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.

Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.

Microvascular hyperpermeability is a hallmark of inflammation. Many negative effects of hyperpermeability are due to its persistence beyond what is required for preserving organ function. Therefore, we propose that targeted therapeutic approaches focusing on mechanisms that terminate hyperpermeability would avoid the negative effects of prolonged hyperpermeability while retaining its short-term beneficial effects. We tested the hypothesis that inflammatory agonist signaling leads to hyperpermeability and initiates a delayed cascade of cAMP-dependent pathways that causes inactivation of hyperpermeability. We applied platelet-activating factor (PAF) and vascular endothelial growth factor (VEGF) to induce hyperpermeability. We used an Epac1 agonist to selectively stimulate exchange protein activated by cAMP (Epac1) and promote inactivation of hyperpermeability. Stimulation of Epac1 inactivated agonist-induced hyperpermeability in the mouse cremaster muscle and in human microvascular endothelial cells (HMVECs). PAF induced nitric oxide (NO) production and hyperpermeability within 1 min and NO-dependent increased cAMP concentration in about 15-20 min in HMVECs. PAF triggered phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in a NO-dependent manner. Epac1 stimulation promoted cytosol-to-membrane eNOS translocation in HMVECs and in myocardial microvascular endothelial (MyEnd) cells from wild-type mice, but not in MyEnd cells from VASP knockout mice. We demonstrate that PAF and VEGF cause hyperpermeability and stimulate the cAMP/Epac1 pathway to inactivate agonist-induced endothelial/microvascular hyperpermeability. Inactivation involves VASP-assisted translocation of eNOS from the cytosol to the endothelial cell membrane. We demonstrate that hyperpermeability is a self-limiting process, whose timed inactivation is an intrinsic property of the microvascular endothelium that maintains vascular homeostasis in response to inflammatory conditions.NEW & NOTEWORTHY Termination of microvascular hyperpermeability has been so far accepted to be a passive result of the removal of the applied proinflammatory agonists. We provide in vivo and in vitro evidence that 1) inactivation of hyperpermeability is an actively regulated process, 2) proinflammatory agonists (PAF and VEGF) stimulate microvascular hyperpermeability and initiate endothelial mechanisms that terminate hyperpermeability, and 3) eNOS location-translocation is critical in the activation-inactivation cascade of endothelial hyperpermeability.

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.

The efficacy and safety of Chinese herbal medicine in the treatment of painful diabetic neuropathy: A systematic review and meta-analysis.

Objective: The objective of this systematic review and meta-analysis is to assess the effectiveness and security of Chinese herbal medicine (CHM) in the therapy of painful diabetic neuropathy (PDN). Methods: We searched databases for randomized controlled trials (RCTs) of CHM in the treatment of PDN. Outcome indicators included nerve conduction velocity, clinical efficiency, pain score, TCM syndrome score, and adverse events. Stata 16.0 was used to carry out the Meta-analysis. Results: A total of 21 RCTs with 1,737 participants were included. This meta-analysis found that using CHM as adjuvant treatment or as monotherapy for PDN can improve SCV of median nerve [mean difference (MD) = 3.56, 95% Confidence interval (CI) (2.19, 4.92) ], MCV of median nerve [ MD = 3.82, 95% CI (2.51, 5.12) ], SCV of common peroneal nerve [ MD = 4.16, 95% CI (1.62, 6.70) ], MCV of common peroneal nerve [ MD = 4.37, 95% CI (1.82, 6.93) ], SCV of gastrocnemius nerve [ MD = 4.95, 95% CI (3.52, 6.37) ], SCV of tibial nerve [ MD = 3.17, 95% CI (-2.64, 8.99) ], MCV of tibial nerve [MD = 6.30, 95%CI (5.00, 7.60)] and clinical effective rate [ odds ratio (OR) = 4.00, 95% CI (2.89, 5.52) ] and reduce pain score [standardized mean difference (SMD) = -2.23, 95% CI (-3.04, -1.41) ], TCM syndrome score [ MD = -4.70, 95% CI (-6.61, -2.80) ]. In addition, compared to the control group, adverse events of Chinese medicine intervention occurred less. Conclusion: CHM as adjuvant therapy or single treatment has a good curative effect and is safe for patients with PDN, which is worthy of clinical promotion and use, however; higher quality clinical studies are still needed to prove. Systematic Review Registration: https://www.crd.york.ac.uk/, identifier CRD42022327967.

