Sodium-glucose cotransporter 2 inhibitors attenuate vascular calcification by suppressing endoplasmic reticulum protein thioredoxin domain containing 5 dependent osteogenic reprogramming.

AIMS: Vascular calcification is strongly linked to the development of major adverse cardiovascular events, but effective treatments are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an emerging category of oral hypoglycemic drugs that have displayed marked effects on metabolic and cardiovascular diseases, including recently reported vascular medial calcification. However, the roles and underlying mechanisms of SGLT2 inhibitors in vascular calcification have not been fully elucidated. Thus, we aimed to further determine whether SGLT2 inhibitors protect against vascular calcification and to investigate the mechanisms involved. METHODS AND RESULTS: A computed tomography angiography investigation of coronary arteries from 1554 patients with type 2 diabetes revealed that SGLT2 inhibitor use was correlated with a lower Agatston calcification score. In the vitamin D3 overdose, 5/6 nephrectomy chronic kidney disease-induced medial calcification and Western diet-induced atherosclerotic intimal calcification models, dapagliflozin (DAPA) substantially alleviated vascular calcification in the aorta. Furthermore, we showed that DAPA reduced vascular calcification via Runx2-dependent osteogenic transdifferentiation in vascular smooth muscle cells (VSMCs). Transcriptome profiling revealed that thioredoxin domain containing 5 (TXNDC5) was involved in the attenuation of vascular calcification by DAPA. Rescue experiments showed that DAPA-induced TXNDC5 downregulation in VSMCs blocked the protective effect on vascular calcification. Furthermore, TXNDC5 downregulation disrupted protein folding-dependent Runx2 stability and promoted subsequent proteasomal degradation. Moreover, DAPA downregulated TXNDC5 expression via amelioration of oxidative stress and ATF6-dependent endoplasmic reticulum stress. Consistently, the class effects of SGLT2 inhibitors on vascular calcification were validated with empagliflozin in intimal and medial calcification models. CONCLUSIONS: SGLT2 inhibitors ameliorate vascular calcification through blocking endoplasmic reticulum stress-dependent TXNDC5 upregulation and promoting subsequent Runx2 proteasomal degradation, suggesting that SGLT2 inhibitors are potentially beneficial for vascular calcification treatment and prevention.

Anomalous origin of the coronary artery: prevalence and coronary artery disease in adults undergoing coronary tomographic angiography.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital coronary anomaly with the potential to cause adverse cardiac events. However, there is limited data on the association between AAOCA and coronary artery disease (CAD). Therefore, the aim of this study is to determine the prevalence and symptoms of patients with AAOCA, as well as investigate the correlation between AAOCA and CAD in a population referred for coronary computed tomographic angiography (CTA). METHODS AND RESULTS: All consecutive patients who underwent CTA from 2010 to 2021 were included. Characteristics, symptoms, coronary related adverse events and CTA information were reviewed by medical records. Separate multivariable cumulative logistic regressions were performed, using the stenosis severity in each of the four coronaries as individual responses and as a combined patient clustered response. Finally, we identified 207 adult patients with AAOCA, the prevalence of AAOCA is 0.23% (207/90,501). Moreover, this study found no significant association between AAOCA and CAD. AAOCA did not contribute to higher rates of hospitalization or adverse cardiac events, including calcification. CONCLUSION: AAOCA is a rare congenital disease that is not associated with increased presence of obstructive CAD in adults.

B-type natriuretic peptide levels at admission predict the prognosis of patients with infective endocarditis undergoing cardiac surgery.

Purpose: The objective of this study was to explore the relationship between elevated B-type natriuretic peptide (BNP) levels and the prognosis of patients with infective endocarditis (IE) undergoing cardiac surgery. Methods: In total, 162 IE patients with recorded BNP levels upon admission were included in the present study. The primary end point was all-cause mortality. Results: Multivariate Cox analysis revealed a significant association between log BNP and all-cause mortality. Kaplan-Meier analysis revealed a poorer prognosis for patients with BNP levels ≥ the 75th percentile. Furthermore, the linear trend test indicated a significant link between BNP quartiles and the primary end point within the models. Conclusion: Elevated BNP levels upon admission could predict all-cause mortality in IE patients undergoing cardiac surgery.

