Cardiovascular mechanisms of exercise intolerance in individuals with chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis
Authors: Germain E , Foulkes S , Hewitt D , Wang J , Howden E J , Nelson M D , Claessen G , La Gerche A , Haykowsky M J 
Published: June 2024

Abstract

Background
Reduced exercise tolerance – measured as decreased peak oxygen uptake (peak VO2) – is a hallmark feature of chronic thromboembolic pulmonary hypertension (CTEPH). However, the mechanisms underlying decreased peak VO2 in individuals with CTEPH are unclear.

Purpose
To evaluate the degree of impairment in peak VO2 and its underlying mechanisms in individuals with CTEPH versus healthy controls (CON).

Methods
A systematic search was conducted using PubMed (January 1993 to May 2023) for studies evaluating peak VO2 with or without additional evaluation of exercise hemodynamics in individuals with CTEPH and healthy controls. Studies were included if they met the following criteria: 1a) evaluation of peak VO2 from maximal cardiopulmonary testing with or without additional evaluation of exercise hemodynamics; 2) individuals with confirmed CTEPH; 3) ≥18 years of age 4) inclusion of a non-CTEPH healthy control group. A meta-analysis of included studies was performed, with values for CTEPH and CON compared using a fixed-effects model. Results (CTEPH vs CON) are reported as weighted mean differences (WMD) with 95% confidence interval (95% CI), with heterogeneity assessed using the I2 statistic.

Results
Of 286 studies identified in the initial search, nine studies met the inclusion criteria and were included in the meta-analysis, encompassing 189 individuals with CTEPH (mean age: 57 yrs) and 115 CON (mean age: 47 yrs). Peak VO2 was assessed during upright exercise in 8 studies, whilst hemodynamic assessments were performed during semi-supine exercise echocardiography in one study, or supine exercise cardiac magnetic resonance imaging in six studies. Peak VO2 (Figure 1A) was significantly lower in CTEPH vs CON (WMD: -13.8 mL/kg/min, 95% CI: -15.0 to -12.6; I2: 93%). This coincided with decreased maximal heart rate assessed during upright (WMD: -26 b/min, 95% CI: -31 to -21; I2: 81%) or supine exercise (WMD: -25 b/min, 95% CI: -28 to -21; I2: 0%), and a lower supine peak exercise stroke volume index (WMD: -25 mL/m2, 95% CI: -30 to -20; I2: 0%), resulting in a decreased supine peak cardiac index (WMD: -4.05 L/min/m2, 95% CI: 4.53 to -3.56; I2: 62%). Individuals with CTEPH also demonstrated substantial reduction in peak exercise right (RVEF, Figure 1B - WMD: -37.7%, 95% CI: -39.8 to -35.6; I2: 0%) and left-ventricular ejection fraction (LVEF, Figure 1C - WMD: -4.0%, 95% CI: -6.2 to -1.8; I2: 0%). In CTEPH, the average peak exercise RVEF was 34% lower than LVEF, indicative of adverse biventricular interaction that may be mediated by the exaggerated mean peak pulmonary artery pressures during exercise (+43 mmHg, 95% CI: 40 to 46; I2: 0%).

Conclusion
CTEPH is associated with a severely marked impairment in peak VO2 that is secondary to multifactorial impairments in cardiovascular function. This highlights the need for tailored, multi-component therapies aimed at addressing the complex pathophysiology driving exercise intolerance in CTEPH.