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Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Posted in Acute Myocardial Infarction, Biological Networks, Gene Regulation and Evolution, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, De novo synthesis, Diabetes Mellitus, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Endothelial cells, Epigenetics and Cardiovascular Risks, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical Devices R&D and Inventions, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged Absorb™ Bioresorbable Vascular Scaffold, Acute coronary syndrome, Acute decompensated heart failure, Angioplasty, Array-comparative genomic hybridization, Ca2+/calmodulin-dependent protein kinase, Cardiac & Vascular Repair, cardiac arrhythmias, cardiac biomarkers, cardiac myocyte regeneration, cardiomyocyte transformation, cardiovascular complications, Cardiovascular Risk Reduction, cEPC as Biomarker, Circulating Progenitor Endothelial Cells, comparative genomic hybridization, complement activation, endothelial cell, Endothelial Cell Coagulation Activation, functional genomics, Genome Biology, Genome engineering, Human Umbilical Vein Endothelial Cells (HUVECS), Induced pluripotent stem cells (iPS), regenerative medicine, Therapeutic Potential of cEPCs on April 27, 2014| Leave a Comment »

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This document is entirely devoted to medical and surgical therapies that have made huge strides in

simplification of interventional procedures,
reduced complexity, resulting in procedures previously requiring surgery are now done, circumstances permitting, by medical intervention.

This revolution in cardiovascular interventional therapy is regenerative medicine. It is regenerative because it is largely driven by

the introduction into the impaired vasculature of an induced pleuripotent cell, called a stem cell, although
the level of differentiation may not be a most primitive cell line.

There is also a very closely aligned development in cell biology that extends beyond and including vascular regeneration that is called synthetic biology. These developments have occurred at an accelerated rate in the last 15 years. The methods of interventional cardiology were already well developed in the mid 1980s. This was at the peak of cardiothoracic bypass surgery.

Research on the endothelial cell,

endothelial cell proliferation,
shear flow in small arteries, especially at branch points, and
endothelial-platelet interactions

led to insights about plaque formation and vessel thrombosis.

Much was learned in biomechanics about the shear flow stresses on the luminal surface of the vasculature, and there was also

the concomitant discovery of nitric oxide,
oxidative stress, and
the isoenzymes of nitric oxide synthase (eNOS, iNOS, and nNOS).

It became a fundamental tenet of vascular biology that

atherogenesis is a maladjustment to oxidative stress not only through genetic, but also
non-genetic nutritional factors that could be related to the balance of omega (ω)-3 and omega (ω)-6 fatty acids,
a pro-inflammatory state that elicits inflammatory cytokines, such as, interleukin-6 (IL6) and c-reactive protein(CRP),
insulin resistance with excess carbohydrate associated with type 2 diabetes and beta (β) cell stress,
excess trans- and saturated fats, and perhaps
the now plausible colonic microbial population of the gastrointestinal tract (GIT).

There is also an association of abdominal adiposity,

including the visceral peritoneum, with both T2DM and with arteriosclerotic vessel disease,
which is presenting at a young age, and has ties to
the effects of an adipokine, adiponectin.

Much important work has already been discussed in the domain of cardiac catheterization and research done to

prevent atheroembolization.and beyond that,
research done to implant an endothelial growth matrix.

Even then, dramatic work had already been done on

the platelet structure and metabolism, and
this has transformed our knowledge of platelet biology.

The coagulation process has been discussed in detailed in a previous document. The result was the development of a

new class of platelet aggregation inhibitors designed to block the activation of protein on the platelet surface that
is critical in the coagulation cascade.

In addition, the term long used to describe atherosclerosis, atheroma notwithstanding, is “hardening of the arteries”. This is particularly notable with respect to mid-size arteries and arterioles that feed the heart and kidneys. Whether it is preceded by or develops concurrently with chronic renal insufficiency and lowered glomerular filtration rate is perhaps arguable. However, there is now a body of evidence that points to

a change in the vascular muscularis and vessel stiffness, in addition to the endothelial features already mentioned.

