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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]
  • Reply The Importance of Ventricular-Vascular Uncoupling
    • Authors: Pfister R; Michels G, Sharp SJ, et al.
      Abstract: In their letter, Drs. Raggi and Bellasi propose myocardial-vascular uncoupling as a potential mechanism underlying the association between low bone mineral density and risk of heart failure as observed in our study (1). In the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk Prospective Study, measures of vascular calcification or aortic stiffness were not available to examine the proposed mechanism. However, the correlation of pulse wave velocity as a measure of aortic stiffness and bone mineral density in patients on hemodialysis, as reported by Drs. Raggi and Bellasi, might not be generalizable to elderly and otherwise healthy subjects in the population. Vascular calcification and stiffness in patients on hemodialysis is excessive, as indicated by an almost 2-fold higher pulse wave velocity in these patients compared with elderly subjects in the general population (2,3). Furthermore, there seems to be a striking sex divergence in the association between pulse wave velocity and bone mineral density and also between pulse wave velocity and diastolic dysfunction, with a significant association observed only in women (2,4). In contrast, we did not observe a significant sex interaction in the association between bone mineral density and risk of heart failure. The mechanism linking vascular stiffness and heart failure is largely unclear but might be mediated through systolic blood pressure (5). However, adjustment for systolic blood pressure did not change the results of our analysis. Finally, to the best of our knowledge, vascular stiffness has been associated only with diastolic dysfunction, whereas we showed a clear association with systolic heart failure. Taken together, the latter data do not support myocardial-vascular uncoupling as the exclusive mechanism underlying the association of bone mineral density and risk of heart failure, but it may play a role in a subset of patients (e.g., women with diastolic heart failure).
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Biomarkers, Mineralocorticoid Receptor Antagonism, and Cardiorenal
           Remodeling ∗
    • Authors: Fiuzat M; Burnett JC.
      Abstract: “We cannot solve our problems with the same thinking we used when we created them.”—Albert Einstein (1)
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Delineating Survival Outcomes in Children <10 kg Bridged to
           Transplant or Recovery With the Berlin Heart EXCOR Ventricular
           Assist Device
    • Authors: Conway J; St. Louis J, Morales DS, et al.
      Abstract: ObjectivesThe goal of this study was to delineate outcomes of children weighing 
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Mineralocorticoid Receptor Antagonists Modulate Galectin-3 and
           Interleukin-33/ST2 Signaling in Left Ventricular Systolic Dysfunction
           After Acute Myocardial Infarction
    • Authors: Lax A; Sanchez-Mas J, Asensio-Lopez MC, et al.
      Abstract: ObjectivesThis study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI).BackgroundThe molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood.MethodsMI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-β and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined.ResultsIn the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected.ConclusionsMRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • The Impact of Galectin-3 Inhibition on Aldosterone-Induced Cardiac
           and Renal Injuries
    • Authors: Calvier L; Martinez-Martinez E, Miana M, et al.
      Abstract: ObjectivesThis study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction.BackgroundAldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside–binding lectin, is increased in heart failure and kidney injury.MethodsRats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed.ResultsHypertensive aldosterone-salt–treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects.ConclusionsIn experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Effects of Left Ventricular Assist Device Support on Biomarkers of
           Cardiovascular Stress, Fibrosis, Fluid Homeostasis, Inflammation, and
           Renal Injury
    • Authors: Ahmad T; Wang T, O'Brien EC, et al.
