Background-The impact of estimated glomerular filtration rate (eGFR) on clinical short-term outcomes after stroke thrombolysis with tissue plasminogen activator remains controversial. Methods and Results-We analyzed 18 320 ischemic stroke patients who received intravenous tissue plasminogen activator at participating hospitals in the Chinese Stroke Center Alliance between June 2015 and November 2017. Multivariate logistic regression models were used to evaluate associations between eGFR (<45, 45-59, 60-89, and >= 90 mL/min per 1.73 m(2)) and in-hospital mortality and symptomatic intracerebral hemorrhage, adjusting for patient and hospital characteristics and the hospital clustering effect. Of the 18 320 patients receiving tissue plasminogen activator, 601 (3.3%) had an eGFR <45, 625 (3.4%) had an eGFR 45 to 59, 3679 (20.1%) had an eGFR 60 to 89, and 13 415 (73.2%) had an eGFR >= 90. As compared with eGFR >= 90, eGFR values <45 (6.7% versus 0.9%, adjusted odds ratio, 3.59; 95% CI, 2.18-5.91), 45 to 59 (4.0% versus 0.9%, adjusted odds ratio, 2.00; 95% CI, 1.18-3.38), and 60 to 89 (2.5% versus 0.9%, adjusted odds ratio, 1.67; 95% CI, 1.20-2.34) were independently associated with increased odds of in-hospital mortality. However, there was no statistically significant association between eGFR and symptomatic intracerebral hemorrhage. Conclusions-eGFR was associated with an increased risk of in-hospital mortality in acute ischemic stroke patients after treatment with tissue plasminogen activator. eGFR is an important predictor of poststroke short-term death but not of symptomatic intracerebral hemorrhage.
Background-Active commuting is related to a higher level of physical activity but more exposure to ambient air pollutants. With the rather serious air pollution in urban China, we aimed to examine the association between active commuting and risk of incident cardiovascular disease in the Chinese population. Methods and Results-A total of 104 170 urban commuters without major chronic diseases at baseline were included from China Kadoorie Biobank. Self-reported commuting mode was defined as nonactive commuting, work at home or near home, walking, and cycling. Multivariable Cox regression was used to examine associations between commuting mode and cardiovascular disease. Overall, 47.2% of the participants reported nonactive commuting, 13.4% reported work at home or work near home, 20.1% reported walking, and 19.4% reported cycling. During a median follow-up of 10 years, we identified 5374 incidents of ischemic heart disease, 664 events of hemorrhagic stroke, and 4834 events of ischemic stroke. After adjusting for sex, socioeconomic status, lifestyle factors, sedentary time, body mass index, comorbidities, household air pollution, passive smoking, and other domain physical activity, walking (hazard ratio, 0.90; 95% CI, 0.84-0.96) and cycling (hazard ratio, 0.81; 95% CI, 0.74-0.88) were associated with a lower risk of ischemic heart disease than nonactive commuting. Cycling was associated with a lower risk of ischemic stroke (hazard ratio, 0.92; 95% CI, 0.84-1.00). No significant association was found of walking or cycling with hemorrhagic stroke. The associations of commuting mode with major cardiovascular disease were consistent among men and women and across different levels of other domain physical activity. Conclusions-In urban China, cycling was associated with a lower risk of ischemic heart disease and ischemic stroke. Walking was associated with a lower risk of ischemic heart disease.
