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Upon exposure to high altitude, most mammals develop acute hypoxic pulmonary vasoconstriction (HPV) and, if the high altitude exposure is sustained, pulmonary hypertension, right ventricular hypertrophy, pulmonary vascular remodeling and polycythemia. However, there is a wide variability in the response to both acute and chronic hypoxia across species, strains and individuals. Some species acclimatize to hypoxic conditions successfully and develop mild pulmonary hypertension, whereas others develop severe pulmonary hypertension. For example, llamas at high altitude develop less pulmonary hypertension than cattle (3, 16). Moreover, individuals within species vary in their susceptibility to high altitude. For example, approximately 2-10% of cattle exposed to high altitude develop Brisket's Disease, which is characterized by severe pulmonary hypertension and right heart failure (20, 50), whereas the majority ofcattle are resistant. Likewise, our previous work on Sprague-Dawley rats has shown that the Hilltop strain develops more severe pulmonary hypertension, right ventricular hypertrophy and polycythemia than the Madison strain despite identical exposures to chronic hypoxia (41).

Humans also vary considerably in their response to high altitude or alveolar hypoxia. A small number of people develop chronic mountain sickness, characterized by severe pulmonary hypertension, hypoxemia and polycythemia (33). Although all the factors responsible for these differences between and within species are not completely known, multiple factors including physiological, biochemical, structural and, ultimately, genetic are likely to contribute to the strain differences in the responses to acute and chronic hypoxia, and will be discussed below.

2. Physiological Differences 2.1. Cardiopulmonary Differences

Hypoxia-induced strain-related cardiopulmonary differences have been described between several rat strains that parallel the differences reported between the Hilltop and Madison strains (Table 1). For instance, Wistar-Kyoto rats develop more pulmonary hypertension and muscularization of small pulmonary arteries than Fischer 344 rats (1), and fawn-hooded rats develop severe pulmonary hypertension and vascular remodeling in comparison to to age-matched Sprague-Dawley rats (45).

Table 1. Variability Among Species and Within Species in Response to Chronic Hypoxia

Hyperresponder

Hyporesponder

Reference

Hilltop rat

Madison rat

Ou and Smith, 1983 (41)

Fawn-Hooded rat

Spraguc-Dawley rat

Stelzncretal., 1992(45)

Yak

Domestic cow

Durmowicz et at., 1993 (8)

Wistar-Kyoto rat

Fischcr 344 rat

Aguirrc et al., 2000(1)

Pikas

Wistar Rat

Geet a!., 1998 (3)

Our laboratories have performed a number of detailed physiologic studies in order to elucidate these differences. In a study designed to understand polycythemic responses to hypoxia (34, 41), Ou and Smith first described the fundamentally different cardiopulmonary responses to high altitude in the Hilltop and Madison rats. Rats obtained from Hilltop laboratories (Hilltop, PA) became severely polycythemic and moribund after 4-5 weeks of hypoxic exposure, whereas those from the Madison, Wisconsin facility of Harlan Sprague Dawley were resistant to chronic hypoxia, developing only mild polycythemia and no morbidity after the same hypoxic exposure. Subsequent work demonstrated that the Hilltop rats behaved as though they developed chronic mountain sickness, with more severe polycythemia, pulmonary hypertension and right ventricular hypertrophy than the Madison rats (41). These cardiopulmonary differences were consistently observed regardless of gender, indicating a probable genetic origin (42). The time course of these changes is shown in Figure 1. Greater pulmonary hypertension and right ventricular hypertrophy were apparent in the Hilltops than Madisons as early as 7 days as indicated by differences in the right ventricular peak systolic pressure and the ratios of the left ventricular plus septal weights to right ventricle to (LV+S/RV), respectively (23, 24). However, significant differences in hematocrit between the strains were not apparent until after 2 weeks, suggesting that this difference was probably not primarily responsible for the cardiopulmonary differences.

Figure 1: Time course of changes in right ventricular peak systolic pressure (RVPP) (A), right ventricular to body weight (RV) (B), left ventricular plus septal to right ventricular weight (LV+S/RV) ratios (C) and hematocrit (Hct) (D) over days of hypoxic exposure (left side of panels) and normoxic recovery from hypoxia (right side of panels). *P<0.05 vs. baseline, t-P<0.05

Figure 1: Time course of changes in right ventricular peak systolic pressure (RVPP) (A), right ventricular to body weight (RV) (B), left ventricular plus septal to right ventricular weight (LV+S/RV) ratios (C) and hematocrit (Hct) (D) over days of hypoxic exposure (left side of panels) and normoxic recovery from hypoxia (right side of panels). *P<0.05 vs. baseline, t-P<0.05

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