Aims
Adipose tissue and inflammation may play a role in the pathophysiology of patients with heart failure (HF) with mildly reduced or preserved ejection fraction. We therefore investigated ...epicardial fat in patients with HF with preserved (HFpEF) and mid‐range ejection fraction (HFmrEF), and related this to co‐morbidities, plasma biomarkers and cardiac structure.
Methods and results
A total of 64 HF patients with left ventricular ejection fraction >40% and 20 controls underwent routine cardiac magnetic resonance examination. Epicardial fat volume was quantified on short‐axis cine stacks covering the entire epicardium and was related to clinical correlates, biomarkers associated with inflammation and myocardial injury, and cardiac function and contractility on cardiac magnetic resonance. HF patients and controls were of comparable age, sex and body mass index. Total epicardial fat volume was significantly higher in HF patients compared to controls (107 mL/m2 vs. 77 mL/m2, P <0.0001). HF patients with atrial fibrillation and/or type 2 diabetes mellitus had more epicardial fat than HF patients without these co‐morbidities (116 vs. 100 mL/m2, P =0.03, and 120 vs. 97 mL/m2, P =0.001, respectively). Creatine kinase‐MB, troponin T and glycated haemoglobin in patients with HF were positively correlated with epicardial fat volume (R =0.37, P =0.006; R =0.35, P =0.01; and R =0.42, P =0.002, respectively).
Conclusion
Heart failure patients had more epicardial fat compared to controls, despite similar body mass index. Epicardial fat volume was associated with the presence of atrial fibrillation and type 2 diabetes mellitus and with biomarkers related to myocardial injury. The clinical implications of these findings are unclear, but warrant further investigation.
Cardiomyocyte loss after injury results in adverse remodelling and fibrosis, inevitably leading to heart failure. The ERBB2-Neuregulin and Hippo-YAP signalling pathways are key mediators of heart ...regeneration, yet the crosstalk between them is unclear. We demonstrate that transient overexpression of activated ERBB2 in cardiomyocytes (OE CMs) promotes cardiac regeneration in a heart failure model. OE CMs present an epithelial-mesenchymal transition (EMT)-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration and extracellular matrix turnover. We identified YAP as a critical mediator of ERBB2 signalling. In OE CMs, YAP interacts with nuclear-envelope and cytoskeletal components, reflecting an altered mechanical state elicited by ERBB2. We identified two YAP-activating phosphorylations on S352 and S274 in OE CMs, which peak during metaphase, that are ERK dependent and Hippo independent. Viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Together, we reveal a potent ERBB2-mediated YAP mechanotransduction signalling, involving EMT-like characteristics, resulting in robust heart regeneration.
Patients with decompensated heart failure and cardiorenal syndrome were randomly assigned to ultrafiltration or diuretic therapy. Ultrafiltration was inferior to diuretics with respect to the primary ...end point, a bivariate measure of change in creatinine and body weight.
The acute cardiorenal syndrome (type 1) is defined as worsening renal function in patients with acute decompensated heart failure.
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It occurs in 25 to 33% of patients with acute decompensated heart failure and is associated with poor outcomes.
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,
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Multiple processes contribute to the development of the acute cardiorenal syndrome, including extrarenal hemodynamic changes, neurohormonal activation, intrarenal microvascular and cellular dysregulation, and oxidative stress.
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In some cases, intravenous diuretics, which are often administered in patients with acute decompensated heart failure,
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may directly contribute to worsening renal function.
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The use of diuretics to treat persistent congestion after the onset . . .
BACKGROUND:Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased ...circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors’ aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate(1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers.
METHODS:Study 116 chronic HFrEF patients (left ventricular ejection fraction37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 410 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography.
RESULTS:3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM (P<0.001). CO rose by 2.0±0.2 L/min (P<0.001) because of an increase in stroke volume of 20±2 mL (P<0.001) and heart rate of 7±2 beats per minute (bpm) (P<0.001). Left ventricular ejection fraction increased 8±1% (P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM (P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers.
CONCLUSIONS:3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.