Background-High sodium intake elevates blood pressure and thereby raises cardiovascular diseases (CVDs). Sodium intake is high in northern China, including Shandong province where the SMASH (Shandong-Ministry of Health Action on Sodium and Hypertension) is currently underway. Methods and Results-Blood pressure values and sodium intake measurements using 24-hour urinary excretion were collected from the 2011 SMASH baseline survey, which was conducted in 20 counties/districts using a multistage stratified cluster random sampling method. We derived cause-specific mortality from the Shandong Death Registration System (SDRS) during the same year and used population-attributable fraction to estimate annual CVDs deaths attributable to high sodium intake (mediated through elevated systolic blood pressure) and CVD deaths averted by achieving different sodium-reduction targets. Overall, 16 100 (95% uncertainty intervals, 11 000-22 600) CVD deaths among adults aged 25 to 69 years, including 5600 (4000-6500) for ischemic heart disease and 9000 (6700-11 600) for stroke, were attributable to higher sodium intake (2000 mg/day or 5.0 g/day of salt as a reference) in Shandong in 2011, accounting for 19.9% (13.7-25.0%) of total CVD deaths. The benefit of CVD deaths from sodium reduction is considerable with 8800 (6400-13 600), 6700 (4900-11 600), and 8500 (6000-10 800) averted, respectively, if sodium intake was reduced from the 2011 baseline to 3500 mg/day, 4000 mg/day, or reduced by 30%. Conclusions-Nearly 20% of CVD deaths among adults aged 25 to 69 years could be attributable to the systolic blood pressure- raising effect of high sodium intake in Shandong in 2011. Potential benefits from population reduction of sodium intake are considerable.
Background-Socioeconomic status (SES) is associated with health-related quality of life (HRQOL) for children with critical congenital heart disease; however, literature from newly industrialized countries is scarce. Methods and Results-This cross-sectional study included 2037 surviving patients operated on for critical congenital heart disease at a tertiary hospital in China between May 2012 and December 2015. All eligible patients were aged 2 to 12 years. HRQOL was measured by the Pediatric Quality of Life Inventory 4.0 generic and 3.0 cardiac modules. Family SES was assessed by a composite of household income in the past year and occupation and education level of each parent in the family. Mean scores of major domains in HRQOL were significantly lower in the low-SES group than in the medium- and high-SES groups (total generic scores: 71.2 +/- 7.9 versus 75.0 +/- 8.0 and 76.0 +/- 7.9, respectively [P<0.001]; psychosocial functioning: 70.8 +/- 9.0 versus 74.4 +/- 8.4 and 75.3 +/- 8.4 [P<0.001]; physical functioning: 71.6 +/- 10.4 versus 76.0 +/- 9.7 and 77.1 +/- 9.4 [P<0.001]; heart symptoms: 71.9 +/- 11.6 versus 75.7 +/- 11.0 and 76.8 +/- 10.3 [P<0.001]; cognitive problems: 65.4 +/- 11.1 versus 69.4 +/- 12.1 and 74.6 +/- 13.6 1P<0.0011). After adjustment for other clinical and demographic variables in the multivariable linear regression model, family SES significantly affected all dimensions of HRQOL except for treatment barriers, treatment anxiety, physical appearance and communication. Conclusions-Family SES is an important factor associated with HRQOL in patients with critical congenital heart disease. Further targeted interventions to improve HRQOL that consider the family and environmental issues confronted by those who are economically disadvantaged might help these patients have better outcomes.
Background-The temporal sequence between serum calcium and insulin resistance (IR) and their effects on hypertension are unclear. We studied the association between serum calcium and IR, with risk of hypertension events in a longitudinal cohort conducted in China. Methods and Results-Data from 8653 subjects aged 20 to 74 years with an average follow-up of 5.3 years were analyzed. Serum calcium, and fasting and 2-hour serum glucose and insulin were measured at baseline and follow-up. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between serum calcium and IR and its impact on hypertension incidence. The conjoint effects of serum calcium and IR at baseline on hypertension at follow-up were observed (P=0.029 for HOMA_IR [hepatic IR] and P=0.009 for Gutt index [peripheral IR]). The cross-lagged path coefficient (beta(2)) from baseline serum calcium to follow-up peripheral IR were significantly greater than path coefficient (beta(1)) from baseline peripheral insulin resistance to follow-up serum calcium (beta(2)=-0.354 versus beta(1)=-0.005; P=0.027). However, no directional relationships were observed in the serum calcium <--> hepatic IR analysis. The mediation effect of peripheral IR on the association of serum calcium at baseline with hypertension at follow-up was estimated at 16.4% (P<0.001). Conclusions-Our findings demonstrate that higher serum calcium levels probably precede peripheral IR, and this 1-directional relation plays a role in the development of hypertension.