Klotho Ameliorates Vascular Calcification via Promoting Autophagy.

Vascular calcification (VC) is regarded as a common feature of vascular aging. Klotho deficiency reportedly contributes to VC, which can be ameliorated by restoration of Klotho expression. However, the specific mechanisms involved remain unclear. Here, we investigated the role of autophagy in the process of Klotho-inhibiting VC. The clinical study results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells (MOVAS) under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification. This study is beneficial to exploring the underlying mechanisms of Klotho regulating VC, which has important guiding significance for future clinical studies in the treatment of VC.

Facile Synthesis of Aminated Graphene Quantum Dots for Promising and Selective Detection of Cobalt and Copper Ions in Aqueous Media.

Due to the rapid development of industrialization, various environmental problems such as water resource pollution are gradually emerging, among which heavy metal pollution is harmful to both human beings and the environment. As a result, there are many metal ion detection methods, among which fluorescence detection stands out because of its rapid, sensitive, low cost and non-toxic characteristics. In recent years, graphene quantum dots have been widely used and studied due to their excellent properties such as high stability, low toxicity and water solubility, and have a broad prospect in the field of metal ion detection. A novel high fluorescence Cu2+, Co2+ sensing probe produced by graphene quantum hydrothermal treatment is reported. After heat treatment with hydrazine hydrate, the small-molecule precursor nitronaphthalene synthesized by self-nitrification was transformed from blue fluorescent GQDs to green fluorescent amino-functionalized N-GQDs. Compared with other metal ions, N-GQDs are more sensitive to Cu2+ and Co2+ on the surface, and N-GQDs have much higher selectivity to Cu2+ and Co2+ than GQDs. The strategy proposed here is simple and economical in design.

Fabrication of Orange Fluorescent Boron-Doped Graphene Quantum Dots for Al3+ Ion Detection.

Aluminum is a kind of metal that we often encounter. It can also be absorbed by the human body invisibly and will affect our bodies to a certain extent, e.g., by causing symptoms associated with Alzheimer's disease. Therefore, the detection of aluminum is particularly important. The methods to detect metal ions include precipitation methods and electrochemical methods, which are cumbersome and costly. Fluorescence detection is a fast and sensitive method with a low cost and non-toxicity. Traditional fluorescent nanomaterials have a high cost, high toxicity, and cause harm to the human body. Graphene quantum dots are a new type of fluorescent nanomaterials with a low cost and non-toxicity that can compensate for the defects of traditional fluorescent nanomaterials. In this paper, c-GQDs and o-GQDs with good performance were prepared by a bottom-up hydrothermal method using o-phenylenediamine as a precursor and citric acid or boric acid as modulators. They have very good optical properties: o-GQDs exhibit orange fluorescence under UV irradiation, while c-GQDs exhibits cyan fluorescence. Then, different metal ions were used for ion detection, and it was found that Al3+ had a good quenching effect on the fluorescence of the o-GQDs. The reason for this phenomenon may be related to the strong binding of Al3+ ions to the N and O functional groups of the o-GQDs and the rapid chelation kinetics. During the chelation process, the separation of o-GQDs' photoexcited electron hole pairs leads to their rapid electron transfer to Al3+, in turn leading to the occurrence of a fluorescence-quenching phenomenon. In addition, there was a good linear relationship between the concentration of the Al3+ ions and the fluorescence intensity, and the correlation coefficient of the linear regression equation was 0.9937. This illustrates the potential for the wide application of GQDs in sensing systems, while also demonstrating that Al3+ sensors can be used to detect Al3+ ions.

Amphiphilic Nanointerface: Inducing the Interfacial Activation for Lipase.

Graphene-based materials are widely used in the field of immobilized enzymes due to their easily tunable interfacial properties. We designed amphiphilic nanobiological interfaces between graphene oxide (GO) and lipase TL (Thermomyces lanuginosus) with tunable reduction degrees through molecular dynamics simulations and a facile chemical modulation, thus revealing the optimal interface for the interfacial activation of lipase TL and addressing the weakness of lipase TL, which exhibits weak catalytic activity due to an inconspicuous active site lid. It was demonstrated that the reduced graphene oxide (rGO) after 4 h of ascorbic acid reduction could boost the relative enzyme activity of lipase TL to reach 208%, which was 48% higher than the pristine GO and 120% higher than the rGO after 48 h of reduction. Moreover, TL-GO-4 h's tolerance against heat, organic solvent, and long-term storage environment was higher than that of free TL. The drawbacks of strong hydrophobic nanomaterials on lipase production were explored in depth with the help of molecular dynamics simulations, which explained the mechanism of enzyme activity enhancement. We demonstrated that nanomaterials with certain hydrophilicity could facilitate the lipase to undergo interfacial activation and improve its stability and protein loading rate, displaying the potential of the extensive application.