This has provided a basis for

targeted pharmaceutical intervention, and
reduction in salt intake.

So we have a group of metabolic disorders, which may alone or in combination,

lead to and be associated with the long term effects of cardiovascular disease, including
congestive heart failure.

This has been classically broken down into forward and backward failure,

depending on decrease outflow through the aorta (ejection fraction), or
decreased venous return through the vena cava,

which involves increased pulmonary vascular resistance and decreased return into the left atrium.

This also has ties to several causes, which may be cardiac or vascular. This document, as the previous, has four pats. They are broadly:

Stem Cells in Cardiovascular Diseases
Regenerative Cell and Molecular Biology
Therapeutics Levels In Molecular Cardiology
Research Proposals for Endogenous Augmentation of circulating Endothelial Progenitor Cells (cEPCs)

As in the previous section, we start with the biology of the stem cell and the degeneration in cardiovascular diseases, then proceed to regeneration, then therapeutics, and finally – proposals for augmenting therapy with circulating endogenous endothelial progenitor cells (cEPCs).

stem cells

regeneration

Therapeutics

augmentation

Key pathways involving NO

stem cellLlin28

1479-5876-10-175-1-l translational research with feedback loops

Tranlational Research -Lab to Bedside

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Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

Posted in Accountable Care Organizations, Affordable Care Act, Atherogenic Processes & Pathology, Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Ca2+ triggered activation, Ca2+ triggered activation, Calcium Signaling, Calmodulin, Calmodulin Kinase and Contraction, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Congenital Heart Disease, Curation, Curation methodology, Cytoskeleton, De novo synthesis, Dialectic, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Evolutionary cognition, Experimental validation, Explanatory, Federal Budget Appropriations, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, Healthcare costs and reimbursement, HealthCare IT, Healthcare Reform, Historical relevance, HTN, Indigent Nutrition, Ionic Transporters Na+, K, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Medicare and Medicaid, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Nitric Oxide in Health and Disease, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, PKC, Population Health Management, Genetics & Pharmaceutical, Pre-Clinical Animal Model Development, Regenerative Biology and Medicine, Skilled Nursing Facilities, Stem Cells for Regenerative Medicine, Synaptic vesicle, Technology Advance Assessment of, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, Uninsured and Underinsured, tagged 249 SNPs associated with a number of heart-related conditions and treatments., Accountable Care Organization, acute coronary syndromes, Acute decompensated heart failure, Affordable Care Act, atherogenesis, Atherosclerosis, Atrial Fibrillation: IL6R Polymorphism in Whites and African Americans, calcium calmodulin kinase, calcium efflux, Cardiac & Vascular Repair, cardiac arrhythmias, cardiac biomarkers, Cardiogenesis, cardiomyocyte, cardiomyocyte hypertrophy, Content Curation, Coronary artery disease, Coronary circulation, Curation, efflux transporter, financial cost accounting, ion channels, ion transport, Na-K-Cl cotransporter, PKC, Pyruvate Kinase, seven CYP2C19 SNPs linked to Plavix response, SNPs, Synaptic vesicle on January 2, 2014| Leave a Comment »

Curation, HealthCare System in the US, and Calcium Signaling Effects on Cardiac Contraction, Heart Failure, and Atrial Fibrillation, and the Relationship of Calcium Release at the Myoneural Junction to Beta Adrenergic Release

Curator and e-book Contributor: Larry H. Bernstein, MD, FCAP
Curator and BioMedicine e-Series Editor-in-Chief: Aviva Lev Ari, PhD, RN

and

Content Consultant to Six-Volume e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC

