Exploring Heart Failure With Preserved Ejection Fraction

— The basics on pathogenesis and epidemiology

Illustration of a stethoscope over the letters HFpEF over a heart in failure
Key Points

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Until the 1980s and 1990s, all congestive heart failure was lumped together based on signs and symptoms. Landmark clinical trials of the 1990s moved the field to divide patients into two distinctive groups based on readily available left ventricular ejection fraction (LVEF) measurements. It became clear that ejection fraction distinguished both response to treatments and prognosis.

After a stint as "diastolic heart failure," heart failure with preserved ejection fraction (HFpEF) now defines those with signs and symptoms of HF due to high LV filling pressure despite normal or near-normal LVEF of 50% or greater. (The definition used, however, has been variable in the research literature, with some studies including an EF as low at 40%; the guidelines, though, continue to use a percentage of >50%.)

The increased LV filling pressure is secondary to diastolic dysfunction, can be observed at rest or with exercise, and causes secondary pulmonary hypertension. It also dramatically limits systolic reserve capacity during stress but with little increase in ejection fraction.

"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," noted a review in Nature Reviews Cardiology.


HFpEF accounts for about half of the approximately 6.5 million cases of heart failure in the U.S. Among four community-based cohorts, the incidence of HFpEF was 26.9 per 10,000 person-years.

While heart failure overall is decreasing in age-specific incidence, the trends diverge by ejection fraction. For example, in a study from the Minnesota county near the Mayo Clinic, age- and sex-adjusted incidence of HF declined significantly for both HF types from 2000 to 2010, but with a steeper slope for heart failure with reduced ejection fraction (HFrEF) than for HFpEF (down 45% vs 27.9%). In pooled data from the Framingham Heart Study and the Cardiovascular Health Study, the incidence of HFpEF rose from 4.7 to 6.8 per 1,000 from 1990-1999 to 2000-2009, whereas the rate dropped for HFrEF from 6.6 to 6.2 per 1,000 over that period.

Women have a higher incidence of HFpEF compared with HFrEF. "After adjusting for age and other risk factors, the risk of HFpEF is fairly similar in men and women, unlike the lower risk of HFrEF for women versus men," noted a 2017 review by Margaret Redfield, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues. In the Atherosclerosis Risk in Communities (ARIC) Community Surveillance study, HFpEF was most common in white females, who accounted for 59% of hospitalized HFpEF.

These numbers should be taken with the acknowledgment that challenges in the diagnosis of HFpEF, due to its multiple etiologies and lack of a single diagnostic test, make estimation of incidence and prevalence more difficult, noted a 2020 review by Nandini Nair, MD, of Texas Tech Health Sciences Center in Lubbock.


The heterogeneity continues in the pathophysiology and pathogenesis of HFpEF.

"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," said the authors of a review in Nature Reviews Cardiology.

The variety of etiologies has contributed to challenges in finding effective treatments, as another review points out.

"Pathophysiology of HFpEF is multifaceted stemming from several disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and fibrosis, ventricular-vascular uncoupling, pulmonary hypertension, and chronotropic incompetence," those authors added. Peripheral impairments in endothelial function, body composition, and skeletal muscle function also play an important role in HFpEF.

Although development of animal models of HFpEF and other mechanistic research has lagged, some findings are emerging implicating nitric oxide synthase suppression and lipotoxicity as well as upregulation of reactive oxygen species.

Myocardial remodeling research has also shown that abnormal fibroblasts in HFpEF are "apoptosis resistant and initiate the development of an abnormal myocardial matrix resulting in initiation and progression of the disease," Nair noted in her paper. "Further investigation could provide new avenues to target therapeutics specifically to stop initiation and progression of fibrosis."

Older age is a big risk factor for HFpEF, but others are hypertension, obesity, and coronary artery disease.

Risk factors differ by HF subtype, according to AHA statistics for 2022. Large-scale, community-based studies have shown a greater impact of older age for incident HFpEF than for HFrEF, with a relative hazard ratio of 1.91 vs 1.69 per 10-year age increase, respectively. Male gender, prior myocardial infarction, left ventricular hypertrophy, and left bundle-branch block are all more strongly linked to HFrEF than HFpEF.

HFpEF is increasingly seen as a condition of multimorbidity -- i.e., the co-occurrence of two or more chronic conditions, such as cardiometabolic disorders including diabetes, obesity, sleep apnea, etc.

While both types of patients commonly face multimorbidity, it is slightly more severe in HFpEF, Redfield and co-authors noted. "A majority of deaths in patients with HFpEF are cardiovascular, but the proportion of noncardiovascular deaths is higher in HFpEF than HFrEF."

"Beyond classifications of EF and staging in HF, clinicians should seek the cause of HF because appropriate treatment may be determined by the cause," the 2022 heart failure guidelines state.

There is some evidence that lack of exercise may result in HFpEF, and that increased exercise may be a therapy for HFpEF.

Read Part 1 of this series: Heart Failure: A Look at Low Ejection Fraction

Up next: HFrEF Diagnosis and Evaluation