      Abstract: ObjectivesThe purpose of this study was to examine changes in a broad panel of biomarkers following left ventricular assist device (LVAD) support in advanced heart failure (HF).BackgroundLVAD therapy mechanically unloads the failing heart and may result in reversal of certain aspects of the end-stage HF phenotype. Changes in markers of myocardial stress, fibrosis, inflammation, fluid homeostasis, and renal injury in this setting are unknown.MethodsAmino-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, ST2, copeptin, growth differentiation factor (GDF)-15, C-reactive protein (CRP), and neutrophil gelatinase associated lipocalin (NGAL) levels were measured in frozen plasma collected from 37 individuals prior to continuous flow LVAD implantation and a median of 136 (interquartile range: 94 to 180) days after implantation.ResultsThe median age of patients was 68 years old. LVAD therapy was associated with significant decreases in NT-proBNP (3,093 to 2,090 pg/ml; p = 0.02), ST2 (67.5 to 45.2 ng/ml, p 
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Comparative Assessment of Short-Term Adverse Events in Acute Heart
           Failure With Cystatin C and Other Estimates of Renal
           Function Results From the ASCEND-HF Trial
    • Authors: Tang W; Dupont M, Hernandez AF, et al.
      Abstract: ObjectivesThe purpose of this study was to investigate the predictive values of baseline and changes in cystatin C (CysC) and its derived equations for short-term adverse outcomes and the effect of nesiritide therapy on CysC in acute decompensated heart failure (ADHF).BackgroundNewer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure.MethodsCysC levels were measured in sequential plasma samples from 811 subjects with ADHF who were enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) biomarker sub-study (randomized to nesiritide therapy vs. placebo), and followed for all-cause death (180 days) and recurrent hospital stay (30 days).ResultsMedian CysC levels were 1.49 (interquartile range [IQR]: 1.20 to 1.96) mg/l at baseline, 1.56 (IQR: 1.28 to 2.13) mg/l at 48 to 72 h, and 1.58 (IQR: 1.24 to 2.11) mg/l at 30 days. Higher baseline (but not follow-up) CysC levels were associated with increased risk of 30-day adverse events and less improvement in dyspnea after 24 h as well as 180-day mortality, although not incremental to blood urea nitrogen. Worsening renal function (defined as a 0.3 mg/l increase in CysC) occurred in 161 of 701 (23%) patients, but it was not predictive of adverse events. Changes in CysC levels were similar between the nesiritide and placebo groups.ConclusionsOur findings confirmed the prognostic value of baseline CysC levels in the setting of ADHF. However, worsening renal function based on CysC rise was not predictive of adverse events. Nesiritide did not worsen renal function compared with placebo.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Characterization of Pulmonary Hypertension in Heart Failure
           Using the Diastolic Pressure Gradient Limitations of a Solitary
           Measurement ∗
    • Authors: Chatterjee NA; Lewis GD.
      Abstract: When pulmonary hypertension (PH), defined by mean pulmonary artery pressure (mPAP) ≥25 mm Hg, is associated with an abnormally elevated pulmonary capillary wedge pressure (PCWP) >15 mm Hg or left ventricular end-diastolic pressure (LVEDP) >18 mm Hg (1), it has been variably termed World Health Organization Group 2 PH (1), pulmonary venous hypertension (2), “post-capillary PH” (3), or “passive PH” (4). This type of PH is distinct from primary pulmonary arterial hypertension where there is no increase in left ventricular filling pressure (i.e., pre-capillary PH).
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Safety and Tolerability of Omecamtiv Mecarbil During Exercise in Patients
           With Ischemic Cardiomyopathy and Angina
    • Authors: Greenberg BH; Chou W, Saikali KG, et al.
      Abstract: ObjectivesThe goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time.BackgroundOmecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time.MethodsIn this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3).ResultsThe primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events.ConclusionsDoses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565)
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Inside This Issue
    • PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Effect of Macitentan on Hospitalizations Results From the SERAPHIN Trial
    • Authors: Channick RN; Delcroix M, Ghofrani H, et al.
