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#heart-failure #HFpEF #echocardiography #diastolic-function #classification #diagnosis

Heart Failure with Preserved Ejection Fraction (HFpEF)

Contents. #Details · #Key Facts · #Epidemiology · #Pathophysiology · #Diagnosis · #Contradictions / Open Questions · #Connections · #Sources

Management. The treatment pathway — outcome trials, SGLT2i and MRA, obesity-HFpEF, iron and beta-blockers — is on concepts/HFpEF-Management.

Details

HFpEF is defined by HF symptoms and/or signs, LVEF ≥50% that has never previously been below 50%, and objective evidence of cardiac structural or functional abnormality consistent with diastolic dysfunction or raised filling pressures, supported by raised natriuretic peptides. The more abnormalities present, the higher the likelihood. The "never previously <50%" clause is new in 2026 and keeps recovered-EF patients out of this bucket — they are classified as HFimpEF on the parent page instead. In practical terms it is a syndrome of impaired relaxation and increased chamber stiffness driven by systemic comorbidity rather than by a myocardial contractile defect, which is why two decades of trials copying the HFrEF neurohormonal strategy failed. (sources/HF-ESC-2026, rating: very high)

It differs from HFrEF in three ways: diagnosis is probabilistic rather than a single measurement, no therapy has reduced mortality, and comorbidity control carries as much of the burden as the drugs. What changed in 2026 is that HFpEF now has two foundational drugs rather than one — an SGLT2 inhibitor and an MRA, both Class I, Level A.

Part of entities/Heart-Failure — the parent overview, which covers the syndrome definition, staging, decompensated HF, advanced HF and special populations.

Key Facts

Epidemiology

Pathophysiology

Comorbidity-driven mechanisms

Systemic comorbidity — hypertension, obesity, T2DM, CKD, AF — promotes coronary microvascular inflammation, cardiomyocyte hypertrophy and interstitial fibrosis. This, rather than a contractile deficit, is the dominant substrate. COPD activates the same endothelial inflammatory pathway and adds a mechanical problem: tachycardia shortens diastolic filling, bronchial obstruction reduces venous return, and pericardial constraint further impairs filling. (sources/HF-ESC-2021, rating: very high; sources/copd-hfpef-eschf-2025, rating: high)

Obesity-HFpEF phenotype

Obesity produces a phenotype distinct from non-obese HFpEF: concentric remodelling, RV dilatation and dysfunction, pericardial restraint and lower exercise capacity, driven by epicardial fat thickness and volume. H2FPEF weights obesity as its largest single component (2 of 9 points). See entities/Obesity and concepts/Visceral-Adiposity. (sources/obesity-cv-aha-2021, rating: very high; sources/HF-AHA-2022)

Infiltrative and genetic causes

Atrial myopathy

Mechanical atrial dysfunction — impaired LA reservoir strain, elevated LAVi — is an independent and better predictor of HF hospitalisation and cardiovascular mortality than AF itself. LASr correlates with histological atrial fibrosis, and a subset shows "disproportionate LA myopathy" exceeding what LV dysfunction alone predicts. See concepts/Atrial-Cardiomyopathy and concepts/Left-Atrial-Strain. (sources/atrial-cmp-esc-2025, rating: high)

Cardiomyocyte stiffness

Increased passive stiffness arises from extracellular matrix and intrinsic sarcomeric changes. Titin contributes through isoform shift, phosphorylation (N2Bus hypophosphorylation plus PEVK hyperphosphorylation, with cGMP-PKG signalling impaired) and acetylation via reduced SIRT1. The therapeutic corollary has been negative: RELAX, VITALITY and SOCRATES all failed. Full mechanism: concepts/Titin-PTMs and concepts/Titin-Isoform-Switch. (sources/TTN-CVResearch-2022, rating: high)

Clonal haematopoiesis

TET2 clonal haematopoiesis is 2.4-fold enriched in HFpEF — a gene-specific association, with TET2 loss of function overactivating the NLRP3 inflammasome. Full mechanisms: concepts/Clonal-Hematopoiesis. (sources/ch-aha-2026, rating: very high)