Potential Roles of the Gut Microbiota in Pancreatic Carcinogenesis and Therapeutics.

The intestinal microenvironment is composed of normal gut microbiota and the environment in which it lives. The largest microecosystem in the human body is the gut microbiota, which is closely related to various diseases of the human body. Pancreatic cancer (PC) is a common malignancy of the digestive system worldwide, and it has a 5-year survival rate of only 5%. Early diagnosis of pancreatic cancer is difficult, so most patients have missed their best opportunity for surgery at the time of diagnosis. However, the etiology is not entirely clear, but there are certain associations between PC and diet, lifestyle, obesity, diabetes and chronic pancreatitis. Many studies have shown that the translocation of the gut microbiota, microbiota dysbiosis, imbalance of the oral microbiota, the interference of normal metabolism function and toxic metabolite products are closely associated with the incidence of PC and influence its prognosis. Therefore, understanding the correlation between the gut microbiota and PC could aid the diagnosis and treatment of PC. Here, we review the correlation between the gut microbiota and PC and the research progresses for the gut microbiota in the diagnosis and treatment of PC.

Pitavastatin activates mitophagy to protect EPC proliferation through a calcium-dependent CAMK1-PINK1 pathway in atherosclerotic mice.

Statins play a major role in reducing circulating cholesterol levels and are widely used to prevent coronary artery disease. Although they are recently confirmed to up-regulate mitophagy, little is known about the molecular mechanisms and its effect on endothelial progenitor cell (EPC). Here, we explore the role and mechanism underlying statin (pitavastatin, PTV)-activated mitophagy in EPC proliferation. ApoE-/- mice are fed a high-fat diet for 8 weeks to induce atherosclerosis. In these mice, EPC proliferation decreases and is accompanied by mitochondrial dysfunction and mitophagy impairment via the PINK1-PARK2 pathway. PTV reverses mitophagy and reduction in proliferation. Pink1 knockout or silencing Atg7 blocks PTV-induced proliferation improvement, suggesting that mitophagy contributes to the EPC proliferation increase. PTV elicits mitochondrial calcium release into the cytoplasm and further phosphorylates CAMK1. Phosphorylated CAMK1 contributes to PINK1 phosphorylation as well as mitophagy and mitochondrial function recover in EPCs. Together, our findings describe a molecular mechanism of mitophagy activation, where mitochondrial calcium release promotes CAMK1 phosphorylation of threonine177 before phosphorylation of PINK1 at serine228, which recruits PARK2 and phosphorylates its serine65 to activate mitophagy. Our results further account for the pleiotropic effects of statins on the cardiovascular system and provide a promising and potential therapeutic target for atherosclerosis.

A novel echocardiographic parameter to identify individuals susceptible to acute mountain sickness.

BACKGROUND: Acute mountain sickness (AMS) may cause life-threatening conditions. This study aimed to screen echocardiographic parameters at sea level (SL) to identify predictors of AMS development. METHODS: Overall, 106 healthy men were recruited at SL and ascended to 4100 m within 7 days by bus. Basic characteristics, physiological data, and echocardiographic parameters were collected both at SL and 4100 m above SL. AMS was identified by 2018 Lake Louise Questionnaire Score. RESULTS: After acute high altitude exposure (AHAE), 33 subjects were diagnosed with AMS and exhibited lower lateral mitral valve tissue motion annular displacement (MV TMADlateral) at SL than AMS-free subjects (13.09 vs. 13.89 mm, p = 0.022). MV TMADlateral at SL was significantly correlated with AMS occurrence (OR = 0.717, 95% CI: 0.534-0.964, p = 0.028). The MV TMADlateral<13.30-mm group showed over 4-fold risk for AMS development versus the MV TMADlateral≥13.30-mm group. After AHAE, the MV TMADlateral<13.30-mm group had increased HR (64 vs. 74 bpm, p = 0.001) and right-ventricular myocardial performance index (0.54 vs. 0.69, p = 0.009) and decreased left ventricular global longitudinal strain (-21.50 vs. -20.23%, p = 0.002), tricuspid valve E/A ratio (2.11 vs. 1.89, p = 0.019), and MV E-wave deceleration time (169.60 vs. 156.90 ms, p = 0.035). CONCLUSION: MV TMADlateral at SL was a potential predictor of AMS occurrence and might be associated with differential alterations of ventricular systolic and diastolic functions in subjects with different MV TMADlateral levels at SL after AHAE.

