Elevational variation in heart mass and suppression of hypoxia-induced right ventricle hypertrophy in Andean leaf-eared mice (Phyllotis)

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 environmental 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. There was a positive relationship overall between heart mass and elevation that reflected proportional changes in both the right and left ventricles. Thus, elevation-related increases in overall heart mass were 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 transcriptional 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 involved in striated muscle, 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.