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Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

  • Larry H Bernstein, MD, FCAP, Author and Curator, Volume Four, Co-Editor
  • Justin Pearlman, MD, PhD, FACC, Content Consultant for Series A: Cardiovascular Diseases
  • Aviva Lev-Ari, PhD, RN, Co-Editor of Volume Four and Editor-in-Chief, BioMed e-Series

 

This completes Chapter 4 in two parts on the most dynamic developments in the regulatory pathways guiding cardiovascular dynamics and function in health and disease.  I have covered key features of these in two summaries, so I shall try to look further into important expected future directions and their anticipated implications.

1. Mechanisms of Disease

Signal Transduction: Akt Phosphorylates HK-II at Thr-473 and Increases Mitochondrial HK-II Association to Protect Cardiomyocytes

David J. Roberts, Valerie P. Tan-Sah, Jeffery M. Smith and Shigeki Miyamoto
J. Biol. Chem. 2013, 288:23798-23806.  http://dx.doi.org/ 10.1074/jbc.M113.482026

Backgound: Hexokinase II binds to mitochondria and promotes cell survival.
Results: Akt phosphorylates HK-II but not the threonine 473 mutant. The phosphomimetic T473D mutant decreases its dissociation from mitochondria induced by G-6P and increases cell viability against stress.
Conclusion: Akt phosphorylates HK-II at Thr-473, resulting in increased mitochondrial HK-II and cell protection.
Significance: The Akt-HK-II signaling nexus is important in cell survival.

HK-II Phosphorylation

HK-II Phosphorylation

 

 

 

 

 

 

It has been demonstrated that an increased level of HK-II at mitochondria is protective and is increased by protective interventions but decreased under stress.

It   has not  been fully determined   which  molecular  signals  regulate  the    level    of  HK-II at mitochondria.

Thr-473 in HK-II  is phosphorylated by Akt and this phosphorylation  leads to  increases  in  mitochondrial  HK-II binding  through inhibition  of  G-6P-dependent  dissociation, conferring resistance to oxidative stress  (Fig.     7).

Overexpression of  WTHK-II increases mitochondrial HK-II and confers protection against  hydrogen peroxide,  which  is enhanced significantly  in   HK-II   T473D-expressing  cells, whereas  NHK-II, lacking the ability to bind to mitochondria, does not confer protection.   Conversely,  mitochondrial  HK-II from mitochondria (Fig.6, and B) inhibits  the  IGF-1-mediated increase in mitochondrial HK-II and cellular protection.   Similar   dose-dependent  curves were obtained in mitochondrial   HK-II     against stress    (15–25).

Gene Expression and Genetic Variation in Human Atria

Honghuang Lin PhD, Elena V. Dolmatova MD, Michael P. Morley, PhD, Kathryn L. Lunetta PhD, David D. McManus MD, ScM, et al.
Heart Rhythm  2013   http://dx.doi.org/10.1016/j.hrthm.2013.10.051

Background— The human left and right atria have different susceptibilities to develop atrialfibrillation (AF). However, the molecular events related to structural and functional changes that
enhance AF susceptibility are still poorly understood.
Objective— To characterize gene expression and genetic variation in human atria.
Results— We found that 109 genes were differentially expressed between left and right atrial tissues. A total of 187 and 259 significant cis-associations between transcript levels and genetic
variants were identified in left and right atrial tissues, respectively. We also found that a SNP at a known AF locus, rs3740293, was associated with the expression of MYOZ1 in both left and right
atrial tissues.
Conclusion— We found a distinct transcriptional profile between the right and left atrium, and extensive cis-associations between atrial transcripts and common genetic variants. Our results
implicate MYOZ1 as the causative gene at the chromosome 10q22 locus for AF.

Long-Term Caspase Inhibition Ameliorates Apoptosis, Reduces Myocardial Troponin-I Cleavage, Protects Left Ventricular Function, and Attenuates Remodeling in Rats With Myocardial Infarction

Y. Chandrashekhar,  Soma Sen, Ruth Anway,  Allan Shuros,  Inder Anand,

J Am Col  Cardiol  2004; 43(2)   http://dx.doi.org/10.1016/j.jacc.2003.09.026

This study was designed to evaluate whether in vivo caspase inhibition can prevent myocardial contractile protein degradation, improve myocardial function, and attenuate ventricular remodeling.
Apoptosis is thought to play an important role in the development and progression of heart failure (HF) after a myocardial infarction (MI). However, it is not known whether inhibiting apoptosis can attenuate left ventricular (LV) remodeling and minimize systolic dysfunction.

A 28-day infusion of caspase inhibitor was administeredimmediately after an anterior MI. In addition, five sham-operated rats given the caspase inhibitor were compared with 17 untreated sham-operated animals to study effects in non-MI rats. Left ventricular function, remodeling parameters, and hemodynamics were studied four weeks later. Myocardial caspase 3 activation and troponin-I contractile protein cleavage were studied in the non-infarct, remote LV myocardium using Western blots. Apoptosis was assessed using immunohistochemistry for activated caspase-positive cells as well as the TUNEL method. Collagen volume was estimated using morphometry.

Caspase inhibition reduced myocardial caspase 3 activation. This was accompanied by less cleavage of troponin-I, an important component of the cardiac contractile apparatus, and fewer apoptotic cardiomyocytes. Furthermore, caspase inhibition reduced LV-weight-to- body-weight ratio, decreased myocardial interstitial collagen deposition, attenuated LV remodeling, and better preserved LV systolic function after MI.

Caspase inhibition, started soon after MI and continued for four weeks, preserves myocardial contractile proteins, reduces systolic dysfunction, and attenuates ventricular remodeling.

These findings may have important therapeutic implications in post-MI HF. J Am Col Cardiol 2004;43:295–301)

Precardiac deletion of Numb and Numblike reveals renewal of cardiac progenitors

Lincoln T Shenje,  Peter P Rainer , Gun-sik Cho , Dong-ik Lee , Weimin Zhong , Richard P Harvey , David A Kass , Chulan Kwon *,  et al.
eLife 2014.    http://dx.doi.org/10.7554/eLife.02164.001

Cardiac progenitor cells (CPCs) must control their number and fate to sustain the rapid heart growth during development, yet the intrinsic factors and environment governing these processes remain unclear. Here, we show that deletion of the ancient cell-fate regulator Numb (Nb) and its homologue Numblike (Nbl) depletes CPCs in second pharyngeal arches (PA2s) and is associated with an atrophic heart. With histological, fow cytometric and functional analyses, we fnd that CPCs remain undifferentiated and expansive in the PA2, but differentiate into cardiac cells as they exit the arch. Tracing of Nb- and Nbl-defcient CPCs by lineage-specifc mosaicism reveals that the CPCs normally populate in the PA2, but lose their expansion potential in the PA2. These fndings demonstrate that Nb and Nbl are intrinsic factors crucial for the renewal of CPCs in the PA2 and
that the PA2 serves as a microenvironment for their expansion.

2. Diagnostics and Risk Assessment

Classical and Novel Biomarkers for Cardiovascular Risk Prediction in the United States

Aaron R. Folsom
J Epidemiol 2013;23(3):158-162   http://dx.doi.org/10.2188/jea.JE20120157

Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of
cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction
beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely,

  1. hemoglobin A1c (in all adults),
  2. microalbuminuria (in patients with hypertension or diabetes), and
  3. C-reactive protein,
  4. lipoprotein-associated phospholipase,
  5. coronary calcium,
  6. carotid intima-media thickness, and
  7. ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).

