Heart Failure With Preserved Ejection Fraction: Diagnosis and Treatment

Definition and classification

Heart failure (HF) is a clinical syndrome in which the heart cannot deliver blood at a rate appropriate to tissue requirements unless filling pressures are elevated. The syndrome is therefore defined by symptoms and signs of congestion or impaired cardiac performance rather than by ejection fraction alone.

Heart failure with preserved ejection fraction (HFpEF) is characterized by:

• Symptoms and/or signs of HF.

• A left ventricular ejection fraction (LVEF) ≥50%.

• Objective evidence of structural or functional cardiac abnormality consistent with left ventricular diastolic dysfunction or increased filling pressures, including raised natriuretic peptides.

HF with mildly reduced ejection fraction (HFmrEF) is defined by symptoms and/or signs of HF with LVEF 41–49%. In this group, structural abnormalities such as left atrial enlargement or left ventricular hypertrophy, or echocardiographic evidence of impaired filling, make the diagnosis more likely. HFpEF and HFmrEF together account for approximately half of patients with symptomatic HF.

The distinction is clinically useful but not absolute. Ejection fraction is a continuous variable and echocardiographic measurement has meaningful variability. Patients with LVEF >40% have substantial morbidity and mortality, despite often having a greater burden of cardiovascular and non-cardiovascular comorbidity than patients with reduced EF.

Pathophysiology

Abnormal ventricular relaxation and increased filling pressures

The central hemodynamic abnormality in HFpEF is impaired diastolic function. The left ventricle may have apparently preserved global systolic emptying while exhibiting impaired relaxation, increased passive stiffness, or both. Consequently, relatively small increases in venous return can produce disproportionate increases in left ventricular and left atrial pressure.

At rest, filling pressures may be normal or only mildly elevated, particularly early in the disease or after treatment. During exertion, however, the limited diastolic reserve becomes evident, with a rise in left atrial and pulmonary pressures that contributes to exertional breathlessness and reduced exercise capacity.

Multiorgan and comorbidity-driven disease

HFpEF is heterogeneous rather than a single pathophysiologic entity. Hypertension and diabetes contribute to its development, and obesity is increasingly recognized as an important contributor. Older age, female sex, atrial fibrillation (AF), chronic kidney disease (CKD), and multiple non-cardiovascular conditions are frequent features.

A proposed disease pathway involves systemic and coronary microvascular endothelial inflammation associated with comorbidities. This may promote myocardial remodeling, fibrosis, impaired coronary microvascular function, and altered cardiomyocyte relaxation. Coronary microvascular rarefaction and myocardial fibrosis have been described in HFpEF, while nitrosative stress and abnormalities of cellular and molecular myocardial function may further impair contraction and relaxation.

Structural and vascular consequences

Common structural consequences include left ventricular hypertrophy, left atrial enlargement, and abnormalities of diastolic filling. Mitral regurgitation may develop through papillary-muscle displacement, annular dilatation, or both; progressive ventricular remodeling may also occur in primary valvular disease. Increasing severity of mitral regurgitation is associated with worse outcomes.

Pulmonary hypertension secondary to left heart disease may occur because elevated left-sided filling pressures are transmitted to the pulmonary circulation. Persistent pulmonary vascular disease can lead to right ventricular strain and dysfunction, which is associated with poor outcomes. Preserving right ventricular function is therefore an important therapeutic objective.

Exercise intolerance

Exercise limitation is multifactorial. In addition to elevated exercise-induced filling pressures, patients may have:

• Impaired chronotropic response and abnormal heart-rate recovery.

• Limited cardiac reserve.

• Pulmonary vascular and right ventricular abnormalities.

• Coronary microvascular dysfunction.

• Skeletal-muscle abnormalities.

• Impaired peripheral oxygen extraction.

• Abnormalities of preload reserve and autonomic function.

• Obesity, deconditioning, lung disease, anaemia, or other non-cardiac contributors.

These mechanisms explain why symptoms may be severe even when resting LVEF is normal.

Clinical presentation and symptoms

Typical symptoms include:

• Exertional dyspnoea.

• Fatigue and reduced exercise tolerance.

• Peripheral oedema.

• Breathlessness related to pulmonary congestion.

• Symptoms associated with AF or other comorbidities.

Signs of congestion may be absent in early HFpEF and in patients receiving effective treatment. This absence does not exclude the diagnosis.

HFpEF commonly occurs in older patients and is more frequent in women than HFrEF. AF, CKD, and non-cardiovascular comorbidities are also more prevalent. Clinical assessment must therefore distinguish HFpEF from disorders that produce similar symptoms, including lung disease, anaemia, obesity, and deconditioning. These conditions may coexist with HF and worsen the clinical syndrome, but symptoms alone do not establish HF in the absence of cardiac dysfunction.

