Response by Bhatnagar to Letter Regarding Article, “Environmental Determinants of Cardiovascular Disease”

In Response

Dr Calderon-Gerstein raises interesting issues related to the cardiovascular effects of high altitude. These effects could be categorized into (1) acute or chronic effects in lowlanders moving to high altitude, (2) partial adaptation to high altitude in populations of recent altitude ancestry (eg, Andean natives), and (3) long-term adaptations in populations of old altitude ancestry (eg, Sherpa and Tibetans). Some of these effects are similar, whereas others are not. Although, in lowlanders, moving from low to high altitude triggers hypoxia-related changes, populations with long altitude ancestry have adapted to low oxygen levels and other environmental features unique to high altitude and, therefore, are relatively insensitive to hypoxia.¹ Dr Calderon-Gerstein correctly points out that individuals with recent altitude ancestry, such as the Andean natives, develop right, not left, ventricular hypertrophy. In newborns at sea level, right ventricular hypertrophy decreases promptly after birth, but it persists throughout life in Andean children living at 4540 m.² Similarly, as discussed later in the review,³ when lowlanders ascend to high altitude, there is an increase in pulmonary artery pressure and pressure load on the right ventricle. However, increased right ventricular afterloads lead to a decrease in left ventricular (LV) filling pressure and delayed LV untwist⁴ and decreased LV volumes.⁵ In adapted populations, such as the Tibetans, right ventricular abnormalities are less common than among Han immigrants to the area or patients with chronic mountain sickness.⁶ Moreover, there is evidence to suggest that despite a lower risk of coronary heart disease, Tibetans display ECG characteristics consistent with LV hypertrophy.⁷

A similar distinction can be made about leptin levels. Hypoxia stimulates the hypoxia-induced factor (HIF)-α–dependent expression of the leptin gene, but conflicting effects of hypoxia on leptin have been reported in the literature.⁸ The transient increase in leptin reported by some investigators^9–11 is associated with lowlanders moving to a higher altitude. Similarly, a transient decrease in ghrelin levels was observed in individual moving from low to high altitude.¹² In contrast, individuals acclimatized to high altitude, as discussed in the review, show a decrease in leptin levels,^13,14 and leptin levels in mountain dwellers show an inverse relationship with altitude.^15,16 This inverse relationship persisted even after adjusting for age, body-mass index, physical activity, blood pressure, and alcohol.¹⁶ Such divergent effects of altitude may be because of the stimulation of HIF-α by hypoxia in nonadapted, but not in adapted, individuals.¹ Finally, even though the pioneering work of Arias-Stella et al² shows higher elaboration of coronary microcirculation in Andean natives, it is unclear whether other populations show similar adaptations. High-altitude residents in general have normal or even decreased coronary blood flow.¹⁷ Indeed, skeletal muscle angiogenesis and the levels of vascular endothelial growth factor were found not to be different in Aymara high-altitude natives compared with sea-level residents.¹⁸ Therefore, even though some Andean natives have more elaborate coronary microcirculation, the relative contribution of this adaptation to lower rates of cardiovascular disease in this and other high-altitude populations, vis-à-vis other physiological differences (eg, in lipid metabolism, blood pressure regulation, or other metabolic processes), remains unclear and deserves further study.