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Ischemic Stable CAD: Medical Therapy and PCI no difference in End Point: Meta-Analysis of Contemporary Randomized Clinical Trials

Reporter: Aviva Lev-Ari, PhD, RN

 

SOURCE

Stergiopoulos K, Boden WE, Hartigan P, et al. Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: A collaborative meta-analysis of contemporary randomized clinical trialsJAMA Intern Med 2013; DOI:10.1001/jamainternmed.2013.12855. Available at:http://www.jamainternalmedicine.com.

 

PCI No Benefit Over Medical Therapy in Ischemic Stable CAD

December 02, 2013

NEW YORK, NY — A new analysis is calling into question the de facto rationale for many of the revascularization procedures taking place today, at least in patients with stable coronary artery disease[1]. In a meta-analysis of more than 5000 patients, PCI was no better than medical therapy in patients with documented ischemia by stress testing or fractional flow reserve (FFR).

“Cardiology has a long history of finding a marker of a bad outcome and treating that marker of that bad outcome as if it were the cause of the bad outcome,” senior author on the study, Dr David Brown (State University of New York [SUNY]–Stony Brook School of Medicine), told heartwire . In the case of proceeding to PCI on the basis of documented ischemia, that stems from evidence that patients with ischemia have a worse prognosis than patients who don’t.”It has gotten to the point that a positive stress test [is the gateway] to doing an intervention, even if the ischemia is not in the same ischemic territory as the vessel being treated,” he said. “The medical/industrial complex in cardiology is now focused on finding and treating ischemia, and I think that’s not justified, and these data suggest that that’s not justified.”

Brown and colleagues, with first author Dr Kathleen Stergiopoulus (SUNY–Stony Brook School of Medicine), reviewed the literature for randomized clinical trials of PCI and medical therapy for stable CAD conducted over the past 40 years, ultimately including five trials of 5286 patients. These were a small German trial published in 2004, plus MASS II COURAGE , BARI 2D , and FAME 2 . In all, 4064 patients had myocardial ischemia documented by exercise, nuclear or echo stress imaging, or FFR.

Over a median follow-up of five years, mortality, nonfatal MI, unplanned revascularization, and angina were no different between patients treated medically vs those treated with PCI.

Odds Ratio, PCI vs Medical Therapy

Outcome Odds ratio 95% CI
Death 0.90 0.71–1.16
Nonfatal MI 1.24 0.99–1.56
Unplanned revascularization 0.64 0.35–1.17
Angina 0.91 0.57–1.44

“These findings are unique in that this is the first meta-analysis to our knowledge limited to patients with documented, objective findings of myocardial ischemia, almost all of whom underwent treatment with intracoronary stents and disease-modifying secondary-prevention therapy,” Stergiopoulus et al write.

The findings, they continue, “strongly suggest that the relationship between ischemia and mortality is not altered or ameliorated by catheter-based revascularization of obstructive, flow-limiting coronary stenosis.”

To heartwire , Brown pointed out that their analysis could not separate out patients who had small amounts of ischemia from those with larger ischemic territories. “Maybe that’s where the differentiating factor will be,” he acknowledged, adding that the 8000-patient ISCHEMIA trial, still ongoing, will hopefully yield some insights.

Current practice, however, is to check for ischemia and to proceed with catheterization and, usually, revascularization when ischemia is confirmed by stress testing or during FFR. “But if that doesn’t improve outcomes, why are we doing it?” Brown asked. “We think that needs to be rethought.”

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Information from Industry

Commenting on the study for heartwire Dr Peter Berger(Geisinger Health System, Danville, PA) pointed out: “There is no question that PCI is more effective than medical therapy for relief of symptoms: the more severe the angina and the more active the patient, the greater the superiority of PCI.” And, as Berger noted, most of the studies included in this analysis documented ischemia but did not report on the frequency or severity of angina at baseline.

That said, “Patients with minimal angina—and certainly those with silent ischemia but no angina—are unlikely to have a significantly greater reduction of symptoms with PCI, and PCI is rarely beneficial in such patients.”

Moreover, Berger continued, it has been clearly established that PCI does not reduce the risk of death or MI in most such patients.

“I very much agree with the authors, however, that just because more severe ischemia has been shown to be associated with a worse long-term prognosis, reducing the ischemic burden ought not be assumed to reduce the likelihood of death or MI. In most such patients, it does not.”

Stergiopoulos and Brown had no disclosures. Disclosures for the coauthors are listed in the paper.

SOURCE 
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Reporter: Aviva Lev-Ari, PhD, RN

We decided to include ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery in this Scientific Journal as a Reference resource to all our Experts, Authors, Writers.

Example of the Guidelines in use in this Journal:

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?

https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

SOURCE

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

http://circ.ahajournals.org/content/100/13/1464.long

  • ACC/AHA Practice Guidelines

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)

  1. Committee Members
  1. Kim A. Eagle, MD, FACC, Cochair;
  2. Robert A. Guyton, MD, FACC, Cochair;
  3. Ravin Davidoff, MB, BCh, FACC;
  4. Gordon A. Ewy, MD, FACC;
  5. James Fonger, MD;
  6. Timothy J. Gardner, MD, FACC;
  7. John Parker Gott, MD, FACC;
  8. Howard C. Herrmann, MD, FACC;
  9. Robert A. Marlow, MD, MA, FAAFP;
  10. William Nugent, MD;
  11. Gerald T. O’Connor, PhD, DSc;
  12. Thomas A. Orszulak, MD;
  13. Richard E. Rieselbach, MD, BS, FACP;
  14. William L. Winters, MD, FACC;
  15. Salim Yusuf, MB, BS, PhD
  1. Task Force Members
  1. Raymond J. Gibbons, MD, FACC, Chair;
  2. Joseph S. Alpert, MD, FACC;
  3. Kim A. Eagle, MD, FACC;
  4. Timothy J. Gardner, MD, FACC;
  5. Arthur Garson Jr, MD, MPH, FACC;
  6. Gabriel Gregoratos, MD, FACC;
  7. Richard O. Russell, MD, FACC;
  8. Thomas J. Ryan, MD, FACC;
  9. Sidney C. Smith Jr, MD, FACC

Key Words:

I. Introduction

The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines was formed to make recommendations regarding the appropriate use of diagnostic tests and therapies for patients with known or suspected cardiovascular disease. Coronary artery bypass graft (CABG) surgery is among the most common operations performed in the world and accounts for more resources expended in cardiovascular medicine than any other single procedure. Since the original Guidelines were published in 1991, there has been considerable evolution in the surgical approach to coronary disease, and at the same time there have been advances in preventive, medical, and percutaneous catheter approaches to therapy. These revised guidelines are based on a computerized search of the English literature since 1989, a manual search of final articles, and expert opinion.

As with other ACC/AHA guidelines, this document uses ACC/AHA classifications I, II, and III as summarized below:

Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness or efficacy of a procedure.

Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy.

Class IIb: Usefulness/efficacy is less well established by evidence/opinion.

Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful.

II. Outcomes

A. Hospital Outcomes

Seven core variables (priority of operation, age, prior heart surgery, sex, left ventricular [LV] ejection fraction [EF], percent stenosis of the left main coronary artery, and number of major coronary arteries with significant stenoses) are the most consistent predictors of mortality after coronary artery surgery. The greatest risk is correlated with the urgency of operation, advanced age, and 1 or more prior coronary bypass surgeries. Additional variables that are related to mortality include coronary angioplasty during index admission; recent myocardial infarction (MI); history of angina, ventricular arrhythmias, congestive heart failure, or mitral regurgitation; and comorbidities such as diabetes, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease, and renal dysfunction. Table 1 shows a method by which key patient variables can be used to predict an individual patient’s operative risk of death, stroke, or mediastinitis.

B. Morbidity Associated With Bypass Surgery

1. Neurological Events

Neurological impairment after bypass surgery may be attributable to hypoxia, emboli, hemorrhage, and/or metabolic abnormalities. Postoperative neurological deficits have been divided into 2 types: type 1, associated with major, focal neurological deficits, stupor, or coma; and type 2, in which deterioration in intellectual function is evident. Adverse cerebral outcomes are observed in ≈6% of patients after bypass surgery and are equally divided between type 1 and type 2 deficits. Predictors of cerebral complications after bypass surgery include advanced age and a history of hypertension. Particular predictors of type 1 deficits include proximal aortic atherosclerosis as defined by the surgeon at operation, history of prior neurological disease, use of the intra-aortic balloon pump, diabetes, hypertension, unstable angina, and increased age. Predictors of type 2 deficits include a history of excess alcohol consumption; dysrhythmias, including atrial fibrillation; hypertension; prior bypass surgery; peripheral vascular disease; and congestive heart failure. Estimation of a patient’s risk for postoperative stroke can be calculated from Table 1.

2. Mediastinitis

Deep sternal wound infection occurs in 1% to 4% of patients after bypass surgery and carries a mortality of ≈25%. Predictors of this complication include obesity, reoperation, use of both internal mammary arteries at surgery, duration and complexity of surgery, and diabetes. An individual patient’s risk of postoperative mediastinitis can be estimated from Table 1.

3. Renal Dysfunction

Postoperative renal dysfunction occurs in as many as 8% of patients. Among patients who develop postoperative renal dysfunction (defined as a postoperative serum creatinine level >2.0 mg/dL or an increase in baseline creatinine level of >0.7 mg/dL), 18% require dialysis. Overall mortality among patients who develop postoperative renal dysfunction is 19% and approaches two thirds among patients requiring dialysis. Predictors of renal dysfunction include advanced age, a history of moderate or severe congestive heart failure, prior bypass surgery, type 1 diabetes, and prior renal disease. Table 2 can be used to estimate the risk for an individual patient. Patients with advanced preoperative renal dysfunction who undergo CABG surgery have an extraordinarily high rate of requiring postoperative dialysis. Among patients with a preoperative creatinine level >2.5 mg/dL, 40% to 50% require hemodialysis.

Table 2.

Risk of Postoperative Renal Dysfunction (PRD) After Coronary Artery Bypass Graft Surgery

C. Long-Term Outcomes

Predictors of poor long-term survival after bypass surgery include advanced age, poor LVEF, diabetes, number of diseased vessels, and female sex. In some studies, additional predictors include angina class, hypertension, prior MI, renal dysfunction, and clinical congestive heart failure. Predictors of the recurrence of angina, late MI, or any cardiac event also include obesity and lack of use of an internal mammary artery, as well as those factors identified above. Of these events, the return of angina is the most common and is primarily related to late vein-graft atherosclerosis and occlusion.

III. Comparison of Medical Therapy Versus Surgical Revascularization

The comparison of medical therapy with coronary surgical revascularization is primarily based on randomized, clinical trials and large registries. Although clinical trials have provided valuable insights, there are limitations to their interpretation in the current era. Patient selection had primarily included individuals ≤65 years of age, very few included large cohorts of women, and for the most part, the studies evaluated patients at low risk who were clinically stable. In addition, because the studies were done in the late 1970s and early 1980s, only 1 of the trials used arterial grafts, and even that trial had no arterial grafts in 86% of patients. Newer modalities of cardioprotection during cardiopulmonary bypass were not used, nor were minimally invasive or off-bypass techniques. Finally, medical therapy was not optimized in the trials. Lipid-lowering therapy had not yet become standard, aspirin was not widely used, and β-blockers were used in just half of the patients. Angiotensin-converting enzyme inhibitors were not being routinely used in patients with congestive heart failure or dilated cardiomyopathy. Accordingly, although the clinical trials have provided important insights, their interpretation must be viewed with caution, given the evolution in all types of coronary therapies.

For the most part, stratification of patients in the trials was based on the number of vessels with anatomically significant disease, whether or not the major epicardial obstruction was proximal, and the extent of LV dysfunction as determined by global EF. The end point of the trials was primarily survival.

Overview: Randomized Trials

There were 3 major, randomized trials and several smaller ones. A collaborative meta-analysis of 7 trials with a total enrollment of 2649 patients has allowed comparison of outcomes at 5 and 10 years (Tables 3, 4, and 5 and the Figure). Among all patients, the extension survival of CABG surgical patients compared with medically treated patients was 4.3 months at 10 years of follow-up. The benefit of CABG compared with medical therapy in various clinical subsets is presented below.

Figure 1.

Extension of survival after 10 years of follow-up in various subgroups of patients, from a meta-analysis of 7 randomized studies. LV indicates left ventricular; VA, Veterans Administration.

Table 3.

Total Mortality at 5 and 10 Years

Table 4.

Subgroup Results at 5 Years

Table 5.

Subgroup Analysis of 5-Year Mortality by Risk Stratum

1. Left Main Coronary Artery Disease

The trials defined significant left main coronary artery stenosis as a >50% reduction in lumen diameter. Median survival for surgically treated patients was 13.3 years versus 6.6 years in medically treated patients. Left main equivalent disease (≥70% stenosis in both the proximal left anterior descending [LAD] and proximal left circumflex arteries) appeared to behave similarly to true left main coronary artery disease. Median survival for surgical patients was 13.1 years versus 6.2 years for medically assigned patients. The benefit of surgery for left main coronary artery disease patients continued well beyond 10 years. By 15 years, it was estimated that two thirds of patients originally assigned to medical therapy and who survived would have had surgery. The 15-year cumulative survival for left main coronary artery disease patients having CABG surgery was 44% versus 31% for medical patients.

2. Three-Vessel Disease

If one defines 3-vessel disease as stenosis of 50% or more in all 3 major coronary territories, the overall extension of survival was 7 months in CABG patients compared with medically treated patients. Patients with class III or IV angina, those with more proximal and severe LAD stenosis, those with worse LV function, and/or those with more positive stress tests derived more benefit from surgery.

3. Proximal LAD Disease

In patients with severe, proximal LAD stenosis, the relative risk reduction due to bypass surgery compared with medical therapy was 42% at 5 years and 22% at 10 years. This was even more striking in patients with depressed LV function.

4. LV Function

In patients with mildly to moderately depressed LV function, the poorer the LV function, the greater was the potential advantage of CABG surgery. Although the relative benefit was similar, the absolute benefit was greater because of the high-risk profile of these patients.

5. Symptoms and Quality of Life

Improvement in symptoms and quality of life after bypass surgery parallels the outcome data regarding survival. Beyond survival, bypass surgery may be indicated to alleviate symptoms of angina above and beyond medical therapy or to reduce the incidence of nonfatal complications like MI, congestive heart failure, and hospitalization. Registry studies have shown a reduction in late MI among highest-risk patients, such as those with 3-vessel disease, and/or those with severe angina. In pooled analyses, a benefit on the incidence of MI was not evident. This result likely reflected an early increase in MI perioperatively after CABG, which was balanced by fewer MIs over the long term among CABG recipients. Antianginal medications were required less frequently after bypass surgery. At 5 years, two thirds of bypass patients were symptom-free compared with 38% of medically assigned patients. By 10 years, however, these differences were no longer significant. This result is related to the attrition of vein grafts in the bypass group as well as crossover of medically assigned patients to bypass surgery.

6. Loss of Benefit of Surgery

After 10 to 12 years of follow-up, there was a tendency for the bypass surgery and medical therapy curves to converge, in regard to both survival as well as nonfatal outcomes. This convergence is due to a number of factors. First, the reduced life expectancy of patients with coronary disease (regardless of treatment) leads to a steady attrition. Second, the increased event rate in the late follow-up period of surgically assigned patients was likely related to the progression of native coronary disease and graft disease over time. Finally, medically assigned patients crossed over to surgery late, thus allowing the highest-risk medically assigned patients to gain from the benefit of surgery later in the course of follow-up. By 10 years, 37% to 50% of medically assigned patients had crossed over to surgery. Tables 3, 4, and 5 and the Figure provide estimates of long-term outcomes among patients randomized in the trials. These tables and the Figure can be used to estimate the general survival expectations in various anatomic categories.

IV. Comparison of Bypass Surgery With Percutaneous Revascularization

The results of a number of randomized, clinical trials comparing angioplasty and bypass surgery have been published. The trials excluded patients in whom survival had already been shown to be longer with bypass surgery than with medical therapy. Also, none of the trials was sufficiently large to detect relatively modest differences in survival between the 2 techniques. Most of the trials did not have a long-term follow-up, ie, 5 to 10 years, and therefore were unable to provide clear inferences regarding long-term benefit of the 2 techniques in similar populations. Also, and perhaps most notably, only ≈5% of screened patients with multivessel disease at enrolling institutions were included in the trials. Half of the patients approached were ineligible owing to left main coronary artery disease, insufficient symptoms, or other reasons. Even among a large group of patients with multivessel disease suitable for enrollment, only half were actually randomized. It appeared that physicians elected not to enroll many patients with 3-vessel disease in the trials but rather refer them for bypass surgery, whereas patients with 2-vessel disease tended to be referred for angioplasty rather than be enrolled in the trials.

Overall, procedural complications were low for both procedures but tended to be higher with CABG surgery (Table 6). For patients randomized to angioplasty, CABG was needed in ≈6% during the index hospitalization and in nearly 20% by 1 year. The initial cost and length of stay were lower for angioplasty than for CABG. Patients having angioplasty returned to work sooner and were able to exercise more at 1 month. The extent of revascularization achieved by bypass surgery was generally higher than with angioplasty. Long-term survival was difficult to evaluate owing to the short period of follow-up and the small sample size of the trials. However, for the Bypass Angioplasty Revascularization Investigation (BARI) trial, bypass patients had a 5-year survival of 89.3% compared with 86.3% for angioplasty. Secondary analysis revealed that in treated diabetic patients in the BARI trials, CABG led to significantly superior survival compared with percutaneous transluminal coronary angioplasty (PTCA). However, this finding was not evident in other trials. In long-term follow-up, the most striking difference was the 4- to 10-fold-higher likelihood of reintervention after initial PTCA. Quality of life, physical activity, employment, and cost were similar by 3 to 5 years after both procedures. The BARI trial suggested higher mortality associated with PTCA in several high-risk groups, including those with diabetes, unstable angina, and/or non–Q wave MI, and in patients with heart failure.

Table 6.

CABG vs PTCA: Randomized Controlled Trials

An analysis of registries generally shows data similar to those of the trials. However, a recent analysis of ≈60 000 patients who were treated in New York State in the early 1990s provides a 3-year survival analysis of patients undergoing CABG and PTCA. After adjustment for various covariates, bypass surgery in the New York State registry experience was associated with longer survival in patients with severe proximal LAD stenosis and/or 3-vessel disease. Contrariwise, patients with 1-vessel disease not involving the proximal LAD had improved survival with PTCA. Table 7 summarizes survival data from the New York State registry with respect to various cohorts of patients undergoing angioplasty or bypass surgery. These data can be used to estimate 3-year survival expectations for patients with various anatomic features.

Table 7.

Three-Year Survival by Treatment in Each Anatomic Subgroup

V. Management Strategies

Reduction of Perioperative Mortality and Morbidity

1. Reducing the Risk of Type 1 Brain Injury After CABG

Postoperative neurological complications represent 1 of the most devastating consequences of CABG surgery. Type 1 injury, in which a significant, permanent, neurological injury is sustained, occurs in ≈3% of patients overall and is responsible for a 21% mortality.