Evaluation and physical examination

Evaluation begins with confirmation that a clinical HF syndrome is present and then establishes the EF phenotype. A careful assessment should address:

• The temporal pattern of dyspnoea and exercise limitation.

• Evidence of volume overload.

• Blood-pressure history and control.

• AF and other cardiovascular disease.

• Diabetes, obesity, CKD, lung disease, anaemia, thyroid or hepatic disease.

• Functional limitation and quality of life.

• Potential specific causes or mimics of HFpEF.

Physical findings may include evidence of pulmonary or systemic congestion, although signs can be subtle or absent. Assessment of blood pressure and volume status is particularly important because both hypertension and excess volume increase filling pressures.

Findings suggesting cardiac amyloidosis

Certain findings should raise suspicion for cardiac amyloidosis, including:

• Low or low-normal blood pressure in a patient previously described as hypertensive.

• Intolerance of beta-blockers or angiotensin-converting enzyme inhibitors.

• Previous bilateral carpal tunnel syndrome.

• Low-voltage ECG.

• Thickening of the interventricular septum, posterior wall, or right ventricular wall.

• Enlarged atria.

• Small pericardial effusion.

• Valve thickening.

These findings are not diagnostic in isolation but identify patients in whom a specific infiltrative cause requires consideration.

Diagnostic strategy

The diagnosis of HFpEF requires more than a normal LVEF. It requires concordance between the clinical syndrome and objective evidence of abnormal cardiac structure, function, or filling pressures.

A practical diagnostic sequence is:

• Establish symptoms and/or signs compatible with HF.

• Measure LVEF, usually by echocardiography.

• Assess cardiac structure and diastolic function.

• Measure natriuretic peptides where appropriate.

• Identify associated cardiovascular and non-cardiovascular disease.

• Investigate alternative diagnoses and specific causes.

• Use stress testing or invasive hemodynamics when resting assessment is inconclusive.

Several structured approaches have been developed to support diagnosis, including screening scores and the HFA–PEFF diagnostic algorithm. The greater the number of compatible abnormalities, the more likely HFpEF becomes.

Echocardiography

Echocardiography is central to diagnosis and management. It provides:

• LVEF measurement.

• Assessment of left ventricular structure and hypertrophy.

• Evaluation of left atrial size.

• Assessment of diastolic function and filling.

• Detection and quantification of mitral regurgitation.

• Evaluation of right ventricular structure and function.

• Identification of features suggesting infiltrative disease.

Abnormalities of diastolic function are common in HF with both reduced and preserved EF and may have prognostic significance. A normal LVEF does not imply normal myocardial mechanics; strain imaging may demonstrate impaired systolic function despite preserved EF, and left atrial strain has prognostic utility.

Cardiac magnetic resonance

Cardiac magnetic resonance (CMR) may assist with diagnosis and management when echocardiographic findings are inadequate or when myocardial infiltration, fibrosis, or another specific cardiomyopathy is suspected. The source material does not specify a complete CMR protocol or diagnostic thresholds.

Cardiopulmonary exercise testing

Cardiopulmonary exercise testing can help quantify exercise limitation and investigate its mechanism. It may identify abnormal hemodynamic reserve and distinguish cardiac limitation from pulmonary, skeletal-muscle, peripheral oxygen-extraction, or deconditioning mechanisms.

Diastolic stress testing

Exercise echocardiography and simultaneous invasive–echocardiographic assessment can reveal exercise-induced left atrial hypertension in patients whose resting studies are nondiagnostic. Exercise hemodynamics may therefore enhance recognition of early HFpEF.

Invasive hemodynamics

Right-heart catheterization can establish elevated filling pressures and characterize pulmonary hypertension. Passive leg raising during catheterization may provide additional diagnostic information by increasing venous return and unmasking abnormal preload reserve. Invasive exercise hemodynamics are particularly useful when symptoms are disproportionate to resting findings or when the diagnosis remains uncertain.

ECG, imaging, and electrophysiology

Electrocardiography

The ECG contributes to phenotyping and identification of associated disease. Low voltage is a warning sign for cardiac amyloidosis, particularly when accompanied by increased ventricular wall thickness on echocardiography. AF is common in HFpEF and may contribute to symptoms, elevated filling pressures, and impaired exercise capacity.

The source material does not provide a comprehensive ECG pattern or electrophysiologic diagnostic scheme for HFpEF.

