Showing papers in "Circulation-heart Failure in 2014"
TL;DR: Patients enrolled in TOPCAT demonstrated heterogeneous patterns of ventricular remodeling, with high prevalence of structural heart disease, including left ventricular hypertrophy and left atrial enlargement, in addition to pulmonary hypertension, each of which has been associated with adverse outcomes in HFpEF.
Abstract: Background—Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality. Existing data on cardiac structure and function in HFpEF suggest significant heterogeneity in this population. Methods and Results—Echocardiograms were obtained from 935 patients with HFpEF (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial before initiation of randomized therapy. Average age was 70±10 years, 49% were women, 14% were of African descent, and comorbidities were highly prevalent. Centralized quantitative analysis in a blinded core laboratory demonstrated a mean left ventricular ejection fraction of 59.3±7.9%, with prevalent concentric left ventricular remodeling (34%) and hypertrophy (43%), and left atrial enlargement (53%). Diastolic dysfunction was present in 66% of gradable participants and was significantly associated with greater left ventricular hypertrophy and...
357 citations
TL;DR: Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies.
Abstract: Background— No treatment strategies have been demonstrated to be beneficial for the population for patients with heart failure (HF) and preserved ejection fraction (EF).
Methods and Results— The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial was a prospective, single-blinded, randomized controlled clinical trial testing the hypothesis that hemodynamically guided HF management decreases decompensation leading to hospitalization. Of the 550 patients enrolled in the study, 119 had left ventricular EF ≥40% (average, 50.6%), 430 patients had low left ventricular EF ( 6 months for preserved EF patients was 46% lower in the treatment group compared with control (incidence rate ratio, 0.54; 95% confidence interval, 0.38–0.70; P <0.0001). After an average of 17.6 months of blinded follow-up, the hospitalization rate was 50% lower (incidence rate ratio, 0.50; 95% confidence interval, 0.35–0.70; P <0.0001). In response to pulmonary artery pressure information, more changes in diuretic and vasodilator therapies were made in the treatment group.
Conclusions— Hemodynamically guided management of patients with HF with preserved EF reduced decompensation leading to hospitalization compared with standard HF management strategies.
Clinical Trial Registration— URL: . Unique identifier: [NCT00531661][1].
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00531661&atom=%2Fcirchf%2F7%2F6%2F935.atom
351 citations
TL;DR: The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.
Abstract: Background— Probiotics are extensively used to promote gastrointestinal health, and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of postinfarction heart failure.
Methods and Results— Rats were subjected to 6 weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment and gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the 6-week follow-up period including a marked preservation of left ventricular ejection fraction and fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at 4 weeks, suggesting persistence of the GR-1 effects after cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin:adiponectin plasma concentration ratio in rats subjected to coronary ligation, which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels.
Conclusions— The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.
215 citations
TL;DR: In this article, an unbiased system approach was used to define energy metabolic events that occur during pathological cardiac remodeling en route to heart failure, and combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload.
Abstract: Background— An unbiased systems approach was used to define energy metabolic events that occur during the pathological cardiac remodeling en route to heart failure (HF).
Methods and Results— Combined myocardial transcriptomic and metabolomic profiling were conducted in a well-defined mouse model of HF that allows comparative assessment of compensated and decompensated (HF) forms of cardiac hypertrophy because of pressure overload. The pressure overload data sets were also compared with the myocardial transcriptome and metabolome for an adaptive (physiological) form of cardiac hypertrophy because of endurance exercise training. Comparative analysis of the data sets led to the following conclusions: (1) expression of most genes involved in mitochondrial energy transduction were not significantly changed in the hypertrophied or failing heart, with the notable exception of a progressive downregulation of transcripts encoding proteins and enzymes involved in myocyte fatty acid transport and oxidation during the development of HF; (2) tissue metabolite profiles were more broadly regulated than corresponding metabolic gene regulatory changes, suggesting significant regulation at the post-transcriptional level; (3) metabolomic signatures distinguished pathological and physiological forms of cardiac hypertrophy and served as robust markers for the onset of HF; and (4) the pattern of metabolite derangements in the failing heart suggests bottlenecks of carbon substrate flux into the Krebs cycle.
