New England Journal of Medicine, Volume 394, Issue 16 – April 23, 2026

Heart failure with preserved ejection fraction (HFpEF) remains a growing public health challenge, with prevalence estimates rising as populations age and cardiovascular risk factors accumulate. New research published in the New England Journal of Medicine provides updated insights into the epidemiology, diagnostic approaches, and emerging therapeutic strategies for this complex condition, which accounts for approximately half of all heart failure cases worldwide.

HFpEF is characterized by symptoms of heart failure despite a left ventricular ejection fraction of 50% or higher, reflecting impaired ventricular relaxation and increased filling pressures rather than reduced systolic function. Unlike heart failure with reduced ejection fraction (HFrEF), which has seen significant therapeutic advances over the past two decades, HFpEF has lacked disease-modifying treatments until recently. The condition is strongly associated with aging, hypertension, obesity, diabetes, and atrial fibrillation, creating a multifaceted clinical picture that complicates both diagnosis, and management.

Recent epidemiological data indicate that HFpEF affects more than 6.5 million adults in the United States alone, with prevalence increasing sharply after age 60. Women are disproportionately affected, particularly in older age groups, and individuals with obesity or metabolic syndrome face substantially elevated risk. The New England Journal of Medicine review highlights that traditional diagnostic tools such as echocardiography often fail to capture the full hemodynamic profile of HFpEF, leading to underdiagnosis or misattribution of symptoms to pulmonary disease, deconditioning, or normal aging.

To improve diagnostic accuracy, experts recommend a multimodal approach that integrates clinical assessment, biomarkers, imaging, and exercise testing. Elevated levels of natriuretic peptides (BNP or NT-proBNP) remain useful for ruling out heart failure when levels are low, but their sensitivity is limited in HFpEF, especially in obese patients where levels may be falsely normal. Echocardiography should assess not only ejection fraction but also left atrial size, mitral valve inflow patterns, tissue Doppler imaging, and estimated pulmonary artery systolic pressure. In cases of diagnostic uncertainty, invasive cardiopulmonary exercise testing or right heart catheterization during exercise may be employed to demonstrate abnormal hemodynamic responses to exertion.

Therapeutic progress in HFpEF has historically been limited, with earlier trials of agents effective in HFrEF — such as ACE inhibitors, beta-blockers, and angiotensin receptor blockers — failing to show benefit in HFpEF populations. However, recent years have seen the emergence of targeted interventions. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed for diabetes management, have demonstrated consistent reductions in cardiovascular death and heart failure hospitalizations across the ejection fraction spectrum, including in HFpEF. The EMPEROR-Preserved and DELIVER trials, both published in peer-reviewed journals, showed that empagliflozin and dapagliflozin significantly reduced the combined endpoint of cardiovascular death or worsening heart failure compared to placebo.

Other investigational strategies target specific pathophysiological pathways implicated in HFpEF. These include agents targeting inflammation (such as anti-cytokine therapies), myocardial fibrosis (like pirfenidone), and coronary microvascular dysfunction (such as phosphodiesterase-5 inhibitors). While some phase II trials have shown promising signals on surrogate endpoints like exercise capacity or biomarkers of fibrosis, larger phase III studies are needed to confirm clinical benefit. The New England Journal of Medicine article notes that patient heterogeneity remains a major obstacle, suggesting that future treatments may need to be tailored to specific HFpEF phenotypes — such as those driven by obesity, atrial fibrillation, or renal dysfunction — rather than applied uniformly.

Non-pharmacological interventions continue to play a foundational role in management. Guidelines from the American Heart Association and the European Society of Cardiology emphasize lifestyle modification, including sodium restriction, weight management, and supervised exercise training. Cardiac rehabilitation programs adapted for HFpEF patients have been shown to improve quality of life, exercise tolerance, and symptom burden, even in the absence of mortality benefit. Blood pressure control remains critical, given the high prevalence of hypertension in this population, while attention to comorbid conditions such as sleep apnea, anemia, and depression is essential for holistic care.

Despite advances, significant gaps persist in understanding the exact molecular and cellular mechanisms that drive HFpEF in different subgroups. Ongoing research aims to identify reliable biomarkers for phenotyping, refine diagnostic algorithms using artificial intelligence applied to imaging and electronic health records, and enroll more diverse populations in clinical trials — particularly older adults, women, and racial and ethnic minorities who have historically been underrepresented. The journal concludes that while HFpEF is no longer a therapeutic orphan, realizing its full potential for precision medicine will require sustained investment in basic science, clinical investigation, and health systems integration.