Atherosclerotic Ascending Aorta

An important predictor of this complication is the surgeon’s identification of a severely atherosclerotic, ascending aorta before or during the bypass operation. Perioperative atheroembolism from aortic plaque is thought to be responsible for approximately one third of strokes after CABG. Atherosclerosis of the ascending aorta is strongly related to increased age. Thus, stroke risk is particularly increased in patients beyond 75 to 80 years of age. Preoperative, noninvasive testing to identify high-risk patients has variable accuracy. Computed tomography identifies the most severely involved aortas but underestimates mild or moderate involvement. Transesophageal echocardiography is useful for aortic arch examination, but examination of the ascending aorta may be limited by the intervening trachea. Intraoperative assessment with epiaortic imaging is superior to both methods. Intraoperative palpation underestimates the high-risk aorta. The highest-risk aortic pattern is a protruding or mobile aortic arch plaque. An aggressive approach to the management of patients with severely diseased ascending aortas identified by intraoperative echocardiographic imaging reduces the risk of postoperative stroke. For patients with aortic walls ≤3 mm thick, standard treatment is used. For aortas >3 mm thick, the cannulation, clamp, or proximal anastomotic sites may be changed, or a no-clamp, fibrillatory arrest strategy may be used. For high-risk patients with multiple or circumferential involvement or those with extensive middle ascending aortic involvement, replacement of the ascending aorta under hypothermic circulatory arrest may be indicated. Alternatively, a combined approach with off-bypass, in situ internal mammary grafting to the LAD and percutaneous coronary intervention to treat other vessel stenoses has conceptual merit.

Atrial Fibrillation and Stroke

Chronic atrial fibrillation is a hazard for perioperative stroke. Intraoperative surgical manipulation or spontaneous resumption of sinus rhythm during the early postoperative period may lead to embolism of a left atrial clot. One approach to reduce this risk is the performance of preoperative, transesophageal echocardiography. The absence of a left atrial clot would suggest that the operation may proceed with acceptable risk. For elective patients, if a left atrial clot is identified, 3 to 4 weeks of anticoagulation therapy followed by restudy and then subsequent surgery is reasonable. Few clinical trial data are available to assist clinicians in this circumstance.

New-onset postoperative atrial fibrillation occurs in ≈30% of post-CABG patients, particularly on the second and third postoperative days, and is associated with a 2- to 3-fold increased risk of postoperative stroke. Risk factors include advanced age, chronic obstructive pulmonary disease, proximal right coronary disease, prolonged operation, atrial ischemia, and withdrawal of β-blockers. The role of anticoagulants in patients who develop post-CABG atrial fibrillation is unclear. Aggressive anticoagulation and cardioversion may reduce the neurological complications associated with this arrhythmia. Early cardioversion within 24 hours of the onset of atrial fibrillation can probably be performed safely without anticoagulation. However, persistence of the arrhythmia beyond this time argues for the use of oral anticoagulants to reduce stroke risk in patients who remain in atrial fibrillation and/or in those for whom later cardioversion is planned.

Recent MI, LV Thrombus, and Stroke

Patients with a recent, anterior MI and residual wall-motion abnormality are at increased risk for the development of an LV mural thrombus and its potential for embolization. For patients undergoing surgical revascularization after sustaining an anterior MI, preoperative screening with echocardiography may be appropriate to identify the presence of a clot. Detection of an acute LV mural thrombus may call for long-term anticoagulation and reevaluation by echocardiography to ensure resolution or organization of the thrombus before coronary bypass surgery. Additionally, 3 to 6 months of anticoagulation therapy is appropriate for patients with persistent, anterior wall–motion abnormalities after coronary bypass surgery.

Recent, Antecedent Cerebrovascular Event

A recent, preoperative cerebrovascular accident represents a situation in which delaying surgery may reduce the perioperative neurological risk. In particular, evidence of a hemorrhagic component based on computed tomographic scan identifies high risk for the extension of neurological damage with cardiopulmonary bypass. It is generally believed that a delay of 4 weeks or more after a cerebrovascular accident is prudent, if coronary anatomy and symptoms permit, before proceeding with CABG.

Carotid Disease and Neurological Risk Reduction

Hemodynamically significant carotid stenoses are thought to be responsible for up to 30% of early postoperative strokes. The trend for coronary surgery to be performed in an increasingly elderly population and the increasing prevalence of carotid disease in this same group of patients underscore the importance of this issue. Perioperative stroke risk is thought to be <2% when carotid stenoses are <50%, 10% when stenoses are 50% to 80%, and 11% to 19% in patients with stenoses >80%. Patients with untreated, bilateral, high-grade stenoses and/or occlusions have a 20% chance of stroke. Carotid endarterectomy for patients with high-grade stenosis is generally done preceding or coincident with coronary bypass surgery and, with proper teamwork in high-volume centers, is associated with a low risk for both short- and long-term neurological sequelae. Carotid endarterectomy performed in this fashion carries a low mortality (3.5%) and reduces early postoperative stroke risk to <4%, with a concomitant 5-year freedom from stroke of 88% to 96%.

The decision about who should undergo preoperative carotid screening is controversial. Predictors of important carotid stenosis include advanced age, female sex, known peripheral vascular disease, previous transient ischemic attack or stroke, a history of smoking, and left main coronary artery disease. Many centers screen all patients >65 years old. Patients with left main coronary disease are often screened, as are those with a previous transient ischemic attack or stroke. Preoperative central nervous system symptoms suggestive of vertebral basilar insufficiency should lead to an evaluation before elective CABG.

When surgery of both carotid and coronary disease is planned, the most common approach is to perform the operation in a staged manner, in which the patient first has carotid surgery followed by coronary bypass in 1 to 5 days. Alternatively, especially if the patient has compelling cardiac symptoms or coronary anatomy, the operations may be performed during a single period of anesthesia, with the carotid endarterectomy immediately preceding coronary bypass. Neither strategy has been established as being superior. Stroke risk is increased if a reversed-stage procedure is used, in which the coronary bypass operation precedes the carotid endarterectomy by ≥1 day.

2. Reducing the Risk of Type 2 Brain Injury

Type 2 neurological complications are seen in ≈3% of patients and are correlated with a 10% risk of postoperative death, with 40% of patients requiring additional care in a transitional facility after hospital discharge. Microembolization is thought to be a major contributor to the postoperative cerebral dysfunction after CABG. The release of microemboli during extracorporeal circulation, involving small gaseous or lipid emboli, may be responsible. The use of a 40-μm arterial-line filter on the heart-lung machine circuit and routine use of membrane oxygenators rather than bubble oxygenators may reduce such neurological injury. Additional maneuvers to reduce type 2 neurological injury include the maintenance of steady, cerebral blood flow during cardiopulmonary bypass, avoidance of cerebral hyperthermia during and after cardiopulmonary bypass, meticulous control of perioperative hyperglycemia, and avoidance and limitation of postoperative cerebral edema.

3. Reducing the Risk of Perioperative Myocardial Dysfunction

Protection in Patients With Normal LV Function

There is no universally applicable myocardial protection technique. Among patients with preserved preoperative cardiac function, no strong argument can currently be made for warm versus cold and crystalloid versus blood cardioplegia. However, certain techniques may offer a wider margin of safety for special patient subsets.

Myocardial Protection for Acutely Depressed Cardiac Function

Several studies have suggested that blood cardioplegia (compared with crystalloid) may offer a greater margin of safety during CABG performed on patients with acute coronary occlusion, failed angioplasty, urgent revascularization for unstable angina, and/or chronically impaired LV function.

Protection for Chronically Depressed LV Function

The use of a prophylactic intra-aortic balloon pump as an adjunct to myocardial protection may reduce mortality in patients having CABG in the setting of severe LV dysfunction (eg, LVEF <0.25). Placement of the intra-aortic balloon pump immediately before operation appears to be as effective as placement on the day preceding bypass surgery.

Adjuncts to Myocardial Protection

Although it is widely appreciated that use of the internal mammary artery leads to improved long-term survival after coronary bypass surgery, it has also been documented that use of the internal mammary artery influences operative mortality itself. Thus, internal mammary artery use should be encouraged in the elderly, emergent, or acutely ischemic patient and other patient groups.

Inferior Infarct With Right Ventricular Involvement

An acutely infarcted right ventricle is at great risk for severe, postoperative dysfunction and predisposes the patient to a higher postoperative mortality. During operation, loss of the pericardial constraint may lead to acute dilatation of the dysfunctional right ventricle, which then fails to recover even with optimal myocardial protection and revascularization. The best defense against right ventricular dysfunction is its recognition during preoperative evaluation. When possible, CABG should be delayed for ≥4 weeks to allow the right ventricle to recover.

4. Reducing the Systemic Consequences of Cardiopulmonary Bypass

A variety of measures have been tried to reduce the systemic consequences of cardiopulmonary bypass, which elicits a diffuse inflammatory response that may cause transient or prolonged multisystem organ dysfunction. Administration of corticosteroids before cardiopulmonary bypass may reduce complement activation and release of proinflammatory cytokines. Proper timing and duration of corticosteroid application are incompletely resolved. The administration of the serine protease inhibitor aprotinin may attenuate complement activation and cytokine release during extracorporeal circulation. Unfortunately, aprotinin is relatively expensive. Another method to reduce the inflammatory response is perioperative leukocyte depletion through hematologic filtration.

5. Reducing the Risk of Perioperative Infections

Several methods exist to reduce the risk of wound infections in patients undergoing CABG. These begin with interval reporting to individual surgeons regarding their respective wound infection rates and adherence to sterile operative techniques. Additional strategies include skin preparation with topical antiseptics, clipping rather than shaving the skin, avoidance of hair removal, reduction of operating room traffic, laminar-flow ventilation, shorter operation, minimization of electrocautery, avoidance of bone wax, use of double-glove barrier techniques for the operating room team, and routine use of a pleural pericardial flap. Aggressive, perioperative glucose control in diabetics through the use of continuous, intravenous insulin infusion reduces perioperative hyperglycemia and its associated infection risk. Avoidance of homologous blood transfusions after CABG may reduce the risk of both viral and bacterial infections. This is due to an immunosuppressive effect of transfusion. Leukodepletion of transfused blood also reduces this effect. This can be accomplished by regional blood blanks at the time of donation or at the bedside by use of a transfusion filter.

Preoperative antibiotic administration reduces the risk of postoperative infection 5-fold. Efficacy is dependent on adequate drug tissue levels before microbial exposure. Cephalosporins are currently the agents of choice. Table 8 identifies appropriate choices, doses, and routes of therapy. A 1-day course of intravenous antimicrobials is as effective as 48 hours or more. Therapy should be administered within 30 minutes of incision and again in the operating room if the operation exceeds 3 hours. Many centers deliver antibiotics just before incision. One fail-safe method is to have the anesthesiologist administer the cephalosporin after induction but before skin incision. If deep sternal wound infection does occur, aggressive surgical debridement and early vascularized muscle flap coverage are the most effective methods for treatment, along with long-term systemic antibiotics.

Table 8.

Prophylactic Antimicrobials for Coronary Artery Bypass Graft Surgery

6. Prevention of Postoperative Dysrhythmias

Postoperative atrial fibrillation increases the length of stay, cost, and most important, the risk of stroke. Atrial fibrillation occurs in up to 30% of patients, usually on the second or third postoperative day. Methods to avoid atrial fibrillation are several. First, withdrawal of preoperative β-blockers in the postoperative period doubles the risk of atrial fibrillation after CABG. Thus, early reinitiation of β-blockers is critical for avoidance of this complication. Virtually every study of patients receiving β-blockers prophylactically has shown benefit in lowering the frequency of atrial fibrillation. Most have used the drug in the postoperative period, but greater benefit may occur if β-blockade is begun before the operation. More recently, small studies of propafenone, sotalol, and amiodarone have also shown effectiveness in reducing the risk of postoperative atrial fibrillation. Table 9provides a review of pharmacological approaches in the randomized trials. Digoxin and calcium channel blockers have no consistent benefit for preventing atrial fibrillation after CABG, although they are frequently used to control its rate after it does occur. Currently, the routine preoperative or early postoperative administration of β-blockers is considered standard therapy to reduce the risk of atrial fibrillation after CABG.

Table 9.

Pharmacological Strategies for Prevention of Atrial Fibrillation (AF) After Coronary Artery Bypass Graft Surgery

7. Strategies to Reduce Perioperative Bleeding and Transfusion Risk

Transfusion Risk

Despite the increasing safety of homologous blood transfusion, concerns surrounding viral transmission during transfusion remain. Currently, the risks are likely very low and have been estimated to be 1/493 000 for human immunodeficiency virus, 1/641 000 for human T-cell lymphotrophic virus, 1/103 000 for hepatitis C virus, and 1/63 000 for hepatitis B virus.

Perioperative Bleeding

Risk factors for blood transfusion after CABG include advanced age, low preoperative red blood cell volume, preoperative aspirin therapy, urgent operation, duration of cardiopulmonary bypass, recent thrombolytic therapy, reoperation, and differences in heparin management. Institutional protocols that establish minimum thresholds for transfusion lead to a reduced number of units transfused and the percentage of patients requiring blood. Additional strategies can reduce the transfusion requirement after CABG. For stable patients, aspirin and other antiplatelet drugs may be discontinued 7 days before elective CABG. Aprotinin, a serum protease inhibitor with antifibrinolytic activity, also decreases postoperative blood loss and transfusion requirements in high-risk patients. Although there has been some concern that aprotinin may reduce early graft patency, recent studies have failed to document this effect. Routine use of aprotinin is limited by its high cost. Multidisciplinary approaches to conserve blood in single institutions appear to be effective.

For patients without exclusions, such as low hemoglobin values, heart failure, unstable angina, left main coronary artery disease, or advanced anginal symptoms, self-donation of 1 to 3 units of red blood cells over 30 days before operation reduces the need for homologous transfusion during or after operation. Donation immediately before cardiopulmonary bypass yields a higher platelet and hemoglobin count compared with simple hemodilution without pre–cardiopulmonary bypass blood harvesting.

8. Antiplatelet Therapy for Saphenous Vein Graft Patency

Aspirin significantly reduces vein graft closure during the first postoperative year. The aspirin should be started within 24 hours after surgery because its benefit on saphenous vein graft patency is lost when begun later. Dosing regimens from as little as 100 mg/d to as much as 325 mg TID appear to be efficacious. Ticlopidine offers no advantage over aspirin but is an alternative in truly aspirin-allergic patients. Life-threatening neutropenia is a rare but recognized side effect. Clopidogrel offers the potential for fewer side effects compared with ticlopidine as an alternative in aspirin-allergic patients. Its incidence of severe leukopenia is rare.

9. Pharmacological Management of Hyperlipidemia

Aggressive treatment of hypercholesterolemia reduces progression of atherosclerotic vein graft disease in patients after bypass surgery. Statin therapy has been shown to reduce saphenous vein graft disease progression over the ensuing years after bypass. Patients with unknown low-density lipoprotein (LDL) cholesterol levels after bypass should have cholesterol levels determined and treated pharmacologically if the LDL exceeds 100 mg/dL. Patients with treated LDL cholesterol should have their low-fat diet and cholesterol-lowering medications continued after bypass surgery to reduce subsequent graft attrition. Data regarding the benefit of cholesterol lowering after bypass surgery are most supported by studies that have used HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, particularly targeting LDL levels to <100 mg/dL.

10. Hormonal Manipulation

While observational studies have suggested that hormone replacement therapy in postmenopausal women leads to a reduction in all-cause mortality, a recent, randomized trial for secondary coronary prevention failed to show a beneficial effect on the overall rate of coronary events. Thus, hormone replacement therapy should be considered in postmenopausal women after bypass when, in the physician’s judgment, the potential coronary benefit is not offset by an increased risk of uterine or breast cancer.

11. Smoking Cessation

Smoking cessation is the single, most important risk-modification goal after CABG in patients who smoke. Smoking cessation leads to less recurrent angina, improved physical function, fewer admissions, maintenance of employment, and improved survival. Treatment individualized to the patient is crucial. Depression may be an important complicating factor and should be approached with behavioral and drug therapy. Nicotine replacement with a transdermal patch, nasal spray, gum, or inhaler is beneficial. A sustained-release form of bupropion, an antidepressant similar to selective serotonin reuptake inhibitors, reduces the nicotine craving and anxiety of smokers who quit. All smokers should receive educational counseling and be offered smoking cessation therapy after CABG (Table 10).

Table 10.

Proven Management Strategies to Reduce Perioperative and Late Morbidity and Mortality

Table 1.

12. Cardiac Rehabilitation

Cardiac rehabilitation, including early ambulation during hospitalization, outpatient prescriptive exercise, family education, and dietary and sexual counseling, has been shown to improve outcomes after CABG. The benefits include better physical mobility and perceived health. A higher proportion of rehabilitated patients are working at 3 years after CABG. The benefits of rehabilitation extend to the elderly and to women. Cardiac rehabilitation reinforces pharmacological therapy and smoking cessation and should be offered to all eligible patients after CABG.

13. Emotional Dysfunction and Psychosocial Considerations

Lack of social participation and low religious strength are independent predictors of death in elderly patients undergoing CABG. Although controversial, the high prevalence of depression after bypass surgery may reflect a high prevalence preoperatively. Cardiac rehabilitation has a highly beneficial effect in patients who are moderately or severely depressed. Evaluation of social supports and attempts to identify and treat underlying depression should be part of routine post-CABG care.

14. Rapid Sustained Recovery After Operation

Rapid recovery and early discharge are standard goals after CABG. The shortest in-hospital postoperative stays are followed by the fewest rehospitalizations. Important components of “fast-track” care are careful patient selection, patient and family education, early extubation, prophylactic antiarrhythmic therapy, dietary considerations, early ambulation, early outpatient telephone follow-up, and careful coordination with other physicians and healthcare providers.

15. Communication Between Caregivers

Maintenance of appropriate and timely communication between treating physicians regarding care of the patient is crucial. When possible, the primary care physician should follow up the patient during the perioperative course. The referral physician needs to provide clear, written reports of the findings and recommendations to the primary care physician, including discharge medications and dosages along with long-term goals.

VI. Impact of Evolving Technology

A. Less-Invasive Coronary Bypass Surgery

Technical modifications of CABG have been developed to decrease the morbidity of the operation, either by using limited incision or by eliminating cardiopulmonary bypass. Currently, “less-invasive” CABG surgery can be divided into 3 categories: (1) off-bypass CABG performed through a median sternotomy with a smaller skin incision, (2) minimally invasive direct CABG (MID-CAB) performed through a left anterior thoracotomy without cardiopulmonary bypass, and (3) port-access CABG with femoral-to-femoral cardiopulmonary bypass and cardioplegic arrest with limited incision.

Off-bypass coronary surgery is performed on a beating heart after reduction of cardiac motion with a variety of pharmacological and mechanical devices. These include slowing the heart with β-blockers and calcium channel blockers and use of a mechanical stabilizing device to isolate and stabilize the target vessel. Retraction techniques may elevate the heart to allow access to vessels on the lateral and inferior surfaces of the heart. Because this technique generally uses a median sternotomy, its primary benefit is the avoidance of cardiopulmonary bypass, not a less extensive incision.

MID-CAB refers to bypass surgery without median sternotomy and without the use of cardiopulmonary bypass. Generally, this is performed with a small left anterior thoracotomy, exposing the heart through the fourth intercostal interspace with access to the LAD and diagonal branches and occasionally, the anterior marginal vessels. The right coronary artery can be approached by using a right anterior thoracotomy. MID-CAB procedures are generally performed on only 1 or 2 coronary targets. Observational studies have suggested that MID-CAB is associated with a reduced average length of stay and an earlier return to work. Although initial reports of 2-year actuarial and event-free survival are encouraging, the data must be viewed with caution. Because the number of anastomoses performed on a beating heart is usually 1 or occasionally 2, the potential long-term effects of incomplete revascularization are unknown.