Infective endocarditis (IE) refers to an infection affecting the heart lining, heart valves or blood vessels. Despite advancements in medical and surgical interventions, the overall mortality rate remains high among IE patients after surgery. B-type natriuretic peptide (BNP) is a peptide released in response to increased stress on the ventricular and atrial walls and is commonly used as a biomarker for heart failure. This study was aimed to assess the potential of BNP in predicting all-cause mortality in IE patients. The results indicate that elevated BNP levels upon admission could predict a worse prognosis following endocarditis surgery. Additionally, elevated BNP levels upon admission were associated with an increased risk of death.

Predicting Hospital Readmissions in Patients Receiving Novel-Dose Sacubitril/Valsartan Therapy: A Competing-Risk, Causal Mediation Analysis.

Backgrounds: Our study aimed to identify and predict patients with heart failure (HF) taking novel-dose Sacubitril/Valsartan (S/V) at risk for all-cause readmission, as well as investigate the possible role of left ventricular reverse remodeling (LVRR). Methods and results: There were 464 patients recruited from December 2017 to September 2021 in our hospital with a median follow-up of 660 days (range, 17-1494). Competing risk analysis with Gray's Test showed statistically significant differences in all-cause readmission (p-value< .001) across the three different dose groups. Models 1 and 2 were developed based on the results of univariable competing risk analysis, least absolute shrinkage and selection operator approach, backward stepwise regression, and multivariable competing risk analysis. The internal verification (data-splitting method) indicated that Model 1 had better discrimination, calibration, and clinical utility. The corresponding nomogram showed that patients aged 75 years and above, or taking the lowest-dose S/V (≤50 mg twice a day), or diagnosed with ventricular tachycardia, or valvular heart disease, or chronic obstructive pulmonary disease, or diabetes mellitus were at the highest risk of all-cause readmission. In the causal mediation analysis, LVRR was considered as a critical mediator that negatively affected the difference of novel-dose S/V in readmission. Conclusions: A significant association was detected between novel-dose S/V and all-cause readmission in HF patients, in part negatively mediated by LVRR. The web-based nomogram could provide individual prediction of all-cause readmission in HF patients receiving novel-dose S/V. The effects of different novel-dose S/V are still needed to be explored further in the future.

Giant thoracic hematoma post-transradial coronary angiography: a case report and review of the literature.

BACKGROUND: Although there are cardiac interventional procedures, certain transradial access complications might be life-threatening. CASE PRESENTATION: A 67-year-old male was admitted for coronary angiography due to chest tightness and shortness of breath on exertion. Hours after the right transradial access angiography, the patients complained the right side of chest pain. Emergent chest X-ray revealed a giant mass in the right chest. The right radial artery was reaccessed and subsequent arteriograms confirmed that the presence of a rupture of the branch of right internal mammary artery. Simultaneously, a microcoil was implanted to seal the perforation. The perforation caused a thoracic hematoma measuring 13.8 cm × 6.7 cm, along with a decrease in hemoglobin concentration from 14.1 g/dL to a minimum of 7.8 g/dL. Additionally, the drainage of the hematoma and red blood cells transfusion were carried out. Further, the patient underwent ascending aortic replacement, aortic valve replacement, mitral valve replacement, and thoracic hematoma removal. Postoperative echocardiography showed that the prosthetic valves were properly positioned and functioning normally. The patient recovered well after the surgery and remained event-free during the latest 14moth follow-up period. CONCLUSIONS: Vascular perforation and subsequent hematoma might occur due to guidewire maneuvering during transradial approach. Awareness of prevention, early recognition and management of access complications may help reduce the occurrence and severity of complications related to the transradial approach.