Cardiovascular Indicators of Systemic Circulation and Acute Mountain Sickness: An Observational Cohort Study.

Background: Acute high-altitude (HA) exposure results in blood pressure (BP) and cardiac function variations in most subjects, some of whom suffer from acute mountain sickness (AMS). Several previous studies have found that cardiovascular function indicators are potentially correlated with AMS. Objectives: This study aims to examine HA-induced cardiovascular adaptations in AMS patients and compare them with healthy subjects. It also aims to investigate the relationship between cardiovascular function indicators and AMS, as well as to provide some insightful information about the prevention and treatment of AMS. Methods: Seventy-two subjects were enrolled in this cohort study. All the subjects ascended Litang (4,100 m above sea level). They were monitored by a 24-h ambulatory blood pressure (ABP) device and underwent echocardiography examination within 24 h of altitude exposure. The 2018 Lake Louise questionnaire was used to evaluate AMS. Results: Acute mountain sickness group consisted of more women (17 [60.7%] vs. 10 [22.7%], p = 0.001) and fewer smokers (5 [17.9%] vs. 23 [52.3%], p = 0.003). Compared with subjects without AMS, subjects with AMS had lower pulse pressure (PP) (daytime PP, 45.23 ± 7.88 vs. 52.14 ± 4.75, p < 0.001; nighttime PP, 42.81 ± 5.92 vs. 49.39 ± 7.67, p < 0.001) and lower effective arterial elastance (Ea) (1.53 ± 0.24 vs. 1.73 ± 0.39, p = 0.023). Multivariate regression indicated that female sex (OR = 0.23, p = 0.024), lower daytime PP (OR = 0.86, p = 0.004), and lower Ea (OR = 0.03, p = 0.015) at low altitude (LA) were independent risk factors for AMS. Combined daytime PP and Ea at LA had a high predictive value for AMS (AUC = 0.873; 95% CI: 0.789-0.956). Correlation analysis showed that AMS-induced headache correlated with daytime PP (R = -0.401, p < 0.001) and nighttime PP at LA (R = -0.401, p < 0.001). Conclusion: Our study demonstrated that AMS patients had a lower PP and Ea at LA. These baseline indicators of vasodilation at LA were closely associated with AMS, which may explain the higher headache severity in subjects with higher PP at LA.

Echocardiographic Right Ventricular Outflow Track Notch Formation and the Incidence of Acute Mountain Sickness.

Yuan, Fangzhengyuan, Zhexue Qin, Chuan Liu, Shiyong Yu, Jie Yang, Jun Jin, Shizhu Bian, Xubin Gao, Jihang Zhang, Chen Zhang, Mingdong Hu, Jingbin Ke, Yuanqi Yang, Jingdu Tian, Chunyan He, Wenzhu Gu, Chun Li, Rongsheng Rao, and Lan Huang. Echocardiographic right ventricular outflow track notch formation and the incidence of acute mountain sickness. High Alt Med Biol. 22:263-273, 2021. Background: High-altitude exposure causes acute mountain sickness (AMS) and increases pulmonary arterial pressure (PAP). The notching of echocardiographic right ventricular outflow tract flow velocity envelope (right ventricular outflow tract [RVOT] notching), is related to increased PAP. We speculate that acute high-altitude exposure may trigger RVOT notching, which may be associated with AMS. Methods: All 130 subjects, ascended to 4,100 m from low altitude by bus within 7 days, underwent physiological and echocardiographic testing. The subjects with a total score of 3 or above and in the presence of a headache were diagnosed with AMS according to Lake Louise criteria. Results: After high-altitude exposure, the incidence of RVOT notching and AMS was 20% and 28.5%, respectively. The subjects with AMS had a higher incidence (37.8%) of RVOT notching than those without AMS (12.9%). Multivariate logistic regression analysis showed that RVOT notching was associated with systolic pulmonary artery pressure (SPAP) (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.05-1.17; p < 0.001) and the occurrence of AMS (OR, 5.48; 95% CI, 1.96-15.35; p = 0.001). Although linear regression analysis showed a weak correlation between SPAP and Lake Louise AMS score in the overall population (r = 0.20, p = 0.020), this correlation was more pronounced in the subpopulation with RVOT notching (r = 0.44, p = 0.023) and SPAP was not related to Lake Louise AMS score in the subpopulation without RVOT notching (r = 0.03, p = 0.698). Among AMS symptoms, the incidence of headache and fatigue were higher in subjects with RVOT notching than those in subjects without RVOT notching. Conclusions: We first observe that high-altitude exposure triggers RVOT notching formation, which is associated with AMS occurrence. Clinical Trials.gov ID: ChiCTR-RCS-12002232.

