Heart failure with preserved ejection fraction, often shortened to HFpEF, is a form of heart failure in which the heart pumps blood outward with normal or near-normal force but cannot relax and fill properly between beats. The heart’s squeezing power looks fine on an echocardiogram, yet the organ is stiff, the filling pressures are too high, and the person feels breathless and exhausted with everyday activity. HFpEF now makes up roughly three-quarters of all heart failure cases in the United States, and for decades it was poorly understood and essentially untreatable. That picture has shifted meaningfully in the last few years, though the condition remains far more complex than the version of heart failure most people have heard about.
How HFpEF Differs From the More Familiar Type of Heart Failure
Most public awareness of heart failure centers on the “reduced ejection fraction” variety, where the heart muscle weakens and cannot pump enough blood forward. In that scenario, ejection fraction drops well below the normal range. HFpEF flips the problem: ejection fraction stays at 50% or above, yet the left ventricle has become too stiff to fill with blood at normal pressures. Because less blood enters between beats, the heart still cannot deliver enough output to meet the body’s needs, especially during exertion. Fluid backs up into the lungs and body, causing the same swelling, breathlessness, and fatigue seen in other forms of heart failure.
The distinction matters because nearly every landmark heart-failure drug trial before 2020 was designed around the pumping problem. Medications that dramatically improved survival in reduced-ejection-fraction patients repeatedly failed to show clear mortality benefits in HFpEF. That therapeutic gap made HFpEF one of the most frustrating problems in cardiology for the better part of two decades.
Who Gets HFpEF
HFpEF tracks closely with aging, obesity, high blood pressure, diabetes, and sedentary living. The prevalence keeps climbing as those risk factors become more common worldwide.1American College of Cardiology. Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement Women are disproportionately affected. In one large cohort, women made up about 55% of HFpEF patients, and diastolic dysfunction, the hallmark filling problem, was substantially more common among women than men.2PubMed Central. Sex Differences in Heart Failure With Preserved Ejection Fraction More broadly, HFpEF with preserved ejection fraction has a greater prevalence in women, while the reduced-ejection-fraction form is more common in men.3PubMed Central. Sex and Gender Differences in Heart Failure
The economic toll is substantial. Total annual costs for HFpEF patients in the U.S. run roughly $37,000 to $49,000 per person, with hospital stays accounting for close to half. About one in five patients is readmitted within 30 days, and patients who also have diabetes or chronic kidney disease incur nearly double the costs of those without additional conditions.4The American Journal of Managed Care. Clinical Management and Economic Drivers of Heart Failure With Preserved or Mildly Reduced Ejection Fraction
What Is Going Wrong Inside the Heart
The core problem is myocardial stiffness, and two culprits drive it: a giant spring-like protein called titin and the buildup of collagen (fibrosis) between heart cells. In a healthy heart, titin acts like an elastic band inside each muscle cell, allowing the ventricle to stretch open easily during filling. In HFpEF, chronic low-grade inflammation and damage to the tiny blood vessels inside the heart wall reduce the supply of nitric oxide to those muscle cells. Without enough nitric oxide signaling, titin becomes under-phosphorylated, which effectively tightens the spring and raises the passive stiffness of the muscle.5PubMed Central. The Mechanisms Associated with Inflammation and Coronary Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction Studies in both animal models and human tissue confirm that this titin hypophosphorylation accounts for a large share of the increased stiffness.6PubMed. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model
At the same time, collagen deposits accumulate between muscle cells, further resisting stretch. Research on heart tissue from HFpEF patients with hypertension found significant increases in both collagen-dependent and titin-dependent stiffness, alongside elevated markers of inflammation.7PubMed Central. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin So the stiffness is a two-hit process: the cells themselves become rigid, and the scaffolding around them thickens. The upstream trigger for both problems appears to be coronary microvascular endothelial activation and oxidative stress, which reduce nitric oxide signaling from the endothelium to nearby cardiomyocytes.8JACC: Heart Failure. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction
Why Diagnosis Is Tricky
A person with reduced ejection fraction gets an echocardiogram, and the diagnosis is straightforward: the heart is pumping weakly. In HFpEF, the ejection fraction looks normal. The patient’s complaint, feeling winded walking up stairs or needing to prop up on pillows at night, could be explained by deconditioning, obesity, lung disease, or a dozen other things. Clinicians rely on a combination of symptoms, blood biomarkers, echocardiographic measures of diastolic function, and sometimes invasive pressure measurements during exercise.