Background-The poor viability of transplanted mesenchymal stem cells (MSCs) hampers their therapeutic efficacy for ischemic heart disease. MicroRNAs are involved in regulation of MSC survival and function. The present study was designed to investigate the molecular effects of miR-15a/15b on MSC survival, focusing on the role of vascular endothelial growth factor receptor 2. Methods and Results-We first harvested donor luc(Luciferase)-MSCs (5x 10(5)) isolated from the luciferase transgenic mice with FVB background. Luc-MSCs were transfected with miR-15a/15b mimics or inhibitors and cultured under oxygen glucose deprivation condition for 12 hours to mimics the harsh microenvironment in infarcted heart; they were subjected to MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide Thiazolyl Blue Tetrazolium Bromide) assay, bioluminescence imaging, quantitative reverse transcription-polymerase chain reaction, transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling assay, and flow cytometry. Furthermore, the levels of vascular endothelial growth factor receptor 2, protein kinase B, p(Phosphorylate)-protein kinase B, Bcl-2, Bax, and caspase-3 proteins were available by Western blotting assay. In vivo, acute myocardial infarction was induced in 24 mice by coronary ligation, with subsequent receipt of Luc-MSCs, Luc-MSCs+miR-15a/15b inhibitors, or PBS treatment. The therapeutic procedure and treatment effects were tracked and assessed using bioluminescence imaging and echocardiographic measurement. Next, ex vivo imaging and immunohistochemistry were conducted to verify the distribution of MSCs. We demonstrated that miR-15a/15b targeted vascular endothelial growth factor receptor 2 to modulate MSC survival, possibly via phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which was proved by bioluminescence imaging, immunohistochemistry analysis, and echocardiographic measurement. Conclusions-Luc-MSCs could be followed dynamically in vitro and in vivo by bioluminescence imaging, and the role of miR-15a/b could be inferred from the loss of signals from luc-MSCs. This finding may have practical clinical implications in miR-15a/15b- modified MSC transplantation in treating myocardial infarction.
Background-Cardiac fibrosis is a core pathological process associated with heart failure. The recruitment and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. The K(Ca)3.1 channels are expressed in both ventricular fibroblasts and circulating mononuclear cells in rats and are upregulated by angiotensin II. We hypothesized that K(Ca)3.1 channels mediate the inflammatory microenvironment in the heart, promoting the infiltrated bone marrow-derived circulating mononuclear cells to differentiate into myofibroblasts, leading to myocardial fibrosis. Methods and Results-We established a cardiac fibrosis model in rats by infusing angiotensin II to evaluate the impact of the specific K(Ca)3.1 channel blocker TRAM-34 on cardiac fibrosis. At the same time, mouse CD4(+) T cells and rat circulating mononuclear cells were separated to investigate the underlying mechanism of the TRAM-34 anti-cardiac fibrosis effect. TRAM-34 significantly attenuated cardiac fibrosis and the inflammatory reaction and reduced the number of fibroblast precursor cells and myofibroblasts. Inhibition of K(Ca)3.1 channels suppressed angiotensin II-stimulated expression and secretion of interleukin-4 and interleukin-13 in CD4(+) T cells and interleukin-4- or interleukin-13-induced differentiation of monocytes into fibrocytes. Conclusions-K(Ca)3.1 channels facilitate myocardial inflammation and the differentiation of bone marrow-derived monocytes into myofibroblasts in cardiac fibrosis caused by angiotensin II infusion.