Conclusions— Mitochondrial energy metabolic derangements that occur during the early development of pressure overload–induced HF involve both transcriptional and post-transcriptional events. A subset of the myocardial metabolomic profile robustly distinguished pathological and physiological cardiac remodeling.
214 citations
TL;DR: Left ventricular hypertrophy, higher left ventricular filling pressure, and higher pulmonary artery pressure were predictive of heart failure hospitalization, cardiovascular death, or aborted cardiac arrest independent of clinical and laboratory predictors.
Abstract: Background—Abnormalities in cardiac structure and function in heart failure with preserved ejection fraction may help identify patients at particularly high risk for cardiovascular morbidity and mortality. Methods and Results—Cardiac structure and function were assessed by echocardiography in a blinded core laboratory at baseline in 935 patients with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%) enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and related to the primary composite outcome of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest, and its components. At a median follow-up of 2.9 years, 244 patients experienced the primary outcome. Left ventricular hypertrophy (adjusted hazard ratio, 1.52; 95% confidence interval, 1.16–2.00), elevated left ventricular filling pressure (E/E′; adjusted hazard ratio 1.05 per 1 integer increase; 95% confidence interval, 1.02–1.07)...
210 citations
TL;DR: Diuretic efficiency (DE) is defined as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value as mentioned in this paper.
Abstract: Background— Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose.
Methods and Results— We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r2≤0.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission diuretic therapy, traditional baseline characteristics, including right heart catheterization variables, were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04−1.78; P =0.02; ESCAPE: HR, 2.86; 95% CI, 1.53−5.36; P =0.001).
Conclusions— Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure.
196 citations
TL;DR: The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) as discussed by the authors assessed the risk factors for mineralocorticoid receptor antagonist-related renal function (WRF) and hyperkalemia (HK), as well as the association between HK and WRF with clinical outcomes.
Abstract: Background—Mineralocorticoid receptor antagonists improve outcomes in patients with systolic heart failure but may induce worsening of renal function (WRF) and hyperkalemia (HK). We assessed the risk factors for mineralocorticoid receptor antagonist–related WRF and for HK, as well as the association between HK and WRF with clinical outcomes in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Methods and Results—Serial changes in estimated glomerular filtration rate and in serum potassium were available in 2737 patients during a median 21-month follow-up. HK variably defined as serum K >4.5, 5, or 5.5 mmol/L occurred in 74.7%, 32.5%, and 8.9% patients enrolled in EMPHASIS-HF, respectively. WRF defined as a decrease in estimated glomerular filtration rate >20% or >30% from baseline occurred in 27% and 14% of patients, respectively. Patients assigned eplerenone displayed modest and early but significant and persistent (1) rise in serum potassium and (2) reduc...
189 citations
TL;DR: Findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.
Abstract: Background—Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism. Methods and Results—Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated...
178 citations
TL;DR: Reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes in patients with HFpEF, and these associations persisted after additional adjustment for markers of HF severity.
Abstract: Background—Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown. Methods and Results—We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area ...
172 citations
TL;DR: The prevalence of AI is substantially less in patients whose AV opens, and optimized loading conditions may reduce AI prevalence in those patients in whom AV opening cannot be achieved.
Abstract: Background—Aortic insufficiency (AI) is increasingly recognized as a complication of continuous flow left ventricular assist device support; however, its long-term prevalence, clinical significance, and efficacy of potential interventions are not well known. Methods and Results—We studied the prevalence and management of AI in 232 patients with continuous flow left ventricular assist device at our institution. Patients with aortic valve (AV) surgery before left ventricular assist device implantation were excluded from analysis. To examine the prevalence of de novo AI, patients without preoperative AI were divided into a retrospective and a prospective cohort based on whether a dedicated speed optimization study had been performed at the time of discharge. Forty-three patients underwent AV repair at the time of implant, and 3 subsequently developed greater than mild AI. In patients without surgical AV manipulation and no AI at the time of implant, Kaplan–Meier analysis revealed that freedom from greater th...
