HFpEF, Diastolic dysfunction, Global longitudinal strain, Left atrial reservoir strain, Right ventricular systolic pressure, HFA-PEFF, HF2PEF, Echocardiography

HFpEF accounts for approximately half of all heart failure cases, and its prevalence is rising with the aging population [1]. Unlike HFrEF, which is defined by reduced systolic function, HFpEF is diagnosed clinically: patients must have heart failure symptoms (exertional dyspnea, edema, orthopnea), preserved ejection fraction (EF) ≥ 50% and evidence of elevated LV filling pressures via echocardiography, natriuretic peptides, or invasive hemodynamics. The diagnosis is challenging because multiple cardiac and non-cardiac conditions mimic HFpEF, and specific subtypes (e.g., infiltrative disease, cardiotoxicity) require targeted workup where early diagnosis can alter the disease course [1,4]. This review summarizes current diagnostic algorithms and echocardiographic tools to help general internists recognize HFpEF, distinguish it from mimickers, and initiate appropriate management.

This narrative review synthesizes current guidelines, landmark trials, and key literature on HFpEF pathophysiology, diagnostic algorithms, echocardiographic parameters, and guideline-directed medical therapy. Priority was given to clinical practice guidelines from the AHA/ACC/HFSA, ACC Expert Consensus Decision Pathways, and the American Society of Echocardiography. A hypothetical case is used for educational purposes in a case-based review format. All patient data are fictional. The case is introduced at the beginning of the review and revisited at the diagnosis and management sections.

The 2022 AHA/ACC guidelines define four stages of heart failure:

• Stage A (At risk): Risk factors present (obesity, hypertension, diabetes, chronic kidney disease, cardiotoxin exposure) but no symptoms or structural disease.
• Stage B (Pre-Heart Failure): Patients are asymptomatic, but they demonstrate structural abnormalities (e.g., chamber enlargement or hypertrophy, ventricular or atrial strain, wall motion abnormalities), increased filling pressures at rest or with stress, and elevated cardiac biomarkers.
• Stage C (Symptomatic heart failure): Structural disease with current or prior symptoms.
• Stage D (Advanced heart failure): Refractory symptoms despite optimized therapy

The core pathophysiology involves a stiff, poorly relaxing left ventricle that cannot fill adequately at normal pressures [7]. Four interrelated mechanisms drive this process [8,11]:

1. Impaired relaxation: Delayed LV relaxation reduces early diastolic filling. End-diastolic pressures increase while left atrial and pulmonary capillary wedge pressures may remain normal. The left atrium compensates with stronger late-diastolic contraction, but this mechanism fails during stress or exercise, leading to underfilling and eventually elevated left atrial pressures with LA remodeling [25]. Mild slowing of LV relaxation occurs with normal aging and should not be equated with HFpEF in asymptomatic patients [8,13,25].
2. Myocardial stiffening: Chronic inflammation and fibrosis—driven by diabetes, hypertension, and neurohumoral activation—increase chamber stiffness, raising filling pressures. Patients with smaller left ventricles and low afterload may have a “normal” EF despite intrinsically impaired contractility—a key reason EF alone is insufficient to assess cardiac function.
3. Maladaptive ventricular-arterial coupling: Aging and hypertension stiffen the arterial system, increasing ventricular workload. Maladaptive coupling leads to increased contractile resistance, causing the heart in turn to work harder to maintain an adequate cardiac output (Figure 1). Small changes in volume status can produce large blood pressure swings, particularly during exercise.
4. Limited cardiac reserve: HFpEF is fundamentally a disorder of exercise intolerance. The heart cannot augment output appropriately during exertion due to chronotropic incompetence and inadequate contractile reserve, accentuated in patients with obesity, who have higher circulating blood volume and greater myocardial demand [24].

Figure 1. Progression of HFpEF illustrated through pressure-volume loops across four stages. Early diastolic dysfunction causes myocardial stiffening and impaired relaxation, elevating end-diastolic pressure while reducing stroke volume. Ventricular-arterial maladaptive coupling and decreased cardiac reserve led to elevated left atrial pressures and higher isovolumetric contractile pressures, culminating in symptomatic heart failure with pulmonary congestion and dyspnea [11,19,24,25].