Electrophysiology

Electrophysiologic testing is not described as a routine diagnostic component of HFpEF in the source material. Arrhythmia assessment should nevertheless be integrated into the clinical evaluation, particularly for AF and chronotropic incompetence.

Biomarkers and laboratory findings

Natriuretic peptides

Raised natriuretic peptides support the diagnosis by indicating increased cardiac wall stress and elevated filling pressures. They are incorporated into the diagnostic definition and diagnostic algorithms.

Normal natriuretic peptide concentrations do not invariably exclude HFpEF. Normal levels have been reported in patients with clinically recognized HFpEF, and interpretation must account for the broader clinical and echocardiographic context.

Natriuretic peptides may also be influenced by the patient phenotype. Obesity is among the conditions that can complicate diagnosis and may reduce the diagnostic value of peptide concentrations.

Troponin

High-sensitivity troponin may identify myocardial injury in HFpEF. Myocardial injury and impaired cardiac reserve are relevant components of the HFpEF phenotype, although the source material does not specify diagnostic cut-offs or treatment decisions based on troponin concentration.

Other laboratory assessment

The source material emphasizes the importance of identifying comorbidities and mimics, including renal, pulmonary, thyroid, hepatic, and hematologic disease. It does not provide a complete laboratory testing panel, specific reference ranges, or treatment thresholds.

Renal function and potassium are particularly relevant when therapies affecting the renin–angiotensin–aldosterone system or mineralocorticoid pathways are considered, but detailed monitoring schedules are not specified.

Treatment and management

General principles

Management is directed toward:

• Relief and prevention of congestion.

• Treatment of the underlying cause.

• Control of blood pressure and volume load.

• Management of cardiovascular and non-cardiovascular comorbidities.

• Reduction of HF hospitalization and cardiovascular events.

• Improvement of functional capacity and quality of life.

• Preservation of right ventricular function when pulmonary hypertension is present.

Because HFpEF is heterogeneous, treatment should be adapted to the dominant phenotype and associated disease rather than applied as a uniform regimen.

Diuretics and decongestion

Diuretics are recommended for patients with congestion to relieve symptoms and signs. They remain the mainstay of decongestive treatment and the cornerstone of therapy when fluid retention is present, including in pulmonary hypertension due to left heart disease.

The source material does not specify individual diuretic agents, starting doses, dose-escalation protocols, or targets for fluid removal. Treatment requires clinical assessment of volume status and attention to renal function and electrolytes.

Sodium-glucose cotransporter 2 inhibitors

SGLT2 inhibitors have become a standard component of contemporary HFpEF care. Dapagliflozin or empagliflozin is recommended in symptomatic HFpEF to reduce the risk of HF hospitalization or cardiovascular death. The same recommendation applies to HFmrEF.

The recommendation is Class I, Level A. The observed benefit in the cited evidence was driven by reduction in HF hospitalizations; a reduction in cardiovascular mortality was not demonstrated.

The source material does not provide drug doses or detailed initiation criteria.

Blood-pressure control

Blood pressure should be controlled because hypertension contributes to myocardial remodeling, increases filling pressures, and worsens the HFpEF syndrome. Management of blood pressure, volume load, and risk factors may lower filling pressures and pulmonary artery pressure.

The source material does not specify a universal blood-pressure target or a preferred antihypertensive drug sequence for HFpEF.

Renin–angiotensin–aldosterone system therapies

Evidence for angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, mineralocorticoid receptor antagonists, and sacubitril/valsartan has been less consistent in HFpEF than in HFrEF. These therapies may be considered in selected patients according to blood pressure, renal function, potassium, comorbidities, and the individual HF phenotype, but the source material does not provide a universal HFpEF treatment recommendation, dose, or monitoring protocol for these agents.

Patients with HFmrEF may derive benefit from treatments established in HFrEF, including renin–angiotensin system blockade and sacubitril/valsartan.

Sacubitril/valsartan

Sacubitril/valsartan has been evaluated across the EF spectrum, including HFpEF and HFmrEF. The source material indicates that treatment effects may vary with EF and clinical phenotype, but it does not provide a definitive dosing regimen or a general recommendation for all patients with HFpEF.

Mineralocorticoid receptor antagonists

Spironolactone has been studied in HFpEF, including in patients with CKD and across different EF ranges. The source material does not establish a universal recommendation, dose, or monitoring schedule for spironolactone in HFpEF.

Beta-blockers

Beta-blockers are frequently used in HFpEF because of coexisting hypertension, coronary disease, AF, or other indications. However, their role as disease-modifying therapy in HFpEF is not established in the source material. Beta-blockade may be relevant to exercise capacity and chronotropic incompetence, and withdrawal has been studied in relation to functional capacity.

