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  JACC : Heart Failure
   Full-text available via subscription Subscription journal
   ISSN (Online) 2213-1779
   Published by American College of Cardiology Foundation Homepage  [1 journal]
  • Evolving Role of Galectin-3 as a Cardiac Biomarker Heart Failure With
           Preserved Ejection Fraction and Renal Function, Important Pieces of
           the Puzzle ∗
    • Authors: deFilippi CR; Christenson RH.
      Abstract: For more than a decade, galectin-3 (Gal-3) has been known to be an important mediator in the pathophysiology of heart failure (HF) predominantly by promoting fibrosis (1). Several years after that finding, levels of Gal-3 in the blood were recognized to be prognostic for death or recurrent acute HF in patients with acute decompensated HF, and additive to a natriuretic peptide level (2). Subsequently, there has been development and U.S. Food and Drug Administration approval of a commercial assay and discussion of the assay with a class IIb indication for additive risk stratification in patients with established HF in the most recent version of American Heart Association/American College of Cardiology Foundation HF guidelines (3,4). A recent review summarizing prognostic studies showed that Gal-3 concentrations remain prognostic for subjects with acute and chronic HF but that the association with outcomes is often attenuated or absent when adjusted for cardiac-specific biomarkers or renal function (5).
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Standing the Test of Time ∗
    • Authors: Lala A; Hochman JS.
      Abstract: In 1967, Dr. Thomas Killip and Dr. John Kimball (1) reported their experience with a novel construct called the coronary care unit to cluster and care for patients with suspected acute myocardial infarction (MI). “To provide a clinical estimate of the severity of myocardial derangement,” they classified patients into one of four categories: 1) no heart failure (HF); 2) HF as demonstrated by the presence of rales, an S3 gallop, and/or venous hypertension; 3) severe HF or frank pulmonary edema; and 4) cardiogenic shock.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Galectin-3 in Heart Failure With Preserved Ejection Fraction A RELAX
           Trial Substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status
           and Exercise Capacity in Diastolic Heart Failure)
    • Authors: AbouEzzeddine OF; Haines P, Stevens S, et al.
      Abstract: ObjectivesThis study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains.BackgroundGal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF.MethodsTwo hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested.ResultsGal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53).ConclusionsIn overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Improvement in Cardiac Energetics by Perhexiline in Heart Failure Due to
           Dilated Cardiomyopathy
    • Authors: Beadle RM; Williams LK, Kuehl M, et al.
      Abstract: ObjectivesThe aim of this study was to determine whether short-term treatment with perhexiline improves cardiac energetics, left ventricular function, and symptoms of heart failure by altering cardiac substrate utilization.BackgroundPerhexiline improves exercise capacity and left ventricular ejection fraction (LVEF) in patients with heart failure (HF). 31P cardiac magnetic resonance spectroscopy can be used to quantify the myocardial phosphocreatine/adenosine triphosphate ratio. Because improvement of HF syndrome can improve cardiac energetics secondarily, we investigated the effects of short-term perhexiline therapy.MethodsPatients with systolic HF of nonischemic etiology (n = 50, 62 ± 1.8 years of age, New York Heart Association functional class II to IV, LVEF: 27.0 ± 1.44%) were randomized to receive perhexiline 200 mg or placebo for 1 month in a double-blind fashion. Clinical assessment, echocardiography, and 31P cardiac magnetic resonance spectroscopy were performed at baseline and after 1 month. A substudy of 22 patients also underwent cross-heart blood sampling at completion of the study to quantify metabolite utilization.ResultsPerhexiline therapy was associated with a 30% increase in the phosphocreatine/adenosine triphosphate ratio (from 1.16 ± 0.39 to 1.51 ± 0.51; p < 0.001) versus a 3% decrease with placebo (from 1.36 ± 0.31 to 1.34 ± 0.31; p = 0.37). Perhexiline therapy also led to an improvement in New York Heart Association functional class compared with placebo (p = 0.036). Short-term perhexiline therapy did not change LVEF. Cross-heart measures of cardiac substrate uptake and respiratory exchange ratio (which reflects the ratio of substrates used) did not differ between patients who received perhexiline versus placebo.ConclusionsPerhexiline improves cardiac energetics and symptom status with no evidence of altered cardiac substrate utilization. No change in LVEF is seen at this early stage. (Metabolic Manipulation in Chronic Heart Failure; NCT00841139)
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Incidence, Temporal Trends, and Prognostic Impact of Heart Failure
           Complicating Acute Myocardial Infarction The SWEDEHEART Registry (Swedish
           Web-System for Enhancement and Development of Evidence-Based Care in Heart
           Disease Evaluated According to Recommended Therapies): A Study of 199,851
           Patients Admitted With Index Acute Myocardial Infarctions, 1996 to 2008
    • Authors: Desta L; Jernberg T, Löfman I, et al.
