Pulmonary Vascular Distensibility Predicts Pulmonary Hypertension Severity, Exercise Capacity, and Survival in Heart Failure

Abstract

Background: Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity.

Methods and results: Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean±SD, 8.3±2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40±0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92±0.39 and 0.84±0.33% per mm Hg, respectively) compared to the control group (1.39±0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, ρ=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only.

Conclusions: PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

Keywords: heart failure; mortality; physiology; pulmonary heart disease; pulmonary hypertension.

© 2016 American Heart Association, Inc.

Figures

Figure 1. Characterization of pulmonary vascular distensibility in heart failure and pulmonary arterial hypertension patients

Pulmonary vascular distensibility was determined using pulmonary arterial pressure, pulmonary arterial wedge pressure (PAWP), and Fick cardiac output measurements at rest and during exercise, as previously described, in control (n=30), HFpEF (n=48), HFrEF (n=55), and PAH (n=18) patients. Mean ± SD is depicted in the graph. HFpEF (*) and HFrEF (†) patients exhibit a reduced pulmonary vascular distensibility compared to control patients (P

Figure 2. Abnormal pulmonary vascular distensibility is associated with increased pulmonary arterial pressures during exercise

The pressure-flow relationships for a representative HFpEF patient who underwent cardiopulmonary exercise testing are shown (●). Mean pulmonary arterial pressure (PAP), transpulmonary gradient (TPG), and PAWP are depicted. This patient had a resting cardiac output of 4.4 L/min and resting upright mPAP and PAWP of 14 mmHg and 9 mmHg, respectively. With peak exercise, cardiac output increased to 13.3 L/min and upright mPAP and PAWP peaked at 44 and 24 mmHg, respectively. The transpulmonary gradient (TPG) at peak exercise was 20 mmHg. PV distensibility was calculated to be 0.78% per mmHg. To illustrate the physiologic significance of pulmonary vascular distensibility on pulmonary pressures during exercise, we superimposed an idealized pressure-flow relationship based on a normal distensibility of 2.0% per mmHg, while maintaining PAWP and CO fixed (■). At peak exercise, the actual mPAP and TPG are 44 and 20 mmHg, respectively, while the idealized values of mPAP and TPG are 31 and 7 mmHg.

Figure 3. Pulmonary vascular distensibility is associated with change in RVEF with exercise

A scatterplot of change in RVEF versus distensibility of the four patient groups are depicted. Spearman rank correlations were determined. Pulmonary vascular distensibility is a strong determinant of RV function with exercise.

Figure 4. Pulmonary vascular distensibility predicts cardiovascular mortality in heart failure patients

Kaplan-Meier survival curves of HF patients (n=103, both HFpEF and HFrEF) are depicted, dichotomized by pulmonary vascular distensibility value. Compared to those with lower PV distensibility, HF patients with a distensibility ≥0.70% per mmHg exhibit reduced cardiovascular mortality (P=0.03).

Figure 5. Twelve weeks of treatment with sildenafil improves pulmonary vascular distensibility in patients with heart failure and reduced ejection fraction

Sildenafil treatment was associated with a 24.6% increase in distensibility (n=14, P=0.015) while no appreciable change in distensibility was observed in the placebo-treated group (n=12). Treatment with a selective pulmonary vasodilator can therefore improve pulmonary vascular distensibility.