The closed-chest, port-access, video-assisted CABG operation uses cardiopulmonary bypass and cardioplegia of a globally arrested heart. Vascular access for cardiopulmonary bypass is achieved via the femoral artery and vein. A triple-lumen catheter with an inflatable balloon at its distal end is used to achieve endovascular aortic occlusion, cardioplegia delivery, and LV decompression. With cardiopulmonary bypass and cardioplegic arrest, CABG can be performed with video assistance on a still and decompressed heart through several small ports. In comparison with the MID-CAB, port access allows access to different areas of the heart, thus facilitating more complete revascularization, and the motionless heart may allow a more accurate anastomosis. Compared with conventional CABG, median sternotomy is avoided. However, potential morbidity of the port-access operation includes multiple wounds at port sites, the limited thoracotomy, and the groin dissection for femoral-femoral bypass. Vigorous scrutiny of the long-term benefits versus risks of port access is required.

B. Arterial and Alternate Conduits

Another area of evolving technology is the use of arterial and alternate conduits. The 5-year patency of coronary artery–vein bypass grafts is 74%, and at 10 years, just 41%. Contrariwise, patency rates of the internal mammary artery implanted into the LAD are as high as 83% at 10 years. As a consequence of improved patency, patients receiving an LAD graft with an internal mammary artery have improved survival compared with patients receiving only vein grafts. Currently, routine use of the left internal mammary artery for LAD grafting with supplemental saphenous vein grafts to other coronary lesions is generally accepted as a standard grafting method. The use of bilateral internal mammary arteries appears to be safe and efficacious. However, there is a higher rate of deep sternal wound infection when both internal mammary arteries are used. This is particularly true for patients with obesity and diabetes and perhaps for those requiring prolonged ventilatory support. The benefits of bilateral internal mammary artery use include lower rates of recurrent angina, MI, and need for reoperation and a trend for better survival. Recently, the radial artery has been used more frequently as a conduit for coronary bypass surgery. Five-year patency appears to be in the range of 85% (compared with nearly 90% for the internal mammary graft). In patients for whom mammary artery, radial artery, and standard vein conduits are unavailable, the in situ right gastroepiploic artery, the inferior epigastric free artery graft, and either lesser saphenous or upper-extremity vein conduits have been used. Long-term patency of these alternative grafts has not been extensively studied.

C. Percutaneous Technology

Technological improvements in percutaneous coronary angioplasty have included the introduction of new devices and improved medical therapy of patients in whom angioplasty is performed. The most notable improvement has been the introduction of intracoronary stents that have reduced late restenosis and the frequency with which emergency bypass surgery is required after PTCA. Intracoronary stents have been used to treat saphenous vein graft stenosis in patients with previous CABG. However, stented patients still have an ≈25% combined rate of death, MI, need for repeat CABG, or re-revascularization of the target vessel. For some patients, hybrid procedures may be the best choice, such as the combined use of CABG surgery and coronary angioplasty. Such an approach is relevant to the patient whose ascending aorta is involved with severe atherosclerosis, for which the implantation of free vein grafts or arterial grafts leads to risk for atheroembolism. In such a patient, the use of in situ internal mammary artery grafting without cardiopulmonary bypass combined with additional coronary angioplasty in other diseased vessels represents a strategy to provide complete revascularization without the concomitant risks of cardiopulmonary bypass and/or manipulation of the ascending aorta.

D. Transmyocardial Revascularization

A fourth area that is rapidly evolving is transmyocardial revascularization. The use of transmyocardial laser revascularization has generally been performed surgically for patients with severe angina refractory to medical therapy and who are not suitable candidates for standard surgical revascularization, PTCA, or heart transplant. While several studies have suggested improvement in angina severity with transmyocardial laser revascularization, the mechanism by which angina improves and the overall benefit on long-term angina and/or survival await further clarification.

VII. Special Patient Subsets

A. Elderly Patients

Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.

B. Women

A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.

C. Diabetic Patients

Coronary heart disease is the leading cause of death among adult diabetics and accounts for 3 times as many deaths among diabetics as among nondiabetics. While CABG carries an increased morbidity and mortality in diabetics, data suggest that in appropriate candidates, the absolute risk reduction provided by successful revascularization remains high. The BARI trial suggested that diabetics with multivessel coronary disease derived advantage from bypass surgery compared with angioplasty. Several of the other randomized trials, albeit with smaller numbers of patients, failed to show this trend. Diabetics who are candidates for renal transplantation have a particularly high incidence of coronary artery disease, even in the absence of symptoms or signs. In appropriate candidates, CABG appears to offer morbidity and mortality benefit in such patients.

D. Patients With Chronic Obstructive Pulmonary Disease

Because CABG is associated with variable degrees of postoperative respiratory insufficiency, it is important to identify patients at particular risk for pulmonary complications. The intent is to treat reversible problems that may contribute to respiratory insufficiency in high-risk patients, with the hope of avoiding prolonged periods of mechanical ventilation after CABG. High-risk patients often benefit from preoperative antibiotics, bronchodilator therapy, a period of cessation from smoking, perioperative incentive spirometry, deep-breathing exercises, and chest physiotherapy. If pulmonary venous congestion or pleural effusions are identified, diuresis often improves lung performance.

Although preoperative spirometry directed to identifying patients with a low (eg, <1 L) 1-second forced expiratory volume has been used by some to qualify or disqualify candidates for CABG, clinical evaluation of lung function is likely as important if not more so. Patients with advanced chronic obstructive pulmonary disease are at particular risk for postoperative arrhythmias that may be fatal. While moderate to severe degrees of obstructive pulmonary disease represent a significant risk factor for early mortality and morbidity after CABG, it is also true that with careful preoperative assessment and treatment of the underlying pulmonary abnormality, many such patients are successfully carried through the operative procedure.

E. Patients With End-Stage Renal Disease

Coronary artery disease is the most important cause of mortality in patients with end-stage renal disease. Many of such patients have diabetes and other coronary risk factors, including hypertension, myocardial dysfunction, abnormal lipids, anemia, and increased plasma homocysteine levels. Although patients on chronic dialysis are at higher risk when undergoing coronary angioplasty or bypass, they are at even higher risk with conservative medical management. Thus, in patients with modest reductions in LV function, significant left main or 3-vessel disease, and/or unstable angina, coronary revascularization can lead to relief of coronary symptoms, improvement in overall functional status, and improved long-term survival in this select high-risk patient population.

F. Reoperative Patients

Operative survival and long-term benefit of reoperative CABG are distinctly inferior to first-time operations. Patients undergoing repeated CABG have higher rates of postoperative bleeding, perioperative MI, and neurological and pulmonary complications. Nevertheless, reasonable 5- and 10-year survival rates after reoperation for coronary disease can be achieved, and the operation is appropriate if the severity of symptoms and anticipated benefit justify the immediate risk. Data suggest that the need for reoperation is less common in patients undergoing internal mammary artery grafting to the LAD. More recently, short-term follow-up studies suggest that patients undergoing multiple arterial grafts have even lower rates of reoperation. These early results are consistent with the known superior graft patency of arterial conduits compared with vein grafts.

G. Concomitant Peripheral Vascular Disease

The presence of clinical and subclinical peripheral vascular disease is a strong predictor of increased hospital and long-term mortality rates in patients undergoing CABG. However, the absolute benefit offered by coronary revascularization is elevated in patients with peripheral vascular disease, particularly those with 3-vessel coronary disease, more advanced angina, and/or a depressed LVEF. Excess perioperative mortality in such patients is related to an increased incidence of heart failure and dysrhythmias rather than peripheral arterial complications.

H. Poor LV Function

Patients with severe LV dysfunction have increased perioperative and long-term mortality compared with patients with normal LV function. However, studies suggest that the beneficial effects of myocardial revascularization in patients with ischemic heart disease and severe LV dysfunction are sizeable when compared with medically treated patients of similar status in terms of symptom relief, exercise tolerance, and survival.

I. CABG in Acute Coronary Syndromes

Coronary bypass surgery offers a survival advantage compared with medical therapy in patients with unstable angina and LV dysfunction, particularly in the presence of 3-vessel disease. However, the risk of bypass surgery in patients with unstable or postinfarction angina or early after non–Q wave infarction and during acute MI is increased severalfold compared with patients with stable angina. Although this risk is not necessarily higher than that with medical therapy, it has led to the argument to consider angioplasty or to delay CABG in such patients if medical stabilization can be easily accomplished.

VIII. Institutional and Operator Competence

Studies suggest that mortality after CABG is higher when carried out in institutions that annually perform fewer than a minimum number of cases. Similar conclusions have been drawn regarding individual surgeons’ volumes. This observation strengthens the argument for careful outcome tracking and supports the monitoring of institutions or individuals who annually perform <100 cases. It is also true that there is a wide variation in risk-adjusted mortality rates in low-volume situations. Thus, some institutions and practitioners maintain excellent outcomes despite relatively low volumes.

Outcome reporting in the form of risk-adjusted mortality rates after bypass has been effective in reducing mortality rates nationwide. Public release of hospital and physician-specific mortality rates has not been shown to drive this improvement and has failed to effectively guide consumers or alter physician referral patterns.

IX. Cost-Effectiveness of Bypass Surgery

A variety of studies of CABG have found the technique to be cost-effective in patients for whom survival and/or symptomatic benefit is demonstrable. Within these subsets, the cost-effectiveness of CABG compares favorably with that of other accepted medical therapies.

When compared with PTCA, the initial hospital cost of CABG is significantly higher. However, by 5 years, the cumulative cost of PTCA compared with initial surgical therapy is within 5% of CABG, or a difference of <$3000. Observational studies showing a poorer survival effect of PTCA in patients with more advanced disease suggest that there may be a significant cost gradient for PTCA as the extent of disease increases, which is not apparent for coronary bypass surgery.

X. Indications

A. Indications for CABG in Asymptomatic or Mild Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater in patients with abnormal LV function; eg, with an EF <0.50.)

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*1

Class IIb

1. One- or 2-vessel disease not involving the proximal LAD.†2

Class III

See text.

B. Indications for CABG in Stable Angina

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Three-vessel disease. (Survival benefit is greater when LVEF is <0.50.)

4. Two-vessel disease with significant proximal LAD stenosis and either EF <0.50 or demonstrable ischemia on noninvasive testing.

5. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a large area of viable myocardium and high-risk criteria on noninvasive testing.

6. Disabling angina despite maximal medical therapy, when surgery can be performed with acceptable risk. If angina is not typical, objective evidence of ischemia should be obtained.

Class IIa

1. Proximal LAD stenosis with 1-vessel disease.*1

2. One- or 2-vessel coronary artery disease without significant proximal LAD stenosis, but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing.

Class III

1. One- or 2-vessel disease not involving significant proximal LAD stenosis, in patients (1) who have mild symptoms that are unlikely due to myocardial ischemia or have not received an adequate trial of medical therapy and (A) have only a small area of viable myocardium or (B) have no demonstrable ischemia on noninvasive testing.

2. Borderline coronary stenoses (50% to 60% diameter in locations other than the left main coronary artery) and no demonstrable ischemia on noninvasive testing.

3. Insignificant (<50% diameter) coronary stenosis.

C. Indications for CABG in Unstable Angina/Non–Q Wave MI

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Ongoing ischemia not responsive to maximal nonsurgical therapy.

Class IIa

1. Proximal LAD stenosis with 1- or 2-vessel disease.*1

Class IIb

2. One- or 2-vessel disease not involving the proximal LAD.†2

Class III

See text.

D. Indications for CABG in ST-Segment Elevation (Q-Wave) MI

Class I

None.

Class IIa

1. Ongoing ischemia/infarction not responsive to maximal nonsurgical therapy.

Class IIb

1. Progressive LV pump failure with coronary stenosis compromising viable myocardium outside the initial infarct area.

2. Primary reperfusion in the early hours (≤6 to 12 hours) of an evolving ST-segment elevation MI.

Class III

1. Primary reperfusion late (≥12 hours) in evolving ST-segment elevation MI without ongoing ischemia.

E. Indications for CABG in Poor LV Function

Class I

1. Significant left main coronary artery stenosis.

2. Left main equivalent: significant (≥70%) stenosis of proximal LAD and proximal left circumflex artery.

3. Proximal LAD stenosis with 2- or 3-vessel disease.

Class IIa

1. Poor LV function with significant viable, noncontracting, revascularizable myocardium without any of the aforementioned anatomic patterns.

Class III

1. Poor LV function without evidence of intermittent ischemia and without evidence of significant revascularizable, viable myocardium.

F. Indications for CABG in Life-Threatening Ventricular Arrhythmias

Class I

1. Left main coronary artery stenosis.

2. Three-vessel coronary disease.

Class IIa

1. Bypassable 1- or 2-vessel disease causing life-threatening ventricular arrhythmias.‡3

2. Proximal LAD disease with 1- or 2-vessel disease.‡3

Class III

1. Ventricular tachycardia with scar and no evidence of ischemia.

G. Indications for CABG After Failed PTCA

Class I

1. Ongoing ischemia or threatened occlusion with significant myocardium at risk.

2. Hemodynamic compromise.

Class IIa

1. Foreign body in crucial anatomic position.

2. Hemodynamic compromise in patients with impairment of coagulation system and without previous sternotomy.

Class IIb

1. Hemodynamic compromise in patients with impairment of coagulation system and with previous sternotomy.

Class III

1. Absence of ischemia.

2. Inability to revascularize owing to target anatomy or no-reflow state.

H. Indications for CABG in Patients With Previous CABG

Class I

1. Disabling angina despite maximal noninvasive therapy. (If angina is not typical, then objective evidence of ischemia should be obtained.)

Class IIa

1. Bypassable distal vessel(s) with a large area of threatened myocardium on noninvasive studies.

Class IIb

1. Ischemia in the non-LAD distribution with a patent internal mammary graft to the LAD supplying functioning myocardium and without an aggressive attempt at medical management and/or percutaneous revascularization.

Class III

See text.

Footnotes

  • “ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)” was approved by the American College of Cardiology Board of Trustees in March 1999 and by the American Heart Association Science Advisory and Coordinating Committee in July 1999.

  • When citing this document, the American College of Cardiology and the American Heart Association request that the following citation format be used: Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J, Gardner TJ, Gott JP, Herrmann HC, Marlow RA, Nugent W, O’Connor GT, Orszulak TA, Rieselbach RE, Winters WL, Yusuf S. ACC/AHA guidelines for coronary artery bypass graft surgery: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 1999;100:1464-1480.

  • This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). A single reprint of the executive summary and recommendations is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0173. To obtain a reprint of the complete guidelines published in the October 1999 issue of the Journal of the American College of Cardiology, ask for reprint No. 71-0174. To purchase additional reprints (specify version and reprint number): up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or . To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.

  • 1 Becomes Class I if extensive ischemia documented by noninvasive study and/or an LVEF <0.50.

  • 2 If a large area of viable myocardium and high-risk criteria on noninvasive testing, becomes Class I.

  • 3 Becomes Class I if arrhythmia is resuscitated sudden cardiac death or sustained ventricular tachycardia.

  • CPB indicates cardiopulmonary bypass.

  • Data taken from (1) Townsend TR, Reitz BA, Bilker WB, Bartlett JG. Clinical trial of cefamandole, cefazolin, and cefuroxime for antibiotic prophylaxis in cardiac operations. J Thorac Cardiovasc Surg. 1993;106:664–670. (2) Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther. 1997;39:97–101. (3) Vuorisalo S, Pokela R, Syrjala H. Comparison of vancomycin and cefuroxime for infection prophylaxis in coronary artery bypass surgery. Infect Control Hosp Epidemiol. 1998;19:234–239. (4) Romanelli VA, Howie MB, Myerowitz PD, Zvara DA, Rezaei A, Jackman DL, Sinclair DS, McSweeny TD. Intraoperative and postoperative effects of vancomycin administration in cardiac surgery patients: a prospective, double-blind, randomized trial. Crit Care Med. 1993;21:1124–1131.

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  • The midlands trial of empirical amiodarone versus electrophysiology-guided interventions and implantable cardioverter-defibrillators (MAVERIC): a multi-centre prospective randomised clinical trial on the secondary prevention of sudden cardiac deathEuropace. 2004;6:257-266,
  • Patterns of Secondary Prevention in Older Patients Undergoing Coronary Artery Bypass Grafting During Hospitalization for Acute Myocardial InfarctionCirculation. 2003;108:II-24-II-28,
  • Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke AssociationCirculation. 2003;108:1278-1290,
  • Clinical Profiles and Outcomes of Acute Type B Aortic Dissection in the Current Era: Lessons From the International Registry of Aortic Dissection (IRAD)Circulation. 2003;108:II-312-II-317,
  • Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the Stroke Council and the Council on Clinical Cardiology of the American Heart Association/American Stroke AssociationStroke. 2003;34:2310-2322,
  • An evaluation of existing risk stratification models as a tool for comparison of surgical performances for coronary artery bypass grafting between institutionsEur J Cardiothorac Surg. 2003;23:935-942,
  • Validation of four different risk stratification systems in patients undergoing off-pump coronary artery bypass surgery: a UK multicentre analysis of 2223 patientsHeart. 2003;89:432-435,
  • The effect of obesity on mid-term survival following coronary artery bypass surgeryEur J Cardiothorac Surg. 2003;23:368-373,
  • Total arterial revascularisation as a primary strategy for coronary artery bypass graftingPostgrad. Med. J.. 2003;79:43-48,
  • Neurocognitive Sequelae Following Coronary Artery Bypass Graft: A Research Agenda for Behavioral ScientistsBehav Modif. 2003;27:68-82,
  • Risk of morbidity and in-hospital mortality in obese patients undergoing coronary artery bypass surgeryEur J Cardiothorac Surg. 2002;22:787-793,
  • The effect off-pump coronary artery bypass surgery on in-hospital mortality and morbidityEur J Cardiothorac Surg. 2002;22:255-260,
  • ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery–Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery)Circulation. 2002;105:1257-1267,
  • Predicting Death in Patients With Acute Type A Aortic DissectionCirculation. 2002;105:200-206,
  • A Simple Method to Determine Anastomotic Quality of Coronary Artery Bypass Grafting in the Operating RoomVascular. 2001;9:499-503,
  • Admission Plasma Glucose: An independent risk factor in nondiabetic women after coronary artery bypass graftingDiabetes Care. 2001;24:1634-1639,
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Stem Cell Therapy for Coronary Artery Disease (CAD)

Author and Curator: Larry H. Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

 

There is great interest and future promise for stem cell therapy in ischemic heart disease.  This is another report for the active work in cardiology with stem cell therapy by MA Gaballa and associates at University of Arizona.

Stem Cell Therapy for Coronary Heart Disease

Julia N. E. Sunkomat and Mohamed A. Gaballa

The University ofArizona Sarver Heart Center, Section of Cardiology, Tucson, Ar
Cardiovascular Drug Reviews 2003: 21(4): 327–342

Keywords: Angiogenesis — Cardiac therapy — Coronary heart disease — Heart failure — Myoblasts — Myocardial ischemia — Myocardial regenera­tion — Stem cells

ABSTRACT

Coronary artery disease (CAD) remains the leading cause of death in the Western world. The high impact of its main sequelae, acute myocardial infarction and congestive heart failure (CHF), on the quality of life of patients and the cost of health care drives the search for new therapies. The recent finding that

stem cells contribute to neovascularization and possibly improve cardiac function after myocardial infarction makes stem cell therapy the most highly active research area in cardiology. Although the concept of stem cell therapy may revolutionize heart failure treatment, several obstacles need to be ad­dressed. To name a few:

  1.  Which patient population should be considered for stem cell therapy?
  2.  What type of stem cell should be used?
  3.  What is the best route for cell de­livery?
  4.  What is the optimum number of cells that should be used to achieve functional effects?
  5.  Is stem cell therapy safer and more effective than conventional therapies?