      Abstract: ObjectivesThe aim of this study was to examine temporal trends in the incidence and outcomes of heart failure (HF) complicating acute myocardial infarction (AMI) in a large national cohort.BackgroundThere are limited and conflicting data concerning temporal trends in the incidence and prognostic implication of in-hospital HF that complicates AMI.MethodsThe nationwide coronary care unit registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) records baseline characteristics, treatments, and outcome of consecutive patients with AMIs admitted to all hospitals in Sweden. The diagnosis of HF requires the presence of crackles (Killip class ≥II) or the use of intravenous diuretic agents or intravenous inotropes. This study included 199,851 patients admitted for index AMIs between 1996 and 2008.ResultsThe incidence of HF declined from 46% to 28% (p < 0.001). This decrease was more pronounced in patients with ST-segment elevation myocardial infarctions and left bundle branch block (from 50% to 28%) compared with those with non-ST-segment elevation myocardial infarctions (from 42% to 28%) (p < 0.001). The in-hospital, 30-day, and 1-year mortality rates for patients who developed HF during the index myocardial infarction decreased over the years from 19% to 13%, from 23% to 17%, and from 36% to 31%, respectively (p < 0.001 for all). Thirteen-year survival analysis showed higher mortality in patients with HF compared with those without HF (adjusted hazard ratio: 2.1; 95% confidence interval: 2.06 to 2.13).ConclusionsA marked decrease was found in the incidence of HF complicating AMI between 1996 and 2008. However, HF continues to worsen the early-, intermediate-, and long-term adverse prognostic risk after AMI.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • How Many Patients Will Benefit From a New Therapy for Chronic
           Systolic Heart Failure, and What Difference
           Does it Make' ∗
    • Authors: Borer JS.
      Abstract: The importance of heart rate lowering in optimizing natural history among patients with chronic systolic heart failure (HF) has been increasingly clear for 15 years, certainly at least since Kjekshus and Gullestad reported a cross-sectional analysis of the HF mortality trials then completed (1). This assessment revealed that placebo-subtracted mortality changes among the trials were directly proportional to placebo-subtracted heart rate changes. This relationship was most strongly influenced by the trials of beta-blocking drugs by then available, but extended to non–beta-blockers as well. Subsequent meta-regression analyses confirmed these findings (2,3) and further indicated that the mortality benefit was highly significantly related to heart rate reduction, but not at all to beta-blocker dose (2).
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Prescribing Patterns to Optimize Heart Rate Analysis of 1,000
           Consecutive Outpatient Appointments to a Single Heart Failure
           Clinic Over a 6-Month Period
    • Authors: Dierckx R; Cleland JF, Parsons S, et al.