      Abstract: ObjectivesThis study sought to evaluate the effect of macitentan on hospitalization of patients with symptomatic pulmonary arterial hypertension (PAH).BackgroundPAH is a progressive, life-threatening disease often requiring hospitalization.MethodsIn the multicenter, double-blind, randomized, event-driven, phase III SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial, patients with symptomatic PAH were randomized (1:1:1) to receive placebo or 3 mg or 10 mg of macitentan. Effects of macitentan on the risk, rate, and number of hospital days for all-cause and PAH-related hospitalizations were compared with those for placebo. Risk and causes of hospitalizations unrelated to PAH were investigated.ResultsOf 742 randomized patients, 250 received placebo, 250 received 3 mg of macitentan, and 242 received 10 mg of macitentan; the overall median duration of treatment was 115 weeks. Risk of all-cause hospitalization was reduced by 18.9% (p = 0.1208) and 32.3% (p = 0.0051) in the macitentan 3-mg and 10-mg arm, respectively. Rates of all-cause hospitalizations and numbers of hospital days were reduced by 20.5% (p = 0.0378) and 30.6% (p = 0.0278), respectively, with 3 mg of macitentan and by 33.1% (p = 0.0005) and 31.0% (p = 0.0336), respectively, with 10 mg of macitentan. Risk of PAH-related hospitalizations were reduced by 42.7% (p = 0.0015) and 51.6% (p < 0.0001) in the macitentan 3-mg and 10-mg arms, respectively. Rate of PAH-related hospitalizations and numbers of hospital days were reduced by 44.5% (p = 0.0004) and 53.3% (p = 0.0001), respectively, with 3 mg of macitentan, and reduced by 49.8% (p < 0.0001) and 52.3% (p = 0.0003), respectively, with 10 mg of macitentan. Risk of non–PAH-related hospitalization was similar between treatment arms.ConclusionsMacitentan 10 mg significantly reduced the risk and rate of all-cause hospitalization, which was driven by reductions in the risk and rate of PAH-related hospitalization. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension; NCT00660179)
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Conflict of Interest and Transparency Are the Headlights
    • Authors: O’Connor CM.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • The Importance of Ventricular-Vascular Uncoupling
    • Authors: Raggi P; Bellasi A.
      Abstract: We read with pleasure the interesting report by Pfister et al. (1). There in an expanding body of evidence in published reports showing an inverse relationship between bone and vascular health. Schulz et al. (2) showed that the extent of aortic calcification is inversely proportional to bone mineral density (BMD) of the spine in post-menopausal women. Bolland et al. published a subanalysis of a randomized trial and a meta-analysis showing that calcium supplements for healthy post-menopausal women do not substantially increase BMD but may increase the rate of myocardial infarction and stroke (3,4). There is one potential mechanism not considered by Pfister et al. (1) that may be subtending the development of concurrent heart failure in patients with low BMD: the myocardial-vascular uncoupling that occurs with aging even in the absence of coronary artery disease. Our group has had an interest in vascular calcification and vascular stiffness for several years. In a cohort of prevalent hemodialysis patients, who have a particularly high risk of developing vascular calcifications, congestive heart failure, and sudden death, we showed that increased aortic stiffness is associated with low vertebral BMD (5). Other investigators have shown that increased aortic stiffness leads to left ventricular hypertrophy and diastolic dysfunction and, eventually, systolic dysfunction. Similar mechanisms may be operative in patients with normal renal function on the basis of aging and progressive replacement of elastic fibers with collagenous fibers in the media and adventitia of the arterial wall. Thus, we believe that the discussion of the report by Pfister et al. (1) would have benefited from mention of these aspects of myocardial/vascular/bone health uncoupling.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • The Diastolic Pulmonary Gradient Does Not Predict Survival in
           Patients With Pulmonary Hypertension Due to
           Left Heart Disease
    • Authors: Tampakakis E; Leary PJ, Selby VN, et al.
      Abstract: ObjectivesThis study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD).BackgroundPatients with combined post- and pre-capillary PH-LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed.MethodsA retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses.ResultsDPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg.ConclusionsIn this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • An Increased B-Type Natriuretic Peptide in the Absence of a Cardiac
           Abnormality Identifies Those Whose Left Ventricular Mass Will Increase
           Over Time
    • Authors: Nadir M; Gandy S, Ireland S, et al.
