Residency · Residency · Cardiology

Heart Failure with Preserved Ejection Fraction

Definition and Diagnostic Criteria

Current Definition

Heart failure with preserved ejection fraction is defined by the presence of signs and symptoms of heart failure in the setting of an LVEF of 50% or greater. The diagnosis requires evidence of diastolic dysfunction and/or elevated filling pressures, which may be apparent at rest or only provoked during exercise. HFpEF now accounts for approximately 50% of all heart failure cases, and its prevalence continues to rise, driven by the aging population, increasing rates of obesity, and the growing burden of metabolic syndrome.

H2FPEF Score (Mayo Clinic)

The H2FPEF score provides a validated clinical tool for estimating the probability of HFpEF in patients with exertional dyspnea and preserved ejection fraction. Points are assigned as follows: Heavy, defined as a BMI greater than 30, earns 2 points. Hypertensive, requiring two or more antihypertensive medications, contributes 1 point. Atrial fibrillation, whether paroxysmal or persistent, carries the highest weight at 3 points. Pulmonary hypertension, assessed by a pulmonary artery systolic pressure greater than 35 mmHg on echocardiography, adds 1 point. Elder, defined as age greater than 60 years, contributes 1 point. Filling pressure elevation, assessed by an E/e' ratio greater than 9, adds 1 point. A total score of 0 to 1 makes HFpEF unlikely, a score of 2 to 5 is indeterminate and should prompt consideration of invasive hemodynamic assessment, and a score of 6 to 9 makes HFpEF very likely.

HFA-PEFF Diagnostic Algorithm (ESC)

The European Society of Cardiology's HFA-PEFF algorithm employs a stepwise approach. The first step establishes pretest probability through assessment of symptoms and signs of heart failure, relevant comorbidities including obesity, hypertension, diabetes, atrial fibrillation, and chronic kidney disease, natriuretic peptide levels, and echocardiographic abnormalities. The second step incorporates a combined echocardiographic and natriuretic peptide score spanning functional parameters such as e' velocity, E/e' ratio, tricuspid regurgitation velocity, and global longitudinal strain, along with morphological parameters including left atrial volume index, left ventricular mass index, relative wall thickness, and left ventricular wall thickness. BNP of 35 pg/mL or greater or NT-proBNP of 125 pg/mL or greater in sinus rhythm supports the diagnosis. The third step involves a diastolic stress test using exercise echocardiography, where an E/e' ratio greater than 15 and a tricuspid regurgitation velocity greater than 3.4 m/s during exercise confirm elevated filling pressures. The fourth step, reserved for cases remaining indeterminate, employs invasive hemodynamic assessment, where a resting PCWP of 15 mmHg or greater or an exercise PCWP of 25 mmHg or greater serves as the gold standard.

Exclusion of HFpEF Mimics

Before establishing a diagnosis of HFpEF, several important mimics must be systematically excluded. Constrictive pericarditis is characterized by enhanced ventricular interdependence, respirophasic septal shift, annulus paradoxus with preserved or elevated e' velocity, and pericardial thickening or calcification. Hypertrophic cardiomyopathy presents with asymmetric septal hypertrophy, systolic anterior motion of the mitral valve, and dynamic left ventricular outflow tract obstruction. Infiltrative cardiomyopathies, including cardiac amyloidosis with its characteristic granular sparkling and reduced global longitudinal strain with apical sparing, as well as sarcoidosis and Fabry disease with its pattern of concentric LVH and reduced GLS in the basal inferolateral wall, must be considered. High-output heart failure from anemia, thyrotoxicosis, arteriovenous fistula, obesity, or Paget disease represents another category. Valvular heart disease, particularly severe aortic stenosis, mitral stenosis, and significant mitral regurgitation, should also be evaluated and excluded.

<image> A diagnostic algorithm flowchart for HFpEF evaluation. Start with "Clinical Suspicion of HFpEF: dyspnea, edema, exercise intolerance, LVEF >= 50%" at top. Step 1: "Calculate H2FPEF score" with three branches: Score 0-1 (green box: "HFpEF unlikely - consider alternative diagnoses"), Score 6-9 (red box: "HFpEF confirmed - initiate workup for phenotype"), Score 2-5 (yellow box: "Indeterminate"). From indeterminate: "Perform diastolic stress echocardiography" with two branches: "E/e' > 15 or TR velocity > 3.4 m/s with exercise" (red: confirmed) vs "Normal exercise hemodynamics" (green: unlikely). If stress echo indeterminate: "Invasive hemodynamics with exercise - PCWP >= 25 mmHg on exercise confirms HFpEF." Side panel listing HFpEF mimics to exclude: constrictive pericarditis, HCM, amyloidosis, Fabry disease, valvular disease. Use color gradient from green (unlikely) through yellow (indeterminate) to red (confirmed). </image>