The blood marker NT-proBNP, widely used to screen for heart failure, helps rule out severe diastolic impairment at standard cutoffs but is not as reliable a positive screen in HFpEF as it is in the reduced-ejection-fraction form. At the cutoff values recommended by European and British guidelines, the negative predictive value for severe diastolic impairment is around 92–95%, meaning a low reading is fairly reassuring, but a high reading does not seal the diagnosis.9The British Journal of Cardiology. Evaluation of NT-proBNP thresholds and age as diagnostic indicators for heart failure with preserved ejection fraction Obesity in particular can blunt NT-proBNP levels, so a normal reading in an obese patient with exertional breathlessness does not reliably exclude HFpEF.
Two widely used scoring systems, the H₂FPEF score and the HFA-PEFF algorithm, attempt to standardize diagnosis, but they do not always agree. A systematic review found that the two scores disagreed in roughly 28–41% of cases. The H₂FPEF score tends to be more sensitive while the HFA-PEFF score is more specific, but both achieve only moderate accuracy on their own.10PubMed Central. Discordance Between H 2 FPEF Score and HFA-PEFF Diagnostic Score in HFpEF: A Systematic Review and SDoH Integration In ambiguous cases, the gold standard remains exercise right-heart catheterization, where a catheter directly measures filling pressures during activity. That test is invasive and not available everywhere, which helps explain why HFpEF remains under-recognized in routine practice.
The Role of Obesity and Stiff Arteries
Obesity does more than just increase cardiac workload. Fat tissue that wraps directly around the heart, known as epicardial adipose tissue, acts as a metabolically active depot that secretes inflammatory signals straight into the adjacent heart muscle. This fat pad can mechanically compress the ventricles, infiltrate the myocardium with lipids, promote fibrosis, and disrupt microvascular function. Its volume predicts diastolic dysfunction and adverse outcomes more strongly than body mass index does.11PubMed Central. Multifactorial mechanisms of obesity-related HFpEF: the central role of epicardial adipose tissue and therapeutic perspectives The obesity-related HFpEF phenotype is now considered a distinct clinical entity, which partly explains why weight loss has such a dramatic impact on symptoms.
Arterial stiffness is another critical accelerant. As arteries lose compliance, each heartbeat pushes against a harder wall, increasing the afterload on the left ventricle. That added strain promotes the diastolic dysfunction at the center of HFpEF and is closely linked to the same risk factors, hypertension, diabetes, and obesity, that drive the condition in the first place.12PubMed Central. Arterial Stiffness and Heart Failure With Preserved Ejection Fraction
Why Breathlessness During Exercise Does Not Have a Simple Fix
The most disabling symptom of HFpEF is exercise intolerance, the inability to walk, climb stairs, or perform basic tasks without severe breathlessness and fatigue. The obvious explanation would be that rising filling pressures during activity push fluid into the lungs. That is part of the story, but it turns out to be more complicated than that. In a striking study, researchers used nitroglycerin to deliberately lower lung capillary wedge pressure during exercise in HFpEF patients. Instead of feeling better, patients reported worse breathlessness, and measurements showed increased mismatch in how air and blood were distributed in the lungs.13PubMed Central. Reducing Pulmonary Capillary Wedge Pressure During Exercise Exacerbates Exertional Dyspnea in Patients With Heart Failure With Preserved Ejection Fraction Lowering pressure, in other words, made things worse, suggesting that the breathlessness is not simply a backpressure problem that can be fixed by reducing fluid load alone.
Skeletal muscles are part of the puzzle as well. HFpEF patients show measurably impaired mitochondrial function in their leg muscles. Researchers found that muscle oxygen consumption was reduced across every major mitochondrial pathway tested, even after adjusting for age, sex, and body weight. The degree of mitochondrial impairment correlated strongly with how far patients could walk in six minutes and how much oxygen they could consume at peak effort.14JAMA Cardiology. Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction So the exercise limitation in HFpEF is not just a heart problem. It is a whole-body problem involving the heart, the lungs, the blood vessels, and the muscles simultaneously.