Diagnostic accuracy of NT-proBNP ratio (BNP-R) for early diagnosis of tachycardia-mediated cardiomyopathy: a pilot study

Amir M. Nia, Natig Gassanov, Kristina M. Dahlem, Evren Caglayan, Martin Hellmich, et al.
Clin Res Cardiol (2011) 100:887–896    http://dx.doi.org/10.1007/s00392-011-0319-y

Tachycardia-mediated cardiomyopathy (TMC) occurs as a consequence of prolonged high heart rate due to ventricular and supraventricular tachycardia. In animal models, rapid pacing induces severe biventricular remodeling with dilation and dysfunction [7]. On a cellular basis, cardiomyocytes exert fundamental morphological and functional roles.

When heart failure and tachycardia occur simultaneously, a useful diagnostic tool for early discrimination of patients with benign tachycardia-mediated  cardiomyopathy (TMC) versus major structural heart disease  (MSHD) is not available. Such a tool is required to prevent unnecessary and wearing diagnostics in patients with reversible TMC. Moreover, it could lead to early additional diagnostics and therapeutic approaches in patients with  MSHD.

A total of 387 consecutive patients with supraventricular arrhythmia underwent assessment.  Of these patients, 40 fulfilled the inclusion criteria
with a resting heart rate C100 bpm and an impaired left ventricular ejection fraction \40%. In all patients, successful electrical cardioversion was performed. At baseline, day 1 and weekly for 4 weeks, levels of NT-proBNP and echocardiographic parameters were evaluated.

NT-proBNP ratio (BNP-R) was calculated as a quotient of baseline NT-proBNP/follow-up NT-proBNP. After 4 weeks, cardiac catheterization was performed to identify patients with a final diagnosis of TMC versus MSHD.

Initial NT-proBNP concentrations were elevated and consecutively decreased after cardioversion in all patients studied. The area under the ROC curve for BNP-R to detect TMC was 0.90 (95% CI 0.79–1.00; p \ 0.001) after 1 week  and 0.995 (95% CI 0.99–1.00; p \ 0.0001) after 4 weeks. One week after cardioversion already, a BNP-R cutoff C2.3 was useful for TMC diagnosis indicated by an accuracy of 90%, sensitivity of 84% and specificity of 95%.

BNP-R was found to be highly accurate for the early diagnosis of TMC.

Omega-3 Index and Cardiovascular Health

Clemens von Schacky
Nutrients 2014; 6: 799-814;  http://dx. doi.org/10.3390/nu602099

Fish, marine oils, and their concentrates all serve as sources of the two marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as do some products from algae.
To demonstrate an effect of EPA + DHA on heart health, a number of randomized, controlled intervention studies with clinical endpoints like overall mortality or a combination of adverse cardiac events were conducted in populations with elevated cardiovascular risk. One early intervention study with oily fish, rich in EPA + DHA, and some early studies with fish oil or fish oil concentrate or even purified EPA at doses ranging between 0.9 and 1.8 g/day indeed demonstrated effects in terms of fewer sudden cardiac deaths, fatal or non-fatal myocardial infarctions, or a combination of adverse cardiac events.

Recent meta-analyses found no significant benefits on total mortality, cardiovascular mortality, and other adverse cardiac or cardiovascular events [13–18]. This is in contrast to findings in epidemiologic studies, where intake of EPA + DHA had been found to correlate generally with an up to 50% lower incidence of adverse cardiac events [18,19], and in even sharper contrast to epidemiologic studies based on levels of EPA + DHA, demonstrating e.g., a 10-fold lower incidence of sudden cardiac death associated with high levels of the
fatty acids, as compared to low levels.

This seemingly contradictory evidence has led the American Heart Association to recommend “omega-3 fatty acids from fish or fish oil capsules (1 g/day) for cardiovascular disease risk reduction” for secondary prevention, whereas the European Society for Cardiology recommends “Fish at least twice a week, one of which to be oily fish”, but no supplements for cardiovascular prevention.

A similar picture emerges for atrial fibrillation: In epidemiologic studies, consumption of EPA + DHA or higher levels of EPA + DHA were associated with lower risk for developing atrial fibrillation, while intervention studies found no effect. Pertinent guidelines do not mention EPA + DHA. A similar picture also emerges for severe ventricular rhythm disturbances.

Why is it that trial results are at odds with results from epidemiology? What needs to be done to better translate the epidemiologic findings into trial results? The current review will try to shed some light on this  issue, with a special consideration of the Omega-3 Index.

Recent large trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the cardiovascular field did not demonstrate a beneficial effect in terms of reductions of clinical endpoints like

  • total mortality,
  • sudden cardiac arrest or
  • other major adverse cardiac events.

Pertinent guidelines do not uniformly recommend EPA + DHA for cardiac patients. In contrast,

  • in epidemiologic findings, higher blood levels of EPA + DHA were consistently associated with a lower risk for the endpoints mentioned.

The following points argue for the use of erythrocytes: erythrocyte fatty acid
composition has a low biological variability, erythrocyte fat consists almost exclusively of phospholipids, erythrocyte fatty acid composition reflects tissue fatty acid composition, pre-analytical stability, and other points.  In 2004, EPA + DHA in erythrocyte fatty acids were defined as the Omega-3 Index and suggested as a risk factor for sudden cardiac death [39]. Integral to the definition was a specific and standardized analytical procedure, conforming the quality management routinely implemented in the field of clinical chemistry.

The laboratories adhering to the HS-Omega-3 Index methodology perform regular proficiency testing, as mandated in routine Clinical Chemistry labs. So far, the HS-Omega-3 Index is the only analytical procedure used in several laboratories. A standardized analytical procedure is a prerequisite to generate the data base necessary to transport a laboratory parameter from research into clinical routine. Moreover, standardization of the analytical procedure is the first important criterion for establishing a new biomarker for cardiovascular risk set forth by the American Heart Association and the US Preventive Services Task Force.

Because of low biological and analytical variability, a standardized analytical procedure, a large database and for other reasons,

  • blood levels of EPA + DHA are frequently assessed in erythrocytes, using the HS-Omega-3 Index methodology.

Table 1. Mean HS-Omega-3 Index values in various populations, Mean (±standard deviation (SD)). Please note that in every population studied, a lower value was found to be associated with a worse condition than a higher value. References are given, if not, unpublished, n = number of individuals measured.

All levels of fatty acids are determined by the balance of substance entering the body and those leaving the body. Neither a recent meal, even if rich in EPA + DHA, nor severe cardiac events altered the HS-Omega-3 Index. However, while long-term intake of EPA + DHA, e.g., as assessed with food questionnaires, was the main predictor of the HS-Omega-3 Index, long-term intake explained only 12%–25% of its variability. A hereditary component of 24% exists. A number of other factors correlated positively (+) or negatively (−), like age (+), body mass index (−), socioeconomic status (+), smoking (−), but no other conventional cardiac risk factors. More factors determining the level of the HS-Omega-3 Index, especially regarding efflux remain to be  defined. Therefore, it is impossible to predict the HS-Omega-3 Index in an individual, as it is impossible to predict the increase in the HS-Omega-3 Index in an individual in response to a given dose of EPA + DHA. In Table 2, current evidence is presented on the relation of the HS-Omega-3 Index to CV events.

