Don't stop at the top: plasma volume expansion and pulmonary vasodilatation restore left ventricular function at rest but not during exercise at high altitude

At a given level of oxygen consumption, cardiac output is similar at high altitude compared to at sea level; however it is achieved with a greater heart rate and lesser stroke volume (SV), which is related to reduced left ventricular (LV) end-diastolic volume (EDV). In turn, the reduced LV SV mediated by the Frank–Starling mechanism has been suggested to occur secondarily to a decreased circulating blood volume and/or increased pulmonary vascular resistance. At high altitude, total blood volume decreases secondarily to an acute plasma volume loss, and as the partial pressure of oxygen in inspired air decreases, alveolar hypoxia stimulates pulmonary vasoconstriction and increases pulmonary vascular resistance. However, correction of either has not been consistently shown to entirely return SV to sea level values. Further, the maximal value of both oxygen consumption and cardiac output is lower, although the directionality of the association remains unclear. In a recent issue of The Journal of Physiology, Stembridge et al. (2019) aimed to determine the contributions of high altitude-induced hypovolaemia and hypoxic pulmonary vasoconstriction to LV function and maximal oxygen consumption. The authors’ main hypotheses were that both plasma volume expansion (saline infusion) and pulmonary vasodilatation (phosphodiesterase-5 inhibition) would increase LV EDV at rest and exercise; however, only the reversal of hypoxic pulmonary vasoconstriction would increase the maximum oxygen consumption. To this end, 12 healthy male participants were prospectively recruited. Maximal oxygen consumption was determined through a graded exercise test, and cardiac function was assessed by echocardiography at rest and during constant work-rate exercise at 50% peak power. These assessments were then repeated after 5–10 days at high altitude (3800 m) without and with plasma volume expansion to achieve sea level haematocrit values, without and with administration of the pulmonary vasodilator sildenafil, and with both in combination. At high altitude, resting LV EDV and SV were not significantly different compared to at sea level following plasma volume expansion or sildenafil administration. However, neither intervention elicited a significant improvement in LV EDV and SV during exercise at 50% peak power, nor on maximal oxygen consumption. From these findings, the authors concluded that at 3800 m, hypovolaemia and hypoxic pulmonary vasoconstriction contribute to a reduction in LV EDV, yet interventions which normalize LV EDV at rest do not yield improvements during exercise. The study design utilized by Stembridge et al. (2019) has several strengths and some limitations which merit discussion. Study participants were appropriately selected after screening to ensure they had minimal risk factors for cardiovascular disease; however, the study group was relatively small and did not include female participants. Although the sample size limited statistical power, particularly given the inclusion of several repeated measures, the authors effectively illustrated individual data to communicate results to the reader and reported effect sizes; Fig. 2 in Stembridge et al. (2019) is a particularly strong example of effective data presentation. As the authors noted, the study design made controlling for the interaction of menstrual phase and period of acclimatization challenging. Nevertheless, females are historically under-represented in biomedical research, and the need to understand the limits of sex similarities in cardiorespiratory physiology is increasingly recognized. As such, the inclusion of female participants would have added both strength and novelty to the study. Notably, the authors utilized randomization in their study; however, plasma volume expansion appears to have always been the second condition in each visit, which presumably was related to practical time constraints of conducting the study. Thus, the time from either placebo or sildenafil administration to the plasma volume expansion measurements may have been systematically longer than to high altitude or sildenafil conditions. The relationship between total blood volume and LV filling is complex, particularly with exercise and more so at high altitude. Within only a few days at high altitude, total blood volume and plasma volume decrease (Alexander & Grover, 1983), the latter of which is reflected by a haematocrit increase, and can be attributed to increased water loss through ventilation and diuresis. In this study, ascent to high altitude was followed by a plasma volume decrease which was corrected by infusing approximately 420 ml of saline, suggesting that the magnitude of blood volume lost was, on average, slightly less than a routine blood donation. That a similar volume of saline was required at both study visits 2 and 3 suggests a progressive plasma volume loss over the first 10 days of acclimatization, consistent with prior reports (Alexander & Grover, 1983), which washed out the effects of the first infusion. The saline infusion restored LV EDV at rest, but not during submaximal exercise, and did not normalize maximal oxygen consumption. In humans, less than half of the total blood volume is ‘stressed’ or ‘circulating’ volume that contributes to cardiac filling (Magder & De Varennes, 1998), while the remainder is stored in capacitance beds. Ascent to high altitude and hypovolaemia are both associated with elevated sympathetic activation, which may auto-transfuse volume from the venous reservoir to the circulating volume via α- and β2-adrenoceptor-mediated venoconstriction (Gelman & Mushlin, 2004). Further, exercise is associated with a shift in blood volume from the splanchnic circulation to the central circulation (Flamm et al. 1990), which contributes to the normal modest increase in LV EDV. That plasma volume expansion produced no substantial increase in the augmentation of EDV with exercise suggests this mechanism may have already been recruited at rest, although the fact that resting EDV at high altitude was reduced suggests it may not fully defend circulating blood volume in hypovolaemia. Future work may further explore the complex inter-relationships between total blood volume and autonomic regulation of regional volume distribution at rest and during exercise stress. At an altitude of 3800 m, the degree of alveolar hypoxia as a stimulus for pulmonary vasoconstriction may have been insufficient to meaningfully impact cardiodynamics. Although both pulmonary artery systolic pressure and pulmonary vascular resistance increased modestly (to approximately 26 mmHg and 1.5 Wood units), importantly, both metrics on average remained well within normal ranges. Interestingly, in the absence of change in pulmonary vascular resistance, pulmonary vascular compliance may decrease substantially, which augments pulsatile right ventricular afterload (Wright et al. 2016). At altitudes of approximately 5000 m, these authors and others (Naeije et al. 2010) have observed borderline pulmonary hypertension, which may be superimposed upon the hypovolaemia that develops at lower altitudes encountered earlier in real-world ascents. As such, hypoxic pulmonary vasoconstriction may play a greater role in determining LV EDV, SV and maximal oxygen consumption at higher altitudes, when the right ventricle is challenged by both reduced preload and augmented afterload. In the absence of substantial pulmonary hypertension, it would be difficult to demonstrate the efficacy of pulmonary vasodilatation on LV filling at rest or during exercise. In the present study, was performed 170–185 min after sildenafil ingestion with subsequent plasma volume expansion. As the peak efficacy of sildenafil is approximately 60 min after p.o. drug intake, the peak effect on maximal oxygen consumption may have been missed, although it may be relevant to real world two- or three-times daily p.o. intake. Short-term treatment with sildenafil has been shown to reduce hypoxaemic pulmonary vasoconstriction (Xu et al. 2014); however, potential systemic haemodynamic effects may have confounded its cardiodynamic effects. Future studies may consider using inhaled therapies such as supplemental oxygen or nitric oxide to more directly assess the contribution of hypoxic pulmonary vasoconstriction at altitude. In conclusion, Stembridge et al. (2019) conducted a well-designed study and determined that at 3800 m hypovolaemia and hypoxic pulmonary vasoconstriction contribute to a decrease in LV EDV; however, restoring LV EDV does not improve SV or maximal oxygen consumption during exercise. Future work may consider higher altitudes (≥5000 m), the inclusion of female subjects, sympathetic regulation of volume distribution and alternative vasodilating therapies. No competing interests declared All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. SPW was supported by a Canadian Lung Association PhD Scholarship and the Ted Rogers Centre for Heart Research.

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