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Cats were taken from Denver (5,200 ft.) to Mt. Evans (14,150 ft.) anticipating that this degree of hypoxia would induce pulmonary hypertension. Rabbits were included for comparison with the cat. All cats died without developing pulmonary hypertension or right heart failure, and in spite of arterial and mixed venous O2 tensions maintained well above those of the rabbit. Presumably the cat's failure to survive was not a failure of oxygen transport to the arterial blood, or to the systemic capillaries. Paradoxically, five of eight rabbits survived despite poor arterial blood oxygenation. The rabbits developed marked polycythemia associated with modest right ventricular hypertension and dilatation. Submitted on June 6, 1962

The oxygen transport and pulmonary hemodynamics of lambs native to low altitude were evaluated in Denver and on Mount Evans (12,700 ft.). Because the Hb-O2 dissociation curve is placed well to the right of most other mammals, markedly depressed arterial O2 saturations (59%) occurred at high altitude. However, the lambs adapted remarkably well and showed normally rapid growth. The mixed venous Po2 was relatively well maintained, primarily by a narrowing of the A-V Po2 gradient to 11 mm Hg. Despite the marked hypoxemia, elevation of the pulmonary artery pressure was not a consistent finding, and when it occurred it was neither marked nor sustained. Submitted on June 6, 1962

Each of ten steers taken for 9 weeks to 12,700 ft. (Mt. Evans, Colorado) showed a marked increase in pulmonary artery (PA) pressure. Three animals had PA pressures above 90 mm Hg and one developed right heart failure. The bovine species is remarkable for the severe pulmonary hypertension which develops during chronic hypoxia rather than for an excessive PA pressure response to acute hypoxia. The rate at which the pulmonary hypertension developed at 12,700 ft. was extremely rapid compared to that at 10,000 ft. Therefore, not only the duration of the hypoxic stimulus but also its severity determine the response. The severity of the stimulus was augmented by the absence of a sustained increase in ventilation at high altitude. The pressure rise with acute hypoxia during the control period at low altitude and the dramatic fall in PA pressure when oxygen was administered at high altitude provided evidence for hypoxia-induced pulmonary vasoconstriction as an important mechanism in bovine pulmonary hypertension. Submitted on June 6, 1962

Background The relationships among systolic pulmonary artery pressure (SPAP), diastolic pulmonary artery pressure (DPAP), and mean pulmonary artery pressure (MPAP) have been found to be constant in humans breathing air, at rest, while supine. It would be important for those studying the pulmonary circulation if this relationship were maintained under other circumstances, such as change in posture, during exercise, or after pharmacologic manipulation. In particular, it would be useful if the relationship were maintained when treating pulmonary hypertension because this would allow different methods of measurement to be compared, such as SPAP from echocardiography and MPAP from right heart catheterization. Methods Data were reviewed from both healthy subjects and those with pulmonary hypertension (n = 65) who had a micromanometer-tipped, high-fidelity pulmonary artery catheter inserted for between 6 and 36 h in the Scottish Pulmonary Vascular Unit between 1997 and 2003. The 5-min averages, while the patient was supine at rest, were analyzed by linear regression to compare the response of SPAP and DPAP with MPAP. Results There were linear relationships (measured in millimeters of mercury) of SPAP with MPAP (SPAP = 1.50 MPAP + 0.46), and DPAP with MPAP (DPAP = 0.71 MPAP − 0.66). These were maintained with a high degree of accuracy following changes in posture and activity. Conclusions SPAP, MPAP, and DPAP were strongly related, and these relationships were maintained under varying conditions. This finding will allow comparison between invasive and noninvasive descriptions of pulmonary hemodynamics found in the literature.

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.

Increasing pulmonary arterial (Ppa) and wedge (Pw) pressures at high flow (Q) during exercise could distend the thin-walled vessels. A mechanical descriptor of vascular distension, the distensibility (alpha, fractional diameter change/mmHg pressure), has been reported to be approximately 0.02 for isolated large and small arteries, i.e., a 2% change in diameter per millimeter mercury pressure. In this review we used a pulmonary hemodynamic model to estimate alpha for data from exercising humans to determine whether interpretable results might be obtained. In 59 normal sea level subjects having published measurements of Ppa and Pw over a range of Q, we found values of alpha (0.02 +/- 0.002) giving calculated Ppa, which matched measured Ppa to within 1.3 +/- 0.1 (SE) mmHg. When subjects were exposed to chronic hypoxia (n = 6, in Operation Everest II), alpha decreased (0.022 +/- 0.002 vs. 0.008 +/- 0.001, P0.05), but when subjects were exposed to acute hypoxia (Duke chamber study, n = 8), alpha did not decrease (0.014 +/- 0.002 vs. 0.012 +/- 0.002, P = not significant). Values of alpha tended to decrease with age in men60 yr. Thus at rest and during exercise, normal values of alpha in young persons were similar to those measured in vitro, and the values decreased in chronic hypoxia and with aging where vascular remodeling or vascular wall stiffening was expected. We propose that the estimation of pulmonary vascular distensibility in humans may be a useful descriptor of pulmonary hemodynamics.

Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-β1in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.

Pulmonary hypertension had long been suspected in high-altitude natives of the Andes. However, it remained for a team of Peruvian scientists led by Dante Penaloza to provide not only the first clear evidence that humans living at high altitude did indeed have chronic, and occasionally severe, pulmonary hypertension, but more importantly, that this was a consequence of structural changes in the pulmonary vascular bed. Novel histological findings by one of the team, Javier Arias-Stella, indicated that hypoxia-induced thickening of the pulmonary arteriolar walls was the primary cause of the elevated pressure. Because the hypertension was not promptly reversed by vasodilators (oxygen inhalation or acetylcholine infusion), they found it differed from acute hypoxic pulmonary vasoconstriction. The team's other novel findings included a delay in the normal fall in pulmonary vascular resistance after birth and, in adults, a lack of vasodilation with muscular exercise. Furthermore, the altitude-related pulmonary hypertension resolved over time at sea level.

Information is rapidly emerging regarding the important role of the arterial vasa vasorum in a variety of systemic vascular diseases. In addition, increasing evidence suggests that progenitor cells of bone marrow (BM) origin may contribute to postnatal neovascularization and/or vascular wall thickening that is characteristic in some forms of systemic vascular disease. Little is known regarding postnatal vasa formation and the role of BM-derived progenitor cells in the setting of pulmonary hypertension (PH). We sought to determine the effects of chronic hypoxia on the density of vasa vasorum in the pulmonary artery and to evaluate if BM-derived progenitor cells contribute to the increased vessel wall mass in a bovine model of hypoxia-induced PH. Quantitative morphometric analyses of lung tissue from normoxic and hypoxic calves revealed that hypoxia results in a dramatic expansion of the pulmonary artery adventitial vasa vasorum. Flow cytometric analysis demonstrated that cells expressing the transmembrane tyrosine kinase receptor for stem cell factor, c-kit, are mobilized from the BM in the circulation in response to hypoxia. Immunohistochemistry revealed an increase in the expression of c- kit+cells together with vascular endothelial growth factor, fibronectin, and thrombin in the hypoxia-induced remodeled pulmonary artery vessel wall. Circulating mononuclear cells isolated from neonatal calves exposed to hypoxia were found to differentiate into endothelial and smooth muscle cell phenotypes depending on culture conditions. From these observations, we suggest that the vasa vasorum and circulating progenitor cells could be involved in vessel wall thickening in the setting of hypoxia-induced PH.

We have examined the sympathoadrenal responses to both acute and chronic high-altitude exposure at the summit of Pikes Peak, CO, in both men and women. A dissociation between the adrenal medullary response (acute) with that of the sympathetic nervous system (chronic) is observed. Both alpha- and beta-adrenergic contributions to key metabolic and physiologic adjustments to high-altitude exposure are evident.

In Andean natives (NAT), the ventilatory response to hypoxia is blunted at rest but potential interaction with exercise has been little studied. Therefore, during three levels of submaximal exercise, 13 NAT were compared with 6 sojourners (SOJ) acclimatized at 4360 m for an average of 7 months. Exercise ventilation was measured first breathing oxygen (P i O 2 410 Torr) and then ambient air (P i O 2 86 Torr). In SOJ ventilation was increased by hypoxia at all three exercise levels including the mildest. In NAT, however, the threshold for hypoxic sensitivity was displaced, but during exercise above this threshold hypoxia increased ventilation at a rate similar to that seen in SOJ. At the heaviest workload, ventilation was increased by hypoxia 18% in NAT compared with 30% in SOJ. Thus, during exercise Andean NAT do exhibit a ventilatory sensitivity to hypoxia, the magnitude of which is dependent upon exercise intensity.

Proliferation of fibroblasts contributes to the adventitial thickening observed during the development of hypoxia-induced pulmonary hypertension. However, whether all or only specific subpopulations of fibroblasts proliferate during this process is unknown. Because lung, skin, and gingiva contain multiple fibroblast subpopulations, we hypothesized that the pulmonary artery (PA) adventitia of neonatal calves is composed of multiple fibroblast subpopulations and that only selective subpopulations expand under chronic hypoxic conditions. Fibroblast subpopulations were isolated from PA adventitia of control calves using limited dilution cloning techniques. These subpopulations exhibited marked differences in morphology, actin expression, and serum-stimulated growth. Only select fibroblast subpopulations demonstrated the ability to proliferate in response to hypoxia. Fibroblast subpopulations were similarly isolated from calves exposed to hypoxia (14 days). With regard to morphology, actin expression, and serum-stimulated growth of subpopulations, there were no obvious differences in fibroblast subpopulations between the hypoxic and the control calves. However, the number of fibroblast subpopulations with about a twofold increase in hypoxia-induced DNA synthesis was significantly greater in the hypoxic calves (26%) compared with control calves (10%). We conclude that the bovine PA adventitia comprises numerous phenotypically and biochemically distinct fibroblast subpopulations and that select subpopulations expand in response to chronic hypoxia.