Background-Although right ventricular (RV) volume was significantly decreased in symptomatic patients with repaired tetralogy of Fallot (rTOF) after pulmonary valve replacement (PVR), RV size was still enlarged along with RV dysfunction. Methods and Results-A prospective case-control study was conducted in a tertiary hospital; 81 asymptomatic repaired tetralogy of Fallot patients with moderate or severe pulmonary regurgitation were enrolled. The enrolled cohort was divided into 2 groups: PVR group (n=41) and medication group (n=40). Cardiac magnetic resonance, transthoracic echocardiography, and electrocardiography were scheduled after recruitment and 6 months after PVR or recruitment. Adverse events were recorded during follow-up. Three deaths, 1 heart transplantation, 3 PVRs, and 2 symptomatic heart failures in medication group and 1 redo PVR in the PVR group were observed during follow-up. Compared with the medication group, the PVR group had significantly lower adverse events rate (P 0.023; odds ratio, 0.086; 95% CI, 0.010-0.716), and RV function was significantly improved (P<0.05). Binary logistic regression analysis identified preoperative RV end-systolic volume index (10-mL/m(2) increment, P=0.009; odds ratio, 0.64; 95% CI, 0.457-0.893) was an independent predictor of normalization of RV size after PVR. A preoperative RV end-systolic volume index cut-off value of 120 mL/m(2) (area under curve, 0.819; sensitivity, 90.3%; specificity, 70%) was analyzed by receiver operating characteristic curves for normalized RV size after PVR. Conclusions-PVR in asymptomatic repaired tetralogy of Fallot patients is appropriate and effective in reducing right ventricular size and preserving right ventricular function. The recommended criterion of RV end-systolic volume index for PVR is 120 mL/m(2).
Background-Canonical studies indicate that cytochrome P450 2E1 (CYP2E1) plays a critical role in the metabolism of xenobiotics and ultimately participates in tissue damage. CYP2E1 upregulates in the pathophysiological development of multiple diseases; however, the mechanism of CYP2E1 upregulation, particularly in heart disease, remains elusive. Methods and Results-We found that the level of CYP2E1 increased in heart tissues from patients with hypertrophic cardiomyopathy; multiple mouse models of heart diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and myocardial ischemia; and HL-1 myocytes under stress. We determined that Myc bound to the CYP2E1 promoter and activated its transcription by bioinformatics analysis, luciferase activity, and chromatin immunoprecipitation, and Myc expression was modulated by extracellular signal-regulated kinases 1/2 and phosphatidylinositol 3 kinase/protein kinase B pathways under stress or injury in myocardium by signal transduction analysis. In addition, the level of oxidative stress and apoptosis gradually worsened with age in transgenic mice over-expressing CYP2E1, which was significantly inhibited with CYP2E1 knockdown. Conclusions-Our results demonstrated that CYP2E1 is likely a sensor of diverse pathophysiological factors and states in the myocardium. Upregulated CYP2E1 has multiple pathophysiological roles in the heart, including increased oxidative stress and apoptosis as well as energy supply to meet the energy demand of the heart in certain disease states. Our discovery thus provides a basis for a therapeutic strategy for heart diseases targeting Myc and CYP2E1.
Background-The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in neointima formation induced by experimental AVFs in the presence of chronic kidney disease. Methods and Results-From our findings, NLRP3 was upregulated in the intimal lesions of AVFs in both uremic mice and patients. Smooth muscle-specific knockout NLRP3 mice exhibited markedly decreased neointima formation in the outflow vein of AVFs. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle-specific knockout NLRP3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP3 functions, several small-molecule inhibitors were used. The results showed that NLRP3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase-1/interleukin-1 signaling. Unexpectedly, the selective NLRP3-inflammasome inhibitor MCC950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease-promoted AVF failure independent of macrophages. Conclusions-Our findings suggest that NLRP3 in vascular smooth muscle cells may play a crucial role in uremia-associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure.
