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The Cardio-Renal Syndrome (CRS) in Heart Failure (HF)

Posted in Cardiac and Cardiovascular Surgical Procedures, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, tagged Acute decompensated heart failure, Creatinine, CRS, Heart Failure, Kidney, Renal function, Ultrafiltration on June 30, 2013| 2 Comments »

The Cardiorenal Syndrome in Heart Failure: Cardiac? Renal? syndrome?

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

and

Curator: Aviva Lev-Ari, PhD, RN

Triposkiadis F, Starling RC, Boudoulas H, Giamouzis G, Butler J.
Heart Fail Rev. 2012 May;17(3):355-66. http://dx.doi.org/10.1007/s10741-011-9291-x Review

There has been increasing interest on the so-called cardiorenal syndrome (CRS), defined as

a complex pathophysiological disorder of the heart and kidneys where by acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other.

In this review, we contend that there is lack of evidence warranting the adoption of a specific clinical construct such as the CRS within the heart failure (HF) syndrome by demonstrating that:

(a) the approaches and tools regarding the definition of kidney involvement in HF are suboptimal;
(b) development of renal failure in HF is often confounded by age, hypertension, and diabetes;
(c) worsening of renal function (WRF) in HF may be largely independent of alterations in cardiac function;
(d) the bidirectional association between HF and renal failure is not unique and represents one of the several such associations encountered in HF; and
(e) inflammation is a common denominator for HF and associated noncardiac morbidities.

Based on these arguments, we believe that

dissecting one of the multiple bidirectional associations in HF and
constructing the so-called cardiorenal syndrome is not justified pathophysiologically.

Fully understanding of all morbid associations and not only the cardiorenal, that is of great significance for the clinician who is caring for the patient with HF.

Ultrafiltration in Heart Failure with Cardiorenal Syndrome

N Engl J Med 2013; 368:1157-1160 http://dx.doi.org/10.1056/NEJMc1300456

Bart et al. (Dec. 13 issue)1 report the results of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). They state that ultrafiltration was inferior to a strategy of stepped pharmacologic therapy with respect to the

bivariate primary end point of the change in the serum creatinine level and body weight in patients with acute decompensated heart failure.

It is unclear at first sight why renal function should be different at 96 hours only when serum creatinine concentrations are used as a marker of renal function,

but not when the level of cystatin C or the glomerular filtration rate are used.

How can this discrepancy be explained?

According to the study Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

Bart BA., Goldsmith SR., Lee KL, Givertz MM, et al.
N Engl J Med 2012; 367:2296-2304 http://dx.doi.org/10.1056/NEJMoa1210357

Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure.

Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure

complicated by persistent congestion and worsened renal function.

Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of

the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003),
owing primarily to an increase in the creatinine level in the ultrafiltration group.

At 96 hours, the mean change in the creatinine level was −0.04±0.53 mg per deciliter (−3.5±46.9 μmol per liter) in the pharmacologic-therapy group,
as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003).

A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03).
In a randomized trial involving patients hospitalized for acute decompensated heart failure,

worsened renal function, and
persistent congestion,

the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for

the preservation of renal function at 96 hours,
with a similar amount of weight loss with the two approaches.

Advanced heart failure (pharmaceuticalintelligence.com)
Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure. (zedie.wordpress.com)
First drug to improve heart failure mortality in over a decade – HealthCanal.com (pharmaceuticalintelligence.com)
Beta-Blocker Response (23andme.com)
Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure (pharmaceuticalintelligence.com)
Heart-failure admissions and mortality highest in winter and on weekends – TheHeart.Org (pharmaceuticalintelligence.com)
Acute Dialysis Quality Initiative (ADQI) (scicombinator.com)
FDA grants Breakthrough Therapy designation to Novartis’ serelaxin (RLX030) for acute heart failure. (zedie.wordpress.com)

Prognostic Marker Importance of Troponin I in Acute Decompensated Heart Failure (ADHF)

Posted in Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Chemical Biology and its relations to Metabolic Disease, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, tagged Acute decompensated heart failure, ADHF, Heart Failure, Ortho Clinical Diagnostics, Patient, Troponin, Troponin T, Weight loss on June 30, 2013| 1 Comment »

Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Felker GM, Hasselblad V, Tang WH, Hernandez AF, Armstrong PW, et al.
Eur J Heart Fail. 2012 Nov;14(11):1257-64. http://dx.doi.org/10.1093/eurjhf/hfs110 Epub 2012 Jul 4.

AIMS: We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF.

METHODS: Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes.

RESULTS:

Baseline cTnI was undetectable in 22% and
elevated above the 99th percentile URL in 50% of subjects.

cTnI levels did not differ based on HF etiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as

length of stay (P = 0.01) and
worsening HF during the index hospitalization (P = 0.01), but
was not associated with worsened post-discharge outcomes at 30 or 180 days.

The relationship between cTnI and outcomes was generally linear and

there was no evidence of a threshold effect at any particular level of cTnI.

CONCLUSION:

cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and
predicts in-hospital outcome, but
is not an independent predictor of long-term outcomes.

This reviewer finds the results quite interesting, and the study was done with care. The Ortho Diagnostics method of cTnI is high-sensitivity assay, so that the lowest measureable level at < 10% CV is manyfold lower than the 4th generation assay.

Prior to the hs-cTNI, the diagnostic cutoff for

AMI was 1.0 ng/ml vs
the cTnT at 0.1 ng/ml using a ROC curve.

AMI did occur below the ROC cutoff in both cases, but the reasons for elevations other than AMI were determined to be CRF, and this was more accurate (a small probability with the cTnT between 0.085 and 0.1 ng/ml.

However, the findings in this study did indeed exclude symptomatic ACS, or cTnI at the level not > 5x ULN. [0.17 ng/ml] with the hs-TnI. The hs-cTnI assay opened up the identification of non-ACS elevation related to cardiomyocyte damage unrelated to plaque rupture, but related to a persistent coronary ischemia, possibly related to cardiomegaly and/or vascular rigidity.

Test Limitations

Troponins are not normally present in serum, so any amount present in serum (measured at the 99th percentile of the upper limit of normal at a 10% imprecision) indicates structural damage to the heart, although not necessarily AMI.

Both troponin I (TnI) and troponin T (TnT) are affected by renal insufficiency, but TnT is to a greater extent
100% of TnT is excreted in urine, but 70% of TnI is degraded by vascular endothelium; this means that minor elevations of troponins have to be considered in the context of comorbidities, especially renal impairment, and risk factors
Among heart failure patients, the objective parameter of NT-proBNP seems more useful to delineate the “cardiorenal syndrome” than the previous criteria of a clinical diagnosis of heart failure

However, the NT-proBNP is best interpreted by using the log(NT-proBNP)/eGFR with an adjustment.

