of Ireland over a 10 year period, from 1987 – 1996, by including ALL people who died while exercising ostensibly of Sudden Death in ALL sports was obtained from postmortems done by 45 of 49 coroners contacted (80). It was found that of 15 sports surveyed it was Golf that was the game leading to the highest frequency of Sudden Deaths. Golf is the most popular participant sport in Ireland and the ages of the deceased Golfers ranged from 32 to 36 years. Thus age could not have been a predisposing factor (80). An uncritical reading of the data might have suggested that the frequency of Sudden Deaths caused by Golf was 16x higher than that caused by Rugby or Squash (1 each). Dr. Quigley points out that her paper clearly illustrates that despite an assiduous attempt at preventing this source of error – surveyed populations and methods can affect the interpretation with false positives or mis-interpretations which the author has carefully excluded (80).

At best these types of studies show that those with CHD, CVD and CAD should, as has been recommended, be medically counselled before taking to the Squash Court (ref 43, 44).

All the contemporary methods with large Cohort sizes, high resolution GWAS, high intensity sports METs, with strong correlations with Personal Record Maintenance, etc.. included in the analyses show that vigorous physical and fitness activities of intensity (METs = 6 – 12 cals/kg/hr) including Squash, actually decreased the Risk of Cardiac Heart Disease by 30% (SIB-7B,-7F), references: (82 – 90) & therein). And another independent study showed an inverse relationship between vigor of physical activity of sports such as Squash (with METs of 6 – 12 cals/kg/hr and work of 140 – 210 Watts) and Risk Factors actually leading to an even greater decrease of the risk of Coronary Heart Disease CHD by 22% – 40% (SIB-7B,-7F);references: (85 – 90)..

(4) Does Squash cause Coronary Heart Disease (CHD), Coronary Artery Disease (CAD) or Coronary Vein Disease (CVD)?

No! This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar METs actually lower these risk factors by 22% – 40%. Thus Squash would also be expected to slow down the rate of plaque deposits and the resultant CAD (SIB-7B,-7F); references: (82 – 90). These answers to this question requires experimental verification.

(5) Does Squash decrease the Risk Factors associated with Sudden Death or Sudden Cardiac Arrest (SCA)?

Yes! This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar METs 6 – 12 cals/kg/hr, work of 120 – 210 watts, lowers these risk factors by 22% – 40% (SIB-7B,-7F); references: (82 – 90).  This means that the rate of CHD leading to SCA would also be decreased by high intensity sports like Squash. (SIB-7B,-7F); references: (82 – 90). These answers to this question requires experimental verification.

(6) Does Squash decrease the Risk Factors associated with Heart Attacks (Myocardial Infarctions) or Sudden Death?

Yes! This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar METs 6 – 12 cals/kg/hr, work of 120 – 210 watts, lowers these risk factors by 22% – 40% (SIB-7B,-7F); references: (82 – 90). These answers to this question requires experimental verification.

(7)Coronary Artery Disease causes plaque buildup gradually leading to increased hypoxia and when the block is complete it results in (complete) anoxia and cell death. Could cardiomyocytes capable of resisting hypoxia due to increased numbers and sizes of cardiomyonuclei due to overtraining be expected to retain resistance after decades of detraining? Are there plausible molecular mechanisms for sensing and physiologically responding to hypoxia as in squash?

Yes to both questions. This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). The literature clearly demonstrated that Sports of maximal intensity like Squash (conservatively estimated: 6 – 12 cals/kg/hr METs, 12 watts and 517 calories/30 minutes) lowered the risk of all Coronary Diseases (CHD, CAD, CVD, SD) by 22% – 40% has also been reviewed (80 – 90). Additionally the role of molecules such as HIF1, EPAS1, Bcl2, JAK-STAT, Akt, NO2 , Estrogen, IL10, IL1 and Sulindac among others in IPC and cardioprotection that would provide a mechanistic basis for lowering these Risk Factors has also been well documented. Both lowered rates of plaque buildup from CAD and thus the delayed CHD as well as IPC induction by hypoxia reinforcing cardiomyocyte survival could be expected to be elevated by high intensity sports like Squash (SIB-7B,-7F); references: (82 – 90).