The HS-Omega-3 Index has made it possible to reclassify individuals from intermediate cardiovascular risk into the respective high risk and low risk strata, the third criterion for establishing a new biomarker for CV  risk.

A low Omega-3 Index fulfills the current criteria for a novel cardiovascular risk factor.

Increasing the HS-Omega-3 Index by increased intake of EPA + DHA in randomized controlled trials improved a number of surrogate parameters for cardiovascular risk:

  1. heart rate was reduced,
  2. heart rate variability was increased,
  3. blood pressure was reduced,
  4. platelet reactivity was reduced,
  5. triglycerides were reduced,
  6. large buoyant low-density lipoprotein (LDL)-particles were increased and
  7. small dense LDL-particles were reduced,
  8. large buoyant high-density lipoproteins (HDL)2 were increased,
  9. very low-density lipoprotein (VLDL1) + 2 was reduced,
  10. pro-inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin-1β, interleukins-6,8,10 and monocyte chemoattractant protein-1) were reduced,
  11. anti-inflammatory oxylipins were increased.

Importantly, in a two-year randomized double-blind angiographic intervention trial, increased erythrocyte EPA + DHA

  • reduced progression and increased regression of coronary lesions, an intermediate parameter.

Taken together, increasing the HS-Omega-3 Index improved surrogate and intermediate parameters for cardiovascular events. A large intervention trial with clinical endpoints based on the HS-Omega-3 Index remains to be conducted. Therefore, the fourth criterion, proof of therapeutic consequence of determining the HS-Omega- Index, is only partially fulfilled.

 

Neutral results of intervention trials can be explained by issues of bioavailability and trial design that surfaced after the trials were initiated.

In the future, incorporating the Omega-3 Index into trial designs by

  1. recruiting participants with a low Omega-3 Index and
  2. treating them within a pre-specified target range (e.g., 8%–11%),
  3. will make more efficient trials possible and
    • provide clearer answers to the questions asked than previously possible.

 

3. Stem Cells and Regenerative Biology

Adult Stem Cells Reverse Muscle Atrophy In Elderly Mice   http://www.science20.com/profile/news_staff

Bioengineers at the University of California, Berkeley in a new study published in Nature say they have identified two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue. They then tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice’s much younger counterparts. Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), led the research team conducting this study. Because the findings relate to adult stem cells that reside in existing tissue, this approach to rejuvenating degenerating muscle eliminates the ethical and medical complications associated with transplanting tissues grown from embryonic stem cells. The researchers focused on

  • the interplay of two competing molecular pathways that control the stem cells,

which sit next to the mature, differentiated cells that make up our working body parts. When the mature cells are damaged or wear out, the stem cells are called into action to begin the process of rebuilding.

old muscle tissue is left with

old muscle tissue is left with

 

 

 

 

 

 

 

 

 

 

 

 

“We don’t realize it, but as we grow our bodies are constantly being remodeled,” said Conboy. “We are constantly falling apart, but we don’t notice it much when we’re young because we’re always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs.” The good news, the researchers said, is that

  • the stem cells in old tissue are still ready and able to perform their regenerative function
  • if they receive the appropriate chemical signals.

Studies have shown that when old tissue is placed in an environment of young blood, the stem cells behave as if they are young again. “Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice,” said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering.

  • Adult stem cells have a receptor called Notch that, when activated,
  • tells them that it is time to grow and divide
  • stem cells also have a receptor for the protein TGF-beta
  • that sets off a chain reaction activatingthemoleculepSmad3 and
    • ultimately producing cyclin-dependent kinase (CDK) inhibitors, which regulate the cell’s ability to divide.
  • activated Notch competeswithactivatedpSmad3 for
    • binding to the regulatory regions of the same CDK inhibitors in the stem cell

“We found that Notch is capable of physically kicking off pSmad3 from the promoters for the CDK inhibitors within the stem cell’s nucleus, which tells us that a precise manipulation of the balance of these pathways would allow the ability to control stem cell responses.” Notch and TGF-beta are well known in molecular biology, but Conboy’s lab is the first to connect them to the process of aging, and the first to show that they act in opposition to each other within the nucleus of the adult stem cell. Aging and the inevitable march towards death are, in part, due to the progressive decline of Notch and the increased levels of TGF-beta , producing a one-two punch to the stem cell’s capacity to effectively rebuild the body, the researchers said.

The researchers disabled the “aging pathway” that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3. The researchers then examined the muscle of the different groups of mice one to five days after injury to compare how well the tissue repaired itself. As expected,

  •  muscle tissue in the young mice easily replaced damaged cells with new, healthy cells. In contrast,
  • the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue. However,
  • muscles in the old mice whose stem cell “aging pathway”had been dampened showed levels of cellular regeneration that were
    • comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of “untreated” old mice.

Adult Stem Cells To Repair Damaged Heart Muscle

http://www.science20.com/profile/news_staff

In the first trial of its kind in the world, 60 patients who have recently suffered a major heart attack will be injected with selected stem cells from their own bone marrow during routine coronary bypass surgery. The Bristol trial will test

  • whether the stem cells will repair heart muscle cells damaged by the heart attack,
  • by preventing late scar formation and hence impaired heart contraction.

“ Cardiac stem cell therapy aims to repair the damaged heart as it has the potential to replace the damaged tissue.” We have elected to use a very promising stem cell type selected from the patient’s own bone marrow. This approach ensures no risk of rejection or infection. It also gets around the ethical issues that would result from use of stem cells from embryonic or foetal tissue.

In this trial (known as TransACT), all patients will have bone marrow harvested before their heart operation. Then either stem cells from their own bone marrow or a placebo will be injected into the patients’ damaged hearts during routine coronary bypass surgery. The feasibility and safety of this technique has already been demonstrated. As a result of the chosen double blind placebo-controlled design, neither the patients nor the surgeon knows whether the patient is going to be injected with stem cells or placebo. This ensures that results are not biased in any way, and is the most powerful way to prove whether or not the new treatment is effective.

Research of Stem Cells Repair Damaged Heart

By Kelvinlew Minhan | March 26th 2008

Under highly specific growth conditions in laboratory culture dishes, stem cells

  • can be coaxed into developing as new cardiomyocytes and vascular endothelial cells (Kirschstein and Skirboll, 2001).

Discoveries that have triggered the interest in the application of adult stem cells to heart muscle repair in animal models have been made by researchers in the past few years (Kirschstein and Skirboll, 2001). One  study demonstrated that cardiac tissue can be regenerated in the mouse heart attack model through the introduction of adult stem cells from mouse bone marrow (Kirschstein and Skirboll, 2001). These cells were transplanted into the marrow of irradiated mice approximately 10 weeks before the recipient mice were subjected to heart attack thru tying off different major heart blood vessel, the left anterior descending (LAD) coronary artery. The survival rate was 26 percent at two to four weeks after the induced cardiac injury (Kirschstein and Skirboll, 2001). Another study of the region surrounding the damaged tissue in surviving mice showed the presence of donor-derived cardiomyocytes and endothelial cells (Kirschstein and Skirboll, 2001).

  • the mouse hematopoietic stem cells transplanted into the bone marrow had migrated to the border part of the damaged area, and differentiated into several types of tissue for cardiac repair.

