HFpEF: Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction, commonly abbreviated HFpEF (pronounced “heff-peff”), is a form of heart failure in which the heart pumps blood out with normal squeezing strength but struggles to relax and fill properly between beats. It now accounts for more than half of all new heart failure cases and has become one of the fastest-growing cardiovascular diagnoses worldwide, yet it spent decades as a condition doctors could barely define, let alone treat. The landscape has shifted in the past few years with the arrival of drugs that actually improve outcomes, but HFpEF remains uniquely difficult to diagnose, frustratingly varied from person to person, and still poorly understood by many patients who carry the label.

What Makes HFpEF Different from Other Heart Failure

When most people picture heart failure, they imagine a weakened heart that can no longer pump forcefully enough. That picture describes heart failure with reduced ejection fraction, where the heart’s main pumping chamber squeezes out much less blood than it should with each beat. HFpEF flips that expectation. The squeezing function looks normal on an echocardiogram, with ejection fractions at or above 50%, but the heart muscle has become stiff. It cannot relax fully, so the chamber does not fill with enough blood at low pressures. The result is a backup of fluid into the lungs and body, producing breathlessness, fatigue, and swelling that can be indistinguishable from the other type of heart failure.

This stiffening is not a single disease. HFpEF is now recognized as a syndrome driven by multiple overlapping problems. In a large 2023 scientific statement, researchers described it as a heterogeneous condition shaped by aging, obesity, sedentary lifestyles, and a web of metabolic disorders. That heterogeneity is exactly what makes it so hard to study, diagnose, and treat. Two patients with HFpEF can look nothing alike: one might be a 55-year-old with severe obesity and diabetes, while the other is an 80-year-old with high blood pressure and an irregular heartbeat. Both have a stiff heart that fills poorly, but the roads that brought them there are different.

How Common It Is and Why the Numbers Keep Climbing

HFpEF is not a niche diagnosis. Among adults newly hospitalized for heart failure, roughly half now fall into the HFpEF category. In one large cohort study tracking adults diagnosed with heart failure between 2007 and 2015, about 58% had HFpEF, compared with 30% who had the reduced-ejection-fraction type. The incidence of HFpEF has been climbing over time even as the overall rate of new heart failure diagnoses has held relatively steady, rising from roughly 4.7 per 1,000 people in the 1990s to about 6.8 per 1,000 people in the 2000s.¹ The global economic burden of heart failure overall is estimated at around $108 billion per year, with hospitalizations driving the largest share of those costs.

The rising numbers track closely with the epidemics of obesity, type 2 diabetes, and population aging. As more people live longer with these conditions, the pool of individuals whose hearts stiffen gradually under chronic metabolic stress grows larger. Unlike the reduced-ejection-fraction form, which has been declining in incidence partly thanks to better treatments after heart attacks, HFpEF has no such counterbalancing trend.

Why It Is So Hard to Diagnose

Diagnosing HFpEF remains one of the trickiest problems in cardiology. The symptoms, mainly shortness of breath on exertion and fatigue, overlap with dozens of other conditions, from lung disease to deconditioning to obesity itself. And unlike the other form of heart failure, where a quick echocardiogram shows an obviously weak pump, HFpEF patients have echocardiograms that can appear deceptively normal at rest.

Two clinical scoring systems have been developed to help: the H2FPEF score and the HFA-PEFF algorithm. In a study of patients with unexplained breathlessness, the H2FPEF score discriminated HFpEF from non-HFpEF reasonably well, though the HFA-PEFF algorithm missed more than half of confirmed cases at its low-probability threshold.² Agreement between these two systems is surprisingly low. In a registry of over 800 HFpEF patients, the concordance between the two scoring tools was weak, meaning the same patient could receive a high probability of HFpEF from one system and a lower probability from the other.³

Atrial fibrillation complicates matters further. Among patients with atrial fibrillation who were evaluated with invasive pressure measurements as the gold standard, both scoring systems showed only moderate accuracy, and the HFA-PEFF system had a sensitivity of just 40%.⁴ This means a substantial number of patients who genuinely have HFpEF are told their scores are normal.