These investigators used the log(cTnI), which I would not have thought of in this case, but it is important to do because the distribution of the peptide levels in the study population would be nonparametric. The median values at the time points are not given. Actually, there are presumably, not definitely, two populations – if you were to infer short- and long-term outcomes measured as 30-days, and 180-days. That a baseline cTNI was undetectable in 22% of patients is actually not so different than would be found in a random selection from patients presenting to the emergency department. It should not be a surprise that the test as a single predictor, did not meet the requirement for long-term prediction of outcome, despite agreement with the in-hospital outcome. This is consistent with the absence of ACS.

[1] Troponins (Cardiac-specific Troponin I and Troponin T). LH Bernstein. http://PathologyOutlines.com/Chemistry
[2] Effect of renal function loss on NT-proBNP level variations. LH Bernstein, MY Zions, SA Haq, S Zarich, J Rucinski, B Seamonds, et al. Clin Biochem 2009; 42(10-11):1091-1098. ICID: 937529 http://dx.doi.org/10.1016/j.clinbiochem.2009.02.027.
[3] Enhancing the diagnostic performance of troponins in the acute care setting. SA Haq, M Tavakol, S Silber, L Bernstein, J Kneifati-Hayek, M Schleffer, et al. J Emerg Med 2008; x:x ICID: 937619
http://www.nymethodistemergencymedicine.com/program/research.html
[4] Comparison of test characteristics of cardiac troponin T in patients with normal renal function and chronic renal failure evaluated in the emergency department. S Silber, L Melniker, E Haines, LH Bernstein.
Academic Emergency Medicine 2006; 13(5):S1186-187.   ICID: 939943   http://www.nymethodistemergencymedicine.com/program/research.html
[5} The ACC/ESC Recommendation for 99th Percentile of the Reference Normal Troponin I Overestimates the Risk of an Acute Myocardial Infarction: a novel enhancement in the diagnostic performance of troponins. “6th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke.” S Haq, M Tavakol, LH Bernstein, J Kneifati-Hayek, M Schlefer, S Silber, T Sacchi, J Pima. Circulation 2005; 111(20):e313-313. ICID: 939931
http://pt.wkhealth.com/pt/re/circ/toc.00003017-200505240-00000.htm
[6] Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values. SW Zarich, K Bradley, ID Mayall, LH Bernstein.
Clin Chim Acta 2004; 343(1-2):223-229. ICID: 825515   http://www.ncbi.nlm.nih.gov/pubmed/15115700
[7] GOLDmineR: improving models for classifying patients with chest pain. L Bernstein, K Bradley, SW Zarich. Yale J Biol Med 2002; 75(4):183-198. ICID: 825624
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588788/

Vasoplegia in Orthotopic Heart Transplant Patients

Posted in Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, International Global Work in Pharmaceutical, Medical Devices R&D and Inventions, Nitric Oxide in Health and Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged BMI, cardiothoracic surgery, Cheyne-Stokes Respiration, Conditions and Diseases, Heart Failure, Heart Lung Transplant, Larry H. Bernstein, mechanical support, surgery, thyroid disease, vasoplegia on June 30, 2013| Leave a Comment »

Pre-operative Risk Factors and Clinical Outcomes Associated with Vasoplegia in Recipients of Orthotopic Heart Transplantation in the Contemporary Era.

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

and

Curator: Aviva Lev-Ari, PhD, RN

Patarroyo M, Simbaqueba C, Shrestha K, Starling RC, Smedira N, Tang WH, Taylor DO.

J Heart Lung Transplant. 2012 Mar;31(3):282-7. http://dx.doi.org/10.1016/j.healun.2011.10.010 Epub 2011 Nov

BACKGROUND: Patients who underwent orthotopic heart transplant (OHT) can develop vasoplegia, which is

associated with high mortality and morbidity.

Herein we examine the per-operative risk in OHT recipients at Cleveland Clinic. Vasoplegic syndrome is

low systemic vascular resistance ( SVR index <1,600 dyn∙seg/cm5/m2 ) and
high cardiac output ( cardiac index >2.5 l/min/m2 )
within the first 4 postoperative hours.

VPS occurs more frequently after on pump CABG surgery versus off pump CABG surgery.

Methylene blue and vasoplegia: who, when, and how?

Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH.

Department of Surgery, Division of Surgical Critical Care, University of Pennsylvania School of Medicine

Mini Rev Med Chem. 2008 May;8(5):472-90. http://www.ncbi.nlm.nih.gov/pubmed/18473936

Vasoplegia or vasoplegic syndrome (VS) is thought to be due to

dysregulation of endothelial homeostasis and subsequent endothelial dysfunction
secondary to direct and indirect effects of multiple inflammatory mediators.

Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role.

Methylene blue (MB),

an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC),

has been found to improve

the refractory hypotension associated with endothelial dysfunction of VS.

METHODS: We reviewed peri-operative data from 311 consecutive adult patients who underwent OHT between January 2003 and June 2008.

Vasoplegia was defined as

persistent low systemic vascular resistance,
despite multiple intravenous pressor drugs at high dose,
between 6 and 48 hours after surgery.

RESULTS: In our cohort of 311 patients, 35 (11%) patients developed vasoplegia syndrome; these patients were more likely to be UNOS Status 1A, with

a higher body surface area (1.8 ± 0.25 vs 1.63 ± 0.36, p = 0.0007),
greater history of thyroid disease (38.2% vs 18.5%, p = 0.0075) and
a higher rate of previous cardiothoracic surgery (79% vs 48%, p = 0.0006).

Pre-operatively,

they were more frequently treated with aspirin (73% vs 48%, p = 0.005) and
mechanical assist devices (ventricular assist devices [VADs]: 45% vs 17%, p < 0.0001;
total artificial hearts: 8.6% vs 0%, p < 0.0001), and
less treated with milrinone (14.7% vs 45.8%, p = 0.0005).

Bypass time (118 ± 37 vs 142 ± 39 minutes, p = 0.0002) and

donor heart ischemic time (191 ± 46 vs 219 ± 51 minutes, p = 0.002) were longer, with

higher mortality (3.2% vs 17.1%, p = 0.0003) and morbidity in the first 30 days after transplant.

In the multivariate analysis, history of thyroid disease (odds ratio [OR] = 2.7, 95% CI 1.0 to 7.0, p = 0.04) and VAD prior to transplant (OR = 2.8, 95% CI 1.07 to 7.4, p = 0.03)

were independent risk factors for development of vasoplegia syndrome.

CONCLUSIONS:

High body mass index,
long cardiopulmonary bypass time,
prior cardiothoracic surgery,
mechanical support,
use of aspirin, and
thyroid disease

are risk factors associated with development of vasoplegia syndrome.

