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Journal Cover   JACC : Heart Failure
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   Full-text available via subscription Subscription journal
   ISSN (Online) 2213-1779
   Published by American College of Cardiology Foundation Homepage  [1 journal]
  • The Ongoing Evolution of Optimal Clinical Endpoints for Heart Failure
           Trials ∗
    • Authors: Krum H; Hopper I.
      Abstract: Advances in heart failure (HF) drug and device therapies over the past 3 decades have made major inroads into the lethality of this disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), as well as device-based approaches including cardiac resynchronization therapy and implantable cardioverter defibrillator therapy, have resulted in substantial mortality, morbidity and quality of life (QoL) benefits to such patients, particularly those with HF and reduced ejection fraction (HFREF).
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Falling Cardiovascular Mortality in Heart Failure With Reduced
           Ejection Fraction and Implications for Clinical Trials
    • Authors: Rush CJ; Campbell RT, Jhund PS, et al.
      Abstract: ObjectivesThis study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF).BackgroundWith the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing.MethodsIn a systematic review, 2 investigators independently searched online databases to identify clinical trials including >400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups.ResultsSixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p < 0.001).ConclusionsIn trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Perhexiline, Cardiac Energetics, and Heart Failure Lessons
           From the First Law of Thermodynamics
    • Authors: Davogustto G; Taegtmeyer H.
      Abstract: “The sum of the actual and potential energies in the universe is unchangeable.”—William J.M. Rankine, 1853 (1)We read with interest the recent study by Beadle et al. (2), describing the improvement in cardiac energetics of patients with heart failure treated with perhexiline. One of the investigators’ main conclusions is that perhexiline improves cardiac energetics without evidence of altered cardiac substrate utilization. On the basis of the First Law of Thermodynamics and on our experimental observations (3,4), we offer a different interpretation.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Reply Perhexiline, Cardiac Energetics, and Heart Failure: Lessons From the
           First Law of Thermodynamics
    • Authors: Beadle RM; Frenneaux MP.
      Abstract: We thank Drs. Davogustto and Taegtmeyer for their interest in our recent work (1) and for stressing the importance of the First Law of Thermodynamics. We concur that our data do not completely exclude a shift in the dominant substrate use as a mechanism; however, when considered in light of the previous study by Unger et al. (2), we nevertheless contend that it raises the possibility of an alternative or additional mechanism of action of perhexiline. Several of these were discussed in the paper, but these may include an increase in the efficiency of generation of energy from the same substrates, for example through reduced mitochondrial uncoupling. In heart failure, a reduction in CK activity has previously been reported (3) that appears in part as a result of increased oxidative stress, and partially corrected acutely by allopurinol (4). Perhexiline has been reported to reduce NADPH oxidase activity and to reduce cardiac TxNIP levels. Either or both of these mechanisms might contribute to a shift in the ratio of PCr to ATP.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • The Broad Spectrum of HIV-Related Cardiovascular Disease ∗
    • Authors: Shah MR.
      Abstract: In recent years, there has been an explosion of knowledge regarding human immunodeficiency virus (HIV)-related cardiovascular disease (CVD). Contemporary studies have shown that in HIV-infected patients, rates of acute myocardial infarction are up to twice as high as in noninfected patients (1–4). Recent reports have also found that chronic inflammation and immune activation play a more dominant role in HIV-related CVD compared with CVD in the general population (5,6). Although the majority of recent studies on HIV-related CVD have focused on atherosclerosis, a growing body of published reports describes an array of contemporary cardiovascular complications associated with HIV, including sudden cardiac death, pulmonary hypertension (PH), and heart failure (7–11). In this issue of JACC: Heart Failure, Secemsky et al. (12) further contribute to our understanding of the broad spectrum of HIV-related CVD by showing that HIV-infected patients have significantly higher rates of diastolic dysfunction and PH. The authors also show for the first time a strong association between the cardiac biomarkers ST2 and growth differentiation factor (GDF)-15 and cardiac dysfunction and mortality in an HIV-infected cohort.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Beta-Blockers in Acute Heart Failure Do They Cause Harm' ∗
    • Authors: Jondeau G; Milleron O.