Furthermore, the adaptive evolutionary response of the genes encoding HIF1 and EPAS1 to low O2 conditions mimicking CAD and CHD are clearly illustrated by Tibetans resident at high altitudes (>15000 meters) and that of high performance athletes could be expected to set a parallel for selecting Squash Players with similar SNPs (42 – 44).

Of most importance it is now known that detraining of skeletal muscle myocytes following overtraining does not result in the loss of myonuclear resistance to hypoxia induced apoptosis and so the conditioning capacity is retained or restored for at least 3 months if not longer. These trained myonuclei resistant to hypoxia and apoptosis, can serve as templates for newly born myonuclei that are also hypoxia and apoptosis resistant – even extending conditioning well into old age as noted by athletes (67). So cardiomyocytes of Squash Players should be similarly capable of resisting hypoxia due to increased numbers and sizes of myonuclei conferring resistance to hypoxia even after decades of detraining. These answers to all these question requires experimental verification.

(8)Does Squash and training for it qualify for over-training levels which generate long lasting hypoxia induced and apoptosis resistant cardiomyocyte nuclei based on the studies with myocytes ?

Our ‘on- and off-court’ training in Squash met the standards of rigor and intensity by most criteria, including levels of my own game that have been reviewed in previous sections (SIB – 7D); narrative page 7 and references: (4, 94). The literature clearly established that Sports of maximal intensity (6 – 12 METs index, 12 watts and 517 calories/30 minutes) like Squash lowered the risk of all Coronary Diseases (CHD, CAD, CVD, SD) by 22% – 40% and this literature has also been reviewed (85 – 90). The work considered to meet the criteria of overtraining in experimental systems such as rodents was generated by partially ablating their major synergist leading to an overload of their Extensor digitorum longus (EDL) muscles situated at the lateral and front of the leg (SIB – 7D); reference: (67). Additionally SNPs in, prolyl hydroxylase 2 regulating HIF1 stability in high altitude adaptations of Tibetans and SNPs in EPAS1 correlated with Elite Athlete performances with hypoxia apparently serving as an (evolutionary) selective agent in both cases (42 – 44). Hypoxia in Squash could also be expected to correlate with similar SNPs and an elevated frequency of high performance in tournaments among Squash Players harboring them (42 – 44). Taken within the context of the above literature our training regimens in India qualified for high intensity overtraining (4, 94) while in the US it dropped to low intensity overtraining followed by detraining. These answers to this question require experimental verification.

(9) Based on Retrospective Birth Dating (RBD) in a 7- 8 year period of detraining, (2007 – 2014), how many new cardiomyocytes could be expected to be born and become susceptible to hypoxia and apoptosis? Is there a difference between the cardiomyocytes exposed to high intensity overtraining in India 38 years ago (ending in 1976), those exposed to low intensity overtraining in the US (ending in 2006/2007) and those exposed to detraining(ending in 2014)? How many cardiomyocytes would be susceptible to anoxia?

This question was partially addressed in 2 earlier sections in the narrative as well as in (SIB-7C; reference: (58, 59). For various Professional and non-Sports related reasons alluded to and based on various estimated physical and physiological parameters, my personal levels of overtraining for Squash in India were significantly higher than in the US. Based on Dr. Jonas Frisén’s Retrospective Birth Dating (RBD) data for replacement of cardiomyocytes an estimate of ~4.4% of cardiomyocytes would be replaced over the 7 years of detraining (low to non-existent training) in the US (post 2006/2007). This number would rise to ~23.8% of cardiomyocytes that would be replaced during low intensity overtraining in the US over 38 years post 1976. Overtraining at high intensity for Squash in India ceased since 1976 or 38 years ago (narrative pages 7, 39 – 40), (SIB-7C; reference: (4, 58, 59). Contradicting the study on myonuclei (67) and assuming that hypoxia resistance is NOT transferred to these ~4.4% new cardiomyonuclei, at least 95.6% (or 96% – 98% based on experimental error) of the cardiomyocytes would still retain resistance to hypoxia induced apoptosis (SIB-7D; reference: (58, 59). Alternatively, according to the published study the hypoxia resistant cardiomyocyte nuclei in turn should have acted as templates expected to confer hypoxia and apoptosis resistance even on these newly born ~4.4% cardiomyocyte nuclei. This agrees with the general observations of athletes on the long term retention of effects of overtraining! Which makes incomplete transfer of hypoxia resistance to new cardiomyonuclei an unlikely explanation (58, 59, 67)?