Decreased postoperative atrial fibrillation following cardiac transplantation (pharmaceuticalintelligence.com)
6-Year-Old Catonsville Girl Fights For Her Life After Heart Transplant (baltimore.cbslocal.com)
One Year Later, Heart Transplant Recipient Doing Well (foxct.com)
Girl on ventilator after lung transplants (cnn.com)

Heart Failure Treatment Improves, But Death Rate Remains High : NPR (pharmaceuticalintelligence.com)
Heart transplantation research in the next decade – a goal to achieving evidence-based outcomes (pharmaceuticalintelligence.com)
Beta-Blocker Response (23andme.com)
First drug to improve heart failure mortality in over a decade – HealthCanal.com (pharmaceuticalintelligence.com)
Advanced heart failure (pharmaceuticalintelligence.com)
Scientists prevent heart failure in mice (pharmaceuticalintelligence.com)

Mechanical Circulatory Support System, LVAD, RVAD, Biventricular as a Bridge to Heart Transplantation or as “Destination Therapy”: Options for Patients in Advanced Heart Failure

Posted in Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Heart Transplant, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Artificial heart, Circulatory system, Coronary artery disease, Food and Drug Administration, Heart Failure, Heart transplantation, Organ transplantation, Total Artificial Heart, Ventricular assist device on June 30, 2013| 4 Comments »

Mechanical Circulatory Assist Devices as a Bridge to Heart Transplantation or as “Destination Therapy“: Options for Patients in Advanced Heart Failure

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

and

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 10/22/2018

HeartMate 3 gets FDA approval for extended use

Revamped Abbott Labs device is seen as an option for cardiac patients who are unlikely to get transplants.

By Joe Carlson Star Tribune

OCTOBER 19, 2018 — 8:09PM

“When heart failure (HF) progresses to an advanced stage, difficult decisions must be made,” the AHA says on its website. “Do I want to receive aggressive treatment? Is quality of life more important than living as long as possible? How do I feel about resuscitation?”

LVADs can take over the pumping function of a failing heart, but they also present some of the most expensive implantable-device surgeries. An article in the peer-reviewed journal JACC: Heart Failure reported last year that the average total cost to implant an LVAD in Medicare beneficiaries was $175,000, more than double the cost of a heart transplant.

Amador said between 5,000 and 5,500 Americans will have LVAD implants this year. That compares with 2,200 adult heart transplants that happen annually in the U.S., according to the JACC article.

SOURCE

http://www.startribune.com/heartmate-3-gets-fda-approval-for-extended-use/498061451/

Starling RC.
Cleve Clin J Med. 2013 Jan; 80(1):33-40. http://dx.doi.org/10.3949/ccjm.80gr.12003

For patients with advanced heart failure, outcomes are good after heart transplantation, but not enough donor hearts are available. Fortunately, mechanical circulatory assist devices have become an excellent option and should be considered either as a bridge to transplantation or as “destination therapy.” Current mechanical circulatory assist devices improve quality of life in patients who are candidates.

For some patients, conventional treatments are inadequate to relieve the effects of heart failure. Under these circumstances, mechanical circulatory support is considered. There are now a variety of devices capable of pumping blood to restore circulation of vital organs, even temporarily replacing the function of the native heart.

The ABIOMED AB5000™ Circulatory Support System is a short-term mechanical system that can provide left, right, or biventricular support for patients whose hearts have failed but have the potential for recovery. The AB5000™ can be used to support the heart, giving it time to rest – and potentially recover native heart function. The device can also be used as a bridge to definitive therapy.

http://med.umich.edu/cardiac-surgery/images/content/Abiomed_AB5000.jpg

CardioWest™ temporary Total Artificial Heart (TAH-t) http://www.syncardia.com/cardiowesttaht/index.php
This medical device is the modern version of the Jarvik 7 artificial heart first implanted into Barney Clark in 1982. The CardioWest™ temporary Total Artificial Heart is the only FDA approved temporary total artificial heart in the world.
The TAH-t is used as a bridge to heart transplant for eligible patients suffering from end-stage biventricular failure.
http://med.umich.edu/cardiac-surgery/images/content/Cardiowest_TAHt_Photo.jpg

Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure (pharmaceuticalintelligence.com)
First drug to improve heart failure mortality in over a decade – HealthCanal.com (pharmaceuticalintelligence.com)
The Latest Artificial Heart: Part Cow, Part Machine (technologyreview.com)
Beta-Blocker Response (23andme.com)
Scientists prevent heart failure in mice (pharmaceuticalintelligence.com)
Death Rates Among Advanced Heart Failure Patients Decline Due to Increased Availability of New Therapies (medindia.net)
Heart Failure Treatment Improves, But Death Rate Remains High : NPR (pharmaceuticalintelligence.com)
Common Supplement May Help Patients Fight Heart Failure (news.health.com)

Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes

Posted in Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Heart Transplant, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, Medical Devices R&D Investment, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Cardiovascular Disorders, Cheyne-Stokes Respiration, evidence based medicine, Heart Failure, Heart transplantation, Larry H. Bernstein, medicine, Organ transplantation on June 30, 2013| 2 Comments »

Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Heart transplantation research in the next decade–a goal to achieving evidence-based outcomes: National Heart, Lung, And Blood Institute Working Group.

Shah MR, Starling RC, Schwartz Longacre L, Mehra MR; Working Group Participants.

J Am Coll Cardiol. 2012 Apr 3;59(14):1263-9. http://dx.doi.org/10.1016/j.jacc.2011.11.050 Review

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) on August 5 to 6, 2010 in Bethesda, Maryland to discuss future directions of research in heart transplantation (HT). The WG was composed of researchers with expertise in the basic science, clinical science, and epidemiological aspects of advanced heart failure and HT.

These experts were asked to

identify the highest priority research gaps in the field and
make recommendations for future research strategies.

The WG was also asked to include approaches that capitalize on current scientific opportunities and focus on areas that required unique NHLBI leadership. Finally, the WG was charged with developing recommendations that would have short- and long-term impact on the field of HT. The WG participants reviewed key areas in HT and identified the most urgent knowledge gaps.

These gaps were then organized into the following 4 specific research directions:

1) enhanced phenotypic characterization of the pre-transplant population;

2) donor-recipient optimization strategies;

3) individualized immunosuppression therapy; and,

4) investigations of immune and non-immune factors affecting late cardiac allograft outcomes.

Finally, because the HT population is relatively small compared with other patient groups, the WG strongly urged concerted efforts to enroll every transplant recipient into a clinical study and to increase collaborative networks to optimize research in this field.

