Chronic Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction, often shortened to HFpEF, is a form of heart failure in which the heart pumps blood out with normal force but struggles to relax and fill properly between beats. It accounts for roughly a third to half of all heart failure cases in the community and is especially common among older adults and women, with prevalence approaching one in ten in women over 80.¹ Because the standard measure of heart strength, ejection fraction, looks normal on an echocardiogram, HFpEF spent decades as a diagnostic afterthought. That has changed. A growing body of research now recognizes it as a distinct and complex syndrome with its own mechanisms, its own treatment landscape, and its own challenges.

Why the Heart Fails Even When It Pumps Normally

Ejection fraction measures the percentage of blood the left ventricle pushes out with each beat. In HFpEF, that number stays at 50% or above, which sounds reassuring. The problem is that a normal squeeze does not guarantee normal filling. Between beats, the left ventricle needs to relax so blood can flow in from the lungs. In HFpEF, the heart muscle becomes stiff, making that relaxation incomplete. Pressure builds up in the left atrium and backs into the lungs, causing the same congestion, breathlessness, and fluid retention seen in other forms of heart failure.

Two structural changes drive much of that stiffness. One involves collagen, the scaffolding protein that gives tissue its framework. The other involves titin, a giant spring-like protein inside each heart muscle cell that helps the cell snap back after contracting. In patients with HFpEF who also have high blood pressure, collagen-related stiffness can be elevated by roughly 220% and titin-related stiffness by about 92% compared with healthy controls.² Abnormal modifications to titin and shifts in the balance of its different forms are now recognized as key contributors to impaired filling.³

An influential framework published in the Journal of the American College of Cardiology proposed that the chain of events often starts outside the heart entirely. Conditions like obesity, diabetes, and high blood pressure create a low-grade inflammatory state throughout the body. That inflammation damages the lining of tiny blood vessels in the heart, reducing nitric oxide, a molecule that keeps blood vessels relaxed and heart muscle supple. Without enough nitric oxide, heart cells stiffen and enlarge, scar tissue accumulates, and filling pressures climb.⁴ This microvascular inflammation theory has become central to how researchers think about HFpEF and why it is so tightly linked to metabolic diseases.⁵

The Comorbidities That Fuel It

HFpEF rarely arrives on its own. A large meta-analysis of 61 cohort studies quantified how powerfully certain conditions raise the risk: atrial fibrillation nearly tripled it, hypertension roughly doubled it, diabetes raised it by about 88%, obesity by about 70%, and prior heart attack by about 62%.⁶ Those numbers reflect individual risks before adjusting for the fact that these conditions cluster in the same patients. In a university hospital cohort, over 93% of HFpEF patients had hypertension and roughly three-quarters had atrial fibrillation.⁷

Obesity deserves special attention. Compared with weight-matched people without heart failure, patients with HFpEF still show worse kidney function, greater fluid volume expansion, and more cardiovascular problems, which suggests obesity alone does not explain the whole picture.⁸ Still, excess weight plays such a central role in the inflammatory cascade that weight-targeting therapies have become a major area of HFpEF research, as discussed later in this article.

Why Exercise Feels So Much Worse Than the Heart Numbers Suggest

One of the hallmarks of HFpEF is exercise intolerance that seems out of proportion to how the heart looks on imaging. Patients describe getting winded climbing a single flight of stairs or being unable to keep up with normal walking. For years clinicians assumed this was purely a cardiac problem, but the picture is broader than that.

Studies show that blood flow to working muscles during exercise is sharply reduced in HFpEF, and this reduction cannot be fully explained by what the heart is doing. The blood vessels in skeletal muscles fail to dilate normally during exertion.⁹ On top of that, the muscles themselves undergo structural and metabolic changes, including shifts in fiber composition and energy use, that mirror what happens in aging. In many ways HFpEF behaves like an accelerated version of cardiovascular aging, with reductions in heart compliance, slowed heart-rate responses, increased arterial resistance, and poor energy handling in muscle tissue.¹⁰ This multi-organ involvement helps explain why purely cardiac treatments have historically underperformed in HFpEF.

The Diagnostic Puzzle

Diagnosing HFpEF is harder than diagnosing classic heart failure with a weak pump. The ejection fraction is normal. Symptoms like shortness of breath, fatigue, and ankle swelling overlap with obesity, deconditioning, and lung disease. Blood tests that are reliable red flags in other types of heart failure can be misleading here.