Pathophysiology

Diastolic Dysfunction

The pathophysiology of HFpEF is fundamentally rooted in impaired diastolic function, although the disease is now understood as far more complex than simple diastolic dysfunction. Active relaxation is impaired through reduced SERCA2a activity, increased myofilament calcium sensitivity related to titin mutations, and delayed calcium reuptake during diastole. Passive stiffness is increased through a shift in titin isoform expression from the more compliant N2BA form to the stiffer N2B isoform, through collagen cross-linking mediated by advanced glycation end-products that are particularly prevalent in diabetes, and through interstitial fibrosis.

These abnormalities result in elevated left ventricular filling pressures that are transmitted retrograde to the left atrium, pulmonary veins, and pulmonary vasculature. The left atrium itself undergoes a myopathic process characterized by progressive dilation, fibrosis, and reduced reservoir, conduit, and booster pump function. Left atrial stiffness has emerged as an independent predictor of clinical outcomes in HFpEF.

Systemic and Myocardial Inflammation

A distinctive feature of HFpEF pathophysiology is the role of comorbidity-driven systemic inflammation. Obesity, diabetes, chronic kidney disease, and chronic obstructive pulmonary disease produce elevated levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein that create a pro-inflammatory milieu. This systemic inflammation drives coronary microvascular endothelial inflammation, leading to reduced nitric oxide bioavailability, decreased cyclic GMP levels, reduced protein kinase G activity, and consequently impaired titin phosphorylation with increased cardiomyocyte stiffness.

Epicardial adipose tissue plays an increasingly recognized role as a metabolically active depot that exerts paracrine pro-inflammatory and pro-fibrotic effects on the adjacent myocardium. The volume of epicardial fat correlates with the severity of HFpEF, establishing it as both a biomarker and a potential therapeutic target.

Hemodynamic Phenotypes

HFpEF encompasses several distinct hemodynamic phenotypes with different pathophysiologic drivers and therapeutic implications. The classic high filling pressure phenotype manifests with elevated PCWP at rest and is predominantly congestion-driven. The exercise-induced phenotype presents with normal resting hemodynamics but demonstrates an inability to augment stroke volume with exercise and exhibits a steep rise in PCWP to above 25 mmHg during exertion. The pulmonary vascular phenotype is characterized by combined pre- and post-capillary pulmonary hypertension with a PVR exceeding 2 Wood units despite elevated PCWP, reflecting pulmonary vascular remodeling and carrying a worse prognosis. The right heart failure phenotype presents with right ventricular dilation and dysfunction, elevated right atrial pressure, peripheral edema, and hepatic congestion, and is frequently a late-stage manifestation. Chronotropic incompetence, defined as the failure to achieve at least 80% of the age-predicted maximum heart rate, is present in 30 to 50% of HFpEF patients and contributes significantly to exercise intolerance.

Obesity-Related HFpEF

Obesity-related HFpEF accounts for an increasing proportion of HFpEF diagnoses and involves multiple interconnected mechanisms including increased plasma volume, epicardial fat accumulation, systemic inflammation, insulin resistance, and sleep-disordered breathing. An important diagnostic consideration is that natriuretic peptide levels may appear falsely low in obese patients because adipose tissue clears natriuretic peptides via the NP receptor-C pathway, necessitating a higher threshold for suspecting HFpEF. Weight loss through GLP-1 receptor agonists or bariatric surgery is associated with improved hemodynamics, exercise capacity, and quality of life. The STEP-HFpEF trial demonstrated that semaglutide improved the Kansas City Cardiomyopathy Questionnaire score by 7.8 points and reduced body weight by 13%.

Pharmacotherapy

SGLT2 Inhibitors -- Class I Recommendation

SGLT2 inhibitors represent the only drug class with a Class I guideline recommendation for reducing heart failure hospitalizations in HFpEF. The EMPEROR-Preserved trial demonstrated a 21% reduction in cardiovascular death and heart failure hospitalization with empagliflozin across the spectrum of ejection fraction above 40%, with benefit that was consistent across the ejection fraction range, greatest in the 40 to 50% range, and still statistically significant in patients with ejection fraction above 60%. The DELIVER trial showed an 18% reduction in cardiovascular death and heart failure hospitalization with dapagliflozin in HFmrEF and HFpEF with ejection fraction above 40%, and notably included patients who were recently hospitalized and allowed both inpatient and outpatient initiation.