Teen prospers 17 years after heart transplant (KOB.com)
Decreased postoperative atrial fibrillation following cardiac transplantation (pharmaceuticalintelligence.com)

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

Heart Failure Treatment Improves, But Death Rate Remains High : NPR (A Lev-Ari)
http://pharmaceuticalintelligence.com/2013/05/29/heart-failure-treatment-improves-but-death-rate-remains-high-npr/

The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN (Aviva Lev-Ari)
http://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

Resident-cell-based Therapy (Aviva Lev-Ari)
http://pharmaceuticalintelligence.com/2012/04/30/93/

Amyloidosis with Cardiomyopathy (larryhbern)
http://pharmaceuticalintelligence.com/2013/03/31/amyloidosis-with-cardiomyopathy/

Blood-vessels-generating stem cells discovered (ritu.saxena)
http://pharmaceuticalintelligence.com/2012/10/22/blood-vessel-generating-stem-cells-discovered/

Stem Cell Research — The Frontier is at the Technion in Israel (A Lev-Ari)
http://pharmaceuticalintelligence.com/2012/09/06/stem-cell-research-the-frontier-is-at-the-technion-in-israel/

First drug to improve heart failure mortality in over a decade – HealthCanal.com (A Lev-Ari)
http://pharmaceuticalintelligence.com/2013/06/03/first-drug-to-improve-heart-failure-mortality-in-over-a-decade-healthcanal-com/

Scientists prevent heart failure in mice (Aviva Lev-Ari)
http://pharmaceuticalintelligence.com/2013/05/29/scientists-prevent-heart-failure-in-mice/

Stenosis, ischemia and heart failure (Aviva Lev-Ari)
http://pharmaceuticalintelligence.com/2013/05/16/stenosis-ischemia-and-heart-failure/

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony (A lev-Ari)
http://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

First case in the US: Valve-in-Valve (Aortic and Mitral) Replacements with Transapical Transcatheter Implants – The Use of Transfemoral Devices (larryhbern)
http://pharmaceuticalintelligence.com/2013/06/23/valve-in-valve-replacements-with-transapical-transcatheter-implants/
Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable

Cardiogenic Shock (larryhbern)
http://pharmaceuticalintelligence.com/2013/06/18/a-recommended-approach-to-the-treatmnt-of-intractable-cardiogenic-shock/

Forrester-classification for classification of Congestive heart failure ; Forrester-Klassifikation zur Einteilung einer akuten Herzinsuffizienz (Photo credit: Wikipedia)

Artificial heart: JARVIK-7 Heart, provided to the National Heart, Lung and Blood Institute (NHLBI) by the University of Utah. (Photo credit: Wikipedia)

Schematic of a transplanted heart with native lungs and the great vessels. (Photo credit: Wikipedia)

English: Ventricular assist device (Photo credit: Wikipedia)

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After Cardiac Transplantation: Sirolimus acts as immunosuppressant Attenuates Allograft Vasculopathy

Posted in Aortic Valve: TAVR, TAVI vs Open Heart Surgery, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiovascular Pharmacogenomics, Chemical Biology and its relations to Metabolic Disease, Drug Delivery Platform Technology, Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, International Global Work in Pharmaceutical, PCI, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, tagged Allotransplantation, Coronary artery disease, Drug-eluting stent, Heart transplantation, immunosuppression, Immunosuppressive drug, Intravascular ultrasound, myocardial infarction, Organ transplantation, Sirolimus, Stent, surgery on June 30, 2013| 1 Comment »

After Cardiac Transplantation: Sirolimus acts as immunosuppressant Attenuates Allograft Vasculopathy

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation

Topilsky Y, Hasin T, Raichlin E, Boilson BA, Schirger JA, et al.
Circulation. 2012 Feb 7;125(5):708-20. http://dx.doi.org/10.1161/CIRCULATIONAHA.111.040360. Epub 2011 Dec 29

BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant

in the long-term attenuation of cardiac allograft vasculopathy progression and
the effects on cardiac-related morbidity and mortality.

METHODS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors.

Age,
sex,
ejection fraction, and
time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups;
neither were secondary immunosuppressants and
use of steroids.

Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later.

RESULTS: Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to

reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and
improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation.

Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations.

Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006),
There was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002).

CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant

attenuates long-term cardiac allograft vasculopathy progression and
may improve long-term allograft survival owing to favorable coronary remodeling.

Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

Novartis Japan Achieves Primary Endpoint In HER2 Positive Advanced Breast Cancer Phase III Afinitor Trials (saminakhanpakistan.wordpress.com)
Biodegradable stent proves non-inferior to drug-eluting stent (eurekalert.org)

Orthotopic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

Posted in Biomedical Measurement Science, CABG, Cardiac & Vascular Repair Tools Subsegment, Ecosystems & Industrial Concentration in the Medical Device Sector, Electrophysiology, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Medical Devices R&D Investment, Pharmaceutical Industry Competitive Intelligence, Pharmacotherapy of Cardiovascular Disease, tagged Atrial fibrillation, Cardiology, Cardiovascular Disorders, Cedars-Sinai Medical Center, Heart disease, Los Angeles on June 30, 2013| 3 Comments »

Orthotopic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

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

and

Curator: Aviva Lev-Ari, PhD, RN

Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects.

Noheria A, Patel SM, Mirzoyev S, Madhavan M, Friedman PA, Packer DL, Daly RC, Kushwaha SS, Edwards BS, Asirvatham SJ.

Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California.
Pacing Clin Electrophysiol. 2013 Jun;36(6):741-7. http://dx.doi.org/10.1111/pace.12102. Epub 2013 Feb 25.

http://www.cvphysiology.com/Blood%20Pressure/ANS-medulla.gif

The medulla, located in the brainstem above the spinal cord, is the primary site in the brain for regulating sympathetic and parasympathetic (vagal) outflow to the heart and blood vessels. The nucleus tractus solitarius (NTS) of the medulla receives sensory input from different systemic and central receptors (e.g., baroreceptors and chemoreceptors).

The heart is innervated by vagal and sympathetic fibers. The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, there can be significant overlap in the anatomical distribution. Atrial muscle is also innervated by vagal efferents, whereas the ventricular myocardium is only sparsely innervated by vagal efferents. Sympathetic efferent nerves are present throughout the atria (especially in the SA node) and ventricles, including the conduction system of the heart.

Cardiac function is altered by neural activation. Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects. Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.

The overall effect of sympathetic activation is to increase cardiac output, systemic vascular resistance (both arteries and veins), and arterial blood pressure. Enhanced sympathetic activity is particularly important during exercise, emotional stress, and during hemorrhagic shock.

The actions of autonomic nerves are mediated by the release of neurotransmitters that bind to specific cardiac receptors and vascular receptors. These receptors are coupled to signal transduction pathways that evoke changes in cellular function.

Sympathetic Parasympathetic

Heart

Chronotropy (rate)

+ + + − − −

Inotropy (contractility)

+ + + − 1

Lusitropy (relaxation)

+ + + – 1

Dromotropy (conduction velocity)

+ + − − −

Vessels

Arterial constriction + + + 0

Venous constriction + + + 0

Relative magnitude of responses indicated by number of + or – signs.
1 More pronounced in atria than ventricles.