168 citations
TL;DR: In this paper, the authors assessed incidence and predictors of hyperkalemia (potassium ≥ 5.5 mmol/L) and hypokalemia, and the relationship to outcomes in 1663 patients with class III or IV heart failure and left ventricular ejection fraction <35% randomized to treatment with spironolactone 25 mg or placebo in the Randomized Aldactone Evaluation Study (RALES) trial.
Abstract: Background—Mineralocorticoid receptor antagonists reduce morbidity and mortality in patients with heart failure but can cause hyperkalemia, which contributes to reduced use of these drugs. Hypokalemia also leads to worse outcomes in patients with heart failure and may be attenuated by mineralocorticoid receptor antagonists. Methods and Results—We assessed incidence and predictors of hyperkalemia (potassium ≥5.5 mmol/L) and hypokalemia (potassium <3.5 mmol/L) and the relationship to outcomes in 1663 patients with class III or IV heart failure and left ventricular ejection fraction <35% randomized to treatment with spironolactone 25 mg or placebo in the Randomized Aldactone Evaluation Study (RALES) trial. All-cause mortality rates and the influence of potassium levels on the effectiveness of spironolactone were assessed in a landmark analysis and in relation to time-varying potassium levels. After 1 month, mean potassium levels increased in the spironolactone group but not in the placebo group (4.54±0.49 ve...
TL;DR: A novel beneficial effect of Ang 1–7 on diabetic cardiomyopathy that involved a reduction in cardiac hypertrophy and lipotoxicity, adipose inflammation, and an upregulation of adipose triglyceride lipase is identified.
Abstract: Background—The angiotensin-converting enzyme 2 and angiotensin-(1–7) (Ang 1–7)/MasR (Mas receptor) axis are emerging as a key pathway that can modulate the development of diabetic cardiomyopathy. We studied the effects of Ang 1–7 on diabetic cardiomyopathy in db/db diabetic mice to elucidate the therapeutic effects and mechanism of action. Methods and Results—Ang 1–7 was administered to 5-month-old male db/db mice for 28 days via implanted micro-osmotic pumps. Ang 1–7 treatment ameliorated myocardial hypertrophy and fibrosis with normalization of diastolic dysfunction assessed by pressure–volume loop analysis and echocardiography. The functional improvement by Ang 1–7 was accompanied by a reduction in myocardial lipid accumulation and systemic fat mass and inflammation and increased insulin-stimulated myocardial glucose oxidation. Increased myocardial protein kinase C levels and loss of phosphorylation of extracellular signal-regulated kinase 1/2 were prevented by Ang 1–7. Furthermore, Ang 1–7 treatment d...
TL;DR: Fuid challenge at the time of right heart catheterization is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to pulmonary hypertension.
Abstract: Background—Determining the cause for pulmonary hypertension is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure (PWP) >15 mm Hg in PVH. Patients undergoing right heart catheterization for evaluation of pulmonary hypertension may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during right heart catheterization would identify occult pulmonary venous hypertension (OPVH). Methods and Results—We reviewed the results of patients undergoing fluid challenge in our pulmonary hypertension database from 2004 to 2011. Baseline hemodynamics were obtained and repeated after infusion of 0.5 L of normal saline for 5 to 10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. After fluid challe...
TL;DR: The aim was to perform a systematic review of Danon disease, provide a comprehensive clinical and molecular update, and propose diagnostic and management guidelines for clinicians and researchers working with patients withDanon disease.
