Correlation of acute with chronic hypoxic pulmonary hypertension in cattle.

We investigated acute and chronic hypoxic pulmonary pressor responses in two groups of calves, one bred to be susceptible, the other resistant to high-altitude pulmonary hypertension. Twelve 5-mo-old susceptible calves residing at 1,524 m increased their mean pulmonary arterial pressure from 26 +/- 2 (SE) to 55 +/- 4 mmHg during 2 h at a simulated altitude of 4,572 m. In 10 resistant calves pressure increased from 22 +/- 1 to 37 +/- 2 mmHg. Five calves were selected from each group for further study. When 9 mo old, the 5 susceptible calves again showed a greater pressor response to acute hypoxia (27 +/- 1 to 55 +/- 4 mmHg) than did 5 resistant calves (23 +/- 1 to 41 +/- 3 mmHg). When 12 mo old, the 5 susceptible calves also developed a greater increase in pulmonary arterial pressure (21 +/- 2 to 9 +/- 4 mmHg) during 18 days at 4,572 m than did the 5 resistant calves (21 +/- 1 to 64 +/- 4 mmHg). Acute and chronic hypoxic pulmonary pressor responses were highly correlated (r = 0.91; P less than 0.001) indicating that they were probably produced through a common mechanism.     

Influence of altitude and age on pulmonary arterial pressure in cattle.

Pulmonary arterial pressures in native cattle ranging in age from 3 months to 10 yr were found to be increased with increasing altitudes of residence from sea level to 3048 m. At altitudes of 2590 and 3048 m, but not at sea level or 1524 m, the pressures were higher in older than in younger cattle. The magnitude of the pulmonary arterial pressure, and probably the rate of progression of pulmonary hypertension at high altitude, were much less in native cattle than in cattle that were newcomers from low altitude. Natural and artificial selection are believed to have minimized the level of pulmonary hypertension in native high altitude cattle, thus protecting them from high mountain or brisket disease.     

Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude

Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 +/- 12 and 58 +/- 10 mmHg for noninvasive and invasive determination, respectively; means +/- SD) than subjects resistant to HAPE (37 +/- 8 and 37 +/- 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30-83 mmHg). Spearman test showed a highly significant correlation (r = 0.89, P < 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 +/- 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement.     

Interaction between cold and altitude exposure on pulmonary circulation of cattle

Hereford calves were exposed in a temperature-controlled hypobaric chamber to environmental temperatures of -2 to 1 degree C (cold) at altitudes of 1,524 m (resident altitude) and 3,048 m 1) to characterize the effects of cold exposure on the pulmonary circulation; 2) to examine the role of cold-induced hypoventilation on the pulmonary circulation; and 3) to examine the interaction between cold and hypoxia on the pulmonary circulation. Cold exposure produced a significant increase in pulmonary arterial pressure (Ppa), pulmonary arterial wedge pressure (Ppaw), and pulmonary vascular resistance (PVR) at both 1,524 and 3,048 m without affecting cardiac output. Concomitantly, cold exposure caused reductions in minute ventilation, respiratory rate, end-tidal O2 tension (PETO2), and arterial O2 tension (PaO2). Tidal volume, end-tidal CO2 tension, and arterial CO2 tension increased. Neither arterial pH nor O2 consumption changed during cold exposure. These results indicated that both pulmonary arterial and venous vasoconstriction were responsible for the pulmonary hypertension associated with cold exposure. Acute exposure to 3,048 m during cold exposure produced increases in Ppa and PVR that were similar to those elicited by cold exposure at 1,524. It was concluded that altitude exposure neither attenuated nor potentiated the effect of cold exposure on the pulmonary circulation; rather, altitude and cold exposure interacted additively. O2 administered during cold exposure to restore PETO2 and PaO2 to control values partially restored Ppa and PVR to control values. This suggested that a portion of the pulmonary hypertension associated with cold exposure was due to hypoxic pulmonary vasoconstriction elicited by the cold-induced alveolar hypoventilation.     

Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension

Previous studies have demonstrated that environmentally or genetically induced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because neonatal right ventricular myocytes are immature and are in the process of significant cytoskeletal change, we hypothesized that they may be particularly susceptible to pressure stress. Newborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe pulmonary hypertension (pulmonary arterial pressure = 101 +/- 6 vs. 27 +/- 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial striations in the failing neonatal right but not left ventricles and in neither ventricle of adolescent cattle dying of altitude-induced right heart failure. In neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed selectively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within myocytes from the failing ventricles, vinculin and desmin were observed to redistribute diffusely within the cytosol, metavinculin appeared in disorganized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions; metavinculin total content was markedly decreased, tubulin content increased, particularly in the structural fraction, and cadherin total content and distribution were unchanged. We conclude that hypoxic pulmonary hypertensive-induced neonatal right ventricular failure is associated with disorganization of the cytoskeletal architecture.     

Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen

High altitude increases pulmonary arterial pressure (PAP), but no measurements have been made in humans above 4,500 m. Eight male athletic volunteers were decompressed in a hypobaric chamber for 40 days to a barometric pressure (PB) of 240 Torr, equivalent to the summit of Mt. Everest. Serial hemodynamic measurements were made at PB 760 (sea level), 347 (6,100 m), and 282/240 Torr (7,620/8,840 m). Resting PAP and pulmonary vascular resistance (PVR) increased from sea level to maximal values at PB 282 Torr from 15 +/- 0.9 to 34 +/- 3.0 mmHg and from 1.2 +/- 0.1 to 4.3 +/- 0.3 mmHg.l-1 X min, respectively. During near maximal exercise PAP increased from 33 +/- 1 mmHg at sea level to 54 +/- 2 mmHg at PB 282 Torr. Right atrial and wedge pressures were not increased with altitude. Acute 100% O2 breathing lowered cardiac output and PAP but not PVR. Systemic arterial pressure and resistance did not rise with altitude but did increase with O2 breathing, indicating systemic control differed from the lung circulation. We concluded that severe chronic hypoxia caused elevated pulmonary resistance not accompanied by right heart failure nor immediately reversed by O2 breathing.     

Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude

It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.     

Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after N(G)-nitro-L-arginine methyl ester (20.9 ± 1.1 vs. 13.7 ± 0.5 mmHg; 39.9 ± 5.0 vs. 18.3 ± 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K(+) (1.34 ± 0.05 vs. 1.16 ± 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 ± 2.9 vs. 21.1 ± 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 ± 0.1 vs. 1.1 ± 0.2), phosphodiesterase (1.4 ± 0.1 vs. 0.7 ± 0.1), and Ca(2+)-activated K(+) channel (0.76 ± 0.16 vs. 0.30 ± 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 ± 0.26 vs. 2.22 ± 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level.     

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m

Some human newborns have a syndrome characterized by irreversible pulmonary hypertension and severe hypoxemia and by medial hypertrophy and adventitial thickening of pulmonary arteries. We considered that newborn calves made severely hypoxic might reproduce features of the human disease. When 2-day-old calves were placed at 4,300 m simulated altitude, pulmonary arterial pressure was increased and could be reversed by 100% O2. However, after 2 wk at 4,300 m, pulmonary arterial pressures were suprasystemic and there was right-to-left shunting probably through the foramen ovale and a patent but restrictive ductus arteriosus. Suprasystemic pulmonary pressure and hypoxemia persisted with 100% O2 breathing. Morphometrical examination of the lung arteries showed a markedly thickened adventitia with cellular proliferation and collagen and elastin deposition. There was increased medial thickness and distal muscularization of the pulmonary arteries associated with decreased luminal diameter. The rapid development of severe pulmonary hypertension and poor responsiveness to O2 was associated with increased arterial wall thickness, particularly involving the adventitia. Thus the pulmonary arterial circulation in these calves, which were placed at high altitude for 2 wk, exhibited features resembling persistent pulmonary hypertension in newborn infants.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

Impact of acute hypoxic pulmonary hypertension on LV diastolic function in healthy mountaineers at high altitude

