Pulmonary hypertension in healthy men born and living at high altitudes

doi:10.1016/0002-9149(63)90055-9

The American Journal of Cardiology

Volume 11, Issue 2, February 1963, Pages 150-157

https://doi.org/10.1016/0002-9149(63)90055-9 Get rights and content

Abstract

Right heart catheterization studies were performed in 38 healthy men 17 to 34 years of age born and living at high altitudes. In order to obtain comparative data, a similar investigation was made in 25 healthy men born and living at sea level. Previously, a physical examination was performed, and roentgenograms of the chest, hematological, electrocardiographic and vectorcardiographic data were obtained.

Mild pulmonary hypertension and a moderate increase of the pulmonary vascular resistance and right ventricular work were found in men living permanently at high altitudes. Pulmonary wedge pressure, cardiac output and heart rate did not show significant differences from the data obtained at sea level.

The changes occurring in the heart and pulmonary circulation in men living permanently at high altitudes are not quite comparable with the changes described in temporary residents at high altitudes, nor with those experimentally obtained by acute hypoxia. This means that when studying the effects of hypoxia upon the heart and pulmonary circulation, it is important to bear in mind not only the degree of hypoxia but also the time of exposure to it.

The augmented pulmonary vascular resistance in the high altitude dweller is related to the anatomic changes in the small pulmonary arteries and arterioles which have been described by other investigators. Functional factors such as vasoconstriction, hypervolemia and polycythemia do not play an important role in the mechanism of the pulmonary hypertension at high altitudes.

The role of the pulmonary hypertension in the complex mechanism of acclimatization to life at high altitude is not well understood. Apparently pulmonary hypertension would not accomplish a useful part in this mechanism. It is possible, however, that pulmonary hypetension, in association with other factors such as hyperventilation and an extensive capillary bed of the lungs, does play a role in improving the arterial oxygenation in men living at high altitude.

