Almaz Aldashev

Phosphodiesterase type 5 and high altitude pulmonary hypertension

Background: This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH). Methods: 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 mm Hg. 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. Results: At 3 months, patients on sildenafil 25 mg 8 hourly (nu200a=u200a9) had a significantly (pu200a=u200a0.018) lower mean PAP (−6.9 mm Hg) at the end of the dosing interval than those on placebo (nu200a=u200a8) (95% CI −12.4 to −1.3). The treatment effect for sildenafil 100 mg 8 hourly (nu200a=u200a5) 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; pu200a=u200a0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; pu200a=u200a0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles. Conclusions: 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.

Penitentiary population of Mycobacterium tuberculosis in Kyrgyzstan: Exceptionally high prevalence of the Beijing genotype and its Russia-specific subtype

Here, we present results of the first study of the Mycobacterium tuberculosis genotypes circulating in Kyrgyzstan. We focused on the incarcerated population known to be at high-risk for tuberculosis (TB) and with a significant impact on TB incidence in the general population. Beijing genotype was detected in 42 of 56 M. tuberculosis sputum-extracted DNA samples from newly-diagnosed adult pulmonary TB patients. RIF and INH resistance was genotypically detected in 28% and 55% samples; 13 of 15 MDR strains belonged to Beijing genotype. 12-locus MIRU-VNTR typing showed 8 of 56 samples to be mixed cases; 7 of them contained a Beijing strain. MIRU analysis demonstrated a high homogeneity of the studied collection (HGI=0.66) while 28 of 56 strains had a profile 223325153533 corresponding to Beijing/M2 subtype highly prevalent in different Russian settings. Three hypervariable loci, QUB-3232, VNTR-3820 and VNTR-4120, permitted to further subdivide 28 Beijing/M2 strains into 11 subtypes shared by 1 to 9 strains. To conclude, all markers taken together, the penitentiary population of M. tuberculosis in Kyrgyzstan exhibited a strong genetic affinity to Russia and a weak relatedness to East Asia.

An association between TRP64ARG polymorphism of the B3 adrenoreceptor gene and some metabolic disturbances.

BackgroundsB3 adrenoreceptors (ADRB3) are abundant in adipose tissue and play the role in its metabolism and lipolysis. Some variants of the ADRB3 gene may predispose subjects for the development obesity and metabolic abnormalities in the setting of modern sedentary lifestyle. ADRB3 gene polymorphism association with metabolic disturbances has never been studied before in the ethnic Kyrgyz population.AimTo study an association between Trp64Arg polymorphism of the ADRB3 and metabolic syndrome (MS) components in an ethnic Kyrgyz group.Materials and methods213 Ethnic Kyrgyz volunteers over the age of 30 were enrolled in the study. The assessment plan for each individual comprised of general physical and anthropometric exams as well as laboratory tests (glucose, lipid panel, insulin) and genotyping by Trp64Arg polymorphism of the ADRB3. MS diagnosis was consistent with modified ATP III criteria (2005). Logistic regression analysis was performed to test the potential independent association between Arg64 allele with obesity, abdominal obesity (AO) and arterial hypertension (AH).ResultsTrp64Arg polymorphism of the ADRB3 was assessed in 213 individuals (145 men, 68 women) aged 30-73 (mean age 50.7 ± 7.6). Arg64 allele frequency was 0.239; ADRB3 genotype distribution among participants was: Trp64 homozygotes 54.5%, Trp64Arg 43.2% and Arg64 homozygotes 2.3%. There was an association between Trp64Arg и Arg64Arg genotypes and higher BMI, WC and obesity frequency (p < 0.00009), AO (p < 0.01), type 2 diabetes mellitus (DM) (p < 0.005) and lower high density cholesterol (HDL-C) level (p < 0.03). The logistic regression analysis showed the correlation of the Arg64 allele with obesity (OR 3.159; 95% CI 1.789-5.577) and AO (OR 1.973; 95% CI 1.118-3.481). The association between Arg64 allele and AH lost its significance after adjustment for obesity.ConclusionArg64 allele of the ADRB3 gene in the studied group has an association with MS components such as obesity, AO and decreased HDL-C level.

Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family

We report a genome-wide scan for susceptibility loci to hypertension in a single Kyrgyz family where 10 of the affected relatives developed hypertension before the age of 35 years, and some members have suffered stroke. The early onset of disease and the geographic isolation of the Kyrgyz population are both expected to select for an increased influence of genetic factors in hypertension. We genotyped 44 individuals from this Krygyz family with 374 microsatellite markers, covering a 10-centimorgan map. Nonparametric analysis suggests that affected status is linked to loci in the chromosome 2q23 to q37 genomic interval, whereas 2-point parametric analysis returned a logarithm of odds score of 2.67 for marker D2S2330 (2q24.3). Multipoint linkage analysis substantiated the evidence for a hypertension susceptibility allele in the chromosome 2q23 to q36 region. Fine mapping and haplotype analysis implicate that the genetic lesion resides between markers D2S2380 (166.5 cM) and D2S335 (175.9 cM). This finding supports other recent studies of early onset hypertension suggesting that the region 2q24.3 to q31.1 encompasses a novel locus for premature hypertension.

