Subtypes identification on heart failure with preserved ejection fraction via network enhancement fusion using multi-omics data.
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ABSTRACT:
SUBMITTER: Wu Y
PROVIDER: S-EPMC8039555 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:(1) Background: There are no successive treatments for heart failure with preserved ejection fraction (HFpEF) because of complex interactions between environmental, histological, and genetic risk factors. The objective of the study is to investigate changes in cardiomyocytes and molecular networks associated with HFpEF. (2) Methods: Dahl salt-sensitive (DSS) rats developed HFpEF when fed with a high-salt (HS) diet for 7 weeks, which was confirmed by in vivo and ex vivo measurements. Shotgun proteomics, microarray, Western blot, and quantitative RT-PCR analyses were further carried out to investigate cellular and molecular mechanisms. (3) Results: Rats with HFpEF showed diastolic dysfunction, impaired systolic function, and prolonged repolarization of myocytes, owing to an increase in cell size and apoptosis of myocytes. Heatmap of multi-omics further showed significant differences between rats with HFpEF and controls. Gene Set Enrichment Analysis (GSEA) of multi-omics revealed genetic risk factors involved in cardiac muscle contraction, proteasome, B cell receptor signaling, and p53 signaling pathway. Gene Ontology (GO) analysis of multi-omics showed the inflammatory response and mitochondrial fission as top biological processes that may deteriorate myocyte stiffening. GO analysis of protein-to-protein network indicated cytoskeleton protein, cell fraction, enzyme binding, and ATP binding as the top enriched molecular functions. Western blot validated upregulated Mff and Itga9 and downregulated Map1lc3a in the HS group, which likely contributed to accumulation of aberrant mitochondria to increase ROS and elevation of myocyte stiffness, and subsequent contractile dysfunction and myocardial apoptosis. (4) Conclusions: Multi-omics analysis revealed multiple pathways associated with HFpEF. This study shows insight into molecular mechanisms for the development of HFpEF and may provide potential targets for the treatment of HFpEF.
| S-EPMC7247709 | 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:BACKGROUND:Heart failure (HF) is a prevalent and deadly disease, and preventive strategies focused on at-risk individuals are needed. Current HF prediction models have not examined HF subtypes. We sought to develop and validate risk prediction models for HF with preserved and reduced ejection fraction (HFpEF, HFrEF). METHODS AND RESULTS:Of 28,820 participants from 4 community-based cohorts, 982 developed incident HFpEF and 909 HFrEF during a median follow-up of 12 years. Three cohorts were combined, and a 2:1 random split was used for derivation and internal validation, with the fourth cohort as external validation. Models accounted for multiple competing risks (death, other HF subtype, and unclassified HF). The HFpEF-specific model included age, sex, systolic blood pressure, body mass index, antihypertensive treatment, and previous myocardial infarction; it had good discrimination in derivation (c-statistic 0.80; 95% confidence interval [CI], 0.78-0.82) and validation samples (internal: 0.79; 95% CI, 0.77-0.82 and external: 0.76; 95% CI: 0.71-0.80). The HFrEF-specific model additionally included smoking, left ventricular hypertrophy, left bundle branch block, and diabetes mellitus; it had good discrimination in derivation (c-statistic 0.82; 95% CI, 0.80-0.84) and validation samples (internal: 0.80; 95% CI, 0.78-0.83 and external: 0.76; 95% CI, 0.71-0.80). Age was more strongly associated with HFpEF, and male sex, left ventricular hypertrophy, bundle branch block, previous myocardial infarction, and smoking with HFrEF (P value for each comparison ?0.02). CONCLUSIONS:We describe and validate risk prediction models for HF subtypes and show good discrimination in a large sample. Some risk factors differed between HFpEF and HFrEF, supporting the notion of pathogenetic differences among HF subtypes.
| S-EPMC4902276 | 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