How does heart rate variability (HRV) impact right ventricular-pulmonary arterial (RV-PA) uncoupling in patients with heart failure with preserved ejection fraction (HFpEF)?

Heart Rate Variability Does Not Directly Impact RV-PA Uncoupling in HFpEF

The available evidence does not establish a relationship between heart rate variability (HRV) and right ventricular-pulmonary arterial (RV-PA) uncoupling in patients with heart failure with preserved ejection fraction (HFpEF). The primary drivers of RV-PA uncoupling in HFpEF are increased RV afterload (both pulsatile and resistive), intrinsic RV contractile impairment, and pulmonary vascular dysfunction—not autonomic modulation reflected by HRV 1.

What Actually Drives RV-PA Uncoupling in HFpEF

Pulmonary Vascular Dysfunction

• Increased pulsatile afterload, quantified by characteristic pulmonary impedance (ZC), is the key mechanism driving RV-PA uncoupling during exercise in HFpEF 2.
• In HFpEF patients, ZC increases with exercise while the end-systolic elastance (Ees) to effective arterial elastance (Ea) ratio decreases, demonstrating a significant negative correlation (slope -0.96, r² = 0.18, P < 0.0001) 2.
• Approximately 70% of HFpEF patients with RV dysfunction have concomitant pulmonary hypertension at rest 3.

Intrinsic RV Contractile Impairment

• RV contractile reserve is markedly reduced in HFpEF patients with abnormal pulmonary vascular response during exercise 1.
• Exercise-induced increase in Ees (RV contractility) is significantly blunted in HFpEF patients with elevated pulmonary vascular resistance, resulting in decreased Ees/Ea ratio and RV-PA uncoupling 1.
• RV dysfunction, defined by various metrics (TAPSE <16 mm, RV fractional area change <35%, or RV S'), is present in 13-33% of HFpEF patients depending on the measurement method used 3.

Clinical Significance of RV-PA Uncoupling

Prognostic Impact

• RV-PA uncoupling, measured by TAPSE/pulmonary artery systolic pressure (PASP) ratio <0.46 mm/mm Hg, independently predicts adverse outcomes in HFpEF 4.
• Two-year mortality is approximately 45% in HFpEF patients with RV dysfunction compared to 7% in those without 3.
• RV-PA uncoupling is associated with a 1.77-fold increased risk of the composite endpoint of all-cause death, HF rehospitalization, and cerebrovascular events (HR 1.77,95% CI 1.34-2.32, P<0.0001) 4.
• Among patients with RV-PA uncoupling, larger RV dimension (>31.9-33.3 mm) further worsens prognosis 5.

Exercise Intolerance

• RV-PA uncoupling correlates with markedly decreased peak oxygen consumption, decreased oxygen delivery, and impaired chronotropic response 1.
• Patients with HFpEF demonstrate impaired RV systolic and diastolic functional enhancement during exercise, with increased left- and right-sided filling pressures and limitations in cardiac output reserve 3.
• Lower pulmonary artery compliance and lower stroke volume are observed in HFpEF patients with exercise-induced RV-PA uncoupling 1.

Assessment of RV-PA Coupling

Echocardiographic Measures

• TAPSE/PASP ratio <0.46 mm/mm Hg indicates RV-PA uncoupling and should be calculated in all HFpEF patients 4.
• TAPSE/RV systolic pressure (RVSP) ratio <0.31 by receiver operating characteristic analysis identifies patients at highest risk for mortality or HF hospitalizations (HR 2.61,95% CI 1.28-5.33, P=0.008) 6.
• RV fractional area change <35% and RV longitudinal systolic strain abnormalities provide additional assessment of RV function 3.

Invasive Hemodynamic Assessment

• Single-beat analysis of RV pressure waveforms computes Ees (RV contractility) and Ea (pulmonary arterial elastance), with Ees/Ea ratio quantifying RV-PA coupling 1.
• Exercise testing with repeated measurements of characteristic impedance and coupling (Ees/Ea ratio from RV pressure-volume loops) precisely detects abnormal cardiopulmonary function 2.
• The slope of mean pulmonary artery pressure versus cardiac output during exercise provides additional coupling assessment 3.

Clinical Implications

Risk Stratification

• All HFpEF patients should undergo echocardiographic assessment of RV function and estimation of pulmonary artery pressures to calculate TAPSE/PASP ratio 3.
• Patients with TAPSE <16 mm at rest warrant further evaluation with exercise testing to assess RV contractile reserve 3.
• Male sex, renal impairment, atrial fibrillation, and coronary artery disease are more prevalent in HFpEF patients with RV dysfunction 3.

Management Considerations

• SGLT2 inhibitors (dapagliflozin or empagliflozin) should be initiated immediately upon HFpEF diagnosis, as these are the only medications proven to reduce cardiovascular death and heart failure hospitalizations 7, 8.
• Diuretics should be titrated to the lowest effective dose that maintains euvolemia, as excessive diuresis leads to hypotension and impaired RV function 7, 8.
• Blood pressure control to <130/80 mmHg is essential, as hypertension drives HFpEF pathophysiology and contributes to pulmonary vascular dysfunction 7, 8.

Common Pitfalls

• Do not assume traditional heart failure medications work in HFpEF—most have not shown efficacy in this population 8.
• Avoid attributing all RV dysfunction to primary RV pathology, as it is difficult to distinguish from secondary pulmonary hypertension given the afterload dependency of RV function 3.
• Do not overlook the contribution of pulmonary vascular dysfunction to RV failure, as pulsatile afterload (not just resistive afterload) is a critical determinant of RV-PA uncoupling 2, 1.