In pulmonary hypertension right ventricular pressure overload leads to abnormal left ventricular (LV) diastolic function. Acute high-altitude exposure is associated with hypoxia-induced elevation of pulmonary artery pressure particularly in the setting of high-altitude pulmonary edema. Tissue Doppler imaging (TDI) allows assessment of LV diastolic function by direct measurements of myocardial velocities independently of cardiac preload. We hypothesized that in healthy mountaineers, hypoxia-induced pulmonary artery hypertension at high altitude is quantitatively related to LV diastolic function as assessed by conventional and TDI Doppler methods. Forty-one healthy subjects (30 men and 11 women; mean age 41 +/- 12 yr) underwent transthoracic echocardiography at low altitude (550 m) and after a rapid ascent to high altitude (4,559 m). Measurements included the right ventricular to right atrial pressure gradient (DeltaP(RV-RA)), transmitral early (E) and late (A) diastolic flow velocities and mitral annular early (E(m)) and late (A(m)) diastolic velocities obtained by TDI at four locations: septal, inferior, lateral, and anterior. At a high altitude, DeltaP(RV-RA) increased from 16 +/- 7 to 44 +/- 15 mmHg (P < 0.0001), whereas the transmitral E-to-A ratio (E/A ratio) was significantly lower (1.11 +/- 0.27 vs. 1.41 +/- 0.35; P < 0.0001) due to a significant increase of A from 52 +/- 15 to 65 +/- 16 cm/s (P = 0.0001). DeltaP(RV-RA) and transmitral E/A ratio were inversely correlated (r(2) = 0.16; P = 0.0002) for the whole spectrum of measured values (low and high altitude). Diastolic mitral annular motion interrogation showed similar findings for spatially averaged (four locations) as well as for the inferior and septal locations: A(m) increased from low to high altitude (all P < 0.01); consequently, E(m)/A(m) ratio was lower at high versus low altitude (all P < 0.01). These intraindividual changes were reflected interindividually by an inverse correlation between DeltaP(RV-RA) and E(m)/A(m) (all P < 0.006) and a positive association between DeltaP(RV-RA) and A(m) (all P < 0.0009). In conclusion, high-altitude exposure led to a two- to threefold increase in pulmonary artery pressure in healthy mountaineers. This acute increase in pulmonary artery pressure led to a change in LV diastolic function that was directly correlated with the severity of pulmonary hypertension. However, in contrast to patients suffering from some form of cardiopulmonary disease and pulmonary hypertension, in these healthy subjects, overt LV diastolic dysfunction was not observed because it was prevented by augmented atrial contraction. We propose the new concept of compensated diastolic (dys)function.     

Pulmonary hypertention,blood coagulation and aspirin treatment in high altitude exposed cattle

Six calves resident at 400 m altitude were exposed for 2 weeks to a simulated altitude of 4,500 m. This exposure produced the following changes: increases in heart rate (34 b/min), mean pulmonary arterial pressure (8 Torr), erythrocyte number (22%), haemoglobin (32%), haematocrit (34%), blood pH (0.037 units), leucocyte number (21%), blood clotting time (18%), and prothrombin time (7%). Decreases were found in thrombocyte number (8%) and clot retraction (22%). Orally administered acetylsalicylic acid (aspirin) over 14 days (90 mg/(kg.day)) had no effect on these responses to high altitude. The results provide further evidence against the involvement of prostaglandin as mediator in pulmonary hypertension.     

Pulmonary vascular response of the coati to chronic hypoxia.

The unusually muscular pulmonary arteries normally present in cattle and swine residing at low altitude are associated with a rapid development of severe pulmonary hypertension when those animals are moved to high altitude. Because these species lack collateral ventilation, they appear to have an increased dependence on hypoxic vasoconstriction to maintain normal ventilation-perfusion balance, which, in turn, maintains thickened arterial walls. The only other species known to lack collateral ventilation is the coati, which, similarly, has thick-walled pulmonary arteries. We tested the hypothesis that coatis will develop severe high-altitude pulmonary hypertension by exposing six of these animals (Nasua narica) to a simulated altitude of 4,900 m for 6 wk. After the exposure, pulmonary arterial pressures were hardly elevated, right ventricular hypertrophy was minimal, there was no muscularization of pulmonary arterioles, and, most surprising of all, there was a decrease in medial thickness of muscular pulmonary arteries. These unexpected results break a consistent cross-species pattern in which animals with thick muscular pulmonary arteries at low altitude develop severe pulmonary hypertension at high altitude.     

Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du,James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible tochronic mountain sickness. J. Appl.Physiol. 83(1): 25-31, 1997.Hilltop (H) strainSprague-Dawley rats are more susceptible to chronic mountain sicknessthan are the Madison (M) strain rats. It is unclear what role pulmonaryvascular remodeling, polycythemia, and hypoxia-induced vasoconstrictionplay in mediating the more severe pulmonary hypertension that developsin the H rats during chronic hypoxia. It is also unclear whether theincreased sensitivity of the H rats to chronic mountain sickness isspecific for a hypoxia effect or, instead, reflects a generalpropensity toward the development of pulmonary hypertension.Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonaryhypertension. We hypothesized that the difference in the pulmonaryvascular response to chronic hypoxia between H and M rats reflects anincreased sensitivity of the H rats to any pulmonary hypertensivestimuli. Consequently, we expected the two strains to also differ intheir susceptibility to MCT-induced pulmonary hypertension. Pulmonaryarterial pressures in conscious H and M rats were measured 3 wk after asingle dose of MCT, exposure to a simulated high altitude of 18,000 ft(barometric pressure = 380 mmHg), and administration of a single doseof saline as a placebo. The H rats had significantlyhigher pulmonary arterial pressures and right ventricular weights afterMCT and chronic hypoxia than did the M rats. The H rats also had morepulmonary vascular remodeling, i.e., greater wall thickness as apercentage of vessel diameter, after MCT and chronic hypoxia than didthe M rats. The H rats had significantly lower arterialPO₂ than did the M rats after MCT,but the degree of hypoxemia was mild [arterialPO₂ of 72.5 ± 0.8 (SE) Torr for Hrats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H ratshad lower arterial PCO₂ and largerminute ventilation values than did the M rats after MCT. Theseventilatory differences suggest that MCT caused more severe pulmonaryvascular damage in the H rats than in the M rats. These data supportthe hypothesis that the H rats have a general propensity to developpulmonary hypertension and suggest that differences in pulmonaryvascular remodeling account for the increased susceptibility of H rats,compared with M rats, to both MCT and chronic hypoxia-induced pulmonaryhypertension.

     

Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension

To evaluate pulmonary vasodilation in a structurally altered pulmonary vascular bed, we gave endothelium-dependent (acetylcholine) and endothelium-independent [sodium nitroprusside, prostaglandin I2 (PGI2)] vasodilators in vivo and to isolated lobar pulmonary arteries from neonatal calves with severe pulmonary hypertension. Acetylcholine, administered by pulmonary artery infusion, decreased pulmonary arterial pressure from 120 +/- 7 to 71 +/- 6 mmHg and total pulmonary resistance from 29.4 +/- 2.6 to 10.4 +/- 0.9 mmHg.l-1.min without changing systemic arterial pressure (90 +/- 5 mmHg). Although both sodium nitroprusside and PGI2 lowered pulmonary arterial pressure to 86 +/- 4 and 96 +/- 4 mmHg, respectively, they also decreased systemic arterial pressure to 65 +/- 4 and 74 +/- 3 mmHg, respectively. Neither sodium nitroprusside nor PGI2 was as effective as acetylcholine at lowering total pulmonary resistance (18.0 +/- 3.6 and 19.1 +/- 2.2 mmHg.l-1.min, respectively). Right-to-left cardiac shunt through the foramen ovale was decreased by acetylcholine from 1.6 +/- 0.4 to 0.1 +/- 0.2 l/min but was not changed by sodium nitroprusside or PGI2. Isolated lobar pulmonary arteries from pulmonary hypertensive calves did not relax in response to acetylcholine, whereas isolated pulmonary arteries from age-matched control calves did relax in response to acetylcholine. Control and pulmonary hypertensive lobar pulmonary arteries relaxed equally well in response to sodium nitroprusside. We concluded that acetylcholine vasodilation was impaired in vitro in isolated lobar pulmonary arteries but was enhanced in vivo in resistance pulmonary arteries in neonatal calves with pulmonary hypertension.     

Pulmonary artery pressure and cardiac function in children and adolescents after rapid ascent to 3,450 m

High-altitude destinations are visited by increasing numbers of children and adolescents. High-altitude hypoxia triggers pulmonary hypertension that in turn may have adverse effects on cardiac function and may induce life-threatening high-altitude pulmonary edema (HAPE), but there are limited data in this young population. We, therefore, assessed in 118 nonacclimatized healthy children and adolescents (mean ± SD; age: 11 ± 2 yr) the effects of rapid ascent to high altitude on pulmonary artery pressure and right and left ventricular function by echocardiography. Pulmonary artery pressure was estimated by measuring the systolic right ventricular to right atrial pressure gradient. The echocardiography was performed at low altitude and 40 h after rapid ascent to 3,450 m. Pulmonary artery pressure was more than twofold higher at high than at low altitude (35 ± 11 vs. 16 ± 3 mmHg; P < 0.0001), and there existed a wide variability of pulmonary artery pressure at high altitude with an estimated upper 95% limit of 52 mmHg. Moreover, pulmonary artery pressure and its altitude-induced increase were inversely related to age, resulting in an almost twofold larger increase in the 6- to 9- than in the 14- to 16-yr-old participants (24 ± 12 vs. 13 ± 8 mmHg; P = 0.004). Even in children with the most severe altitude-induced pulmonary hypertension, right ventricular systolic function did not decrease, but increased, and none of the children developed HAPE. HAPE appears to be a rare event in this young population after rapid ascent to this altitude at which major tourist destinations are located.     