Impact of coronary artery disease in patients with hypertrophic cardiomyopathy.

BACKGROUND: Atherosclerotic coronary artery disease (CAD) often occurs concurrently with hypertrophic cardiomyopathy (HCM). However, the influence of concomitant CAD has not been fully assessed in patients with HCM. METHODS: Invasive or computed tomography coronary angiography was performed in 461 patients with HCM at our hospital to determine the presence and severity of CAD from March 2010 to April 2022. The primary end points were all-cause, cardiovascular, and sudden cardiac deaths. The survival of HCM patients with severe CAD was compared with that of HCM patients without severe CAD. RESULTS: Of 461 patients with HCM, 235 had concomitant CAD. During the median (interquartile range) follow-up of 49 (31-80) months, 75 patients (16.3%) died. The 5-year survival estimates were 64.3%, 82.5%, and 86.0% for the severe, mild-to-moderate, and no-CAD groups, respectively (log-rank, p = 0.010). Regarding the absence of cardiovascular death, the 5-year survival estimates were 68.5% for patients with severe CAD, 86.4% for patients with mild-to-moderate CAD, and 90.2% for HCM patients with no CAD (log-rank, p = 0.001). In multivariate analyses, severe CAD was associated with all-cause and cardiovascular death after adjusting for age, left ventricular ejection fraction, hypertension, and atrial fibrillation. CONCLUSIONS: This study showed a worse prognosis among HCM patients with severe CAD than among HCM patients without severe CAD. Therefore, timely recognition of severe CAD in HCM patients and appropriate treatment are important.

Effect of social app-assisted education and support on glucose control in patients with coronary heart disease and diabetes mellitus.

Background: Social app-assisted education and support may facilitate diabetes self-management. We aim to evaluate the effect of WeChat, a popular social app, on glycemic control in patients with coronary heart disease (CHD) and diabetes mellitus (DM). Methods: We conducted a parallel-group, open-label, randomized clinical trial that included 160 patients with both CHD and diabetes mellitus from a tertiary hospital in China. The intervention group (n = 80) received educational materials (information on glucose monitoring, drug usage, medication, and lifestyle) and reminders in response to individual blood glucose values via WeChat. The control group (n = 80) received usual care. The primary outcome was a change in glycated hemoglobin (HbA1C) levels over 3 months. Secondary outcomes included fasting blood glucose (FBG), systolic blood pressure, and low-density lipoprotein (LDL) cholesterol from baseline to 3 months. Analysis was conducted using a linear mixed model. Results: The intervention group had a greater reduction in HbA1C (-0.85 vs. 0.15%, between-group difference: -1.00%; 95% CI -1.31 to -0.69%; p < 0.001) compared with the control group. Change in fasting blood glucose was larger in the intervention group (-1.53 mmol/L; 95% CI -1.90 to -1.17; p < 0.001) and systolic blood pressure (-9.06 mmHg; 95% CI -12.38 to -5.73; p < 0.001), but not LDL (between-group difference, -0.08 mmol/L; 95% CI -0.22 to 0.05; p = 0.227). Conclusion: The combination of social app with education and support resulted in better glycemic control in patients with CHD and DM. These results suggest that education and support interaction via social app may benefit self-management in CHD and DM.

Hospitalized patients with isolated distal deep vein thrombosis: anticoagulation therapy or not?