The published studies vary significantly in design, making it difficult to draw conclusions on the efficacy of this treatment. For example, different models of

  1. ischemia,
  2. species of donors and recipients,
  3. techniques of cell delivery,
  4. cell types,
  5. cell numbers and
  6. timing of the experiments

have been used. However, these studies highlight the landmark concept that stem cell therapy may play a major role in treating cardiovascular diseases in the near future. It should be noted that stem cell therapy is not limited to the treatment of ischemic cardiac disease.

  • Non-ischemic cardiomyopathy,
  • peripheral vascular disease, and
  • aging may be treated by stem cells.

Stem cells could be used as vehicle for gene therapy and eliminate the use of viral vectors. Finally, stem cell therapy may be combined with phar­macological, surgical, and interventional therapy to improve outcome. Here we attempt a systematic overview of the science of stem cells and their effects when transplanted into ischemic myocardium.

INTRODUCTION

Background

Congestive heart failure (CHF) is the leading discharge diagnosis in patients over the age of 65 with estimates of $24 billion spent on health care in the US (1,11). The number one cause of CHF is coronary artery diseases (CAD). Coronary care units, reperfusion therapy (lytic and percutaneous coronary intervention) and medical therapy with anti-pla­telet agents, statins, ACE-inhibitors and â-adrenoceptor antagonists all significantly reduce morbidity and mortality of CAD and CHF (9), but it is very difficult to regenerate new viable myocardium and new blood vessels.

Identification of circulating endothelial progenitor cells in peripheral blood that incor­porated into foci of neovascularization in hindlimb ischemia (4) and the successful engraftment of embryonic stem cells into myocardium of adult dystrophic mice (31) intro­duced a new therapeutic strategy to the field of cardiovascular diseases: tissue regeneration. This approach is supported by the discovery of primitive cells of extracardiac origin in cardiac tissues after sex-mismatched transplants suggesting that an endogenous repair mechanism may exist in the heart (35,45,54). The number of recruited cells varied significantly from 0 (19) to 18% (54), but the natural course of ischemic cardiomyopathy implies that cell recruitment for tissue repair in most cases is insufficient to prevent heart failure. Therefore, investigational efforts are geared towards

  • augmenting the number of multipotent stem cells and endothelial and myocardial progenitor cells at the site of ischemia to induce clinically significant angiogenesis and potentially myogenesis.

Stem and Progenitor Cells

Stem cells are defined by their ability to give rise to identical stem cells and progenitor cells that continue to differentiate into a specific tissue cell phenotype (23,33). The po­tential of mammalian stem cells varies with stage of development and age (Table 1).

In mammals, the fertilized oocyte and blastomere cells of embryos of the two to eight cell stage can generate a complete organism when implanted into the uterus; they are called totipotent stem cells. After the blastocyst stage, embryonic stem cells retain the ability to differentiate into all cell types, but

  • cannot generate a complete organism and thus are denoted pluripotent stem cells.

Other examples of pluripotent stem cells are embryo­nic germ cells that are derived from the gonadal ridge of aborted embryos and embryonic carcinoma cells that are found in gonadal tumors (teratocarcinomas) (23,33). Both these cell types can also differentiate into cells of all three germ layers, but are not as well inves­tigated as embryonic stem cells.

It is well established that embryonic stem cells can differentiate into cardiomyocytes (7,10,13,14,31,37,76), endothelial cells (55), and smooth muscle cells (5,22,78) in vitro, but it is unclear whether

  • pure populations of embryonic stem cell-derived cardiomyocytes can integrate and function appropriately in the heart after transplantation.
  • one study reported arrhythmogenic potential of embryonic stem cell-derived cardiomyocytes in vitro (80).

Adult somatic stem cells are cells that have already committed to one of the three germ layers: endoderm, ectoderm, or mesoderm (76). While embryonic stem cells are defined by their origin (the inner cell mass of the blastocyst), the origin of adult stem cells in mature tissues is still unknown. The primary role of adult stem cells in a living organism is thought to be maintaining and repairing the tissue in which they reside. They are the source of more identical stem cells and cells with a progressively more distinct phenotype of specialized tissue cells (progenitor and precursor cells) (Fig. 1). Until recently adult stem cells were thought to be lineage-specific, meaning that they can only differentiate into the cell-type of their original tissue. This concept has now been challenged with the discovery of multipotent stem and progenitor cells (26, 50, 51).

The presence of multipotent stem and progenitor cells in adult mammals has vast im­plications on the availability of stem cells to research and clinical medicine. Recent publi­cations, however, have questioned whether the adaptation of a phenotype in those dogma-challenging studies is really a result of trans-differentiation or rather a result of cell and nuclear fusion (60,68,75,79). Spontaneous fusion between mammalian cells was first re­ported in 1961 (8), but how frequently fusion occurs and whether it occurs in vivo is not clear.

The bone marrow is a known source of stem cells. Hematopoietic stem cells are fre­quently used in the field of hematology. Surface receptors are used to differentiate hematopoietic stem and progenitor cells from mature cells. For example, virtually all

  • hematopoietic stem and progenitor cells express the CD34+ glycoprotein antigen on their cell membrane (73),

though a small proportion of primitive cells have been shown to be CD34 negative (58).

The function of the CD34+ receptor is not yet fully understood. It has been suggested that it may act as a regulator of hematopoietic cell adhesion in the bone marrow microenvironment. It also appears to be involved in the maintenance of the hematopoietic stem/progenitor cell phenotype and function (16,21). The frequency of immature CD34+ cells in peripheral circulation diminishes with age.

  • It is the highest (up to 11%) in utero (69) and decreases to 1% of nucleated cells in term cord blood (63).
  • This equals the per­centage of CD34+ cells in adult bone marrow.
  • The number of circulating stem cells in adult peripheral blood is even lower at 0.1% of nucleated cells.

Since hematopoietic stem cells have been identified as endothelial progenitor cells (29,30,32) their low density in adult bone marrow and blood could explain the inadequacy of endogenous recruitment of cells to injured organs such as an ischemic heart. The bone marrow is also home to another stem cell population the so-called mesenchymal stem cells. These may constitute a subset of the bone marrow stromal cells (2,43). Bone marrow stromal cells are a mixed cell popu­lation that generates

  1. bone,
  2. cartilage,
  3. fat,
  4. connective tissue, and
  5. reticular network that sup­ports cell formation (23).

Mesenchymal stem cells have been described as multipotent (51,52) and as a source of myocardial progenitor cells (41,59). They are, however, much less defined than the hematopoietic stem cells and a characteristic antigen constellation has not yet been identified (44).

Another example of an adult tissue containing stem cells is the skeletal muscle. The cells responsible for renewal and growth of the skeletal muscle are called satellite cells or myoblasts and are located between the sarcolemma and the basal lamina of the muscle fiber (5). Since skeletal muscle and cardiac muscle share similar characteristics such as they both are striated muscle cells, satellite cells are considered good candidates for the repair of damaged myocardium and have been extensively studied (20,25,38–40,48,56, 64–67). Myoblasts are particularly attractive, because they can be autotransplanted, so that issues of donor availability, ethics, tumorigenesis and immunological compatibility can be avoided. They also have been shown to have a high growth potential in vitro and a strong resistance to ischemia in vivo (20). On the down side

  • they may have more arrhythmogenic potential when transplanted into myocardium than bone marrow or peripheral blood de­rived stem cells and progenitor cells (40).

Isolation of Cells Prior to Transplantation

Hematopoietic stem and progenitor cells are commonly identified by the expression of a profile of surface receptors (cell antigens). For example, human hematopoietic stem cells are defined as CD34+/CD59+/Thy-1+/CD38low//c-kit/low/lin, while mouse hema-topoietic stem cells are defined as CD34low//Sca-1+/Thy-1+/low/CD38+/c-kit+/lin (23). Additional cell surface receptors have been identified as markers for subgroups of hema-topoietic stem cells with the ability to differentiate into non-hematopoetic tissues, such as endothelial cells (57,78). These can be specifically targeted by isolation methods that use the receptors for cell selection (positive selection with antibody coated magnetic beads or fluorescence-activated cell sorting, FACS). Other stem cell populations are identified by their behavior in cell culture (mesenchymal stem cells) or dye exclusion (SP cells). Finally, embryonic stem cells are isolated from the inner cell mass of the blastocyst and skeletal myoblasts are mechanically and enzymatically dissociated from an easily acces­sible skeletal muscle and expanded in cell culture.

FIG. 1. Maturation process of adult stem cells: with acquisition of a certain phenotype the cell gradually loses its self-renewal capability.  (unable to transfer)

METHODICAL APPROACHES 

j.1527-3466.2003.tb00125.x  fig stem cell

FIG. 2. Intramyocardial injection:

the cells are injected directly into the myocardium through the epicardium. Usually a thoracotomy or sternotomy is required. Transendocardial injection: access can be gained from the ar­terial vasculature. Cells are injected through the endocardium into the myocardium, ideally after identifying the ischemic myocardium by perfusion studies and/or electromechanical mapping. Intracoronary injection: the coronary artery is accessed from the arterial vasculature. Stem cells are injected into the lumen of the coronary artery. Proximal washout is prevented by inflation of a balloon. Cells are then distributed through the capillary system. They eventually cross the endothelium and migrate towards ischemic areas.

The intracoronary delivery of stem cells (Fig. 2) and distribution through the coronary system has also been explored (6,62,74). This approach was pioneered by Robinson et al. (56), who demonstrated successful engraftment within the coronary distribution after intracoronary delivery of genetically labeled skeletal myoblasts. The risk of intracoronary injection is comparable to that of a coronary angiogram and percutaneous transluminal coronary angioplasty (PTCA) (62), which are safe and clinically well established.

RESULTS IN ANIMAL STUDIES AND HUMAN TRIALS

Dif­ferentiation into cardiomyocytes was observed after transplantation of embryonic stem cells, mesenchymal stem cells, lin/c-kit+ and SP cells. The induction of angiogenesis was observed after transplantation of embryonic stem cells, mesenchymal stem cells, bone marrow-derived mononuclear cells, circulating endothelial progenitor cells, SP cells and lin/c-kit+ cells.

The use of embryonic stem cells in ischemia was examined in two studies (42,43). These studies demonstrated that mice embryonic stem cells transplanted into rat myo­cardium exhibited cardiomyocyte phenotype at 6 weeks after transplantation. In addition, generation of myocardium and angiogenesis were observed at 32 weeks after allogenic transplantation in rats. In these two studies no arrhythmias or cardiac tumors were reported.

Several studies have shown retardation of LV remodeling and improvement of cardiac function after administration of bone marrow-derived mononuclear cells. For example, decreases in infarct size, and increase in ejection fraction (EF), and left ventricular (LV) time rate change of pressure (dP/dtmax) were observed after direct injection of bone marrow-derived mononuclear cells 60 min after ischemia in swine (28). In humans, intra-coronary delivery and transendocardial injection of mononuclear cells leads to a decrease in LV dimensions and improvement of cardiac function and perfusion (49,62). A decrease in end systolic volume (ESV) and an increase in EF as well as regional wall motion were observed following intracoronary administration of CD34+/CD45+ human circulating en­dothelial cells (6). Injection of circulating human CD34+/CD117+ cells into infarcted rat myocardium induced neoangiogenesis and improved cardiac function (32). This study suggests that the improvement in LV remodeling after infarction appears to be in part me­diated by a decrease in apoptosis within the noninfarcted myocardium. Two other studies reported increased fractional shortening, improved regional wall motion and decreased left ventricular dimensions after transplantation of human CD34+ cells (29,30). Improved global left ventricular function and infarct perfusion was demonstrated after intramyo-cardial injection of autologous endothelial progenitor cells in humans (61).

DISCUSSION AND OUTLOOK

The idea of replacing damaged myocardium by healthy cardiac tissue is exciting and has received much attention in the medical field and the media. Therefore, it is important for the scientist to know what is established and what is based on premature conclusions. Currently, there are data from animal studies and human trials (Table 2). However, some of these data are not very concrete. For example,

  • many animal studies do not report the level of achieved neoangiogenesis and/or regeneration of myocardium.
  • In studies where the numbers of neovessels and new cardiomyocytes are specified, these numbers are often very low.

While these experiments confirm the concept that bone marrow and peripheral blood-derived stem and progenitor cells can differentiate into cardiomyocytes and endo­thelial cells when transplanted into ischemic myocardium, they also raise the question how effective this treatment is.

The results of the clinical trials that have been conducted are encouraging, but they need to be interpreted with caution. The common endpoints of these studies include left ventricular dimensions, perfusion, wall motion and hemodynamic function. While all studies report improvement after mononuclear cell, myoblast or endothelial progenitor cell transplantation, it is difficult to separate the effects of stem cell transplantation from the effects of the state-of-the art medical care that the patients typically received.

CONCLUSION

While the majority of studies demonstrate neoangiogenesis and some studies also show regeneration of myocardium after stem/progenitor cell transplantation, it remains unclear whether the currently achieved level of tissue regeneration is sufficient to affect clinical outcome. Long-term follow-up of patients that received stem/progenitor cells in clinical trials will provide important information on the potential risks of neoplasm and arrhythmias and, therefore, safety of this treatment. Ultimately, postmortem histological confirmation of scar tissue repair by transplanted cells and randomized placebo control trials with long-term follow-up are required to prove efficacy of this treatment.

REFERENCES (10)

1. American Heart Association Disease and Stroke Statistics-2003 Update, Dallas TX, American Heart Associ­ation; 2002 http://http://www.americanheart.org/downloadable/heart/10461207852142003HDSStatsBook.pdf

2. Arai A, Sheikh F, Agyeman K, et al. Lack of benefit from cytokine mobilized stem cell therapy for acute myocardial infarction in nonhuman primates. J Am Coll Cardiol 2003;41(Suppl 6A):371.

3. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999;85:221–228.

4. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–967.

5. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki M. Myogenic specification of side population cells in skeletal muscle. J Cell Biol 2002;159(1):123–134.

6. Assmus B, Schaechinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration en­hancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002;106:r53–r61.

7. Bader A, Al-Dubai H, Weitzer G. Leukemia inhibitory factor modulates cardiogenesis in embryoid bodies in opposite fashions. Circ Res 2000;86(7):787–794.

8. Barski G, Sorieul S, Cornefert F. “Hybrid” type cells in combined cultures of two different mammalian cell strains. J Natl Cancer Inst 1961;26:1269–1291.

9. Boersma E, Mercado N, Poldermans D, Gardien M, Vos J, Simoons M. Acute myocardial infarction. Lancet 2003;361:847–58.

  1. 10.          Boheler K, Czyz J, Tweedie D, Yang H, Anisimov S, Wobus A. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res 2002;91:189–201.

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Progenitor Cell Transplant for MI and Cardiogenesis  (Part 1

Author and Curator: Larry H. Bernstein, MD, FCAP
and
Curator: Aviva Lev-Ari, PhD, RN
This article is Part I of a review of three perspectives on stem cell transplantation onto a substantial size of infarcted myocardium to generate cardiogenesis in tissue that is composed of both repair fibroblasts and cardiomyocytes, after essentially nontransmural myocardial infarct.

Progenitor Cell Transplant for MI and Cardiogenesis (Part 1)

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/28/progenitor-cell-transplant-for-mi-and-cardiogenesis/

Source of Stem Cells to Ameliorate Damage Myocardium (Part 2)

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013-10-29/larryhbern/Source_of_Stem_Cells_to_Ameliorate_ Damaged_Myocardium/

An Acellular 3-Dimensional Collagen Scaffold Induces Neo-angiogenesis
 (Part 3)

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013-10-29/larryhbern/An_Acellular_3-Dimensional_Collagen_Scaffold _Induces_Neo-angiogenesis/

The same approach is considered for stroke in one of these studies.  These are issues that need to be considered
  1. Adult stem cells
  2. Umbilical cord tissue sourced cells
  3. Sheets of stem cells
  4. Available arterial supply at the margins
  5. Infarct diameter
  6. Depth of ischemic necrosis
  7. Distribution of stroke pressure
  8. Stroke volume
  9. Mean Arterial Pressure (MAP)
  10. Location of infarct
  11. Ratio of myocytes to fibrocytes
  12. Coexisting heart disease and, or
  13. Comorbidities predisposing to cardiovascular disease, hypertension
  14. Inflammatory reaction against the graft

Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function

L Zakharova1, D Mastroeni1, N Mutlu1, M Molina1, S Goldman2,3, E Diethrich4, and MA Gaballa1*
1Center for Cardiovascular Research, Banner Sun Health Research Institute, Sun City, AZ; 2Cardiology Section, Southern Arizona VA Health Care System, and 3Department of Internal Medicine, The University of Arizona, Tucson, AZ; and 4Arizona Heart Institute, Phoenix, AZ
Cardiovascular Research (2010) 87, 40–49   http://dx.doi.org/10.1093/cvr/cvq027

Abstract

Aims

Cell-based therapy for myocardial infarction (MI) holds great promise; however, the ideal cell type and delivery system have not been established. Obstacles in the field are the massive cell death after direct injection and the small percentage of surviving cells differentiating into cardiomyocytes. To overcome these challenges we designed a novel study to deliver cardiac progenitor cells as a cell sheet.

Methods and results

Cell sheets composed of rat or human cardiac progenitor cells (cardiospheres), and cardiac stromal cells were transplanted onto the infarcted myocardium after coronary artery ligation in rats. Three weeks later, transplanted cells survived, proliferated, and differentiated into cardiomyocytes (14.6 ± 4.7%). Cell sheet transplantation suppressed cardiac wall thinning and increased capillary density (194 ± 20 vs. 97 ± 24 per mm2, P < 0.05) compared with the untreated MI. Cell migration from the sheet was observed along the necrotic trails within the infarcted area. The migrated cells were located in the vicinity of stromal-derived factor (SDF-1) released from the injured myocardium, and about 20% of these cells expressed CXCR4, suggesting that the SDF-1/CXCR4 axis plays, at least, a role in cell migration. Transplantation of cell sheets resulted in a preservation of cardiac contractile function after MI, as was shown by a greater ejection fraction and lower left ventricular end diastolic pressure compared with untreated MI.

Conclusion

The scaffold-free cardiosphere-derived cell sheet approach seeks to efficiently deliver cells and increase cell survival.These transplanted cells effectively rescue myocardium function after infarction by promoting not only neovascular-ization but also inducing a significant level of cardiomyogenesis
Keywords  Myocardial infarction • Cardiac progenitor cells • Cardiospheres • Cardiac regeneration • Contractility

Introduction

Despite advances in cardiac treatment after myocardial infarction (MI), congestive heart failure remains the number one killer world-wide. MI results in an irreversible loss of functional cardiomyocytes followed by scar tissue formation. To date, heart transplant remains the gold standard for treatment of end-stage heart failure, a procedure which will always be limited by the availability of a donor heart. Hence, developing a new form of therapy is vital.
A number of adult non-cardiac progenitor cells have been tested for myocardial regeneration, including skeletal myoblasts,1 bone-marrow2, and endothelial progenitor cells.3,4 In addition, several cardiac resident stem cell populations have been characterized based on the expression of stem cell marker proteins.5–8 Among these, the c-Kit+ population has been reported to promote myocardial repair.5,9 Recently, an ex vivo method to expand cardiac-derived progenitor cells from human myocardial biopsies and murine hearts was developed.10 Using this approach, undifferentiated cells (or cardiospheres) grow as self-adherent clusters from postnatal atrium or ventricular biopsy specimens.11
To date, the most common technique for cell delivery is direct injection into the infarcted myocardium.12 This approach is inefficient because more than 90% of the delivered cells die by apoptosis and only a small number of the survived cells differentiated into cardiomyocytes.13 An alternative approach to cell delivery is a biodegradable scaffold-based engineered tissue.14,15 This approach has the clear advantage in creating tissue patches of different shapes and sizes and in creating a beating heart by decellularization technology.16 Advances are being made to overcome the issue of small patch thickness and to minimize possible toxicity of the degraded substances from the scaffold.15 Recently, scaffold-free cell sheets were created from fibroblasts, mesenchymal cells, or neonatal myocytes.17,18 Transplantation of these sheets resulted in a limited improvement in cardiac function due to induced neovascularization and angiogenesis through secretion of angiogenic factors.17–19 However, few of those progenitor cells have differentiated into cardiomyocytes.17 The need to improve cardiac contractile function suggests focusing on cells with higher potential to differentiate to cardiomyocytes with an improved delivery method.
In the present study, we report a cell-based therapeutic strategy that surpasses limitation inherent in previously used methodologies. We have created a scaffold-free sheet composed of cardiac progenitor cells (cardiospheres) incorporated into a layer of cardiac stromal cells. The progenitor cells survived when transplanted as a cell sheet onto the infarcted area, improved cardiac contractile functions, and supported recovery of damaged myocardium by promoting not only vascularization but also a significant level of cardiomyogenesis. We also showed that cells from a sheet can be recruited to the site of injury driven, at least partially, by the stromal-derived factor (SDF-1) gradient.

