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

Abstract

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.

Keywords: adaptation; altitude; blood volume; cardiac function; hypoxaemia; hypoxia; pulmonary hypoxic vasoconstriction; twist.

Figure 1. Adjustments of global and regional ventricular mechanics with hypoxia, at rest and during exercise

A, global left ventricular (LV) mechanics are elevated with both acute and prolonged hypoxia, where the LV twist is often augmented as a result of increased rotation at both the base and apex. B, recent work has assessed regional myocardial mechanics to determine whether subendocardial (square symbols, dashed line) vs. subepicardial mechanics (open circle symbols, dotted line) become impaired with hypoxia (HX) compared to normoxia (NX). There appear to be no indications of subendocardial dysfunction, as previously hypothesized, given the consistent increase in local strain in the basal (left), apical (middle) and longitudinal axes (right with acute and prolonged hypoxia. C, the increases to systolic mechanics are largely attributable to amplified sympathetic activation, as determined via administration of a cardiac‐specific ß‐adrenergic receptor blockade (ß₁‐AR block). D, during exercise, LV twist mechanics become augmented from an elevated hypoxic baseline but reach a peak exercising twist similar to sea level. Representative data from Williams et al. (2019) and Stembridge et al. (2015).

Figure 2. Alterations to cardiac pressures and dimensions with acclimatization or adaptation to hypoxia/high‐altitude

Left: normal health range of atrial and pulmonary arterial pressures, as well as ventricular‐septal geometry, at sea level or long‐term normoxia. Right: shifts in these parameters with prolonged or lifelong hypoxia. Here, atrial pressures are lowered as a result of reduced filling via lower blood volume, as well as hypoxic pulmonary vasoconstriction, which imposes a greater afterload on the right side of the heart, reduces right ventricular (RV) output and leads to RV expansion. Consequently, left ventricular (LV) end‐diastolic volume and left‐sided filling are reduced via direct ventricular interaction (septal shift) and series ventricular interaction (reduced RV output due to higher afterload). Figure based on reports from (Boussuges et al., ; Fowles & Hultgren, ; Reeves et al., 1990, 1987)

Figure 3. Comparison of total blood volume and its components

Comparison of total blood volume and its components amongst lowlander populations at sea level (left) and with prolonged hypoxia (middle), as well as populations residing at high altitude (right). Total fill indicates the relative proportions (i.e. scaled to body mass, ml/kg) of total blood volume, whereas red and yellow fills represent the relative red cell volume and plasma volume, respectively (representative data from Stembridge, Williams et al., . In the earlier stage of prolonged hypoxia (∼10–14 days), lowlanders initially experience plasma volume constriction, whereas the red cell volume generally remains unchanged, resulting in an increased haemoglobin concentration. As duration exposure increases from weeks to months, blood volume is gradually restored via erythrocytosis (Pugh, ; Reynafarje et al., 1959). Compared to lowlanders, high‐dwelling populations have substantially larger blood volumes for their body size; however, Andean individuals often present with much higher proportions of red cell volumes, whereas Sherpa have haemoglobin concentrations comparable to those seen in acclimatized lowlanders (Stembridge, Williams et al., 2019).