The DNA methyltransferase-mediated proinflammatory activation of macrophages is causally linked to the development of atherosclerosis (AS). However, the role of DNMT1, a DNA methylation maintenance enzyme, in macrophage polarization and AS development remains obscure. Here, we established transgenic mice with macrophage-specific overexpression of DNMT1 (TgDNMT1) or PPAR-γ (TgPPAR-γ) to investigate their effects on AS progression in ApoE-knockout mice fed an atherogenic diet. Primary macrophages were extracted to study the role of the DNMT1/PPAR-γ pathway in regulating inflammatory cytokine production. We demonstrated that TgDNMT1 significantly increased proinflammatory cytokine production in macrophages and plasma, and it accelerated the progression of AS in the atherogenic diet-treated ApoE-knockout mice. Further, we found that the DNA methylation status of the proximal PPAR-γ promoter was regulated by DNMT1 in macrophages. Notably, additional TgPPAR-γ or pharmacological activation of PPAR-γ effectively prevented TgDNMT1-induced proinflammatory cytokine production in macrophages and AS development in the mouse model. Finally, we demonstrated that elevated DNMT1 was correlated with decreased PPAR-γ, and increased proinflammatory cytokine production in the peripheral blood monocytes isolated from the patients with AS, compared to those of healthy donors. Our findings shed light on a novel strategy for the prevention and therapy of AS.

Both inhaled budesonide (200 μg, bid) and oral dexamethasone (4 mg, bid) were effective for the prevention of acute mountain sickness, especially its severe form, compared with placebo. Budesonide caused fewer adverse reactions than dexamethasone.

The aims of this study were to explore the effect of high-altitude (HA) exposure on the incidence, determinants, and impacts of right ventricular dyssynchrony (RVD). In our study, 108 healthy young men were enrolled, and physiological and echocardiographic variables were recorded at both sea level and 4,100 m. By using two-dimensional speckle-tracking echocardiography, RVD was evaluated by calculating the R-R intervalcorrected standard deviation of the time-to-peak systolic strain for the four mid-basal RV segments (RVSD4) and defined by RVSD4 > 18.7 ms. After HA exposure, RVSD4 was significantly increased, and the incidence of RVD was approximately 32.4%. Subjects with RVD showed lower oxygen saturation (SaO 2) and RV global longitudinal strain and higher systolic pulmonary artery pressure than those without RVD. Moreover, myocardial acceleration during isovolumic contraction was increased in all subjects and those without RVD, but not in those with RVD. Multivariate logistic regression revealed that SaO 2 is an independent determinant of RVD at HA (odds ratio: 0.72, 95% CI: 0.56-0.92; P = 0.009). However, the mean pulmonary artery pressure was linearly correlated with the magnitude of RVD in the presence of Notch. No changes were found in RV fractional area change, tricuspid annular motion, or tricuspid s' velocity between subjects with and without RVD. Collectively, we demonstrated for the first time that HA exposure could induce RVD in healthy subjects, which may be mainly attributed to the decline in SaO 2 as well as RV overload; the incidence of RVD was associated with reduced RV regional function and blunted myocardial acceleration.

BackgroundThis prospective and observational study aimed to identify demographic, physiological and psychological risk factors associated with high-altitude headache (HAH) upon acute high-altitude exposure.MethodsEight hundred fifty subjects ascended by plane to 3700 m above Chengdu (500 m) over a period of two hours. Structured Case Report Form (CRF) questionnaires were used to record demographic information, physiological examinations, psychological scale, and symptoms including headache and insomnia a week before ascending and within 24 hours after arrival at 3700 m. Binary logistic regression models were used to analyze the risk factors for HAH.ResultsThe incidence of HAH was 73.3%. Age (p =0.011), physical labor intensity (PLI) (p =0.044), primary headache history (p <0.001), insomnia (p <0.001), arterial oxygen saturation (SaO2) (p =0.001), heart rate (HR) (p =0.002), the Self-Rating Anxiety Scale (SAS) (p <0.001), and the Epworth Sleepiness Scale (ESS) (p <0.001) were significantly different between HAH and non-HAH groups. Logistic regression models identified primary headache history, insomnia, low SaO2, high HR and SAS as independent risk factors for HAH.ConclusionsInsomnia, primary headache history, low SaO2, high HR, and high SAS score are the risk factors for HAH. Our findings will provide novel avenues for the study, prevention and treatment of HAH.