The standard screening blood marker, NT-proBNP, tends to run lower in HFpEF patients. About 23% of HFpEF patients in one large study had NT-proBNP levels below the European guideline threshold of 125 pg/mL, and those patients had milder echocardiographic abnormalities and better outcomes.¹¹ The upside is that extremely low levels suggest lower risk. The downside is that a “normal” NT-proBNP can lull doctors into missing the diagnosis altogether. Optimal cutoff values also vary depending on whether the patient has atrial fibrillation, kidney disease, or obesity, with safety thresholds ranging from around 329 to 929 pg/mL across subgroups.¹² A single threshold for all patients does not work well, and research into population-specific cutoffs remains active.¹³

To deal with this uncertainty, two scoring systems have gained traction. The H2FPEF score uses variables like body mass index, number of blood pressure medications, and echocardiographic filling pressures. The HFA-PEFF algorithm from the European Society of Cardiology follows a stepwise process using imaging, biomarkers, and sometimes exercise testing. A meta-analysis found that H2FPEF has higher sensitivity (catching about 76% of true cases) while HFA-PEFF has stronger specificity (correctly ruling out about 90% of non-cases). When both are applied to the same patients, they disagree in about 41% of cases, which underscores how difficult diagnosis remains.¹⁴ One practical strategy researchers have proposed is to use H2FPEF as an initial screen and HFA-PEFF for confirmation, with advanced testing reserved for discordant cases.

Treatments That Are Finally Making a Difference

For decades, almost every drug that worked in heart failure with a reduced ejection fraction flopped in HFpEF trials. That frustrating streak began to break in the early 2020s, primarily with a class of drugs originally developed for diabetes.

SGLT2 Inhibitors

The landmark EMPEROR-Preserved trial showed that 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. This benefit held regardless of whether patients had diabetes.¹⁵ A subsequent meta-analysis of randomized trials confirmed that SGLT2 inhibitors as a class cut heart failure hospitalizations by about 25% in HFpEF, though the effect on overall death did not quite reach statistical significance.¹⁶ Broader analyses across heart failure, diabetes, and kidney disease populations found consistent benefits for this drug class.¹⁷ SGLT2 inhibitors have become the first drug class with robust, replicated evidence in HFpEF, and guidelines now recommend them.

Sacubitril/Valsartan and Other Neurohormonal Agents

Sacubitril/valsartan, a combination drug that blocks a harmful hormone pathway while boosting protective proteins, showed modest benefit in HFpEF. A meta-analysis found it reduced heart failure decompensation by about 15% compared with valsartan alone, though it did not significantly lower death rates.¹⁸ Subgroup analyses from major trials suggest that sacubitril/valsartan, spironolactone, and some blood-pressure-lowering drugs may work best in patients whose ejection fraction sits at the lower end of the preserved range, closer to the borderline with reduced-ejection-fraction heart failure.¹⁹ A network meta-analysis comparing multiple drug classes found that finerenone, a newer mineralocorticoid receptor antagonist, also reduced rehospitalization, although it increased the risk of high potassium levels. Notably, no drug in the analysis significantly reduced death from all causes.²⁰

Weight Loss With GLP-1 Receptor Agonists

Perhaps the most striking recent result came from a trial of semaglutide in patients with HFpEF and obesity. Over 52 weeks, patients on semaglutide lost an average of about 13% of their body weight (compared with roughly 3% on placebo) and experienced substantially larger improvements in symptoms and quality of life, with a nearly 8-point greater gain on a standard heart-failure quality-of-life questionnaire.²¹ Given that obesity drives so much of the underlying inflammation in HFpEF, targeting weight directly may address the disease closer to its roots than any prior cardiac drug has managed to do.

Exercise and Diet as Treatment

Drugs are not the only story. A randomized trial in obese older patients with HFpEF found that a structured aerobic exercise program and a calorie-restriction diet each independently improved peak oxygen consumption by a similar amount. Combining the two was additive, producing roughly double the improvement of either one alone.²² A follow-up trial tested whether adding resistance training to the mix would provide further gains; both groups improved significantly in exercise capacity and quality of life, though resistance training did not add a measurable extra benefit beyond what aerobic exercise plus dieting already provided.²³ For patients who can engage in it safely, regular moderate exercise combined with weight loss remains one of the best-supported interventions available.

Not One Disease but Several

One reason HFpEF has been so difficult to treat is that the label likely encompasses several distinct conditions with overlapping symptoms. Researchers have turned to machine learning to sort patients into subgroups based on clusters of clinical features, an approach called phenomapping.²⁴

A major analysis from the TOPCAT trial identified three distinct groups. One was younger with fewer comorbidities and relatively preserved function. A second was older with prominent atrial fibrillation, enlarged left atria, and stiff arteries. A third was heavily burdened by obesity, diabetes, kidney disease, and markers of active inflammation and tissue remodeling.²⁵ An independent clustering study found a similar pattern: the group with the heaviest comorbidity burden had the worst outcomes across every measured endpoint, while the group with the worst filling abnormalities but fewer comorbidities had higher hospitalization rates but not higher mortality.²⁶ The hope is that matching patients to their phenogroup will eventually allow targeted treatment rather than one-size-fits-all approaches.

