How preserved is right ventricular reserve in hypoxia?

The right ventricle (RV) utilizes oxygen to perform the work that drives blood through the pulmonary vasculature for gas exchange. The vasculature normally has high capacitance to receive pulsatile inflow and offers low resistance while conducting steady flow through the microcirculation. As such, modest RV systolic performance is required to develop pressure and eject stroke volume against low afterload at rest. The RV is often considered highly afterload-sensitive. However, it has substantial capacity to augment systolic performance and maintain or enhance stroke volume, even when afterload is elevated within ranges characteristic for the RV (Pahuja & Burkhoff, 2019). This systolic reserve can be conceptualized simply as the difference between operating (e.g. rest or submaximal exercise) and maximal (e.g. peak exercise or inotropic stimulation) performance (Fig. 1). However, normal reserve remains incompletely quantified because absolute maximal performance in healthy humans has not been well-defined. Because hypoxia elicits pulmonary vasoconstriction (elevating RV afterload) and reduces arterial oxygen content (possibly limiting myocardial oxygen delivery and systolic performance), it may dually challenge RV reserve and constrain cardiac output (Stembridge et al., 2019). In this issue of The Journal of Physiology, Forbes et al. (2024) advance our understanding of RV reserve by examining its performance during exercise in hypoxia. They studied 10 healthy adults, half with fluid-filled pulmonary artery catheters and half with RV pressure–volume loop catheters, at rest and exercise in normoxia and experimental hypoxia. V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{peak}}}}$ was determined in each condition before catheterization. Haemodynamics were subsequently assessed during cycling exercise at work-rates eliciting V ̇ O 2 ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}}}$ uptakes of 50% of the respective conditional peaks. If work-rates eliciting 50% of the normoxic V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{peak}}}}$ had been used for both normoxic and hypoxic haemodynamic assessments, the RV may have been challenged near to its limit. However, because the hypoxic haemodynamic assessment occurred well below the hypoxic V ̇ O 2 peak ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{peak}}}}$ , it appears that RV reserve would be adequate by design. Indeed, RV systolic performance indices augmented with exercise and matched the pulmonary arterial load under both conditions. Somewhat unexpectedly, the elastance-based metrics changed little, requiring careful consideration of RV–pulmonary arterial interaction (Tedford, 2014). The significant strength of the study lies in its direct RV and pulmonary artery haemodynamic measurements with acute interventions, which provide insight into an under-studied circulatory unit that is challenging to interrogate. An easily seen limitation is the small sample, with only five undergoing RV pressure–volume loop catheterization. However, invasive human research is challenging, particularly in conjunction with dynamic exercise. For this reason and others, existing 'control' data have often been derived from patients undergoing clinically indicated catheterization. This prospectively recruited, apparently healthy sample adds a new dimension to existing healthy, normal data and Forbes et al. (2024) should be commended. Hypoxic pulmonary vasoconstriction increases vascular resistance and elevates the steady component of RV afterload, leading to increased pulmonary artery pressure and/or reduced stroke volume. Less appreciated is the substantial pulsatile component that is influenced by vascular capacitance and wave reflections. Previous work in healthy humans has shown that pulmonary artery capacitance is high at rest, but decreases with exercise (Wright et al., 2016). Forbes et al. (2024) replicated this finding, and extend our understanding by demonstrating that hypoxia reduces pulmonary artery capacitance at rest, augmenting pulsatile RV afterload. This response is consistent with the concept that when pulmonary vascular resistance increases, capacitance often decreases reciprocally, both augmenting total RV afterload (Tedford, 2014). However, capacitance paradoxically increased during hypoxic exercise, such that it appeared negligibly different compared to normoxia. If the resistive and pulsatile components of RV afterload varied with exercise and hypoxia, why was arterial elastance, an index of total load, unchanged? Arterial elastance is a lumped parameter that reflects the 'effective' arterial load, and is estimated as the end-systolic pressure/stroke volume ratio. This relationship was first derived from the roughly rectangular left ventricular pressure–volume loop. The normal RV pressure–volume loop is triangular, with pressure peaking early in systole then declining, whereas chronic pulmonary hypertension is associated with RV loops becoming rectangular. Forbes et al. (2024) demonstrate that acute hypoxia provokes greater increases in early-systolic than end-systolic RV pressure, and the pressure–volume loops remain triangular. This is important because augmented RV pressure early in systole when RV volume is high could elevate peak wall stress, along with myocardial work and oxygen demand (Fukumitsu et al., 2022), dramatically, without being fully reflected by end-systolic pressure–volume relations. Disproportionate changes in peak and end-systolic pressure may explain why indices influenced by peak systolic pressures, such as pulmonary vascular resistance and capacitance, +dP/dtmax, and stroke work augmented, but end-systolic elastance and arterial elastance did not. Future work deconstructing pulmonary arterial haemodynamics in hypoxia and the impact on RV systolic loading would be valuable. Does the RV–pulmonary arterial circulatory unit ultimately limit exercise capacity at high altitude? Beyond the afterload-increasing effects of hypoxic pulmonary vasoconstriction, reduced arterial oxygen content could impair myocardial oxygen delivery and constrain RV stroke work when myocardial oxygen demand rises. However, as Forbes et al. (2024) note, the RV normally has greater extraction reserve compared to the left ventricle. In the bigger picture, models have suggested that cardiac output and haemoglobin concentration's influence on V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ diminish with increasing altitude, whereas elements such as ventilation, as well as pulmonary and muscle diffusion capacity, contribute more substantially. Consistent with this, several interventional studies have not shown a primary limiting role of the RV, or indeed cardiovascular system, during exercise at high altitude (Williams et al., 2022). For example, pulmonary vasodilators and plasma volume expansion may improve haemodynamics but not exercise capacity (Stembridge et al., 2019). Comprehensively studying the RV–pulmonary arterial circulatory unit as individuals approach their exertional limits in hypoxia may clarify whether the RV forms a rate-limiting step in oxygen transport in this unique environment. More broadly, quantifying systolic performance during strenuous exercise or inotropic stimulation in healthy adults across a range of fitness will better characterize its upper limits. Such work conducted in the future will improve our understanding of the magnitude of systolic reserve in the people's ventricle, as well as the responsible mechanisms. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. S.P.W. and T.G.D. each contributed to the drafting and revision of the manuscript. S.P.W. was supported by Canadian Institutes of Health Research Fellowship Award (#472 517).