Abstract: Danon disease is an X-linked dominant skeletal and cardiac muscle disorder with multisystem clinical manifestations. It was first described in boys presenting with cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability.1 As histological findings of glycogen buildup in muscle tissue similar to those seen in Pompe disease were noted, the condition was originally considered to be a lysosomal storage disease and was termed glycogen storage disease type IIb. In 2000, Nishino et al2 identified the genetic defects in the lysosome-associated membrane protein 2 ( LAMP2 ) gene, encoding the LAMP2 protein. Most Danon disease mutations lead to an absence of LAMP2 protein expression,2 a situation more problematic in men who are hemizygous for LAMP2 . For reasons not yet fully understood, reduction in LAMP2 disrupts intracytoplasmic trafficking and leads to accumulation of autophagic material and often glycogen in skeletal muscle and cardiac muscle cells (Figure 1).2 Major clinical features include skeletal and cardiac myopathy, cardiac conduction abnormalities, mild intellectual difficulties, and retinal disease. Men are typically affected earlier and more severely than women. The disease is unfamiliar to many practitioners, and the majority of published data stem from case reports with a brief clinical review published in 2002.4 Our aim was to perform a systematic review of Danon disease, provide a comprehensive clinical and molecular update, and propose diagnostic and management guidelines for clinicians and researchers working with patients with Danon disease.
Figure 1.
Histological images from skeletal muscle biopsy and endomyocardial biopsy.3 Electron microscopy shows intracytoplasmic vacuoles (arrows) containing autophagic material and glycogen in both ( A ) skeletal muscle (bar 1 μm) and ( B ) endomyocardial tissue biopsy (bar 1 μm). Reprinted from Taylor et al3 with permission of the publisher. Copyright © 2007, Nature Publishing Group. Authorization for this adaptation has been obtained both from …
TL;DR: Post-MCS, early improvement in renal function is common but seems to be largely transient and not necessarily indicative of an improved prognosis, and additional research is necessary to better understand the mechanistic basis for these complex post- MCS changes in renalfunction and their associated survival disadvantage.
Abstract: Background—The long-term durability and prognostic significance of improvement in renal function after mechanical circulatory support (MCS) has yet to be characterized in a large multicenter population. The primary goals of this analysis were to describe serial post-MCS changes in estimated glomerular filtration rate (eGFR) and determine their association with all-cause mortality. Methods and Results—Adult patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with serial creatinine levels available (n=3363) were studied. Early post-MCS, eGFR improved substantially (median improvement, 48.9%; P<0.001) with 22.3% of the population improving their eGFR by ≥100% within the first few weeks. However, in the majority of patients, this improvement was transient, and by 1 year, eGFR was only 6.7% above the pre-MCS value (P<0.001). This pattern of early improvement followed by deterioration in eGFR was observed with both pulsatile and continuous-flow devices. Intere...
TL;DR: In this paper, the authors aimed to summarize the current evidence on outcomes of continuous-flow left ventricular assist devices (LVAD) for the full range of possible outcomes.
Abstract: Background—Conveying the complex trade-offs of continuous-flow left ventricular assist devices is challenging and made more difficult by absence of an evidence summary for the full range of possible outcomes. We aimed to summarize the current evidence on outcomes of continuous-flow left ventricular assist devices. Methods and Results—PubMed and Cochrane Library were searched from January 2007 to December 2013, supplemented with manual review. Three reviewers independently assessed each study for saliency on patient-centered outcomes. Data were summarized in tabular form. Overall study characteristics encouraged inclusion of all indications (destination therapy and bridge to transplant) and prevented meta-analysis. The electronic search identified 465 abstracts, of which 50 met inclusion criteria; manual review added 2 articles in press. The articles included 10 industry-funded trials and registries, 10 multicenter reports, and the remainder single-center observational experiences. Estimated actuarial surv...
TL;DR: The RELAX (Phosphodiesterase-5 inhibition to improve clinical status and exercise capacity in atrial fibrillation) trial as mentioned in this paper was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF.
Abstract: Background—Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. Methods and Results—RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left v...
TL;DR: Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid intima-media thickness or stroke.
Abstract: Background —Fibroblast growth factor-23 (FGF-23) is a phosphate regulatory hormone that directly stimulates left ventricular hypertrophy in experimental models. The role of FGF-23 in cardiovascular disease development in the general population is unclear. We tested associations of FGF-23 with major subclinical and clinical cardiovascular disease outcomes in a large prospective cohort.