That still requires an explanation for the observed disparity between the magnitude of the blockage and the low levels of cardiomyocyte cell death. Despite the near complete blockage of (95-99%/CA x 5 CA) in blood flow and so O2 supply through 5 major coronary arteries only ~2% of cardiomyocytes succumbed to cell death as determined by Acoustic ECG during catheterization and angiography (personal communication: Dr. Andrew Shanahan, MD, Cardiologist and Nurse Rhonda Sabel, RN).

An alternative possibility is provided by the known lethality of 5 minutes of anoxia for cardiomyocytes which could reveal their cardiac location and so yield a more plausible explanation. Those ~2% (of a total of ~4.4% new cells) of either old or newly born cardiomyocytes that succumbed to cell death could have been localized in a segment of the Heart in which the ‘cutoff’ of blood and so O2 supply was complete, thus sending them into a lethal anoxic condition.

The anoxic condition is equivalent to that of a ‘cutoff’ of all O2 during Atrial Fibrillation (AF) or Ventricular Fibrillation (VF) both of which cause Sudden Cardiac Arrest (SCA) or Sudden Death (SD) within 5 minutes in the absence of intervention with an Automated External Defibrillator (AED). Anoxia for these ~2% cells would be lethal regardless of the presence of hypoxia and apoptosis resistant 98% cardiomyocyte nuclei as templates as even they would succumb to anoxia,and through various pathways of lethality (SIB- 7A, 7B, 7C, 7D, 7E, 7F). These answers to this question requires experimental verification.

(10)Would ~98% of these cardiomyocytes be sufficient to confer the resistance that explains the difference between the level of the block 95% – 99% in 5 major coronary arteries and ~2% cardiomyocyte cell death?

This question was addressed in the answer to the above question and in the section on GWAS and Risk Factors for MI, CHD, CAD, and SD or SCA (SIB-7B,-7F). Squash and activities of similar intensity (METs = 6-12 cals/kg/hr), lowers these risk factors for CAD 22% – 40%, so slows down CAD and induces IPC in 98% cardiomyoctes through hypoxic and apoptotic survival which translated to survival during an MI incident (SIB-7B,-7F; references: (36 – 45, 85 – 90). However, the ~2% cardiomyocytes that succumbed were likely resident in a cardiac segment that did not receive any supply of blood and so O2 and thus became anoxic and suffered lethality. Thus the ~98% hypoxia and apoptosis resistant cardiomyocytes were irrelevant to the survival of the ~2% in an anoxic cardiac segment and so succumbed to lethal anoxia. The answers to this question requires experimental verification.


narrative resumed:

SUMMARY:

  1. In other words, the literature supports the inference that, my competitive days in the game of Squash Rackets and high intensity overtraining for it, had delayed the deposition of plaques by CAD so it only gradually rose to 95-99%/CA/5xCA and conferred hypoxia and apoptosis resistance due to IPC that was retained on ~98% of my cardiomyocytes. When this near complete blockage and other Risk Factors (professional pressures, family background, etc..) finally precipitated the MI the extent of cell death and so cardiac damage was limited to ~2% cardiomyocytes. Thus enabling the Cardiologists, Cardiac Surgeons and their teams to save my life!
  2. Although we cannot prove it for the MI affecting my heart, the current literature establishes that overtraining in high intensity sports like Squash (with an underestimated METs index of 6 – 12 cals/kg/hr), elevates the level of general and cardiac conditioning, both slowing down and diminishing the risk of Coronary Artery Disease (CAD) or Coronary Heart Disease (CHD) by 22% – 40% while also allowing cardiomyocytes to resist oxygen deprivation (hypoxia) from constricted coronary arteries due to ischemic preconditioning or IPC (SIB-7).
  3. As far as the Open Heart Surgery goes, there were mixed reactions as is to be expected. Although there was post-surgical pain, some unpredictable vacillations of vital signs, an acute weakness that permeated my being, including a temporary 30 lb loss of weight (which was much needed), for a period from a week to a month, the overall impression I have is one in which all of these factors were of much lower intensity than expected for such a drastic procedure. I have changed my life style drastically at least partly in gratitude for all that was done by these professionals to save my life!
  4. We begin with the central players in all this! Despite the conceptual and technical complexities of the procedures involved, namely the catheterization and angiography done by Dr. Andrew Shanahan and the coronary artery bypass graft (CABG) done by Dr. George Batsides and their respective teams, they met the requirements of the daunting success rate of 98% because their work was carried out flawlessly. This, despite the various pathological obstacles that arose and the impending urgency of the circumstances in my thorax! The CABG procedure involved surgically opening a chamber, the thorax, which has remained hermetically sealed, for good reason, across Vertebrate Evolution. This was followed by their Bypass work on the heart, which as robust and active an organ as it is, is still susceptible to all manner of electrical and other failings. All this was done while I as the patient was on pump assisted breathing and circulation! And finally there was the required resealing of the thorax without allowing a leak to develop (the consequences of which are amply demonstrated by the associated pathologies). All this is done with the high success rate of 98% – which is unbelievable for those of us who are Experimental Biologists! All the Physicians, Surgeons, Nurses, Technological Staff were always completely professional, dedicated and technically skilled and yet remained kind, warm and deeply concerned about my wellbeing! There was never any panic on their part despite the unpredictable pathological problems that arose under highly urgent circumstances – in which the possibility of fatality always loomed! And this only led to further reassurance for me as the patient!
  5. The entire sequence of pre-events and events related to the Myocardial Infarction (heart Attack) that I had, from its beginnings on the 25th of December 2014 to the present day and the time of submission of the manuscript (9th May 2015) was played out flawlessly by the Biomedical Professionals, Physicians, Surgeons, Nurses, Technological Staff, Family and Friends with myself as the beneficiary. Which is probably why I am alive! They are all listed in the copied Portable Document Format (or pdf) file entitled ACKNOWLEDGEMENTS.
  6. My family and friends, some with whom I had lost touch, simply leapt to my rescue when the news got out! They were on the phone or appeared by my hospital bedside dropping urgent matters in their own lives, and in some cases risking their own healths with long and arduous journeys, to do so. None more so than my brother Cyrus Nallaseth who despite his own dangerous health circumstances, caught the first available flight out of Mumbai (Bombay) India to be by my bedside! This alone gives me the impetus to not waste their time and effort! I am still soaking up the enormous sense of having been sheltered and so remaining alive!
  7. My fellow patients and I at the Cardiac Pulmonary Rehab Facility at UMCPrinceton at Plainsboro cannot overemphasize the importance of systematically surveying the usefulness of catheterization and angiography as opposed to non-invasive Stress Tests and Radioisotopic or Acoustic tests to detect certain ‘silent’ cardiac pathologies so as to establish their true frequency. Perhaps in conjunction with the development of a new more reliable method. This is especially so with athletes or those who have overtrained at one time, so as to acquire IPC, which is likely retained even if they have subsequently detrained. This as we saw since the cardiac muscles are likely to have retained the capacity of hypoxia resistance and so are not stressed by standard Stress tests and would mask cardiac pathologies. In my case, despite chest spasms, and the likely presence of advanced CAD the other non-invasive tests had failed to detect effects of cardiac or coronary artery plaques over a period of a decade. So cardiac involvement was inaccurately if understandably excluded with a 95% confidence a short 4.5 years ahead of the MI incidence.
  8. So while the hypoxia resistance of the cardiomyocytes prevented the various cardiac Stress Tests from stressing the heart sufficiently to allow detection of CHD/CAD, for 10 years, when the Myocardial Infarction (Heart Attack) finally occurred, ~98% of the cardiomyocytes could resist prolonged hypoxia and I likely escaped a major and possibly lethal, attack! As was inferred those ~2% cardiomyocytes that succumbed to cell death during or prior to the MI were either anoxic for more than 5 minutes or less likely not resistant to hypoxia due to the incomplete transfer of hypoxia resistance from the resistant templates (page 38 – 39 of narrative, SIB-7). The former parallels events in Sudden Death or in Sudden Cardiac Arrest (induced by Atrial or Ventricular Fibrillation, (SIB-7). The latter could occur when cardiomyonuclei may not have acquired hypoxia (and apoptosis) resistance from the resistant template nuclei of overtrained cardiomyonuclei (SIB-7).
  9. Although invasive tests (catheterization and angiography) are more revealing and reliable than non-invasive tests (Stress, Acoustic, ECG, Tests etc..) in diagnosing Cardiac mal-function, they bring greater associated risks to the process. A need exists for the development of an alternative method of diagnosis which incorporates all the advantages without the risks associated with these 2 methods. Of necessity preceded by a re-evaluation of the methods for detection of all types of silent diseases affecting the Cardiac system. For example considering development of various Tomography approaches e.g. Multi Spectral Optoacoustic Tomography (MSOT) without catheterization (97, 98)
  10. An attempt has also been made to come to terms with perhaps an insidious process that is still underway – somewhere in the back of my mind. This includes, the many communities in any life – family, friends, medical, professional and social networks. Those who were either at one with me, or leapt to my rescue, and also included adversaries or onlookers who seemed to be genuinely concerned. Possibly as the Specter of Mortality is always intriguing?
  11. Of course work that is unfinished due to unavoidable circumstances that were alluded to earlier, and the transience of life were the compelling, if sub conscious, forces over the past ~40 years that also occupied my thoughts immediately after the Myocardial Infarction episode. I am now moving as quickly as possible to put this and other unfinished work into the literature!
  12. Last but not the least I simply cannot but marvel at the magnificent social processes that were at play in all the Biomedical facilities and which represented the most redeeming characteristics of Humankind! It left me as the beneficiary with a new lease on Life! I was, as someone unknown, to the Biomedical communities in those hospitals, carried in from the street, and yet in effect made as one of their own! They showed remarkable concern, kindness, warmth, empathy, generosity, graciousness, and yet retained all the skill, dedication and the professionalism that was so important to the recovery of the patient – myself (99)! And so they will remain among those to whom I owe my life!