Sex-Dependent Association Between Early Morning Ambulatory Blood Pressure Variations and Acute Mountain Sickness.

BACKGROUND: Acute high altitude (HA) exposure elicits blood pressure (BP) responses in most subjects, and some of them suffer from acute mountain sickness (AMS). However, a 24-h ambulatory BP (ABP) change and the correlation with the occurrence of AMS in different sexes are still unclear. OBJECTIVES: This prospective study aimed to investigate HA induced BP responses in males and females and the relationship between AMS and 24-h ABP. METHODS: Forty-six subjects were matched according to demographic parameters by propensity score matching with a ratio of 1:1. All the subjects were monitored by a 24-h ABP device; the measurement was one period of 24 h BP. 2018 Lake Louise questionnaire was used to evaluate AMS. RESULTS: Both the incidence of AMS (14 [60.9%] vs. 5 [21.7%], P = 0.007) and headache (18 [78.3%] vs. 8 [34.8%], P = 0.003) were higher in females than in males. All subjects showed an elevated BP in the early morning [morning systolic BP (SBP), 114.72 ± 13.57 vs. 120.67 ± 11.10, P = 0.013]. The elevation of morning SBP variation was more significant in females than in males (11.95 ± 13.19 vs. -0.05 ± 14.49, P = 0.005), and a higher morning BP surge increase (4.69 ± 18.09 vs. -9.66 ± 16.96, P = 0.005) was observed after acute HA exposure in the female group. The increase of morning SBP was associated with AMS occurrence (R = 0.662, P < 0.001) and AMS score (R = 0.664, P = 0.001). Among the AMS symptoms, we further revealed that the incidence (R = 0.786, P < 0.001) and the severity of headache (R = 0.864, P < 0.001) are closely correlated to morning SBP. CONCLUSIONS: Our study demonstrates that females are more likely to suffer from AMS than males. AMS is closely associated with elevated BP in the early morning period, which may be correlated to higher headache incidence in subjects with higher morning SBP.

The Association Between Notching of the Right Ventricular Outflow Tract Flow Velocity Doppler Envelope and Impaired Right Ventricular Function After Acute High-Altitude Exposure.

INTRODUCTION: Pulmonary 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. METHODS: A 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. RESULTS: After 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. CONCLUSION: HA 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.

Blood pressure and left ventricular function changes in different ambulatory blood pressure patterns at high altitude.

Acute high-altitude (HA) exposure induces physiological responses of the heart and blood pressure (BP). However, few studies have investigated the responses associated with dipper and non-dipper BP patterns. In this prospective study, 72 patients underwent echocardiography and 24-h ambulatory BP testing at sea level and HA. Patients were divided into dipper and non-dipper groups according to BP at sea level. Acute HA exposure elevated 24-h systolic and diastolic BP and increased BP variability, particularly in the morning. Moreover, acute exposure increased left ventricular torsion, end-systolic elastance, effective arterial elastance, and untwisting rate, but reduced peak early diastolic velocity/late diastolic velocity and peak early diastolic velocity/early diastolic velocity, implying enhanced left ventricular systolic function but impaired filling. Dippers showed pronounced increases in night-time BP, while non-dippers showed significant elevation in day-time BP, which blunted differences in nocturnal BP fall, and lowest night-time and evening BP. Dippers had higher global longitudinal strain, torsion, and untwisting rates after acute HA exposure. Variations in night-time systolic BP correlated with variations in torsion and global longitudinal strain. Our study firstly demonstrates BP and cardiac function variations during acute HA exposure in different BP patterns and BP increases in dippers at night, while non-dippers showed day-time increases. Furthermore, enhanced left ventricular torsion and global longitudinal strain are associated with BP changes. Non-dippers showed poor cardiac compensatory and maladaptive to acute HA exposure. However, the exact mechanisms involved need further illumination.