High altitude (HA) exposure has been considered as a cardiac stress and might impair ventricular diastolic function. Atrial contraction is involved in ventricular passive filling, however the atrial performance to HA exposure is poorly understood. This study aimed to evaluate the effect of short-term HA exposure on bi-atrial function. Physiological and 2D-echocardiographic data were collected in 82 healthy men at sea level (SL, 400 m) and 4100 m after an ascent within 7 days. Atrial function was measured using volumetric and speckle-tracking analyses during reservoir, conduit and contractile phases of cardiac cycle. Following HA exposure, significant decreases of reservoir and conduit function indexes were observed in bi-atria, whereas decreases of contractile function indexes were observed in right atrium (RA), estimated via RA active emptying fraction (SL 41.7 ± 13.9% vs. HA 35.4 ± 12.2%, p = 0.001), strain during the contractile phase [SL 13.5 (11.4, 17.8) % vs. HA 12.3 (9.3, 15.9) %, p = 0.003], and peak strain rate during the contractile phase [SL − 1.76 (− 2.24, − 1.48) s−1 vs. HA − 1.57 (− 2.01, − 1.23) s−1, p = 0.002], but not in left atrium (LA). In conclusion, short-term HA exposure of healthy individuals impairs bi-atrial performance, mostly observed in RA. Especially, atrial contractile function decreases in RA rather than LA, which seems not to compensate for decreased ventricular filling after HA exposure. Our findings may provide a novel evidence for right-sided heart dysfunction to HA exposure.

IntroductionPulmonary artery pressure (PAP) is increased and right ventricular (RV) function is well preserved in healthy subjects upon exposure to high altitude (HA). An increase in PAP may trigger notching of the right ventricular outflow tract Doppler flow velocity envelope (RVOT notch), which is associated with impaired RV function in patients with pulmonary hypertension. However, whether HA exposure can induce RVOT notch formation and the subsequent impact on cardiac function in healthy subjects remains unclear.MethodsA total of 99 subjects (69 males and 30 females) with a median age of 25 years were enrolled in this study; they traveled from 500 to 4100 m by bus over a 2-day period. All subjects underwent a comprehensive physiological and echocardiographic examination 1 day before ascension at low altitude and 15 ± 3 h after arrival at HA. The RVOT notch was determined by the presence of a notched shape in the RVOT Doppler flow velocity envelope. The systolic PAP (SPAP) was calculated as Bernoulli equation SPAP = 4 × (maximum tricuspid regurgitation velocity)2+5 and mean PAP (mPAP) = 0.61 × SPAP+2. Cardiac output was calculated as stroke volume × heart rate. Pulmonary capillary wedge pressure (PCWP) was calculated as 1.9+1.24 × mitral E/e’. Pulmonary vascular resistance (PVR) was calculated as (mPAP-PCWP)/CO.ResultsAfter HA exposure, 20 (20.2%) subjects had an RVOT notch [notch (+)], and 79 (79.8%) subjects did not have an RVOT notch [notch (−)]. In the multivariate logistic regression analysis, the SPAP, right ventricular global longitude strain (RV GLS), and tricuspid E/A were independently associated with the RVOT notch. The SPAP, mPAP, PVR, standard deviations of the times to peak systolic strain in the four mid-basal RV segments (RVSD4), peak velocity of the isovolumic contraction period (ICV), and the peak systolic velocity (s’) at the mitral/tricuspid annulus were increased in all subjects. Conversely, the pulse oxygen saturation (SpO2), RV GLS, and tricuspid annulus plane systolic excursion (TAPSE)/SPAP were decreased. However, the increases of SPAP, mPAP, PVR, and RVSD4 and the decreases of SpO2, RV GLS, and TAPSE/SPAP were more pronounced in the notch (+) group than in the notch (−) group. Additionally, increased tricuspid ICV and mitral/tricuspid s’ were found only in the notch (−) group.ConclusionHA exposure-induced RVOT notch formation is associated with impaired RV function, including no increase in the tricuspid ICV or s’, reduction of RV deformation, deterioration in RV-pulmonary artery coupling, and RV intraventricular synchrony.