This portion summarises what we have covered and is now familiar to the reader. There are three related topics, and an extension of this embraces other volumes and chapters before and after this reading. This approach to the document has advantages over the multiple authored textbooks that are and have been pervasive as a result of the traditional publication technology. It has been stated by the founder of ScoopIt, that amount of time involved is considerably less than required for the original publications used, but the organization and construction is a separate creative process. In these curations we amassed on average five articles in one curation, to which, two or three curators contributed their views. There were surprises, and there were unfulfilled answers along the way. The greatest problem that is being envisioned is the building a vision that bridges and unmasks the hidden “dark matter” between the now declared “OMICS”, to get a more real perspective on what is conjecture and what is actionable. This is in some respects unavoidable because the genome is an alphabet that is matched to the mino acid sequences of proteins, which themselves are three dimensional drivers of sequences of metabolic reactions that can be altered by the accumulation of substrates in critical placements, and in addition, the proteome has functional proteins whose activity is a regulatory function and not easily identified. In the end, we have to have a practical conception, recognizing the breadth of evolutionary change, and make sense of what we have, while searching for more.

We introduced the content as follows:

1. We introduce the concept of curation in the digital context, and it’s application to medicine and related scientific discovery.

Topics were chosen were used to illustrate this process in the form of a pattern, which is mostly curation, but is significantly creative, as it emerges in the context of this e-book.

Alternative solutions in Treatment of Heart Failure (HF), medical devices, biomarkers and agent efficacy is handled all in one chapter.
PCI for valves vs Open heart Valve replacement
PDA and Complications of Surgery — only curation could create the picture of this unique combination of debate, as exemplified of Endarterectomy (CEA) vs Stenting the Carotid Artery (CAS), ischemic leg, renal artery stenosis.

2. The etiology, or causes, of cardiovascular diseases consist of mechanistic explanations for dysfunction relating to the heart or vascular system. Every one of a long list of abnormalities has a path that explains the deviation from normal. With the completion of the analysis of the human genome, in principle all of the genetic basis for function and dysfunction are delineated. While all genes are identified, and the genes code for all the gene products that constitute body functions, there remains more unknown than known.

3. Human genome, and in combination with improved imaging methods, genomics offers great promise in changing the course of disease and aging.

4. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.

Curation

Curation is an active filtering of the web’s and peer reviewed literature found by such means – immense amount of relevant and irrelevant content. As a result content may be disruptive. However, in doing good curation, one does more than simply assign value by presentation of creative work in any category. Great curators comment and share experience across content, authors and themes.
Great curators may see patterns others don’t, or may challenge or debate complex and apparently conflicting points of view. Answers to specifically focused questions comes from the hard work of many in laboratory settings creatively establishing answers to definitive questions, each a part of the larger knowledge-base of reference. There are those rare “Einstein’s” who imagine a whole universe, unlike the three blindmen of the Sufi tale. One held the tail, the other the trunk, the other the ear, and they all said this is an elephant!
In my reading, I learn that the optimal ratio of curation to creation may be as high as 90% curation to 10% creation. Creating content is expensive. Curation, by comparison, is much less expensive. The same source says “Scoop.it is my content marketing testing “sandbox”. In sharing, he says that comments provide the framework for what and how content is shared.

Healthcare and Affordable Care Act

We enter year 2014 with the Affordable Care Act off to a slow start because of the implementation of the internet signup requiring a major repair, which is, unfortunately, as expected for such as complex job across the US, and with many states unwilling to participate. But several states – California, Connecticut, and Kentucky – had very effective state designed signups, separate from the federal system. There has been a very large rush and an extension to sign up. There are many features that we can take note of:

1. The healthcare system needed changes because we have the most costly system, are endowed with advanced technology, and we have inexcusable outcomes in several domains of care, including, infant mortality, and prenatal care – but not in cardiology.

2. These changes that are notable are:

The disparities in outcome are magnified by a large disparity in highest to lowest income bracket.
This is also reflected in educational status, and which plays out in childhood school lunches, and is also affected by larger class size and cutbacks in school programs.
This is not helped by a large paralysis in the two party political system and the three legs of government unable to deal with work and distraction.
Unemployment is high, and the banking and home construction, home buying, and rental are in realignment, but interest rates are problematic.