Exercise stress echocardiography, which captures how the heart behaves during physical effort rather than just at rest, is often needed to unmask the problem. But even this approach lacks standardization. An international survey of cardiologists found that the proportion of patients diagnosed with HFpEF after exercise echocardiography varied widely depending on which criteria were applied, ranging from 20% to 44%. Half to two-thirds of cases remained indeterminate after the test, and only about 41% of surveyed cardiologists said they would proceed to invasive exercise catheterization to resolve the ambiguity.⁵

The Obesity Blind Spot in Blood Tests

Blood levels of a protein called NT-proBNP are a standard first-line test for heart failure. When the heart is under stress and pressures rise inside its chambers, cells release this protein into the bloodstream. Higher levels suggest heart failure; lower levels are supposed to rule it out. But HFpEF in obese patients breaks that logic. In hospitalized HFpEF patients, NT-proBNP was inversely related to body mass: the most severely obese patients had the lowest levels, and about 13% of confirmed HFpEF patients had NT-proBNP readings in the normal range.⁶

A separate study found that in an obese cohort with confirmed HFpEF, half had NT-proBNP levels below the standard diagnostic cutoff, and those patients had the same degree of diastolic dysfunction and exercise limitation as the patients with elevated levels.⁷ The takeaway is that relying on a normal blood test to exclude HFpEF in someone who is overweight or obese can send patients home with a missed diagnosis.

What Goes Wrong Inside the Heart

The stiffness at the core of HFpEF arises from changes at several levels, from the individual muscle cell to the tissue surrounding it. Inside each heart muscle cell, a giant spring-like protein called titin is a major determinant of how easily the cell stretches when blood flows in. In HFpEF, changes in the chemical tagging of titin make it stiffer than normal, and animal models of metabolic disease show that roughly 80% of the increased muscle stiffness can be traced to this one protein.⁸ Beyond titin, the tissue between muscle cells accumulates excess collagen, adding another layer of rigidity.⁹

Inflammation and damage to the smallest blood vessels in the heart also play a role. About a third of HFpEF patients show impaired function in the coronary microvascular system, the tiny vessels that feed the heart muscle itself. This microvascular damage correlates with worse diastolic function and is tightly linked to circulating inflammatory signals.¹⁰ This is one reason researchers now view HFpEF less as a purely cardiac problem and more as a systemic inflammatory and metabolic disease that happens to express itself most visibly in the heart.

The Obesity Phenotype and Epicardial Fat

Among the several recognized subtypes of HFpEF, the obesity-driven phenotype has attracted the most research attention. Patients with obesity and type 2 diabetes often develop an enlarged pad of fat directly on the heart’s surface, called epicardial adipose tissue. Unlike fat stored under the skin, this cardiac fat sits inside the pericardial sac and acts as an active endocrine organ, releasing inflammatory and fibrotic signals directly into the heart muscle.¹¹

The mechanical effects are equally important. Excess epicardial fat physically constrains the heart within the pericardium. In obese HFpEF patients, a thicker layer of epicardial fat was associated with higher filling pressures at rest and during exercise, more severe pulmonary hypertension, and significantly worse exercise capacity.¹² The combination of chemical toxicity from inflammatory signaling and physical squeezing from the fat itself creates a double mechanism by which excess weight worsens HFpEF.

