Nitrosative stress drives heart failure with preserved ejection fraction.
Ontology highlight
ABSTRACT:
SUBMITTER: Schiattarella GG
PROVIDER: S-EPMC6635957 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Nitrosative stress drives heart failure with preserved ejection fraction.
Schiattarella Gabriele G GG Altamirano Francisco F Tong Dan D French Kristin M KM Villalobos Elisa E Kim Soo Young SY Luo Xiang X Jiang Nan N May Herman I HI Wang Zhao V ZV Hill Theodore M TM Mammen Pradeep P A PPA Huang Jian J Lee Dong I DI Hahn Virginia S VS Sharma Kavita K Kass David A DA Lavandero Sergio S Gillette Thomas G TG Hill Joseph A JA
Nature 20190410 7752
Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using N<sup>ω</sup>-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unf ...[more]
Similar Datasets
Project description:AimsPCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function.Methods and resultsWild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects.ConclusionPCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF.
| S-EPMC8380058 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) represents a heterogeneous collection of conditions that are unified by the presence of a left ventricular ejection fraction ?50%, evidence of impaired diastolic function and elevated natriuretic peptide levels, all within the context of typical heart failure signs and symptoms. However, while HFpEF is steadily becoming the predominant form of heart failure, disease-modifying treatment options for this population remain sparse. This review provides an overview of the diagnosis, management and prevention of HFpEF for general physicians.
| S-EPMC6334030 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence as the general population ages. Poorly managed heart failure symptoms of decompensated HFpEF is one of the most common reasons for prolonged hospital admission. The high rate of morbidity and mortality associated with HFpEF is compounded by a poor understanding of the underpinning pathophysiology. Randomized controlled trials have so far been unable to identify an evidence base for reducing morbidity and mortality in patients with HFpEF, although there is some evidence to support quality of life (QOL) improvement. In this review, we described the recent advances on the pathophysiological understanding of HFpEF, the current and emerging treatment strategies, and what this may mean for individual patients. Potential treatments for HFpEF were divided into their relative management strategies and the current evidence assessed for effect on HFpEF mortality, hospital admission frequency, and QOL improvement. Overall, the understanding of HFpEF pathophysiology is improving and has been made a priority in identifying potential therapeutic targets. There is growing evidence that patients with ejection fractions (EF) of less than 60% may obtain a mortality benefit from ACE-inhibitors, angiotensin-neprilysin inhibitors, Angiotensin Receptor Blockers, and Mineralocorticoid Receptor Antagonists. However, this covers only a small proportion of the HFpEF spectrum. Therefore, currently there are no universal treatment strategies recommended for HFpEF, and management should focus on an individualised approach and this should take into account the comorbidities of each patient.
| S-EPMC7186731 | biostudies-literature
Project description:The aim of this study was to determine whether left atrial ejection fraction (LAEF) quantified with cardiovascular magnetic resonance (CMR) was different between heart failure with preserved ejection fraction (HFpEF) and controls, and its relation to prognosis. As part of our single-centre, prospective, observational study, 188 subjects (HFpEF n?=?140, controls n?=?48) underwent phenotyping with contrast-enhanced CMR, transthoracic echocardiography, blood sampling and six-minute walk testing. LAEF was calculated using the biplane method. Atrial fibrillation (AF) was present in 43 (31%) of HFpEF subjects. Overall, LAEF (%) was lower in HFpEF patients inclusive of AF (32?±?16) or those in sinus rhythm alone (41?±?12) compared to controls (51?±?11), p?<?0.0001. LAEF correlated inversely with maximal and minimal left atrial volumes indexed (r?=??-?0.602, r?=??-?0.762), and plasma N-terminal pro-atrial natriuretic peptide (r?=??-?0.367); p?<?0.0001. During median follow-up (1429 days), there were 67 composite events of all-cause death or hospitalization for heart failure (22 deaths, 45 HF hospitalizations) in HFpEF. Lower LAEF (below median) was associated with an increased risk of composite endpoints (Log-Rank: all p?=?0.028; sinus p?=?0.036). In multivariable Cox regression analysis, LAEF (adjusted hazard ratio [HR] 0.767, 95% confidence interval [CI] 0.591-0.996; p?=?0.047) and indexed extracellular volume (HR 1.422, CI 1.015-1.992; p?=?0.041) were the only parameters that remained significant when added to a base prognostic model comprising age, prior HF hospitalization, diastolic blood pressure, lung disease, NYHA, six-minute-walk-test-distance, haemoglobin, creatinine and B-type natriuretic peptide. CMR-derived LAEF is lower in HFpEF compared to healthy controls and is a strong prognostic biomarker.