A Treatable Cause Hiding in Plain Sight

Among patients carrying an HFpEF diagnosis, a meaningful fraction actually has a specific and increasingly treatable condition: transthyretin amyloid cardiomyopathy, in which a misfolded protein accumulates in the heart muscle and stiffens it. In a community-based study that actively screened for the disease, about 6% of HFpEF patients had it. Prevalence climbed steeply with age, reaching 21% among those 90 and older, and was far more common in men (roughly 10%) than women (about 2%).²⁷ A Japanese study using nuclear imaging found positive results in about 14% of HFpEF patients, with biopsy confirming amyloidosis in every case that was tested. These patients had notably higher troponin levels and thicker heart walls than those without amyloid.²⁸

This matters because amyloid cardiomyopathy now has a targeted drug (tafamidis) that slows progression. Missing the diagnosis means missing a treatment that can genuinely alter the disease course. Current guidance increasingly favors screening older HFpEF patients, particularly men with unexplained wall thickening, using a widely available nuclear scan.

Prognosis and How It Differs From Other Heart Failure

The common assumption that HFpEF carries a better prognosis than heart failure with a weak pump is only partly true. Thirty-day mortality after a hospitalization is about 10% lower in HFpEF than in reduced-ejection-fraction heart failure. But readmission rates are virtually identical, and hospital stays are nearly the same length.²⁹ In a large cohort, about 28% of readmissions in HFpEF patients were for heart failure itself, compared with 45% in reduced-ejection-fraction patients, meaning the remaining readmissions were for other medical problems like infections, kidney trouble, or lung disease.³⁰

The pattern of death also differs. Cardiovascular death is more common in reduced-ejection-fraction heart failure, while non-cardiovascular death, from cancer, sepsis, kidney failure, and other causes, is relatively more frequent in HFpEF.³¹ That distinction reinforces the picture of HFpEF as a systemic disease driven by multiple organ systems rather than a purely cardiac condition.

Sex Differences in Who Gets HFpEF and How It Behaves

Women make up a disproportionate share of HFpEF patients, and the disease presents and progresses differently in them. Women tend to report worse symptoms, more severe congestion, and lower quality of life, yet they generally have better survival than men with the same diagnosis.³² The reasons are not fully understood but likely involve differences in how male and female hearts remodel in response to high blood pressure and aging, hormonal influences on vascular stiffness and inflammation, and the fact that women develop concentric thickening of the heart wall more readily while men are more prone to chamber dilation.

These differences have practical implications. Women have historically been underrepresented in heart failure trials, and diagnostic thresholds for things like wall thickness and NT-proBNP may not perform equally across sexes. Researchers have called for sex-specific diagnostic criteria and for trials to be powered to detect treatment effects separately in men and women.³³

Effects Beyond the Heart

Because HFpEF is driven by systemic inflammation and vascular dysfunction, its effects extend well beyond the chest. One area receiving growing attention is the brain. A study that assessed cognitive function and brain volume in HFpEF patients found that their global cognitive performance was comparable to that of people with mild cognitive impairment, and their gray matter volume was significantly reduced.³⁴ The shared risk factors of hypertension, diabetes, and obesity likely damage small blood vessels in the brain much as they damage those in the heart, meaning HFpEF and cognitive decline may be parallel consequences of the same underlying process rather than one causing the other.

Devices and Monitoring on the Horizon

Beyond drugs and lifestyle, device-based approaches are being explored. One concept involves creating a small passage between the left and right atria using a catheter-delivered shunt. The idea is to give the overloaded left atrium a pressure relief valve. In a phase 2 sham-controlled trial, the interatrial shunt device reduced filling pressures during exercise compared with a sham procedure, with no major adverse events at one month.³⁵ Follow-up analysis showed improvements in pulmonary vascular function, including a 17% reduction in pulmonary vascular resistance and a 24% increase in lung artery compliance, without compromising blood flow to the rest of the body.³⁶ Larger trials are underway to see whether these hemodynamic improvements translate into fewer hospitalizations and better long-term outcomes.

Remote monitoring using implantable pressure sensors is another strategy gaining traction. A small device placed in the pulmonary artery wirelessly transmits daily pressure readings to a clinician, who can adjust medications before symptoms worsen. In the PROACTIVE-HF trial, patients managed with this technology had a heart-failure event rate at 12 months that was roughly half the expected rate based on historical controls.³⁷ While this approach applies to heart failure broadly and not just HFpEF, the condition’s diagnostic ambiguity and tendency toward sudden decompensation make it a natural fit for pressure-guided management.

The Search for Better Biomarkers

NT-proBNP remains useful but limited, as the diagnostic challenges above illustrate. Researchers are exploring a wider panel of blood markers that reflect the diverse biology of HFpEF: markers of inflammation, fibrosis, kidney injury, and metabolic stress. Advances in large-scale protein and gene analysis are enabling researchers to measure hundreds of circulating signals at once, with the goal of identifying patterns that distinguish HFpEF subtypes and predict which patients will respond to specific treatments.³⁸ None of these newer markers has entered routine clinical use yet, but the trajectory is toward a more precise, biology-driven approach to diagnosing and treating what was once considered a single uniform disease.