      Abstract: Within the last 40 years beta-blocker therapy status in chronic heart failure has changed from being the most hazardous drug to the most effective therapy. This has been a long journey, because it has been a long time from the first publication of Waagstein et al. (1) to the demonstration of benefit on mortality in double-blind randomized clinical trials (2–7). Moreover the prescription of beta-blockers in daily practice remains an issue because it is known from registries that beta-blockers are still the last drug introduced, the drug for which an increase in dosage is the most difficult so that dosage remains lower than recommended in daily practice (8,9).
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • The Globalization of Heart Failure Research
    • Abstract: “The world is flat.”—Thomas L. Friedman (1)
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Novel Biomarkers of Cardiac Stress, Cardiovascular Dysfunction, and
           Outcomes in HIV-Infected Individuals
    • Authors: Secemsky EA; Scherzer R, Nitta E, et al.
      Abstract: ObjectivesThis study sought to determine whether biomarkers ST2, growth differentiation factor (GDF)-15, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin I are elevated in patients infected with human immunodeficiency virus (HIV) and are associated with cardiovascular dysfunction and all-cause mortality.BackgroundHIV-infected patients have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information.MethodsBiomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and sex-matched control subjects. Left ventricular systolic dysfunction was defined as ejection fraction 
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Neprilysin Biotarget and Biomarker in Heart Failure ∗
    • Authors: Seronde M; Mebazaa A.
      Abstract: Neprilysin (NEP) is a membrane-bound enzyme with a large extracellular component that hydrolyzes atrial natriuretic peptide (ANP), but less so brain natriuretic peptide (BNP), and degrades various very important endogenous vasoactive peptides, including adrenomedullin and bradykinin for the vasodilators and angiotensin I and II and endothelin-1 for the vasoconstrictors and substance P (1).
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Effects of Beta-Blocker Withdrawal in Acute Decompensated Heart
           Failure A Systematic Review and Meta-Analysis
    • Authors: Prins KW; Neill JM, Tyler JO, et al.
      Abstract: ObjectivesThis study sought to evaluate the effects of beta-blocker withdrawal in acute decompensated heart failure (ADHF).BackgroundPublished reports showed trends for either no harm or increased risk of in-hospital mortality, short-term mortality, and rehospitalization rates in patients admitted for ADHF that discontinued beta-blockers; however, a comprehensive analysis has not been conducted.MethodsRelevant studies from January 2000 through January 2015 were identified in the PubMed, EMBASE, and COCHRANE electronic databases. Where appropriate data were available, weighted relative risks were estimated using random-effects meta-analysis techniques.ResultsFive observational studies and 1 randomized clinical trial (n = 2,704 patients who continued beta-blocker therapy and n = 439 patients who discontinued beta-blocker therapy) that reported the short-term effects of beta-blocker withdrawal in ADHF were included in the analyses. In 2 studies, beta-blocker withdrawal significantly increased risk of in-hospital mortality (risk ratio: 3.72; 95% confidence interval [CI]: 1.51 to 9.14). Short-term mortality (relative risk: 1.61; 95% CI: 1.04 to 2.49; 4 studies) and combined short-term rehospitalization or death (relative risk: 1.59; 95% CI: 1.03 to 2.45; 4 studies) were also significantly increased.ConclusionsDiscontinuation of beta-blockers in patients admitted with ADHF was associated with significantly increased in-hospital mortality, short-term mortality, and the combined endpoint of short-term rehospitalization or mortality. These data suggest beta-blockers should be continued in ADHF patients if their clinical picture allows.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Prognostic Value and Kinetics of Soluble Neprilysin in Acute Heart
           Failure A Pilot Study