Methods and Results —We evaluated 6,547 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were initially free of cardiovascular disease. We measured serum FGF-23 using the Kainos immunoassay. The MESA measured left ventricular (LV) mass by magnetic resonance imaging, coronary calcium (CAC) by computed tomography, and carotid intima-medial thickness (IMT) by ultrasound. The MESA adjudicated incident heart failure, coronary heart disease, and stoke by medical record review. After adjustment, the highest FGF-23 quartile was associated with an estimated 2.4 gram greater LV mass (95% CI 0.4, 4.5 greater) and a 26% greater odds of higher CAC scores (95% CI 9% to 46% greater) compared to the lowest quartile. Over 7.5 years follow-up, each 20-pg/mL higher FGF-23 concentration was associated with a 19% greater risk of heart failure (95% CI 3% to 37% greater) and a 14% greater risk of coronary heart disease (95% CI 1% to 28% greater). FGF-23 was not associated with carotid IMT or stroke.
Conclusions —Higher serum FGF-23 concentrations are associated with subclinical cardiac disease and with new heart failure and coronary disease events, but not with carotid IMT or stroke. FGF-23 may be a novel cardiovascular risk factor in the general population.
TL;DR: Rates of cardiovascular death or HF hospitalization are greatest in those who have been previously hospitalized for HF, and recent HFospitalization identifies a high-risk population for future clinical trials in HF and reduced ejection fraction and HF with preserved ejections fraction.
Abstract: Background—Hospitalization for acute heart failure (HF) is associated with high rates of subsequent mortality and readmission. We assessed the influence of the time interval between previous HF hospitalization and randomization in the Candesartan in Heart failure: Reduction in Mortality and morbidity (CHARM) trials on clinical outcomes in patients with both reduced and preserved ejection fraction. Methods and Results—CHARM enrolled 7599 patients with New York Heart Association class II to IV HF, of whom 5426 had a history of previous HF hospitalization. Cox proportional hazards regression models were used to assess the association between time from previous HF hospitalization and randomization and the primary outcome of cardiovascular death or unplanned admission to hospital for the management of worsening HF during a median of 36.6 months. For patients with HF and reduced or preserved ejection fraction, rates of cardiovascular mortality and HF hospitalization were higher among patients with previous HF h...
TL;DR: In this article, a continuous relationship between sST2 and the log hazard ratio for outcomes was modeled as two linear segments with a significant decrease in the rate of increase in hazard ratios above 33.2 ng/mL.
Abstract: Background —Soluble ST2 (sST2), a biomarker related to inflammation, is associated with outcomes of patients with heart failure (HF). In depth analyses of the relationship between sST2, changes in sST2 and patient outcomes are reported.
Methods and Results —sST2 was measured at baseline (n=1,650), 4-months (n=1,345) and 12-months (n=1,094) in Valsartan Heart Failure Trial. Baseline sST2 averaged 28.7±16.2 ng/mL; significantly (p<0.001) higher in men than women, but supra-normal in only 9 and 15%, respectively. A continuous relationship between sST2 and the log hazard ratio for outcomes was modeled as two linear segments with a significant decrease in the rate of increase in hazard ratios above 33.2 ng/mL. Each segment of the sST2 distribution was significantly (p<0.0001) associated with the risks of morbid event, mortality and hospitalization for HF. Only sST2 values <33.2 ng/mL were significantly related to the outcomes when 23 readily available clinical variables including NT-proBNP were included in the Cox regression model. sST2 didn't improve discrimination of patient outcomes. Compared to placebo, valsartan significantly (p<0.001) reduced the rate of increase in sST2. Increases in sST2 over 12-months, but not decreases, were significantly associated with subsequent outcomes independent of clinical variables, sST2 and valsartan treatment.
Conclusions —In this study, baseline sST2 was nonlinearly associated with patient outcomes, but didn't provide substantial prognostic information when added to a clinical prediction model that included NT-proBNP. An increase but not decrease in sST2 was independently associated with outcomes. Further research is needed to determine whether monitoring ST2 levels can improve patient outcomes.