Regenerating heart tissue through stem cell therapy

http://www.mayo.edu/research/discoverys-edge/regenerating-heart-tissue-stem-cell-therapy

Summary

A groundbreaking study on repairing damaged heart tissue through stem cell therapy has given patients hope that they may again live active lives. An international team of Mayo Clinic researchers and collaborators has done it by discovering a way to regenerate heart tissue.

“It’s a paradigm shift,” says Andre Terzic, M.D., Ph.D., director of Mayo Clinic’s Center for Regenerative Medicine and senior investigator of the stem cell trial. “We are moving from traditional medicine, which addresses the symptoms of disease to cure disease.” Treating patients with cardiac disease has typically involved managing heart damage with medication.  In collaboration with European researchers, Mayo Clinic researchers have discovered a novel way to repair a damaged heart. In Mayo Clinic’s breakthrough process,
  • stem cells are harvested from a patient’s bone marrow.
  •  undergo a laboratory treatment that guides them into becoming cardiac cells,
  • which are then injected into the patient’s heart in an effort to grow healthy heart tissue.
The study is the first successful demonstration in people of the feasibility and safety of transforming adult stem cells into cardiac cells. Beyond heart failure, the Mayo Clinic research also is a milestone in the emerging field of regenerative medicine, which seeks to fully heal damaged tissue and organs.

Creating a heart repair kit

Process of converting bone marrow cells to heart cells
This image shows the process used in the clinical trials to repair damaged hearts. Cardioprogenitor cells is another term for cardiopoietic cells, those that were transformed into cardiac cells.
Stem cells transforming to cardiac tissue
Transformation: The cardiopoietic cells on the left react to the cardiac environment, cluster together with like cells and form tissue.
 Mayo Clinic researchers pursued this research, inspired by an intriguing discovery. In the early 2000s, they analyzed stem cells from 11 patients undergoing heart bypass surgery. The stem cells from two of the patients had an unusually high expression of certain transcription factors — the proteins that control the flow of genetic information between cells. Clinically, the two patients appeared no different from the others, yet their stem cells seemed to show unique capacity for heart repair.
That observation drove them to  determine how to convert  nonreparative stem cells to become reparative. Doing so required determining precisely how the human heart naturally develops, at a subcellular level. That painstaking work was led by Atta Behfar, M.D., Ph.D., a cardiovascular researcher at Mayo Clinic in Rochester, Minn. With other members of the Terzic research team, Dr. Behfar identified hundreds of proteins involved in the process of heart development (cardiogenesis). The researchers then set out to identify which of these proteins are essential in driving a stem cell to become a cardiac cell. Using computer models,
  • they simulated the effects of eliminating proteins one by one from the process of heart development.
  • That method yielded about 25 proteins.
    • The team then pared that number down to 8 proteins that their data indicated were essential.
The research team was then able to develop the lab procedure that guides stem cells to become heart cells.
The treated stem cells were dubbed cardiopoietic, or heart creative. A proof of principle study about guided cardiopoiesis, whose results were published in the Journal of the American College of Cardiology in 2010, demonstrated that animal models with heart disease that had been injected with caridiopoietic cells had improved heart function compared with animals injected with untreated stem cells. Hailed as “landmark work,” by the journal’s editorial writer, the study showed it was indeed possible to teach stem cells to become cardiac cells. Stem cells from each patient in the cardiopoiesis group were successfully guided to become cardiac cells. The treated cells were injected into the heart wall of each of those patients without apparent complications.
“Ihis newprocessofcardiopoiesiswas achieved in 100 percent of cases, with a very good safety profile,” Dr.Terzic says. “We are enabling the heart toregainitsinitial structure and function,” Dr.Terzic says, “and we will not stop here.” The clinicaltrialfindingsareexpectedto be published in the Journal of the American College of Cardiology in 2013.  Meanwhile, research to improve the injection process and effectiveness is underway.

Stem Cells from Humans Repair Heart Damage in Monkeys

GEN News Highlights  May1, 2014

GPCR Insights Brighten Drug Discovery Outlook

Ken Doyle, Ph.D.

GEN Apr 15, 2014 (Vol. 34, No. 8)

Recent years have seen major advances in understanding the structure-function relationships of G protein-coupled receptors (GPCRs). This large superfamily of transmembrane receptors comprises over 800 members in humans.

GPCRs regulate a wide variety of physiological processes including

  • sensation (vision, taste, and smell),
  • growth,
  • hormone responses, and
  • regulation of the immune and
  • autonomic nervous systems.

Their involvement in multiple disease pathways makes GPCRs attractive targets for drug discovery efforts.

These multifaceted proteins will be the subject of “GPCR Structure, Function and Drug Discovery,” a Global Technology Community conference scheduled to take place May 22–23 in Boston. The conference is expected to cover a broad range of topics including biased signaling, membrane protein structures, GPCR signaling dynamics, computational approaches to disease.

According to Bryan Roth, M.D., Ph.D., Michael Hooker Distinguished Professor at the University of North Carolina, Chapel Hill,

  • drugs that can selectively target various downstream GPCR pathways hold the most promise.

Dr. Roth’s laboratory studies approximately 360 different GPCRs with therapeutic potential using massively parallel screening methods. His research focuses on “functional selectivity,” which he describes as

  • “the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor.”

Dr. Roth notes that structural data have demonstrated that GPCRs exist in multiple conformations: “The structures of the 5-hydroxytryptamine 2B receptor and the recent high-resolution delta-opioid receptor structure have provided evidence for conformational rearrangements that contribute to functional selectivity.” Drugs that take advantage of this selectivity by preferentially stabilizing certain conformations may have unique therapeutic utility.

“Generally, we look at G protein versus arrestin-based signaling, although it’s also possible to examine how drugs activate one G protein-mediated signaling pathway versus another.

 

fluorescently tagged Arrestin and GPRC of interest

fluorescently tagged Arrestin and GPRC of interest

 

 

 

 

 

 

 

  • β-Arrestins constitute a major class of intracellular scaffolding proteins that regulate GPCR signaling by preventing or enhancing the binding of GPCRs to intracellular signaling molecules. Laura Bohn, Ph.D., associate professor at Scripps Florida,  studies the roles that β-arrestins play in GPCR-mediated signaling.
  • a particular β-arrestin can play multiple, tissue-specific roles—shutting down the signaling of a receptor in one tissue while activating signaling in another.
  • different ligands can direct GPCR signaling to different effectors, which could result in different physiological effects,” comments Dr. Bohn. “Our challenge is in determining what signaling pathways to harness to promote certain effects, while avoiding others.”
Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

Arrestin binding to active GPCR kinase (GRK)-phosphorylated GPCRs blocks G protein coupling

 

 

 

 

 

 

 

 

 

 

 

Using Designer Proteins

The multifunctional signaling abilities of β-arrestins has prompted large-scale study of their properties. Vsevolod Gurevich, Ph.D., professor of pharmacology at Vanderbilt University, studies

  1. the structure,
  2. function, and
  3. biology of arrestin proteins.

β-arrestins have three main functions.

  1. First, they prevent the coupling of GPCRs to G proteins, thereby blocking further G protein-mediated signaling (a process known as desensitization).
  2. Second, the binding of a GCPR releases the β-arrestin’s carboxy-terminal “tail” and promotes internalization of the receptor.
  3. Third, receptor-bound β-arrestins bind other signaling proteins, resulting in a second wave of arrestin-mediated signaling.