Clinical implication for the internist

These mechanisms explain why HFpEF patients can be asymptomatic at rest but develop dyspnea with exertion—and why resting echocardiographic parameters may be normal in early disease.

When patients present with heart failure signs and symptoms, providers should exclude cardiac and non-cardiac mimickers of heart failure, employ diagnostic scoring systems, and use echocardiographic imaging to assess structural abnormalities and diastolic dysfunction. Mimickers include parenchymal or vascular lung disease, anemia, neuromuscular disease, renal insufficiency, coronary ischemia, pericardial disease, valvular damage, arrhythmias, infiltrative disorders (e.g. amyloidosis, sarcoidosis), genetic storage disorders (e.g. Fabry disease), and high output heart states.

HFpEF is a clinical diagnosis requiring heart failure symptoms, LVEF ≥ 50%, and at least one of the following [5,8,13]:

1. Abnormal diastolic parameters (e.g., E/E’ ≥ 15, which is an echocardiogram estimation of left ventricular filling pressures)
2. Structural heart disease which includes LA or LV dilation, LV hypertrophy, and/or moderate to severe valvular disease.

These findings are corroborated by elevated natriuretic peptides (Ambulatory: BNP ≥ 35 or NT-proBNP ≥ 125; hospitalized: BNP ≥ 100 or NT-proBNP ≥ 300) or objective evidence of congestion either at rest or with exercise. Approximately 35% of patients with HFpEF have elevated filling pressures only during exercise, making resting studies insufficient to rule out the diagnosis [19]. A normal resting echocardiogram does not rule out HFpEF; additional stress testing should be considered. Importantly, diastolic dysfunction alone does not equate HFpEF—asymptomatic patients with diastolic dysfunction should be categorized as at risk or pre-heart failure.

BNP and NT-proBNP support the diagnosis and severity of heart failure, but have important limitations in HFpEF [1,29]. Approximately 29% of patients with catheterization-confirmed HFpEF have BNP < 100 pg/mL, and levels are disproportionately lower in patients with obesity [1,5,26]. Conversely, BNP can be elevated in non-heart failure conditions (atrial fibrillation, renal failure, pulmonary disease, etc) [1,19]. A normal BNP does not rule out HFpEF. Prognostically, natriuretic peptides predict hospitalizations and mortality, even in patients with GFR < 60 ml/min/1.73 m [26–28,30].

Diagnostic scoring systems for HFpEF include:

1. HF2PEF score: weighted score ranging from 0 to 9 based on clinical variables, such as hypertension, body mass index, atrial fibrillation, pulmonary hypertension, elderly age, and filling pressures. Scores 0–2 indicate low probability, 2–5 intermediate probability requiring exercise testing, and >5 showing high probability for HFpEF [8].
2. HFA-PEFF score: Stepwise algorithm in the ambulatory setting, requiring echocardiography and natriuretic peptide scores, functional testing including diastolic stress tests or right heart catheterization, and special imaging, biopsy, or genetic testing. Scores 5 or greater are diagnostic for HFpEF [20].
3. Exercise Stress Echocardiography (ESE score) [17]: Incorporation of resting Left Atrial Reservoir Strain (LARS) <20%, exercise septal E/e’ ratio >13, and increase in B lines with exercise as independent predictors of HFpEF. Scoring ranges from 0 to 5, with 1–2 points having 60–80% probability of HFpEF, and ≥3 having near 100% probability of HFpEF.

When scores indicate high probability of HFpEF (>90%), formal filling pressure confirmation is practically not required—all three scoring systems already incorporate filling pressure proxies [20].

Diagnostic echocardiogram parameters for HFpEF include:

1. Left ventricular diastolic dysfunction [8,13]: By ASE criteria, diastolic dysfunction is present when more than half of the following are abnormal:

• Average E/e’ >14
• Septal e’ <7 cm/s or lateral e’ <10 cm/s
• TR velocity >2.8 m/s
• LA volume index >34 ml/m²

Diastolic dysfunction in the absence of symptoms does not equate to HFpEF. Asymptomatic individuals should be categorized into at-risk or pre-heart failure depending on structural or biomarker abnormalities.

2. LV global longitudinal strain [3,8]: GLS measures myocardial fiber shortening during systole, detecting intrinsic systolic impairment despite a normal EF. This is particularly useful in patients with pulmonary congestion where a primary myocardial cause is uncertain. As diastolic dysfunction often progresses into systolic dysfunction, an abnormal GLS (less negative than -16%) in dyspneic patients suggests underlying LV filling abnormalities.