Methods

Detailed methods are provided in the Supplementary Methods

Animals

Three-month-old Sprague Dawley male rats were used. Rats were randomly placed into four groups:
(1) sham-operated rats, n = 12;
(2) MI, n = 12;
(3) MI treated with rat sheet, n = 10; and
(4) MI treated with human sheet, n = 10.

Myocardial infarction

MI was created by the ligation of the left coronary artery.20 Animals were intubated and ventilated using a small animal ventilator (Harvard Apparatus). A left thoracotomy was performed via the third intercostal rib, and the left coronary artery was ligated. The extent of infarct was verified by measuring the area at risk: heart was perfused with PBS containing 4 mg/mL Evans Blue as previously described by our laboratory.20 The area at risk was estimated by recording the size of the under-perfused (pale-colored) area of myocardium (see Supplementary material online, Figure S1). Only animals with an area at risk >30% were used in the present study. Post-mortem infarct size was measured using triphenyl tetrazolium chloride staining as previously described by our laboratory.20

Isolation of cardiosphere-forming cells

Cardiospheres were generated as described10 from atrial tissues obtained from:
(1) human atrial resection samples obtained from patients (aged from 53 to 73 years old) undergoing cardiac bypass surgery at Arizonam Heart Hospital (Phoenix, AZ) in compliance with Institutional Review Board protocol (n = 10),
(2) 3-month-old SD rats (n = 10). Briefly, tissues were cut into 1–2 mm3 pieces and tissue fragments were cultured ‘as explants’ in a complete explants medium for 4 weeks (Supplementary Methods).
Cell sheet preparation, labelling, handling, and transplantation
Cardiosphere-forming cells (CFCs) combined with cardiac stromal cells were seeded on double-coated plates (poly-L-lysine and collagen type IV from human placenta) in cardiosphere growing medium (Supplementary Methods). The sheets created from the same cell donors were divided into two groups,
one for transplantation and the other for characterization by immunostaining and RT–PCR (Supplementary Methods).
Prior to transplantation, rat cell sheets were labelled with 2 mM 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine, DiI, for tracking transplanted cells in rat host myocardium (Molecular Probes, Eugene, OR). Sheets created using human cells were transplanted unlabelled. Sheets were gently peeled off the collagen-coated plate and folded twice to form four layers. The entire sheet with 200 ml of media was
  • gently aspirated into the pipette tip,
  • transferred to the supporting polycarbonate filter (Costar) and
  • spread off by adding media drops on the sheet (Figure 2A).
Polycarbonate filter was used as a flexible mechanical support for cell sheet to facilitate handling during the transplantation. Immediately after LAD occlusion, the cell sheet was transplanted onto the infarcted area, allowed to adhere to the ventricle for 5–7 min, and the filter was removed before closing the chest (Figure 2A).

Cardiac function

Three weeks after MI, closed-chest in vivo cardiac function was measured using a Millar pressure conductance catheter system (Millar Instruments, Houston, TX) (Supplementary Methods).

Cell sheet survival, engraftment, and cell migration

Rat host myocardium and cell sheet composition after transplantation were characterized by immunostaining (Supplementary Methods). Rat-originated cells were traced by DiI, while human-originated cells were identified by immunostaining with anti-human nuclei or human lamin antibodies.
  1. To assess sheet-originated cardiomyocytes within the host myocardium, the number of cells positive for both human nuclei and myosin heavy chain (MHC) (human sheet); or both DiI and MHC (rat sheet) were counted.
  2. To assess sheet-originated capillaries within the rat host myocardium, the number of cells positive for both human nuclei and von Willebrand factor (vWf) (human sheet); or both DiI and vWf (rat sheet) were counted. Cells were counted in five microscopic fields within cell sheet and area of infarct (n = 5). The number of cells expressing specific markers was normalized to the total number of cells determined by 40,6-diamidino-2-phenylindole staining of the nuclei DNA.
  3. To assess the survival of transplanted cells, sections were stained with Ki-67 antibody followed by fluorescent detection and caspase 3 primary antibodies followed by DAB detection (Supplementary Methods).
  4. To evaluate human sheet engraftment, sections were stained with human lamin antibody followed by fluorescent detection (Supplementary Methods).
  5. Rat host inflammatory response to the transplanted human cell sheet 21 days after transplantation was evaluated by counting tissue mononuclear phagocytes and neutrophils (Supplementary Methods).

Imaging

Images were captured using Olympus IX70 confocal microscope (Olympus Corp, Tokyo, Japan) equipped with argon and krypton lasers or Olympus IX-51 epifluorescence microscope using excitation/emission maximum filters: 490/520 nm, 570 /595 nm, and 355 /465 nm. Images were processed using DP2-BSW software (Olympus Corp).

Statistics

All data are represented as mean ± SE Significance (P < 0.05) was deter-mined using ANOVA (StatView).

Results

Generation of cardiospheres

Cardiospheres were generated from atrial tissue explants. After 7–14 days in culture, a layer of stromal cells arose from the attached explants (Supplementary material online, Figure S2a). CFCs, small phase-bright single cells, emerged from explants and bedded down on the stromal cell layer (Supplementary material online, Figure S2b).
  • After 4 weeks, single CFCs, as well as cardiospheres (spherical colonies generated from CFCs) were observed (Supplementary material online, Figure S2c).
Cellular characteristics of cardiospheres in vitro
Immunocytochemical analysis of dissociated cardiospheres revealed that
  • 30% of cells were c-Kitþ indicating that the CFCs maintain multi-potency. About
  • 22 and 28% of cells expressed a, b-MHC and cardiac troponin I, respectively.
These cells represent an immature cardiomyocyte population because they were smaller (10–15 pm in length vs. 60–80 pm for mature cardiomyocytes) and no organized structure of MHC was detected. Furthermore
  • 17% of the cells expressed a-smooth muscle actin (SMA) and
  • 6% were positive for vimentin,
    • both are mesenchymal cell markers (Supplementary material online, Figure S3a and b).
  • Less then 5% of cells were positive for endothelial cell marker; vWf.
Cell characteristics of human cardiospheres are similar to those from rat tissues (Supplementary material online, Figure S3c).
Cardiospheres were further characterized based on the expression of c-Kit antigen. RT–PCR analysis was performed on both c-Kitþ and c-Kit2 subsets isolated from re-suspended cardiospheres. KDR, kinase domain protein receptor, was recently identified as a marker for cardiovascular lineage progenitors in differentiating embryonic stem cells.21 Here, we found that
  • the c-Kitþ cells were also Nkx2.5 and GATA4-positive, but were low or negative for KDR (Supplementary material online, Figure S3d). In contrast,
  • c-Kit2 cells strongly expressed KDR and GATA4, but were negative for Nkx2.5.
  • Both c-Kitþ and c-Kit2 subsets did not express Isl1, a marker for multipotent secondary heart field progenitors.22
Characteristics of cell sheet prior to transplantation
The cell sheet is a layer of cardiac stromal cells in which the cardiospheres were incorporated at a frequency of 21 ± 0.5 spheres per 100,000 viable cells (Figure 1A). The average diameter of cardiospheres within a sheet was 0.13 ± 0.02 mm and their average area was 0.2 ± 0.06 mm2 (Figure 1A). After sheets were peeled off the plate, it exhibited a heterogeneous thickness ranging from 0.05– 0.1 mm (n 1/4 10), H&E staining (Figure1B) and Masson’s Trichrome staining (Figure 1C) of the sheet sections revealed tissue-like organized structures composed of muscle tissue intertwined with streaks of collagen with no necrotic core. Based on the immunostaining results, sheet compiled of several cell types including
  • SMAþ cardiac stromal cells (50%),
  • MHCþ cardiomyocytes (20%), and
  • vWfþ endothelial cells (10%) (Figure 1D and E).
  • 15% of the sheet-forming cells were c-Kitþ suggesting the cells multipotency (Figure 1E).
  • Cells within the sheet expressed gap-junction protein C43, an indicator of electromechanical coupling between cells (Figure 1D).
  • 40% of cells were positive for the proliferation marker Ki-67 suggesting an active cell cycle state (Figure 1D, middle panel).
Human sheet expressed genes
  1. known to be upregulated in undifferentiated cardiovascular progenitors such as c-Kit and KDR;
  2. cardiac transcription factors Nkx2.5 and GATA4; genes related to adhesion, cell homing, and
  3. migration such as ICAM (intercellular adhesion molecule), CXCR4 (receptor for SDF-1), and
  4. matrix metalloprotease 2 (MMP2).
No expression of Isl1 was detected in human sheet (Figure 1F).
sheet transplant on MI_Image_2
Figure 1 Cell sheet characteristics. (A) Fully formed cell sheet. Arrow indicates integrated cardiosphere. (B) H&E staining; pink colour (arrowhead) indicates cytosol and blue (arrows) indicates nuclear stain. Note that there is no necrotic core within the cell sheet. (C) Masson’s Trichrome staining of sheet section. Arrowhead indicates collagen deposition within the sheet. (D and E) Sheet sections were labelled with antibodies against following markers: (D) vWf (green), Ki-67 (green), C43 (green); (E) c-Kit (green), MHC (red), SMA (red) as indicated on top of each panel. Nuclei were labelled with blue fluorescence of 40,6-diamidino-2-phenylindole (DAPI). (F) Gene expression analysis of the cell sheet. Scale bars, 200 pm (A) or 50 pm (B–E).

Cell sheet survival and proliferation

Two approaches were used to track transplanted cells in the host myocardium.
  • rat cell sheets were labelled with red fluorescent dye, DiI, prior to the transplantation.
  • the sheet created from human cells (human sheet) were identified in rat host myocardium by immunostaining with human nuclei antibodies.
DiI-labelling together with trichrome staining showed engraftment of the cardiosphere-derived cell sheet to the infarcted myocardium (Figure 2B–D). In vivo sheets grew into a stratum with heterogeneous thickness ranging from 0.1–0.5 mm over native tissue. The percentage of Ki-67þ cells within the sheet was 37.5 ± 6.5 (Figure 2F) whereas host tissue was mostly negative (except for the vasculature).
To assess the viability of transplanted cells, the heart sections were stained with the apoptosis marker, caspase 3. A low level of caspase 3 was detected within the sheet, suggesting that the majority of transplanted cells survived after transplantation (Figure 2G).
sheet transplant on MI_Image_3
Figure 2 Transplantation and growth of cell sheet after transplantation.
(A) Sheet transplantation onto infarcted heart. Detached cell sheet on six-well plate (left); cell sheet folded on filter (middle); and transplanted onto left ventricle (right). Scale bar 2 mm. DiI-labelled cell sheets grafted above MI area at day 3
(B) and day 21
(C) after transplantation.
(D) LV section of untreated MI rat at day 21 showing no significant red fluorescence background.
Bottom row (B–D) demonstrates the enlargement of box-selected area of corresponding top panels.
(E) Similar sections stained with Masson’s Trichrome. Section of rat (F) or human (G) sheet treated rat at day 21 after MI.
(F) Section was stained with antibody against Ki-67 (green). Cell sheet was pre-labelled with DiI (red). Nuclei stained with blue fluorescence of DAPI.
(G) Section was double stained with human nuclei (blue) and caspase 3 (brown, arrows) antibodies and counterstained with eosin.
Asterisks (**) indicate cell sheet area. Scale bars 200 mm (B–D, top row), 100 mm (B–D, bottom row, and E) or 50 mm (F, G).
Identification of inflammatory response
Twenty-one days after transplantation of human cell sheet, inflammatory response of rat host was examined. Transplantation of human sheet on infarcted rats reduced the number of mononuclear phagocytes (ED1-like positive cells) compared with untreated MI control (Supplementary material online, Figure S4a–e and l). In addition, the number of neutrophils was similar in both control untreated MI and sheet-treated sections (Supplementary material online, Figure S4f–k and m). These data suggest that at 21 days post transplantation, human cell sheet was not associated with significant infiltration of host immune cells.

Cell sheet engraftment and migration

Development of new vasculature was determined in cardiac tissue sections by co-localization of DiI labelling and vWf staining (Figure 3C). Three weeks after transplantation, the capillary density of ischaemic myocardium in the sheet-treated group significantly increased compared with MI animals (194 ± 20 vs. 97 ± 24 per mm2, P < 0.05, Figure 3A and B). The capillaries originated from the sheet ranged in diameter from 10 to 40 jim (n 1/4 30). A gradient in capillary density was observed with higher density in the sheet area which was decreased towards underlying infarcted myocardium. Mature blood vessels were identified within the sheet area and in the underlying myocardium in close proximity to the sheet evident by vWf and SMA double staining (Figure 3D).
sheet transplant on MI_Image_4
Figure 3 Neovascularization of infarcted wall. (A) Frozen tissue sections stained with vWf antibody (green). LV section of control (sham), infarcted (MI), and MI treated with cell sheet (sheet) rats. Scale bar, 100 jim. (B) Capillary density decreased in the MI compared with sham (*P < 0.05) and improved after cell sheet treatment (#P < 0.05). (C) Neovascularization within cell sheet area was recognized by co-localization of DiI- (red) and vWf (green) staining. Scale bar 100 jim. (D) Mature blood vessels (arrows) were identified by co-localization of SMA (red) and vWf (green) staining. Scale bar 50 jim.
Furthermore, 3 weeks after transplantation, a large number of labelled human nuclei positive or DiI-labelled cells were detected deep within the infarcted area indicating cell migration from the epicardial surface to the infarct (Figure 4A, B, and D). Minor or no migration was detected when the cell sheet was transplanted onto non-infarcted myocardium, sham control (Figure 4C). To evaluate engraftment of sheet-originated cells, sections were labelled with anti-human nuclear lamin antibody. Quantification of engraftment was performed using two approaches: fluorescence intensity and cell counting. Fluorescence intensity of the signal was analysed and compared for different areas of myocardium (Figure 4E–J). Since the transplanted sheets are created by human cells and are stained with human nuclear lamin-labelled with green fluorescence, the signal intensity of the sheet is set to 100% (100% of cells are lamin-positive). Myocardial area with no or limited number of labelled cells had the lowest level of fluorescence signal (13%, or 3.2 ± 1.4% of total number of cells), while
  1. the area where the cell migrated from the sheet to the infarcted myocardium had higher signal intensity (47%, or 11.9 ± 1.7% of total number of cells), indicating a higher number of sheet-originated cells are engrafted in the infarcted area.) (Figure 4K and L).
  2. Migrated cells were positive for KDR (Supplementary material online, Figure S5).
sheet transplant on MI_Image_5
Figure 4 Engraftment quantification of cells migrated from the sheet into the infarcted area of MI. Animals were treated with rat (A) or human (B–F) sheets. Cardiomyocytes were labelled with MHC antibody (A, green or B, red). Rat sheet-originated cells were identified with DiI-labelling, red (A). Arrows indicate the track of migrating cells. Human sheet-originated cells were identified by immunostaining with human nuclei antibody followed by secondary antibodies conjugated with either Alexa 488 (B, E and F, green) or AP (C, D, blue). No migration was detected when the cell sheet was transplanted onto non-infarcted myocardium (C). Heart sections were counterstained with eosin, pink (C–D). Higher magnification of area selected in the box is presented (D, right). Immunofluorescence of sheet (green) grafted to the myocardium surface (E) or cells migrated to the infarction area (F). Fluorescence profiles acrossthe cell sheet itself(G, box 1), area underlying cell sheet (I, box 2) and infarction areawith migrated cells (F, box 3). Mean fluorescence intensityofthe grafted human (K) cells was determined by outlining the region of interest (ROI) and subtracting the background fluorescence for the same region. Fluorescence intensity was normalized to the area of ROI (ii 1/4 6). (L) Percent engraftment was defined as number of lamin-positive cells divided by total number of cells per ROI. ‘M’, myocardium,’S’ sheet, ‘I’ infarction. Scale bars 100 mm (A–C, D, left, E and F), or 50 mm (D, right).
To elucidate a possible mechanism of cell migration, sections were stained to detect SDF1 and its unique receptor CXCR4. The migration patterns of cells from the sheet coincided with SDF-1 expression. Within 3 days after MI, SDF-1 was expressed in the injured myocardium (Figure 5A). At 3 weeks after MI and sheet transplantation, SDF-1 was co-localized with the migrated labelled cells (Figure 5B). PCR analysis revealed CXCR4 expression in cell sheet before transplantation (Figure 1F). However, after transplantation only a fraction of migrated cells expressed CXCR4 (Figure 5C).
sheet transplant on MI_Image_6
Figure 5 Migration of sheet-originated cells into the infarcted area. Confocal images of MI animals treated with sheets from rats (A and B) or human (C). SDF1 (green) was detected at border zone of the infarct at day 3 (A) and day 21 (B). Rat sheet-originated cells were identified with DiI-labelling (red). Note co-localization of DiI-positive sheet-originated cells with SDF1 at 21 days after MI (B). Human cells were identified by immunostaining with human nuclei antibody, red, (C). Note human cells that migrated to the area of infarct express CXCR4 (green) (C). Scale bar, 200 mm (A, B) or 50 mm (C). ‘M’, myocardium, ‘S’ sheet, ‘I’ infarct.

3.7 Cardiac regeneration

The differentiation of migrating cells into cardiomyocytes was evident by the co-localization of MHC staining with either human nuclei (Figure 6A) or DiI (Figure 6B and C). In contrast to the immature cardiomyocyte-like cells within the pre-transplanted cell sheet, the migrated and newly differentiated cells within the myocardium were about 30–50 mm in size and co-expressed C43 (see Supplementary material online, Figure S6). Cardiomyogenesis within the infarcted myocardium was observed in the sheets created from either rat or human cells.
sheet transplant on MI_Image_6
Figure 6 Cardiac regeneration. Sections of MI animals treated with human (A) or rat (B, C) sheets. Human sheet was identified by immunostaining with human nuclei antibody (green). Section was double-stained with MHC (red) antibody. Newly formed cardiomyocytes was identified by co-localization of human nuclei and MHC (yellow, arrow). (B) Rat sheet-originated cells were identified by DiI labelling (red). Section was double-stained with MHC (green) antibody. Newly formed cardiomyocytes were detected by co-localization of DiI with MHC (yellow, arrows). (C) Higher magnification of area selected in the boxes (B). Scale bars 200 mm (B), or 20 mm (A, C). ‘M’, myocardium, ‘S’ sheet, ‘I’ infarct.