Dr. Gurevich’s laboratory studies β-arrestin biology through the use of three types of specially designed mutants—

  1. enhanced phosphorylation-dependent,
  2. receptor-specific, and
  3. signaling-biased mutants.

an enhanced mutant of visual β-arrestin-1 partially compensates for defects of rhodopsin phosphorylation in vivo,

“Several congenital disorders are caused by mutant GPCRs that cannot be normally phosphorylated because they have lost GPCR kinase (GRK) sites. Enhanced super-active arrestins have the potential to compensate for these defects, bringing the signaling closer to normal.”

  • Dr. Gurevich explains the strategy involved in creating designer β-arrestins: “We identify residues critical for individual β-arrestin functions by mutagenesis, using limited structural information as a guide.
  • We also work on getting more structural information. In collaboration with different crystallographers, we solved the crystal structures of all four vertebrate β-arrestin subtypes in the basal state, as well as the structure of the arrestin-1-rhodopsin complex.”
  • Dr. Gurevich believes that designer β-arrestins “are the next step in research and therapy, moving way beyond what small molecules can achieve.
  • The difference in capabilities between redesigned signaling proteins, including β-arrestins, and conventional small molecule drugs is about the same as that between airplanes and horse-driven carriages.”
  • Dr. Gurevich observes that redesigned signaling proteins face considerable obstacles in terms of gene delivery, but that the efforts are worth it. “Using designer signaling proteins, we can tell the cell what to do in a language it cannot disobey,” asserts Dr. Gurevich.

Synthesis and Antihypertensive Screening of Novel Substituted 1,2- Pyrazoline Sulfonamide Derivatives

Avinash M. Bhagwat , Anilchandra R. Bha , Mahesh S. Palled , Anand P. Khadke , Anuradha M. Patil, et al.

Am. J. PharmTech Res. 2014; 4(2).    http://www.ajptr.com/ 

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension, diabetic nephropathy and congestiveheart failure. These substances are AT1-receptor antagonists which

  • block the activationof angiotensin II AT1 receptors.

Blockade of AT1 receptors directly causes

1 vasodilation,

2 reduces secretion of vasopressin,

3 reduces production and secretion of aldosterone, amongst other actions –

4 the combined effect of which is reduction of blood pressure.

Irbesartan is a safe and effectiveangiotensin II receptor antagonist with an affinity for the AT1 receptor that is more than 8,500times greater than its affinity for AT2 receptor. This agent has a higher bioavailability (60-80%) than other drugs in its class . In both Losartan and Irbesartan structures imidazole moiety is being present. A structure analog of losartan and Irbesartan are designed by incorporating the heterocycles like pyrazoline group. We felt it would be interesting to explore the possibilities of 1,2-pyrazoline derivatives for Angiotensin II receptor antagonistic activity.

The Irbesartan structure was a modified Losartan structure, which had all the identity of a Losartan molecule but with groups that would fit the hydrophobic cavity with a tetramethylene group and an alkyl side chain that would fit in the pocket in the AT1 receptor. The hydroxyl methyl group of Losartan being replaced with carbonyl group of Irbesartan. With a view to introduce a hydrogen bonding interaction with AT1 receptor, these structures were further modified with a view of retaining both hydrogen bonding characteristics and as well as lipophilic groups. Losartan and Irbesartan structure contains a diphenyl molecule & imidazole ring.

In Losartan and Irbesartan diphenyl molecule is attached to the nitrogen of the imidazole ring. It is interesting to to see the activity of compounds containing two phenyl rings attached at two different positions namely3,5 position of 1, 2-pyrazoline ring. The sulphonamide derivatives known for its diuretics activity which reduces renal hypertension. We use to synthesize sulphonamide and pyrazoline in one molecule to check its possible Angiotensin II receptor antagonist property. For this reason chalcones were synthesized reacted with hydrazine hydrate to yield the corresponding 1,2-pyrazoline derivatives which further condensed with sulphanilamide and formaldehyde by mannich condensation reaction.

Acute Toxicity Study (LD50)

This study was carried out in order to establish the therapeutic and toxic doses of the newly synthesized 1,2 pyrazoline derivatives. To establish LD50 of these compounds the method described by Miller & Tainter was employed.

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More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes

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

 

UPDATED on 8/7/2018

Siemens’ high-sensitivity Troponin I (TnIH) assaysgot FDA clearance for use in diagnosing acute myocardial infarction. (Cardiovascular Business) The first high-sensitivity Troponin T test was cleared last year, as MedPage Today reported.

SOURCE

https://www.medpagetoday.com/cardiology/prevention/74423?xid=nl_mpt_cardiobreak2018-08-06&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=Ca

 

This is the final up to date review of the status of hs troponin T (or I) with or without the combined use of the Brain Type Natriuretic Peptide or its Amino Terminal peptide precursor.  In addition, a new identification of the role of the Atrial Natriuretic Peptide has been reported with respect to arrythmogenic activity.  On the one hand, the diagnostic value of the NT-proBNP has been seen as disappointing, in part because of the question of what information is gained by the test in overt known congestive heart failure, and in part because of uncertainty about following the test during a short hospital stay.  At least, this is the view of this reviewer.  However, in the last several years there has been an emphasis on the value this test adds to prediction of adverse outcomes.   In addition, there has been a hidden nvariable that has much to do with the original reference values that were established for age ranges, without any consideration of pathophysiology that might affect the values within those ranges, leading one to consider values in an aging population as normal, that might well be high.  Why is this?  Aging patients are more likely to have hypertension, and also the onset of type-2 diabetes mellitus, with cardiovascular disease consequences.  Type-2 diabetes mellitus (T2DM), for instance, is associated with insulin resistance and also fat gain with generation of adipokines, but the is also a hyalinization of insulin forming beta-cells of the pancreas, and there is hyalinization of glomeruli (glomerulosclerosis) and afferent arteriolonephrosclerosis with expected decline in glomerular filtrattion rate and hypertension as well.   Of course, this is also associated with hepatosteatosis.   Nevertheless, a reference range is established that takes none of this pathophysiology into account.   While a more reasonable approach has been pointed out, there has been no followup in the literature.

On the other hand, there has been much confusion over the restandardization of a high sensitivity troponin I or T test (hs-Tn(I or T).  The reference range declines precipitously, and there is a good identification of patients who are for the most part disease free, but there is no delineation of patients who are at high risk of acute coronary syndrome with plaque rupture, vs a  host of other cardiovascular conditions.  These have no relationship to plaque rupture, but may be serious and require further evaluation.  The question then becomes whether to admit for a hospital stay, to refer to clinic after an evaluation in the ICU without admission, or to do an extensive evaluation in the emergency department overnight before release for followup.  There is still another dimension of this that has to do with prediction of outcomes using hs-Tn(s) with or without the natriuretic peptides.  Another matter that is not for discussion in this article is the underutilization of hs-CRP.  Originally used for a marker of sepsis in the 1970s, it has come to be tied in with identification of an ongoing inflammatory condition.  Therefore, the existence of a known inflammatory condition in the family of autoimmune diseases, with one exception, might make it unnecessary.

The discussion is broken into three parts:

Part 1.   New findings on the troponins.
Part 2.  The use of combined hs-Tn with a natriuretic peptide (NT-proBNP)
Part 3.  Atrial natriuretic peptide

Part 1.    New findings on the troponins.

