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Heart failure with preserved ejection fraction (HFpEF) has grown to become the dominant form of heart failure worldwide, in tandem with ageing of the general population and the increasing prevalences of obesity, diabetes mellitus and hypertension. The clinical syndrome of HFpEF is heterogeneous and must be distinguished from heart failure with reduced ejection fraction as well as other aetiologies that have different treatment strategies. The diagnosis of HFpEF is challenging and ultimately relates to the conceptual definition of heart failure as a clinical syndrome characterized by symptoms that are associated with a reduced capacity of the heart to pump blood adequately at normal filling pressures during diastole. Clinical trials to date have been largely unsuccessful in identifying effective treatments for HFpEF but evidence supports the use of diuretics, mineralocorticoid antagonists and lifestyle interventions. Pathophysiological heterogeneity in the presentation of HFpEF is substantial, and ongoing studies are underway to evaluate the optimal methods to classify patients into phenotypically homogeneous subpopulations to facilitate better individualization of treatment.Heart failure with preserved ejection fraction (HFpEF) is the predominant form of heart failure among elderly patients. In this Review, Borlaug describes the challenges of diagnosing HFpEF, summarizes the current recommendations for treatment and describes a new strategy of categorizing patients with HFpEF into phenotypically homogeneous subgroups to facilitate the individualization of treatment.

Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is an important public health issue. Projections estimate a sixfold increase in the number of adults with obesity in 40 years and an increase in the number of individuals with diabetes to 642 million by 2040. Increased adiposity is the strongest risk factor for developing diabetes. Early detection of the effects of diabesity on the cardiovascular system would enable the optimal implementation of effective therapies that prevent atherosclerosis progression, cardiac remodelling, and the resulting ischaemic heart disease and heart failure. Beyond conventional imaging techniques, such as echocardiography, CT and cardiac magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this Review, we summarize the effects of obesity and diabetes on myocardial structure and function and illustrate the use of state-of-the-art multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.In this Review, Bax and colleagues summarize the effects of obesity and diabetes on myocardial structure and function and evaluate the role of multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P  = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P  = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P  = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P  = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P  = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P  = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P  = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF. In a multicenter, randomized trial, the SGLT2 inhibitor dapagliflozin improved the health status and exercise function of patients with heart failure with preserved ejection fraction (HFpEF), a condition for which effective treatments are lacking.

In a randomized trial involving 110 patients with heart failure with a preserved ejection fraction, those who received 120 mg of isosorbide mononitrate daily for 6 weeks had a lower daily activity level than those who received placebo, as assessed by accelerometry. Approximately half of patients with heart failure have a preserved ejection fraction. 1 Exercise intolerance is a cardinal feature of this syndrome and perpetuates sedentary behavior, deconditioning, and frailty. 2 – 4 In early studies in patients with heart failure with a reduced ejection fraction, long-acting nitrates improved activity tolerance, as assessed by submaximal 5 , 6 or maximal 7 exercise tests. Although nitrates are commonly prescribed for symptom relief in heart failure, 8 – 12 the effects of nitrates in patients with heart failure and a preserved ejection fraction have not been extensively studied. The hemodynamic effects of nitrates might attenuate pulmonary congestion with exertion and improve . . .

Key Points Heart failure with preserved ejection fraction (HFpEF) is an increasingly common form of cardiac disease associated with ageing, obesity, and hypertension, for which no treatment has proven effective HFpEF is characterized by increased left ventricular (LV) filling pressure secondary to diastolic dysfunction; this pressure elevation can be observed at rest or during exercise and causes secondary pulmonary hypertension Despite normal ejection fraction, HFpEF is characterized by mild systolic dysfunction and dramatic limitations in systolic reserve capacity during stress, with blunted increases in ejection fraction Chronotropic incompetence, left atrial dysfunction, atrial fibrillation, arterial stiffening, autonomic imbalance, and endothelial dysfunction contribute to diastolic and systolic dysfunction to limit cardiac output reserve and increase LV filling pressures Peripheral impairments, including abnormalities in endothelial function, body composition, and skeletal muscle function, also have an important role in HFpEF These impairments in cardiac, vascular, and peripheral reserve can be caused by common risk factors for HFpEF, such as ageing, adiposity, hypertension, and metabolic stress Approximately half of all patients with heart failure have preserved ejection fraction (HFpEF), a syndrome for which no treatment has proven to be effective in clinical trials. The pathophysiology of HFpEF is heterogeneous, with multiple individual mechanisms frequently coexisting within the same patient to cause symptomatic heart failure. In this Review, Barry Borlaug discusses the current understanding of the pathophysiological mechanisms underlying HFpEF, and how they might be mechanistically related to typical risk factors for HFpEF, including ageing, obesity, and hypertension. Approximately half of all patients with heart failure have preserved ejection fraction (HFpEF) and, as life expectancies continue to increase in western societies, the prevalence of HFpEF will continue to grow. In contrast to heart failure with reduced ejection fraction (HFrEF), no treatment has been proven in pivotal clinical trials to be effective for HFpEF, largely because of the pathophysiological heterogeneity that exists within the broad spectrum of HFpEF. This syndrome was historically considered to be caused exclusively by left ventricular diastolic dysfunction, but research has identified several other contributory factors, including limitations in left ventricular systolic reserve, systemic and pulmonary vascular function, nitric oxide bioavailability, chronotropic reserve, right heart function, autonomic tone, left atrial function, and peripheral impairments. Multiple individual mechanisms frequently coexist within the same patient to cause symptomatic heart failure, but between patients with HFpEF the extent to which each component is operative can differ widely, confounding treatment approaches. This Review focuses on our current understanding of the pathophysiological mechanisms underlying HFpEF, and how they might be mechanistically related to typical risk factors for HFpEF, including ageing, obesity, and hypertension.