      Abstract: ObjectivesThis study sought to characterize patients attending a community heart failure (HF) clinic and identified those who were eligible for optimization of beta-blockers (BB) or ivabradine.BackgroundAmong patients with HF due to left ventricular systolic dysfunction in sinus rhythm, those with higher resting heart rate have a worse prognosis. Reducing sinus rate to 50 to 60 beats/min might improve outcomes.MethodsA total of 1,000 consecutively scheduled HF clinic follow-up appointments over a 6-month period were reviewed. Demographic, clinical, and echocardiographic data were collected for patients who attended (824 unique patients; 555 men). Mean age was 74 ± 11 years, median N-terminal pro–B-type natriuretic peptide levels were 1,002 ng/l (interquartile range: 367 to 2,151 ng/l), and the mean left ventricular ejection fraction (LVEF) was 44 ± 11%. A total of 202 (25%), 252 (31%), and 370 (45%) patients had LVEFs of ≤35%, 36% to 49%, and ≥50%, respectively. Of patients with LVEF ≤35%, 142 (70%) were in sinus rhythm.ResultsAt 70 clinic visits, 58 patients with LVEFs of ≤35% were in sinus rhythm and had heart rates ≥70 beats/min. Of these, 13 patients had their BB dose increased, 20 were potentially eligible for, but did not have, BB uptitration, 15 were already taking target doses of BBs, and 10 patients were reported to be intolerant of higher doses. Thus, 25 patients were potentially eligible for ivabradine according to European Society of Cardiology guidelines; this number dropped to 14 when the United Kingdom National Institute for Health and Care Excellence guidelines were applied.ConclusionsAmong patients with LVEFs of ≤35%, most are treated with BBs and have a heart rate at rest of 
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Perhexiline: Lessons for Heart Failure Therapeutics ∗
    • Authors: Cappola TP.
      Abstract: In heart failure with reduced ejection fraction, mechanical work produced by the left ventricle to support the systemic circulation decreases over time despite relatively constant myocardial oxygen consumption. The resulting decrease in the ratio of mechanical work to oxygen consumed, or mechanical efficiency, is a cardinal feature of heart failure (1). Extensive research in experimental models and human subjects has shown that treatment with neurohormonal blockade and cardiac resynchronization induces secondary improvements in efficiency in patients with heart failure over time. As such, there has been a long-standing interest in understanding cardiac metabolism with the goal of improving efficiency as a primary therapeutic target (2).
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Early and Late Effects of High- Versus Low-Dose Angiotensin Receptor
           Blockade on Renal Function and Outcomes in Patients With Chronic
           Heart Failure
    • Authors: Kiernan MS; Gregory D, Sarnak MJ, et al.
      Abstract: ObjectivesThis study investigated the dose-related effect of losartan on changes in renal function using data from the HEAAL (Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan) trial.BackgroundAngiotensin receptor blockers adversely affect renal function in patients with heart failure (HF). The time course and dose dependency of this time course, as well as the clinical implications of these changes in renal function, are not well described.MethodsSubjects in the HEAAL dataset (n = 3,843) were studied. Changes in estimated glomerular filtration rate (eGFR) over time were compared between dose groups. The association between the timing of incident increases in serum creatinine (SCr) >0.3 mg/dl and clinical outcomes was explored.ResultsCompared with 50 mg, 150 mg losartan led to a greater reduction in eGFR across time (mean difference: −3.79 ml/min/1.73 m2; p < 0.0001). This difference was driven by early changes, and differences in eGFR after 4 months were not significant (mean difference: 0.40 ml/min/1.73 m2; p = 0.16). Although an increase in SCr >0.3 mg/dl from baseline was associated with increased risk of death or hospitalization for HF (hazard ratio [HR]: 1.36; p 
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Hop, Skip, and Jump Do We Need Phase II Cardiovascular
           Clinical Trials'
    • Authors: O’Connor CM.
      Abstract: I was recently asked to present the following topic at a cardiovascular symposium: “Do We Need Phase II Clinical Trials in the Development of Important Therapeutics in Cardiology'” The presenters reviewed the program of LCZ696, a novel angiotensin receptor neprilysin inhibitor (ARNI) with outstanding phase III clinical trial results, and provided other examples of how drug development can be streamlined to shorten development times and costs, but more importantly, to bring life-saving therapies to our patients in a timely fashion. Traditional drug development has been advocated to proceed in a stepwise fashion including phase I: early exposure safety trials; phase II: early trials to assess treatment efficacy, exploratory examination of error rates, and selection of doses for further development; and phase III: large-scale controlled trials with clinical outcomes and confirmatory in nature, with error rates controlled to give definitive conclusions.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Reply Coenzyme Q 10 : Will This Natural Substance Become a
           Guideline-Directed Adjunctive Therapy in Heart Failure'
    • Authors: Ezekowitz JA.
      Abstract: Dr. Mortensen raises a number of points that need clarification and context.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Coenzyme Q 10 Will This Natural Substance Become a Guideline-Directed
           Adjunctive Therapy in Heart Failure'
    • Authors: Mortensen S.