Cell sheet improved cardiac contractile function and retarded LV remodelling after MI

Closed-chest in vivo cardiac function was derived from left ventricle (LV) pressure–volume loops (PV loops), which were measured using a solid-state Millar conductance catheter system. MI resulted in a characteristic decline in LV systolic parameters and an increase in diastolic parameters (Table 1). Cell sheet treatment improved both systolic and diastolic parameters (Table 1). Specifically, load-dependent parameters of systolic function: ejection fraction (EF), dP/dTmax, and cardiac index (CI) were decreased in MI rats and increased towards sham control with the cell sheet treatment (Table 1). Diastolic function parameters, dP/dTmin, relaxation constant (Tau), EDV, and EDP were increased in the MI rats and returned towards sham control parameters after sheet treatment (Table 1). However, load-independent systolic function, Emax, was decreased after MI. Treatment with human sheet improved Emax, while treatment with rat sheet had no effect (Table 1). Treatment with either rat or human sheets retarded LV remodelling; as such that it increased the ratio of anteriolateral wall thickness/LV inner diameter (t/Di) and wall thickness/LV outer diameter (t/Do) (see Supplementary material online, Table S3). However, human sheets appear to further improve LV remodelling compared with rat sheets as indicated by increased ratio of wall thickness to ventricular diameter and decreased both EDV and EDP (Table 1 and see Supplementary material online, Table S3).
Table 1 Hemodynamic parameters
Table 1. hemodynamic parameters

Discussion

The majority of the cardiac progenitor cells delivered using our scaffold-free cell sheet survived after transplantation onto the infarcted heart. A significant percentage of transplanted cells migrated from the cell sheet to the site of infarction and differentiated into car-diomyocytes and vasculature leading to improving cardiac contractile function and retarding LV remodelling. Thus, delivery of cardiac progenitor cells together with cardiac mesenchymal cells in a form of scaffold-free cell sheet is an effective approach for cardiac regeneration after MI.
Consistent with previous studies,5,11 here we showed that cardio-spheres are composed of multipotent precursors, which have the capacity to differentiate to cardiomyocytes and other cardiac cell types. When we fractioned cardiospheres based on c-Kit expression, we identified two subsets: Kitþ /KDR2/low/Nkx2.5þ and Kit2/KDRþ/ Nkx2.52(Supplementary material online, Figure S3d), which are likely reflecting cardiac and vascular progenitors.20
In the present study, delivery of cardiac progenitor cells as a cell sheet facilitates cell survival after transplantation. Necrotic cores, commonly observed in tissue engineered patches,23,24 are absent in cardiosphere sheets prior to transplantation (Figure 1B and C). Poor cell survival is caused by multiple processes such as: ischemia from the lack of vasculature and anoikis due to cell detachment from sub-strate.25 A possible mechanism of cell survival within the sheet is the induction of neo-vessels soon after transplantation due to the presence of endothelial cells within the sheet before transplantation (Figure 10). The cell sheet continued to grow in vivo (Figure 2B and C), suppressed cardiac wall thinning, and prevented LV remodelling at 21 days after transplantation (see Supplementary material online, Table S3). This maybe due to the induction of neovascularization (Figure 3), which may prevents ischemia-induced cell death (Figure 2G). Another likely mechanism of cell survival is that the cells within the scaffold-free sheet maintained cell-to-cell adhesion16 as shown by ICAM expression (Figure 1F). The cells also exhibit C43-positive junctions (Figure 10, see Supplementary material online, Figure S6), which may facilitate electromechanical coupling between the transplanted cells and the native myocardium.
We observed cell migration from the sheet to the infarcted myocardium (Figure 4A and B, E and F), which may be facilitated by the strong expression of MMP2 in the cell sheet (Figure 1F). Although, the mechanism of cardiac progenitor cell migration remains unclear, previous observations showed that SDF-1 is upregulated after MI and plays a role in bone-marrow and cardiac stem cell migration.26,27 Our data suggest that SDF-1-CXCR4 axis plays, at least in part, a role in cardiac progenitor cell migration from cell sheet to the infarcted myocardium. This conclusion is based on the following observations: (1) cell sheet expresses CXCR4 prior to transplantation (Figure 1F), (2) migrated cells are located in the vicinity of SDF-1 release (Figure 5A and B), and (3) about 20% of migrated cells expressed CXCR4. Note, not all the migrated cells expressed CXCR4 suggesting other mechanisms are involved in cell migration (Figure 5C).
Here we report that implanting cardiosphere-generated cell sheet onto infarcted myocardium not only improved vascularization but also promoted cardiogenesis within the infarcted area (Figure 6). A larger number of newly formed cardiomyocytes were found deep within the infarct compared with the cell sheet periphery. Notably the transplantation of the cell sheet resulted in a significant improvement of the cardiac contractile function after MI, as was shown by an increase of EF and decrease of LV end diastolic pressure (Table 1).
The beneficial effect of cell sheet is, in part, due to the presence of a large number of activated cardiac mesenchymal stromal cells (myofibroblasts) within the sheet. Myofibroblasts are known to provide a mechanical support for grafted cells, facilitating contraction28 and to induce neovascularization through the release of cytokines.17 In addition, mesenchymal cells are uniquely immunotolerant. In xenograft models unmatched mesenchymal cells transplanted to the heart of immunocompetent rats were shown to suppress host immune response29 presumably due to inhibition of T-cell activation.30 Consistently with previous study from our laboratory,31 here, we demonstrated host tolerance to the cell sheet 21 days after MI. Finally, phase II and III clinical trials are currently undergoing in which allogeneic MSCs are used to treat MI in patients (Osiris Therapeutic, Inc.).
In summary, our results show that cardiac progenitor cells can be delivered as a cell sheet, composed of a layer of cardiac stromal cells impregnated with cardiospheres. After transplantation, cells from the cell sheet migrated to the infarct, partially driven by SDF-1 gradient, and differentiated into cardiomyocytes and vasculature. Transplantation of cell sheet was associated with prevention of LV remodelling, reconstitution of cardiac mass, reversal of wall thinning, and significant improvement in cardiac contractile function after MI. Our data also suggest that strategies, which utilize undigested cells, intact cell–cell interactions, and combined cell types such as our scaffold-free cell sheet should be considered in designing effective cell therapy.

References

Fuchs JR, Nasseri BA, Vacanti JP, Fauza DO. Postnatal myocardial augmentation with skeletal myoblast-based fetal tissue engineering. Surgery 2006;140:100–107.
Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant 2003;7(Suppl. 3):86–88.
Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 2003;107:461–468.
Iwasaki H, Kawamoto A, Ishikawa M, Oyamada A, Nakamori S, Nishimura H et al. Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction. Circulation 2006;113:1311–1325.
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114: 763–776.
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 2003;100:12313–12318.
Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S et al. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005;433: 647–653.
Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A et al. CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 2005;97:52–61.
Dawn B, Stein AB, Urbanek K, Rota M, Whang B, Rastaldo R et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 2005;102:3766–3771.

 

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Cardiovascular Genetics: Functional Characterization and Clinical Applications  @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

Reporter: Aviva Lev- Ari, PhD, RN

Sessions and Events 

The 63rd Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013

http://www.ashg.org/cgi-bin/2013/ashg13SOE.pl 

PLATFORM ABSTRACTS

http://www.ashg.org/2013meeting/pdf/46025_Platform_bookmark%20for%20Web%20Final%20from%20AGS.pdf

We express a special interest in Session 58

Friday, October 25, 2013 Boston Convention Center 

2:00 PM–4:15 PM

Concurrent Platform (abstract-driven) Session E (54-62)

SESSION 58 – Cardiovascular Genetics: Functional Characterization and Clinical Applications

Room 205, Level 2, Convention Center

Moderators: Dan E. Arking, Johns Hopkins Univ. Sch. of Med.
Myriam Fornage, Univ. of Texas Hlth Sci. Ctr. at Houston

Human Syndromic Atrioventricular Septal Defect

367/2:00 A homozygous mutation in Smoothened, a member of the Sonic hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect. W. S. Kerstjens-Frederikse, Y. Sribudiani, M. E. Baardman, L. M. A. Van Unen, R. Brouwer, M. van den Hout, C. Kockx, W. Van IJcken, A. J. Van Essen, P. A. Van Der Zwaag, G. J. Du Marchie Sarvaas, R. M. F. Berger, F. W. Verheijen, R. M. W. Hofstra.

A homozygous mutation in Smoothened, a member of the Sonic Hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect.

W.S. Kerstjens-Frederikse1, Y. Sribudiani2, M.E. Baardman1, L.M.A. Van Unen2, R. Brouwer2, M. van den Hout2, C. Kockx2, W. Van IJcken2, A.J. Van Essen1, P.A. Van Der Zwaag1, G.J. Du Marchie

Sarvaas3, R.M.F. Berger3, F.W. Verheijen2, R.M.W. Hofstra2.

1) Dept Gen, Univ of Groningen, Univ Med Ctr Groningen, Netherlands;

2) Dept Gen, Erasmus Med Ctr, Rotterdam, Netherlands; 3) Dept Ped Cardiol, Univ of Groningen, Univ Med Ctr Groningen, Netherlands.

Introduction: Atrioventricular septal defect (AVSD) is a common congenital heart disease with a high impact on personal health. It is often accompanied by other congenital anomalies and in many of these syndromic AVSDs, defects in the sonic hedgehog (SHH)-GLI signalling pathway have been detected. SMO codes for the transmembrane protein smoothened (SMO), which is active in cells with a primary cilium and is located on the ciliary membrane. SMO is a key protein in the SHH-GLI signaling cascade.

Methods: Two probands, a twin boy and girl, presented with an AVSD, large fontanel, postaxial polydactyly and skin syndactyly of the second and third toes of both feet. The boy also had hypospadias. The parents were consanguineous and they had one healthy older child. Karyotyping was normal and Smith-Lemli-Opitz syndrome (SLOS) was excluded. Exome sequencing was performed and candidate variants were validated by Sanger sequencing.

Results: A novel homozygous missense mutation c.1725C>T (p.R575W) in SMO (7q32.3) was detected. Functional studies in fibroblasts of the patients showed normal expression of SMO protein but an abnormal localization of SMO, outside the cilia. Moreover we show severely reduced downstream GLI1 mRNA expression after stimulation with the SMO agonist purmorphamine. These results, together with the previously described association of SHH signalling defects with AVSD and SLOS, suggest that this SMO mutation is involved in syndromic AVSD in these patients.

Conclusion: We present the first reported smoothened mutation in humans, in two patients with an AVSD and a phenotype resembling Smith-Lemli-Opitz syndrome

Left Ventricular Noncompaction – Model in Zebrafish

368/2:15 Identification of PRDM16 as a disease gene for left ventricular non-compaction and the efficient generation of a personalized disease model in zebrafish. A.-K. Arndt, S. Schaefer, R. Siebert, S. A. Cook, H.-H. Kramer, S. Klaassen, C. A. MacRae.

 

Identification of PRDM16 as a disease gene for left ventricular noncompaction

and the efficient generation of a personalized disease

model in zebrafish. A.-K. Arndt1,2, S. Schaefer3, R. Siebert4, S.A. Cook5,

H.-H. Kramer2, S. Klaassen6, C.A. MacRae1. 

1) Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA;

2) Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig- Holstein, Kiel, Germany,;

3) Max-Delbruck-Center for Molecular Medicine, Berlin, Germany; 4) Institute of Human Genetics, University Hospital Schleswig Holstein, Kiel, Germany;

5) National Heart Centre, Singapore;

6) Department of Pediatric Cardiology, Charité, Berlin, Germany.

Using our own data and publically available array comparative genomic hybridization data, we identified the transcription factor PRDM16(PR domain containing 16) as a causal gene for the cardiomyopathy associated with monosomy 1p36, and confirmed its role in individuals with non-syndromic left ventricular noncompaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM). In a cohort of 75 non-syndromic patients with LVNC we detected 3 sporadic mutations, including 1 truncation mutant, 1 frameshift null mutation, and a single missense mutant. In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported non-synonymous variants in the coding region of PRDM16. None of the PRDM16 mutations identified were observed in over 6500 controls.

PRDM16 has not previously been associated with cardiovascular disease. Modeling of PRDM16 haploinsufficiency and a human truncation mutant in zebrafish resulted in impaired cardiomyocyte proliferation with associated physiologic defects in cardiac contractility and cell-cell coupling.

Using a phenotype-driven screening approach in the fish, we have identified 5 compounds that are able to rescue the physiologic defects associated with mutant or haploinsufficient PRDM16. Notably, all of the compounds had the capacity to restore cardiomyocyte proliferation and to prevent apoptosis in the model. Wildtype zebrafish also demonstrated a significant increase in cardiomyocyte numbers after treatment with the compounds suggesting a pro-proliferative effect of the compounds. In addition, the compounds also rescued the contractile and electrical defects observed in these disease models. These findings underline the importance of personalized disease models for specific pathways, to accelerate the exploration of disease biology and the development of innovative therapeutic approaches.

Genetics of Cerebral Small Vessel Disease

369/2:30 Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C. R. French, S. Seshadri, A. L. Destefano, M. Fornage, D. J. Emery, M. Hofker, J. Fu, A. J. Waskiewicz, O. J. Lehmann.

Mutation and copy number variation of FOXC1 causes cerebral small vessel disease. C.R. French1, S. Seshadri2, A.L Destefano3, M. Fornage4, D.J. Emery5, M. Hofker6, J. Fu6, A.J. Waskiewicz7, O.J. Lehmann1, 8.

1) Ophthalmology, University of Alberta, Edmonton, AB, Canada;

2) Department of Neurology, Boston University, Boston, MA, U. S. A;

3) School of Public Health, Boston University, Boston, MA, U. S. A;

4) Institute of Molecular Medicine and School of Public Health, University of Texas Health Sciences

Center, Houston, TX, U.S.A;

5) Department of Radiology, University of Alberta, Edmonton, AB, Canada;

6) Department of Medical Genetics, University Medical Center Groningen, Groningen, The Netherlands;

7) Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada;

8) Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

Cerebral small vessel disease (CSVD) represents a major risk factor for stroke and cognitive decline in the elderly. The ability to readily visualize its microangiopathic features by magnetic resonance imaging provides opportunities for using markers of CSVD to identify novel stroke associated pathways. Using targeted genome-wide association analysis we identified CSVD associated single nucleotide polymorphisms (SNPs) adjacent to the forkhead transcription factor FOXC1, and using eQTL analysis in two independent data sets, demonstrate that such SNP’s are associated with FOXC1 expression levels.

We further demonstrate, using magnetic resonance imaging, that patients with either FOXC1 mutation or copy number variation exhibit CSVD. These findings, present in patients as young as two years of age and observed with missense and nonsense mutations as well as FOXC1-encompassing segmental deletion and duplication, demonstrate FOXC1 dysfunction induces cerebral small vessel pathology. A causative role for FOXC1 in the development and maintenance of cerebral vasculature is supported by the cerebral hemorrhage generated by morpholino-induced suppression of FOXC1 orthologs in a zebrafish model system. Furthermore, in vivo imaging demonstrates profoundly impaired migration of neural crest cells and their subsequent association with nascent vasculature, a process required for the differentiation of perivascular mural cells. In addition, foxc1 inhibition reduces the expression of pdgfra, a gene critically required for vascular stability via its role in mural cell recruitment. Taken together, these data support a requirement for Foxc1 in stabilizing newly formed vasculature via recruitment of neural crest derived mural cells, and define a casual role for FOXC1 in cerebrovascular pathology.

Genetics & Brugada Syndrome

370/2:45 Genetic association of common variants with a rare cardiac disease, the Brugada syndrome, in a multi-centric study. C. Dina, J. Barc, Y. Mizusawa, C. A. Remme, J. B. Gourraud, F. Simonet, P. J. Schwartz, L. Crotti, P. Guicheney, A. Leenhardt, C. Antzelevitch, E. Schulze-Bahr, E. R. Behr, J. Tfelt-Hansen, S. Kaab, H. Watanabe, M. Horie, N. Makita, W. Shimizu, P. Froguel, B. Balkau, M. Gessler, D. Roden, V. M. Christoffels, H. Le Marec, A. A. Wilde, V. Probst, J. J. Schott, R. Redon, C. R. Bezzina.

Genetic association of common variants with a rare cardiac disease,

the Brugada Syndrome, in a multi-centric study. C. Dina1,2, J. Barc3, Y.

Mizusawa3, C.A. Remme3, J.B. Gourraud1,2, F. Simonet1, P.J. Schwartz4,

L. Crotti4, P. Guicheney5, A. Leenhardt6, C. Antzelevitch7, E. Schulze-Bahr8,

E.R. Behr9, J. Tfelt-Hansen10, S. Kaab11, H. Watanabe12, M. Horie13, N.

Makita14, W. Shimizu15, P. Froguel 16, B. Balkau17, M. Gessler18, D.

Roden19, V.M. Christoffels3, H. Le Marec1,2, A.A. Wilde3, V. Probst1,2, J.J.

Schott1,2, R. Redon1,2, C.R. Bezzina3.

1) Thorx Inst, INSERM UMR 1087, CNRS, Nantes, France;

2) CHU Nantes, l’institut du thorax, Nantes, France;

3) Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands;

4) University of Pavia, Pavia, Italy;

5) InsermUMR956, UPMC, Paris, France;

6) Cardiology Unit, Hôpital Bichat, Assistance Publique- Hôpitaux de Paris, Nantes, France;

7) Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY, United States;

8) Department of Cardiovascular Medicine, University Hospital, Münster, Germany;

9) Cardiovascular Sciences Research Centre, St George’s University, London, United Kingdom;

10) Laboratory of Molecular Cardiology, University of Copenhagen, Copenhagen, Denmark;

11) 1Department of Medicine I, Ludwig-Maximilians University, Munich, Germany;

12) Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

13) Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan;

14) Department of Molecular Physiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan;

15) Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan;

16) CNRS UMR 8199, Pasteur Institute, Lille, France;

17) Inserm UMR 1018, Centre for research in Epidemiology and Population Health, Villejuif, France;

18) Theodor-Boveri-Institute, University of Wuerzburg, Wuerzburg, Germany;

19) Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States.

The Brugada Syndrome (BrS) is considered as a rare Mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific electrocardiographic features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A, encoding the pore-forming subunit of the cardiac sodium channel (Nav1.5), are identified in ~20% of patients. However, studies in families harbouring mutations in SCN5A have demonstrated low disease penetrance and in some instances absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Two genomic regions displayed significant association. Both associations were replicated on two independent case/control sets from Europe (598/855) and Japan (208/1016) and a third locus emerged, all three with extremely significant p-values (1.10-14 down to 1.10-68). To our knowledge, this is the first time that several common variants are associated with a rare disease, with very high effect (Osdds-ratio) ranging from 1.58 to 2.55. While two loci displaying association hits had already been shown to influence ECG parameters in the general population, the third one encompasses a transcription factor which had never been related to cardiac arrhythmia. We showed that this factor regulates Nav1.5 channel expression in hearts of homozygous knockout embryos and influence cardiac conduction velocity in adult heterozygous mice. At last, we found that the cumulative effect of the 3 loci on disease susceptibility was unexpectedly large, indicating that common genetic variation may have a strong impact on predisposition to rare disease.

