Determinants of Abnormal Pulmonary Vasodilatory Response With Exercise in <scp>HFpEF</scp> : Pulmonary Vascular‐Left Atrial Axis Abnormalities

ABSTRACT Background Inability to decrease pulmonary vascular resistance (PVR) with exercise may lead to right ventricular failure. In this two‐step study, we define an unfavorable exercise PVR response among a broad cohort and then determine its high‐risk correlates in HFpEF. Methods 164 participants (80 HFpEF, 57 pre‐capillary PH, 27 non‐cardiac dyspnea) underwent invasive cardiopulmonary exercise test. Dichotomous groups were created with a stepwise approach: “unfavorable exercise PVR” ( n = 85, HFpEF = 46) defined as exercise PVR &gt; 1.74Woods unit (WU) and ∆PVR decrease with exercise of &lt; 22%, the remainder of the cohort was labeled as “favorable exercise PVR” ( n = 79, HFpEF = 34). Stepwise approach included: physiological groups (tertiles) using exercise PVR cutoff = 1.74 WU and median approach with ∆PVR decrease with exercise. Results In unfavorable (vs. favorable) PVR HFpEF subgroups, rest PVR = 3.4 ± 2.0 vs. 2.9 ± 2.0WU, exercise PVR = 3.7 ± 2.6 vs. 2.0 ± 1.3WU, and ∆PVR = +11% ± 39% vs. −26% ± 22%. Correlates of unfavorable exercise PVR with univariate regression were: atrial fibrillation, COPD, increased LAVI, lower TAPSE, and lower TAPSE/PASP. Multivariate model (including clinical data: age, sex, BMI) revealed that atrial fibrillation (β‐estimate = 1.93, p = 0.003) and COPD (β‐estimate = 1.74, p = 0.03) were significant. However, with multivariate model (including LAVI and TAPSE), COPD remained significant (β‐estimate = 3.26, p = 0.02), while atrial fibrillation (β‐estimate = 1.60, p = 0.06) and LAVI (β‐estimate = 0.05, p = 0.09) approached significance. The unfavorable versus favorable exercise PVR HFpEF subgroups had similar biventricular morphology by cardiac MRI ( p &lt; 0.30). Conclusions Compared to traditional cardiometabolic comorbidities, COPD and atrial fibrillation are uniquely linked to pulmonary vascular remodeling in HFpEF. The impact of these two comorbidities on pulmonary vascular‐left atrial axis is highlighted by the shared biventricular morphology among HFpEF subgroups.