Sleep disturbances and psychiatric repercussions pose great challenges at high altitude; however, few studies have investigated sleep disturbance and anxiety profiles and their associations after acute exposure in consecutive patients. Thus, we aimed to study the profiles of sleep disturbances in consecutive patients after high-altitude exposure and the association of such disturbances with anxiety. A total of 668 participants were recruited at sea level and 3700 m. The trials were performed at sea level (1 week prior to a 2-h flight to a high-altitude destination) and at 3700 m (24, 72, and 168 h). Sleep disturbances were assessed by self-reported sleep patterns and scores on the Athens Insomnia Scale (AIS). State anxiety was assessed using the Self-Rating Anxiety Scale (SAS). In our study, the incidence of sleep disturbances increased significantly after acute high-altitude exposure (65.3%, 434/668) and then gradually decreased after 72 h (50%, 141/282) and 168 h (44%, 124/282). The sleep assessments AIS [2.0 (4.0) vs. 4.0 (5.0)] and ESS [4.0 (4.0) vs. 5.0 (5.0)] increased significantly ( p < 0.05). Also, the SAS increased significantly from 26.25 (3.75) to 28.75 (7.5). The SAS was significantly high in sleep disturbance group [31.25 (7.5) vs. 27.5 (5), p < 0.001] than in the non-sleep- disturbance group. The baseline SAS and AIS scores were significantly higher in participants with sleep disturbances than in those without ( p < 0.01). Age, baseline insomnia, sleepiness, fatigue, and higher SAS were predictors of sleep disturbances in univariate regression (all p values < 0.05). However, only an older age ( p = 0.045) and a higher baseline SAS ( p = 0.018) remained independent predictors of sleep disturbances. Our findings indicated that acute high-altitude exposure triggers the onset of sleep disturbances, which are closely associated with anxiety. Furthermore, baseline state anxiety and age are independent predictors of sleep disturbances at high altitude.

BackgroundExcessive elevation of arterial blood pressure (BP) at high altitude can be detrimental to our health due to acute mountain sickness (AMS) or some AMS symptoms. This prospective and observational study aimed to elucidate blood pressure changes induced by exposure to high-altitude hypoxia and the relationships of these changes with AMS prevalence, AMS severity, sleep quality and exercise condition in healthy young men.MethodsA prospective observational study was performed in 931 male young adults exposed to high altitude at 3,700 m (Lhasa) from low altitude (LA, 500 m). Blood pressure measurement and AMS symptom questionnaires were performed at LA and on day 1, 3, 5, and 7 of exposure to high altitude. Lake Louise criteria were used to diagnose AMS. Likewise, the Athens Insomnia Scale (AIS) and the Epworth Sleepiness Scale (ESS) were filled out at LA and on day 1, 3, and 7 of exposure to high altitude.ResultsAfter acute exposure to 3,700 m, diastolic blood pressure (DBP) and mean arterial blood pressure (MABP) rose gradually and continually (P < 0.05). Analysis showed a relationship with AMS for only MABP (P < 0.05) but not for SBP and DBP (P > 0.05). Poor sleeping quality was generally associated with higher SBP or DBP at high altitude, although inconsistent results were obtained at different time (P < 0.05). SBP and Pulse BP increased noticeably after high-altitude exercise (P < 0.05).ConclusionsOur data demonstrate notable blood pressure changes under exposure to different high-altitude conditions: 1) BP increased over time. 2) Higher BP generally accompanied poor sleeping quality and higher incidence of AMS. 3) SBP and Pulse BP were higher after high-altitude exercise. Therefore, we should put more effort into monitoring BP after exposure to high altitude in order to guard against excessive increases in BP.