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


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:

  1. Stem Cells in Cardiovascular Diseases
  2. Regenerative Cell and Molecular Biology
  3. Therapeutics Levels In Molecular Cardiology
  4. 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).

 

context

stem cells

 

theme

regeneration

 

 

 

 

theme

Therapeutics

 

theme

augmentation

 

 

 

 

 

 

 

 

 

 

Key pathways involving NO

Key pathways involving NO

 

 

 

 

stem cell lin28

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


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 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

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

  1. the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003),
  2. 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,

  1. worsened renal function, and
  2. 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. 

Other related articles published on this Open Access Online Scientific Journal 

Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone (Justin Pearlman, (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2013/05/22/acute-and-chronic-myocardial-infarction-quantification-of-myocardial-viability-fdg-petmri-vs-mri-or-pet-alone/

Accurate Identification and Treatment of Emergent Cardiac Events (larryhbern)
https://pharmaceuticalintelligence.com/2013/03/15/accurate-identification-and-treatment-of-emergent-cardiac-events/

Nitric Oxide and it’s Impact on Cardiothoracic Surgery (tildabarliya)
https://pharmaceuticalintelligence.com/2012/12/15/nitric-oxide-and-its-impact-on-cardiothoracic-surgery/

CABG or PCI: Patients with Diabetes – CABG Rein Supreme (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2012/11/05/cabg-or-pci-patients-with-diabetes-cabg-rein-supreme/

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

Critical Care | Abstract | Cardiac ischemia in patients with septic … (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2013/06/26/critical-care-abstract-cardiac-ischemia-in-patients-with-septic/

Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays (larryhbern)
https://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA (Aviva Lev-ARi)
https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Assessing Cardiovascular Disease with Biomarkers (larryhbern)
https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

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

Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

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

Congestive Heart Failure & Personalized Medicine: Two-gene Test predicts response to Beta Blocker Bucindolol (Aviva Lev-Ari)
https://pharmaceuticalintelligence.com/2012/10/17/chronic-heart-failure-personalized-medicine-two-gene-test-predicts-response-to-beta-blocker-bucindolol/

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

Long-Term Mortality in Treated Hypertensive Patients: Serum Uric Acid Level, Longitudinal Blood Pressure and Renal Function

Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/20/long-term-mortality-in-treated-hypertensive-patients-serum-uric-acid-level-longitudinal-blood-pressure-and-renal-function/

Renal Sympathetic Denervation: Updates on the State of Medicine

Aviva Lev-Ari, PhD,RN

https://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

Chapter 8: Nitric Oxide and Kidney Dysfunction

https://pharmaceuticalintelligence.com/biomed-e-books/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

8.1 Part I: The Amazing Structure and Adaptive Functioning of the Kidneys: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.2 Part II: Nitric Oxide and iNOS have Key Roles in Kidney Diseases

Larry H. Bernstein, MD, FCAP

8.3 Part III: The Molecular Biology of Renal Disorders: Nitric Oxide

Larry H. Bernstein, MD, FCAP

8.4 Part IV: New Insights on Nitric Oxide Donors

Larry H. Bernstein, MD, FCAP

8.5 The Essential Role of Nitric Oxide and Therapeutic Nitric Oxide Donor Targets in Renal Pharmacotherapy

What is Acute Heart Failure?

What is Acute Heart Failure? (Photo credit: Novartis AG)

English: Physiology of Nephron

English: Physiology of Nephron (Photo credit: Wikipedia)

Forrester-classification for classification of...

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

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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/

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

High-Sensitivity Cardiac Troponin Assays- Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Reporter: Larry Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/06/13/high-sensitivity-cardiac-troponin-assays/

Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays

Larry Bernstein and Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA
Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

  • Redberg’s conclusions are correct for the initial screening. The issue has been whether to do further testing for low or intermediate risk patients.
  • The most intriguing finding that is not at all surprising is that the CCTA added very little in the suspect group with small or moderate risk.
  • The ultra sensitive troponin threw the ROC out the window
  • The improved assay does pick up minor elevations of troponin in the absence of MI.

Critical Care | Abstract | Cardiac ischemia in patients with septic …
Aviva Lev-Ari
https://pharmaceuticalintelligence.com/2013/06/26/critical-care-abstract-cardiac-ischemia-in-patients-with-septic/

  • refer to:  Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine

Mehta S, Granton J,  Gordon AC, Cook DJ, et al.
Critical Care 2013, 17:R117   http://dx.doi.org/10.1186/cc12789
Troponin and CK levels, and rates of ischemic ECG changes were similar in the VP and NE groups. In multivariable analysis

  • only APACHE II was associated with 28-day mortality (OR 1.07, 95% CI 1.01-1.14, p=0.033).

Assessing Cardiovascular Disease with Biomarkers
larryhbern
https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

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