High-altitude Pulmonary Hypertension Research Articles

Gene Expression in Chronic High Altitude Diseases

Chronic mountain sickness (CMS) and high altitude pulmonary hypertension (HAPH) have been well described in different mountainous regions of the world as chronic high altitude (HA) diseases. This review briefly summarizes the available data from some genes known to be regulated by hypoxia-inducible factor 1 (HIF-1) and/or by hypoxia that have been studied in populations from these regions suffering from CMS and/or HAPH. Excessive erythrocytosis, caused by a lower oxygen saturation and hypoxic ventilatory response and/or ventilatory inefficiency, is the outstanding sign of CMS, and right ventricular enlargement, pulmonary hypertension, and remodeling of pulmonary arterioles are hallmarks of HAPH. Familial character and heritability studies have suggested that genetic factors could make a contribution to the pathogenesis of CMS and HAPH. Even though some alleles are more prevalent (G allele of eNOS polymorphism Glu298Asp in Sherpas and ACE I allele in HAPH Kyrgyz) or less prevalent (ACE D allele in HA Andeans) in the different high altitude populations, published data to date are insufficient for a rigorous test of any hypothesis regarding the implications of these gene polymorphims in CMS or HAPH.

Indirect markers of pulmonary endothelial dysfunction correlate with high-altitude induced pulmonary hypertension

Indirect markers of pulmonary endothelial dysfunction correlate with high-altitude induced pulmonary hypertension

Indirect markers of pulmonary endothelial dysfunction correlate with high-altitude induced pulmonary hypertension

Berger, M. M.; Bärtsch, P.; Mairbäurl, H.; Swenson, E. R.; Dehnert, C. Author Information

Postnatal cardiopulmonary adaptations to high altitude

Postnatal cardiopulmonary adaptations to high altitude constitute a key component of any set of responses developed to face high altitude hypoxia. Such responses are required ultimately to meet the energy demands necessary for adequate functioning at cell and organism level. After a brief insight on general and cardiopulmonary comparative studies in growing and adult organisms, differences and possible explanations for varying cardiopulmonary pathology, pulmonary artery hypertension, persistent right ventricular predominance and subacute high altitude pulmonary hypertension in different populations of children living at high altitude are discussed. Potential long-term implications of early chronic hypoxic exposure on later diseases are also presented. It is hoped that this review will help the practicing physician working at high altitude to make informed decisions concerning individual pediatric patients, specifically with regard to diagnosis and management of altitude-related cardiopulmonary pathology. Finally, plausibility and the knowledge-base of public health interventions to reduce the risks posed by suboptimal or inadequate postnatal cardiopulmonary responses to high altitude are discussed.

Treatment of chronic mountain sickness: Critical reappraisal of an old problem

A review is made on the different treatment strategies essayed to date in the management of chronic mountain sickness (CMS). After a brief presentation of the epidemiology and of the pathophysiological mechanisms proposed for explaining the disease, the advantages and drawbacks of the different treatment approaches are discussed, along with their pathopysiological rationale. A particular emphasis is dedicated to the scientific foundations underlying the development of acetazolamide and angiotensin-converting enzyme inhibitors as promising therapeutic agents for CMS, as well as the clinical evidence existing so far on their usefulness in the treatment of CMS. Various methodological issues that need to be addressed in future clinical studies on efficacy of therapies for CMS are discussed. There is also a brief discussion on potential treatment options for chronic high altitude pulmonary hypertension. Closing remarks on the need of taking increasingly into account the development and implementation of preventive measures are made.

Noninvasive and invasive evaluation of pulmonary arterial pressure in highlanders

The purpose of the present study was to evaluate Doppler echocardiography for the detection of pulmonary hypertension in high-altitude inhabitants. In total, 60 (55 male) patients aged 18-71 yrs were recruited from an ECG screening programme applied to 1,430 inhabitants living at an altitude of 2,500-3,600 m in Kyrgyzstan. Of these, 44 met ECG criteria for right ventricular hypertrophy. All underwent Doppler echocardiography followed by a cardiac catheterisation within 7 days of arrival in Bishkek (Kyrgyzstan; altitude 760 m). Pulmonary flow acceleration time and the maximum velocity of tricuspid regurgitation were measured. Sufficient quality tricuspid regurgitant jets were recovered in only 28% of the patients. Therefore, pulmonary artery pressure was estimated from the pulmonary flow acceleration time, which was recovered in 100% of the patients. It was found that 37 (62%) of the patients had pulmonary hypertension on echocardiography. Pulmonary hypertension was confirmed in 29 patients on catheterisation. Pulmonary hypertension was detected with 70% sensitivity and 88% specificity by echocardiography, as compared to 59% sensitivity and 81 % specificity by ECG. The correlation coefficient between echocardiography and catheterisation studies was r(2) = 0.78. It is concluded that a combination of ECG and echocardiography may be useful for screening high-altitude pulmonary hypertension.