BACKGROUND: Isolated distal deep vein thrombosis (IDDVT), a disease frequently detected in hospitalized patients, can progress to proximal deep vein thrombosis (PDVT) and pulmonary embolism (PE). Here, we evaluated the effects of anticoagulation in hospitalized IDDVT patients. METHODS: We conducted a retrospective study in our hospital and enrolled hospitalized IDDVT patients diagnosed by compression ultrasonography (CUS) from January to December 2020. Participants were divided into anticoagulation (AC) and non-anticoagulation (non-AC) groups. After propensity score matching (PSM), multivariate Cox regression analyses were performed to assess whether anticoagulation was associated with PDVT/PE, and all-cause mortality. RESULTS: A total of 426 IDDVT inpatients with CUS follow-up were screened from 1502 distal DVT patients and finally enrolled. The median age was 67 years with 51.4% males and 15.5% cancer patients. The median follow-up was 11.6 months. There were 288 and 138 patients treated with or without anticoagulants, respectively. Patients in the non-AC group had less body mass index and more comorbidities. Patients in the AC group were treated with rivaroxaban or dabigatran (52.1%), low molecular weight heparin (42.7%), and warfarin (5.2%). The PSM generated 111 pairs of well-matched IDDVT patients with or without anticoagulation. The Kaplan-Meier analysis demonstrated that neither the incidence of PDVT/PE (5.4% vs. 2.7%, log-rank p = 0.313) nor all-cause mortality (27.9% vs. 18.9%, log-rank p = 0.098) was significant different between groups. Anticoagulation was not associated with PDVT/PE and all-cause mortality in the multivariable Cox regression analyses using the matched cohorts. The main risk factors for all-cause mortality were age, malignancy history, BMI, sepsis, heart failure, and white blood cell (WBC) count. CONCLUSIONS: In hospitalized IDDVT patients, the thrombosis extension rate to PDVT/PE was low. Anticoagulation did not reduce the incidence of thrombosis extension of IDDVT and was not associated with all-cause mortality.

Maintenance of recovered dilated cardiomyopathy patients with half-dose neurohumoral blockades (MED-CHARM): A protocol for an open-label, pilot, randomized trial.

Dilated cardiomyopathy (DCM) has brought great damage to the patients' health and social economy. The number of patients with recovered dilated cardiomyopathy (recDCM) has increased over the years as treatment progresses. However, there is a lack of relevant evidence to support the clinical management of patients with recDCM, thereby, the recommendations in guidelines remains sparse. Accordingly, the exploration of recDCM is important to improve patient prognosis and reduce societal burden. This is an open-label, randomized controlled, prospective study that will compare the safety and efficacy of original dose and halved dose of neurohumoral blockades for patients with recDCM. Methods: An open-label, randomized controlled, prospective study will be conducted among eligible patients with recDCM. During the pilot study phase, we will recruit 50 patients. The primary endpoint is hospitalization for heart failure or heart failure relapse within 12 months. Secondary endpoint is major adverse cardiovascular events, including cardiovascular mortality, myocardial infarction, stroke, sustained atrial tachycardia, or ventricular tachycardia. The results will be analyzed using intention-to-treatment analysis. Discussion: The study will provide important evidence of whether it is safe and effective to halve the dosage of neurohumoral blockades in recDCM patients. Trial registration number: ChiCTR2100054051 (www.chictr.org.cn).

Risk factors for incomplete thrombosis in false lumen in sub-acute type B aortic dissection post-TEVAR.

There is scarce information about the risk factors for incomplete false lumen thrombosis (FLT) among type B aortic dissection (AD) patients, particularly in the sub-acute phase following thoracic endovascular aortic repair (TEVAR). We enrolled consecutive sub-acute type B AD patients at Xinqiao Hospital (Chongqing, China) from May 2010 to December 2019. Patients with severe heart failure, cancer, and myocardial infarction were excluded. The postoperative computed tomography angiography (CTA) data were extracted from the most recent follow-up aortic CTA. Multivariate logistic regressions were applied to identify the association between FLT and clinical or imaging factors. Fifty-five subjects were enrolled in our study. Twelve participants showed complete FLT, and 2 of these died during the follow-up, while 8 patients died in incomplete FLT group. In the multivariate analysis, maximum abdominal aorta diameter (OR 1.20, 95% CI 1.016-1.417 p = 0.032) and the number of branches arising from the false lumen (FL) (OR 15.062, 95% 1.681-134.982 p = 0.015) were significantly associated with incomplete FLT. The C-statistics was 0.873 (95% CI 0.773-0.972) for the model. The FL diameter (p < 0.001) was significantly shorter following TEVAR, while the true lumen diameter (p < 0.001) and maximum abdominal aorta diameter (p = 0.011) were larger after the aortic repair. There were 21.8% of sub-acute type B AD patients presented complete FLT post-TEVAR. Maximum abdominal aorta diameter and the number of branches arising from the FL were independent risk factors for incomplete FLT. The true lumen diameter, maximum abdominal aorta diameter, and FL diameter changed notably following TEVAR.

