Effect of ubiquinol on electrophysiology during high-altitude acclimatization and de-acclimatization: A substudy of the Shigatse CARdiorespiratory fitness (SCARF) randomized clinical trial.

BACKGROUND: High-altitude exposure changes the electrical conduction of the heart. However, reports on electrocardiogram (ECG) characteristics and potent prophylactic agents during high-altitude acclimatization and de-acclimatization are inadequate. This study aimed to investigate the effects of ubiquinol on electrophysiology after high-altitude hypoxia and reoxygenation. METHODS: The study was a prospective, randomized, double-blind, placebo-controlled trial. Forty-one participants were randomly divided into two groups receiving ubiquinol 200 mg daily or placebo orally 14 days before flying to high altitude (3900 m) until the end of the study. Cardiopulmonary exercise testing was performed at baseline (300 m), on the third day after reaching high altitude, and on the seventh day after returning to baseline. RESULTS: Acute high-altitude exposure prolonged resting ventricular repolarization, represented by increased corrected QT interval (455.9 ± 23.4 vs. 427.1 ± 19.1 ms, P < 0.001) and corrected Tpeak-Tend interval (155.5 ± 27.4 vs. 125.3 ± 21.1 ms, P < 0.001), which recovered after returning to low altitude. Ubiquinol supplementation shortened the hypoxia-induced extended Tpeak-Tend interval (-7.7 ms, [95% confidence interval (CI), -13.8 to -1.6], P = 0.014), Tpeak-Tend /QT interval (-0.014 [95% CI, -0.027 to -0.002], P = 0.028), and reserved maximal heart rate (11.9 bpm [95% CI, 3.2 to 20.6], P = 0.013) during exercise at high altitude. Furthermore, the decreased resting amplitude of the ST-segment in the V3 lead was correlated with decreased peak oxygen pulse (R = 0.713, P < 0.001) and maximum oxygen consumption (R = 0.595, P < 0.001). CONCLUSIONS: Our results illustrated the electrophysiology changes during high-altitude acclimatization and de-acclimatization. Similarly, ubiquinol supplementation shortened the prolonged Tpeak-Tend interval and reserved maximal heart rate during exercise at high altitude. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR2200059900.

Effect of ubiquinol on cardiorespiratory fitness during high-altitude acclimatization and de-acclimatization in healthy adults: the Shigatse CARdiorespiratory fitness study design.

Cardiorespiratory function influences exercise capacity and is an important determinant of high-altitude adaptation. Some studies have investigated the characteristics of changes in cardiorespiratory fitness during high-altitude acclimatization. However, studies on changes in cardiorespiratory fitness during high-altitude de-acclimatization are still lacking and have not yet been elucidated. Furthermore, few drugs have been studied to improve cardiorespiratory function during both processes. The Shigatse CARdiorespiratory Fitness (SCARF) study is a single-center, randomized, double-blind, placebo-control clinical trial to explore the effects of ubiquinol on cardiorespiratory fitness during high-altitude acclimatization and de-acclimatization in healthy adults. Participants will be randomly assigned 1:1 to ubiquinol 200 mg daily or a placebo for 14 days before departure until the end of data collection after return in 7 days. Cardiorespiratory fitness is the primary outcome, while acute mountain sickness and high-altitude de-acclimatization symptoms are secondary endpoints. In addition, laboratory measurements, including routine blood tests and serological measurements, will be performed. To the best of our knowledge, the SCARF study will be the first to reveal the changes in the cardiorespiratory fitness characteristics during high-altitude acclimatization and de-acclimatization. Furthermore, the results of this study will contribute to exploring whether ubiquinol supplementation could be beneficial for endurance exercise capacity at different altitudes and help improve adaptation to acute hypoxia and de-acclimatization. Clinical Trial Registration: This study has been registered in the Chinese Clinical Trial Register (www.chictr.org.cn) as ChiCTR2200059900 and ChiCTR2200066328.

Smartwatch-Based Maximum Oxygen Consumption Measurement for Predicting Acute Mountain Sickness: Diagnostic Accuracy Evaluation Study.