Hoarseness -As a presenting feature of aortic arch aneurysm.

Hoarseness due to left recurrent laryngeal nerve paralysis (LRLN) caused by identifiable cardiovascular disease is described as Ortner's syndrome or Cardiovocal syndrome. This was first described by Ortner in 1897 to describe left recurrent laryngeal nerve palsy secondary to Mitral Stenosis. The common conditions which gave rise to Ortners' syndrome include mitral stenosis, mitral valve prolapse, aortic aneurysm, septal defect, following cardiothoracic surgery, high altitude pulmonary hypertension, ductal aneurysm, aortic dissection etc. Herewith we are presenting an unusual presentation of Aortic arch aneurysm.

Evidence for a Genetic Basis for Altitude-Related Illness

Altitude-related illnesses are a family of interrelated pulmonary, cerebral, hematological, and cardiovascular medical conditions associated with the diminished oxygen availability at moderate to high altitudes. The acute forms of these debilitating and potentially fatal conditions, which include acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE), often develop in incompletely acclimatized lowlanders shortly after ascent, whereas, the chronic conditions, such as chronic mountain sickness (CMS) and high altitude pulmonary hypertension (HAPH), usually afflict native or long-term highlanders and may reflect a loss of adaptation. Anecdotal reports of particularly susceptible people or families are frequently cited as evidence that certain individuals have an innate susceptibility (or resistance) to developing these conditions and, in recent decades, there have been a number of studies designed to characterize the physiology of individuals predisposed to these conditions, as well as to identify the specific genetic variants that contribute to this predisposition. This paper reviews the epidemiological evidence for a genetic component to the various forms of altitude-related illness, such as innate susceptibility, familial clustering, and patterns of population susceptibility, as well as the molecular evidence for specific genetic risk factors. While the evidence supports some role for genetic background in the etiology of altitude-related illness, limitations in individual studies and a general lack of corroborating research limit the conclusions that can be drawn about the extent of this contribution and the specific genes or pathways involved. The paper closes with suggestions for future work that could support and expand on previous studies, as well as provide new insights.

Cardiopulmonary Pathology Among Children Resident at High Altitude in Tintaya, Peru: A Cross-Sectional Study

Symptomatic high-altitude pulmonary hypertension and structural cardiac abnormalities related to high altitude have been reported previously. However, their true prevalence has not been systematically determined. We assessed clinical indicators of cardiovascular health or disease and correlated them with anatomic and physiologic cardiovascular features in preschool and schoolchildren living at 4000 m. We also estimated the prevalence of cardiovascular problems in the population, with emphasis on symptomatic high altitude pulmonary hypertension and structural cardiopathies. Three hundred and twenty-six children residents of Tintaya, Peru, were cross-sectionally studied. Methods included structured interviews, anthropometry and physical examination, arterial oxygen saturation, hemoglobin determination, electrocardiography, and echocardiography. The prevalence of structural cardiac problems was 1.5%, with less than 1% possibly attributable to high altitude. All children with structural cardiac abnormalities were identified by a focused physical exam prior to echocardiography. None were identified by the health interview. No symptomatic high altitude pulmonary hypertension was identified in the absence of underlying structural anomalies. The prevalence of structural cardiac problems was consistent with data from sea level. Active monitoring of the health status of a pediatric population at high altitude is valuable in the timely detection of cardiac abnormalities. Although our study children enjoyed generally excellent health, comparative, longitudinal studies are warranted to determine the incidence of high altitude cardiopulmonary problems and to identify risk factors and early markers for later disorders associated to life at high altitude. Our findings are applicable to children with some degree of high altitude genetic background and high mobility patterns to lower altitudes and living in comparatively good nutritional and socioeconomic conditions.

Phosphodiesterase type 5 and high altitude pulmonary hypertension

This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH). 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks. At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles. PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

High altitude pulmonary hypertension: role of K+ and Ca2+ channels.

