High Altitude-induced Pulmonary Hypertension Research Articles

Acute changes in cardiac dimensions, function, and longitudinal mechanics in healthy individuals with and without high-altitude induced pulmonary hypertension at 4559m.

High-altitude pulmonary hypertension (HAPH) has a prevalence of approximately 10%. Changes in cardiac morphology and function at high altitude, compared to a population that does not develop HAPH are scarce. Four hundred twenty-one subjects were screened in a hypoxic chamber inspiring a FiO2 =12% for 2h. In 33 subjects an exaggerated increase in systolic pulmonary artery pressure (sPAP) could be confirmed in two independent measurements. Twenty nine of these, and further 24 matched subjects without sPAP increase were examined at 4559m by Doppler echocardiography including global longitudinal strain (GLS). SPAP increase was higher in HAPH subjects (∆=10.2vs. ∆=32.0mm Hg, p<.001). LV eccentricity index (∆=.15vs. ∆=.31, p=.009) increased more in HAPH. D-shaped LV (0 [0%] vs. 30 [93.8%], p=.00001) could be observed only in the HAPH group, and only in those with a sPAP ≥50mm Hg. LV-EF (∆=4.5vs. ∆=6.7%, p=.24) increased in both groups. LV-GLS (∆=1.2vs. ∆=1.1 -%, p=.60) increased slightly. RV end-diastolic (∆=2.20vs. ∆=2.7cm2 , p=.36) and end-systolic area (∆=2.1vs. ∆=2.7cm2 , p=.39), as well as RA end-systolic area index (∆=-.9vs. ∆=.3cm2 /m2 , p=.01) increased, RV-FAC (∆=-2.9vs. ∆=-4.7%, p=.43) decreased, this was more pronounced in HAPH, RV-GLS (∆=1.6vs. ∆=-.7 -%, p=.17) showed marginal changes. LV and LA dimensions decrease and left ventricular function increases at high-altitude in subjects with and without HAPH. RV and RA dimensions increase, and RV longitudinal strain increases or remains unchanged in subjects with HAPH. Changes are negligible in those without HAPH.

Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season.

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

N-carbamylglutamate restores nitric oxide synthesis and attenuates high altitude-induced pulmonary hypertension in Holstein heifers ascended to high altitude

BackgroundHigh-altitude pulmonary hypertension (HAPH) is a life-threating condition for animals in high altitude, and disturbance of endothelial nitric oxide (NO) synthesis contributes to its pathogenesis. N-carbamylglutamate (NCG), which enhances arginine synthesis, promotes endogenous synthesis of NO. In this study, we determined the effects of NCG on alleviating HAPH in Holstein heifers that ascended to Tibet (Lhasa, 3,658 m).MethodsExp. 1, 2,000 Holstein heifers were transported from low elevation (1,027 m) to Lhasa. After being exposed to hypoxia for 1 yr, Holstein heifers were assigned to a healthy group (Control, n = 6) with mean pulmonary hypertension (mPAP) < 41 mmHg, and an HAPH affected group (HAPH, n = 6) with mPAP > 49 mmHg. Lung tissues were collected to evaluate histopathological changes and the expression of endothelial nitric oxide synthase (eNOS). Exp. 2, ten healthy heifers and 10 HAPH affected heifers were supplemented with NCG (20 g/d per heifer) for 4 wk. Physiological parameters were determined and blood samples were collected on d − 1 and d 28 of the feeding trial.ResultsExpression of eNOS in small pulmonary arteriole intima was higher in the healthy than HAPH group (P = 0.006), whereas HAPH group had significantly thicker media and adventitia than healthy group (all P < 0.05). The mRNA of eNOS and protein level of eNOS were higher in the lungs of heifers in the healthy group than in the HAPH group (both P < 0.001), whereas endothelin-1 protein levels were higher in HAPH group than in the healthy group (P = 0.025). NCG supplementation decreased mPAP and ammonia (both P = 0.001), whereas it increased the expression of eNOS, arginine, and plasma NO (all P < 0.05).ConclusionsThe expression of eNOS was decreased in Holstein heifers with HAPH. NCG supplementation decreased mPAP through the restoration of eNOS and endogenous NO synthesis.