The mechanisms of benefit are multifaceted and include natriuresis and osmotic diuresis producing 1 to 2 kilograms of weight loss in the initial weeks, improved ventricular-arterial coupling, reduced epicardial fat, anti-inflammatory effects, and improved cardiac energetics through enhanced ketone body metabolism. Treatment is straightforward: dapagliflozin 10 mg or empagliflozin 10 mg daily, with no titration required.

Diuretics

Loop diuretics remain essential for congestion management in HFpEF, though volume management presents a particular challenge due to the narrow optimal filling pressure window in these patients. Both over-diuresis and under-diuresis produce symptoms, requiring careful titration.

The TOPCAT trial evaluated spironolactone in HFpEF and showed benefit in the Americas cohort with an 18% reduction in heart failure hospitalization, though no benefit was seen in the Russia/Georgia cohort, likely due to enrollment issues. Regional post-hoc analysis supports the use of spironolactone at 25 mg daily in HFpEF, particularly in patients with elevated natriuretic peptides and in the absence of significant renal dysfunction or hyperkalemia.

RAAS Inhibitors

The evidence for RAAS inhibitors in HFpEF is less compelling than in HFrEF. The CHARM-Preserved trial with candesartan showed only a borderline reduction in heart failure hospitalization without a mortality benefit. The PARAGON-HF trial with sacubitril/valsartan narrowly missed its primary endpoint, though subgroup analysis suggested benefit in women and in patients with an ejection fraction below 57%, prompting the FDA to expand the label to include ejection fraction "below normal." There is no Class I recommendation for RAAS inhibitors in HFpEF, though their use remains reasonable for managing comorbid conditions such as hypertension and chronic kidney disease with proteinuria.

GLP-1 Receptor Agonists (Obesity-HFpEF Phenotype)

The STEP-HFpEF and STEP-HFpEF DM trials evaluated semaglutide 2.4 mg weekly in obese patients with HFpEF and demonstrated significant improvement in symptoms as measured by the Kansas City Cardiomyopathy Questionnaire, improvement in 6-minute walk distance by 20 to 30 meters, substantial body weight reduction, decreased C-reactive protein levels, and reduced heart failure events. The mechanisms of benefit include weight loss, visceral and epicardial fat reduction, systemic anti-inflammatory effects, and improved insulin sensitivity. GLP-1 receptor agonists are emerging as a phenotype-specific therapy for obese HFpEF, though they have not yet been incorporated into formal heart failure guidelines as the evidence continues to evolve rapidly.

Other Therapies Under Investigation

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in the FINEARTS-HF trial, which showed a reduction in heart failure events with less hyperkalemia risk compared to spironolactone. Tirzepatide, a dual GIP/GLP-1 receptor agonist, showed positive results in the SUMMIT trial for HFpEF with obesity. Ziltivekimab, an anti-interleukin-6 antibody, is being investigated to target the inflammatory pathway. Exercise training, as demonstrated in HF-ACTION and Ex-DHF, improves peak VO2 and quality of life, with current recommendations targeting 20 to 30 minutes of moderate aerobic exercise 5 days per week.

Invasive Hemodynamic Assessment

Right Heart Catheterization

Resting hemodynamics provide the foundation of invasive assessment. A PCWP of 15 mmHg or greater confirms elevated filling pressures, while a right atrial pressure of 10 mmHg or greater suggests right-sided congestion. A passive leg raise maneuver that produces a 10 to 15 mmHg increase in PCWP supports the diagnosis when resting values are borderline. A rapid volume challenge with 500 mL of saline may be performed, where a PCWP rise to 18 mmHg or greater suggests limited left ventricular compliance.

Exercise Hemodynamics

Exercise hemodynamic assessment, performed with supine or upright bicycle ergometry during catheterization, provides critical diagnostic information when resting hemodynamics are inconclusive. A normal PCWP response remains below 25 mmHg at peak exercise, and a PCWP of 25 mmHg or greater with exercise represents the most widely used threshold for diagnosing exercise-induced HFpEF. A PCWP/cardiac output slope exceeding 2 mmHg/L/min suggests reduced left ventricular compliance with exercise-induced filling pressure elevation. When elevated PCWP of 15 mmHg or greater is accompanied by a PVR exceeding 2 Wood units, combined pre- and post-capillary pulmonary hypertension is present, indicating pulmonary vascular remodeling superimposed on elevated filling pressures.