TL;DR: Under most scenarios, OHT prolongs life and is cost effective in eligible patients, and destination therapy-LVAD significantly improves life expectancy in OHT-ineligible patients, however, further reductions in adverse events or improved quality of life are needed to be cost effective.
Abstract: Background—Treatment options for end-stage heart failure include inotrope-dependent medical therapy, orthotopic heart transplantation (OHT), left ventricular assist device (LVAD) as destination therapy or bridge to transplant. Methods and Results—We developed a state-transition model to simulate 4 treatment options and associated morbidity and mortality. Transition probabilities, costs, and utilities were estimated from published sources. Calculated outcomes included survival, quality-adjusted life-years, and incremental cost-effectiveness. Sensitivity analyses were performed on model parameters to test robustness. Average life expectancy for OHT-eligible patients is estimated at 1.1 years, with 39% surviving to 1 year. OHT with a median wait time of 5.6 months is estimated to increase life expectancy to 8.5 years, and costs <$100 000/quality-adjusted life-year gained, relative to inotrope-dependent medical therapy. Bridge to transplant-LVAD followed by OHT further is estimated to increase life expectancy...
TL;DR: The pathophysiologic and clinical implication of LA remodeling in HFpEF is discussed and the left atrial (LA) remodeling is now considered a potential therapeutic target and an end point for evaluation of novel therapies.
Abstract: Cardiac remodeling is a fundamental part of the heart failure (HF) syndrome, representing a common response to various pathological stimuli that result in changes in the structural and functional properties of the heart. To date, most studies in HF have focused on ventricular remodeling, and much less emphasis has been placed on atrial structural and functional changes. Specifically, in the context of HF with preserved ejection fraction (HFpEF), more attention has recently been placed on the left atrial (LA) remodeling, which is now considered a potential therapeutic target and an end point for evaluation of novel therapies. In this review, we discuss the pathophysiologic and clinical implication of LA remodeling in HFpEF.
Left atrium is a thin-walled structure located in the inflow path from the pulmonary veins to the left ventricle (LV) and is characterized by (a) main body with smooth walls that embryologically is developed from the outgrowth of the pulmonary veins and (b) by a finger-like trabeculated appendage, which is a remnant of the original embryonic left atrium.1 Distribution of atrial myocyte fibers is highly variable, but some components are relatively constant. In particular, the Bachmann’s bundle is the most superficial group of circumferential myofibers located close to the atrioventricular groove. In this bundle, the electric conduction from right to LA preferentially occurs. Other myocardial longitudinal fibres are likely responsible for upward motion of mitral annulus during atrial contraction.
### Mechanical Function
The mechanical function of LA is usually defined by 3 phases of LA volume variations during the cardiac cycle. The reservoir phase takes place during ventricular systole when the LA collects blood coming from the pulmonary veins. This phase is mechanistically determined by LA relaxation and by LV contraction, which moves the mitral annulus toward the apex, resulting in increased LA volume.2 Atrial compliance allows chamber volume …
TL;DR: In this paper, the authors explored the predictive value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set.
Abstract: Background— Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set.
Methods and Results— The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70, and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72.
Conclusions— A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required.
Clinical Trial Registration— URL: . Unique identifiers: [NCT00328692][1] and [NCT00354458][2].
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00328692&atom=%2Fcirchf%2F7%2F1%2F76.atom
[2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00354458&atom=%2Fcirchf%2F7%2F1%2F76.atom
TL;DR: Both physical activity and sedentary time may be appropriate intervention targets for preventing heart failure in men from the California Men’s Health Study.
Abstract: Background— Although the benefits of physical activity for risk of coronary heart disease are well established, less is known about its effects on heart failure (HF). The risk of prolonged sedentary behavior on HF is unknown.