Addendum added by FSN

 Something that might have contributed to my escape from certain death by MI and by the minimal odds of 48:1 requires emphasis! In the paper by Northcote et al (83), which is actually often misquoted on Google as Squash Causing Heart Attacks), of 60 deaths on the Squash Court, postmortems showed that at least 48 players had advanced CAD/CHD. They were ~20 or 30 years younger than I, could not possibly have had a greater extent of CAD than I did (95%-99%/CAx 5CA) and were certainly in  better condition than I was at age 62. So why did I live – at 48:1 if not greater odds? The answer may be that I had stopped playing at anywhere near the intensity (maximal METs index) as hard as I did, ~7 years earlier. Although I almost certainly had IPC preconditioned cadiomyocytes they may not be able to survive this combination of maximal intensity and CAD which is the reason for the reported fatalities on the court (83)! And since I did not get anywhere near that level on the court after 2007, I survived!​

ACKNOWLEDGEMENTS:

I cannot express enough gratitude for the innumerable and different ways in which all of those listed below contributed to saving my life. As well as in making it possible for me to eventually emerge from Open Heart Surgery while remaining as comfortable as was possible given the circumstances! Should I have inadvertently left out a name please accept my sincerest apology. Ferez

See additional acknowledgemnents at the following link: Acknowledgements.5.9.2015.pdf

FSN would like to acknowledge the editorial assistance of Dr. Stephen J. Williams, Ph.D.

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No evidence to change current transfusion practices for adults undergoing complex cardiac surgery: RECESS evaluated 1,098 cardiac surgery patients received red blood cell units stored for short or long periods

Reporter: Aviva Lev-Ari, PhD, RN

No evidence to change current transfusion practices for adults undergoing complex cardiac surgery

A National Institutes of Health-funded study found no statistical difference in the primary clinical measure — which assessed changes in function of six organs from before to seven days after surgery — between complex cardiac surgery patients receiving transfusions of red blood cell units stored for short (up to 10 days) versus long (21 or more days) periods. These findings indicate there is no need to alter how hospitals currently transfuse blood in adults going through complex cardiac surgical procedures.

