Exercise intolerance in pulmonary arterial hypertension: insight into central and peripheral pathophysiological mechanisms

Abstract

Exercise intolerance is a cardinal symptom of pulmonary arterial hypertension (PAH) and strongly impacts patients' quality of life (QoL). Although central cardiopulmonary impairments limit peak oxygen consumption (V′O2peak) in patients with PAH, several peripheral abnormalities have been described over the recent decade as key determinants in exercise intolerance, including impaired skeletal muscle (SKM) morphology, convective O2 transport, capillarity and metabolism indicating that peripheral abnormalities play a greater role in limiting exercise capacity than previously thought. More recently, cerebrovascular alterations potentially contributing to exercise intolerance in patients with PAH were also documented. Currently, only cardiopulmonary rehabilitation has been shown to efficiently improve the peripheral components of exercise intolerance in patients with PAH. However, more extensive studies are needed to identify targeted interventions that would ultimately improve patients' exercise tolerance and QoL. The present review offers a broad and comprehensive analysis of the present literature about the complex mechanisms and their interactions limiting exercise in patients and suggests several gaps in knowledge that need to be addressed in the future for a better understanding of exercise intolerance in patients with PAH.

Right ventricular energetic biomarkers from 4D Flow CMR are associated with exertional capacity in pulmonary arterial hypertension

“…Exercise intolerance is a cardinal symptom of PAH that impacts quality of life and survival [ 15 ]. The cardiopulmonary exercise test (CPET) quantifies the cardiovascular, respiratory, metabolic and muscular response to physical effort and provides an objective assessment of functional capacity and limitation [ 16 ].…”

SPECTRA Phase 2b Study: Impact of Sotatercept on Exercise Tolerance and Right Ventricular Function in Pulmonary Arterial Hypertension

“…21,22 The factors leading to impaired exercise capacity in PAH are multifactorial and include reduced cardiac output, impaired gas exchange, and peripheral skeletal muscle metabolism. 23 Since previous data have shown decrements in peak exercise variables to be poorly responsive to intervention, 24 little is known about the therapeutic reversal of these mechanisms. Improvements in peak VO 2 can be difficult to determine when applying the Fick principle to examine central (cardiac output) versus peripheral (circulatory, skeletal muscle) components due to mathematical and physical coupling.…”

“…Outside of exercise rehabilitation, no therapy has been shown to improve PAH-associated skeletal muscle dysfunction. 23 This may represent a novel therapeutic target of sotatercept. Although sotatercept is known to increase hemoglobin, 3 this would not account for the improved peak VO 2 seen in our study given Ca-vO 2 corrected for hemoglobin remained unchanged.…”

Skeletal muscle deficits are associated with worse exercise performance in pediatric pulmonary hypertension

“…While peak VO 2 is a common outcome reported in research and clinical care, CPET measures of submaximal performance including VO 2 at VAT and peak work rate relative to respiratory exchange ratio as well as measures of anaerobic strength may better reflect a patient's daily activities and may also be targets for improvement. PH patients rapidly reach anaerobic threshold when performing activities of daily living such as doing laundry and folding clothes, cooking and setting the table, and walking outside with moderate effort (57,58). These activities are often performed with short bursts of activity.…”