Methods and Results— The study cohort included 82 695 men aged ≥45 years from the California Men’s Health Study without prevalent HF who were followed up for 10 years. Physical activity, sedentary time, and behavioral covariates were obtained from questionnaires, and clinical covariates were determined from electronic medical records. Incident HF was identified through International Classification of Diseases, Ninth Revision codes recorded in electronic records. During a mean follow-up of 7.8 years (646 989 person-years), 3473 men were diagnosed with HF. Controlling for sedentary time, sociodemographics, hypertension, diabetes mellitus, unfavorable lipid levels, body mass index, smoking, and diet, the hazard ratio (95% confidence interval [CI]) of HF in the lowest physical activity category compared with those in the highest category was 1.52 (95% CI, 1.39–1.68). Those in the medium physical activity category were also at increased risk (hazard ratio, 1.17 [95% CI, 1.06–1.29]). Controlling for the same covariates and physical activity, the hazard ratio (95% CI) of HF in the highest sedentary category compared with the lowest was 1.34 (95% CI, 1.21–1.48). Medium sedentary time also conveyed risk (hazard ratio, 1.13 [95% CI, 1.04–1.24]). Results showed similar trends across white and Hispanic subgroups, body mass index categories, baseline hypertension status, and prevalent coronary heart disease.
Conclusions— Both physical activity and sedentary time may be appropriate intervention targets for preventing HF.
TL;DR: Chronic intermittent low-level transcutaneous electric stimulation of auricular branch of vagus nerve can attenuate LV remodeling in conscious dogs with healed MI.
Abstract: Background—Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI). Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low-level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. Methods and Results—Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with ear-clips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7–9 am and 4–6 pm on conscious dogs. At the end of 90-day follo...
TL;DR: This review focuses on recent developments detailing the role of miRNAs in the pathogenesis of HF, their potential role as biomarkers, and their use as therapeutic targets.
Abstract: With 550 000 new cases diagnosed annually and $37 billion spent per year,1 heart failure (HF) with reduced ejection fraction is one of the largest contributors to disease burden and healthcare expenditure in the United States. Despite significant progress in the treatment of HF2,3 with medications, the prognosis of HF remains dismal, with a mortality rate of 42% at 5 years after diagnosis. Therefore, understanding the underlying molecular pathways in the transition from established cardiovascular disease to HF may spur the development of novel biomarkers and therapeutic targets.
The heart responds to stressors such as hypoxia (in myocardial infarction [MI]), increased wall stress (in valvular heart disease), and neurohormonal/metabolic stress (in diabetes mellitus and hypertension) by cardiomyocyte hypertrophy and fibrosis. Although initially compensatory for increased wall stress or myocyte loss, the molecular pathways that underlie pathological hypertrophy are ultimately maladaptive, recapitulating further hypertrophy, contractile dysfunction, apoptosis, and fibrosis. The progression to HF is associated with a characteristic cascade of altered intracellular signaling and gene expression, representing a final common pathway to ultimate decompensation. The various signaling pathways that underlie pathological hypertrophy and the progression to HF have been the subject of intense investigation and are summarized in multiple review publications.4–9. More recently, considerable attention has been paid to microRNAs (miRNAs), a novel biological control mechanism with the ability to regulate entire molecular networks by complex feedback and feed-forward mechanisms. Several reviews have summarized recent findings implicating miRNAs in cardiac development and disease.10,11 In the past few years, the discovery of circulating miRNAs has led to their investigation as biomarkers and mediators of cell–cell communication. This review focuses on recent developments detailing the role of miRNAs in the pathogenesis of HF, their potential role as biomarkers, and their use as …
TL;DR: Plasma NGAL predicts mortality in patients with heart failure, both in Patients with and without chronic kidney disease and is a stronger predictor for mortality than the established renal function indices eGFR and cystatin C.
Abstract: Background In patients with heart failure, renal dysfunction is associated with a poor outcome. We aimed to assess the prognostic value of plasma neutrophil gelatinase-associated lipocalin (NGAL), ...
TL;DR: Bridge-to-decision therapy with CentriMag VAD is feasible in a variety of refractory cardiogenic shock settings, and the failure of medical management and the graft failure post–heart transplantation groups had higher 30-day survival compared with the postcardiotomy shock group.
