Showing papers in "Circulation-heart Failure in 2019"
TL;DR: An overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping are described.
Abstract: Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in variou...
287 citations
TL;DR: RV-pulmonary arterial coupling (Ees/Ea) has considerable reserve, from normal values of 1.5–2 to <0.8, and has the ability to detect pending RV failure in patients with pulmonary hypertension.
Abstract: Background: Right ventricular (RV) maladaptation and failure determine outcome in pulmonary hypertension. The adaptation of RV function to loading (RV-pulmonary arterial coupling) is defined by a r...
136 citations
TL;DR: The incidence and prevalence rates of cardiac amyloidosis among hospitalized patients have increased since 2000, particularly among specific patient subgroups and after 2006, suggesting improved amyloidsosis awareness and higher diagnostic rates with noninvasive imaging.
Abstract: Background: Cardiac amyloidosis is a substantially underdiagnosed disease, and contemporary estimates of the epidemiology of amyloidosis are lacking. This study aims to determine the incidence and ...
117 citations
TL;DR: Black and Latinx patients were less likely to be admitted to cardiology for HF care, and admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race.
Abstract: Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unkno...
93 citations
TL;DR: In AMI admissions, a steady increase was noted in the utilization of ECMO alone and with concomitant procedures (percutaneous coronary intervention, intra-aortic balloon pump, and percutaneous LVAD), and in-hospital mortality, and resource utilization.
Abstract: Background: Extracorporeal membrane oxygenation (ECMO) is increasingly used in acute myocardial infarction (AMI); however, there are limited large-scale national data. Methods: Using the National I...
90 citations
TL;DR: These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
Abstract: Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
85 citations
TL;DR: This study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload–induced hypertrophy and suggests that Sac/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.
Abstract: Background Heart failure (HF) is invariably accompanied by development of cardiac fibrosis, a form of scarring that increases muscular tissue rigidity and decreases cardiac contractility. Cardiac fibrosis arises from a pathological attempt to repair tissue damaged during maladaptive remodeling. Treatment options to block or reverse fibrosis have proven elusive. Neprilysin is an endopeptidase that degrades vasoactive peptides, including atrial natriuretic peptide. Thus, neprilysin inhibition reduces hypertension, ultimately limiting maladaptive cardiac remodeling. LCZ696, which consists of an angiotensin receptor blocker (valsartan [VAL]) and a neprilysin inhibitor (sacubitril [SAC]), was shown to be well tolerated and significantly reduced the risk of death and hospitalization in HF patients with reduced ejection fraction. We hypothesized that SAC/VAL directly inhibits fibroblast activation and development of pathological fibrosis. Methods and Results We used a mouse model of left ventricle pressure overload coupled to in vitro studies in primary mouse and human cardiac fibroblasts (CFs) to study the impact of SAC/VAL on CF activation and cardiac fibrosis. SAC/VAL significantly ameliorated pressure overload-induced cardiac fibrosis by blocking CF activation and proliferation, leading to functional improvement. Mechanistically, the beneficial impact of SAC/VAL at least partially stemmed from restoration of PKG (protein kinase G) signaling in HF patient-derived CF, which inhibited Rho activation associated with myofibroblast transition. Conclusions This study reveals that SAC/VAL acts directly on CF to prevent maladaptive cardiac fibrosis and dysfunction during pressure overload-induced hypertrophy and suggests that SAC/VAL should be evaluated as a direct antifibrotic therapeutic for conditions such as HF with preserved ejection fraction.
83 citations
TL;DR: In this article, the authors found that Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure, and these activities may be influenced by the saturated fatty acid carried by the c...
Abstract: Background: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the c...
70 citations
TL;DR: LV venting, especially if done early (<12 hours), appears to be associated with an increased success of weaning and reduced short-term mortality.
Abstract: Background: Veno-arterial extracorporeal life support (VA-ECLS) is widely used to treat refractory cardiogenic shock. However, increased left ventricular (LV) afterload in VA-ECLS can worsen pulmon...
70 citations
University of Glasgow1, Copenhagen University Hospital2, McGill University Health Centre3, Sapienza University of Rome4, University of Minnesota5, Georgetown University6, Brigham and Women's Hospital7, Duke University8, Exempla Saint Joseph Hospital9, University of Western Ontario10, Montreal Heart Institute11, University of Michigan12, University of Gothenburg13, National Institutes of Health14, Medical University of South Carolina15
TL;DR: Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men, and the risk of sudden death was half that of men.
Abstract: Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of lif...
66 citations
TL;DR: These findings in human myocardium confirm studies in rodents where contractile dysfunction is associated with activation of the FOXO3a-BNIP3 pathway and altered mitochondrial dynamics, biogenesis, and function.
Abstract: Background: The FOXO3a (forkhead box O3a)-BNIP3 (B-cell lymphoma 2/adenovirus E1B 19kDa interacting protein 3) pathway modulates mitochondrial dynamics and function and contributes to myocardial re...
TL;DR: Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans, and therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.
