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.

FIGURE 1

Exercise intolerance has a major impact on daily life activities. Patients rapidly reach anaerobic threshold in their daily activities, making sustained efforts difficult. Average peak oxygen uptake (V′_O2peak) used for comparison was 16.1 (1.4) mL O₂.kg⁻¹·min⁻¹ based on six studies [–9]. V′O₂: standing quietly in a queue: 4.6 mL O₂·kg⁻¹·min⁻¹; standing, fidgeting: 6.3 mL O₂·kg⁻¹·min⁻¹; doing the laundry, folding clothes: 9.8 mL O₂·kg⁻¹·min⁻¹; cooking, laying the table: 11.6 mL O₂·kg⁻¹·min⁻¹; walking outside, moderate effort: 12.3 mL O₂·kg⁻¹·min⁻¹; mowing the lawn, with a power mower: 15.6 mL O₂·kg⁻¹·min⁻¹. Specific physical activity intensity was determined using the 2011 Compendium of Physical Activities [10]. NYHA: New York Heart Association; PAH: pulmonary arterial hypertension. Data from [11].

FIGURE 2

Impaired cardiac adaptation and ventilatory response to exercise in patients with pulmonary arterial hypertension (PAH). RV: right ventricle; LV: left ventricle; V_D/V_T: dead space/tidal volume ratio; V′/Q′: ventilation-perfusion ratio (normal ratio average 0.8).

FIGURE 3

Skeletal muscle (SKM) determinants of exercise intolerance in patients with pulmonary arterial hypertension (PAH).

FIGURE 4

The Wagner diagram. Oxygen uptake is plotted as a function of microvascular oxygen pressure. Black line: diffusive (Fick law) and convective (Fick principal) components that interact to determine peak oxygen uptake (V′_O2peak). The Fick principle line is not straight because it directly represents the haemoglobin dissociation curve (greater haemoglobin O₂ affinity), resulting in a lower venous O₂ partial pressure [130]. The slope of the straight line (Fick law) is determined by the diffusing capacity of the muscles [130]. Red line: in patients with heart failure, a left-shifted haemoglobin dissociation curve (greater haemoglobin O₂ affinity), resulting in a lower venous O₂ partial pressure, and a lower slope of the Fick law line results in earlier bisection of both diffusive and convective components and reduced V′_O2peak. a-vO₂: arterio-venous difference; DO₂: oxygen delivery; HFrEF: heart failure with reduced ejection fraction; PO₂: partial pressure of oxygen; CO: cardiac output.