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.

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.

Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide nanoparticles-induced endothelial cell death.

With the abundant production and wide application of zinc oxide nanoparticles (ZnONPs), the potential health risks of ZnONPs have raised serious concerns. Oxidative stress is recognized as the most important outcome of the toxicity induced by ZnONPs. The Nrf2-Keap1 system and its downstream antioxidative genes are the fundamental protective mechanisms for redox hemeostasis. However, the detailed mechanisms of Nrf2 activation in ZnONPs-treated endothelial cells and murine blood vessels have yet to be elucidated. Herein, we show that Nrf2 was activated and played a negative role in cell death induced by ZnONPs. Moreover, we demonstrate that HO-1 was the most extensively upregulated antioxidative gene-activated by Nrf2. Forced overexpression of HO-1, pharmacological activation of HO-1 with the agonists RTA-408 (omaveloxolone, an FDA-approved drug) and RTA-402 repressed cell death, and treatment with HO-1 antagonist SnPP exacerbated the cell death. Importantly, loss of HO-1 diminished the cytoprotective role induced by Nrf2 in ZnONPs-treated HUVEC cells, indicating that the Nrf2-HO-1 axis was the crucial regulatory mechanism for the antioxidative response in the context of ZnONPs-induced endothelial damage. Mechanistically, we demonstrate that the p62-Keap1 axis was not involved in the activation of Nrf2. Intriguingly, the degradation half-life of Nrf2 in HUVEC cells was increased from less than 1 h under quiescent conditions to approximately 6 h under ZnONPs treatment condition; moreover, ZnONPs treatment induced activation of Nrf2/HO-1 and accumulation of ubiquitin in the aorta ventralis of mouse, suggesting that the ubiquitin-proteasome system had been perturbed, which subsequently led to the stabilization of Nrf2 and activation of HO-1. This study might contribute to a better understanding of ZnONPs-associated toxicity.

Prognostic Significance of B-Type Natriuretic Peptide in Patients With Left Ventricular Thrombus.

Background and Aims: There is sparse information on the prognostic value of B-type natriuretic peptide (BNP) for the outcomes in patients with left ventricular thrombus (LVT). Methods: Patients diagnosed with LVT by transthoracic echocardiography between November 2009 to July 2020 at our institution were included. The endpoints were all-cause mortality and systemic embolism. Results: Ninety-two subjects were finally included in the study. The mean age of the cohort was 56.73 ± 14.12, and 80.4% of the patients were male. The median BNP (1st quartile-3rd quartile) was 437.5 (112.74-1317.5). The total all-cause mortality rate was 30.44% (28/92), and the 1-year, 2-year, and 3-year cumulative survival rates were 85.4, 75.5, and 66.5%, respectively. Systemic embolism was identified in 10 subjects. COX multivariate analysis showed that Log BNP (HR, 4.16; 95%CI, 1.81-9.56; P = 0.001) and BMI (HR, 0.86; 95%CI, 0.73-0.99; P = 0.048) were significantly associated with all-cause mortality. In addition, patients with BNP levels in the upper median (≥ 437.5 pg/ml) had significantly higher all-cause mortality rate compared to those with lower median BNP (<437.5 pg/ml; P = 0.004). The area under the receiver operating characteristic curve for BNP and all-cause mortality was 0.71. In the linear trend test, BNP quartiles were significantly related to all-cause mortality in all models, and the P-values for trend in models 1, 2, and 3 were 0.005, 0.006, and 0.048, respectively. Conclusion: BNP level is a prognostic factor for all-cause mortality in LVT patients, and elevated BNP is indicative of a higher risk of LVT.