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.

We evaluated the hypotheses that on acute exposure to hypobaric hypoxia, sympathetic stimulation leads to augmented muscle lactate production and circulating [lactate] through a β-adrenergic mechanism and that β-adrenergic adaptation to chronic hypoxia is responsible for the blunted exercise lactate response after acclimatization to altitude. Five control and 6 β-blocked men were studied during rest and exercise at sea level (SL), on acute exposure to 4,300 m (A1), and after a 3-wk sojourn at altitude (A2). Exercise was by leg cycling at 49% of SL peak O2 consumption (V˙o 2 peak) (65% of altitude V˙o 2 peak or 87 ± 2.6 W); β-blockade was by propranolol (80 mg 3× daily), femoral arterial and venous blood was sampled; leg blood flow (Q˙) was measured by thermodilution, leg lactate net release [L˙ = (2) (1-leg Q) venous-arterial concentrationL] was calculated, and vastus lateralis needle biopsies were obtained. Muscle [lactate] increased with exercise and acute altitude exposure but regressed to SL values with acclimatization; β-blockade had no effect on muscle [lactate]. Arterial [lactate] rose during exercise at SL (0.9 ± 0.1 to 1.5 ± 0.3 mM); exercise at A1 produced the greatest arterial [lactate] (4.4 ± 0.8 mM), and exercise at A2 an intermediate response (2.1 ± 0.6 mM). β-Blockade reduced circulating [lactate] ∼45% during exercise under all altitude conditions. L˙ increased transiently at exercise onset but then declined over time under all conditions. Blood and muscle “lactate paradoxes” occurred independent of β-adrenergic influences, and the hypotheses relating the blood lactate response at altitude to β-adrenergic mechanisms are rejected. During exercise at altitude, arterial [lactate] is determined by factors in addition to hypoxemia, circulating epinephrine, and net lactate release from active muscle beds.

Oddly, Carl Wiggers (1883–1962), who is remembered for his work on the systemic circulation, may be considered the “American father of the pulmonary circulation.” In nearly 20 papers published in the American Journal of Physiology between 1909 and 1925, he reported the first reliable pressure contours in the pulmonary artery, inquired into the relationship between respiration and pulmonary arterial pressure, examined right atrial and right ventricular function, and demonstrated how right and left heart dynamics relate to heart sounds. He also stimulated direct visualization of the lung microcirculation. Method and concept are inextricably linked in the progress of science. His contributions to the pulmonary circulation were based on his high-fidelity pressure and sound recording instruments, which he ultimately applied in the left heart. Wiggers’ search for excellence in method brought him well-deserved fame in the systemic circulation, but the search began in the lung.

Recent clinical observations of a high incidence of preexisting respiratory infections in pediatric cases of high-altitude pulmonary edema prompted us to ask whether such infections would increase the susceptibility to hypoxia-induced pulmonary edema in young rats. We infected weanling rats with Sendai virus, thus causing a mild respiratory infection. Within 7 days of infection, Sendai virus was essentially undetectable by using viral culture and immunohistochemical techniques. Animals at day 7 of Sendai virus infection were then exposed to normobaric hypoxia (fraction of inspired O2= 0.1) for 24 h and examined for increases in gravimetric lung water and in vascular permeability, as well as for histological evidence of increased lung water. Bronchoalveolar lavage was performed on a separate series of animals. Compared with control groups, infected hypoxic animals showed significant increases in perivascular cuffing, gravimetric lung water, and lung protein leak. In addition, infected hypoxic animals had increases in lavage fluid cell counts and protein content compared with controls. We conclude that young rats, exposed to moderate hypoxia while recovering from a mild viral respiratory infection, may demonstrate evidence of early pulmonary edema formation, a finding of potential relevance to human high-altitude pulmonary edema.

When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the beta-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic beta-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21-33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PV(sub EB)), BV by the carbon monoxide method (BV(sub CO)), red cell volume (RCV)was calculated from hematocrit (Hct) and BV(sub CO), and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9-11 (ALT-10) and 9-20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg/day), and five received a placebo (pla). Effective beta-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU/ml] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PV(sub EB)[pla: -15.8 (3.8) vs pro: -19.9 (2.8)%], RCV(sub CO) [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BV(sub CO) [pla: -7.3 (2.3) vs pro: -7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the beta-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects.