CV Physiology: Autonomic Innervation of the Heart and Vasculature
http://www.cvphysiology.com/Blood%20Pressure/BP008.htm

Ablation Therapy for Cardiac Arrhythmias

By Richard N. Fogoros, M.D., About.com Guide Updated November 18, 2011

The most common form of ablation is done during a specialized form of cardiac catheterization, performed by a type of doctor known as a cardiac electrophysiologist (heart rhythm specialist). These procedures are sometimes called “trans-catheter ablations.”

During trans-catheter ablation procedures, specialized electrode catheters are positioned inside the heart, and the cardiac electrical system is mapped, showing the abnormal electrical pathways that are often responsible for producing the rapid heart rate. If these abnormal pathways are identified, the tip of the catheter (a tube) is placed on the abnormal pathway and the pathway is ablated (eliminated). The ablation itself is accomplished by transmitting some form of energy through the catheter (heat energy, freezing energy, or microwave energy), in order to damage the tissue at the tip of the catheter.

Decreased postoperative atrial fibrillation following cardiac transplantation: the significance of autonomic denervation.

BACKGROUND: Endocardial ablation approaches have been proposed to targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) . The potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance.

The investigators hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins.

METHODS: We reviewed 155 OHTs (mean age 52 ± 11 years, 72% males) and used 1:1 age-, sex-, and date-of-surgery-matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls.

RESULTS: Postoperative AF occurred in 10/155 (6.5%) OHT patients.

The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13-0.57], vs CABG: OR 0.38 [0.17-0.81], P = 0.003; and
on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13-0.60], vs CABG: OR 0.14 [0.04-0.47], P = 0.0009).

CONCLUSIONS:

Risk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but

only OHT causes disruption of autonomic innervation,

this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation.

What Is Atrial Fibrillation? (afibrunner.wordpress.com)
Atrial fibrillation symptoms (findmedicalsolutions.com)
Promising Mid-Term Results From Thoracoscopic Ablation of Persistent Atrial Fibrillation Presented a (dailyfinance.com)
Atrial Fibrillation Genetic Risk (23andme.com)
Atrial Fibrillation: Preliminary Research Genetic Risk (23andme.com)
Intermountain Medical Center reseachers develop new 3-D technology to treat atrial fibrillation (eurekalert.org)
Excessive Supraventricular Ectopic Activity Is Indicative of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia (plosone.org)
Heart repair process found in zebrafish (utsandiego.com)
Paroxysmal Atrial Fibrillation Patients Should Undergo Depression Screening (medindia.net)
New risk assessment tool to predict stroke in patients with atrial fibrillation (medfinder.wordpress.com)

CABG Survival in Multivessel Disease Patients: Comparison of Arterial Bypass Grafts vs Saphenous Venous Grafts

Posted in Biomedical Measurement Science, CABG, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Medical Devices R&D and Inventions, Medical Devices R&D Investment, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, Pharmaceutical Industry Competitive Intelligence, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, tagged CABG, Coronary artery bypass surgery, Coronary artery disease, Heart disease, Internal thoracic artery, Mayo Clinic, Percutaneous coronary intervention, surgery on June 30, 2013| 2 Comments »

CABG Survival in Multivessel Disease Patients: Comparison of Arterial Bypass Grafts vs Saphenous Venous Grafts

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

and

Curator: Aviva Lev-Ari, PhD, RN

This article examines 10-year to 15-year survivals from arterial bypass grafts using arterial vs saphenous venous grafts.

Locker C, Schaff HV, Dearani JA, Joyce LD, Park SJ, et al.

Division of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. lekerlocker.chaim@mayo.edu

Circulation. 2012 Aug 28;126(9):1023-30. PMID: 22811577 http://dx.doi.org/10.1161/CIRCULATIONAHA.111.084624. Epub 2012 Jul 18. Review.

Coronary artery bypass surgery (CABG) , is performed to relieve angina and reduce the risk of death from coronary artery disease. Arteries or veins from elsewhere in the patient’s body are grafted to the coronary arteries to bypass atherosclerotic narrowings and improve the blood supply to the coronary circulation supplying the myocardium. This surgery is usually performed with the heart stopped, necessitating the usage of cardiopulmonary bypass; techniques are available to perform CABG on a beating heart, so-called “off-pump” surgery.

Russian cardiac surgeon, Dr. Vasilii Kolesov, performed the first successful internal mammary artery–coronary artery anastomosis in 1964. Using a standard suture technique in 1964, and over the next five years he performed 33 sutured and mechanically stapled anastomoses in St. Petersburg, Russia.

Dr. René Favaloro, an Argentine surgeon, achieved a physiologic approach in the surgical management of coronary artery disease—the bypass grafting procedure—at the Cleveland Clinic in May 1967. His new technique used a saphenous vein autograft to replace a stenotic segment of the right coronary artery, and he later successfully used the saphenous vein as a bypassing channel, which has become the typical bypass graft technique we know today; in the U.S., this vessel is typically harvested endoscopically, using a technique known as endoscopic vessel harvesting (EVH). Soon Dr. Dudley Johnson extended the bypass to include left coronary arterial systems. In 1968, Doctors Charles Bailey, Teruo Hirose and George Green used the internal mammary artery instead of the saphenous vein for the grafting.

A person with a large amount of coronary artery disease (CAD) may receive fewer bypass grafts owing to the lack of suitable “target” vessels. A coronary artery may be unsuitable for bypass grafting if

it is small (< 1 mm or < 1.5 mm depending on surgeon preference),
heavily calcified (meaning the artery does not have a section free of CAD) or
intramyocardial (the coronary artery is located within the heart muscle rather than on the surface of the heart).

Similarly, a person with a single stenosis (“narrowing”) of the left main coronary artery requires only two bypasses (to the LAD and the LCX). However, a left main lesion places a person at the highest risk for death from a cardiac cause.

Both PCI and CABG are more effective than medical management at relieving symptoms, (e.g. angina, dyspnea, fatigue).
CABG is superior to PCI for some patients with multivessel CAD.

The Surgery or Stent (SoS) trial was a randomized controlled trial that compared CABG to PCI with bare-metal stents. The SoS trial demonstrated CABG is superior to PCI in multivessel coronary disease.

The SYNTAX trial was a randomized controlled trial of 1800 patients with multivessel coronary disease, comparing CABG versus PCI using drug-eluting stents (DES). The study found that

rates of major adverse cardiac or cerebrovascular events at 12 months were significantly higher in the DES group (17.8% versus 12.4% for CABG; P=0.002).

This was primarily driven by

higher need for repeat revascularization procedures in the PCI group with no difference in repeat infarctions or survival.
Higher rates of strokes were seen in the CABG group.

http://upload.wikimedia.org/wikipedia/commons/thumb/c/c3/Coronary_artery_bypass_surgery_Image_657C-PH.jpg/230px-Coronary_artery_bypass_surgery_Image_657C-PH.jpg

http://upload.wikimedia.org/wikipedia/commons/thumb/3/30/Heart_saphenous_coronary_grafts.jpg/220px-Heart_saphenous_coronary_grafts.jpg

Left Internal Mammary Artery Usage in Coronary Artery Bypass Grafting: A Measure of Quality Control

S Karthik and BM Fabri
Ann R Coll Surg Engl 2008; 85(4):367-69.