BACKGROUND: Cardiorespiratory fitness plays an important role in coping with hypoxic stress at high altitudes. However, the association of cardiorespiratory fitness with the development of acute mountain sickness (AMS) has not yet been evaluated. Wearable technology devices provide a feasible assessment of cardiorespiratory fitness, which is quantifiable as maximum oxygen consumption (VO2max) and may contribute to AMS prediction. OBJECTIVE: We aimed to determine the validity of VO2max estimated by the smartwatch test (SWT), which can be self-administered, in order to overcome the limitations of clinical VO2max measurements. We also aimed to evaluate the performance of a VO2max-SWT-based model in predicting susceptibility to AMS. METHODS: Both SWT and cardiopulmonary exercise test (CPET) were performed for VO2max measurements in 46 healthy participants at low altitude (300 m) and in 41 of them at high altitude (3900 m). The characteristics of the red blood cells and hemoglobin levels in all the participants were analyzed by routine blood examination before the exercise tests. The Bland-Altman method was used for bias and precision assessment. Multivariate logistic regression was performed to analyze the correlation between AMS and the candidate variables. A receiver operating characteristic curve was used to evaluate the efficacy of VO2max in predicting AMS. RESULTS: VO2max decreased after acute high altitude exposure, as measured by CPET (25.20 [SD 6.46] vs 30.17 [SD 5.01] at low altitude; P<.001) and SWT (26.17 [SD 6.71] vs 31.28 [SD 5.17] at low altitude; P<.001). Both at low and high altitudes, VO2max was slightly overestimated by SWT but had considerable accuracy as the mean absolute percentage error (<7%) and mean absolute error (<2 mL·kg-1·min-1), with a relatively small bias compared with VO2max-CPET. Twenty of the 46 participants developed AMS at 3900 m, and their VO2max was significantly lower than that of those without AMS (CPET: 27.80 [SD 4.55] vs 32.00 [SD 4.64], respectively; P=.004; SWT: 28.00 [IQR 25.25-32.00] vs 32.00 [IQR 30.00-37.00], respectively; P=.001). VO2max-CPET, VO2max-SWT, and red blood cell distribution width-coefficient of variation (RDW-CV) were found to be independent predictors of AMS. To increase the prediction accuracy, we used combination models. The combination of VO2max-SWT and RDW-CV showed the largest area under the curve for all parameters and models, which increased the area under the curve from 0.785 for VO2max-SWT alone to 0.839. CONCLUSIONS: Our study demonstrates that the smartwatch device can be a feasible approach for estimating VO2max. In both low and high altitudes, VO2max-SWT showed a systematic bias toward a calibration point, slightly overestimating the proper VO2max when investigated in healthy participants. The SWT-based VO2max at low altitude is an effective indicator of AMS and helps to better identify susceptible individuals following acute high-altitude exposure, particularly by combining the RDW-CV at low altitude. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200059900; https://www.chictr.org.cn/showproj.html?proj=170253.

Single-cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types. METHODS: Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro. RESULTS: In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5+/- ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs. CONCLUSIONS: This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.

Mitochondria-associated membrane protein PACS2 maintains right cardiac function in hypobaric hypoxia.

Hypobaric hypoxia (HH) is the primary challenge at highland. Prolonged HH exposure impairs right cardiac function. Mitochondria-associated membrane (MAM) plays a principal role in regulating mitochondrial function under hypoxia, but the mechanism was unclear. In this study, proteomics analysis identified that PACS2, a key protein in MAM, and mitophagy were downregulated in HH. Metabolomics analysis indicated suppression of glucose and fatty acids aerobic oxidation in HH conditions. Cardiomyocyte Pacs2 deficiency disrupted MAM formation and endoplasmic reticulum (ER)-mitochondria calcium flux, further inhibiting mitophagy and energy metabolism in HH. Pacs2 overexpression reversed these effects. Cardiac-specific knockout of Pacs2 exacerbated mitophagy inhibition, cardiomyocyte injury, and right cardiac dysfunction induced by HH. Conditional knock-in of Pacs2 recovered HH-induced right cardiac impairment. Thus, PACS2 is essential for protecting cardiomyocytes through ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism. Our work provides insight into the mechanism of HH-induced cardiomyocyte injury and potential targets for maintaining the right cardiac function at the highland.

[Study of hrpN(CSDS001) and the gene expression profile of Arabidopsis thaliana induced by Harpin(CSDS001)].

Erwinia carotovora subsp. carotovora CSDS001 elicits hypersensitive reaction (HR) in tobacco. From the genomic libraries of Erwinia carotovora subsp. carotovora CSDS001, the hrpNCSDS001 gene (GenBank number AY939927), was isolated. The hrpNCSDS001 fusion protein was produced in Escherichia coli, and was used to induce HR by injecting into tobacco. We further examined the global regulation of Arabidopsis thaliana genes in response to HarpinCSDS001 at a concentration of 30 miccrog/mL. We indicated that 912, 1787, 2393, 1833 and 1,755 genes that were regulated significantly (log ratio or=1) at 3 h, 12 h, 24 h, 36 h and 48 h respectively after the treatment. Analysis of some transcription factors (TF) showed that 13 TF families responded to HarpinCSDS001 including ZIM, BES1, TCP, C2C2, AP2/EREBP, WRKY, bHLH, bZIP, GARP, MYB, NAC, HB, C2H2. These families mainly function in biological processes of plant defense, pho-tosynthesisdevelopment and flowering.