Mutations, Vasculopathy with Fever and Early Onset Strokes

371/3:00 Loss-of-function mutations in CECR1, encoding adenosine deaminase 2, cause systemic vasculopathy with fever and early onset strokes. Q. Zhou, A. Zavialov, M. Boehm, J. Chae, M. Hershfield, R. Sood, S. Burgess, A. Zavialov, D. Chin, C. Toro, R. Lee, M. Quezado, A. Ombrello, D. Stone, I. Aksentijevich, D. Kastner.

Loss-of-Function Mutations in CECR1, Encoding Adenosine Deaminase

2,Cause Systemic Vasculopathy with Fever and Early Onset

Strokes. Q. Zhou1, A. Zavialov2, M. Boehm3, J. Chae1, M. Hershfield4, R.

Sood5, S. Burgess6, A. Zavialov2, D. Chin1, C. Toro7, R. Lee8, M. Quezado9,

A. Ombrello1, D. Stone1, I. Aksentijevich1, D. Kastner1.

1) Inflammatory Disease Section, NHGRI, Bethesda, USA;

2) Turku Centre for Biotechnology, University of Turku, Turku, Finland;

3) Laboratory of Cardiovascular Regenerative Medicine, NHLBI, Bethesda, USA;

4) Department of Medicine, Duke University Medical Center, Durham, USA;

5) Zebrafish Core, NHGRI, Bethesda, USA;

6) Developmental Genomics Section, NHGRI, Bethesda, USA;

7) NIH Undiagnosed Diseases Program, NIH, Bethesda, USA;

8) Translational Surgical Pathology Section, NCI, Bethesda, USA;

9) General Surgical Pathology Section, NCI, Bethesda, USA.

We recently observed 5 unrelated patients with fevers, systemic inflammation, livedo reticularis, vasculopathy, and early-onset recurrent ischemic strokes. We performed exome sequencing on affected patients and their unaffected parents. The 5 patients shared 3 missense mutations in CECR1, encoding adenosine deaminase 2 (ADA2), with the genotypes A109D/ Y453C, Y453C/G47A, G47A/H112Q, R169Q/Y453C, and R169Q/28kb genomic deletion encompassing the 5’UTR and first exon of CECR1.

All mutations are either novel or present at low frequency (<0.001) in several large databases, consistent with the recessive inheritance. The Y453C mutation was present in 2/13004 alleles in an NHLBI database. Both alleles are found in 2 affected siblings who suffered from late-onset ischemic stroke, indicating that heterozygous mutations in ADA2 might be associated with susceptibility to adult stroke. Computer modeling based on the crystal structure of the human ADA2 suggests that CECR1 mutations either disrupt protein stability or impair ADA2 enzyme activity. All patients had at least a 10-fold reduction in serum and plasma concentrations of ADA2, and reduced ADA2-specific adenosine deaminase activity. Western blots showed a decrease in protein expression in supernatants of cultured patients’ cells. ADA2 is homologous to ADA1, which is mutated in some patients with SCID.

In contrast to ADA1, ADA2 is expressed predominantly in myeloid cells and is a secreted protein, and its affinity for adenosine is much less than ADA1. Animal models suggest that ADA2 is the prototype for a family of growth factors (ADGFs).Although there is no mouse homolog of CECR1, there are 2 zebrafish homologs, Cecr1a and Cecr1b. Using morpholino technology to knock down the expression of the ADA2 homologs, we observed intracranial hemorrhages in approximately 50% of the zebrafish embryos harboring the knockdown construct, relative to 3% in controls. Immunohistochemical studies of endothelial cells from patients’ skin biopsies demonstrate a diffuse systemic vasculopathy characterized by impaired endothelial integrity, endothelial cellular activation, and a perivascular infiltrate of CD8 T-cells and CD163-positive macrophages. ADA2 is not expressed in the endothelial cells. Our data suggest that ADA2 may be necessary for vascular integrity in the developing zebrafish as an endothelial cell-extrinsic growth factor, and that the near absence of functional ADA2 in patients may lead to strokes by a similar mechanism.

Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease

372/3:15 Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enriched GWAS study among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial. L. Warren, L. Li, D. Fraser, J. Aponte, A. Yeo, R. Davies, C. Macphee, L. Hegg, L. Tarka, C. Held, R. Stewart, L. Wallentin, H. White, M. Nelson, D. Waterworth.

Genetic influence on LpPLA2 activity at baseline as evaluated in the exome chip-enrichedGWASstudy among ~13600 patients with chronic coronary artery disease in the STABILITY (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) trial.

L. Warren1, L. Li1, D. Fraser1, J. Aponte1, A. Yeo2, R. Davies3, C. Macphee3, L. Hegg3,

L. Tarka3, C. Held4, R. Stewart5, L. Wallentin4, H. White5, M. Nelson1, D.

Waterworth3.

1) GlaxoSmithKline, Res Triangle Park, NC;

2) GlaxoSmithKline, Stevenage, UK;

3) GlaxoSmithKline, Upper Merion, Pennsylvania, USA;

4) Uppsala Clinical Research Center, Department of Medical Sciences, Uppsala University, Uppsala, Sweden;

5) 5Green Lane Cardiovascular Service, Auckland Cty Hospital, Auckland, New Zealand.

STABILITY is an ongoing phase III cardiovascular outcomes study that compares the effects of darapladib enteric coated (EC) tablets, 160 mg versus placebo, when added to the standard of care, on the incidence of major adverse cardiovascular events (MACE) in subjects with chronic coronary heart disease (CHD). Blood samples for determination of the LpPLA2 activity level in plasma and for extraction of DNA was obtained at randomization. To identify genetic variants that may predict response to darapladib, we genotyped ~900K common and low frequency coding variations using Illumina OmniExpress GWAS plus exome chip in advance of study completion. Among the 15828 Intent-to-Treat recruited subjects, 13674 (86%) provided informed consent for genetic analysis. Our pharmacogenetic (PGx) analysis group is comprised of subjects from 39 countries on five continents, including 10139 Whites of European heritage, 1682 Asians of East Asian or Japanese heritage, 414 Asians of Central/South Asian heritage, 268 Blacks, 1027 Hispanics and 144 others. Here we report association analysis of baseline levels of LpPLA2 to support future PGx analysis of drug response post trial completion. Among the 911375 variants genotyped, 213540 (23%) were rare (MAF < 0.5%).

Our analyses were focused on the drug target, LpPLA2 enzyme activity measured at baseline. GWAS analysis of LpPLA2 activity adjusting for age, gender and top 20 principle component scores identified 58 variants surpassing GWAS-significant threshold (5e-08).

Genome-wide stepwise regression analyses identified multiple independent associations from PLA2G7, CELSR2, APOB, KIF6, and APOE, reflecting the dependency of LpPLA2 on LDL-cholesterol levels. Most notably, several low frequency and rare coding variants in PLA2G7 were identified to be strongly associated with LpPLA2 activity. They are V279F (MAF=1.0%, P= 1.7e-108), a previously known association, and four novel associations due to I1317N (MAF=0.05%, P=4.9e-8), Q287X (MAF=0.05%, P=1.6e-7), T278M (MAF=0.02%, P=7.6e-5) and L389S (MAF=0.04%, P=4.3e-4).

All these variants had enzyme activity lowering effects and each appeared to be specific to certain ethnicity. Our comprehensive PGx analyses of baseline data has already provided great insight into common and rare coding genetic variants associated with drug target and related traits and this knowledge will be invaluable in facilitating future PGx investigation of darapladib response.

Genetics of influence IL-18 regulation in patients with Acute Coronary Syndrome

373/3:30 Genome-wide association study identifies common and rare genetic variants in caspase-1-related genes that influence IL-18 regulation in patients with acute coronary syndrome. A. Johansson, N. Eriksson, E. Hagström, C. Varenhorst, A. Åkerblom, M. Bertilsson, T. Axelsson, B. J. Barratt, R. C. Becker, A. Himmelmann, S. James, H. A. Katus, G. Steg, R. F. Storey, A. Syvänen, L. Wallentin, A. Siegbahn.

Genome-wide association study identifies common and rare genetic

variants in caspase-1-related genes that influence IL-18 regulation in

patients with Acute Coronary Syndrome. A. Johansson1, 2, N. Eriksson1,

E. Hagström1,3, C. Varenhorst1,3, A. Åkerblom1,3, M. Bertilsson1, T. Axelsson4,

B.J. Barratt5, R.C. Becker6, A. Himmelmann7, S. James1,3, H.A.

Katus8, G. Steg9, R.F. Storey10, A. Syvänen4, L. Wallentin1,3, A. Siegbahn1,11.

1) Uppsala Clinical Research Center, Uppsala University, Sweden;

2) Department of Immunoloy, Genetics and Pathology, Uppsala University, Sweden;

3) Department of Medical Sciences, Cardiology, Uppsala University, Sweden;

4) Department of Medical Sciences, Molecular Medicine, Science for Life Laboratory, Uppsala University, Sweden;

5) AstraZeneca R&D, Alderley Park, Cheshire, UK;

6) Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA;

7) AstraZeneca Research and Development, Mölndal, Sweden;

8) Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany;

9) INSERM-Unité 698, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France; Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France;

10) Department of Cardiovascular Science, University of Sheffield, Sheffield, UK;

11) Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.

 

Interleukin 18 (IL-18) levels are increased in patients with acute coronary syndromes (ACS) and correlated with myocardial injury. We performed a genome-wide association study (GWAS) to identify genetic determinants of IL-18 levels in patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, enrolling a broad selection of ACS patients, baseline plasma IL-18 levels were measured in 16633 patients. Of these, 9340 were successfully genotyped using Illumina HumanOmni2.5 or HumanOmniExpressExome BeadChip and SNPs imputed using 1000 Genomes Phase I integrated variant set. Seven independent associations, in five chromosomal regions, were identified. The first region, with two independent (r2 = 0.11) association signals (rs34649619, p = 1.17*10−50 and rs360718, p = 2.03*10−12), is located within IL18. Both top SNPs are located in predicted promoter regions, and the insertion polymorphism rs34649619 (T/TA) disrupts a transcription factor binding site for FOXI1, FOXD3 and FOXA2. The second region, also represented by two independent (r2 = 0.003) association signals (rs385076, p = 6.99*10−72 and rs149451729, p = 3.79*10−16), is located in NLRC4. While rs385076 overlaps with a regulatory region, rs149451729 is a rare coding variant resulting in an amino acid substitution, predicted to be deleterious. The third region is located upstream of CARD16, CARD17, and CARD18 and one of the top SNPs (rs17103763, p = 6.19*10−9) has previously been associated with expression levels of CARD16. The two remaining chromosomal regions are located within GSFMF/MROH6 (rs2290414, p = 5.66*10−17) and RAD17 (rs17229943, p = 5.00*10−12).

While the latter genes have not been associated with IL-18 production previously, others are known to be involved in IL-18 release. NLRC4 is an inflammasome that activates the inflammatory cascade in the presence of bacterial molecules. It recruits and activates procaspase-1, which in its turn is responsible for the maturation of pro-IL-18. CARD16-18, also known as COP1, INCA and ICEBERG, encode caspase inhibitors, known to bind to and prevent procaspase-1 activation. Our results suggest that SNPs in IL18 and caspase-1-associated genes are important for IL-18 production. By combining the identified SNPs in a Mendelian randomization study, the causal effect of IL-18 on clinical endpoints could be further evaluated in a longitudinal study.

Thoracic Aortic Aneurysmal Genes

374/3:45 Prevalence and predictors of pneumothorax in patients with connective tissue disorders enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry. J. P. Habashi, G. L. Oswald, K. W. Holmes, E. M. Reynolds, S. LeMaire, W. Ravekes, N. B. McDonnell, C. Maslen, R. V. Shohet, R. E. Pyeritz, R. Devereux, D. M. Milewicz, H. C. Dietz, GenTAC Registry Consortium.

Prevalence and Predictors of Pneumothorax in Patients with Connective Tissue Disorders Enrolled in the GenTAC (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry.

J.P. Habashi1, G.L. Oswald2, K.W. Holmes1,5, E.M.

Reynolds10, S. LeMaire3, W. Ravekes1, N.B. McDonnell4, C. Maslen5, R.V.

Shohet6, R.E. Pyeritz7, R. Devereux8, D.M. Milewicz9, H.C. Dietz2, GenTAC

Registry Consortium.

1) Dept Pediatric Cardiology, Johns Hopkins Univ, Baltimore, MD;

2) Dept. Medical Genetics, Johns Hopkins Univ, Baltimore, MD;

3) Baylor College of Medicine, Houston TX;

4) NIA at Harbor Hospital, Baltimore, MD;

5) Oregon Health & Science University, Portland, OR;

6) Queen’s Medical Center, Honolulu, HI;

7) The University of Pennsylvania, Philadelphia, PA; 8) Weill Cornell Medical College of Cornell University, New York NY;

9) University of Texas Medical School at Houston, Houston, TX;

10) University of Maryland, Baltimore, MD.

Spontaneous pneumothorax—described as escape of air into the pleural space surrounding the lung in the absence of traumatic injury—is a rare occurrence in the general population (0.1-0.5%), however is well recognized in Marfan syndrome (MFS)(4-5%). Associations between pneumothorax and other connective tissue disorders (CTDs) are less well recognized. We sought to examine potential associations of

  • pneumothorax with MFS,
  • vascular Ehlers-Danlos syndrome (vEDS) and other CTDs.

 

Phenotypic data were analyzed on all GenTAC patients with confirmed diagnoses of

  • MFS,
  • vEDS,
  • Loeys-Dietz syndrome (LDS),
  • bicuspid aortic valve with aortic enlargement (BAVe) or
  • familial thoracic aortic aneurysm and dissection (FTAAD)

to assess the prevalence of pneumothorax and associated features (1918 total pts).

Of 695 patients with Ghent criteria-confirmed MFS, 73 had experienced a spontaneous pneumothorax (prevalence 10.5%), higher than reported in the literature. The frequency of pneumothorax in vEDS patients (16/107, 15%) was similar to the frequency in the MFS group. The prevalences of pneumothorax in LDS (4/73, 5.5%), FTAAD (13/237, 5.5%), and BAVe (19/ 806, 2.4%) were significantly less than that for MFS and vEDS (p<0.001), yet greater than reported for the general population. In MFS patients with a pneumothorax, there was a three-fold increase in reported skeletal features of pectus carinatum, pectus excavatum, scoliosis and/or kyphosis compared to those without pneumothorax. Similarly, in vEDS, there was a four-fold increase in pectus carinatum, scoliosis and kyphosis in those patients with a pneumothorax compared to those without pneumothorax. In a subset of patients with self-reported data (n=846), smoking was not associated with increased prevalence of pneumothorax. Gender was not a predictor of pneumothorax in any of the diagnostic categories analyzed despite literature reports of increased prevalence in males. In patients enrolled in the GenTAC registry with a diagnosis of MFS, vEDS, BAVe, FTAAD or LDS, the prevalence of pneumothorax was significantly increased in all CTDs analyzed as compared to the general population. The prevalence of pneumothorax was significantly higher in patients with MFS or vEDS than in the other CTDs.

These data suggest that skeletal features may be a predictor for pneumothorax. Patients presenting with a spontaneous pneumothorax should be evaluated for several potential CTDs; such an evaluation could unmask an undiagnosed aortic aneurysm.

 

375/4:00 Surprising clinical lessons from targeted next-generation sequencing of thoracic aortic aneurysmal genes. B. Loeys, D. Proost, G. Vandeweyer, S. Salemink, M. Kempers, G. Oswald, H. Dietz, G. Mortier, L. Van Laer.

Surprising clinical lessons from targeted next generation sequencing of thoracic aortic aneurysmal genes. B. Loeys1,2, D. Proost1, G. Vandeweyer1, S. Salemink2, M. Kempers2, G. Oswald3, H. Dietz3, G. Mortier1, L. Van Laer1.

1) Center for Medical Genetics, University of Antwerp/ Antwerp University Hospital, Antwerp, Belgium;

2) Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;

3) Mc Kusick Nathans Institute for Genetic Medicine, Johns Hopkins University Hospital, Baltimore, USA.

Thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world, is genetically heterogeneous and at least 14 causative genes have been identified, accounting for both syndromic and non-syndromic forms. The diagnosis is not always straightforward because a considerable clinical overlap exists between patients with mutations in different genes, and mutations in the same gene cause a wide phenotypic variability. Molecular confirmation of the diagnosis is becoming increasingly important for gene-tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor-intensive. To shorten the turn-around-time, to increase mutation-uptake and to reduce the overall cost of molecular testing, we developed a TAA gene panel for next generation sequencing (NGS) of 14 TAA genes (ACTA2, COL3A1, EFEMP2, FBN1, FLNA, MYH11, MYLK, NOTCH1, SKI, SLC2A10, SMAD3, TGFB2, TGFBR1 and TGFBR2). We obtained enrichment with Haloplex technology and performed 2×150 bp paired-end runs on a Miseq sequencer in a series of 57 consecutive TAA patients, both syndromic and non-syndromic.

The sensitivity and false positive rate were previously shown to be 100% and 3%, respectively. Applying our NGS approach, we identified a causal mutation in 16 patients (28%). This uptake is really high as on average one molecular study per patient (range 0-6) was performed prior to inclusion in this study. One mutation was found in each of the 6 following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous); two mutations inNOTCH1and eight in FBN1. An additional 6 variants of unknown significance were identified: 2 in FLNA, 2 in NOTCH1, 1 in FBN1 and 1 heterozygous in EFEMP2. All variants were confirmed by Sanger sequencing.

Remarkably, from the eight FBN1 positive patients, three patients had previously been tested FBN1 negative by certified labs, indicating that the sensitivity of Sanger sequencing is not 100%. Interestingly, in two FBN1 mutation positive patients

  • the clinical diagnosis of Marfan syndrome was unsuspected. Similarly,
  • the clinical diagnosis of vascular Ehlers-Danlos syndrome (COL3A1) had not been made. Finally,
  • the ACTA2 mutation was identified postmortem from paraffin-embedded extracted DNA.

We conclude that our NGS approach for TAA genetic testing overcomes the intrinsic hurdles of Sanger sequencing and becomes a powerful tool in the elaboration of clinical phenotypes assigned to different genes.

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Comment by Cardiologists posted on LinkedIn’s

European Cardiovascular Medical Devices Group, a subgroup of Cardiovascular Medical Devices Group

on Stenting for Proximal LAD Lesions: In Reference to the Invasive Procedure performed on former President George W. Bush

UPDATED on 8/7/2018

Long-Term Outcomes of Stenting the Proximal LAD

Study Questions:

What are the outcomes of patients undergoing drug-eluting stent (DES) implantation according to lesion location within or outside the proximal left anterior descending (LAD) artery?

Methods:

Among the 8,709 patients enrolled in PROTECT (Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial), a multicenter percutaneous coronary intervention (PCI) trial, the investigators compared the outcomes of 2,534 patients (29.1%; 3,871 lesions [31.5%]) with stents implanted in the proximal LAD with 6,172 patients (70.9%; 8,419 lesions [68.5%]) with stents implanted outside the proximal LAD. For each event, a multivariate model was constructed that examined the effect of several individual baseline clinical and angiographic characteristics, including proximal LAD target lesion, on outcomes (i.e., MACE [major adverse cardiac events], target vessel failure [TVF], and myocardial infarction [MI]).

Results:

At 4-year follow-up, death rates were the same (5.8% vs. 5.8%; p > 0.999), but more MIs occurred in the proximal LAD group (6.2% vs. 4.9%; p = 0.015). The rates of clinically driven TVF (14.8% vs. 13.5%; p = 0.109), MACE (15.0% vs. 13.7%; hazard ratio, 1.1; 95% CI, 0.97-1.31; p = 0.139), and stent thrombosis (2.1% vs. 2.0%; p = 0.800) were similar. DES type had no interaction with MACE or TVF. In multivariate analysis, the proximal LAD was a predictor for MI (p = 0.038), but not for TVF (p = 0.149) or MACE (p = 0.069).