Changes in Plasma Bradykinin Concentration and Citric Acid Cough Threshold at High Altitude

Abstract Objective.—Altitude-related cough is a troublesome condition of unknown etiology. Inhaled tussive agents are used to quantify cough, and the citric acid cough threshold has been shown to fall on ascent to altitude. Cough can occur in patients taking angiotensin-converting enzyme inhibitors due to stimulation of airway sensory receptors by increased levels of bradykinin. We hypothesized that increased levels of bradykinin could be responsible for the decrease in citric acid cough threshold on exposure to altitude and a possible etiologic factor in altitude-related cough. Methods.—Twenty healthy volunteers underwent baseline tests at 700 m before a 2-week stay at 3800 m. Angiotensin-converting enzyme activity and plasma bradykinin were measured at baseline and altitude. Citric acid cough threshold and nocturnal cough frequency were measured at baseline and throughout the 2 weeks at altitude. Results.—Citric acid cough threshold fell from 3.7 g/dL at baseline to 2.1 g/dL on the second day at 3800 m (geometric mean difference 1.8, 95% CIs 1.0–5.0, P u200a=u200a .025) and remained reduced throughout the stay at altitude. Nocturnal cough frequency was unchanged compared to baseline. Plasma bradykinin fell from 0.43 ng/mL at baseline to 0.08 ng/mL at altitude (geometric mean difference 5.7, 95% CIs 2.1–15.5, P u200a=u200a .002), but angiotensin-converting enzyme activity was unchanged (mean difference 0.06, 95% CIs –2.7–2.8, P u200a=u200a .97). There was no correlation between plasma bradykinin and citric acid cough threshold. Conclusions.—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.

The α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection from Pulmonary Hypertension among Kyrgyz Highlanders

Background—Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. Methods and Results—Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an &agr;1-A680T soluble guanylate cyclase (sGC) variant. Expression of the &agr;1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified &agr;1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. Conclusions—The &agr;1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.

Blunted Activation of Rho-Kinase in Yak Pulmonary Circulation

Yaks have adapted to high altitude and they do not develop hypoxic pulmonary hypertension. Although we previously identified the important role of augmented nitric oxide synthase activity in the yak pulmonary circulatory system, evidence of the direct involvement of Rho-kinase as a basal vascular tone regulator is lacking. Four domesticated male pure-bred yaks and four bulls that were born and raised at an altitude of 3000u2009m in the Tien-Shan mountains were studied at an altitude of 3,100u2009m. Mean pulmonary artery pressure (mPAP) was measured before and after fasudil (60u2009mg in 20u2009mL of saline) was intravenously administered using a Swan-Ganz catheter at a rate of 3.3u2009mL/min for 30u2009min. Fasudil decreased mPAP in bulls from 67.8±14.9 to 32.3±5.3u2009mmHg (P < 0.05) after 15u2009min and the level was maintained for 30u2009min, but it merely blunted mPAP in yaks from 28.2±4.5 to 25.1±11.1 and 23.2±2.7u2009mmHg after 5 and 30u2009min, respectively. These findings comprise the first evidence of a modest role of Rho-kinase in the maintenance of pulmonary artery pressure in the yak.

α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

Background—Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. Methods and Results—Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an &agr;1-A680T soluble guanylate cyclase (sGC) variant. Expression of the &agr;1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified &agr;1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. Conclusions—The &agr;1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.

Endogenous Asymmetric Dimethylarginine Pathway in High Altitude Adapted Yaks

Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

The association of Val109Asp polymorphic marker of intelectin 1 gene with abdominal obesity in Kyrgyz population

BackgroundThe aim of this study was to quantify the association of Val109Asp polymorphism of intelectin 1 (ITLN1) gene with the abdominal obesity (AO) in Kyrgyz population.MethodsPatients admitted to annual screening at a local outpatient facility were enrolled or this study. We genotyped 297 nonrelated adults of Kyrgyz ethnicity, of whom 127 were AO patients, including 46 men and 81 women with the mean age 53.2u2009±u20097.1xa0years, and 170 non-obese controls, including 61 men and 109 women with the mean age 52.0u2009±u20099.0xa0years. AO was defined as having waist circumferences ≥u2009102xa0cm in men and ≥u200988xa0cm in women. We used PCR-RFLP method to define Val109Asp polymorphism of ITLN1 gene.ResultsAsp109Asp, Asp109Val and Val109Val genotypes were found in 48%, 40%, and 12% of AO patients respectively, and in 53%, 43%, and 4% of controls, whereas Val109Val homozygous genotype of ITLN1 gene Val109Asp polymorphic marker was significantly more prevalent in AO patients. In Kyrgyz population, Val109Val genotype of ITLN1 gene increased the risk of AO (odds ratio (OR) 3.12, 95% CI 1.23–7.90). Asp109Asp homozygous genotype, on opposite, was not associated with this condition (OR 0.82, 95% CI 0.53–1.30). Finally, the allelic variants of Val109Asp polymorphism of ITLN1 gene were not associated with AO.ConclusionSignificant increase in the frequency of Val109Val genotype of ITLN1 gene in AO patients may be indicative of some potential role of ITLN1 gene in molding genetic predisposition to AO in the Kyrgyz. This requires further elaboration in the future studies.