3.Left atrial reservoir strain (LARS) [12]: LARS measures total LA deformation at end-systole via speckle tracking echocardiography and outperforms E/e’, GLS, and LA volume in differentiating HFpEF from noncardiac dyspnea. The 2025 ASE guidelines establish resting LARS <18% as the optimal cutoff for elevated LV filling pressures [8]. Exercise testing can unmask abnormal LA strain in patients with normal resting values [14]. The LA stiffness index (E/e' ÷ LARS) has higher diagnostic utility for HFpEF than either parameter alone [8].

4.Right ventricular systolic pressure (RVSP) [8–10]: RVSP noninvasively estimates pulmonary artery systolic pressures (PASP) via TR jet velocity with a modified Bernoulli equation. In the absence of primary pulmonary or vascular disease, elevated RVSP reflects chronic left-sided filling pressure elevation. RVSP >35 mmHg was present in 83% of HFpEF patients in a community-based study and was higher than preclinical hypertensive heart disease, supporting its prognostic value [10]. RVSP can identify higher risk patients who may benefit from more aggressive therapy [9] and can guide volume management in low-resource settings when right heart catheterization is unavailable.

• When ordering a TTE for suspected HFpEF, specifically request diastolic function assessment, including E/e’ ratio, LA volume index, TR velocity, and (if available), GLS and LA reservoir strain. These measurements can be technically difficult to obtain, however, and some sonographers may not be skilled enough to capture this data.
• If resting parameters are normal but clinical suspicion remains (H2FPEF score 2–5), consider stress echocardiography to unmask exercise-induced elevation of filling pressures (exercise E/e’ >14–15) (Table 1).
• If diagnosis remains uncertain after noninvasive testing, refer to cardiology for invasive hemodynamic assessment.

Management of HFpEF encompasses diagnostic monitoring, imaging, hemodynamic assessment, and pharmacologic therapy. Current practice guideline recommendations include [1]_:

Natriuretic peptides

• Screening BNP for evaluation of dyspnea (Class I), serial BNP for chronic HFpEF risk stratification (Class I), and admission BNP for prognosis in acute decompensation (Class I).
• STOP HF trial showed reduction of LV dysfunction and new onset heart failure with routine BNP screening.
• Pre-discharge BNP for trajectory assessment (Class II, LOE A)

Echocardiography and imaging

• Initial TTE for suspected cardiopulmonary dyspnea (Class I). Repeat echocardiography for clinical change or after initiation of guideline-directed medical therapy (GDMT) (Class I).
• EF reassessment timing: 40 days post-MI, 90 days post-revascularization, 90 days post-GDMT initiation
• Cardiac MRI or CT when echocardiography is inadequate for EF assessment (Class I).

Hemodynamic monitoring

• Right heart catheterization for persistent or worsening symptoms despite medical therapy (Class IIb). Routine pulmonary artery (PA) catheter monitoring has not shown mortality benefit (ESCAPE, GUIDE-HF), though the CHAMPION trial demonstrated a 28% reduction in HF hospitalizations with implantable PA monitoring, although this was a nonblinded study.
• CardioMEMS (Class IIb) may benefit patients with recurrent admissions but requires dedicated infrastructure.

Exercise and functional capacity testing

• Cardiopulmonary Exercise testing and 6-minute walking tests (Class I) are useful to evaluate for candidacy for advanced HF therapies (LVAD, transplantation).

HF with improved ejection fraction

• Continue GDMT indefinitely, even if asymptomatic (Class I). Withdrawal of GDMT in patients whose LVEF had improved to ≥ 50% resulted in relapse of cardiomyopathy in 40% of patients [21].

Additional screening

• Patients at risk for sleep apnea should undergo formal sleep assessment (Class II, LOE A)
• First degree relatives of patients with genetic or inherited cardiomyopathies should undergo genetic screening and counseling

Clinical judgment remains paramount, particularly in resource-limited settings where PA monitoring is not routinely available.

