A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia

Over the last 100 years, high-altitude researchers have amassed a comprehensive understanding of the global cardiac responses to acute, prolonged and lifelong hypoxia. When lowlanders are exposed to hypoxia, the drop in arterial oxygen content demands an increase in cardiac output, which is facilitated by an elevated heart rate at the same time as ventricular volumes are maintained. As exposure is prolonged, haemoconcentration restores arterial oxygen content, whereas left ventricular filling and stroke volume are lowered as a result of a combination of reduced blood volume and hypoxic pulmonary vasoconstriction. Populations native to high-altitude, such as the Sherpa in Asia, exhibit unique lifelong or generational adaptations to hypoxia. For example, they have smaller left ventricular volumes compared to lowlanders despite having larger total blood volume. More recent investigations have begun to explore the mechanisms underlying such adaptive responses by combining novel imaging techniques with interventions that manipulate cardiac preload, afterload, and/or contractility. This work has revealed the contributions and interactions of (i) plasma volume constriction; (ii) sympathoexcitation; and (iii) hypoxic pulmonary vasoconstriction with respect to altering cardiac loading, or otherwise preserving or enhancing biventricular systolic and diastolic function even amongst high altitude natives with excessive erythrocytosis. Despite these advances, various areas of investigation remain understudied, including potential sex-related differences in response to high altitude. Collectively, the available evidence supports the conclusion that the human heart successfully adapts to hypoxia over the short- and long-term, without signs of myocardial dysfunction in healthy humans, except in very rare cases of maladaptation.