Abstract: Background—Mortality for refractory cardiogenic shock remains high. In this patient cohort, there have been mixed results in mechanical circulatory support device use as a bridge-to-decision therapy. We evaluated a continuous-flow external ventricular assist device (VAD), CentriMag VAD (Thoratec Corp., Pleasanton, CA), in patients with various causes of refractory cardiogenic shock. Methods and Results—This is a retrospective review of adult patients who underwent surgical CentriMag VAD insertion as bridge-to-decision therapy. From January 2007 through June 2012, 143 patients received CentriMag VAD. The cause of refractory cardiogenic shock was failure of medical management in 71 patients, postcardiotomy shock in 37, graft failure post–heart transplantation in 22, and right ventricular failure post–implantable left VAD in 13. Mean age was 52±16 years, and 71% were in INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 1. Among 158 device runs, device configuration was Bi...
TL;DR: As a consequence of hemodynamic and functional perturbations, PH-HFpEF develops as a more advanced corollary of diastolic HF, leading to abnormal phenotypes of the lung microcirculation,7,8 the arterial system, and right heart function (Figure 1).
Abstract: An elevation of left ventricular diastolic and pulmonary venous pressure is typical of heart failure (HF) regardless of left ventricular (LV) ejection fraction. Normal left ventricular diastolic function keeps both pressures low (<12 mm Hg), although some increase may be observed during stress conditions, such as volume overload1 and exercise.2 When these changes occur within a range of transient periods and in a normal heart, they are well tolerated because of the pulmonary vasculature ability to recruit and distend the capillary network.3
Heart failure with preserved ejection fraction (HFpEF) is a condition presenting, by definition, with an impaired relaxation and stiffened myocardium, which is in part consequence of an increased load to the left ventricle attributable to the stiff arterial system and resulting in a well-defined ventricular–vascular uncoupling. These main hemodynamic alterations expose the lung vasculature to pressure-induced challenges whose most immediate acute threat is pulmonary edema.4 In the long term, the sustained backward hemodynamic transmission, along with the potential contribution of mitral insufficiency, increases the pulsatile loading on the right ventricle (RV)5 and triggers pulmonary hypertension (PH) development and symptom exacerbation.6 Thus, as a consequence of hemodynamic and functional perturbations, PH-HFpEF develops as a more advanced corollary of diastolic HF, leading to abnormal phenotypes of the lung microcirculation,7,8 the arterial system, and right heart function9–11 (Figure 1).
Figure 1.
From heart failure with preserved ejection fraction (HFpEF) to pulmonary hypertension (PH) HFpEF: hemodynamic components and pathophysiological correlates. In HFpEF, the central pathophysiological role is played by an impaired left ventricle (LV) filling mechanics that can arise both from intrinsic structural and molecular alterations in the LV (stiff heart) secondary to myocite hypertrophy, fibrosis, and impaired coronary reserve and as a consequence of an increased load to the heart …
TL;DR: Large artery stiffness is an independent predictor of incident HF in chronic kidney disease, an association with strong biological plausibility given the known effects of large artery stiffening of left ventricular pulsatile load.
Abstract: Background—Chronic kidney disease is associated with an increased risk of heart failure (HF). We aimed to evaluate the role of large artery stiffness, brachial, and central blood pressure as predictors of incident hospitalized HF in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic, multicenter prospective observational study of patients with chronic kidney disease. Methods and Results—We studied 2602 participants who were free of HF at baseline. Carotid-femoral pulse wave velocity (CF-PWV; the gold standard index of large artery stiffness), brachial, and central pressures (estimated via radial tonometry and a generalized transfer function) were assessed at baseline. Participants were prospectively followed up to assess the development of new-onset hospitalized HF. During 3.5 years of follow-up, 154 participants had a first hospital admission for HF. CF-PWV was a significant independent predictor of incident hospitalized HF. When compared with the lowest tertile, the hazard ratios among subject...