High altitude-induced borderline pulmonary hypertension impaired cardiorespiratory fitness in healthy young men

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.

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Abnormal Left Ventricular Diastolic Filling Patterns in Acute Hypoxic Pulmonary Hypertension at High Altitude

American Journal of Noninvasive Cardiology ◽

10.1159/000470246 ◽

1993 ◽

Vol 7 (1) ◽

pp. 33-38 ◽

Cited By ~ 7

Author(s):

Manfred Ritter ◽

Rolf Jenni ◽

Marco Maggiorini ◽

Jörg Grimm ◽

Oswald Oelz

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Left Ventricular ◽

Diastolic Filling ◽

Hypoxic Pulmonary Hypertension ◽

Left Ventricular Diastolic Filling

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Unobtrusive Estimation of Cardiorespiratory Fitness with Daily Activity in Healthy Young Men

Journal of Korean Medical Science ◽

10.3346/jkms.2017.32.12.1947 ◽

2017 ◽

Vol 32 (12) ◽

pp. 1947 ◽

Cited By ~ 2

Author(s):

Joong Woo Ahn ◽

Se Hee Hwang ◽

Chiyul Yoon ◽

Joonnyong Lee ◽

Hee Chan Kim ◽

...

Keyword(s):

Cardiorespiratory Fitness ◽

Daily Activity ◽

Young Men

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Transpulmonary Plasma Catecholamines in Acute High-Altitude Pulmonary Hypertension

Wilderness and Environmental Medicine ◽

10.1016/j.wem.2010.11.011 ◽

2011 ◽

Vol 22 (1) ◽

pp. 37-45 ◽

Cited By ~ 5

Author(s):

Marc M. Berger ◽

Andrew M. Luks ◽

Damian M. Bailey ◽

Elmar Menold ◽

Guido C. Robotti ◽

...

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Plasma Catecholamines

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.4.h2013 ◽

2000 ◽

Vol 279 (4) ◽

pp. H2013-H2016 ◽

Cited By ~ 85

Author(s):

Yves Allemann ◽

Claudio Sartori ◽

Mattia Lepori ◽

Sébastien Pierre ◽

Christian Mélot ◽

...

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Doppler Echocardiography ◽

Systolic Pulmonary Arterial Pressure ◽

Wide Range ◽

High Altitude Pulmonary Edema ◽

Reproducible Method ◽

Pulmonary Arterial ◽

Spearman Test ◽

Invasive Measurement

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

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Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude

Circulation ◽

10.1161/circ.142.suppl_3.14359 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Juliane Hannemann ◽

Julia Zummack ◽

PATRICIA SIQUES ◽

JULIO BRITO ◽

Rainer Boeger

Keyword(s):

Pulmonary Hypertension ◽

Relative Risk ◽

Genetic Variability ◽

High Altitude ◽

Acute Mountain Sickness ◽

Minor Allele ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Mountain Sickness ◽

Study Participants

Introduction: Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension. Hypothesis: We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension. Methods: We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation. Results: Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness. Conclusions: We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.

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