Roberts, A. C., G. E. Butterfield, A. Cymerman, J. T. Reeves, E. E. Wolfel, and G. A. Brooks. Acclimatization to 4,300-m altitude decreases reliance on fat as a substrate. J. Appl. Physiol. 81(4): 1762–1771, 1996.—We tested the hypothesis that exposure to altitude decreases reliance on free fatty acids (FFA) as substrates and increases dependency on blood glucose. Therefore, the effects of exercise, hypobaric hypoxia, and altitude acclimatization on FFA, glycerol and net glucose uptake and release [ = 2(leg blood flow)(arteriovenous concentration)] and on fatty acid (FA) consumption by the legs (= 3 × glycerol release + FFA uptake) were measured. Because sympathetic responses have been implicated, we utilized nonspecific β-blockade and observed responses to exercise, altitude, and altitude acclimatization. We studied six healthy β-blocked men (β) and five matched controls (C) during rest and cycle ergometry exercise (88 W) at 49% of sea-level (SL) peak O2 uptake at the same absolute power output on acute altitude exposure (A1; barometric pressure = 430 Torr) and after 3 wk of chronic altitude exposure to 4,300 m (A2). During exercise at SL, FA consumption rates increased ( P < 0.05). On arrival at 4,300 m, resting leg FFA uptake and FA consumption rates were not significantly different from those at SL. However, after acclimatization to altitude, at rest leg FA consumption decreased to essentially zero in both C and β groups. During exercise at altitude after acclimatization, leg FA consumption increased significantly, but values were less than at SL or A1 ( P < 0.05), whereas glucose uptake increased relative to SL values. Furthermore, β-blockade significantly increased glucose uptake relative to control. We conclude that 1) chronic altitude exposure decreases leg FA consumption during rest and exercise; 2) relative to SL, FFA uptake decreases while glucose uptake increases during exercise at altitude; and 3) β-blockade potentiates these effects.

To test the hypothesis that altitude exposure increases glucose utilization and that this increment is mediated by a beta-adrenergic mechanism, the effects of hypobaric hypoxia and beta-blockade on glucose rates of appearance (Ra), disappearance (Rd), oxidation (Rox), and leg uptake [G = 2(arteriovenous glucose difference)(1 - leg blood flow)] were measured during rest and a given submaximal exercise task. We studied six healthy beta-blocked (beta) men [26.7 +/- 1.2 (SE) yr, 74.0 +/- 6.6 kg] and five matched controls (C; 26 +/- 1.2 yr, 69.3 +/- 2.6 kg) in energy and nitrogen balance during rest and leg cycle-ergometer exercise at sea level, on acute altitude exposure to 4,300 m (barometric pressure = 463 Torr), and after 3 wk of habituation. Subjects received a primed continuous infusion of [6,6-2H]- and [1-13C]glucose, rested for = or = 90 min, and then immediately exercised for 45 min at 89 W, which elicited 49% of sea-level peak O2 consumption (VO2peak; 65% of altitude VO2peak). At sea level, resting Ra was 1.47 +/- 0.19 and 1.66 +/- 0.16 mg x kg-1 x min-1 for C and beta, respectively, and increased to 3.04 +/- 0.25 and 3.56 +/- 0.27 mg x kg-1 x min-1, respectively, during exercise. Thus glucose Ra was significantly increased by beta-blockade during rest and exercise at sea level. At sea level, beta-blockade increased leg G, which accounted for 49 and 69% of glucose disposal during exercise in C and beta, respectively. On acute altitude exposure, glucose Ra rose significantly during rest and exercise relative to sea level, whereas blockade continued to augment this increment. During exercise on acute exposure, G increased more than at sea level and accounted for a greater percentage (80 and 97%, respectively) of Rd in C and beta during exercise. Similarly, Rox values, particularly during exercise, were increased significantly at altitude relative to sea level, and beta-blockade potentiated this effect. During a given submaximal exercise task after acclimatization, glucose Ra, Rox, and G were increased relative to sea level, but these increments were less than those in response to exercise measured on acute exposure. We conclude that altitude exposure increases glucose use during rest and a given submaximal exercise bout and beta-blockade exaggerates the response.

Atrial fibrillation (AF) progression to a more sustained form is associated with increased morbidities and mortality. The specific aims of the present study were to identify risk factors of AF progression and the effect of management approaches on AF progression in the RecordAF-U.S. cohort. The

The adaptive responses of the cardiovascular system to altitude appear to be dominated by increased sympathetic neural activity. We investigated the combined roles of the sympathetic and parasympathetic nervous systems (SNS and PNS, respectively) in the early (days 4–5) and subsequent (days 11–12) phases of acclimatization on Pike's Peak, CO (4,300 m), by spectral analysis of heart rate variability. Male subjects were randomly assigned to groups receiving oral propranolol (240 mg/day; n = 6) or a matched placebo (n = 3). On ascent to altitude, the high-frequency, fractal, and total spectral powers were reduced in the placebo group during days 4–5 and 11–12. At altitude during days 4–5, all three placebo group subjects increased SNS and decreased PNS activities compared with at sea level, and during days 11–12 SNS decreased and PNS increased compared with days 4–5. Relative to the placebo group, propranolol caused lengthening of the R-R interval; increases in high-frequency power, total spectral power, and the PNS indicator; and a decrease in the SNS indicator. Total spectral power tended to decrease at altitude, but there were no effects of altitude on PNS and SNS indicators in the propranolol group. The data from the placebo and propranolol groups suggest that both the PNS and SNS are involved in the elevated heart rate during the early phase of altitude acclimatization. Changes in heart rate variability during days 11–12 at altitude must be considered in light of the possible reductions in sympathetic receptor number noted in previous studies.

