Uncoupling in HFpEF: Right Ventricular-Pulmonary Arterial Dysfunction
Uncoupling in HFpEF refers to right ventricular-pulmonary arterial (RV-PA) uncoupling, a pathophysiologic state where the right ventricle fails to adequately match its contractile function to the increased pulmonary vascular load, measured as a decreased ratio of end-systolic elastance (Ees) to effective arterial elastance (Ea). 1
Definition and Measurement
RV-PA uncoupling is quantified as an Ees/Ea ratio, with values below normal indicating mismatch between RV contractility and afterload. 1 A practical clinical surrogate is the TAPSE/PASP ratio, where values <0.46 mm/mm Hg indicate RV-PA uncoupling. 2
Mechanisms of Uncoupling in HFpEF
The development of RV-PA uncoupling in HFpEF involves two distinct pathophysiologic processes:
Pulmonary Vascular Dysfunction
- Increased RV pulsatile afterload is the primary driver of resting and dynamic RV-PA uncoupling in HFpEF, rather than resistive afterload alone. 1
- Pulmonary hypertension occurs in 52-83% of HFpEF patients, contributing significantly to RV dysfunction. 3
- Abnormal characteristic pulmonary impedance (ZC) during exercise correlates negatively with Ees/Ea ratio in HFpEF patients (slope -0.96, r²=0.18, P<0.0001), indicating that abnormal pulsatile hemodynamics drive RV failure. 4
Intrinsic RV Contractile Impairment
- HFpEF patients with abnormal pulmonary vascular response during exercise demonstrate markedly reduced exercise-induced increase in Ees, resulting in decreased Ees/Ea and frank RV-PA uncoupling. 1
- Even HFpEF patients with normal pulmonary vascular resistance show decreased Ees/Ea during exercise despite preserved Ees response, indicating partially preserved but insufficient RV contractile reserve. 1
Clinical Manifestations and Exercise Physiology
RV-PA uncoupling worsens dynamically during exercise in HFpEF, particularly when increased resistive afterload compounds the baseline pulsatile afterload elevation. 1
Key exercise findings include:
- Markedly decreased peak oxygen consumption (VO₂) in both uncoupled and coupled HFpEF patients 1
- Decreased oxygen delivery and impaired chronotropic response 1
- Lower pulmonary artery compliance and stroke volume in patients with exercise-induced decrease in Ees/Ea 1
Prognostic Significance
Among HFpEF patients with RV-PA uncoupling (TAPSE/PASP <0.46), larger RV dimension (RVD) carries additional prognostic importance for cardiac mortality and HF readmission. 2 In a multicenter cohort of 288 RV-PA uncoupled HFpEF patients, RVD was independently prognostic (HR 1.036,95% CI 1.001-1.072, P=0.0438) after adjusting for age, atrial fibrillation, renal function, and NT-proBNP. 2
Relationship to Vascular Stiffening
Vascular stiffening contributes to ventricular-vascular uncoupling in aged HFpEF patients, with autophagy-mediated vascular senescence potentially playing a mechanistic role. 5 This represents a broader concept of uncoupling beyond just RV-PA relationships, encompassing left ventricular-arterial coupling as well. 5
Clinical Implications
The presence of RV-PA uncoupling helps explain why:
- Reduced arteriovenous O₂ difference accounts for >50% of the reduction in peak VO₂ in HFpEF and is a stronger independent predictor than exercise cardiac output. 3
- Standard steady-state hemodynamic metrics (like pulmonary vascular resistance) may appear normal despite significant functional impairment 4
- Exercise intolerance in HFpEF involves both cardiac and extracardiac mechanisms, consistent with HFpEF being a systemic syndrome 3