Treatments That Have Changed the Outlook
For years, the therapeutic story of HFpEF was a litany of failed trials. ACE inhibitors, beta-blockers, and other staples of reduced-ejection-fraction treatment showed little or no benefit. That changed decisively with SGLT2 inhibitors, the class of drugs originally developed for diabetes. In the EMPEROR-Preserved trial, empagliflozin reduced the combined risk of cardiovascular death or heart failure hospitalization by about 21% compared with placebo over roughly two years, driven mainly by fewer hospitalizations.15PubMed. Empagliflozin in Heart Failure with a Preserved Ejection Fraction A meta-analysis of randomized trials confirmed the class effect: SGLT2 inhibitors reduced heart failure hospitalizations by about 25%, though the reduction in overall death did not quite reach statistical significance.16PubMed Central. The role of SGLT 2 inhibitors in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis of randomized controlled trials
Beyond SGLT2 inhibitors, a network meta-analysis found that the triple combination of sacubitril/valsartan, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor appeared to halve the composite of cardiovascular death or hospitalization compared with placebo. SGLT2 inhibitors were the only class that showed consistent benefit across all ejection fraction subgroups, while the triple combination showed its greatest effect at moderately preserved ejection fractions and more marginal benefit at ejection fractions above 60%.17PubMed. Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis None of these drugs, individually or combined, has yet shown a robust reduction in all-cause mortality in HFpEF, a sobering reminder that the condition still resists the kind of dramatic survival gains seen in reduced-ejection-fraction heart failure.
Weight Loss and the Semaglutide Results
Given the central role of obesity in many HFpEF patients, targeting weight directly has attracted intense interest. In the STEP-HFpEF trial, once-weekly semaglutide, a GLP-1 receptor agonist, produced striking improvements in obese HFpEF patients. Participants on semaglutide lost about 13% of their body weight over a year, compared with roughly 3% in the placebo group. More importantly, their heart-failure symptoms improved substantially: the heart failure quality-of-life score improved by nearly eight points more than placebo, and six-minute walk distance increased by about 20 meters more.18PubMed. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity Those improvements in symptoms, physical limitations, and exercise function held up regardless of baseline health status or sex.19American College of Cardiology. Semaglutide Treatment Effect in People With Obesity and HFpEF – STEP-HFpEF
The semaglutide trial did not have enough power to evaluate hard endpoints like hospitalization or death, so the drug is not yet proven to prevent heart failure events the way SGLT2 inhibitors are. Still, for patients whose daily lives are dominated by breathlessness and immobility, the symptom and function gains are meaningful in their own right.
Exercise Training and Caloric Restriction
Non-drug approaches remain a cornerstone. A randomized trial in obese older adults with HFpEF tested aerobic exercise, caloric restriction, and both together. Each intervention alone improved peak oxygen consumption by about 1.2–1.3 mL/kg/min, and the combination appeared additive, yielding an improvement of roughly 2.5 mL/kg/min. Neither intervention alone significantly improved quality of life on a standard questionnaire, but the gains in exercise capacity are clinically relevant for a population that often struggles with basic mobility.20PubMed Central. Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction Exercise training programs for HFpEF now appear in clinical guidelines, though access to supervised cardiac rehabilitation remains uneven.