Table of Contents Preamble777 Introduction779 Methodology and Evidence Review779 Organization of the Writing Group779 Document Review and Approval779 Initial and Serial Evaluation of the HF ...Patient780 Biomarkers780 Biomarkers for Prevention: Recommendation781 Biomarkers for Diagnosis: Recommendation782 Biomarkers for Prognosis or Added Risk Stratification: Recommendations782 Treatment of Stages A to D784 Stage C784 Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations784 Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendation791 Treating Hypertension in Stage C HFrEF: Recommendation791 Treating Hypertension in Stage C HFpEF: Recommendation791 Sleep-Disordered Breathing: Recommendations792 References793 Appendix 1 Author Relationships With Industry and Other Entities (Relevant)798 Appendix 2 Reviewer Relationships With Industry and Other Entities (Comprehensive)800 Appendix 3 Abbreviations803 Preamble Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines (guidelines) with recommendations to improve cardiovascular health. Effects of more vs. less intensive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials, J Hypertens, Vol. 34, 2016, 613-622 191 J.T. Wright Jr., J.D. Williamson, P.K. Whelton, A Randomized Trial of Intensive versus Standard Blood-Pressure Control, N Engl J Med, Vol. 373, 2015, 2103-2116 192 J.D. Williamson, M.A. Supiano, W.B. Applegate, JAMA, Vol. 315, 2016, 2673-2682 193 J. Lv, P. Ehteshami, M.J. Sarnak, Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis, CMAJ, Vol. 185, 2013, 949-957 194 Deleted in press. 195 W.S. Aronow, J.L...
IMPORTANCE: Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF). OBSERVATIONS: Heart ...failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor–neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology. CONCLUSIONS AND RELEVANCE: HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.
Epidemiology of patients with worsening heart failure and reduced ejection fraction (HFrEF) in the real-world setting is not well described.
The purpose of this study was to describe incidence, ...clinical characteristics, treatment, and outcomes of patients with HFrEF who develop worsening heart failure (HF) in the real-world setting.
Data on patients with incident HFrEF from the National Cardiovascular Data Registry PINNACLE were linked to pharmacy, private practitioner, and hospital claims databases. Incidence, clinical characteristics, treatment (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist) and outcomes of patients with worsening HF, defined as ≥90 days of stable HF with subsequent worsening requiring intravenous diuretic agents, were assessed.
Of 11,064 HFrEF patients, 1,851 (17%) developed worsening HF on average 1.5 years following initial HF diagnosis. Patients who developed worsening HF were more likely to be African American, be octogenarians, and have higher comorbidity burden (p < 0.001). At the onset of worsening HF, 42.4% of patients were on monotherapy, 43.4% were on dual therapy, and 14.1% were on triple therapy. A total of 48%, 61%, and 98% of patients were on >50% target dose for angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist, respectively. The 2-year mortality rate was 22.5%, and 56% of patients were rehospitalized within 30 days of the worsening HF event.
In the real-world setting, 1 in 6 patients with HFrEF develop worsening HF within 18 months of HF diagnosis. These patients have a high risk for 2-year mortality and recurrent HF hospitalizations. The use of standard-of-care therapies both before and after the onset of worsening HF is low. With high unmet medical need, patients with worsening HF require novel treatment strategies as well as greater optimization of existing guideline-directed therapy.
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The objective is to define the clinical echocardiographic characteristics and cardiovascular outcome in patients with acute heart failure (HF) with versus without diabetes mellitus (DM). Demographic, ...clinical, laboratory, and echocardiographic data were collected in Olmsted County adults hospitalized for acute HF between 2005 and 2008. Analyses were performed for mortality and acute HF hospitalization outcomes stratified by diabetic status, systolic function, and diastolic function. There were 912 subjects who met inclusion criteria, and mean age was 79 (SD 13.1) years with 53% women. Prevalence of DM was 42% in the study population, and those with DM had worse diastolic function and increased mortality and HF rehospitalization. Among those with DM and acute HF, reduced left ventricular ejection fraction and worse diastolic function conferred increased HF rehospitalization (p = 0.010 and p = 0.022, respectively). In conclusion, DM is common in those hospitalized for acute HF and is associated with worse long-term clinical outcomes. The subgroup of DM with acute HF and left ventricular systolic dysfunction or diastolic dysfunction had worse HF rehospitalization outcomes.
Heart Failure (HF) is a multi-faceted and life-threatening syndrome characterized by significant morbidity and mortality, poor functional capacity and quality of life, and high costs. HF affects more ...than 64 million people worldwide. Therefore, attempts to decrease its social and economic burden have become a major global public health priority. While the incidence of HF has stabilized and seems to be declining in industrialized countries, the prevalence is increasing due to the ageing of the population, improved treatment of and survival with ischaemic heart disease, and the availability of effective evidence-based therapies prolonging life in patients with HF. There are geographical variations in HF epidemiology. There is substantial lack of data from developing countries, where HF exhibits different features compared with that observed in the Western world. In this review, we provide a contemporary overview on the global burden of HF, providing updated estimates on prevalence, incidence, outcomes, and costs worldwide.
Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we hypothesized that ...circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by sacubitril/valsartan in comparison to enalapril.
The purpose of this study was to examine the effects of sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers.
Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome.
At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes.
Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure PARADIGM-HF; NCT01035255)
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