Abstract: Background Anthracycline chemotherapeutics, such as doxorubicin, are used widely in the treatment of numerous malignancies. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that often presents as heart failure due to dilated cardiomyopathy years after anthracycline exposure. Recent data from animal studies indicate that anthracyclines cause cardiac atrophy. The timing of onset and underlying mechanisms are not well defined, and the relevance of these findings to human disease is unclear. Methods and Results Wild-type mice were sacrificed 1 week after intraperitoneal administration of doxorubicin (1-25 mg/kg), revealing a dose-dependent decrease in cardiac mass ( R2=0.64; P<0.0001) and a significant decrease in cardiomyocyte cross-sectional area (336±29 versus 188±14 µm2; P<0.0001). Myocardial tissue analysis identified a dose-dependent upregulation of the ubiquitin ligase, MuRF1 (muscle ring finger-1; R2=0.91; P=0.003) and a molecular profile of muscle atrophy. To investigate the determinants of doxorubicin-induced cardiac atrophy, we administered doxorubicin 20 mg/kg to mice lacking MuRF1 (MuRF1-/-) and wild-type littermates. MuRF1-/- mice were protected from cardiac atrophy and exhibited no reduction in contractile function. To explore the clinical relevance of these findings, we analyzed cardiac magnetic resonance imaging data from 70 patients in the DETECT-1 cohort and found that anthracycline exposure was associated with decreased cardiac mass evident within 1 month and persisting to 6 months after initiation. Conclusions Doxorubicin causes a subacute decrease in cardiac mass in both mice and humans. In mice, doxorubicin-induced cardiac atrophy is dependent on MuRF1. These findings suggest that therapies directed at preventing or reversing cardiac atrophy might preserve the cardiac function of cancer patients receiving anthracyclines.
TL;DR: LVAD patients, in whom hemodynamics were optimized, had a significantly lower rate of hospital readmissions, primarily because of fewer heart failure admissions, highlighting the importance of achieving hemodynamic optimization in LVAD patients.
Abstract: Background: Left ventricular assist device (LVAD) therapy improves the hemodynamics of advanced heart failure patients. However, it is unknown whether hemodynamic optimization improves clinical out...
TL;DR: In this paper, the optimal form of percutaneous mechanical actuator was found to be optimal for VSD in acute myocardial infarction (AMI) and is associated with cardiogenic shock.
Abstract: Background: Ventricular septal defect (VSD) is a lethal complication of acute myocardial infarction (AMI) and is often associated with cardiogenic shock. The optimal form of percutaneous mechanical...
University of Lorraine1, Maastricht University Medical Centre2, University of London3, Maastricht University4, École Normale Supérieure5, Hannover Medical School6, Hull York Medical School7, Robertson Centre for Biostatistics8, University of Glasgow9, University of Navarra10, Carlos III Health Institute11, Leiden University Medical Center12, Mario Negri Institute for Pharmacological Research13, Boston University14, Lille University of Science and Technology15, National Institutes of Health16, Katholieke Universiteit Leuven17
TL;DR: In this article, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20,000 individuals). Controls were matched on cohort, follow-up time, age, and sex.
Abstract: Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.
Brigham and Women's Hospital1, MedStar Washington Hospital Center2, New York University3, Mayo Clinic4, Yale University5, Lehigh Valley Hospital6, Duke University7, St Vincent Hospital8, Cleveland Clinic9, University of California, San Diego10, University of Louisville11, Stanford University12, Cooper University Hospital13, University of North Carolina at Chapel Hill14, University of Florida15, Virginia Commonwealth University16, Toronto General Hospital17, Johns Hopkins University School of Medicine18, University of Utah19, Rush University Medical Center20, National Institutes of Health21, University of Alberta22
TL;DR: There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs in North America, and hospital-level variation appears to be related, at least in part, to illness severity.
Abstract: Background: Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices o...
TL;DR: For example, women represent <25% of heart transplant recipients as discussed by the authors and the reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer women.
Abstract: Background: Currently, women represent <25% of heart transplant recipients. Reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer ou...
TL;DR: In this paper, the authors investigated the effects of HR-guided managemen on the optimization of left ventricular assist device (LVAD) speed and direct medical therapy and found that HR tests can guide the optimization.
Abstract: Background: Hemodynamic ramp (HR) tests can guide the optimization of left ventricular assist device (LVAD) speed and direct medical therapy. We investigated the effects of HR-guided LVAD managemen...
TL;DR: Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction.
Abstract: Background: Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload...
TL;DR: The methylation-sensitive and disease-associated genes/ncRNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and therapeutic target in HF and warrant further investigation.
Abstract: Background: Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in heart failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methyl...
TL;DR: Metformin is a beneficial pharmacological tool that mitigates heart failure caused by anddgr;-sarcoglycan deficiency in association with enhanced autophagy.
Abstract: Background: Metformin is a popular antidiabetic agent that is also used to treat heart failure patients with type 2 diabetes mellitus. Several reports suggest that metformin may also have cardiopro...