Allele distribution and testing for association between an oxygen dependent degradation domain SNP in EPAS1 and pulmonary arterial pressures in yearling Angus cattle

At altitudes >1500 m, measurements of mean pulmonary arterial pressures (mPAP; mmHg) are a measure of pulmonary hypertension (PH) in cattle. Genotypes of a G/A single nucleotide polymorphism (SNP; rs208684340) in the endothelial PAS domain protein 1 (EPAS1) gene were determined for mPAP categories (low, moderate, high) on Angus cattle. The A allele of this SNP was postulated to be associated with altitude-induced PH. The first objective was to estimate allele and genotypic frequencies in Angus cattle at high- (elevation 1850 to 2800 m) and low-altitude (elevation 91 to 1192 m) ranches (n = 118; random sample of 1275). Percent of cattle at these low elevation ranches with genotypes G/G, G/A, and A/A were 64.4, 33.9, and 1.7%, respectively, and a minor allele frequency (MAF; A allele) of 18.6%. Bulls, steers, and heifers (n = 691) from 4 high-altitude Angus herds in Colorado and Wyoming were genotyped. Percent of cattle with genotypes G/G, G/A, and A/A were 48.6, 34.3, and 17.1%, respectively, with a MAF of 34.2%. Average mPAP was 40.5 ± 8.8 mmHg. Low, moderate, and high-mPAP category MAF were similar (χ2 = 3.03; P = 0.22), with values of 35.4, 31.0, and 37.8%, respectively. Additionally we sought to evaluate the genotype-to-phenotype association of this SNP with mPAP phenotypes (n = 532) from the Colorado State University Beef Improvement Center (elevation 2150 m) Angus herd. Linear mixed model analysis suggested genotype was not a predictor (P = 0.61) of mPAP. Results do not suggest the A allele of SNP in EPAS1 is associated with high altitude-induced PH in yearling Angus cattle.

Altered Left Ventricular Geometry and Torsional Mechanics in High Altitude-Induced Pulmonary Hypertension: A Three-Dimensional Echocardiographic Study

Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long-standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude-induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics. Twenty-three volunteers were prospectively studied at low altitude and after the second (D3) and third night (D4) at high altitude (4,559m). LV ejection fraction, multidirectional strains and torsion, LV volumes, sphericity, and eccentricity were derived by speckle-tracking on three-dimensional echocardiographic data sets. Pulmonary pressure was estimated from the transtricuspid pressure gradient (TRPG), LV preload from end-diastolic LV volume, and transmitral over mitral annular E velocity (E/e'). At high altitude, oxygen saturation decreased by 15%-20%, heart rate and cardiac index increased by 15%-20%, and TRPG increased from 21±2 to 37±9mm Hg (P<.01). LV volumes, preload, ejection fraction, multidirectional strains, and sphericity remained unaffected, but diastolic (1.04±0.07 to 1.09±0.09 on D3/D4, P<.05) and systolic (1.00±0.06 to 1.08±0.1 [D3] and 1.06±0.07 [D4], P<.05) eccentricity slightly increased, indicating mild septal flattening. LV torsion decreased from 2.14±0.85 to 1.34±0.68 (P<.05) and 1.65±0.54 (P=.08) degrees/cm on D3/D4, respectively. Changes in torsion showed a weak inverse relationship to changes in systolic (r=-0.369, P=.013) and diastolic (r=-0.329, P=.032) eccentricity but not to changes in TRPG, heart rate or preload. High-altitude exposure was associated with mild septal flattening of the LV and reduced ventricular torsion at unchanged global LV function and preload, suggesting a relation between LV geometry and torsional mechanics.