Background The involvement of vaspin (visceral adipose tissue derived serpin) in the development of atherosclerotic cardiovascular diseases has been documented. This study was designed to explore the prognostic value of serum vaspin in patients with acute myocardial infarction (AMI). Methods and Results We included 1036 AMI patients in a cohort study and determined the association between serum vaspin and major adverse cardiac events (MACE) using Cox regression analysis. The receiver operating characteristic curve indicated that serum vaspin could significantly differentiate patients with MACE, and the optimal cutoff value was 0.62 ng/m L. The Kaplan-Meier survival curve showed that patients with lower vaspin levels had higher incidence of MACE. Multivariate Cox regression analysis revealed that low vaspin was an independent predictor of MACE (hazard ratio: 0.74; 95% CI, 0.48-0.96; P=0.029), together with age; previous histories of AMI, heart failure, hypertension, and diabetes mellitus; Killip class; revascularization; CRP (C-reactive protein); and NT-proBNP (N-terminal pro B-type natriuretic peptide). Integrated discrimination and net reclassification improvements for MACE were significantly improved by addition of vaspin to the model of traditional risk factors. Moreover, low vaspin was a valuable predictor of heart failure hospitalization (hazard ratio: 0.58; 95% CI, 0.37-0.89; P=0.005) and recurrent AMI (hazard ratio: 0.72; 95% CI, 0.53-0.95; P=0.036) after adjustment for conventional cardiovascular risk factors. Conclusions Our study suggests that serum vaspin is a significant prognostic marker of MACE in AMI patients.
Background Intrauterine growth retardation (IUGR) is related to pulmonary artery hypertension in adults, and microRNA-206 (miR-206) is proposed to affect the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) via post transcriptional regulation. Methods and Results In an IUGR rat model, we found that the expression and function of potassium voltage-gated channel subfamily A member 5 (Kv1.5) in PASMCs was inhibited, and pulmonary artery hypertension was exaggerated after chronic hypoxia (CH) treatment as adults. microRNA expression was investigated in PASMCs from 12-week-old male IUGR rats with CH by microarray, polymerase chain reaction, and in situ hybridization. The expression levels of Kv1.5 in primary cultured PASMCs and pulmonary artery smooth muscle from IUGR or control rats were evaluated with and without application of an miR-206 inhibitor. Right ventricular systolic pressure, cell proliferation, luciferase reporter assay, and /(kv) wee also calculated. We found increased expression of miR-206 in resistance pulmonary arteries of IUGR rats at 12 weeks compared with newborns. Application of an miR-06 inhibitor in vivo or in vitro increased expression of Kv1.5 alpha-protein and KCNA5. Also, decreased right ventricular systolic pressure and cell proliferation were observed in PASMCs from 12-week-old control and IUGR rats after CH, while inhibitor did not significantly affect control and IUGR rats. Conclusions These results suggest that expression of Kvl.5 and 4-aminopyridine (Kv channel special inhibitor)-sensitive Kv current were correlated with the inhibition of miR-206 in PA rings of IUGR-CH rats and cultured IUGR PASMCs exposed to hypoxia. Thus, miR-206 may be a trigger for induction of exaggerated CH pulmonary artery hypertension of IUGR via Kv1.5.
Background-The prognostic significance of obstructive sleep apnea (OSA) in patients with acute coronary syndrome (ACS) in the contemporary era is unclear. We performed a large, prospective cohort study and did a landmark analysis to delineate the association of OSA with subsequent cardiovascular events after ACS onset. Methods and Results-Between June 2015 and May 2017, consecutive eligible patients admitted for ACS underwent cardiorespiratory polygraphy during hospitalization. OSA was defined as an apnea-hypopnea index >= 15 events.h(-1). The primary end point was major adverse cardiovascular and cerebrovascular event (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, or hospitalization for unstable angina or heart failure. OSA was present in 403 of 804 (50.1%) patients. During median follow-up of 1 year, cumulative incidence of MACCE was significantly higher in the OSA group than in the non-OSA group (log-rank, P=0.041). Multivariate analysis showed that OSA was nominally associated with incidence of MACCE (adjusted hazard ratio, 1.55; 95% CI, 0.94-2.57; P=0.085). In the landmark analysis, patients with OSA had 3.9 times the risk of incurring a MACCE after 1 year (adjusted hazard ratio, 3.87; 95% CI, 1.20-12.46; P=0.023), but no increased risk was found within 1-year follow-up (adjusted hazard ratio, 1.18; 95% CI, 0.67-2.09; P=0.575). No significant differences were found in the incidence of cardiovascular death, myocardial infarction, and ischemia-driven revascularization, except for a higher rate of hospitalization for unstable angina in the OSA group than in the non-OSA group (adjusted hazard ratio, 2.10; 95% CI, 1.09-4.05; P=0.027). Conclusions There was no independent correlation between OSA and 1-year MACCE after ACS. The increased risk associated with OSA was only observed after 1-year follow-up. Efficacy of OSA treatment as secondary prevention after ACS requires further investigation.
