Elevational variation in heart mass and suppression of hypoxia‐induced right ventricle hypertrophy in Andean leaf‐eared mice ( <i>Phyllotis</i> )

In lowland mammals that ascend to high elevation, hypoxia-induced changes in the pulmonary circulation can give rise to hypoxic pulmonary hypertension (HPH) and associated right-ventricle (RV) hypertrophy. Some mammals that are native to high elevation have evolved a means of attenuating HPH, demonstrating how genetic mechanisms of hypoxia adaptation may sometimes counteract the effects of ancestral acclimatization responses. Here, we examine elevational variation in heart mass and measures of RV hypertrophy in four closely-related species of leaf-eared mice (genus Phyllotis) that are broadly co-distributed across a steep elevational gradient on the western slope of the Andes. All species exhibited a positive relationship between heart mass and elevation that reflected proportional changes in both the right and left ventricles. Thus, elevation-related increases in overall heart mass are not generally attributable to RV hypertrophy, suggesting that this group of predominantly highland species have evolved a means of avoiding HPH and/or attenuating the cardiac response to HPH. To gain insight into possible regulatory mechanisms, we examined patterns of transcriptomic variation in the right ventricles of Phyllotis vaccarum from two geographically distinct highland populations (both from elevations >5000 m) that exhibit strikingly different levels of RV hypertrophy. Suppression of RV hypertrophy is associated with differential expression of key regulatory genes related to striated muscle structure, immune processes, and the inflammatory response. Analysis of co-expression modules identified a promising set of candidate genes for mediating the development of RV hypertrophy at extremely high elevations. KEY POINTS: Hypoxic pulmonary hypertension (HPH) and associated right-ventricle hypertrophy are common maladies at high elevation. Some animal species that are native to especially high elevations appear to have evolved a means of attenuating the effects of HPH. Species of Andean leaf-eared mice (Phyllotis) that have extraordinarily broad elevational distributions exhibit elevational increases in overall heart mass. Elevation-related increases in heart mass are not generally attributable to right-ventricle hypertrophy, indicating that highland species of Phyllotis have evolved a means of avoiding HPH and/or attenuating the cardiac response to HPH. In populations of Phyllotis vaccarum from elevations >5000 m, analysis of co-expression modules in the right ventricle transcriptome identified candidate genes for mediating hypoxia-induced hypertrophy.