Getting to the heart of the matter: understanding cardiovascular limitations at high altitude

Following acclimatization to high altitude, resting stroke volume is reduced, necessitating an increase in heart rate in order to maintain cardiac output. One proposed mechanism to explain this is decreased blood volume; however, stroke volume is not consistently improved when blood volume is restored to sea level values. A second potential mechanism can be characterized by interventricular interdependence, whereby the increased pulmonary artery pressure with hypoxia necessitates greater right ventricular work/strain, resulting in reduced left ventricular filling. How high altitude-induced hypovolemia and hypoxic pulmonary vasoconstriction affect resting cardiac function as well as peak oxygen consumption () was the focus of the paper by Stembridge et al (2019) in this issue of The Journal of Physiology. The investigators examined cardiac function and exercise tolerance at sea level (344 m), and following 5–10 days at the Barcroft Laboratory in White Mountain, CA, USA (3800 m, barometric pressure (Pb) ∼480 mmHg). At altitude, plasma volume was normalised to sea level values with plasma volume expansion, and hypoxic pulmonary vasoconstriction was reversed by sildenafil (50 mg) to create four conditions: 1) high altitude, 2) plasma volume expansion, 3) sildenafil, and 4) plasma volume expansion and sildenafil. Plasma volume expansion at altitude returned blood volume, as well as resting end-diastolic volume and stroke volume, to sea level values. Sildenafil normalized pulmonary artery systolic pressure to sea level values, but did not fully restore resting end-diastolic volume and stroke volume. Neither plasma volume expansion nor the combined effects of plasma volume expansion and sildenafil improved exercise end-diastolic volume, stroke volume or at altitude. Stembridge et al. concluded that hypovolemia and hypoxic pulmonary vasoconstriction contribute to the reduced resting left ventricular filling at altitude, but the reversal of neither hypovolemia nor hypoxic pulmonary vasoconstriction translated to improved . The publication by Stembridge et al. represents an outstanding example of mechanistic physiology. The authors are to be congratulated for completing this complicated study under the difficult circumstances associated with field work at altitude. As with any great study that presents a wealth of data, the work provides as many questions as answers for future research. The authors present a wealth of resting high altitude cardiac mechanics data for which anyone interested in high altitude and cardiac function is encouraged to review. The data nicely demonstrate that the improvement in resting stroke volume at high altitude with plasma volume expansion is secondary to greater preload as early transmitral filling velocity and correspondingly end-diastolic volume were increased. The abolition of pulmonary hypertension with sildenafil did not reduce right ventricular strain or strain rate, nor improve early transmitral filling velocity, but still improved left ventricular end-diastolic volume. It is somewhat surprising that the combination of plasma volume expansion and sildenafil was not additive, and the combined response paralleled the response of sildenafil alone. While the data provide a wonderfully comprehensive evaluation of cardiovascular physiology, some of the surprising cardiac mechanic responses likely highlight the complexities of evaluating acute cardiac interventions using ultrasound within a background of chronic hypoxia, hypovolemia and adrenergic activation. That the improvement in resting cardiac function with plasma volume expansion and sildenafil did not translate to enhanced submaximal exercise cardiac function or , was contrary to the authors’ original hypotheses. Interestingly, previous mathematical modelling by Dr Peter Wagner at a similar altitude (∼4572 m, Pb 464 mmHg) to that of the study by Stembridge et al. would suggest that modifications of exercising cardiac output would have a minimal effect on (Wagner, 1996). Stembridge et al. suggest that improved exercise performance with sildenafil may be seen at more extreme altitudes (i.e. above 4500–5000 m), and there is evidence to support this proposition (Ghofrani et al. 2004). Wagner's modelling work would suggest that improvements in cardiac output at Everest (8848 m, Pb 253 mmHg) would have virtually no improvement in (Wagner, 1996). In follow-up work highlighting Habeler and Messner's ascent of Everest without oxygen, Wagner demonstrated that a 25% increase in cardiac output would confer an increase in of less than 2% (Wagner, 2017). Thus, it remains unclear whether reversal of hypovolemia or pulmonary hypertension would result in improved exercise performance at a higher altitude. Of course, a model is only useful if it supported by data. One hopes Stembridge et al. and their outstanding team are packing their bags to answer this question at an even more extreme altitude. None declared.

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