Global alveolar hypoxia, as experienced at high-altitude living, has a serious impact on vascular physiology, particularly on the pulmonary vasculature. The effects of sustained hypoxia on pulmonary arteries include sustained vasoconstriction and enhanced medial hypertrophy. As the major component of the vascular media, pulmonary artery smooth muscle cells (PASMC) are the main effectors of the physiological response(s) induced during or following hypoxic exposure. Endothelial cells, on the other hand, can sense humoral and hemodynamic changes incurred by hypoxia, triggering their production of vasoactive and mitogenic factors that then alter PASMC function and growth. Transmembrane ion flux through channels in the plasma membrane not only modulates excitation- contraction coupling in PASMC, but also regulates cell volume, apoptosis, and proliferation. In this review, we examine the roles of K+ and Ca2+ channels in the pulmonary vasoconstriction and vascular remodeling observed during chronic hypoxia-induced pulmonary hypertension.

Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp

Study Question: Does sildenafil improve exercise capacity under the conditions of hypoxic pulmonary hypertension? Methods: A randomized, double-blind, placebo-controlled crossover study was conducted in 14 healthy mountain climber volunteers in Giessen, Germany, and the base camp on Mount Everest. Measurements included systolic pulmonary artery pressure (sPAP) by echo-Doppler, cardiac output by a gas re-breathing method, and peripheral arterial oxygen saturation (SAO 2) at rest and during assessment of maximum exercise capacity on cycle ergometry while 1) breathing a hypoxic gas mixture with an FI-O 2 of 10% at low altitude (Giessen) and 2) while at high altitude (the Mount Everest base camp). Intervention was oral sildenafil, 50 mg, or placebo. Crossover study followed 1 day for washout. Results: Median age was 36.5 years, and 12 subjects were men. Median low altitude sBP was 148 mm Hg, SAO 2 99%, sPAP 17.5 mm Hg, and CO 6.0 L/min. At low altitude, acute hypoxia reduced the SAO 2 to 72.0% (95% CI, 66.5–77.5%) at rest and 60.8% (CI, 56.0–64.5%) at maximum exercise capacity. Systolic PAP increased from 30.5 mm Hg (CI, 26.0–35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6–53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased SAO 2 during exercise (p=0.005) and reduced sPAP at rest (p<0.001) and during exercise (p=0.031). Of note, sildenafil increased maximum workload achieved (172.5 W vs. 130.6 W, p<0.001) and maximum cardiac output (p<0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced sPAP at rest (p=0.003) and during exercise (p=0.02) and increased maximum workload (p=0.002) and cardiac output (p=0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants. Conclusions: Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. Sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude. Perspective: Acute hypoxic pulmonary hypertension can result in severe dyspnea and syncope. Sildenafil, a phosphodiesterase-5 inhibitor, prolongs the half life of cyclic-GMP, which is responsible for the pulmonary vasodilator effect of endothelial-derived nitric oxide. The results should not be used to justify sildenafil for preventing high-altitude pulmonary hypertension in skiers or hikers. Whether sildenfil would reduce or enhance the probability of high-altitude pulmonary edema is not known, and it may aggravate high-altitude migraine. MR

High altitude induced Ortner's syndrome

Ortner's syndrome, a clinical entity first described by Ortner over a hundred years ago, is characterised by hoarseness of voice due to left recurrent laryngeal nerve palsy secondary to cardiac disease [1]. Although Ortner originally described this cardiovocal syndrome in association with mitral stenosis, it is now a recognised complication of a number of cardiac conditions. A series of rare cases of Ortner's syndrome induced by high altitude pulmonary hypertension, a hithertofore unreported aetiology, which presented at a tertiary referral hospital are reported here.

Cardiopulmonary transition in the high altitude infant.

The perinatal cardiopulmonary transition at high altitude differs from that at sea level because oxygen plays a fundamental role in the developmental changes from fetus to newborn infant. Under conditions of high altitude hypoxia, arterial oxygen saturations are lower, breathing patterns and maturation of respiratory control reflexes differ, and regression of fetal characteristics of the pulmonary vasculature proceeds more slowly. Several aspects of transition vary not only with postnatal age and altitude, but also with population group, suggesting an effect of genetic adaptation on perinatal physiology. Exposure to chronic high altitude hypoxia during the perinatal transition also results in apparent lifelong alterations in respiratory reflex responses and pulmonary vasoreactivity. Disruption of the normal process of cardiopulmonary transition can result in symptomatic high altitude pulmonary hypertension. The exaggerated hypoxemia associated with acute respiratory infections in young infants still undergoing transition contributes to infant mortality at high altitude.

Cardio-pulmonary interactions at high altitude. Pulmonary hypertension as a common denominator.