Patients with established HFpEF should undergo workup for underlying etiology (ischemic, infiltrative, toxic, infectious, etc.) while initiating GDMT. The 2023 ACC Expert Consensus Decision Pathway recommends SGLT2 inhibitors for all HFpEF patients without contraindications, with additional consideration of MRAs and ARNi particularly in patients with LVEF at the lower end of the preserved range. The 2025 AHA/ACC hypertension guidelines recommend RAAS inhibitors to target SBP <130 mmHg in HFpEF and advise against beta-blockers for blood pressure management in HFpEF given negative chronotropic effects.

Key Pharmacologic Considerations:

• Diuretics (Class I): OPTIMIZE-HF showed reduced 30-day mortality and HF hospitalization with discharge diuretics. Loop diuretics are preferred, and thiazides can be added for refractory edema.
• SGLT2 inhibitors (Class II, LOE A): A meta-analysis of EMPEROR-Preserved and DELIVER showed a consistent 20% reduction in composite of HF hospitalization and CV death (HR 0.80; 95% CI 0.73-0.87), though the benefit was driven primarily by reduced hospitalizations rather than CV mortality. SGLT2 inhibitors are especially beneficial for diabetic management and CKD [2,22].
• MRAs (Class II, LOE B): The TOPCAT trial showed a modest reduction in HF hospitalizations with spironolactone, though the primary composite endpoint was not met and geographic cohort heterogeneity raised questions about adherence and HFpEF diagnosis [19,37]. FINEARTS-HF showed finerenone reduced composite HF events and CV death, although also driven by hospitalization reduction, with higher hyperkalemia rates versus placebo [35]. Monitor potassium closely, especially with concurrent RAAS inhibitors and/or reduced eGFR [31].
• ARNi (Class II, LOE B): PARAGON-HF did not meet primary endpoint overall, but subgroup analysis showed benefit with LVEF 40-55%. ARBS have not shown benefit with cardiovascular mortality, all-cause mortality, or HF hospitalizations [23].
• Beta Blockers: No HFpEF specific benefit. Consider in patients with history of myocardial infarction and/or atrial fibrillation for rate control [1,2].
• GLP1 receptor agonists: STEP-HFpEF showed meaningful improvements in symptoms, functional capacity, and weight loss in patients with obesity and HFpEF [35,36]. Consider in patients with obesity, diabetes, and CKD.
• Comorbidity Management: HFpEF is a systemic disease with multiple phenotypes (obesity related, ischemic, vascular, fibrotic). Management requires treating underlying contributors, including AF, obesity, hypertension, diabetes, anemia, and sleep apnea, as emphasized in the 2023 ACC Expert Consensus Decision Pathway [2].
• When to refer to cardiology: Equivocal, diagnostic uncertainty, need for stress echocardiography or invasive hemodynamics, evaluation for specific etiologies (amyloidosis, infiltrative disease), or advanced HF therapies. Additionally, because coronary disease is common in HFpEF patients, revascularization can be considered to improve cardiac function and survival [24].

Figure 2. Diagnostic and management framework for HFpEF. This flow sheet diagram maps out various cardiac and non-cardiac mimickers of heart failure and the diagnostic tools for HFpEF. It also emphasizes management of chronic comorbidities and the multidisciplinary approach to heart failure.

This case-based review illustrates that HFpEF diagnosis requires integration of clinical context, natriuretic peptides, validated scoring systems, and targeted echocardiographic parameters including GLS, LA reservoir strain, and RVSP. HFpEF frequently coexists with conditions that mimic or compound the presentation—including liver disease, pulmonary hypertension, and infiltrative cardiomyopathy—making systematic evaluation of mimickers essential before attributing the clinical picture to HFpEF alone. For the general internist, the most impactful practice changes are:

1. Maintain clinical suspicion for HFpEF even when BNP and resting echo are unremarkable; request diastolic function testing and strain imaging and consider stress echocardiography when resting studies are equivocal.
2. Initiate SGLT2 inhibitors early in confirmed HFpEF and address modifiable comorbidities.
3. Recognize red flags for specific etiologies—particularly cardiac amyloidosis—that require targeted workup and referral. Early and accurate phenotyping and target therapies can meaningfully change outcomes.

HFpEF is a systemic disease that benefits from multidisciplinary collaboration among internists, cardiologists, hepatologists, nephrologists, and pulmonologists. Early recognition, accurate phenotyping, and timely initiation of guideline-directed therapy can meaningfully improve outcomes.

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