The sympathoadrenal system plays a major role in adjustments to both short- and long-term high-altitude exposure. Thus, this study investigated catecholamine responses in blood, urine, and muscle during 3 weeks' exposure to 4,300 m in control and beta-blocked subjects. Eleven healthy, sea level (SL)-resident men (aged 26 +/- 1 years) were studied under resting conditions at SL and on arrival and during 21 days at 4,300 m (Pikes Peak). Six subjects received 240 mg/d propranolol, and five were administered a placebo. Compared with SL values (38.7 +/- 4.3 v 32.4 +/- 2.8 micrograms/d for control and beta-blocked, respectively), urinary norepinephrine (NE) excretion increased significantly during altitude exposure, reaching peak values on days 6 to 7 (105.5 +/- 16.1 v 88.4 +/- 12.3 micrograms/d, respectively). Furthermore, resting arterial NE levels (increases 87%), as well as net NE release (decreases 219%) across the leg, both increased during acclimatization, indicating elevated sympathetic activity. Systemic vascular resistance and arterial pressures increased with time at altitude and correlated with NE measurements. Resting heart rates increased initially and then declined steadily after day 4 at altitude in both groups of subjects. Urinary epinephrine (EPI) excretion increased with initial exposure as compared with SL values (5.1 +/- 0.8 to 6.6 +/- 0.7 micrograms/d for control, 4.5 +/- 0.5 to 5.2 +/- 1.3 micrograms/d for beta-blocked); however, no consistent pattern was observed for the following 20 days at altitude. Arterial EPI increased upon acute exposure, but declined after 21 days' acclimatization. No changes in dopamine excretion were observed with beta-blockade or altitude exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Residence at high altitude has been associated with elevation in systemic arterial blood pressure, but the time course has been little studied and the mechanism is unknown. Because plasma epinephrine (E) and norepinephrine (NE) also increase at altitude, we hypothesized that heightened sympathoadrenal activity may cause increased arterial pressure. We measured ambulatory blood pressure by cuff monitor in relation to 24-h urinary excretion of E and NE at sea level and during 3 wk of residence at 4,300 m (Pikes Peak, CO) in 11 healthy men. In five subjects taking placebo, arterial pressure progressively increased at 4,300 m from 82 +/- 1 (SE) mmHg at sea level to 88 +/- 3 on day 2, 91 +/- 3 on day 8, and 97 +/- 6 on day 17. In six subjects, propranolol (240 mg/day) decreased pressure from 85 +/- 4 to 77 +/- 1 mmHg at sea level but did not prevent sustained increase in pressure at 4,300 m (84 +/- 1, 81 +/- 1, and 85 +/- 3 mmHg on days 2, 8, and 17, respectively). Compared with the placebo group, blood pressure did not increase further over the initial elevation observed on day 2 in the propranolol group. There was interindividual variability in the blood pressure responses in both groups, with some subjects demonstrating a more marked increase in blood pressure. Urinary excretion of NE increased concomitantly with pressure at altitude in both groups, with a greater rise in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined the extent to which epinephrine influences blood lactate adjustments to exercise during both acute (AC) and chronic (CH) high-altitude exposure. Eleven male sea level residents were divided into a control group (n = 5) receiving a placebo or a drug group (n = 6) receiving 240 mg/day of propranolol. All subjects were studied at rest and during 45 min of submaximal exercise (approximately 50% of sea level maximal O2 uptake) at sea level (SL) and within 4 h of exposure to and after 3 wk residence at 4,300 m (summit of Pikes Peak). Blood samples were collected from the femoral artery for epinephrine and lactate concentration. Exercising blood lactate concentration was significantly different across all altitude conditions such that AC > CH > SL (P < 0.05). For a given arterial O2 saturation, mean exercising blood lactates were lower for the beta-blocked group compared with controls; however, both groups demonstrated similar patterns across all conditions. Epinephrine levels during exercise followed a similar pattern to that of lactate, averaging 0.67, 0.43, and 0.29 ng/ml for AC, CH, and SL, respectively. The correlation between lactate and epinephrine was 0.93 and 0.84 for control and beta-blocked subjects, respectively. Whereas during exercise epinephrine was consistently higher for the beta-blocked group than controls, this difference was only significant during CH exposure. The epinephrine response was related to the extent of hypoxia in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine if spirometric changes reflect early high-altitude pulmonary edema (HAPE) formation, we measured the FVC, FEV 1 , and FEF25–75 serially during the short-term period following simulated altitude exposure (4,400 m) in eight male subjects, four with a history of HAPE and four control subjects who had never experienced HAPE. Three of the four HAPE-susceptible subjects developed acute mountain sickness (AMS), based on their positive Environmental Symptom Questionnaire (AMS-C) scores. Clinical signs and symptoms of mild pulmonary edema developed in two of the three subjects with AMS after 4 h of exposure, which prompted their removal from the chamber. Their spirometry showed small decreases in FVC and greater decreases in FEV 1 and FEF25–75 after arrival at high altitude in the presence of rales or wheezing on clinical examination and normal chest radiographs. One of the two subjects had desaturation (59 percent) and tachycardia during mild exercise, and excessive fatigue and inability to complete the exercise protocol developed in the other at 4 h. The six other subjects had minimal changes in spirometry and did not develop signs of lung edema. Further, we measured each subject's ventilatory response to hypoxia (HVR) prior to decompression to determine whether the HVR would predict the development of altitude illness in susceptible subjects. In contrast to anticipated results, high ventilatory responses to acute hypoxia, supported by increased ventilation during exposure to high altitude, occurred in the two subjects in whom symptoms of HAPE developed. The results confirm that HAPE can occur in susceptible individuals despite the presence of a normal or high ventilatory response to hypoxia.

Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations. Lifelong high-altitude residents of North and South America acquire blunted hypoxic ventilatory responses and exhibit decreased ventilation compared with acclimatized newcomers. The ventilatory characteristics of Himalayan high-altitude residents are of interest in the light of their reportedly lower hemoglobin levels and legendary exercise performance. Until recently, Sherpas have been the only Himalayan population available for study. To determine whether Tibetans exhibited levels of ventilation and hypoxic ventilatory drives that were as great as acclimatized newcomers, we compared 27 lifelong Tibetan residents of Lhasa, Tibet, China (3,658 m) with 30 acclimatized Han ("Chinese") newcomers matched for age, body size, and extent of exercise training. During room air breathing, minute ventilation was greater in the Tibetan than in the Han young men because of an increased respiratory frequency, but arterial O2 saturation and end-tidal PCO2 did not differ, indicating similar levels of effective alveolar ventilation. The Tibetan subjects had higher hypoxic ventilatory response shape parameter A values and hypercapnic ventilatory responsiveness than the Han subjects. Among the Han subjects, duration of high-altitude residence correlated with the degree of blunting of the hypoxic ventilatory drive. Paradoxically, hyperoxia (inspired O2 fraction 0.70) increased minute ventilation and decreased end-tidal PCO2 in the Tibetan but not in the Han men. We concluded that lifelong Tibetan residents of high altitude neither hypoventilated nor exhibited blunted hypoxic ventilatory responses compared with acclimatized Han newcomers, suggesting that the effects of lifelong high-altitude residence on ventilation and ventilatory response to hypoxia differ in Tibetan compared with other high-altitude populations.

Cerebral blood flow increases with acute exposure to high altitude, but the effect of hypoxia on the cerebral circulation at rest and during exercise appears influenced by the duration of high-altitude exposure. To determine whether internal carotid artery flow velocity increased with exercise in long-term residents of high altitude and whether resting values and the response to exercise differed in lifelong vs. acclimatized newcomer male residents of high altitude, we studied 15 native Tibetan and 11 Han (“Chinese”) 6 +/- 2-yr residents of Lhasa (3,658 m), Tibet Autonomous Region, China. Noninvasive Doppler ultrasound was used to measure internal carotid artery diameter, mean flow velocity, and, in combination, hemoglobin and arterial O2 saturation to assess cerebral O2 delivery. Tibetan and Han groups were similar in body size and resting internal carotid artery diameter, blood pressure, hemoglobin concentration, internal carotid artery mean flow velocity, and calculated cerebral O2 delivery. Submaximal exercise increased internal carotid artery mean flow velocity and cerebral O2 delivery in the Tibetan and Han subjects. At peak exercise, the Tibetans sustained the increase in flow velocity and cerebral O2 delivery, whereas the Hans did not. Across all exercise levels up to and including peak effort, the Tibetans demonstrated a greater increase in internal carotid artery flow velocity and cerebral O2 delivery relative to resting values than did the Hans. The greater cerebral O2 delivery was accompanied by increased peak exercise capacity in the Tibetan compared with the Han group. Our findings suggest that the cerebral blood flow response to exercise is maintained in Tibetan lifelong residents of high altitude.

The hypothesis that high-altitude weight loss can be prevented by increasing energy intake to meet energy requirement was tested in seven men, 23.7 +/- 4.3 (SD) yr, taken to 4,300 m for 21 days. Energy intake required to maintain body weight at sea level was found to be 3,118 +/- 300 kcal/day, as confirmed by nitrogen balance. Basal metabolic rate (BMR), determined by indirect calorimetry, increased 27% on day 2 at altitude and then decreased and reached a plateau at 17% above the sea level BMR by day 10. Energy expended during strenuous activities was 37% lower at altitude than at sea level. Fecal excretion of energy, nitrogen, total fiber, and total volatile fatty acids was not significantly affected by altitude. Energy intake at altitude was adjusted after 1 wk, on the basis of the increased BMR, to 3,452 +/- 452 kcal/day. Mean nitrogen balance at altitude was negative (-0.25 +/- 0.71 g/day) before energy intake was adjusted but rose significantly thereafter (0.20 +/- 0.71 and 0.44 +/- 0.66 g/day during weeks 2 and 3). Mean body weight decreased 2.1 +/- 1.0 kg over the 3 wk of the study, but the rate of weight loss was significantly diminished after the increase in energy intake (201 +/- 75 vs. 72 +/- 48 g/day). Individual regression lines drawn through 7-day segments of body weight showed that in four of seven subjects the slopes of body weight were not significantly different from zero after the 2nd wk. Thus weight loss ceased in four of seven men in whom increased BMR at altitude was compensated with increased energy intake.(ABSTRACT TRUNCATED AT 250 WORDS)