Why Patients Feel So Limited During Exercise

Exercise intolerance is the hallmark complaint in HFpEF, but the cause is not just the stiff heart. Research has uncovered widespread skeletal muscle abnormalities in these patients, including a shift away from endurance-type muscle fibers, reduced blood vessel density within the muscles, fat infiltration into muscle tissue, and impaired energy production within muscle cell mitochondria.¹³ These changes appear to be intrinsic to the HFpEF syndrome rather than simply a consequence of being unfit. In older HFpEF patients, biopsies showed a shift toward fast-twitch muscle fibers at the expense of the slow-twitch fibers that are better suited for sustained aerobic activity.¹⁴

When researchers directly measured oxygen extraction from the blood during exercise, they found that the muscles of HFpEF patients were significantly worse at pulling oxygen out of the blood compared with healthy controls. This impaired peripheral oxygen extraction was a major determinant of exercise capacity, independent of how well the heart was pumping.¹⁵ This finding matters practically: treatments that target only the heart may leave patients still feeling limited if the muscle and microvascular problems persist.

Atrial Fibrillation and Kidney Disease

Two comorbidities deserve particular attention because they are both extremely common in HFpEF and actively worsen the underlying disease. Atrial fibrillation, an irregular heart rhythm originating in the upper chambers, creates a vicious cycle. As HFpEF progresses, rising pressures stretch the atria, which promotes atrial fibrillation. The fibrillation then enlarges the atria further, increases pericardial constraint, and drives filling pressures even higher. In patients with permanent atrial fibrillation, the total heart volume is markedly increased due to atrial dilation, leading to greater congestion and worse right-sided heart function.¹⁶

Kidney disease is equally intertwined. The failing heart and the kidneys interact in ways that amplify each other’s problems, a dynamic sometimes called cardiorenal syndrome. In HFpEF, elevated venous pressures, activation of hormonal systems that retain salt and water, and pulmonary hypertension all conspire to impair kidney function, which in turn worsens fluid retention and makes heart failure harder to manage.¹⁷ As HFpEF progresses, the right side of the heart often begins to fail as well, and imaging studies have identified right ventricular dysfunction as a major independent predictor of poor outcomes.¹⁸

Drug Treatments That Actually Work

For years, HFpEF was considered untreatable because every major drug trial failed. That changed with SGLT2 inhibitors, a class of medications originally developed for diabetes. In the EMPEROR-Preserved trial, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure by about 21% compared with placebo, driven primarily by fewer hospitalizations. The benefit held regardless of whether patients had diabetes.¹⁹ The DELIVER trial showed a similar result with dapagliflozin, which cut the risk of worsening heart failure or cardiovascular death by about 18% over roughly two years of follow-up.²⁰ These trials were practice-changing. SGLT2 inhibitors are now the most well-established drug class for HFpEF.²¹

For obese patients specifically, GLP-1 receptor agonists have emerged as a second breakthrough. In the STEP-HFpEF trial, weekly semaglutide produced striking improvements in symptoms, quality of life, and exercise capacity compared with placebo. Patients on semaglutide walked an average of about 20 meters further on a six-minute walk test and lost roughly 13% of their body weight, compared with less than 3% in the placebo group.²² The benefits appear to extend beyond weight loss alone; semaglutide also cut C-reactive protein, a marker of systemic inflammation, by over 40%, suggesting anti-inflammatory effects that target the underlying disease biology.²³ Recent analyses suggest these drugs work through both weight-dependent and weight-independent pathways, including metabolic and cardiovascular effects.²⁴

Other drug classes have a more complicated track record. Sacubitril/valsartan, a combination drug that is standard in reduced-ejection-fraction heart failure, narrowly missed its primary endpoint in HFpEF in the PARAGON-HF trial. However, subgroup analyses revealed that the drug significantly reduced hospitalizations in patients with ejection fractions below the study’s median of 57%, and in women, who showed a 27% reduction in the primary outcome compared with no benefit in men.²⁵ The benefit from sacubitril/valsartan appears to be greatest at lower ejection fractions, with women deriving benefit up to higher ejection fractions than men.²⁶ Mineralocorticoid receptor antagonists like spironolactone have shown improvements in measures of diastolic function and reductions in markers of cardiac fibrosis in pooled analyses.²⁷ Newer non-steroidal versions of these drugs, which may have stronger anti-fibrotic properties and fewer hormonal side effects, are being explored as potential additions to the treatment toolkit.²⁸