The purpose of this review is to find the evidence that a disproportionate pulmonary vasoconstriction persisting for days, weeks and years during residence at high altitude is the common pathophysiologic mechanism of high altitude pulmonary edema (HAPE), subacute mountain sickness and chronic mountain sickness. A recent finding in early HAPE suggests that transmission of excessively elevated pulmonary artery pressure to the pulmonary capillaries leading to alveolar hemorrhage as the pathophysiologic mechanism of HAPE. The elevated incidence of HAPE in Indian soldiers led the Indian Army to extend the acclimatization period from a few days to 5 weeks. Using this protocol, HAPE was prevented, but after several weeks of residence at an altitude of 6000m dyspnea, anasarca and pleuro-pericardial effusion developed. Clinical examination revealed severe congestive right heart failure. This condition has been previously described in long-term high altitude residents of the Himalaya and the Andes. In rats, smooth muscle cells appear in normally non-muscular arterioles within days of simulated altitude. Rapid remodeling of the small precapillary arteries may prevent HAPE but increase pulmonary vascular resistance leading to pulmonary hypertension in long-term high altitude residents. Symptoms and signs of HAPE, subacute mountain sickness and chronic mountain sickness reverse completely after residents are transfered to low altitude. In conclusion, these findings strongly suggest that pulmonary hypertension at high altitude, which could be named "high altitude pulmonary hypertension", is the principal and common pathogenic factor of all three cardio-pulmonary manifestations of high altitude illness. Accordingly, subacute mountain sickness and chronic mountain sickness could be renamed in "acute-" and "chronic right heart failure of high altitude", respectively.

Role of vascular smooth muscle in the development of high altitude pulmonary hypertension: an interspecies evaluation.

There is a marked variability in the degree of pulmonary hypertension induced by long-term exposure to altitudes above 3000 m among low altitude species, ranging from hyporesponders (sheep and dogs) to hyper-responders (cattle and pigs). The amount of inherent muscularization of small pulmonary arteries appears to be a determinant of this hypertensive response, as does the presence or absence of collateral ventilation. Hyper-responders also exhibit marked pulmonary vascular hypertrophy when exposed to long-term hypoxia. Humans exhibit similar inter- and intra-population variability. Animal species indigenous to high altitudes exhibit less variable, attenuated pulmonary hypertensive responses with little pulmonary vascular hypertrophy. This attenuated response is also apparent among human high altitude populations, particularly in Andean and Tibetan populations. Thus, successful adaptation to high altitudes is evident in species that do not sustain the acute cardiopulmonary compensations that occur upon initial exposure to high altitude.

High-Altitude Pulmonary Hypertension and Signal Transduction in the Cardiovascular System

(2000). High-Altitude Pulmonary Hypertension and Signal Transduction in the Cardiovascular System. Journal of Receptors and Signal Transduction: Vol. 20, No. 4, pp. 255-278.

ACE genotype and risk of high altitude pulmonary hypertension in Kyrghyz highlanders

It is known that prolonged residence at high altitude leads to the development of hypoxia-induced pulmonary arterial hypertension in some people.1 However, marked individual variation exists in the severity of this response and there is evidence from animal studies, that the susceptibility to high altitude pulmonary hypertension (HAPH) has a genetic basis.2,3 No study has identified genetic determinants of susceptibility to HAPH in human beings. In the Kyrghyz Republic, 90% of the territory is high mountains of the Tien Shan and Pamir ranges, and more than 200 000 people live at an altitude greater than 3000 m above sea level.

Herbert N. Hultgren, MD

Herbert N. Hultgren, Professor of Medicine Emeritus at Stanford, died in October 1997 at age 80 of complications of acute myelogenous leukemia. Herb was a native of northern California and graduated from Stanford University in 1939 and from its School of Medicine in 1943. He completed residency training in medicine and pathology at Stanford and served in Europe in World War II with the US Army Medical Corps. He was a research fellow in cardiology at the Thorndike Memorial Laboratory in Boston, Mass, and then returned to Stanford in 1948, where he established the first cardiac catheterization laboratory in northern California and in 1955 became chief of cardiology at Stanford. In 1968, after the Stanford Medical School had relocated from San Francisco to Palo Alto, Calif, Herb was appointed chief of cardiology at the Palo Alto Veterans Administration Hospital, a position he held until 1984. I worked with him at Stanford as a cardiology fellow and then as junior faculty member in the cardiology division from 1970 to 1977. I and numerous Stanford students, …

Atrial Natriuretic Factor in High-Altitude Pulmonary Hypertension

Since the renin-angiotensin-aldosterone system and atrial natriuretic factor are directly involved in the regulation of hemodynamics and structural alterations in the circulatory system, the interest of investigators in the observed changes in this system during exogenous hypoxia and the resultant development of high-altitude pulmonary hypertension is quite understandable. The authors measured the plasma levels of hormones from the major vasoconstrictor neurohumoral system and from one vasodilatory system and correlated them with hemodynamic variables in native highlanders of Tien-Shan.