Treatment should therefore be guided by a specific indication rather than by the assumption that beta-blockers provide the same benefit as in HFrEF.

Management of pulmonary hypertension

In pulmonary hypertension associated with left heart disease, the primary strategy is optimization of the underlying cardiac condition. Diuretics remain central when fluid retention is present.

Drugs approved for pulmonary arterial hypertension have not shown consistent benefit in HFpEF-associated pulmonary hypertension. Endothelin-receptor antagonists, including bosentan and macitentan, were associated with adverse effects such as fluid retention without demonstrated efficacy in the described populations. Sildenafil had no benefit in patients with a predominantly isolated post-capillary profile, whereas limited evidence suggested possible benefit in a predominantly combined post- and pre-capillary profile. These observations do not support routine use of pulmonary arterial hypertension therapies in HFpEF.

Nitrates, phosphodiesterase-5 inhibitors, and other agents

Studies of long-acting nitrates, inorganic nitrite, phosphodiesterase-5 inhibition, vericiguat, and ivabradine have been conducted in HFpEF populations. The source material does not support routine use of these therapies for general HFpEF management.

Obesity and metabolic phenotype

Obesity is both a potential contributor to HFpEF development and a major determinant of functional limitation. Trials of semaglutide in patients with obesity-related HFpEF, including patients with type 2 diabetes, and of tirzepatide in obesity-related HFpEF are identified in the source material. However, drug doses and a complete guideline position are not provided.

Management should address obesity as a disease-associated phenotype and distinguish obesity-related dyspnoea from cardiac congestion, while recognizing that both may coexist.

Exercise training and rehabilitation

Exercise intolerance is a major determinant of quality of life. Exercise training has been studied using aerobic exercise, moderate continuous training, high-intensity interval training, caloric restriction, and guideline-based physical-activity advice. The source material supports the clinical importance of exercise rehabilitation but does not specify a single preferred training prescription.

Exercise assessment should account for pulmonary disease, skeletal-muscle dysfunction, impaired peripheral oxygen extraction, autonomic dysfunction, and deconditioning.

Interatrial shunt devices and hemodynamic monitoring

Wireless pulmonary artery pressure monitoring and interatrial shunt devices have been investigated in HFpEF. The source material does not establish these approaches as routine treatment. Their role remains dependent on the specific evidence and clinical setting.

Guideline recommendations

The principal recommendations provided are summarized below.

The SGLT2 inhibitor recommendation is based on reduction in the composite outcome used in the relevant trials and pooled analyses, with the principal observed effect attributable to fewer HF hospitalizations rather than reduced cardiovascular mortality.

Prognosis

HFpEF is not benign. Patients have substantial morbidity and mortality and a significantly higher risk of death and hospitalization than the general population. The overall risk is amplified by the high prevalence of AF, CKD, obesity, diabetes, hypertension, pulmonary hypertension, and other comorbidities.

Hospitalization is an important marker of subsequent risk. Patients with previous HF hospitalization have a considerable burden of recurrent hospitalization and post-hospitalization mortality. Modes of death are heterogeneous and include both cardiovascular and non-cardiovascular causes.

Prognosis is influenced by:

• Age and comorbidity burden.

• Previous HF hospitalization.

• Degree of congestion.

• Pulmonary hypertension and right ventricular dysfunction.

• Renal dysfunction.

• AF.

• Myocardial injury.

• Exercise capacity and cardiac reserve.

• Specific etiologies such as amyloidosis.

• Structural abnormalities, including left atrial enlargement and significant mitral regurgitation.

Follow-up

Follow-up should be longitudinal and multidisciplinary, with repeated assessment of:

• Symptoms, exercise tolerance, oedema, and congestion.

• Blood pressure and volume status.

• AF and other clinically important arrhythmias.

• Renal function and electrolytes when clinically indicated.

• Response and tolerability to diuretics and SGLT2 inhibitors.

• Control of hypertension, diabetes, obesity, CKD, and other comorbidities.

• Functional capacity and health-related quality of life.

• Need for reassessment of EF, diastolic function, valvular disease, pulmonary pressures, or right ventricular function.

Because resting signs may be absent and symptoms may arise from several interacting mechanisms, persistent or unexplained limitation warrants reconsideration of alternative diagnoses, repeat echocardiography, cardiopulmonary exercise testing, stress echocardiography, CMR, or invasive hemodynamic assessment as appropriate. Patients with red flags for infiltrative cardiomyopathy require targeted evaluation rather than continued empirical treatment alone.