Troponin: more lessons to learn

C Liebetrau,HM Nef,andCW.Hamm*
KerckhoffHeartandThoraxCenter;DepartmentofCardiology,BadNauheim,
Germany; (GermanCentreforCardiovascularResearch),partnersite
RheinMain,BadNauheim, Germany; and UniversityofGiessen,Medizinische
KlinikI,KardiologieundAngiologie,Giessen,Germany
European Hear tJournal
http://dx.doi.org/10.1093/eurheartj/eht357This editorial refers to ‘Risk stratification in patients with acute chest pain
using three high-sensitivity cardiac troponin assays’,
by P. Haafetal. http://dx.doi.org/10.1093/eurheartj/eht218Cardiac troponin entered our diagnostic armamentarium 20 years ago and –
unlike any other biomarker –

  • is going through constant expansion in its application.

Troponin started out as a marker of risk in unstable angina’, then was used

  • as gold standard for risk stratification and therapy guiding in acute coronary syndrome
  •  served further to redefine myocardial infarction, and
  • has also become a risk factor in apparently healthy subjects.

The recently introduced high-sensitivity cardiac troponin (hs-cTn) assays

  • have not only expanded the potential of troponins, but
  • have also resulted in a certain amount of confusion
    • among unprepared users.

After many years troponins were accepted as the gold standard in

  • patients with chest pain by
  • classifying them into troponin-positive and
    • troponin-negative patients.

The new generation of hs-cTn assays has

  • improved the accuracy at the lower limit of detection and
  • provided incremental diagnostic information especially
    • in the early phase of myocardial infarction.

Moreover, low levels of measurable troponins

  • unrelated to ACS have been associated with
    • an adverse long-term outcome.

Several studies demonstrated that

  • these low levels of cardiac troponin measureable 
    • only by hs-Tn assays
  • are able to predict mortality in patients with ACS
  • as well as patients with assumed
    • stable coronary artery disease.

Furthermore, hs-cTn has the potential

  • to play a role in the care of patients
    • undergoing non-cardiac surgery.

The additional determination of hs-cTn

  • improves risk stratification despite
  • established risk scores providing both diagnosis and
  • for prognosis prediction in chest pain patients.

The daily clinical challenge in using the highly sensitive assays is to 

  • interpret the troponin concentrations, especially
  • in patients with concomitant diseases
    • independently from myocardial ischaemia
  • influencing cardiac troponin concentrations
    (e.g. chronic kidney disease, or stroke). 

The troponin test lost its ‘pregnancy test’ quality with the different users.
Different opinions exist on

  • the change of hs-cTn levels compared to simple ‘positive–negative’ interpretation
  • and thereby makes diagnosis finding more complex than before.

This uncertainty probably has the paradigm that

  • serial measurements of troponins are necessary, and also
    • boosted the number of diagnoses of ACS and
    • invasive diagnostic procedures in some locations.

This is more than understandable, with acute chest pain using

  • three high-sensitivity cardiac troponins with their respective baseline value
    • before the diagnosis of acute myocardial infarction (AMI) can be made.

What is a relevant change in concentrations compatible with acute myocardial necrosis and

  • what is only biological variation for the specific biomarker and assay?

Changes in serial measurements between 20% and 200% have been debated, and
the discussion is ongoing. Furthermore, it has been proposed that

  • absolute changes in cardiac troponin concentrations 
    • have a higher diagnostic accuracy for AMI
  • compared with relative changes, and

it might be helpful in distinguishing AMI from other causes of cardiac troponin elevation.

Do we obtain any helpful directives from experts and guidelines for our daily practice?
Foreseeing this dilemma, the 2011 European Society of Cardiology (ESC) Guidelines

  • on non ST-elevation ACS acted.
  • Minor elevations of  troponins were accepted as hs-cTn values in the ‘grey zone’.

This was and still is the rule, but

  • the ESC provided a general algorithm on how to manage patients with limited data.

The ‘Study Group on Biomarkers in Cardiology’ suggested

  • a rise of 50% from the baseline value at low concentrations.

However, this group of experts could also not find a substitute for the missing data

  • needed to validate the proposed recommendation.

The story is just too complex:

  • different troponin assays with
  • different epitope targets,
  • different patient populations,
  • different sampling protocols,
  • different follow-up lengths, and much more.

Therefore, any study that helps us to see better through the fog is welcome here.

Haaf et al. have now presented the results of their study of

  • different hs-cTn assays
    (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; and  hs-cTnI, Siemens)

    • with respect to the -outcome of patients with acute chest pain.

The authors examine 1117 consecutive patients presenting with acute chest pain.
[340 patients with ACS (30.5%)] from the Advantageous Predictors of Acute Coronary Syndrome
Evaluation (APACE) study. Blood was collected

  • directly on admission and
  • serially thereafter at 2, 3, and 6h.

Eighty-two patients (7.3%) died during the 2-year follow-up. The main finding of the study is that

  1. hs-cTnT predicts mortality more accurately than the hs-cTnI assays, 
  2. -that a single measurement is sufficient
  3. challenges causes of cardiac troponin elevation.

These results of APACE remain in contrast to recent findings from a GUSTO IV cohortof 1335 patients with ACS (Table1).

Table1 Studies investigating high sensitivity troponins for long-term prognosis

Variable                                                       APACE (n 5 1117)              GUSTO IV (n 5 1335)              PEACE (n 5 3567)

………………………………………………………………………………………………………………………………………………………….

Patient cohort                                                   Unstable                            Unstable                               Stable

Blood sampling                                     On admission,1,2,3,6h                    48h after
study randomization           Before randomization

No. of patients with detection limit             883 (79.1%)                                 UKN                                      UKN

No. of patients with hs-cTnT.
99thpercentile                                        401 (35.9%)                              1015 (76%)                          395 (10.9%)

No. of patients with hs-cTnI (Abbott).
detection limit                                           UKN                                             UKN                              3567 (98.5%)

No.of patients with hs-cTnI (Abbott).
99th percentile                                          UKN                                         988(74%)                           105 (2.9%)

No. of patients with NSTEMI                     170 (15.2%)                              100 (100%)                             0 (0%)

Follow-up                                               24 months                                  12 months                            5.2 years

Non-fatal AMI                                           UKN                                              UKN                               209 (5.9%)

Mortality or primary endpoint                    82 (7.3%)                                 119(8.9%)                           203 (5.7%)

………………………………………………………………………………………………………………………………………………………….

Key findings                                    cTnT better than cTnI                      cTnI ¼cTnT                   cTnI better than cTnT

Single cTn sample sufficient

AMI, acute mycordial infaction; cTn, cardiac tropononin; NSTEMI ,non-ST-elevation myocardial infarction; UKN, unknown

NSTEMI defined in the GUSTO IV trial:
  1. one or more episodes of angina lasting ≥ 5min,
  2. within 24h of admission and
  3. either a positive cardiac TnT or I test
    (above the upper limit of a normal for the local assay; during the years 1999 and 2000)
  4. or ≥ 0.5 mm of transient or persistent ST-segment depression.

the prognostic capacity of four different sensitive cardiac troponin assays were compared

  1. hs-cTnT; Roche Diagnostics,
  2. cTnI and hs-cTnI;
  3. Abbott Diagnostics, and
  4. Acc-cTnI; Beckman-Coulter.

In total, 119 patients (8.9%) died during the 1-year follow-up. Looking at their

  • receiver operating characteristic curve (ROC) analyses,
  • there were only negligible diffferences
    • in the area under the curves between the assays.