Results of the Red Cell Storage Duration Study (RECESS), supported by the NIH’s National Heart, Lung, and Blood Institute (NHLBI), appear today in the New England Journal of Medicine.

In the United States, red blood cell units can be stored up to 42 days after collection. Basic research has documented changes in red blood cell units the longer that they are stored. Some studies, primarily observational, have found an association between the transfusion of blood stored for a longer duration and increased morbidity and mortality. However, the clinical significance of these findings is difficult to determine due to study-design limitations.

RECESS was a multicenter trial conducted at more than two dozen U.S. hospitals from January 2010 to January 2014 by the NHLBI-funded Transfusion Medicine and Hemostasis Clinical Trial Network (TMH CTN). The TMH CTN includes 17 core clinical centers and a data coordinating center. Patients were enrolled at most TMH CTN core clinical centers and some non-network centers.

RECESS evaluated 1,098 cardiac surgery patients who were randomized to receive red blood cell units stored for short or long periods. Patients in the longer storage period group received their transfusions using current care practices.

There was no statistical difference in the change in the primary clinical measure, the Multiple Organ Dysfunction Score (MODS), or mortality from before cardiac surgery to seven or 28 days after the operation for both transfusion groups.  The MODS was evaluated because it is an objective and validated way to assess small changes in six organ systems, which includes respiratory, renal, hepatic, cardiovascular, hematologic and neurologic. There were no statistical differences in the mean number of serious and non-serious adverse events between the two groups.

“RECESS contributes to a long-standing question about whether red blood cell storage duration impacts a patient’s clinical outcome after transfusion.” said Keith Hoots, M.D., director of the NHLBI Division of Blood Diseases and Resources. “These findings are reassuring because they do not support the need to modify transfusion practices in adult patients undergoing complex cardiac surgery. In particular, there does not appear to be something gained by only transfusing red blood products stored for ten days or less.”

Because very few RECESS patients were under 18 years of age, findings primarily apply to adult patients undergoing complex cardiac surgery.

Centers that Participated in RECESS

TMH CTN Core Clinical Centers

  • BloodCenter of Wisconsin, Milwaukee
  • Children’s Hospital, Boston
  • Weill Cornell Medical College, Cornell University, New York City
  • Duke University, Durham, North Carolina
  • Emory University, Atlanta
  • Johns Hopkins Hospital, Baltimore
  • Massachusetts General Hospital, Boston
  • Puget Sound Blood Center, Seattle
  • University of Iowa, Iowa City
  • University of Maryland, Baltimore
  • University of Minnesota, Minneapolis
  • University of North Carolina, Chapel Hill
  • University of Oklahoma Health Sciences Center, Oklahoma City/UT Southwestern Medical Center, Dallas
  • University of Pittsburgh

TMH CTN Data Coordinating Center

  • New England Research Institutes, Watertown, Massachusetts

Non-Network Centers

  • Mayo Clinic, Rochester, Minnesota
  • Vanderbilt University, Nashville, Tennessee
  • Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
  • St. Luke’s Episcopal — Texas Heart Institute, Houston
  • Baystate Medical Center, Springfield, Massachusetts
  • Indiana/Ohio Heart, Fort Wayne, Indiana
  • Indiana/Ohio Heart, St. Joseph Hospital, Fort Wayne, Indiana
  • University of Florida, Gainesville
  • St. Elizabeth’s Medical Center, Brighton, Massachusetts,
  • Newark Beth Israel Medical Center, New Jersey
  • Aspirus Heart and Vascular Institute, Wausau, Wisconsin
  • Sanford Heart Center, Fargo, North Dakota
  • Columbia University Medical Center, New York City

The National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases, and sleep disorders. More information about NHLBI is available at http://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

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SOURCE

http://www.nih.gov/news/health/apr2015/nhlbi-08.htm

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