      Abstract: Ezekowitz expressed in an editorial comment (1) his opinion about the Q-SYMBIO study (Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status [Brain-Natriuretic Peptide (BNP)], and long-term Outcome [hospitalisations/mortality]) (2) with the following conclusion: “Heart failure (HF) patients are spending a lot of energy trying to be normal. Let us help them.”
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Reply Effect of Ivabradine on Early Readmissions After Hospitalization for
           Worsening Heart Failure
    • Authors: Gheorghiade M; Vaduganathan M, Fonarow GC.
      Abstract: We agree with Dr. Borer and colleagues that the retrospective analysis of the SHIFT (Systolic Heart failure treatment with the I[f] inhibitor ivabradine Trial) showed a significant reduction in readmissions in response to ivabradine therapy; however, this reduction occurred over a relatively long period of time in patients already receiving this medication. In our paper (1), we are referring to a specific time frame soon after hospitalization, which in the past, we called “the vulnerable phase.” Simply defined, the vulnerable phase is the immediate postdischarge period. Although morbidity and mortality during hospitalization may still occur, a substantial number of patients are readmitted for worsening heart failure within 30 days after discharge. Available data suggest that the congestion manifested by dyspnea most likely due to high left ventricular filling pressures is the main reason for hospitalization and rehospitalization. Most patients admitted with worsening chronic heart failure improve in response to diuretic therapy with minimal clinical congestion at the time of discharge (e.g., edema). Despite this, their natriuretic peptide levels remain persistently high, which suggests that they are being sent home with relatively high ventricular filling pressures (2). We call this “hemodynamic” congestion, which reflects an increase in intravascular volume. In the first few weeks after discharge, a significant number of patients develop worsening congestion that requires hospitalization. This is due to abnormal hemodynamics, mainly an increase in pulmonary capillary wedge pressure and/or a low cardiac output. Early readmission is often not related to progression of heart failure but to less than optimal treatment of congestion during hospitalization. In patients with left ventricular systolic dysfunction, the maintenance of cardiac output may be achieved by a compensatory increase in heart rate, which is a poor prognostic indicator (3). Thus, elevated heart rate may be a marker rather than a therapeutic target. Accordingly, reducing heart rate that is compensatory may worsen hemodynamics and therefore precipitate clinical congestion. To the best of our knowledge, ivabradine is not known to improve hemodynamics other than by its predominant effect in decreasing heart rate. Alternatively, reduction in heart rate during or early after hospitalization could be of benefit in those patients whose increase in heart rate is not compensatory. We need to keep in mind that the retrospective analysis by Dr. Borer and colleagues was conducted in patients already receiving ivabradine. This is different than starting ivabradine pre-discharge or soon after discharge in the vulnerable phase during which hemodynamics continue to be abnormal and often worsens. We welcome a prospective study assessing the effects of ivabradine started prior to or soon after discharge in patients hospitalized for heart failure. We recommend that congestion during the vulnerable phase be effectively treated with loop diuretic, mineralocorticoid receptor antagonist, and digoxin therapy. In terms of digoxin, it is known to have very little effect on the sinus node, and the decrease in heart rate is secondary to an improvement in hemodynamics that is noted within hours after it is administered (4).
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Effect of Ivabradine on Early Readmissions After Hospitalization for
           Worsening Heart Failure
    • Authors: Borer JS; Böhm M, Ford I, et al.
      Abstract: We have read with interest the editorial of Vaduganathan et al. (1). We strongly agree with the authors regarding the importance for our patients and our health care system of reducing readmissions for heart failure among those initially admitted to hospital, as well as reducing initial admissions. In addition, we recognize the appropriateness of the authors’ caveat regarding potential benefits of devices, educational initiatives and other nonpharmacological approaches when drugs also are used. Nonetheless, given recent publications in this field, including our own, we believe the authors may wish to reconsider some of their statements about strategies for reduction in early readmissions.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Risk Prediction Tools in Patients With Heart Failure
    • Authors: Lupón J; Vila J, Bayes-Genis A.