Contrasting results have also been reported in patients(n 1/4 3.623)

  • with stable coronary artery disease and preserved systolic left ventricular function

from the PEACE trial (Table1).

During a median follow-up period of 5.2 years,

  • there were 203 (5.6%) cardiovascular deaths or
  • first hospitalization for heart failure.

Concentrations of hs-cTnI (Abbott Diagnostics) at or above

  • the limit of detection of the assay were measured in 3567 patients (98.5%), but
  • concentrations of hs-cTnI at or above the gender-specific 99th percentile
    • were found in only 105 patients (2.9%).

This study revealed that

  • there was a strong and graded association
  • between increasing quartiles of hs-cTnI concentrations and
  • the risk for cardiovascular death or heart failure.

Hs-cTnI provided incremental prognostication information

  • over conventional risk markers and
  • other established cardiovascular biomarkers,
  • including hs-cTnT.

In contrast to the APACE results, only hs-cTnI, but

  • no ths-cTnT, was significantly
  • associated with the risk for AMI.

Is there a real difference between cardiac troponin T and cardiac troponin I

  • in predicting long term prognosis?

The question arises of whether there is a true clinically relevant

  • difference between cTnT and cTnI.

Given the biochemical and analytical differences,the two

  • troponins display rather similar serum profiles during AMI.

While minor biological differences between cTnT and cTnI are

  • apparently not relevant for diagnosis
  • and clinical management in the acute setting of ACS.

This is a provocative theory, but appears premature in our opinion.
Above all, the results of the current study appear

  • too inconsistent to allow such conclusions.

In the present study, hs-cTnT (Roche Diagnostics) outperformed

  • hs-cTnI (Siemens and Beckman-Coulter) in terms of
  • very long term prediction of cardiovascular death and
    • heart failure in stable patients.

We don’t know how hs-cTnI from Abbott Diagnostics

  • performs in the APACE consort.

The number of patients and endpoints provided

  • by the APACE registry are rather low.
  • The results could, therefore, be a chance finding.

It is far too early to favour one high sensitivity assay over the other. The findings need confirmation.

Implications for clinical practice

There is no doubt that high-sensitivity assays

  • are the analytical method of choice
    • in terms of risk stratification in patients with ACS.

What is new?
A single measurement of hs-cTn seems to be adequate

  • for long-term risk stratification in patients without AMI.

However, the question of which troponin might be preferable

  • for long-term risk stratification remains unanswered.

Part 2. ability of high-sensitivity cTnT and NT pro-BNP to predict cardiovascular events and death in patients with T2DM

Hillis GS; Welsh P; Chalmers J; Perkovic V; Chow CK; Li Q; Jun M; Neal B; Zoungas S; Poulter N; Mancia G; Williams B; Sattar N; Woodward M
Diabetes Care.  2014; 37(1):295-303 (ISSN: 1935-5548)

OBJECTIVE

Current methods of risk stratification in patients with

  • type 2 diabetes are suboptimal.

The current study assesses the ability of

  • N-terminal pro-B-type natriuretic peptide (NT-proBNP) and
  • high-sensitivity cardiac troponin T (hs-cTnT)

to improve the prediction of cardiovascular events and death in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease:

Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

RESULTS

Seven hundred nine (18%) patients experienced a

  • major cardiovascular event

(composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and

  • 706 (18%) died during a median of 5 years of follow-up.

In Cox regression models, adjusting for all established risk predictors,

  • the hazard ratio for cardiovascular events for NT-proBNP was 1.95 per 1 SD increase (95% CI 1.72, 2.20) and
  • the hazard ratio for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36, 1.65). The hazard ratios for death were
    • 1.97 (95% CI 1.73, 2.24) and
    • 1.52 (95% CI 1.37, 1.67), respectively.

The addition of either marker improved 5-year risk classification for cardiovascular events
(net reclassification index in continuous model,

  • 39% for NT-proBNP and 46% for hs-cTnT).

Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted.
The combination of both markers provided optimal risk discrimination.

CONCLUSIONS

NT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the

  • risk of cardiovascular events or death can be estimated in patients with type 2 diabetes.

PreMedline Identifier: 24089534


Part 3. M-Atrial Natriuretic Peptide

M-Atrial Natriuretic Peptide and Nitroglycerin in a Canine Model of Experimental Acute Hypertensive Heart Failure:
Differential Actions of 2 cGMP Activating Therapeutics.

Paul M McKie, Alessandro Cataliotti, Tomoko Ichiki, S Jeson Sangaralingham, Horng H Chen, John C Burnett
Journal of the American Heart Association 01/2014; 3(1):e000206. http://dx.doi.org/10.1161/JAHA.113.000206
Source: PubMed

ABSTRACT

Systemic hypertension is a common characteristic in

  • acute heart failure (HF).

This increasingly recognized phenotype

  • is commonly associated with renal dysfunction and
  • there is an unmet need for renal enhancing therapies.

In a canine model of HF and acute vasoconstrictive hypertension

  • we characterized and compared the cardiorenal actions of M-atrial natriuretic peptide (M-ANP),
    a novel particulate guanylyl cyclase (pGC) activator, and
  • nitroglycerin, a soluble guanylyl cyclase (sGC) activator.

HF was induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II
infusion. We characterized the cardiorenal and humoral actions

  • prior to,
  • during, and
  • following intravenous infusions of
  1. M-ANP (n=7),
  2. nitroglycerin (n=7),
  3. and vehicle (n=7) infusion.

Mean arterial pressure (MAP) was reduced by

  1. M-ANP (139±4 to 118±3 mm Hg, P<0.05) and
  2. nitroglycerin (137±3 to 116±4 mm Hg, P<0.05);

similar findings were recorded for

  1. pulmonary wedge pressure (PCWP) with M-ANP (12±2 to 6±2 mm Hg, P<0.05)
  2. and nitroglycerin (12±1 to 6±1 mm Hg, P<0.05).

M-ANP enhanced renal function with significant increases (P<0.05) in

  • glomerular filtration rate (38±4 to 53±5 mL/min),
  • renal blood flow (132±18 to 236±23 mL/min), and
  • natriuresis (11±4 to 689±37 mEq/min) and
  • also inhibited aldosterone activation (32±3 to 23±2 ng/dL, P<0.05), whereas

nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.

Our results advance

the differential cardiorenal actions of

  • pGC (M-ANP) and sGC (nitroglycerin) mediated cGMP activation.

These distinct renal and aldosterone modulating actions make

M-ANP an attractive therapeutic for HF with concomitant hypertension, where

  • renal protection is a key therapeutic goal.

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Reporter: Aviva Lev-Ari, PhD, RN

Tool Identifies Risk in Stenting ACS Patients

By Todd Neale, Senior Staff Writer, MedPage Today

Published: November 19, 2012
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new, easy-to-calculate risk score developed for patients with non-ST-segment elevation acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) had better prognostic accuracy than other widely used risk scores, researchers found.

The ACUITY-PCI risk score includes six variables — insulin-treated diabetes, renal insufficiency, baseline cardiac biomarker elevation or ST-segment deviation, presence of a bifurcation lesion, small vessel/diffuse coronary artery disease, and extent of coronary artery disease, according to Gregg Stone, MD, of Columbia University Medical Center in New York City, and colleagues.

The 1-year rate of death or MI significantly increased from 5.3% in the lowest risk tertile to 9.1% in the middle tertile to 19% in the highest tertile (P<0.001), the researchers reported in the November issue of JACC: Cardiovascular Interventions.

