Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation

 Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. exposure to high altitude (HA) challenges the cardiovascular system to meet the metabolic demand for oxygen (O2) in an environment where arterial O2 content is markedly reduced. The drop in arterial O2 has both direct and indirect consequences for the heart, including depressed inotropy of cardiac muscle (40, 44), changes in blood volume and viscosity, and vasoconstriction of the pulmonary arteries (33). Despite these broad physiological changes, which have been reviewed previously (28, 49), there is evidence that the heart copes relatively well at HA (29, 34). Short-term HA exposure in lowland natives is characterized by a decreased plasma volume (PV), an increased sympathetic nerve activity, and pulmonary vasoconstriction (17, 30, 37), all of which have considerable impact on cardiac function and in time, could stimulate cardiac remodeling. Himalayan native Sherpa, who are of Tibetan lineage and have resided at HA for ∼25,000 yr (2), are well adapted to life at HA, demonstrating greater lung-diffusing capacity (11) and an absence of polycythemia compared with acclimatized lowlanders (4). Previous studies have also reported Sherpa to have higher maximal heart rates (HRs) and only moderate pulmonary hypertension compared with lowlanders at HA (11, 25). Due to their longevity at HA, Sherpa provide an excellent model to investigate the effects of chronic hypoxic exposure. Despite this, neither the acute nor lifelong effects of HA on right- and left-ventricular (RV and LV, respectively) structure and function have been fully assessed in lowlanders or the unique Sherpa population. Due to the unique arrangement of myofibers, cardiac form and function are intrinsically linked, as reflected in the cardiac mechanics (LV twist and rotation and ventricular strain) that underpin ventricular function. In response to altered physiological demand, ventricular mechanics acutely change (16, 41) and chronically remodel (31, 42) to reduce myofiber stress and achieve efficient ejection (5, 47). Therefore, concomitant examination of myocardial mechanics and ventricular structure in both the acute and chronic HA setting will provide novel insight into human adaptation to hypoxia. To investigate the effects of chronic hypoxic exposure, we compared ventricular volumes and mechanics in Sherpa at 5,050 m with lowlanders at sea level (SL). In addition, to reveal potential stimuli for remodeling and to examine the time course of adaptation, we compared Sherpa with lowlanders after short-term HA exposure. We hypothesized that: 1) Sherpa would exhibit smaller LV volumes and a higher RV/LV ratio than lowlanders at SL, 2) LV mechanics in Sherpa will closely resemble those of lowlanders at SL, and 3) following partial acclimatization to HA, LV volumes would be reduced in lowlanders and LV mechanics acutely increased.