Complications That Change the Game
As HFpEF progresses, two complications in particular can accelerate decline. The first is pulmonary hypertension, high pressure in the blood vessels of the lungs. Most HFpEF patients develop some degree of it, because chronically elevated filling pressures in the left heart back up into the pulmonary circulation. In some patients, the lung vasculature itself begins to remodel, adding a precapillary component on top of the postcapillary pressure. This combined form carries a worse prognosis than the pure backup type.21PubMed Central. Pulmonary Hypertension in the Context of Heart Failure With Preserved Ejection Fraction Echocardiographic measures of right ventricular function and pulmonary pressure, particularly the ratio of right ventricular contraction to systolic pulmonary pressure, independently predict death even after adjusting for other risk factors.22European Heart Journal – Cardiovascular Imaging. Right ventricular-vascular coupling in heart failure with preserved ejection fraction and pre- vs. post-capillary pulmonary hypertension
The second major complication is atrial fibrillation. The left atrium in HFpEF is chronically stretched and remodeled, a condition sometimes called left atrial myopathy. This structural damage sets the stage for chaotic electrical activity. Once atrial fibrillation develops, it further impairs filling, worsens symptoms, and accelerates the decline in heart failure status. Left atrial myopathy in HFpEF is distinct in character from that seen in reduced-ejection-fraction heart failure, and it both drives and is driven by atrial fibrillation in a reinforcing cycle.23PubMed Central. Left Atrial Myopathy in Atrial Fibrillation and Heart Failure: Clinical Implications, Mechanisms, and Therapeutic Targets
Not One Disease but Several
A growing consensus holds that HFpEF is not a single disease but a syndrome encompassing multiple overlapping phenotypes. Machine learning applied to biomarker profiles from HFpEF patients has identified at least four distinct clusters: one dominated by diabetes and kidney disease; another by advanced age and age-related conditions; a third with younger, larger-bodied patients who had the fewest symptoms and lowest natriuretic peptide levels; and a fourth marked by ischemic heart disease, smoking, lung disease, and the highest biomarker levels and symptom burden.24European Journal of Heart Failure. Machine Learning Based on Biomarker Profiles Identifies Distinct Subgroups of Heart Failure with Preserved Ejection Fraction
This heterogeneity helps explain why so many one-size-fits-all drug trials failed. A medication that helps the obesity-driven phenotype may do little for the patient whose HFpEF is primarily driven by stiff arteries and advanced age. Clinical research is increasingly moving toward phenotype-guided therapy, matching treatments to the specific pathological drivers in each patient rather than lumping everyone with a preserved ejection fraction into one trial arm.
Devices and Drugs in the Pipeline
Several new approaches are in clinical testing. Interatrial shunt devices aim to decompress the overloaded left atrium by creating a small, permanent, pressure-dependent hole between the two upper chambers of the heart. The concept is simple: when left atrial pressure rises, blood flows through the shunt to the right atrium, relieving congestion. Multiple designs are in various stages of investigation in both preserved and reduced ejection fraction populations.25PubMed Central. Interatrial Shunt Devices Early results have been mixed, and larger pivotal trials are underway to determine whether the hemodynamic improvements translate into fewer hospitalizations and better survival.
On the drug side, soluble guanylate cyclase stimulators like praliciguat aim to restore the nitric oxide signaling pathway that becomes deficient in HFpEF, the same pathway whose disruption stiffens titin and promotes fibrosis.26PubMed. Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF) Vericiguat, a related compound already approved for reduced-ejection-fraction heart failure, has not fared well in HFpEF analyses, with some signal toward increased cardiovascular risk rather than benefit.27medRxiv. Efficacy and Safety of Pharmacologic Therapies in HFpEF: A Systematic Review and Network Meta-Analysis Epigenetic targets, including specific microRNAs, are also under investigation as both diagnostic biomarkers and potential therapeutic handles, though none has been validated enough for clinical use yet.28PubMed Central. Genetic and Molecular Mechanisms of Non-Ischemic Heart Failure with Preserved Ejection Fraction: Pathway Crosstalk, Translational Implications, and Regional Genetic Context
Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has shown promise in reducing rehospitalizations in network analyses, though it raises the risk of elevated potassium levels and requires close monitoring.29medRxiv. Efficacy and Safety of Pharmacologic Therapies in HFpEF: A Systematic Review and Network Meta-Analysis Tirzepatide, a dual GIP/GLP-1 receptor agonist already approved for diabetes and obesity, has also begun showing favorable signals in the HFpEF space, adding another weight-loss-based strategy alongside semaglutide. The pipeline is more crowded than at any point in the condition’s history, which is itself a sign of how seriously the field now takes a syndrome that was once dismissed as merely “diastolic dysfunction.”