      Abstract: We read with interest the papers from Ouwerkerk et al. (1), Rahimi et al. (2), and Levy and Anand (3), and we would like to comment on mortality risk prediction models in contemporary heart failure (HF) management, with biomarkers already incorporated into routine practice. The 2013 American College of Cardiology Foundation/American Heart Association HF guidelines state that biomarkers are powerful adjuncts to current standards for acute and chronic HF, and we deeply agree with the discussion remark of Ouwerkerk et al. (1): “Developing a model using a systems biology approach, incorporating information from demographic, biomarker, genomic, proteomic, and initial responses to therapy might create a more effective model.” Moreover, Levy and Anand (3) elegantly point out in their editorial comment that HF risk models would improve if: 1) they were properly validated; 2) state-of-the-art discrimination (starting the model with age and sex), calibration, and reclassification analyses were performed to assess the incremental value of adding new variables to the model; and 3) online calculators were made to allow for easy provider use.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Association of Cardiomyopathy With Adverse Cardiac Events in Pregnant
           Women at the Time of Delivery
    • Authors: Lima FV; Parikh PB, Zhu J, et al.
      Abstract: ObjectivesThe aim of this study was to determine the predictors of adverse events in pregnant women with cardiomyopathy (CDM) and CDM subtypes at the time of delivery.BackgroundInvestigation of patients’ characteristics and outcomes in women with CDM at the time of delivery has been limited.MethodsThe Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with CDM from 2006 to 2010. Clinical characteristics and maternal outcomes were identified in women with and without CDM and in CDM subtypes. The primary outcome of interest was major adverse clinical events (MACE), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, or embolic event.ResultsOur study population comprised 2,078 patients with CDM and 4,438,439 patients without CDM. Of those with CDM, 52 (2.5%) were hypertrophic, 1,039 (50.0%) were peripartum, and 987 (47.5%) were classified as other. Women with CDM were older, white, and insured by Medicaid. MACE rates were significantly higher in women with peripartum CDM (46%), compared with hypertrophic CDM (23%) and all others (39%) (p < 0.001). In multivariable analysis, the presence of peripartum cardiomyopathy (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.1 to 4.6), valvular disease (OR: 2.11; 95% CI: 1.6 to 2.9), and eclampsia (OR: 5.0; 95% CI: 1.6 to 1.9) was independently associated with MACE.ConclusionsPresence of CDM is independently predictive of MACE during hospitalization for delivery. Patients with peripartum CDM had the highest likelihood of MACE compared with other CDM subtypes.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Inside This Issue
    • PubDate: Sun, 01 Mar 2015 00:00:00 GMT
  • Heart Failure Therapeutics on the Basis of a Biased
           Ligand of the Angiotensin-2 Type 1 Receptor Rationale and
           Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin
           Receptor Study in Acute Heart Failure)
    • Authors: Felker G; Butler J, Collins SP, et al.
      Abstract: The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and no currently-available therapies have been shown to favorably affect outcomes. TRV027 is a novel biased ligand of the angiotensin-2 type 1 receptor that antagonizes angiotensin-stimulated G-protein activation while stimulating β-arrestin. In animal models, these effects reduce afterload while increasing cardiac performance and maintaining stroke volume. In initial human studies, TRV027 appears to be hemodynamically active primarily in patients with activation of the renin-angiotensin-aldosterone system, a potentially attractive profile for an AHF therapeutic. BLAST-AHF is an international prospective, randomized, phase IIb, dose-ranging study that will randomize up to 500 AHF patients with systolic blood pressure ≥120 mm Hg and ≤200 mm Hg within 24 h of initial presentation to 1 of 3 doses of intravenous TRV027 (1, 5, or 25 mg/h) or matching placebo (1:1:1:1) for at least 48 h and up to 96 h. The primary endpoint is a composite of 5 clinical endpoints (dyspnea, worsening heart failure, length of hospital stay, 30-day rehospitalization, and 30-day mortality) combined using an average z-score. Secondary endpoints will include the assessment of dyspnea and change in amino-terminal pro–B-type natriuretic peptide. The BLAST-AHF study will assess the efficacy and safety of a novel biased ligand of the angiotensin-2 type 1 receptor in AHF.
      PubDate: Sun, 01 Mar 2015 00:00:00 GMT
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