    • Abstract: ObjectivesThis study sought to examine the prognostic value of the soluble form of neprilysin (sNEP) in acute heart failure (AHF) and sNEP kinetics during hospital admission.BackgroundsNEP was recently identified in chronic heart failure (HF) and was associated with cardiovascular outcomes.MethodsA total of 350 patients (53% women, mean 72.6 ± 10.7 years of age) were included in the study. Primary endpoints were composites of cardiovascular death or HF hospitalizations at short-term (2 months) and long-term (mean: 1.8 ± 1.2 years) follow-up. sNEP was measured using an ad hoc–modified enzyme-linked immunosorbent assay, and its prognostic value was assessed using Cox regression analyses. In a subgroup of patients, sNEP was measured both at admission and at discharge (n = 92).ResultsMedian admission sNEP concentrations were 0.67 ng/ml (Q1 to Q3: 0.37 to 1.29), and sNEP was significantly associated, in age-adjusted Cox regression analyses, with the composite endpoint at short-term (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 1.04 to 1.61; p = 0.02) and long-term (HR: 1.23; 95% CI: 1.01 to 1.05; p = 0.003) follow-up. In multivariate Cox analyses that included clinical variables and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration, sNEP concentration at admission showed a clear trend toward significance for the composite endpoint at 2 months (HR: 1.22; 95% CI: 0.97 to 1.53; p = 0.09) and remained significant at the end of follow-up (HR: 1.21; 95% CI: 1.04 to 1.40; p = 0.01). At discharge, sNEP levels decreased from 0.70 to 0.52 ng/ml (p = 0.06).ConclusionsAdmission sNEP concentration was associated with short- and long-term outcomes in AHF, and dynamic sNEP concentrations were observed during hospital admission. These preliminary data may be hypothesis-generating for the use of NEP inhibitors in AHF.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Light Chains and the Failing Heart Important Mechanistic Link or Fifty
           Shades of Gray' ∗
    • Authors: Januzzi JL, Jr; Mann DL.
      Abstract: Since the first description by Elster et al. (1) in 1956 of the presence of elevated concentrations of C-reactive protein (CRP) in patients with heart failure (HF), the importance of inflammation in the genesis and progression of the diagnosis has gained substantial attention. Indeed, since this first seminal observation, many thousands of research publications focused on broad-based aspects of inflammation in HF have been published. Studies in this area have focused not only on mechanistic aspects of inflammation and how it affects the heart, but several important trials have also attempted to modulate inflammation in patients with HF with the hopes that such anti-inflammatory therapies might retard ventricular remodeling and improve outcomes; such trials met with little success (2,3) despite early phase data suggesting the treatments studied might actually be beneficial.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Combined Free Light Chains Are Novel Predictors of Prognosis in Heart
    • Authors: Jackson CE; Haig C, Welsh P, et al.
      Abstract: ObjectivesThis study investigated the prevalence and potential incremental prognostic value of combined free light chains (cFLCs) in patients recently hospitalized with decompensated heart failure (HF).BackgroundInflammatory pathways are recognized in the pathogenesis and progression of HF. Free light chain (FLC) elevation is conventionally associated with monoclonal gammopathies, including multiple myeloma. Polyclonal increases in both kappa and lambda FLCs occur in autoimmune and other chronic inflammatory conditions. Recently, a novel assay for measuring kappa and lambda immunoglobulin FLCs together, known as combined free light chain (cFLC) has been developed.MethodsSix hundred twenty-eight patients recently hospitalized with decompensated HF were studied. cFLCs were measured by turbidimetry using an immunoassay. The incremental prognostic value of cFLCs for mortality was evaluated using Cox proportional hazard models including 22 established predictors of outcome in HF.ResultsOf 628 patients, 290 (46%) died during a follow-up of 3.2 ± 1.5 years. Two hundred seventy patients (43%) had elevated cFLCs. There was a clear gradient in the risk of death according to cFLC quartile, with those in the top quartile having an unadjusted risk of mortality more than twice that of those in the lowest quartile (hazard ratio: 2.38; p < 0.0001). After multivariable analysis, cFLC remained an independent predictor of mortality, with an almost 50% higher adjusted risk for those in the top compared with bottom quartile. Older age, lower body mass index, New York Heart Association classification III/IV, previous myocardial infarction, current smoking and B-type natriuretic peptide, bilirubin, high-sensitivity C-reactive protein, glycated hemoglobin, and lymphocyte concentrations were also independent predictors of mortality.ConclusionscFLCs are an independent predictor of mortality in patients recently hospitalized with decompensated HF. Further work is required to assess the effects of HF therapies on cFLC concentrations and whether or not directly targeting this marker of inflammation improves prognosis for patients with HF.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Inside This Issue
    • PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Human Immunodeficiency Virus and Heart Failure in Low- and
           Middle-Income Countries
    • Authors: Bloomfield GS; Alenezi F, Barasa FA, et al.