Discrimination and calibration were greater with the ACUITY-PCI score than with other established scores.

“Although the TIMI and the GRACE scores have been shown to be valuable prognostic tools at the time of hospital admission for selecting pharmacological strategies and identifying those patients most likely to benefit from an invasive strategy, they have not been optimized for patients undergoing PCI and, thus, have relatively poor prognostic power to further risk stratify acute coronary syndrome patients undergoing PCI,” Stone and colleagues wrote.

“The ACUITY-PCI score is therefore intended to supplement the TIMI and GRACE scores when an invasive strategy has been undertaken and PCI is being considered.”

The researchers created the risk score using data from 1,692 patients enrolled in the angiographic substudy of the ACUITY trial, which was a comparison of heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin (Angiomax) plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone in patients with ACS undergoing an early invasive strategy. They then validated the score using another 846 patients from the same study.

Multivariate analysis revealed six variables that were significantly associated with 1-year mortality and MI and were included in the score. The researchers assigned points based on the strength of the predictor:

  • Insulin-treated diabetes (12 points)
  • Renal insufficiency (12 points)
  • Baseline cardiac biomarker elevation or ST-segment deviation (8 points)
  • Bifurcation lesion (4 points)
  • Small vessel/diffuse coronary artery disease (2 points)
  • Extent of coronary artery disease (1 point for each 10 mm of disease)

The C-statistic for the risk score — a measure of discrimination — was 0.67 in the derivation cohort and 0.70 in the validation cohort. In the validation cohort, the chi-square statistic for calibration was 6.2 and the index of separation was 0.44.

All of those values were better than those seen for four other established risk scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX. In addition, the net reclassification improvement with the new score ranged from 9% to 38% and the integrated discrimination index varied from 1.9% to 2.7%.

The researchers noted that the ACUITY-PCI score also was a good predictor of 1-year definite or probable stent thrombosis, with a C-statistic of 0.72.

In another study in the same journal, George Dangas, MD, PhD, of Mount Sinai Medical Center in New York City, and colleagues — including Stone — reported on the development of a risk score specifically for stent thrombosis in patients with ACS undergoing PCI.

The study included 6,139 patients from the HORIZONS-AMI and ACUITY trials, which included those with ST-segment elevation MI (STEMI) in the former trial and those with non-STEMI and unstable angina in the latter. The researchers used 4,093 patients for the derivation cohort and 2,046 for the validation cohort.

The risk score included 10 variables that were significantly associated with the risk of Academic Research Consortium-defined definite or probable stent thrombosis at 1 year:

  • Type of acute coronary syndrome (4 points for STEMI, 2 points for non-ST-segment elevation ACS with ST deviation, and 1 point for non-ST-segment elevation ACS without ST changes)
  • Current smoking (1 point)
  • Insulin-dependent diabetes (2 points)
  • Prior PCI (1 point)
  • Baseline platelet count (1 point for 250 to 400 K/µL and 2 points for more than 400 K/µL)
  • Absence of pre-PCI heparin therapy (1 point)
  • Aneurysmal/ulcerated lesion (2 points)
  • Baseline TIMI flow grade 0/1 (1 point)
  • Final TIMI flow grade less than 3 (1 point)
  • Number of treated vessels (1 point for two vessels and 2 points for three vessels)

Scores from 1 to 6 are considered low risk, 7 to 9 are intermediate risk, and 10 or higher are high risk.

The rates of stent thrombosis at 1 year were 1.36%, 3.06%, and 9.18% across the three risk tertiles in the derivation cohort (P<0.001 for trend), with a similar trend seen in the validation cohort.

The C-statistics were 0.67 in the derivation cohort and 0.66 in the validation cohort. Performance was comparable for events occurring both early (within the first 30 days) and late (from 1 month to 1 year).

“We believe that the development and initial validation of this stent thrombosis risk score can be a useful tool for both clinical practice and future clinical investigation (future analyses of trials or registries), as it can be a simple way to risk stratify patients immediately following a procedure,” Dangas and colleagues wrote. “The risk score could also be used in the informed consent process to better inform patients of their individual risk of stent thrombosis.”

But Ron Waksman, MD, and Israel Barbash, MD, of MedStar Washington Hospital Center in Washington, D.C., noted some limitations of the tool, including the pooling of different types of patients, the exclusion of important variables associated with stent thrombosis risk, and the use of mostly first-generation drug-eluting stents in the trials.

“It is imperative that the user of such a prediction tool be aware of its capabilities and performance, as well as its limitations, in various clinical scenarios,” they wrote in an accompanying editorial.

“A newly developed risk score for stent thrombosis should be robust and should be tested across broad study populations, stents, and antiplatelet regimens. A new model should also be validated in a setting different from the one in which it was derived,” they wrote. “Unfortunately, this is not the case with the newly proposed model.”

“Until such an encompassing tool is developed and validated,” they wrote, “one should rely on the known stent thrombosis risk factors and tailor an appropriate treatment for each patient.”

The ACUITY trial was funded by The Medicines Company and Nycomed.

Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, and The Medicines Company. His co-authors reported relationships with Abbott, Regado, Ortho McNeil, Janssen, Merck, Maya Medical, AstraZeneca, Sanofi/Bristol-Myers Squibb, Eli Lilly, and Daiichi Sankyo.

The HORIZONS-AMI trial was supported by the Cardiovascular Research Foundation, with grant support from Boston Scientific and The Medicines Company.

Dangas has received speaker honoraria from AstraZeneca, Bristol-Myers Squibb, The Medicines Company, sanofi-aventis, and Abbott Vascular. His co-authors reported relationships with sanofi-aventis, The Medicines Company, Abbott Vascular, Bristol-Myers Squibb, Cordis, AstraZeneca, Daiichi Sankyo, Eli Lilly, Maquet, Roche, Boehringer Ingelheim, Liposcience, Merck, Pozen, Gilead Sciences, WebMD, the NIH, Pfizer, Johnson & Johnson, Schering-Plough, Merck Sharpe and Dohme, GlaxoSmithKline, Regado Biosciences, Boston Scientific, and Bristol-Myers Squibb/Sanofi.

Waksman and Barbash reported that they had no conflicts of interest.

From the American Heart Association:

Primary source: JACC: Cardiovascular Interventions
Source reference:
Palmerini T, et al “A new score for risk stratification of patients with acute coronary syndromes undergoing percutaneous coronary intervention: the ACUITY-PCI (Acute Catheterization and Urgent Intervention Triage Strategy-Percutaneous Coronary Intervention) risk score” JACC Cardiovasc Interv 2012; 5: 1108-1116.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Dangas G, et al “Development and validation of a stent thrombosis risk score in patients with acute coronary syndromes” JACC Cardiovasc Interv 2012; 5: 1097-1105.

Additional source: JACC: Cardiovascular Interventions
Source reference:
Waksman R, Barbash I “The appropriate use of risk scores” JACC Cardiovasc Interv 2012; 5: 1106-1107.

Todd Neale

Senior Staff Writer

Todd Neale, MedPage Today Staff Writer, got his start in journalism at Audubon Magazine and made a stop in directory publishing before landing at MedPage Today. He received a B.S. in biology from the University of Massachusetts Amherst and an M.A. in journalism from the Science, Health, and Environmental Reporting program at New York University. He is based atMedPage Today headquarters in Little Falls, N.J.

SOURCE:

http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/36010

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