We hypothesized that the increased exercise arterial lactate concentration on arrival at high altitude and the subsequent decrease with acclimatization were caused by changes in blood lactate flux. Seven healthy men [age 23 +/- 2 (SE) yr, wt 72.2 +/- 1.6 kg] on a controlled diet were studied in the postabsorptive condition at sea level, on acute exposure to 4,300 m, and after 3 wk of acclimatization to 4,300 m. Subjects received a primed-continuous infusion of [6,6–2D]glucose (Brooks et al. J. Appl. Physiol. 70:919–927, 1991) and [3–13C]lactate and rested for a minimum of 90 min followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the sea level peak O2 consumption (VO2peak; 65 +/- 2% of both acute altitude and acclimatization). During rest at sea level, lactate appearance rate (Ra) was 0.52 +/- 0.03 mg.kg-1.min-1; this increased sixfold during exercise to 3.24 +/- 0.19 mg.kg-1.min-1. On acute exposure, resting lactate Ra rose from sea level values to 2.2 +/- 0.2 mg.kg-1.min-1. During exercise on acute exposure, lactate Ra rose to 18.6 +/- 2.9 mg.kg-1.min-1. Resting lactate Ra after acclimatization (1.77 +/- 0.25 mg.kg-1.min-1) was intermediate between sea level and acute exposure values. During exercise after acclimatization, lactate Ra (9.2 +/- 0.7 mg.kg-1.min-1) rose from resting values but was intermediate between sea level and acute exposure values. The increased exercise arterial lactate concentration response on arrival at high altitude and subsequent decrease with acclimatization are due to changes in blood lactate appearance.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the hypothesis that altitude exposure and acclimatization result in increased dependency on blood glucose as a fuel, seven healthy males (23 +/- 2 yr, 72.2 +/- 1.6 kg, mean +/- SE) on a controlled diet were studied in the postabsorptive condition at sea level (SL), on acute altitude exposure to 4,300 m (AA), and after 3 wk of chronic altitude exposure to 4,300 m (CA). Subjects received a primed continuous infusion of [6,6-2D]glucose and rested for a minimum of 90 min, followed immediately by 45 min of exercise at 101 +/- 3 W, which elicited 51.1 +/- 1% of the SL maximal O2 consumption (VO2 max; 65 +/- 2% of altitude VO2 max). At SL, resting arterial glucose concentration was 82.4 +/- 3.2 mg/dl and rose significantly to 91.2 +/- 3.2 mg/dl during exercise. Resting glucose appearance rate (Ra) was 1.79 +/- 0.02 mg.kg-1.min-1; this increased significantly during exercise at SL to 3.71 +/- 0.08 mg.kg-1.min-1. On AA, resting arterial glucose concentration (85.8 +/- 4.1 mg/dl) was not different from sea level, but Ra (2.11 +/- 0.14 mg.kg-1.min-1) rose significantly. During exercise on AA, glucose concentration rose to levels seen at SL (91.4 +/- 3.0 mg/dl), but Ra increased more than at SL (to 4.85 +/- 0.15 mg.kg-1.min-1; P less than 0.05). Resting arterial glucose was significantly depressed with CA (70.8 +/- 3.8 mg/dl), but resting Ra increased to 3.59 +/- 0.08 mg.kg-1.min-1, significantly exceeding SL and AA values.(ABSTRACT TRUNCATED AT 250 WORDS)

Persons with chronic mountain sickness (CMS) hypoventilate and are more hypoxemic than normal individuals, but the cause of the hypoventilation is unclear. Studies of 14 patients with CMS and 11 healthy age-matched control subjects residing in Lhasa, Tibet, China (3,658 m) were conducted to test the hypothesis that hypoventilation, blunted hypoxic ventilatory responsiveness (HVR), and hypoxic ventilatory depression of CMS were due to increased endogenous opioid production. Patients with CMS compared with control subjects exhibited hypoventilation (end-tidal carbon dioxide pressure [PETCO2] = 36.6 +/- 1.0 versus 31.5 +/- 0.5 mm Hg, p less than 0.05), lower tidal volume (VT = 0.54 +/- 0.02 versus 0.61 +/- 0.02 ml BTPS, p less than 0.05), blunted HVR (shape parameter A = 17 +/- 8 versus 114 +/- 22 mm Hg/L BTPS/min, p less than 0.05), and a depressant effect of ambient hypoxia on ventilation (delta PETCO2 with acute hyperoxia = -3.5 +/- 0.5 versus -1.0 +/- 0.6 mm Hg, p less than 0.05). Reduced forced expiratory volume in 1 s to vital capacity ratios (FEV1/VC) and a higher proportion of cigarette smokers in the group of patients with CMS compared with control subjects suggested that at least some patients with CMS had mild airway obstructive lung disease. Naloxone infusion (0.14 mg/kg) to six patients with CMS did not change resting VT, PETCO2, HVR, or SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibroblasts adhere to, and readily grow into, fibrin clots that form as a result of the cleavage of fibrinogen by thrombin. Subsequent fibroblast replication is believed to be stimulated by mitogens released by entrapped platelets, such as platelet-derived growth factor. We suggest that the supernatant remaining after the fibrinogen-thrombin reaction could stimulate fibroblast replication, even in the absence of other blood components. To examine this hypothesis we expressed liquid from a fibrin clot and measured its mitogenic activity on human lung fibroblasts, in serum-free conditions, using a colorimetric assay based on uptake and subsequent release of Methylene Blue. The clot supernatant caused a mitogenic response of 51 +/− 6% above control and was equivalent to about half that elicited by medium containing 10% newborn calf serum. On their own, both thrombin and fibrinopeptides A and B (small molecular weight cleavage products released from fibrinogen) showed some mitogenic activity, but there was also activity in higher molecular weight cleavage products, suggesting the presence of uncharacterized mitogens. It is proposed that these agents may play important roles in wound healing and diseases associated with vascular leakage and fibrosis, by stimulating fibroblast replication.