<image> A hemodynamic waveform illustration showing right heart catheterization tracings in HFpEF. Display four panels stacked vertically: (1) Right atrial pressure tracing showing elevated mean RAP of 12 mmHg with prominent V waves, with normal tracing (mean 5 mmHg) overlaid in dashed gray for comparison. (2) Pulmonary artery pressure tracing showing mean PAP 32 mmHg (elevated). (3) Pulmonary capillary wedge pressure tracing at rest showing mean PCWP 18 mmHg with prominent V waves (labeled), with normal dashed overlay at 10 mmHg. (4) Exercise PCWP showing marked rise to 32 mmHg during supine cycling. Each panel should have a standard pressure scale in mmHg on the y-axis, time on x-axis, and clear waveform morphology with labeled a, c, v waves where appropriate. Use red for actual tracings and gray dashed for normal reference values. </image>

Phenotyping and Targeted Therapy

Obesity-Metabolic Phenotype

The obesity-metabolic phenotype, characterized by a BMI exceeding 30, metabolic syndrome, insulin resistance, and elevated epicardial fat, is the most rapidly growing HFpEF subgroup. Targeted interventions include SGLT2 inhibitors, GLP-1 receptor agonists such as semaglutide, structured exercise programs, and bariatric surgery in selected patients. Screening for obstructive sleep apnea is essential given a prevalence of 50 to 70% in this population, and treatment with CPAP improves both symptoms and hemodynamics.

Aging-Fibrotic Phenotype

The aging-fibrotic phenotype typically presents in elderly patients with concentric left ventricular hypertrophy, left atrial fibrosis and dilation, and chronotropic incompetence. Management focuses on SGLT2 inhibitors, mineralocorticoid receptor antagonists, rate-adaptive pacing in cases of severe chronotropic incompetence, and atrial fibrillation management.

Pulmonary Vascular Phenotype

The pulmonary vascular phenotype is defined by combined pre- and post-capillary pulmonary hypertension with a PVR exceeding 2 Wood units and right ventricular dysfunction. Aggressive decongestion is the first priority. Pulmonary vasodilators have not demonstrated benefit in Group 2 pulmonary hypertension in trials such as MELODY-1 and SoPHIE, and should be avoided unless PVR is markedly elevated and a carefully supervised hemodynamic assessment has been performed.

Atrial Fibrillation-Dominant Phenotype

Atrial fibrillation is present in 50 to 70% of HFpEF patients and exacerbates the hemodynamic derangement through loss of atrial kick, shortened diastolic filling time, and tachycardia-mediated obstruction to filling. Rhythm control is increasingly favored, extrapolating from CASTLE-AF evidence, although this data was primarily derived from HFrEF patients. Rate control with a target heart rate below 110 bpm is supported by the RACE II trial. Catheter ablation for atrial fibrillation in HFpEF has limited data and carries a higher recurrence rate than in the general atrial fibrillation population, with approximately 40 to 50% recurrence at 5 years due to left atrial dilation and fibrosis, although it remains reasonable for drug-refractory symptomatic atrial fibrillation.

Right Heart Failure Phenotype

The right heart failure phenotype, characterized by right ventricular dilation, elevated right atrial pressure, peripheral edema, and hepatic congestion, carries the worst prognosis among HFpEF phenotypes. Management centers on aggressive diuresis, with consideration of inotropic support during acute decompensation. Aggressive vasodilation should be avoided, as it may worsen right ventricular preload dependence.

Key Clinical Pearls

• HFpEF is a clinical diagnosis requiring integration of symptoms, imaging, biomarkers, and often invasive hemodynamics -- no single test is diagnostic in isolation
• Natriuretic peptides are less elevated in HFpEF than HFrEF, and may be falsely low in obese patients (BNP < 100 pg/mL does not exclude HFpEF in BMI > 35)
• Diastolic stress echocardiography is the most important noninvasive test when resting echo is indeterminate -- exercise E/e' > 15 has high specificity for elevated exercise PCWP
• SGLT2 inhibitors are the only drug class with robust, guideline-endorsed evidence for reducing HF hospitalizations in HFpEF -- prioritize initiation
• Always screen for specific etiologies that mimic HFpEF but have targeted therapies: cardiac amyloidosis (TTR or AL), Fabry disease (enzyme replacement), constrictive pericarditis (pericardiectomy), HCM (mavacamten)
• Weight loss of >= 5-10% in obese HFpEF patients significantly improves hemodynamics, exercise capacity, and quality of life -- GLP-1 RAs and bariatric surgery are emerging therapeutic pillars

References

• Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145:e895-e1032.
• Anker SD, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved). NEJM. 2021;385:1451-1461.
• Solomon SD, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER). NEJM. 2022;387:1089-1098.
• Kosiborod MN, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity (STEP-HFpEF). NEJM. 2023;389:1069-1084.
• Reddy YNV, et al. A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure with Preserved Ejection Fraction (H2FPEF). Circulation. 2018;138:861-870.

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