Conclusions:

The authors concluded that proximal LAD location was associated with higher rates of MI during the long-term follow-up, but there were no differences in stent thrombosis, death, TVF, or overall MACE.

Perspective:

This post hoc analysis of a prospective, multicenter study reports no difference in the rates of death, MACE, or TVF at 4 years according to intervention at a proximal LAD or nonproximal LAD lesion. The occurrence of the predefined primary endpoint of stent thrombosis was also not dependent on whether a proximal LAD or nonproximal LAD site was treated. However, of note, stenting of proximal LAD lesions was associated with significantly higher rates of MI compared with stenting of nonproximal LAD lesions. Overall, these findings appear to suggest that proximal LAD lesions may not have additional risk in the contemporary DES era, but the higher risk of MI needs to be studied further. Future studies should compare longer-term clinical outcomes between proximal LAD PCI with DES and minimally invasive left internal mammary artery to LAD.

SOURCE

https://www.acc.org/latest-in-cardiology/journal-scans/2017/03/22/15/11/long-term-outcomes-of-stenting-the-proximal-lad

 

Stenting for Proximal LAD Lesions

Curator: Aviva Lev-Ari, PhD, RN

Michael Reinhardt • First, the media really should not be calling this “stent surgery” its a stent procedure just ask any post-CABG patient… Anyway it really is not possible to determine whether or not is was “unnecessary” without all the relevant patient data; which coronary vessel(s) involved, percent stenosis, etc. Actually I find it interesting that they apparently decided to stent the former president on the basis of a CT Angiogram which is not the standard of care for coronary imaging. I have to assume they performed an additional testing like a CT perfusion analysis and saw a clinically relevant defect and this support the decision to stent. Regarding the post-stent drugs cloplidigrel is not a benign drug but benefits far outweigh the downside of a sub-acute thrombosis which might result in a more serious future event = acute MI.

Rafael Beyar • This was absolutely an indicated procedure and almost all rational physician will treat a young patient with proximal LAD lesions with either a stent or bypass surgery

Dov V Shimon MD • No doubt! Proximal (‘close to origin’) LAD lesions are the leading “Widow makers”. Reestablishing of flow in the artery is saving from cardiac damage and death. Drug eluting stent have 2nd and 3rd generations with very low and acceptable reclosure rates and almost no abrupt closure (thrombosis). True, CTA is a screening test, but it astablishes the need for diagnostic and therapeutic angiogram. We, heart surgeons can provide long-term patency to the LAD using LIMA arterial bypass. The current advantage of stent is the incovenience and pain of surgery. Any responsible physician would opt the procedure even for himself, his relatives , his patients and for definitely for GW Bush.

http://www.linkedin.com/groupItem?view=&gid=3358310&type=member&item=265974376&commentID=157366758&goback=%2Egmr_3358310&report%2Esuccess=8ULbKyXO6NDvmoK7o030UNOYGZKrvdhBhypZ_w8EpQrrQI-BBjkmxwkEOwBjLE28YyDIxcyEO7_TA_giuRN#commentID_157366758

Coronary anatomy and anomalies

On the left an overview of the coronary arteries in the anterior projection.

Coronary anatomy and anomalies

RCA, LAD and Cx in the anterior projection

On the left an overview of the coronary arteries in the lateral projection.

  • Left Main or left coronary artery (LCA)
    • Left anterior descending (LAD)
      • diagonal branches (D1, D2)
      • septal branches
    • Circumflex (Cx)
      • Marginal branches (M1,M2)
  • Right coronary artery
    • Acute marginal branch (AM)
    • AV node branch
    • Posterior descending artery (PDA)

Eur J Cardiothorac Surg. 2004 Apr;25(4):567-71.

Isolated high-grade lesion of the proximal LAD: a stent or off-pump LIMA?

Source

Thoraxcentre, Groningen University Hospital, Groningen, The Netherlands.

Abstract

OBJECTIVES:

The objective of this study was to compare the long-term outcome of patients with an isolated high-grade stenosis of the left anterior descending (LAD) coronary artery randomized to percutaneous transluminal coronary angioplasty with stenting (PCI, stenting) or to off-pump coronary artery bypass grafting (surgery).

METHODS:

Patients with an isolated high-grade stenosis (American College of Cardiology/American Heart Association classification type B2/C) of the proximal LAD were randomly assigned to stenting (n=51) or to surgery (n=51) and were followed for 3-5 years (mean 4 years). Primary composite endpoint was freedom from major adverse cardiac and cerebrovascular events (MACCEs), including cardiac death, myocardial infarction, stroke and repeat target vessel revascularization. Secondary endpoints were angina pectoris status and need for anti-anginal medication at follow-up. Analysis was by intention to treat.

RESULTS:

MACCEs occurred in 27.5% after stenting and 9.8% after surgery (P=0.02; absolute risk reduction 17.7%). Freedom from angina pectoris was 67% after stenting and 85% after surgery (P=0.036). Need for anti-anginal medication was significantly lower after surgery compared to stenting (P=0.002).

CONCLUSION:

Patients with an isolated high-grade lesion of the proximal LAD have a significantly better 4-year clinical outcome after off-pump coronary bypass grafting than after PCI.

Daily Dose

08/12/2013 | 5:48 PM

Was George Bush’s stent surgery really unnecessary?

By Deborah Kotz / Globe Staff

VIEW VIDEO

Ever since President George W. Bush had stent surgery last Tuesday to open a blocked artery, leading physicians who weren’t involved in his care have wondered publically why he had this “unnecessary” procedure. Large clinical trials have demonstrated that stent placement doesn’t extend lives or prevent a future heart attack or stroke in those with stable heart disease.

What’s more, Bush could wind up with complications like a reblockage where the stent was placed or excessive bruising or internal bleeding from the blood thinners that he must take likely for the next year.

Dr Richard Besser, the chief medical correspondent for ABC News, questioned why Bush had an exercise stress test as part of his routine physical exam given that he had no symptoms like chest pain or shortness of breath. The stress test indicated signs of an artery blockage.

“In people who are not having symptoms, the American Heart Association says you should not do a stress test,” Besser said, “since the value of opening that artery is to relieve the symptoms.”

Cleveland Clinic cardiologist Dr. Steve Nissen agreed in his interview with USA Today. Bush, he said, likely “got the classical thing that happens to VIP patients, when they get so-called executive physicals and they get a lot of tests that aren’t indicated. This is American medicine at its worst.”

Two physicians wrote in an Washington Post op-ed column titled “President Bush’s unnecessary surgery” that they worry that the media coverage of Bush’s stent will lead “patients to pressure their own doctors for unwarranted and excessive care.”

But none of these doctors actually treated Bush or examined his medical records, so I’m a little surprised they’re making such firm calls.

Bush, an avid biker who recently completed a 100-kilometer ride, probably shouldn’t have had the exercise stress test if he wasn’t having any heart symptoms. “Routine stress testing used to be done 20 years ago, but isn’t recommended any longer since it doesn’t have any benefit,” said Brigham and Women’s cardiologist Dr. Christopher Cannon.

But Bush’s spokesman insisted the stent was necessary after followup heart imaging via a CT angiogram “confirmed a blockage that required opening.”

Cannon said Bush’s doctors may have seen signs that blood flow wasn’t getting to a significant part of the heart muscle, a condition known as ischemia. Researchers have found that those with moderate to severe ischemia appear to experience a reduction in fatal heart attacks when they have a stent placement along with medical therapy, rather than just taking medications alone. (Larger studies, though, are needed to confirm this finding.)

“If a blockage occurs at the very start of the artery and it’s extensive—95 percent blocked—then chances are it will cause significant ischemia,” Cannon said. While severe ischemia usually causes light-headedness or dizziness during exercise, Bush may have had more moderate ischemia that didn’t cause such symptoms.

It’s impossible to know for certain, he added, without seeing his medical records firsthand.

http://www.boston.com/lifestyle/health/blogs/daily-dose/2013/08/12/was-george-bush-stent-surgery-really-unnecessary/DzklhNCGVlgriNxgpKZtuO/blog.html

President Bush’s unnecessary heart surgery

  • By Vinay Prasad and Adam Cifu, Published: August 9

Vinay Prasad is chief fellow of medical oncology at the National Cancer Institute and the National Institutes of Health. Adam Cifu is a professor of medicine at the University of Chicago.

Former president George W. Bush, widely regarded as a model of physical fitness, received a coronary artery stent on Tuesday. Few facts are known about the case, but what is known suggests the procedure was unnecessary.

Before he underwent his annual physical, Mr. Bush reportedly had no symptoms. Quite the opposite: His exercise tolerance was astonishing for his age, 67. He rode more than 30 miles in the heat on a bike ride for veterans injured in the wars in Iraq and Afghanistan.

If Mr. Bush had visited a general internist practicing sound, evidence-based care, he would not have had cardiac testing. Instead, the doctor would have had conducted age-appropriate cancer screening. For the former president, this would include only colon cancer screening. It no longer would include even prostate-specific antigen testing for cancer. The doctor would have screened for cholesterol, checked for hypertension and made sure the patient was up to date on age-appropriate vaccinations, including those for pneumococcal pneumonia and shingles. Presumably Mr. Bush got these things, and he got the cardiac test as well.What value does a stress test add for an otherwise healthy 67-year-old?No study has shown that this examination improves outcomes. The trials that have been done for so-called routine stress testing examined higher-risk patients. They found that performing stress tests on people at high risk of cardiovascular disease may detect blockages but does not improve symptoms or survival. Routine stress testing does, however, increase the use of procedures such as coronary stenting.Unfortunately, Mr. Bush, like many VIPs, may be paying the price of these in-depth investigations. His stress test revealed an abnormality, prompting another test: a CT angiogram. This study showed a blockage, which was stented open during an invasive procedure. It is worth noting that at least two large randomized trials show that stenting these sorts of lesions does not improve survival. Because Mr. Bush had no symptoms, it is impossible that he felt better after these procedures.

Instead, George W. Bush will have to take two blood thinners, aspirin and Plavix, for at least a month and probably a year. (The amount of time a blood thinner is needed depends on the type of stent placed). While he takes these medications, he will have a higher risk of bleeding complications with no real benefit.

Although this may seem like an issue important only to the former president, consider the following: Although the price of excessive screening of so-called VIPs is usually paid for privately, follow-up tests, only “necessary” because of the initial unnecessary screening test, are usually paid for by Medicare, further stressing our health-care system. The media coverage of interventions like Mr. Bush’s also leads patients to pressure their own doctors for unwarranted and excessive care.

http://www.washingtonpost.com/opinions/president-bushs-unnecessary-heart-surgery/2013/08/09/c91c439c-0041-11e3-9a3e-916de805f65d_story.html

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AHA, ACC Change in Requirement for Surgical Support for PCI Performance: Class IIb -> Class III, Level of Evidence A: Support Nonemergent PCI without Surgical Backup (Change of class IIb, Level of evidence B).


AHA, ACC Change in Requirement for Surgical Support:  Class IIb -> Class III, Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, Level of Evidence B).

Larry H Bernstein, MD, FCAP, Author, Curator, Volumes 1,2,3,4,5,6 Co-Editor and Author, Volume Two & Five, Co-Editor and Justin Pearlman, MD, PhD, FACC, Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases

 

Voice of content consultant: Justin Pearlman, MD, PhD, FACC

The American Heart Association (AHA) and the American College of Cardiology (ACC) have convened teams of experts to summarize evidence and opinion regarding a wide range of decisions relevant to cardiovascular disease. The system accounts for some of the short comings of “evidence based medicine” by allowing for expert opinion in areas where evidence is not sufficient. The main argument for evidence-based medicine is the existence of surprises, where a plausible decision does not actually appear to work as desired when it is tested. A major problem with adhesion to evidence based medicine is that it can impede adaptation to individual needs (we are all genetically and socially/environmentally unique) and impede innovation. Large studies carry statistical weight but do not necessary consider all relevant factors. Commonly, the AFFIRM trial is interpreted as support that rate control suffices for most atrial fibrillation (AFIB), but half of those randomized to rhythm control were taken off anticoagulation without teaching patients to check their pulse daily for recurrence of AFIB. Thus the endorsed “evidence” may have more to do with the benefits of anticoagulation for both persisting and recurring AFIB and rhythm control may yet prove better than rate control. However, with wide acceptance of a particular conclusion, randomizing to another treatment may be deemed unethical, or may simply not get a large trial due to lack of economic incentive, leaving only the large trial products as the endorsed options. A medication without patent protection, such as bismuth salts for H Pylori infection, lacks financial backing for large trials.

The American Heart Association Evidence-Based Scoring System
Classification of Recommendations

● Class I: Conditions for which there is evidence, general

agreement, or both that a given procedure or treatment is

useful and effective.

● Class II: Conditions for which there is conflicting evidence,

a divergence of opinion, or both about the usefulness/

efficacy of a procedure or treatment.

● Class IIa: Weight of evidence/opinion is in favor of

usefulness/efficacy.

● Class IIb: Usefulness/efficacy is less well established by

evidence/opinion.

● Class III: Conditions for which there is evidence, general

agreement, or both that the procedure/treatment is not useful/

effective and in some cases may be harmful.

Level of Evidence

● Level of Evidence A: Data derived from multiple randomized

clinical trials

● Level of Evidence B: Data derived from a single randomized

trial or nonrandomized studies

● Level of Evidence C: Consensus opinion of experts

Circulation 2006 114: 1761 – 1791.

Assessment of Coronary Artery Disease by Cardiac Computed Tomography

A Scientific Statement From the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology

Reported by Chris Kaiser, Cardiology Editor, MedPage  7/2013  

 

Action Points

  1. Patients with indications for nonemergency PCI who presented at hospitals without on-site cardiac surgery, were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery or at a hospital with on-site cardiac surgery.
  2. The rates of death, myocardial infarction, repeat revascularization, and stroke did not differ significantly between the groups.
  3. Community hospitals without surgical services can safely perform percutaneous coronary intervention (PCI) in low-risk patients — and not refuse higher-risk patients either, the MASS COMM trial found.

Summary

  • The co-primary endpoint of major adverse cardiac events (MACE) at 30 days occurred at a rate of 9.5% in the 10 hospitals without surgical backup versus 9.4% in the seven hospitals with onsite surgery (P<0.001 for noninferiority), Alice K. Jacobs, MD, of Boston University School of Medicine, and colleagues found.
  • The other co-primary endpoint of MACE at 12 months was also significant, occurring in 17.3% of patients in hospitals without backup versus 17.8% in centers with surgical services (P<0.001 for non-inferiority), they reported in the study published online by the New England Journal of Medicine. The findings were also reported at the American College of Cardiology meeting.

Study Characteristics and Results

Primary Endpoints

  1. death
  2. myocardial infarction
  3. repeat revascularization
  4. stroke
no significant differences between the two groups at 30 days and at 12 months.

Rate of stent thrombosis at 30 days

similar in both groups (0.6% versus 0.8%) and at 12 months (1.1% versus 2.1%).
Jacobs and colleagues noted that the 2011 PCI guidelines lacked evidence to fully support nonemergent PCI without surgical backup (class IIb, level of evidence B).

CPORT – E trial

Even though those guidelines came out before the results of the CPORT-E trial were published, CPORT-E trial showed similar non-inferiority at 9 months between centers that perform PCI with or without surgical backup in a cohort of nearly 19,000 non-emergent patients. The CPORT-E results were published in the March 2012 issue of the New England Journal of Medicine, and in May three cardiology organizations published an update to cath lab standards allowing for PCI without surgical.

 MASS COMM study

To further the evidence, Jacobs and colleagues in 2006  had designed and carried out the Randomized Trial to Compare Percutaneous Coronary Intervention between Massachusetts Hospitals with Cardiac Surgery On-Site and Community Hospitals without Cardiac Surgery On-Site (MASS COMM) in collaboration with the Massachusetts Department of Public Health who collaborated to obtain “evidence on which to base regulatory policy decisions about performing non-emergent PCI in hospitals without on-site cardiac surgery.”

  • Hospitals without backup surgery were required to perform at least 300 diagnostic catheterizations per year, and operators were mandated to have performed a minimum of 75 PCI procedures per year.
  • The researchers randomized 3,691 patients to each arm in a 3:1 ratio (without/with backup). The median follow-up was about 1 year.
  • The median age of patients was 64, one-third were women, and 92% were white. Both groups had similar median ejection fractions at baseline (55%).
  • The mean number of vessels treated was 1.17 and most patients (84%) had one vessel treated. The mean number of lesions treated was 1.45 and most patients (67%) had one lesion treated.

The indications for PCI were:

1. ST-segment elevated MI (>72 hours before PCI of infarct-related or non–infarct-related artery — 19% and 17%
2. Unstable angina — 45% and 47%
3. Stable angina — 27% and 28%
4. Silent ischemia — 5% and 6%
5. Other — 2.5% and 2.8%
Regarding secondary endpoints, both groups had similar rates of emergency CABG and urgent or emergent PCI at 30 days. Results at 30 days and 12 months were similar for rates of ischemia-driven target-vessel revascularization and target-lesion revascularization. Other endpoints as well were similar at both time points, including
  • all-cause death
  • repeat revascularization
  • stroke
  • definite or probable stent thrombosis
  • major vascular complications
Researchers adjusted for a 1.3 greater chance of MACE occurring at a randomly selected hospital compared with another randomly selected hospital and found
  • the relative risks at 30 days and 12 months “were consistent with those of the primary results” (RR 1.02 and 0.98, respectively).

However, they cautioned that new sites perhaps should be monitored as they gain experience.

A prespecified angiographic review of 376 patients who were in the PCI-without-backup arm and 87 in the other arm showed no differences in
  1. rates of procedural success,
  2. proportion with complete revascularization, or
  3. the proportion of guideline-indicated appropriate lesions for PCI.
Such results show consistent practice patterns between the groups, they noted.
The study had several limitations including the
  • loss of data for 13% of patients, the
  • exclusion of some patients for certain clinical and anatomical features, and
  • not having the power to detect non-inferiority in the separate components of the primary endpoint, researchers wrote.

Cardio Notes: Score Predicts PCI Readmission

Published: Jul 15, 2013

By Chris Kaiser, Cardiology Editor, MedPage Today
  

A simple calculation of patient variables before PCI may help stem the tide of readmission within the first month. Also this week, two blood pressure drugs that benefit diabetics and imaging cardiac sympathetic innervation.

Pre-PCI Factors Predict Return Trip

A new 30-day readmission risk prediction model for patients undergoing percutaneous coronary intervention (PCI) showed it’s possible to predict risk using only variables known before PCI, according to a study published online in Circulation: Cardiovascular Quality and Outcomes.

After multivariable adjustment, the 10 pre-PCI variables that predicted 30-day readmission were older age (mean age 68 in this study), female sex, insurance type (Medicare, state, or unknown), GFR category (less than 30 and 30-60 mL/min per 1.73m2), current or history of heart failure, chronic lung disease, peripheral vascular disease, cardiogenic shock at presentation, admit source (acute and non-acute care facility or emergency department), and previous coronary artery bypass graft surgery.

Additional significant variables post-discharge that predicted 30-day readmission were beta-blocker prescribed at discharge, post-PCI vascular or bleeding complications, discharge location, African American race, diabetes status and modality of treatment, any drug-eluting stent during the index procedure, and extended length of stay.

A risk score calculator using the pre-PCI variables will be available online soon, according to Robert W. Yeh, MD, MSc, of Massachusetts General Hospital in Boston, and colleagues.

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