Prognostic Value of Preoperative Hemoglobin Levels for Long-Term Outcomes of Acute Type B Aortic Dissection Post-thoracic Endovascular Aortic Repair.

Background and Aims: There is scant information available about the prognostic value of preoperative hemoglobin (Hb) levels on the long-term outcomes of acute type B aortic dissection (ABAD) following thoracic endovascular aortic repair (TEVAR). Methods: A retrospective analysis of consecutive patients from 2010 to 2018 regarding the relationship between Hb level and long-term outcomes was conducted. The primary endpoint was all-cause mortality. Major adverse cardiovascular events (MACEs) included all-cause death, recurrent ruptures, and secondary procedures. Results: In total, 391 subjects treated by TEVAR were enrolled, with a mean age of 57.1 ± 12.0 years; 79.5% of them were male. Cox multivariate analysis showed that the preoperative Hb level was independently associated with all-cause death [adjusted hazard ratio (HR) 0.797 (per 1 g/dl), 95% confidence interval (CI) 0.693-0.918, p = 0.002] and MACEs (adjusted HR 0.795, 95% CI 0.672-0.871, p = 0.000). The area under the receiver operating characteristic curve of Hb for all-cause death and MACEs were 0.617 (95% CI 0.548-0.687, p = 0.008) and 0.617 (95% CI 0.551-0.684, p = 0.005), respectively. In the linear trend test, Hb concentration was significantly related to all-cause mortality (p for trend = 0.001) and MACEs (p for trend = 0.000). Moreover, in Kaplan-Meier analysis, lower Hb levels (< 12 g/dl) were significantly different from higher Hb (≥12 g/dl) levels for both all-cause death (log-rank p = 0.001) and MACEs (log-rank p = 0.001). Similar results were found when assessing the prognostic value of red blood cell count and anemia. Conclusions: Preoperative Hb may serve as a prognostic marker for long-range adverse outcomes for ABAD patients post-TEVAR.

Pulmonary function tests at low altitude predict pulmonary pressure response to short-term high altitude exposure.

BACKGROUND: Travelling to high altitude (HA) presents a risk of the high levels of pulmonary artery pressure (PAP) at altitude, which is associated with impaired exercise capacity and fatal HA pulmonary oedema. However, prediction of high levels of PAP at altitude is still unclear. METHODS: Echocardiography and pulmonary function tests were performed on 121 healthy men at low altitude (LA) and 4100 m (5 ± 2 h after a 7 day ascent). RESULTS: HA exposure increased the levels of FEV1/FVC ratio, FEF25%, 50%, 75%, MMEF, mPAP, total pulmonary vascular resistance (PVR) and systolic pulmonary arterial pressure (SPAP). More smokers and lower forced expiratory flow at 25% of forced vital capacity (FEF25%) at LA were observed in subjects with mPAP≥30 mmHg than those with mPAP<30 mmHg at HA. Multivariate logistic regression identified that FEF25% at LA [odds ratio (OR) 0.50, 95%CI 0.33-0.76, p = 0.001] and smoking (OR 3.09, 95%CI 1.31-7.27, p = 0.010) were the independent predictors for identifying subjects with mPAP≥30 mmHg at HA. Moreover, FEF25% at LA was linearly correlated with mPAP at HA (r = -0.31, p < 0.001), which mainly existed in smokers. Compared to subjects with FEF25% ≥7.55 L/sec at LA, those with FEF25% <7.55 L/sec at LA showed higher levels of mPAP, and total PVR, and a multivariable OR of 11.16 (95%CI, 3.48-35.81) for developing mPAP ≥ 30 mmHg at HA. However, there was no significant difference in the incidences of AMS and its related clinical symptoms in subjects with different levels of FEF25%. CONCLUSIONS: Thus, these findings suggest that subjects with low FEF25% values at LA are susceptible to high levels of PAP at altitude but not the incidence of AMS following short-term HA exposure, especially in smokers.