Altitude exposure provides a natural laboratory for the study of the effects of low oxygen (hypoxia). Oxygen is the most necessary of substances in our environment, and without it we become unconscious within seconds. When O2 is available, but in low concentrations, the body has elaborate defense systems and compensatory mechanisms that are progressively called into play as the duration of hypoxia increases. When these mechanisms fail or when they are stretched beyond their capacity, organ malfunction occurs. This chapter will focus primarily on the mechanisms of response to hypoxia and to a lesser extent on the disorders that result when the response is inadequate. For more information the reader is referred to other reviews (Penulosa and Sime, 1971; Reeves, 1973; Reeves and Grover, 1974; Dempsey and Forster, 1982; Winslow and Monge, 1987; Kawashima, 1989; Hackett and Roach, 1990; Weil, 1990; Reeves and Groves et al., 1991; Moore, 1992; Oelz et al, 1992; Honigman, 1993; Ward, 1995).

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

We investigated retrospectively whether the preexistence of inflammation-producing illnesses such as viral respiratory tract infections contributed to the development of high-attitude pulmonary edema in children. We found that the large majority of native low-attitude children, but not adults, who had this form of edema after traveling to high altitude also had evidence of a preexisting illness. We speculate that the release of inflammatory mediators associated with these illnesses may be tolerated at sea level but may predispose children to increased capillary permeability when superimposed on hypoxia and, possibly, cold and exercise.

This is an international consensus statement of an ad hoc committee formed by the International Society for Mountain Medicine (ISMM) at the VI World Congress on Mountain Medicine and High Altitude Physiology (Xining, China; 2004) and represents the committee's interpretation of the current knowledge with regard to the most common chronic and subacute high altitude diseases. It has been developed by medical and scientific authorities from the committee experienced in the recognition and prevention of high altitude diseases and is based mainly on published, peer-reviewed articles. It is intended to include all legitimate criteria for choosing to use a specific method or procedure to diagnose or manage high altitude diseases. However, the ISMM recognizes that specific patient care decisions depend on the different geographic circumstances involved in the development of each chronic high altitude disease. These guidelines are established to inform the medical services on site who are directed to solve high altitude health problems about the definition, diagnosis, treatment, and prevention of the most common chronic high altitude diseases. The health problems associated with life at high altitude are well documented, but health policies and procedures often do not reflect current state-of-the-art knowledge. Most of the cases of high altitude diseases are preventable if on-site personnel identify the condition and implement appropriate care.

Although an increase in hemoglobin concentration [Hb] in high altitude residents assists oxygen transport, excessive polycythemia ([Hb] > or = 21 g/100 mL) may cause the syndrome of chronic mountain sickness (CMS). A recent theoretical analysis has suggested that increasing [Hb] above 18 g/100 mL provides no further benefit in oxygen transport at rest. To test this hypothesis, we examined oxygen transport at rest for given arterial oxygen saturations (Sa(O2), in classes at intervals of 5%) as reported in 206 residents of various altitudes. For Sa(O2) of 97% versus 87%, [Hb] and a-v oxygen content difference increased (respectively, 14.5 to 17.5 g/100 mL and 4.11 to 5.03 volume %). As Sa(O2) fell further to 66%, a-v progressively decreased to 3.77 volume %, despite an increase in [Hb] to 24.2 g/100 mL. Over the Sa(O2) range of 97% to 66%, the a-v difference changed little (-8%) compared to other subjects made acutely hypoxic (-33%), for Sa(O2) change from 97% to 75%. The results suggest that increasing [Hb] allows greater oxygen extraction (a cardiac output sparing effect), which is maximal at Sa(O2) of 87% and a [Hb] of 17.5 g/100 mL. For more severe hypoxemia, even to Sa(O2) of 66%, both increasing [Hb] and increasing output are utilized for oxygen transport.