3. The medical care system is affected by the issues above, but the complexity is not to be discounted.

The medical schools are unable at this time to provide the influx of new physicians needed, so we depend on a major influx of physicians from other countries
The technology for laboratories, proteomic and genomic as well as applied medical research is rejuvenating the practice in cardiology more rapidly than any other field.
In fields that are imaging related the life cycle of instruments is shorter than the actual lifetime use of the instruments, which introduces a shortening of ROI.
Hospitals are consolidating into large consortia in order to maintain a more viable system for referral of specialty cases, and also is centralizing all terms of business related to billing.
There is reduction in independent physician practices that are being incorporated into the hospital enterprise with Part B billing under the Physician Organization – as in Partners in Greater Boston, with the exception of “concierge” medical practices.
There is consolidation of specialty laboratory services within state, with only the most specialized testing going out of state (Quest, LabCorp, etc.)
Medicaid is expanded substantially under the new ACA.
The federal government as provider of services is reducing the number of contractors for – medical devices, diabetes self-testing, etc.
The current rearrangements seeks to provide a balance between capital expenses and fixed labor costs that it can control, reduce variable costs (reagents, pharmaceutical), and to take in more patients with less delay and better performance – defined by outside agencies.

Cardiology, Genomics, and calcium ion signaling and ion-channels in cardiomyocyte function in health and disease – including heart failure, rhythm abnormalities, and the myoneural release of neurotransmitter at the vesicle junction.

This portion is outlined as follows:

2.1 Human Genome: Congenital Etiological Sources of Cardiovascular Disease	2.2 The Role of Calcium in Health and Disease	2.3 Vasculature and Myocardium: Diagnosing the Conditions of Disease
Genomics & Genetics of Cardiovascular Disease Diagnoses	actin cytoskeleton	wall stress, ventricular workload, contractile reserve
Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging	calcium and actin skeleton, signaling, cell motility	hypertension & vascular compliance
Genetics of Conduction Disease	Ca+ stimulated exostosis: calmodulin & PKC (neurotransmitter)	complications & MVR
	disruption of Ca2+ homeostasis cardiac & vascular smooth muscle
	synaptotagmin as Ca2+ sensor & vesicles
	atherosclerosis & ion channels

It is increasingly clear that there are mutations that underlie many human diseases, and this is true of the cardiovascular system. The mutations are mistakes in the insertion of a purine nucleotide, which may or may not have any consequence. This is why the associations that are being discovered in research require careful validation, and even require demonstration in “models” before pursuing the design of pharmacological “target therapy”. The genomics in cardiovascular disease involves very serious congenital disorders that are asserted early in life, but the effects of and development of atherosclerosis involving large and medium size arteries has a slow progression and is not dominated by genomic expression. This is characterized by loss of arterial elasticity. In addition there is the development of heart failure, which involves the cardiomyocyte specifically. The emergence of regenerative medical interventions, based on pleuripotent inducible stem cell therapy is developing rapidly as an intervention in this sector.

Finally, it is incumbent on me to call attention to the huge contribution that research on calcium (Ca2+) signaling has made toward the understanding of cardiac contraction and to the maintenance of the heart rhythm. The heart is a syncytium, different than skeletal and smooth muscle, and the innervation is by the vagus nerve, which has terminal endings at vesicles which discharge at the myocyte junction. The heart specifically has calmodulin kinase CaMK II, and it has been established that calmodulin is involved in the calcium spark that triggers contraction. That is only part of the story. Ion transport occurs into or out of the cell, the latter termed exostosis. Exostosis involves CaMK II and pyruvate kinase (PKC), and they have independent roles. This also involves K+-Na+-ATPase. The cytoskeleton is also discussed, but the role of aquaporin in water transport appears elsewhere, as the transport of water between cells. When we consider the Gibbs-Donnan equilibrium, which precedes the current work by a century, we recall that there is an essential balance between extracellular Na+ + Ca2+ and the intracellular K+ + Mg2+, and this has been superceded by an incompletely defined relationship between ions that are cytoplasmic and those that are mitochondrial. The glass is half full!

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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/