TL;DR: LVEF remained ≥50% in the majority of patients with HFpEF for 11 years and no significant relationship was found between LVEF dynamics in the immediate preceding period and mortality.
Abstract: Background: Long-term trajectories of left ventricular ejection fraction (LVEF) in heart failure (HF) patients with preserved EF (HFpEF) remain unclear. Our objective was to assess long-term longit...
TL;DR: The findings of the current study suggested that close clinical follow-up of RBM20-carriers is important which may ensure early detection of disease development and thereby improve management.
Abstract: Background As pathogenic variants in the gene for RBM20 appear with a frequency of 6% among Danish patients with dilated cardiomyopathy (DCM), it was the aim to investigate the associated disease e...
TL;DR: In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers.
Abstract: Background The relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown. Methods and Results We used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers ( r=0.14; P=0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P=0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, Pinteraction=0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P=0.015), and paradoxically, better recovery of creatinine at 60 days ( P=0.01). Conclusions In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00608491.
TL;DR: A state-of-the-art review expands on the current consensus by critically reviewing current studies supporting available objective assessment tools, proposing a psychosocial evaluation framework that uses a multidisciplinary approach and offering future directions for research.
Abstract: Advanced heart failure therapies, including heart transplantation and durable mechanical circulatory support, are available to a limited number of patients because of the scarcity of donors, expense, and large burden of care. The importance of psychological and social determinants of health, including cognitive status, health literacy, psychopathology, social support, medical adherence, and substance abuse, are emphasized in advanced heart failure and further amplified in the context of mechanical circulatory support and heart transplantation. The psychosocial assessment of advanced heart failure therapy candidates remains largely subjective, requiring a multidisciplinary evaluation, which may include psychiatrists, social workers, case managers, financial coordinators, pharmacists, and clinicians. Objective tools-including the Stanford Integrated Psychosocial Assessment for Transplantation, Psychosocial Assessment of Candidates for Transplantation, and Transplant Evaluation Rating Scale-were developed and validated in limited populations to help standardize the evaluation process. Small, retrospective studies have inconsistently shown that these tools may predict clinical outcomes in the transplant population, with higher-risk scores associated with readmissions, rejection episodes, and infections. However, it has been more difficult to show that these tools can predict mortality, and their applicability to the mechanical circulatory support population is less studied. The International Society for Heart and Lung Transplantation released a consensus statement in 2018 to promote consistency of psychosocial evaluation across advanced heart failure programs, but it lacks specific recommendations given the current state of evidence. This state-of-the-art review expands on the current consensus by critically reviewing current studies supporting available objective assessment tools, proposing a psychosocial evaluation framework that uses a multidisciplinary approach and offering future directions for research.
TL;DR: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy.
Abstract: Background: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs)....
TL;DR: An overview of the complexity to be faced and how it may be tackled in the development of therapeutics for tyrosine kinase receptors is given.
Abstract: Heart failure is a complex syndrome whose phenotypic presentation and disease progression depends on a complex network of adaptive and maladaptive responses. One of these responses is the endotheli...
TL;DR: In the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) as discussed by the authors, the authors evaluated the kidney outcomes in patients with or without heart failure.
Abstract: Background In EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) empagliflozin significantly reduced the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus and established cardiovascular disease. Post hoc, we evaluated empagliflozin on kidney outcomes in patients with or without heart failure (HF). Methods and Results Individuals were randomized to empagliflozin 10 mg, 25 mg, or placebo. Prespecified analyses by baseline HF status included risk of incident or worsening nephropathy and estimated glomerular filtration rate slope analyses. Cox proportional hazards models assessed consistency of treatment effect across subgroups. Safety evaluations included kidney-related adverse events. At baseline, 244 (10.5%) and 462 (9.9%) patients had HF in the placebo and empagliflozin groups, respectively. Overall, the incidence of kidney outcome events was numerically higher in patients with than without HF. In the HF group, empagliflozin reduced risk of incident or worsening nephropathy or cardiovascular death by 43% (hazard ratio, 0.57 [95% CI, 0.42-0.77]) and progression to macroalbuminuria by 50% (hazard ratio, 0.50 [0.33-0.75]). After an initial transient decrease, estimated glomerular filtration rate stabilized over time with empagliflozin but gradually declined with placebo. Kidney effects in patients with HF were consistent with those in the overall study population (all P values for interaction >0.05). Across groups, the incidence rate of kidney-related adverse events/100 patient-years was higher in patients with than without HF; however, overall rates were comparable between groups. Conclusions These findings from EMPA-REG OUTCOME support the hypothesis that empagliflozin could reduce the risk of clinically relevant kidney events and may slow progression of chronic kidney disease in individuals with type 2 diabetes mellitus regardless of HF status. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.
TL;DR: In this article, early right heart failure (RHF) occurs commonly in left ventricular assist device (LVAD) recipients, and increased right ventricular (RV) afterload may contribute.
Abstract: Background: Early right heart failure (RHF) occurs commonly in left ventricular assist device (LVAD) recipients, and increased right ventricular (RV) afterload may contribute. Selective pulmonary v...