      Abstract: Successful combination therapy for human immunodeficiency virus (HIV) has transformed this disease from a short-lived infection with high mortality to a chronic disease associated with increasing life expectancy. This is true for high- as well as low- and middle-income countries. As a result of this increased life expectancy, people living with HIV are now at risk of developing other chronic diseases associated with aging. Heart failure has been common among people living with HIV in the eras of pre- and post- availability of antiretroviral therapy; however, our current understanding of the pathogenesis and approaches to management have not been systematically addressed. HIV may cause heart failure through direct (e.g., viral replication, mitochondrial dysfunction, cardiac autoimmunity, autonomic dysfunction) and indirect (e.g., opportunistic infections, antiretroviral therapy, alcohol abuse, micronutrient deficiency, tobacco use) pathways. In low- and middle-income countries, 2 large observational studies have recently reported clinical characteristics and outcomes in these patients. HIV-associated heart failure remains a common cardiac diagnosis in people living with heart failure, yet a unifying set of diagnostic criteria is lacking. Treatment patterns for heart failure fall short of society guidelines. Although there may be promise in cardiac glycosides for treating heart failure in people living with HIV, clinical studies are needed to validate in vitro findings. Owing to the burden of HIV in low- and middle-income countries and the concurrent rise of traditional cardiovascular risk factors, strategic and concerted efforts in this area are likely to impact the care of people living with HIV around the globe.
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Neprilysin in Heart Failure From Oblivion to Center Stage ∗
    • Abstract: Neprilysin (NEP), also known as neutral endopeptidase, CD10, enkephalinase, common acute lymphoblastic leukemia antigen, and endopeptidase 24.11, is a well-known enzyme that was described several decades ago and fully characterized at the turn of the century. NEP is quite ubiquitous; it is expressed in the kidneys, lungs, endothelial cells, vascular smooth-muscle cells, cardiac myocytes, fibroblasts, neutrophils, adipocytes, testes, and brain, with the highest concentrations in the proximal tubules of nephrons. NEP is also quite “promiscuous”; in the cardiovascular system, NEP cleaves numerous vasoactive peptides, including natriuretic peptides, adrenomedullin, angiotensin I and II, bradykinin, substance P, and others (Figure 1A).
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
  • Elevated Plasma B-Type Natriuretic Peptide Concentrations Directly
           Inhibit Circulating Neprilysin Activity in Heart Failure
    • Abstract: ObjectivesThis study sought to hypothesize that elevated B-type natriuretic peptide (BNP) could act as an endogenous neprilysin inhibitor.BackgroundA hallmark of acute decompensated heart failure (ADHF) is the overproduction of natriuretic peptides (NPs) by stretched cardiomyocytes. Various strategies have been developed to potentiate the beneficial effect of the NPs, including the recent use of neprilysin angiotensin receptor inhibitors. Contrary to rodents, human BNP is poorly sensitive to neprilysin degradation while retaining affinity to neprilysin.MethodsWe enrolled 638 patients presenting to the emergency department with acute dyspnea of which 468 had ADHF and 169 had dyspnea of noncardiac origin. We also included 46 patients with stable chronic heart failure (HF) and 10 age-matched healthy subjects. Plasma samples were collected within 4 h after emergency department admission. BNP, neprilysin concentration and activity, and the neprilysin substrate substance P concentration were measured.ResultsWe found that when plasma BNP rose above 916 pg/ml, neprilysin activity was markedly reduced (p 
      PubDate: Sat, 01 Aug 2015 00:00:00 GMT
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