Exercise Training and Weight Loss

Even without drugs, lifestyle interventions produce measurable improvements. In a randomized trial of obese older HFpEF patients, both aerobic exercise training and caloric restriction independently improved peak oxygen consumption, and the combination was additive: exercise alone added about 1.2 mL/kg/min, caloric restriction added about 1.3 mL/kg/min, and together they produced a gain of 2.5 mL/kg/min.²⁹ For context, a gain of 2.5 mL/kg/min in peak oxygen uptake is clinically meaningful and can translate into noticeably better function in daily life.

Adding resistance training to the mix of aerobic exercise and caloric restriction did not produce additional fitness gains in one trial, though both the resistance-training group and the control group improved significantly in fitness and quality-of-life scores.³⁰ The practical message is clear: regular aerobic exercise and weight loss, when achievable, remain foundational regardless of what medications a patient is on.

Devices and the Search for Mechanical Solutions

Because high left atrial pressure is a central driver of symptoms, several companies have developed small implantable devices that create a tiny hole between the two atria of the heart, essentially a controlled pressure-release valve. These interatrial shunt devices allow blood to flow from the high-pressure left atrium to the lower-pressure right atrium, reducing pulmonary congestion.³¹ Early-stage trials have shown improvements in exercise hemodynamics, though the evidence is still developing and questions remain about long-term safety, patient selection, and whether the benefits translate into fewer hospitalizations and improved survival.

Artificial Intelligence as a Screening Tool

Given how difficult diagnosis can be, researchers have turned to artificial intelligence to spot HFpEF earlier. A deep-learning model trained on standard 12-lead electrocardiograms, a test available in virtually every clinic, achieved strong diagnostic accuracy for detecting HFpEF in both internal and external validation. Among individuals initially without HFpEF, those flagged as high risk by the algorithm were four times as likely to develop the condition as those in the low-risk group.³² The model appeared to focus on subtle features in the electrical tracing of the heartbeat that human readers typically cannot discern.

AI applied to echocardiograms has also shown promise. In an external validation study comparing an AI echocardiogram model against the H2FPEF and HFA-PEFF clinical scores, the AI model achieved similar discrimination but classified more patients definitively, producing fewer ambiguous results than the clinical scores.³³ If these tools mature into routine clinical use, they could help address one of HFpEF’s biggest problems: the sheer number of patients who go unrecognized for years because conventional testing leaves results in a gray zone.

The Role of Hypertension Without Obesity

Not all HFpEF is obesity-driven. Long-standing high blood pressure can lead to HFpEF through a different pathway. Hypertension forces the heart to pump against higher resistance, and over time the muscle walls thicken and stiffen. In one study comparing hypertensive patients with and without HFpEF, both groups showed increased stiffness in the heart and blood vessels, but the HFpEF patients had a distinctive additional finding: their heart muscle’s actual ability to contract was depressed at the cellular level, even though the overall ejection fraction looked normal on an echocardiogram.³⁴ This hints at a subtlety that the ejection fraction number can obscure: “preserved” pumping does not always mean truly normal pumping. The number can look fine even while the muscle is working harder and contracting less efficiently at a fundamental level.

Epigenetics and Future Directions in Understanding HFpEF

One frontier that may eventually reshape how HFpEF is classified and treated involves epigenetics, the study of how genes are switched on or off without changes to the DNA sequence itself. The various mechanisms underlying HFpEF, from fibrosis to inflammation to fat accumulation, each appear to be influenced by epigenetic modifications that alter gene expression. These include chemical tags added to DNA, modifications to the proteins DNA wraps around, and small RNA molecules that fine-tune which proteins the cell produces.³⁵ The hope is that mapping these epigenetic signatures will eventually allow clinicians to identify which specific subtype of HFpEF a patient has and match them with the therapy most likely to address their particular biology, moving beyond the current approach of treating a broad syndrome with broad-spectrum drugs.