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Global Research Expedition on Altitude-related Chronic Health 2018 Iron Infusion at High Altitude Reduces Hypoxic Pulmonary Vasoconstriction Equally in Both Lowlanders and Healthy Andean Highlanders
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Citation Excerpt :
The unremarkable influence of a comparable iron infusion on PASP in Andean individuals with CMS14 is intriguing. Certainly, CMS has long been established to coincide with pulmonary vascular remodeling and pulmonary hypertension (during rest and exercise).32,35-39 However, CMS has also been linked to the dysfunction of a myriad of HIF-related factors, including sentrin-specific protease 1,40 prevailing circulatory status of vasoactive peptides (ie, vascular endothelial growth factor and endothelin-1),41 methylation of prolyl hydroxylase activity,42 and/or mutations to the von Hippel-Lindau protein.43
Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated. If the interplay between iron status and pulmonary vascular tone in healthy Andean individuals remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude.
Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion?
In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio₂] of approximately 96 mm Hg) and during exaggerated hypoxia (Pio₂ of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion.
Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg during exaggerated hypoxia (main effect, P < .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andean individuals than in the lowlanders (95% CI, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003).
The pulmonary vasculature of healthy Andean individuals and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS.
Physiologic principles
2022, Goldsmith's Assisted Ventilation of the Neonate: An Evidence-Based Approach to Newborn Respiratory Care, Seventh Edition
Transcatheter closure of a small atrial septal defect with an Amplatzer™ patent foramen ovale occluder in a working dog with cyanosis and exercise intolerance at high altitude
2017, Journal of Veterinary Cardiology
Citation Excerpt :
In humans living chronically at high altitude, adaptive mechanisms develop to allow acclimatization to life in a chronically hypoxic environment [12,13]. Cardiovascular changes in individuals living at high altitudes include PH, right ventricular hypertrophy, and polycythemia [12,14,15]. In addition, the presence of a PFO in humans living at high altitude has been associated with increased pulmonary vasoconstriction and right ventricular systolic dysfunction compared with those without PFO [16].
A 6.5-year-old male Border Collie presented for transcatheter closure of an atrial septal defect due to exercise intolerance and cyanosis while working and training at altitude. A small, left-to-right shunting secundum atrial septal defect was confirmed with no evidence of significant right-sided volume overload. Pulmonary hypertension with subsequent right-to-left interatrial shunting occurring during exercise at high altitude was suspected and prompted the closure of the defect due to the dog's continued athletic requirements. The anatomy of the defect prompted use of a patent foramen ovale occluder rather than an atrial septal defect occluder, which was deployed using a combination of fluoroscopic and transesophageal echocardiographic guidance. The owner did not report continued exercise intolerance or cyanosis and the dog's lifestyle and residence at altitude was unchanged.
Physiologic Principles
2017, Assisted Ventilation of the Neonate: An Evidence-Based Approach to Newborn Respiratory Care: Sixth Edition
Hypoxic Pulmonary Vasoconstriction: From Molecular Mechanisms to Medicine
2017, Chest
Citation Excerpt :
After millennia of living at altitudes > 4,000 m, native Tibetans exhibit minimal hypoxic PH (HPH) or polycythemia.74 In contrast, HPH is prevalent in native Quechua Indians living in the Andean highlands of Ecuador and Bolivia at altitudes of approximately 3,500 to 4,000 m.71,75 Similarly, children in Leadville, Colorado (the highest city in North America at about 3,100 m) commonly exhibit HPH. The severity of HPH in Leadville residents is similar to that of the Quechua, although the Coloradans live at much lower altitudes.
Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po₂ without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.
Exaggerated pulmonary hypertension and right ventricular dysfunction in high-altitude dwellers with patent foramen ovale
2015, Chest
BACKGROUND: There is considerable interindividual variability in pulmonary artery pressure among high-altitude (HA) dwellers, but the underlying mechanism is not known. At low altitude, a patent foramen ovale (PFO) is present in about 25% of the general population. Its prevalence is increased in clinical conditions associated with pulmonary hypertension and arterial hypoxemia, and it is thought to aggravate these problems.
METHODS: We searched for a PFO (transesophageal echocardiography) in healthy HA dwellers (n = 22) and patients with chronic mountain sickness (n = 35) at 3,600 m above sea level and studied its effects (transthoracic echocardiography) on right ventricular (RV) function, pulmonary artery pressure, and vascular resistance at rest and during mild exercise (50 W), an intervention designed to further increase pulmonary artery pressure.
RESULTS: The prevalence of PFO (32%) was similar to that reported in low-altitude populations and was not different in participants with and without chronic mountain sickness. Its presence was associated with RV enlargement at rest and an exaggerated increase in right-ventricular-to-right-atrial pressure gradient (25 ± 7 mm Hg vs 15 ± 9 mm Hg,P< .001) and a blunted increase in fractional area change of the right ventricle (3% [−1%, 5%] vs 7% [3%, 16%],P= .008) during mild exercise.
CONCLUSIONS: These findings show, we believe for the first time, that although the prevalence of PFO is not increased in HA dwellers, its presence appears to facilitate pulmonary vasoconstriction and RV dysfunction during a mild physical effort frequently associated with daily activity.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov

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^☆: This investigation was supported by U. S. Public Health Service research grant RG-8576.

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Clinical studyPulmonary hypertension in healthy men born and living at high altitudes☆

Abstract

Blood

Am. Heart J.

Am. Heart J.

Am. Heart J.

Am. Heart J.

Am. Heart J.

Enfermedad de los Andes. Estudio fisiológico

An. Fac. med. Lima

Influence of anoxemia on the hemopoietic activity

A.M.A. Arch. Int. Med.

Arterial blood gases and acid-base balance at sea level and at high altitudes

J. Appl. Physiol.

Mechanisms of natural acclimatization. Studies on the native resident of Morococha, Peru, at an altitude of 14, 900 feet

Report to the U.S.A.F. School of Aviation Medicine

Estudios de química tisular en la hipoxia

Some clinical aspects of life at high altitudes

Ann. Int. Med.

Observaciones anátomo patológicas en 49 personas normales nativas y residentes en la altura (3, 700–5, 000 mts.) muertas en accidente

Rev. Latinoam. anat. patol.

Right ventricular hypertrophy in native children living at altitudes

Am. J. Path.

The muscular pulmonary arteries in people native to high altitude

Pulmonary circulation at sea level and at high altitudes

J. Appl. Physiol.

Catheterization of right auricle in man

Recording of right heart pressures in man

Pulmonary capillary pressure in man

J. Clin. Invest.

Clinical study
Pulmonary hypertension in healthy men born and living at high altitudes☆