| S-EPMC6942575 | biostudies-literature
Project description:Heart failure is defined as a clinical syndrome and is known to present with a number of different pathophysiological patterns. There is a remarkable degree of variation in measures of left ventricular systolic emptying and this has been used to categorise heart failure into two separate types: low ejection fraction (EF) heart failure or HF-REF and high EF heart failure or HF-PEF. Here we review the pathophysiology, epidemiology and management of HF-PEF and argue that sharp separation of heart failure into two forms is misguided and illogical, and the present scarcity of clinical trial evidence for effective treatment for HF-PEF is a problem of our own making; we should never have excluded patients from major trials on the basis of EF in the first place. Whilst as many heart failure patients have preserved EFs as reduced we have dramatically under-represented HF-PEF patients in trials. Only four trials have been performed in HF-PEF specifically, and another two trials that recruited both HF-PEF and HF-REF can be considered. When we consider the similarity in outcomes and neurohormonal activation between HF-REF and HF-REF, the vast corpus of trial data that we have to attest to the efficacy of various treatment (angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], beta-blockers and aldosterone antagonists) in HF-REF, and the much more limited number of trials of similar agents showing near statistically significant benefits in HF-PEF the time has come rethink our management of HF-PEF, and in particular our selection of patients for trials.
| S-EPMC5490948 | biostudies-other
Project description:PURPOSE OF REVIEW:Heart failure with preserved ejection fraction (HFpEF) is a relatively new disease entity used in medical terminology; however, both the number of patients and its clinical significance are growing. HFpEF used to be seen as a mild condition; however, the symptoms and quality of life of the patients are comparable to those with reduced ejection fraction. The disease is much more complex than previously thought. In this article, information surrounding the etiology, diagnosis, prognosis, and possible therapeutic options of HFpEF are reviewed and summarized. RECENT FINDINGS:It has recently been proposed that heart failure (HF) is rather a heterogeneous syndrome with a spectrum of overlapping and distinct characteristics. HFpEF itself can be distilled into different phenotypes based on the underlying biology. The etiological factors of HFpEF are unclear; however, systemic low-grade inflammation and microvascular damage as a consequence of comorbidities associated with endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis are considered to play a crucial role in the pathogenesis of a disease. The H2FPEF score and the HFpEF nomogram are recently validated highly sensitive tools employed for risk assessment of subclinical heart failure. Despite numerous studies, there is still no evidence-based pharmacotherapy for HFpEF and the mortality and morbidity associated with HFpEF remain high. A better understanding of the etiological factors, the impact of comorbidities, the phenotypes of the disease, and implementation of machine learning algorithms may play a key role in the development of future therapeutic strategies.
| S-EPMC7347676 | biostudies-literature
Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.
| S-EPMC6863599 | biostudies-literature
Project description:Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).
| S-EPMC4712067 | biostudies-literature
Project description:Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine, and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase activators and If current inhibitors have shown benefit in improving diastolic function, and there is a rationale for assessing matrix metalloproteinase 9 inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research and drugs currently in clinical trial that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.
| S-EPMC3724214 | biostudies-literature
Project description:Most elderly patients, particularly women, who have heart failure, have a preserved ejection fraction. Patients with this syndrome have severe symptoms of exercise intolerance, frequent hospitalizations, and increased mortality. Despite the importance of heart failure with preserved ejection fraction (HFpEF), the understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. Unlike the management of HFrEF, there is a paucity of large evidence-based trials demonstrating morbidity and mortality benefit for the treatment of HFpEF. An update is presented on information regarding pathophysiology, diagnosis, management, and future directions in this important and growing disorder.
| S-EPMC5546159 | biostudies-literature