Alpha-2-Antiplasmin : A Fibrinolytic Peptide, could be a Potential Biomarker for Diagnosis of High Altitude Induced Pulmonary Hypertension

&lt;p class="p1"&gt;Prolonged exposure to high altitude is known to cause pulmonary vascular remodeling and pulmonary hypertension. Despite the advancements in diagnostics of pulmonary hypertension (PH), a potential biomarker for early diagnosis of PH progression is still lacking. High altitude induced pulmonary hypertension (HAPH) is great concern in mountain regions across the world. Early diagnosis and monitoring the disease progression are critical for therapeutic decisions. A fibrinolytic peptide, alpha-2-antiplasmin (α2AP) is known to cause tissue and vascular remodeling. Recently, elevated levels of α2AP were reported in different forms of PH; however its role in high altitude induced pulmonary hypertension is not yet known. To assess whether α-2AP can be used as diagnostic marker for HAPH, a cross sectional study was carried out on 100 healthy male Indian army soldiers who were posted to high altitude (14,800 ft to 18,700 ft) for a prolonged period of 6 to 8 months. We used 2D Echocardiography to screen the pulmonary arterial systolic pressure (PASP) and semi-quantitatively ELISA method for estimation of α-2AP in plasma. We found 34 out of 100 subjects have elevated PASP upon immediate screening after de-induction to moderate altitude of 10,000 ft. Age matched 17 subjects with elevated PASP were assessed for plasma levels of α-2AP in comparison to subjects with normal PASP, but posted to same altitude for same duration of time. Here for the first time we demonstrated an increase in plasma level of α-2AP was positively correlated with hypoxia induced elevated pulmonary arterial pressure. However, additional comprehensive investigations are warranted with large sample size to confirm our findings and explore the use of α2AP as potential diagnostic marker for monitoring progression of HAPH.&lt;span class="Apple-converted-space"&gt; &lt;/span&gt;&lt;/p&gt;

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

Sildenafil for the treatment of altitude-induced hypoxaemia

Exposure to high altitude causes alveolar hypoxia and induces pulmonary hypertension (PH) with consequent limitation of exercise capacity. To assess the impact of sildenafil on haemodynamic and clinical parameters, and on aerobic performance, 12 young healthy unacclimatised subjects were studied (6 received sildenafil 40 mg t.i.d. and 6 received placebo) at sea level and high altitude. Systolic pulmonary artery pressure increased at high altitude, but normalised with sildenafil. The altitude-induced decrease in maximal O2 consumption was significantly smaller with sildenafil than with placebo. Enhancing pulmonary circulation with sildenafil safely protects against the high altitude-induced PH and improves gas exchange.

High Altitude Induced Pulmonary Hypertension and Right Heart Failure in Broiler Chickens

A total of 800 broiler chickens was studied; 400 at sea level, and 400 at an altitude of 3,300 m. Only the chickens raised in this latter condition showed an increased mean pulmonary arterial pressure (Ppa), weight of the right ventricle relative to that of both ventricles (RV/TV), haemoglobin concentrations, haematocrit value and red blood cell count. A high correlation between Ppa and R V/TV was found. Twenty per cent of the chickens raised at high altitude died with signs of right heart failure. The calculated Ppa in these birds was found to be greater than that of the high altitude birds which did not develop overt signs of cardiac insufficiency. These results indicate that some broiler chickens raised at high altitude develop right heart insufficiency secondary to pulmonary arterial hypertension.

Cardiac output in man in rest and work during and after acclimatization to 3,800 m.

Cardiac output during rest and work determined via carbon dioxide method at 3800 m altitude

High Altitude-Induced Pulmonary Hypertension in Normal Cattle

Six months residence at an altitude of 10,000 feet produced significant pulmonary hypertension and arterial oxygen desaturation (86 per cent) in 10 normal steers born at 3,600 feet. Six of these animals, during the course of the experiment, showed a rise in mean pulmonary arterial pressure from 27 to 45 mm. Hg. The remaining four animals developed more severe pulmonary hypertension, and two with mean pressures greater than 100 mm. Hg had right heart failure. All 10 showed right ventricular hypertrophy proportional to the degree of pulmonary hypertension. Ten steers of similar age and origin, maintained as controls at 5,000 feet, showed a mean pulmonary arterial pressure of 27 mm. Hg throughout the experiment. The pulmonary hypertension observed at high altitude is considered to be due to an increased pulmonary vascular resistance resulting from a reduction in the total cross-sectional area of the pulmonary vascular bed. Chronic hypoxia appeared to be the most important etilogical factor responsible for initiating the hypertension. The observed beneficial effects of 100 per cent oxygen inhalation and the prompt recovery of an affected animal when moved to lower altitude supported the concept of pulmonary hypertension induced by hypoxia.