Preliminary Study of Right Ventricular Dyssynchrony Under High-Altitude Exposure: Determinants and Impacts.

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 interval-corrected 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 (SaO2) 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 SaO2 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 SaO2 as well as RV overload; the incidence of RVD was associated with reduced RV regional function and blunted myocardial acceleration.

Inactivation of Cys674 in SERCA2 increases BP by inducing endoplasmic reticulum stress and soluble epoxide hydrolase.

BACKGROUND AND PURPOSE: The kidney is essential in regulating sodium homeostasis and BP. The irreversible oxidation of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is increased in the renal cortex of hypertensive mice. Whether inactivation of C674 promotes hypertension is unclear. Here we have investigated the effects on BP of the inactivation of C674, and its role in the kidney. EXPERIMENTAL APPROACH: We used heterozygous SERCA2 C674S knock-in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The BP, urine volume, and urine composition of SKI mice and their littermate wild-type (WT) mice were measured. The kidneys were collected for cell culture, Na+ /K+ -ATPase activity, protein expression, and immunohistological analysis. KEY RESULTS: Compared with WT mice, SKI mice had higher BP, lower urine volume and sodium excretion, up-regulated endoplasmic reticulum (ER) stress markers and soluble epoxide hydrolase (sEH), and down-regulated dopamine D1 receptors in renal cortex and cells from renal proximal tubule. ER stress and sEH were mutually regulated, and both upstream of D1 receptors. Inhibition of ER stress or sEH up-regulated expression of D1 receptors, decreased the activity of Na+ /K+ -ATPase, increased sodium excretion, and lowered BP in SKI mice. CONCLUSIONS AND IMPLICATIONS: The inactivation of SERCA2 C674 promotes the development of hypertension by inducing ER stress and sEH. Our study highlights the importance of C674 redox status in BP control and the contribution of SERCA2 to sodium homeostasis and BP in the kidney.

Nox4 and soluble epoxide hydrolase synergistically mediate homocysteine-induced inflammation in vascular smooth muscle cells.

BACKGROUND: Hyperhomocysteinemia leads to a vascular smooth muscle cell (VSMC) inflammatory response. Meanwhile, Nox4 dependent reactive oxygen species (ROS) signaling and soluble epoxide hydrolase (sEH)/epoxyeicosatrienoic acids (EETs) are both involved in vascular inflammation. Herein, we hypothesized that Nox4 and soluble epoxide hydrolase cross regulated during homocysteine-induced VSMC inflammation. METHODS AND RESULTS: In cultured VSMCs, the expression of the inflammatory factors VCAM1 and ICAM1 was measured by real-time PCR and Western blotting, while supernatant MCP1 was measured by ELISA. Upon VSMC stimulation with 50 µΜ homocysteine, we observed the VCAM1 and ICAM1 mRNA levels were increased by 1.15 and 1.0 folds, respectively. The MCP1 levels in the supernatant of cultured VSMCs treated with 100 µΜ increased to 1.76 folds. As expected, homocysteine induced Nox4 expression and Nox4-dependent ROS generation. The sEH expression was also upregulated in the presence of homocysteine in a dose-dependent manner. Furthermore, we knocked down Nox4 with siRNA. Knockdown of Nox4 decreased ROS generation and homocysteine-induced sEH expression. Overexpression of Nox4 with an adenovirus stimulated sEH expression. Similarly, knockdown or chemical inhibition of sEH blunted the upregulation of Nox4 by homocysteine. In vivo, in homocysteine-fed mice, concomitant upregulation of Nox4 and sEH was associated with increased VCAM1 and ICAM1 expression in the aortic wall. CONCLUSIONS: The inflammatory response induced by homocysteine in VSMCs was accompanied by Nox4 and sEH upregulation. Nox4 and soluble epoxide hydrolase synergistically contribute to homocysteine-induced inflammation.