      Abstract: ObjectivesThe purpose of this study was to identify the relationship of B-type natriuretic peptide (BNP) with evolution of left ventricular mass (LVM) in optimally treated primary prevention patients.BackgroundPatients who have an elevated BNP no cardiac abnormality on echocardiography are common and at increased risk of adverse events. One hypothesis is that an elevated BNP is an early sensitive indicator of who will develop future structural abnormalities such as left ventricular (LV) hypertrophy.MethodsWe identified optimally treated primary prevention patients with no cardiac abnormality at baseline. In particular, they had no myocardial ischemia, LV hypertrophy, LV dysfunction, or left atrial enlargement. They had a diverse range of plasma BNP levels and underwent cardiac magnetic resonance at baseline and 3 years later on a 3-T scanner.ResultsFifty patients with a diverse range of BNP were studied (with BNP ≤10 pg/ml in 25 patients and >10 pg/ml in 25 patients). LVM increased (+4.7 ± 3.5 g) in 24 patients and decreased (–4.9 ± 2.8 g) in 26 patients (p < 0.01). Blood pressure by 24-h monitoring was virtually identical between those whose LVM increased (systolic blood pressure 122 ± 14 mm Hg) and those whose LVM decreased (systolic blood pressure 121 ± 11 mm Hg, p = 0.77). Plasma BNP was nearly 3 times higher in those whose LVM increased versus those in whom LVM decreased (21 ± 9.6 pg/ml vs. 7.9 ± 3.9 pg/ml, p < 0.01). The c-statistic for BNP was 0.88.ConclusionsIn optimally treated primary prevention patients, plasma BNP levels are able to distinguish between those whose LVM will increase during the next 3 years versus those whose LVM will decrease during the next 3 years. This may explain why individuals with high BNP are at increased risk even if no cardiac abnormality can be detected initially.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
  • Natural History and Prognostic Factors in Alcoholic Cardiomyopathy
    • Authors: Guzzo-Merello G; Segovia J, Dominguez F, et al.
      Abstract: ObjectivesThis study sought to determine the natural history of contemporary alcoholic cardiomyopathy (ACM), to compare it with that of idiopathic dilated cardiomyopathy (IDCM), and to identify risk factors for poor outcome.BackgroundACM is a common cause of dilated cardiomyopathy (DCM), but little is known about its natural history or the effect of reducing alcohol intake on disease progression.MethodsWe studied the clinical characteristics and outcomes of 94 consecutive patients with ACM and 188 with IDCM, evaluated over the period between 1993 and 2011.ResultsAfter a median follow-up of 59 months (interquartile range: 25 to 107 months), 14 ACM patients (15%) had died from cardiovascular causes (6 from heart failure and 8 from sudden cardiac death), 14 (15%) underwent heart transplantation, 35 (37%) experienced recovery in left ventricular function, and 31 (33%) remained clinically stable without improvement in systolic function. Transplantation-free survival was higher in ACM patients than in IDCM patients (p = 0.002), and ACM was associated with a favorable outcome on multiple analysis of the entire cohort (odds ratio [OR]: 0.4; 95% confidence interval [CI]: 0.2 to 0.8; p = 0.01). Independent predictors of death or heart transplantation in ACM identified by multiple logistic regression analysis were atrial fibrillation (OR: 9.7; 95% CI: 2.56 to 36.79; p = 0.001); QRS duration >120 ms (OR: 7.2; 95% CI: 2.02 to 26; p = 0.002), and lack of beta-blocker therapy (OR: 4.4; 95% CI: 1.35 to 14.49; p = 0.014). ACM patients who reduced their alcohol intake to moderate levels exhibited similar survival (p = 0.22) and cardiac function recovery (p = 0.8) as abstainers.ConclusionsACM has a better prognosis than IDCM. Atrial fibrillation, QRS width >120 ms, and the absence of beta-blocker therapy identify patients with a poor outcome. Alcohol abstainers and those who reduce intake to a moderate degree show similar clinical outcomes.
      PubDate: Thu, 01 Jan 2015 00:00:00 GMT
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