Prenatal programming of adult blood pressure: role of maternal corticosteroids

Both maternal glucocorticoid administration and maternal dietary protein or food restriction in pregnancy cause fewer nephrons and hypertension in the adult offspring. The purpose of these studies was to determine the extent to which nutritional factors contribute to programming of offspring hypertension by maternal glucocorticoids. Pregnant rats were treated with dexamethasone (100 microg x kg(-1) x d(-1) sc) on days 1-10 (ED) or days 15-20 (LD) of pregnancy. Additional groups of pregnant animals were pair fed to the early (EDPF) and late (LDPF) dexamethasone-treated groups, and another group was untreated or given vehicle (C). The dams treated with dexamethasone reduced their food intake and lost or failed to gain a normal amount of weight during treatment; body weights of ED dams caught up to normal after the treatment period, whereas those of LD dams did not. In adulthood ( approximately 21 wks), chronically instrumented male offspring of ED had normal blood pressures (125 +/- 2 mmHg vs. 126 +/- 1 mmHg in C), whereas LD offspring were hypertensive (136 +/- 3 mmHg). However, LDPF offspring were equally hypertensive (134 +/- 2 mmHg). Glomerular filtration rates normalized to body weight were not significantly different among groups. Qualitatively similar results were found in female offspring. Thus the long-term effects of maternal glucocorticoid administration at this dose on offspring's blood pressure may, in large part, be accounted for by the reduction in maternal food intake. These data suggest that maternal glucocorticoids and maternal food or protein restriction may, at least in part, share a common mechanism in programming offspring for hypertension. The window of sensitivity of future offspring blood pressure to either maternal insult coincides with nephrogenesis in the rat, suggesting that impaired renal development could play an important role in this programming.     

Maternal glucocorticoids and prenatal programming of hypertension

Maternal glucocorticoids have been postulated to play an important role in prenatal programming for adult hypertension in the offspring. However, we have shown previously that offspring hypertension caused by maternal dexamethasone subcutaneous administration at 100 microg x kg(-1) x day(-1) can be accounted for by the corresponding reduction in food intake that these mothers experience. The present studies were designed to determine whether there is a lower dose of dexamethasone that does not reduce maternal food intake yet still causes hypertension in the adult offspring. Pregnant rats were treated with subcutaneous dexamethasone at 50 (D50) or 25 (D25) microg x kg(-1) x day(-1) on days 15-20 of pregnancy. An additional group was untreated or received vehicle injections (control). D25 and D50 dams reduced their food intake by 17% during and after treatment and gained 31% less weight than control over the course of gestation. In adulthood ( approximately 21 wk), chronically instrumented male offspring of D50 and D25 had normal blood pressures (D50: 131 +/- 2 mmHg and D25: 127 +/- 3 mmHg vs. 127 +/- 2 mmHg in control). Qualitatively similar results were found in female offspring. Thus neither dexamethasone per se at these doses nor the accompanying modest reductions in maternal food intake and weight gain have blood pressure programming effects. As far as has been tested, there does not appear to be a dose of dexamethasone that, given over this time period in the rat, programs offspring hypertension without reducing maternal food intake and weight gain. These data do not support the hypothesis that maternal glucocorticoids program offspring hypertension directly.     

Effects of exposure to a simulated altitude of 3,500 m on calves and oxen

Nine calves and nine oxen were divided into 6 groups and exposed in a climatised low pressure chamber to the following conditions: 2 weeks at 400 m and 4 weeks at 3,500 m. High altitude produced the following changes: increases in heart rate and pulmonary artery pressure, both these changes being larger in the calves than in the oxen. During 4 weeks continuous exposure to 3,500 m, heart rate declined, whereas pulmonary arterial pressure rose. There were increments in respiratory rate, blood-pH, leucocyte number, rectal temperature, blood lactate and blood pyruvate, but no changes in the lactate/pyruvate ratio. Increases in erythrocyte number, haemoglobin, haematocrit, blood specific gravity and blood viscosity were more pronounced in the oxen than in the calves. Feed intake in all animals tended to be depressed in the first half of the high altitude periode. Water intake showed a fall during the first day at 3,500 m, but recovered thereafter. It is concluded that in response to high altitude the calves activated preferentially the circulatory, the oxen the erythropoetic system.