Over the last two decades, many studies have shown better long-term patency rates and survival in patients undergoing coronary artery bypass grafting (CABG) with left internal mammary artery (LIMA) to the left anterior descending artery (LAD).
Although the current focus in the UK is on mortality rates, we believe that it will not be long before this will also include the incidence of major morbidity after CABG such as stroke, myocardial infarction (MI), renal failure and sternal wound problems. We also believe that we should now consider LIMA usage as a marker of quality control in CABG. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1964611/

This study very clearly demonstrated that:

Approximately 4% of all patients undergoing first-time CABG do not need a graft to the LAD.
Of the rest, about 92% receive LIMA to LAD.

Six sub-groups of patients in whom LIMA usage was significantly less were:

(i) the elderly (> 70 years of age);

(ii) females;

(iii) diabetics;

(iv) patients having emergency CABG;

(v) poor left ventricular (LV) function (ejection fraction [EF] < 30%); and

(vi) respiratory disease.

LIMA usage was also reduced in patients undergoing combined CABG and valve procedures.

Multiple arterial grafts improve late survival of patients undergoing CABG

BACKGROUND: Use of the left internal mammary artery (LIMA) in multivessel coronary artery disease improves survival after coronary artery bypass graft surgery; however, the survival benefit of multiple arterial (MultArt) grafts is debated. (Perhaps not without reason. One problem is the small size of the left circumflex artery, and where does the right coronary artery have a place?)
METHODS : We reviewed 8622 Mayo Clinic patients who had isolated primary coronary artery bypass graft surgery for multivessel coronary artery disease from 1993 to 2009. Patients were stratified by number of arterial grafts into the LIMA plus saphenous veins (LIMA/SV) group (n=7435) or the MultArt group (n=1187). Propensity score analysis matched 1153 patients.
RESULTS: Operative mortality was 0.8% (n=10) in the MultArt and 2.1% (n=154) in the LIMA/SV (P=0.005) group.This result was not statistically different (P=0.996) in multivariate analysis or the propensity-matched analysis (P=0.818).
Late survival was greater for MultArt versus LIMA/SV (10- and 15-year survival rates were 84% and 71% versus 61% and 36%, respectively [P<0.001], in unmatched groups and 83% and 70% versus 80% and 60%, respectively [P=0.0025], in matched groups). The large difference between the MultiArt versus the LIMA/SV appears to be the 61% and 36% in unmatched and 80% and 60% in matched, evident at 15-years, favorable for the MultiArt group.
MultArt subgroups with bilateral internal mammary artery/SV (n=589) and

bilateral internal mammary artery only (n=271) had improved 15-year survival (86% and 76%; 82% and 75% at 10 and 15 years [P<0.001]), and
bilateral internal mammary artery/radial artery (n=147) and LIMA/radial artery (n=169) had greater 10-year survival (84% and 78%; P<0.001) versus LIMA/SV.

In multivariate analysis, MultArt grafts remained a strong independent predictor of survival (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P=0.007).

CONCLUSIONS:

In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery,

arterial grafting of the non-left anterior descending vessels conferred a survival advantage at 15 years compared with Saphenous Venous (SV) grafting.

It is still unproven whether these results apply to higher-risk subgroups of patients.

Brachytherapy Cardiac and Coronary Artery Disease (heartdisease.answers.com)
Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty (emberbranch.wordpress.com)
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. (zedie.wordpress.com)
Risks of Coronary Artery Bypass Surgery (everydayhealth.com)
The CARP trial: Preoperative revascularization prior to elective vascular surgery [Classics Series] (2minutemedicine.com)
Orsiro From BIOTRONIK, Industry’s First Hybrid Drug-Eluting Stent, Performs as Best in Class (newsmaker.com.au)
Functional Flow Reserve in Diagnostic Coronary Angiography Changes Decisions in 25 Percent of Cases (medindia.net)
Heart Bypass Versus Stent (heartdisease.answers.com)

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI

Posted in Biomarkers & Medical Diagnostics, Biomedical Measurement Science, CABG, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Chemical Biology and its relations to Metabolic Disease, Computational Biology/Systems and Bioinformatics, Ecosystems & Industrial Concentration in the Medical Device Sector, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, International Global Work in Pharmaceutical, Medical Devices R&D and Inventions, Pharmaceutical Industry Competitive Intelligence, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged Aviva Lev-Ari, Cardiovascular disease, Conditions and Diseases, Coronary artery bypass surgery, Drug-eluting stent, Heart disease, Mayo Clinic, Percutaneous coronary intervention, Society of Thoracic Surgeons on June 30, 2013| 9 Comments »

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI

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

and

Curator: Aviva Lev-Ari, PhD, RN

Published on Mar 27, 2012

Mayo Clinic cardiologist Charanjit Rihal, M.D. discusses a recent study conducted by Mayo Clinic that focuses on predicting operator outcomes in coronary angioplasty procedures.

“We’ve been interested in prediction of outcomes after coronary angioplasty and stent procedures for some time,” says Dr. Rihal. “Almost ten years ago, we published a paper called ‘The Mayo Clinic Risk Score for Prediction of Adverse Events following Coronary Angioplasty and Stent Procedures’. We’ve since refined into the ‘New Mayo Clinic Risk Score’, which includes seven key variables that predict bad outcomes following PCI procedures.”

The study, which was presented at the 2012 ACC Annual Scientific Session & Expo, presents a novel application of the Mayo Clinic Risk Score to predict operator specific outcomes in coronary angioplasty procedures.

“We looked at the outcomes of over 8000 procedures performed by 21 Mayo Clinic interventional cardiologists as predicted by the Mayo Clinic Risk Score,” says Dr. Rihal. “On an individual basis, we were able to calculate the expected mortality and adverse event rate and compare that to the actual observed mortality and adverse event rate. We were able to show that in our clinical practice of PCI, this risk score was very useful as a performance measure.

In a pleasant surprise, the study also discovered an outlier whose outcomes for instances of adverse event rates were much better than expected. “We don’t know exactly why this operator has such good results,” remarks Dr. Rihal, “But that will be the next phase of this analysis. We can compare procedural, pre-procedural, and post procedural practices of this operator and see if there are things that are translatable to the rest of us.”

VIEW VIDEO

Singh M, Gersh BJ, Li S, Rumsfeld JS, Spertus JA, O’Brien SM, Suri RM, Peterson ED.