This study aimed to define the influence of healthy aging on the central hemodynamic response to exercise. Advancing age results in numerous alterations to the cardiovascular system and is a major risk factor to develop heart failure. In patients with suspected heart failure with preserved ejection fraction, there is an increasing interest in the incorporation of stress hemodynamic studies into the diagnostic evaluation pathway. However, many patients with suspected heart failure with preserved ejection fraction are older, and there are few data regarding the effect of aging on the normal central hemodynamic responses to exercise. Therefore, we examined 55 healthy patients using right-sided cardiac catheterization with exercise. Mean age was 49.6 years, with 36% older than 55 years. On exercise, the mean pulmonary artery pressure was higher with advancing age (r = 0.412, p = 0.002). Additionally, age was negatively associated with cardiac index (r = 0.407, p = 0.005). The exercise-induced rise in pulmonary capillary wedge pressure (r = 0.378, p = 0.004) was greater with advancing age. Pulse pressure measured during exercise (r = 0.541, p <0.01) increased with age, as did diastolic dysfunction assessed by E/A ratio (r = 0.569, p <0.001). In conclusion, aging was associated with decreased cardiac output and increased pulmonary artery pressure during exercise, which developed as the consequence of both increased pulmonary vasculature resistance and higher left ventricular filling pressures.

Assessment of left ventricular diastolic function plays a major role in the diagnosis and prognosis of cardiac diseases, including heart failure with preserved ejection fraction. We aimed to develop an artificial intelligence (AI)-enabled electrocardiogram (ECG) model to identify echocardiographically determined diastolic dysfunction and increased filling pressure. We trained, validated, and tested an AI-enabled ECG in 98,736, 21,963, and 98,763 patients, respectively, who had an ECG and echocardiographic diastolic function assessment within 14 days with no exclusion criteria. It was also tested in 55,248 patients with indeterminate diastolic function by echocardiography. The model was evaluated using the area under the curve (AUC) of the receiver operating characteristic curve, and its prognostic performance was compared to echocardiography. The AUC for detecting increased filling pressure was 0.911. The AUCs to identify diastolic dysfunction grades ≥1, ≥2, and 3 were 0.847, 0.911, and 0.943, respectively. During a median follow-up of 5.9 years, 20,223 (20.5%) died. Patients with increased filling pressure predicted by AI-ECG had higher mortality than those with normal filling pressure, after adjusting for age, sex, and comorbidities in the test group (hazard ratio (HR) 1.7, 95% CI 1.645–1.757) similar to echocardiography and in the indeterminate group (HR 1.34, 95% CI 1.298–1.383). An AI-enabled ECG identifies increased filling pressure and diastolic function grades with a good prognostic value similar to echocardiography. AI-ECG is a simple and promising tool to enhance the detection of diseases associated with diastolic dysfunction and increased diastolic filling pressure.

Acute decompensated heart failure (ADHF) occurs with preserved (heart failure with preserved ejection fraction [HFpEF] ≥50%) or reduced (heart failure with reduced ejection fraction [HFrEF] <50%) ejection fraction. Natriuretic peptide (NP) levels are lower in HFpEF than HFrEF. We hypothesized that lower NP levels in HFpEF may be associated with other differences in biomarkers, specifically, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, and a biomarker that reflects collagen synthesis. In this prespecified ancillary analysis of patients with ADHF enrolled in the Diuretic Optimization Strategies Evaluation study, clinical features and N-terminal pro–B-type NP, cystatin C, plasma renin activity, aldosterone, oxidative stress (uric acid), and procollagen type III N-terminal peptide were compared in HFpEF and HFrEF at enrollment and 60-day follow-up. Compared with HFrEF (n = 219), HFpEF (n = 81) patients were older, heavier, more commonly female, less treated with RAAS antagonists, but with similar New York Heart Association class, jugular venous pressure, and edema severity. N-terminal pro–B-type NP was lower, and systolic blood pressure and cystatin C were higher in HFpEF. Despite higher systolic blood pressure and less RAAS antagonist use in HFpEF, plasma renin activity and aldosterone levels were similar in HFpEF and HFrEF as were uric acid and procollagen type III N-terminal peptide levels. Changes in biomarker levels from enrollment to 60 days were similar between HFrEF (n = 149) and HFpEF (n = 50). Lower NP levels in decompensated HFpEF occur in association with similar ADHF severity, more impaired vascular and renal function but similar elevation of biomarkers that reflect RAAS activation, oxidative stress, and collagen synthesis as in HFrEF.

In patients with heart failure with preserved ejection fraction and obesity, treatment with tirzepatide led to a lower risk of death from cardiovascular causes or worsening heart-failure events than placebo.

In patients with heart failure and preserved or mildly reduced ejection fractions (EF ≥40%), implantation of an interatrial shunt device (IASD) resulted in heterogenous changes of the left atrial (LA) volume. Baseline characteristics that correlate with a favorable decrease in LA volume are unknown. We hypothesized that a larger ratio of left to right atrial volume at baseline would correlate strongly with LA volume decongestion following IASD implantation. Reduce Elevated LA Pressure in Patients With Heart Failure was a multicenter study of the safety and feasibility of IASD implantation. Sixty-four patients with EF ≥40% underwent device implantation along with baseline conventional echocardiograms, speckle tracking echocardiography, and resting and exercise hemodynamics. Higher LA compliance (−4.2%, p = 0.048) and right atrial reservoir strain (−0.8%, p = 0.005) were independently associated with a percent decrease in the systolic LA volume index from baseline to 6-months. In conclusion, greater LA volume reduction following IASD implantation is associated with higher baseline compliance of the left atrium and higher reservoir strain of the right atrium.