Post-capillary pulmonary hypertension

Post-capillary PH is present in at least half of symptomatic HFpEF and portends worse prognosis, but its pulmonary vascular component is untreatable: PDE5 inhibitors are ineffective (RELAX, NEAT-HFpEF) and riociguat failed. The only positive signal is procedural — pulmonary-artery denervation halved clinical worsening in PADN-HF-PH — but the trial was open-label without a sham control and its hard endpoints were individually null. Group 2 PH framework: concepts/Pulmonary-Hypertension; the trial in full: concepts/Pulmonary-Artery-Denervation. (sources/HF-AHA-2022, rating: very high; sources/padn-hf-ph-nejm-2026, rating: high)

Diagnosis

Guideline definitions: ESC versus ACC/AHA

Simplified echocardiographic criteria (ESC 2026, Table 10) — probability rises with the number of abnormal parameters:

Criterion Threshold
LV hypertrophy LV mass index ≥95 g/m² (female) or ≥115 g/m² (male), or relative wall thickness >0.42
LA dilatation >34 mL/m² in sinus rhythm, >40 mL/m² in AF
Raised filling pressure E/e′ >9 at rest (≥15 more specific, less sensitive)
Pulmonary pressure Estimated systolic PA pressure >35 mmHg, or TR velocity at rest >2.8 m/s

(Table: sources/HF-ESC-2026, rating: very high)

These supersede the 2021 criteria (E/e′ ≥13, mean e′ <9 cm/s, LAVi >34 mL/m²) and are deliberately looser — specificity traded for a pathway elderly patients can complete.

Prediction scores

Score Structure Thresholds
H2FPEF (0–9) Heavy (BMI >30) 2 pts; Hypertensive (≥2 agents) 1; AF 3; Filling (E/e' >9) 1; Elderly (>60) 1; Pulmonary hypertension (PASP >35 mmHg) 1 <2 low; 2–5 intermediate (40–80%); ≥6 high. Each point doubles the odds (OR 1.98; c-statistic 0.841)
HFA-PEFF (ESC) Stepwise: pretest probability → comprehensive echo + natriuretic peptide score → exercise or invasive testing if intermediate Formalises the pathway rather than scoring a single number

(Table: sources/HF-AHA-2022, sources/echo-hfpef-ase-2025, rating: very high)

Intermediate scores should proceed to exercise echocardiography or invasive haemodynamics. The 2025 ASE guideline formally incorporates both scores into the diagnostic workup.

ASE 2025 stepwise algorithm

  1. History, examination, chest radiograph, laboratory tests and natriuretic peptides — exclude non-cardiac dyspnoea.
  2. Comprehensive echocardiography — exclude significant valvular disease, CAD, non-cardiac PH, amyloidosis, HCM and constriction.
  3. Apply the LAP estimation algorithm (e', E/e', TR velocity/PASP as primary variables).
  4. Elevated LAP → HFpEF confirmed. Normal LAP → diastolic exercise echo or RHC.
  5. Exercise echo positive → HFpEF confirmed; negative → non-cardiac dyspnoea; inconclusive → RHC.

Invasive reference standard: rest mean PCWP >15 mmHg, or exercise mean PCWP ≥25 mmHg at end-expiration. (sources/echo-hfpef-ase-2025, rating: very high)

LV diastolic dysfunction and exercise echocardiography

The two-step ASE definition of diastolic dysfunction and the exercise-echo thresholds that separate definite, likely and normal are set out in full on concepts/LV-Diastolic-Function. What matters specifically for HFpEF is that up to 50% of patients have normal resting filling pressures that rise only with exercise, so a normal resting study does not exclude the diagnosis — and that LAVi was demoted from primary to secondary in 2016 in favour of LARS ≤18%, because it tracks acute LAP change poorly and enlarges for non-diastolic reasons (AF, MR, high-output states). (sources/echo-hfpef-ase-2025, rating: very high; sources/lvdiastolic-echo-jaccimaging-2020, rating: high)

Latent HFpEF — invasive provocation

When resting echocardiography is non-diagnostic, right heart catheterisation with provocation can unmask disease present only under load.

Provocation Threshold Interpretation
Exercise Peak PAWP >25 mmHg Diagnostic of HFpEF
Exercise PAWP/CO slope >2 WU Suggestive
Fluid challenge (500 mL rapid saline) PAWP >18 mmHg Suggestive
Passive leg raise PAWP ≥19 mmHg Suggestive

(Table: sources/rhc-hf-ehj-2025, rating: high)

Contradictions / Open Questions

Connections

Sources