What is the role of diastolic dysfunction in causing symptoms of heart failure with preserved ejection fraction?

Diastolic Dysfunction is Central but Not Solely Responsible for HFpEF Symptoms

Diastolic dysfunction is a defining pathophysiologic feature of HFpEF that contributes to elevated left ventricular filling pressures and symptoms, but it operates within a broader systemic cardio-metabolic syndrome involving impaired systolic mechanics, vascular stiffness, metabolic derangements, and chronic inflammation 1, 2.

The Traditional Diastolic Paradigm

Historically, HFpEF was conceptualized purely as "diastolic heart failure," where impaired ventricular relaxation and reduced compliance lead to elevated filling pressures despite preserved ejection fraction 3, 4. This framework identified three progressive stages:

• Stage I: Impaired early diastolic filling with normal pressures
• Stage II (Pseudonormalization): Elevated left atrial pressures masking diastolic abnormalities on Doppler—a critical diagnostic pitfall where severe dysfunction appears normal 3
• Stage III: Restrictive filling with markedly reduced compliance

The transition from asymptomatic diastolic dysfunction to symptomatic HFpEF correlates more strongly with worsening ventricular distensibility (stiffness) than with further deterioration in relaxation 5.

The Systolic Contribution: Beyond Ejection Fraction

Recent evidence demonstrates that subclinical systolic dysfunction coexists with and contributes to HFpEF symptoms, challenging the pure diastolic model 6, 7:

• Global longitudinal strain (GLS) and first-phase ejection fraction (EF1) decline early in HFpEF evolution, often before conventional ejection fraction drops 6, 7
• A GLS cutoff of -18% differentiates symptomatic HFpEF from asymptomatic diastolic dysfunction with 73% sensitivity 6
• EF1 decreases significantly at week 2 in HFpEF models, preceding changes in standard ejection fraction 7
• Both systolic and diastolic mechanical dyssynchrony are impaired in HFpEF patients 6

This means the preserved ejection fraction in HFpEF masks underlying longitudinal systolic impairment that directly correlates with symptom burden.

Diagnostic Limitations of Current Diastolic Grading

A critical caveat: the 2025 ASE diastolic function algorithm shows a 32.8% false-negative rate in ambulatory HFpEF, with >60% of patients graded as "normal" or "Grade 1" having resting pulmonary artery wedge pressure ≥15 mmHg at catheterization 8. Among decompensated HFpEF patients, 51.1% revert to normal or Grade 1 grading after recompensation 8. The stress imaging criteria recommended by ASE detect only 9.5% of cases undergoing simultaneous hemodynamic exercise testing 8.

Therefore, diastolic grading cannot be used in isolation to exclude HFpEF and must be interpreted within HFpEF-specific diagnostic frameworks like H2FPEF or HFA-PEFF scores 1, 8.

The Systemic Cardio-Metabolic Framework

Current guidelines recognize HFpEF as a heterogeneous syndrome driven by multiple phenotypes 9, 1:

• Metabolic phenotype: Visceral adiposity, insulin resistance, mitochondrial dysfunction impairing cardiac energetics 2, 10
• Inflammatory phenotype: Chronic systemic inflammation driving myocardial fibrosis 2, 10
• Vascular phenotype: Arterial stiffness and endothelial dysfunction 2
• Atrial phenotype: Atrial fibrillation with loss of atrial kick exacerbating filling abnormalities 1

This explains why SGLT2 inhibitors (EMPEROR-Preserved, DELIVER trials) and GLP-1 receptor agonists succeed where traditional neuro-hormonal blockade failed—they target the underlying metabolic-inflammatory substrate rather than isolated diastolic parameters 9, 2, 10.

Sex-Specific Considerations

Women with HFpEF demonstrate more concentric remodeling and impaired diastolic relaxation than men, with greater symptom burden despite similar examination findings 1. Sex-neutral ejection fraction thresholds may underestimate left ventricular dysfunction in women 1.

Clinical Algorithm for Symptom Attribution

When evaluating dyspnea in suspected HFpEF:

1. Confirm elevated filling pressures (not just diastolic grade): Use natriuretic peptides, invasive hemodynamics, or stress echocardiography when intermediate probability 1, 8
2. Assess longitudinal systolic function: Measure GLS; values >-18% suggest systolic contribution to symptoms 6
3. Exclude mimics: Chronic kidney disease, cirrhosis, obesity alone, pulmonary disease, infiltrative cardiomyopathy 1
4. Phenotype the patient: Identify dominant metabolic, inflammatory, or vascular drivers to guide therapy 2, 10

Diastolic dysfunction remains necessary but insufficient to explain HFpEF symptoms—it functions as one component of a multi-system disorder where systolic mechanics, metabolic derangements, and vascular abnormalities converge to produce the clinical syndrome.