SOURCE: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN

Circulation. 2008 Jan 22;117(3):356-62. http://dx.doi.org/10.1161/CIRCULATIONAHA.107.711523 Epub 2008 Jan 2. PMID: 18172033

BACKGROUND: Current risk models predict in-hospital mortality after either coronary artery bypass graft surgery or percutaneous coronary interventions. The overlap of models suggests that the same variables can define the risks of alternative coronary reperfusion therapies. We sought a preprocedure risk model that can predict in-hospital mortality after either percutaneous coronary intervention or coronary artery bypass graft surgery.

METHODS AND RESULTS: We tested the ability of the recently validated, integer-based Mayo Clinic Risk Score (MCRS) for percutaneous coronary intervention, which is based solely on preprocedure variables:

age,
creatinine,
ejection fraction,
myocardial infarction < or = 24 hours,
shock,
congestive heart failure
peripheral vascular disease

to predict in-hospital mortality among 370,793 patients in the Society of Thoracic Surgeons (STS) database undergoing isolated coronary artery bypass graft surgery from 2004 to 2006. The median age of the STS database patients was 66 years (quartiles 1 to 3, 57 to 74 years), with 37.2% of patients > or = 70 years old. The high prevalence of comorbid conditions included

diabetes mellitus (37.1%)
hypertension (80.5%)
peripheral vascular disease (15.3%)
renal disease (creatinine > or = 1.4 mg/dL; 11.8%).

A strong association existed between the MCRS and the observed mortality in the STS database. The in-hospital mortality ranged between 0.3% (95% confidence interval 0.3% to 0.4%) with a score of 0 on the MCRS and 33.8% (95% confidence interval 27.3% to 40.3%) with an MCRS score of 20 to 24. The discriminatory ability of the MCRS was moderate, as measured by the area under the receiver operating characteristic curve (C-statistic = 0.715 to 0.784 among various subgroups); performance was inferior to the STS model for most categories tested.

CONCLUSIONS: This model is based on the 7 preprocedure risk variables listed above. However, it may be useful for providing patients with individualized, evidence-based estimates of procedural risk as part of the informed consent process before percutaneous or surgical revascularization.

It appears to this reviewer that the model might provide a better AUC if it were reconstructed as follows:

age
estimated creatinine clearance (which has been improved substantially by the Mayo Clinic)
EF
AMI < 24 hrs
Decompensated CHF or shock
PVD, or carotid artery disease, or PAD
MAP

Mean arterial pressure (MAP) Calculator: Systolic BP: mm Hg: Diastolic BP: mm Hg Background: Equation: MAP = [(2 x diastolic)+systolic] / 3 http://www.globalrph.com/map.htm

There is another question that This reviewer has about the approach to prediction of post-procedural survival from pre-procedural information.

Age falls into interval classes that would suffice for use as classification variables.
Creatinine is a measurement that is a continuous variable, but I call attention to the fact that eGFR would be preferred, as physicians tend to look at the creatinine roughly in relationship to age, gender, and body size or BMI.
The laboratory contribution as powerful information is underutilized.

On the one hand, CHF is important, but how is the distinction made between

stable CHF and
decompensated CHF, or degrees in between?

This is where the amino-terminal pro b-type natriuretic perptide, or the BNP has been used in isolation, but not in a multivariate model such as described. There is a difference between them, but whether the difference makes a difference is unproved.

The BNP, derived from the propeptide is made by the myocardium as a hormonal mediator of sodium retention. The BNP is degraded by the vascular endothelium, so it’s half time of disappearance would not reflect renal dysfunction, which is not the case for the NT proBNP. This observation has nothing to do with the medical use of BNP.

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty (emberbranch.wordpress.com)
Risks of Coronary Artery Bypass Surgery (everydayhealth.com)
Heart Attack Treatment Options (everydayhealth.com)
Cabbage Surgery Overview (surgery.answers.com)
Comparison of cardiothoracic bypass and percutaneous interventional catheterization survivals (pharmaceuticalintelligence.com)
Functional Flow Reserve in Diagnostic Coronary Angiography Changes Decisions in 25 Percent of Cases (medindia.net)
High incidence of acute coronary occlusion in patients without protocol positive ST segment elevation referred to an open access primary angioplasty programme. (zedie.wordpress.com)
Bioresorbable Drug-Eluting Scaffolds Emerging As The Dominant Device Of The Future For Percutaneous Coronary Interventions (medicalnewstoday.com)

The Magic of the Pandora’s Box : Epigenetics and Stemness with Long non-coding RNAs (lincRNA)

Posted in Advanced Drug Manufacturing Technology, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Stem Cells for Regenerative Medicine, tagged Biochemistry and Molecular Biology, Biology, CpG island, DNA, DNA methylation, ENCODE, epigenetic, gene, gene expression, genetics, genome, Genomic imprinting, MicroRNA, Non-coding RNA, RNA, RYBP on June 30, 2013| 8 Comments »

Genome Jigsaws (Photo credit: dullhunk)

Screen Shot 2021-07-19 at 6.31.37 PM

Word Cloud By Danielle Smolyar

Sequencing became the household name. In 2000s, it was thought to be the key of the Pandora’s box for cure. Then, after completion of Human Genome Projects showed that there are less number of genes than expected. This outcome induce to originate yet another set of sequencing programs and collaborations around the world, such as Human Protein Project, Human Microorganisms Projects, ENCODE, Transcriptome Sequencing and Consortiums etc.

It is in humankind to believe in magic and illusion. The strength of biological diversity and complex mechanism of expression may chalanges the set up of a simple but informative specific essay. Thus, there is a new developing field to mash rules of biology with mathematical formulas to develop the best bioinformatics or also called computational biology. Predicting transcription start or termination sites, exon boundaries, possible binding sites of transcription regulators for chromatin modification activities, like histone acetylates and enhancer- and insulator-associated factors based on the human genome sequence. Deep in mind, this assumption supports that the sequence contains signatures for chromatin modifications essential for gene regulation and development.

There are three primary colors, red, yellow and blue, however, an artist can create many shades. Recently, scientists combining and organizing more data to make sense of our blueprint of life to transfer info generation to generation with the hope to cure diseases of human kind.

Analyzing genome and transcriptome open the door. These studies suggested that all eukaryotic cells has a rich portfolio of RNAs. Among these long non-coding RNAs has impact on protein coding gene expression, regulating multiple processes even including epigenetic gene expression.

Epigenetics, stemness and non-coding RNAs play a great role to manipulate and correct the gene expression not only at a proper cell type but also location and time within genome without disturbing the host.

Main concern is differentiation of embryonic stem cells under these epigenetics and influencers. The best known post-transcriptional modifications, which include methylation, acetylation, ubiquination, and SUMOylation of lysine residues, methylation of arginine residues, and phosphorylation of serines, occur on histone tails. “Epi” means “top” or
“above” so this mechanism give a new direction to the genetic pathways as long as the organism live sometime and may lead into evolutions. It is critical to show the complexity of
mechanism and relativity of a gene role with a single example for each.

