Previous studies have suggested a genetic component in susceptibility to hypoxia-induced pulmonary hypertension. We therefore estimated the prevalence of high-altitude pulmonary hypertension (HAPH) in a Kyrgyz population and whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene associates with HAPH. An electrocardiographic survey of 741 highlanders demonstrated electrocardiogram signs of cor pulmonale in 14% of subjects. Pulmonary artery hemodynamics measured in an independent group of 136 male highlanders with symptoms of dyspnea at altitude revealed established pulmonary hypertension (mean pulmonary artery pressure [MPAP] > or = 25 mm Hg) in 20%. However, 26% of the normal subjects demonstrated an exaggerated response (twofold or greater increase in MPAP) to inhalation of 11% oxygen, and were classified as hyperresponsive. Ten-year follow-up of this group revealed increases in the MPAP, but not in normal subjects. Comparison of ACE I/D genotypes in the catheterized group revealed a threefold higher frequency of the I/I genotype in highlanders with HAPH, compared with normal highlanders (chi2 = 11.59, p = 0.003). In addition, MPAP was higher in highlanders with the I/I genotype (26.9 +/- 4.0 mm Hg) compared with the I/D genotype (20.6 +/- 1.2 mm Hg) or the D/D genotype (18.3 +/- 0.9 mm Hg) (p < 0.05). We conclude that HAPH is associated with ACE I/D genotype among Kyrgyz highlanders and the development of HAPH in this population and may be predicted by hyperresponsiveness to acute hypoxia.

No abstract

Chronic alveolar hypoxia due to disease or low atmospheric pressure at high altitude results in the development of hypoxic pulmonary hypertension. The effects of intermittent hypoxia on pulmonary hemodynamics in healthy men have not been studied. We aimed to investigate, prospectively, pulmonary hemodynamics in workers commuting between an elevation of 3700 and 4200 m (4-week working shift) and lowland, below 500 m (4 weeks of holiday). Pulmonary hemodynamics has been investigated by Doppler echocardiography in 26 healthy Caucasian males, mean age 42 +/- 9 yr. First at lowland (760 m) and next during the fourth week of work at high altitude. Investigations were repeated in 21 subjects 1 year later at the end of the high-altitude exposure. The third series of investigations was performed 2 yr after the initial ones in 10 subjects who earlier had shown the strongest hypoxic vasoconstriction. At lowland, subjects presented with normal pulmonary hemodynamics. At high altitude, mean pulmonary artery pressure (PAPm) rose from 14.7 +/- 2.7 mmHg to 25.8 +/- 8.3 mmHg. One year later the PAPm remained unchanged in hypoxic conditions (25.0 +/- 7.3 mmHg). At the end of a 2-year follow-up of 10 "hyperreactors," PAPm measured at the end of the hypoxic exposure was the same as at the initial investigation, averaging 28 +/- 4.0, 28 +/- 3.5, and 29 +/- 2.5 mmHg at the beginning and at 1 and after 2 yr of intermittent exposure to high altitude. We concluded that intermittent exposure to 4000 m lasting 3 yr does not lead to development of permanent pulmonary hypertension.

The international AKTIV register presents a detailed description of out- and inpatients with COVID-19 in the Eurasian region. It was found that hospitalized patients had more comorbidities. In addition, these patients were older and there were more men than among outpatients. Among the traditional risk factors, obesity and hypertension had a significant negative effect on prognosis, which was more significant for patients 60 years of age and older. Among comorbidities, CVDs had the maximum negative effect on prognosis, and this effect was more significant for patients 60 years of age and older. Among other comorbidities, type 2 and 1 diabetes, chronic kidney disease, chronic obstructive pulmonary disease, cancer and anemia had a negative impact on the prognosis. This effect was also more significant (with the exception of type 1 diabetes) for patients 60 years and older. The death risk in patients with COVID-19 depended on the severity and type of multimorbidity. Clusters of diseases typical for deceased patients were identified and their impact on prognosis was determined. The most unfavorable was a cluster of 4 diseases, including hypertension, coronary artery disease, heart failure, and diabetes mellitus. The data obtained should be taken into account when planning measures for prevention (vaccination priority groups), treatment and rehabilitation of COVID-19 survivors.

Background: Pulmonary hypertension (PH) is a life-threatening disease, characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary arterial pressure and right heart hypertrophy. PH can be caused by chronic hypoxia, leading to hyper-proliferation of pulmonary arterial smooth muscle cells (PASMC) and apoptosis-resistant pulmonary microvascular endothelial cells (PMVEC). Upon re-exposure to normoxia, chronic hypoxia-induced PH in mice is reversible. In this study, we aim to identify novel candidate genes involved in pulmonary vascular remodeling specifically in the pulmonary vasculature. Methods: Following a microarray analysis, we assessed the role of secreted protein acidic and rich in cysteine (SPARC) in PH using lung tissue from idiopathic pulmonary arterial hypertension (IPAH) patients as well as from chronic hypoxic mice. In vitro studies were conducted in primary human PASMC and PMVEC. In vivo function of SPARC was proven in chronic hypoxia-induced PH in mice by using an AAV-mediated Sparc knockdown approach. Results: C57BL/6J mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia for different time points. Microarray analysis of the pulmonary vascular compartment after laser microdissection identified Sparc as one of the genes down-regulated at all re-oxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in IPAH, although SPARC plasma levels were not elevated in PH. Transforming growth factor (TGF)-β1 or hypoxia-inducible factor (HIF)-2A signaling pathways induced SPARC expression in human PASMC. In loss of function studies, SPARC silencing enhanced apoptosis and reduced proliferation. In gain of function studies, elevated SPARC levels induced PASMC but not PMVEC proliferation. Co-culture and conditioned medium experiments revealed that PMVEC-secreted SPARC acts as a paracrine factor triggering PASMC proliferation. Against our expectations, in vivo congenital Sparc knockout mice were not protected from hypoxia-induced PH, most probably due to counter-regulatory pro-proliferative signaling. However, AAV-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice. Conclusions: Our study provided evidence for the involvement of SPARC in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, most probably by affecting vascular cell function.

The major difference between the 2 populations was larger lung volumes in the Kyrgyzis compared with the Indians, with no differences seen in their flow rate measures. Also, there was a different time schedule of altitude-induced reductions in FVC and FEF(25-75%).

Increased levels of bradykinin are unlikely to be a significant factor in the increased sensitivity to citric acid seen in hypobaric hypoxia. Further studies are required to elucidate the etiology of altitude-related cough.

Egemnazarov B, Sydykov A, Schermuly RT, Weissmann N, Stasch JP, Sarybaev AS, Seeger W, Grimminger F, Ghofrani HA. Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury.