Diagnosing Heart Failure with Preserved Ejection Fraction: Current Approaches

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge worldwide, characterized by the presence of heart failure symptoms and signs in the context of a normal or near-normal left ventricular ejection fraction. This review synthesizes contemporary approaches to the diagnosis of HFpEF, providing a comprehensive overview of epidemiology, pathophysiology, risk factors, clinical features, and the evolving diagnostic landscape, including recent advances and guideline recommendations. The article emphasizes the complexity of HFpEF diagnosis, highlights key clinical and investigative strategies, and discusses implications for treatment and management in light of current evidence.

Introduction

Heart failure (HF) is a prevalent syndrome with substantial morbidity and mortality. Among its phenotypes, heart failure with preserved ejection fraction (HFpEF) has emerged as a predominant form, particularly in aging populations. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF is distinguished not by contractile dysfunction but by impaired diastolic function and ventricular compliance. The diagnostic process is complex, owing to nonspecific symptoms and overlapping comorbidities. Recent guidelines underscore the need for a multifaceted approach, integrating clinical, imaging, and biomarker data to accurately diagnose HFpEF and differentiate it from other causes of dyspnea and exercise intolerance.

Epidemiology / Disease Burden

HFpEF accounts for approximately 50% of all heart failure cases and its prevalence is rising in parallel with aging demographics and the global burden of comorbidities such as hypertension, obesity, and diabetes. Epidemiological studies reveal higher incidence in women and the elderly, with data from large registries (e.g., the Framingham Heart Study) illustrating increasing recognition over the past two decades. Despite similar or slightly lower short-term mortality rates compared to HFrEF, HFpEF patients experience a comparable burden of hospitalization, reduced quality of life, and substantial healthcare utilization. The chronic, relapsing nature of HFpEF and its association with multiple non-cardiac comorbidities amplify its societal and economic impact.

Pathophysiology

The underlying mechanisms of HFpEF are complex and multifactorial. Key pathophysiological features include left ventricular diastolic dysfunction, increased ventricular stiffness, abnormal relaxation, and elevated filling pressures. Systemic inflammation, endothelial dysfunction, and microvascular rarefaction contribute to myocardial remodeling. Comorbid conditions such as obesity, hypertension, and metabolic syndrome promote a pro-inflammatory milieu and oxidative stress, further impairing myocardial energetics and compliance. Unlike HFrEF, systolic function is typically preserved (ejection fraction ≥50%), but subtle abnormalities in contraction and relaxation may coexist. Recent research highlights the role of atrial dysfunction, pulmonary hypertension, and right ventricular involvement as contributors to clinical manifestations and prognosis.

Risk Factors

HFpEF is strongly associated with advanced age, female sex, hypertension, obesity, type 2 diabetes mellitus, atrial fibrillation, and chronic kidney disease. These risk factors drive myocardial remodeling and dysfunction via neurohormonal activation, impaired vascular compliance, and systemic inflammation. Hypertension and left ventricular hypertrophy are especially important in the genesis of diastolic dysfunction. The clustering of multiple risk factors is common, with multimorbidity compounding the diagnostic challenge and influencing disease trajectory and response to therapy.

Clinical Features

The clinical presentation of HFpEF is heterogeneous and often subtle, with symptoms including exertional dyspnea, fatigue, exercise intolerance, and peripheral edema. Physical examination may reveal elevated jugular venous pressure, pulmonary rales, and an S4 heart sound, but these findings are not specific. The overlap with other conditions such as chronic obstructive pulmonary disease, obesity, and deconditioning complicates clinical assessment. A high index of suspicion is warranted, particularly in at-risk populations with compatible symptoms and comorbidities.

Diagnosis

Diagnosing HFpEF requires a systematic approach integrating patient history, physical examination, laboratory assessment, and multimodality imaging. The cornerstone of diagnosis is the demonstration of heart failure symptoms and signs in the presence of a preserved left ventricular ejection fraction (LVEF ≥50%). Natriuretic peptide levels (BNP or NT-proBNP) are helpful but may be lower than in HFrEF, particularly in obese patients. Echocardiography is central, allowing assessment of diastolic dysfunction (e.g., E/e' ratio, left atrial enlargement, abnormal transmitral flow patterns) and exclusion of alternative causes. Advanced imaging modalities such as cardiac MRI may be utilized for tissue characterization and assessment of fibrosis. In selected cases, invasive hemodynamic assessment during exercise or volume challenge is warranted to confirm elevated filling pressures. Recent diagnostic algorithms, such as the H2FPEF and HFA-PEFF scores, provide structured approaches to guide clinicians through the diagnostic process, balancing sensitivity and specificity.

Treatment & Management

Currently, management of HFpEF focuses on symptom relief, optimization of comorbid conditions, and prevention of hospitalizations. Diuretics are used to control congestion, but caution is advised to avoid hypovolemia. Rigorous blood pressure control, glycemic management, and treatment of atrial fibrillation are essential. Non-pharmacological strategies, including exercise training and dietary modifications, also confer benefit. Unlike HFrEF, evidence for mortality-reducing therapies is limited. Mineralocorticoid receptor antagonists and SGLT2 inhibitors have demonstrated promise in recent clinical trials, although benefits are modest and patient selection is critical. Ongoing research is exploring novel therapeutic targets, including anti-inflammatory and antifibrotic agents.

Recent Advances / Emerging Therapies

The therapeutic landscape of HFpEF is evolving rapidly. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for diabetes, have shown significant reductions in heart failure hospitalizations in HFpEF populations, as demonstrated in the EMPEROR-Preserved and DELIVER trials. Novel agents targeting myocardial fibrosis, inflammation, and the nitric oxide–cGMP pathway are under investigation. Precision medicine approaches, including phenomapping and biomarker-guided therapy, hold promise for individualized management. Additionally, device-based therapies such as interatrial shunt devices are being evaluated for patients with refractory symptoms.

Guideline Recommendations

International guidelines from the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA) emphasize the need for a comprehensive diagnostic approach, combining clinical, biomarker, and imaging criteria. The use of natriuretic peptides, echocardiographic assessment of diastolic function, and structured diagnostic scores is recommended to improve diagnostic accuracy. Management focuses on symptom control, comorbidity optimization, and patient education. Recent updates incorporate SGLT2 inhibitors as a therapeutic option, reflecting emerging evidence. Multidisciplinary care models are encouraged to address the complex needs of HFpEF patients.

Conclusion

Diagnosing HFpEF remains a nuanced and evolving challenge, necessitating a structured, multifaceted approach that integrates clinical assessment, advanced imaging, biomarker analysis, and, where indicated, invasive hemodynamics. As understanding of HFpEF pathophysiology expands, so too does the potential for targeted therapies and improved patient outcomes. Adherence to evidence-based guidelines, ongoing research, and the development of individualized management strategies will be essential in addressing the growing burden of HFpEF in the coming years.