For example, DNA methylation occurs mostly on cytosine residues on the CpG islands usually located on promoter regions that are associated with tissue-specific gene expression. However, there are many other forms of DNA methylations, such as monoallelic methylation in gene imprinting and inactivation of the X chromosome, in repetitive elements, like transposons. There are two main mechanisms but this is not our main topic. Yet, Myc and hypoxia-inducible factor-1α versus certain methyl-CpG-binding proteins, such as MBD1,MBD2, MBD4, MeCP2, and Kaiso works differently.

Stemness is an important factor for an intervention to correct a pathological condition. In terms of epigenetics, regulation and non-coding RNA Vascular endothelial growth factor A (VEGF-A) is an interesting example for differentiation of endothelial cells and morphogenesis of the vascular system during development with several reasons, epigenetics, gene interactions, time and space. Everything has to be just right, because neither less nor too much can fulfill the destiny to become a complete adult cell or an organism. For example, both having only one VEGF-A allele and having two-fold excess of VEGF-A results in death during early embryogenesis, since mice can’t develop proper vascular network. However, explaining diverse mechanisms and functions of VEGF-A is require more information with specific details. VEGF-A plays many roles in many pathological cases, such as cancer, inflammation, retinopathies, and arthritis because VEGF-A has also function in epigenetic reprogramming of the promoter regions of Rex1 and Oct4 genes, that are critical for a stem cell. Preferred mechanism is anti-angiogeneic state but tumor cells prefer hypermethylation to induce pro-angiogeneic state, thus VEGF-A stimulates PIGF in tumour cells among many other factors.

Now, let’s turn around to observe development of a cell with Polycomb repressive complexes (PRCs) because they are important chromatin regulators of embryonic stem (ES) cell function. Originally, RYBP shown to function as transcriptional repressor in reporter assays from both in tissue culture cells and in fruit fly (Drosophila melanogaster ) and as a direct interactor with Ring1A during embryogenesis through methylation. In addition, RYBP in epigenetic resetting during preimplantation development through repression of germ line genes and PcG targets before formation of pluripotent epiblast cells. However, I do believe that the most important element is efficient repression of endogenous retroviruses (murine endogenous retrovirus called MuERV class), preimplantation containing zygotic genome activation stage and germ line specific genes. The selective repressor activity of RYBP is in the ES cell state. When RYBP^−/− ES cells were analyzed by measuring gene expression during differentiation as embryo bodies formed from mutant and wild-type cells, the result presented that expression of pluripotency genes Oct4 and Nanog was usually downregulated. However, RYBP is able to bind genomic regions independently of H3K27me3 and there is no relation between altered RYBP binding in Dnmt1-mutant cells to DNA methylation status. In sum, RYBP has a large value in undifferentiated ES cells and may affect or even reset epigenetic landscape during early developmental stages. These are the gaps filled by long non coding RNAs.

We learn more compelling information by comparing and contrasting what is normal and what is abnormal. As a result, pathology is a key learning canvas for basic mechanisms in molecular genetics. Then peppered with functional genomics completes the story for an edible outcome. We generally refer this as a Translational Research. For example, recent foundlings suggest that H19 contributes to cancer, including hepatocellular carcinoma (HCC) after reviewing Oncomine resource. According to these observations, in most HCC cases there is a lower expression of H19 level is compared to the liver. Thus, in vitro and in vivo studies were undertaken with classical genetic analyzes based on loss- and gain-of-function on H19 to characterize two outcomes depend on H19, that are the effects on gene expression and on HCC metastasis. First, the expression of H19 showed gene expression variation since H19 expression was low in tumor cells than peripheral tumor cells. Second, the metastasis of cancer based on alteration of miR-200 pathway contributing mesenchymal-to-epithelial transition by H19. Therefore, H19 and miR-200 are targets to be utilized during molecular diagnostics development and establishing targeted therapies in cancer.

Long story short, there is a circle of life where everything is connected even though they look different. As a result, when we see a sunflower or a baby we remember to smile, because life is still an act to puzzle human.

References and Further Readings:

“Non-coding RNAs as regulators of gene expression and epigenetics” Cardiovascular Res 1 June 2011: 430-440.

“Epigenetic regulation of key vascular genes and growth factors” Cardiovasc Res 1 June 2011: 441-446.

“Epigenetic Regulation by Long Noncoding RNAs” Science 14 December 2012: 1435-1439.

“Epigenetic control of embryonic stem cell fate” JEM 25 October 2010: 2287-2295.

“Transcribed dark matter: meaning or myth?” Hum Mol Genet 15 October 2010: R162-R168.

“Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma” Carcinogenesis 1 March 2013: 577-586.

“Vernalization-Mediated Epigenetic Silencing by a Long Intronic Noncoding RNA” Science 7 January 2011: 76-79.

“Predicting the probability of H3K4me3 occupation at a base pair from the genome sequence context” Bioinformatics 1 May 2013: 1199-1205.

Further Readings specific to Embryonic Stem Cell Differentiation and Development :

“BMP Induces Cochlin Expression to Facilitate Self-renewal and Suppress Neural Differentiation of Mouse Embryonic Stem Cells” J. Biol. Chem. 2013 288:8053-8060

Abstract

“Regulation of DNA Methylation in Rheumatoid Arthritis Synoviocytes” J. Immunol. 2013 190:1297-1303

Abstract

“DNA methylome signature in rheumatoid arthritis” Ann Rheum Dis 2013 72:110-117

Abstract

“The histone demethylase Kdm3a is essential to progression through differentiation” Nucleic Acids Res 2012 40:7219-7232

Abstract

“Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer” Nucleic Acids Res 2012 40:6725-6740

Abstract

“Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells” Nucleic Acids Res 2012 40:3403-3418

Abstract

“RYBP Represses Endogenous Retroviruses and Preimplantation- and Germ Line-Specific Genes in Mouse Embryonic Stem Cells” Mol. Cell. Biol. 2012 32:1139-1149

Abstract

“Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy” Clin. Cancer Res. 2012 18:77-90

Abstract

“OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes” Proc. Natl. Acad. Sci. USA 2011 108:14497-14502

Abstract

“Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging” Blood 2011 117:e182-e189

Abstract

“The CHD3 Chromatin Remodeler PICKLE and Polycomb Group Proteins Antagonistically Regulate Meristem Activity in the Arabidopsis” RootPlant Cell 2011 23:1047-1060

Abstract

“Chromatin structure of pluripotent stem cells and induced pluripotent stem cells” Briefings in Functional Genomics 2011 10:37-49

Abstract

Abbreviations used:

DNMT DNA methyl transferase

ES embryonic stem

JmjC Jumonji C

lincRNA long ncRNA

ncRNA noncoding RNA

PcG Polycomb group

PRC Polycomb repressive complex

PRE Polycomb repressive element

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