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The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Non, Heinrich, Gu, Alcock, Moya, Lawrence, Tift, O'Brien, Storz, Signore, Khudyakov, Milsom, Wilson, Beall, Villafuerte, Stobdan, Julian, Moore, Fuster, Stokes, Milner, West, Zhang, Shyy, Childebayeva, Vázquez-Medina, Pham, Mesarwi, Hall, Cheviron, Sieker, Blood, Yuan, Scott, Rana, Ponganis, Malhotra, Powell and Simonson.)

Heme oxygenase (HO) enzymes catalyze heme into biliverdin, releasing carbon monoxide (CO) and iron into circulation. These byproducts of heme degradation can have potent cytoprotective effects in the face of stressors such as hypoxia and ischemia-reperfusion events. The potential for exogenous use of CO as a therapeutic agent has received increasing attention throughout the past few decades. Further, HO and CO are noted as putatively adaptive in diving mammals and certain high-altitude human populations that are frequently exposed to hypoxia and/or ischemia-reperfusion events, suggesting that HO and endogenous CO afford an evolutionary advantage for hypoxia tolerance and are critical in cell survival and injury avoidance. Our goal is to describe the importance of examining HO and CO in several systems, the physiological links, and the genetic factors that underlie variation in the HO/CO pathway. Finally, we emphasize the ways in which evolutionary perspectives may enhance our understanding of the HO/CO pathway in the context of diverse clinical settings., (Copyright © 2020 Tift, Alves de Souza, Weber, Heinrich, Villafuerte, Malhotra, Otterbein and Simonson.)

Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals ( n = 63 men; n = 46 women), and sleep measures in 45 of these participants ( n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO 2 ( p < 0.001 and p < 0.002, respectively) and decreased sleep SpO 2 (mean, nadir, and time <80%; all p < 0.02). In men, high Hct was also associated with increased end-tidal P CO2 ( p < 0.009). While ventilatory responses to hypoxia and hypercapnia did not predict Hct, decreased hypoxic ventilatory responses were associated with lower daytime SpO 2 in men ( p < 0.01) and women ( p < 0.009) and with lower nadir sleep SpO 2 in women ( p < 0.02). Decreased ventilatory responses to CO 2 were associated with more time below 80% SpO 2 during sleep in men ( p < 0.05). The obstructive apnea index and apnea-hypopnea index also predicted Hct and CMS scores in men after accounting for age, BMI, and SpO 2 during sleep. Finally, heart rate response to hypoxia was lower in men with higher Hct ( p < 0.0001). These data support the idea that hypoventilation and decreased ventilatory sensitivity to hypoxia are associated with decreased day time and nighttime SpO 2 levels that may exacerbate the stimulus for erythropoiesis in Andean men and women. However, interventional and longitudinal studies are required to establish the causal relationships between these associations., (Copyright © 2020 Heinrich, Orr, Gilbertson, Anza-Ramirez, DeYoung, Djokic, Corante, Vizcardo-Galindo, Macarlupu, Gaio, Powell, Malhotra, Villafuerte and Simonson.)

Background: Ascent to altitude increases the prevalence of arrhythmogenesis in low-altitude dwelling populations (Lowlanders). High altitude populations (i.e., Nepalese Sherpa) may have arrhythmias resistant adaptations that prevent arrhythmogenesis at altitude, though this has not been documented in other High altitude groups, including those diagnosed with chronic mountain sickness (CMS). We investigated whether healthy (CMS-) and CMS afflicted (CMS +) Andeans exhibit cardiac arrhythmias under acute apneic stress at altitude. Methods and Results: Electrocardiograms (lead II) were collected in CMS- ( N = 9), CMS + ( N = 8), and Lowlanders ( N = 13) following several days at 4330 m (Cerro de Pasco, Peru). ECG rhythm and HR were assessed at both rest and during maximal volitional apnea. Both CMS- and CMS + had similar basal HR (69 ± 8 beats/min vs. 62 ± 11 beats/min), while basal HR was higher in Lowlanders (77 ± 18 beats/min; P < 0.05 versus CMS +). Apnea elicited significant bradycardia (nadir -32 ± 15 beats/min; P < 0.01) and the development of arrhythmias in 8/13 Lowlanders (junctional rhythm, 3° atrio-ventricular block, sinus pause). HR was preserved was prior to volitional breakpoint in both CMS- (nadir -6 ± 1 beat/min) and CMS + (1 ± 12 beats/min), with 2/17 Andeans developing arrhythmias (1 CMS+ and 1 CMS-; both Premature atrial contraction) prior to breakpoint. Conclusion: Andeans showed an absence of arrhythmias and preserved HR response to volitional apnea at altitude, demonstrating that potential cardio-resistant adaptations to arrhythmogenesis exist across permanent HA populations. Acclimatized Lowlanders have further demonstrated an increased prevalence of arrhythmias at altitude., (Copyright © 2020 Busch, van Diepen, Steele, Meah, Simpson, Figueroa-Mujíca, Vizcardo-Galindo, Villafuerte, Tymko, Ainslie, Moore, Stembridge and Steinback.)