Background-More intense and longer-lasting heat events are expected in the United States as a consequence of climate change. This study aimed to project the potential changes in maternal heat exposure during early pregnancy (3-8 weeks post conception) and the associated burden of congenital heart defects (CHDs) in the future. Methods and Results-This study expanded on a prior nationwide case-control study that evaluated the association between CHDs and maternal heat exposure during early pregnancy in summer and spring. We defined multiple indicators of heat exposure, and applied published odds ratios obtained for the matching season of the baseline (1995-2005) into the projection period (20252035) to estimate potential changes in CHD burden throughout the United States. Increases in maternal heat exposure were projected across the United States and to be larger in the summer. The Midwest will potentially have the highest increase in summer maternal exposure to excessively hot days (3.42; 95% CI, 2.99-3.88 per pregnancy), heat event frequency (0.52; 95% CI, 0.44-0.60) and heat event duration (1.73; 95% CI, 1.49-1.97). We also found large increases in specific CHD subtypes during spring, including a 34.0% (95% CI, 4.9%-70.8%) increase in conotruncal CHD in the South and a 38.6% (95% CI, 9.9%-75.1%) increase in atrial septal defect in the Northeast. Conclusions-Projected increases in maternal heat exposure could result in an increased CHD burden in certain seasons and regions of the United States.
Background-Whether chronic obstructive sleep apnea (OSA) could promote epicardial adipose tissue (EAT) secretion of profibrotic adipokines, and thereby contribute to atrial fibrosis, and the potential therapeutic effects of metoprolol remain unknown. Methods and Results-A chronic OSA canine model was established by repeatedly clamping the endotracheal tube for and then reopening it for 4 hours every other day for 12 weeks. In a metoprolol treatment group, metoprolol succinate was administered daily for 12 weeks. The EAT infiltration and left atrial fibrosis were examined. The expressions of adipokines secreted by EAT and hypoxic 3T3-L1 adipocytes were detected. The changes in collagen synthesis, transforming growth factor-beta 1 expression, and cell differentiation and proliferation in cardiac fibroblasts induced by hypoxic 3T3-L1 adipocyte-derived conditioned medium were further analyzed. Chronic OSA induced infiltration of EAT into the left atrium. OSA enhanced the profibrotic effect of EAT on the adjacent atrial myocardium. Moreover, OSA induced profibrotic cytokine secretion from EAT. We also found that hypoxia induced adipokine secretion in cultured adipocytes, and the medium conditioned by the hypoxic adipocytes increased collagen and transforming growth factor-b1 protein expression and cell proliferation of cardiac fibroblasts. More importantly, metoprolol attenuated infiltration of EAT and alleviated the profibrotic effect of EAT by inhibiting adipokine secretion. Metoprolol also inhibited hypoxia-induced adipokine secretion in adipocytes and thereby blocked the hypoxic adipocyte-derived conditioned mediuminduced fibrotic response of cardiac fibroblasts. Conclusions-Chronic OSA enhanced the profibrotic effect of EAT on the neighboring atrial myocardium by stimulating the secretion of profibrotic adipokines from EAT, which was significantly attenuated by metoprolol. This study gives insights into mechanisms underlying OSA-induced atrial fibrillation and also provides experimental evidence for the protective effects of metoprolol.