Assessment of right atrial dyssynchrony by 2D speckle-tracking in healthy young men following high altitude exposure at 4100 m.

BACKGROUND: High altitude exposure induces overload of right-sided heart and may further predispose to supraventricular arrhythmia. It has been reported that atrial mechanical dyssynchrony is associated with atrial arrhythmia. Whether high altitude exposure causes higher right atrial (RA) dyssynchrony is still unknown. The aim of study was to investigate the effect of high altitude exposure on right atrial mechanical synchrony. METHODS: In this study, 98 healthy young men underwent clinical examination and echocardiography at sea level (400 m) and high altitude (4100 m) after an ascent within 7 days. RA dyssynchrony was defined as inhomogeneous timing to peak strain and strain rate using 2D speckle-tracking echocardiography. RESULTS: Following high altitude exposure, standard deviation of the time to peak strain (SD-TPS) [36.2 (24.5, 48.6) ms vs. 21.7 (12.9, 32.1) ms, p<0.001] and SD-TPS as percentage of R-R' interval (4.6 ± 2.1% vs. 2.5 ± 1.8%, p<0.001) significantly increased. Additionally, subjects with higher SD-TPS (%) at high altitude presented decreased right ventricular global longitudinal strain and RA active emptying fraction, but increased RA minimal volume index, which were not observed in lower group. Multivariable analysis showed that mean pulmonary arterial pressure and tricuspid E/A were independently associated with SD-TPS (%) at high altitude. CONCLUSION: Our data for the first time demonstrated that high altitude exposure causes RA dyssynchrony in healthy young men, which may be secondary to increased pulmonary arterial pressure. In addition, subjects with higher RA dyssynchrony presented worse RA contractile function and right ventricular performance.

Atrial performance in healthy subjects following high altitude exposure at 4100 m: 2D speckle-tracking strain analysis.

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.

Prediction of High-Altitude Cardiorespiratory Fitness Impairment Using a Combination of Physiological Parameters During Exercise at Sea Level and Genetic Information in an Integrated Risk Model.

Insufficient cardiorespiratory compensation is closely associated with acute hypoxic symptoms and high-altitude (HA) cardiovascular events. To avoid such adverse events, predicting HA cardiorespiratory fitness impairment (HA-CRFi) is clinically important. However, to date, there is insufficient information regarding the prediction of HA-CRFi. In this study, we aimed to formulate a protocol to predict individuals at risk of HA-CRFi. We recruited 246 volunteers who were transported to Lhasa (HA, 3,700 m) from Chengdu (the sea level [SL], <500 m) through an airplane. Physiological parameters at rest and during post-submaximal exercise, as well as cardiorespiratory fitness at HA and SL, were measured. Logistic regression and receiver operating characteristic (ROC) curve analyses were employed to predict HA-CRFi. We analyzed 66 pulmonary vascular function and hypoxia-inducible factor- (HIF-) related polymorphisms associated with HA-CRFi. To increase the prediction accuracy, we used a combination model including physiological parameters and genetic information to predict HA-CRFi. The oxygen saturation (SpO2) of post-submaximal exercise at SL and EPAS1 rs13419896-A and EGLN1 rs508618-G variants were associated with HA-CRFi (SpO2, area under the curve (AUC) = 0.736, cutoff = 95.5%, p < 0.001; EPAS1 A and EGLN1 G, odds ratio [OR] = 12.02, 95% CI = 4.84-29.85, p < 0.001). A combination model including the two risk factors-post-submaximal exercise SpO2 at SL of <95.5% and the presence of EPAS1 rs13419896-A and EGLN1 rs508618-G variants-was significantly more effective and accurate in predicting HA-CRFi (OR = 19.62, 95% CI = 6.42-59.94, p < 0.001). Our study employed a combination of genetic information and the physiological parameters of post-submaximal exercise at SL to predict HA-CRFi. Based on the optimized prediction model, our findings could identify individuals at a high risk of HA-CRFi in an early stage and reduce cardiovascular events.