Description: Several studies have investigated the short-term effects of ambient air pollutants in the development of high blood pressure and hypertension. However, little information exists regarding the health effects of long-term exposure. To investigate the association between residential long-term exposure to air pollution and blood pressure and hypertension, we studied 24 845 Chinese adults in 11 districts of 3 northeastern cities from 2009 to 2010. Three-year average concentration of particles with an aerodynamic diameter ≤10 µm (PM 10 ), sulfur dioxide (SO 2 ), nitrogen dioxides (NO 2 ), and ozone (O 3 ) were calculated from monitoring stations in the 11 districts. We used generalized additive models and 2-level logistic regressions models to examine the health effects. The results showed that the odds ratio for hypertension increased by 1.12 (95% confidence interval [CI], 1.08–1.16) per 19 μg/m 3 increase in PM 10 , 1.11 (95% CI, 1.04–1.18) per 20 μg/m 3 increase in SO 2 , and 1.13 (95% CI, 1.06–1.20) per 22 μg/m 3 increase in O 3 . The estimated increases in mean systolic and diastolic blood pressure were 0.87 mm Hg (95% CI, 0.48–1.27) and 0.32 mm Hg (95% CI, 0.08–0.56) per 19 μg/m 3 interquartile increase in PM 10 , 0.80 mm Hg (95% CI, 0.46–1.14) and 0.31 mm Hg (95% CI, 0.10–0.51) per 20 μg/m 3 interquartile increase in SO 2 , and 0.73 mm Hg (95% CI, 0.35–1.11) and 0.37 mm Hg (95% CI, 0.14–0.61) per 22 μg/m 3 interquartile increase in O 3 . These associations were only statistically significant in men. In conclusion, long-term exposure to PM 10 , SO 2 , and O 3 was associated with increased arterial blood pressure and hypertension in the study population.

Description: Background and Purpose— Brain ischemia causes immediate and delayed cell death that is exacerbated by inflammation. Recent studies show that hypocretin-1/orexin-A (Hcrt-1) reduces ischemic brain injury, and Hcrt-positive neurons modulate infection-induced inflammation. Here, we tested the hypothesis that Hcrt plays a protective role against ischemia by modulating inflammation. Methods— Orexin/ataxin-3 (AT) mice, a transgenic strain in which Hcrt-producing neurons degenerate in early adulthood, and wild-type mice were subjected to transient middle cerebral artery occlusion (MCAO). Infarct volume, neurological score, and spontaneous home cage activity were assessed. Inflammation was measured using immunohistochemistry, ELISA, and assessment of cytokine mRNA levels. Results— Infarct volumes 24 and 48 hours after MCAO were significantly larger, neurological score was worse, and spontaneous activity decreased in AT compared with wild-type mice. Macrophage/microglial infiltration and myeloperoxidase-positive cells were higher in AT compared with wild-type mice. Pre-MCAO intracerebroventricular injection of Hcrt-1 significantly reduced infarct volume and macrophage/microglial infiltration in both genotypes and improved neurological score in AT mice. Post-MCAO treatment decreased infarct size in both wild-type and AT mice, but had no effect on neurological score in either genotype. Microglia express the Hcrt-1 receptor after MCAO. Tumor necrosis factor-α production by lipopolysaccharide-stimulated microglial BV2 cells was significantly reduced by Hcrt-1 pretreatment. Sham AT mice exhibit increased brain tumor necrosis factor-α and interleukin-6 mRNA, suggesting chronic inflammation. Conclusions— Loss of Hcrt neurons in AT mice resulted in worsened stroke outcomes, which were reversed by administration of exogenous Hcrt-1. The mechanism underlying Hcrt-mediated neuroprotection includes attenuation of inflammatory responses after ischemic insult.

Description: The adaptor protein Src homology 2-B3 (SH2B3), which belongs to a subfamily of Src homology 2 proteins, is a broad inhibitor of growth factors and cytokine signaling in hematopoietic cells. However, the role of SH2B3 in nonhematopoietic systems, particularly cardiomyocytes, has not been defined. In this study, we observed noticeable increase in SH2B3 protein expression during pathological cardiac remodeling in both humans and rodents. Follow-up in vitro gain- and loss-of-function studies suggested that SH2B3 promotes the cardiomyocyte hypertrophy response. Consistent with the cell phenotype, SH2B3 knockout (SH2B3 –/– ) mice exhibited attenuated cardiac remodeling with preserved cardiac function after chronic pressure overload. Conversely, cardiac-specific SH2B3 overexpression aggravated pressure overload–triggered cardiac hypertrophy, fibrosis, and dysfunction. Mechanistically, SH2B3 accelerates and exacerbates cardiac remodeling through the activation of focal adhesion kinase, which, in turn, activates the prohypertrophic downstream phosphoinositide 3-kinase-AKT-mammalian target of rapamycin/glycogen synthase kinase 3β signaling pathway. Finally, we generated a novel SH2B3 knockout rat line and further confirmed the protective effects of SH2B3 deficiency on cardiac remodeling across species. Collectively, our data indicate that SH2B3 functions as a novel and effective modulator of cardiac remodeling and failure.

Description: Background Studies in the United States suggested that the characteristics of hospitals providing percutaneous coronary intervention (PCI) differed from those not providing PCI. However, little is known on the differences between the characteristics of early-adopting hospitals and those of late-adopting hospitals, and on their potential impacts on PCI volume and access. Methods and Results We used inpatient claims data from 1997 to 2012 from the Taiwan National Health Insurance program to identify the hospitals offering PCI. Geographic information systems (GIS) were used to determine the population access to PCI hospital. As of 2012, 88 hospitals were capable of providing PCI. On the basis of the year that the hospitals started providing PCI, 32 hospitals were designated as early adopters (before 1998), 23 as early majority (1998–2002), 24 as late majority (2003–2007), and 16 as laggards (2008–2012). Hospitals that adopted PCI later were smaller in size and closer to an existing PCI hospital and had lower PCI volumes performed and less bypass surgery support. The median PCI volumes in 2012 were n=706, 330, 138, and 81 in early adopters, early majority, late majority, and laggards, respectively. Despite the low volume of PCI performed in laggard hospitals, the percentage with ST-elevation myocardial infarction and acute myocardial infarction as principal discharge diagnosis was higher than their early-adopting hospital counterparts. The percentage of the Taiwanese population living within 40 km of PCI hospitals (appropriate access defined in this study) was 95.7% in 1997 and 98.0% in 2002, and this has remained unchanged since 2002. Conclusions The characteristics of early-adopting hospitals differed from those of late-adopting hospitals. Despite lower PCI volume performed in late-adopting hospitals, many of them are in remote areas and provide needed and timely services for patients with acute myocardial infarction.

Description: Background and Purpose— Although the relationship between depression and stroke risk has been investigated, findings in previous reports were conflicting. The aim of this study was to prospectively examine the effect of major depressive episodes (MDE) on stroke incidence and further assess the potential dose–response relationship between number of depression symptoms and subsequent stroke risk in Chinese population. Methods— A total of 199 294 men and 288 083 women aged 30 to 79 years without a history of stroke, heart disease, and cancer in the China Kadoorie Biobank cohort were followed from 2004 to 2013. A World Health Organization Composite International Diagnostic Interview-Short Form was used to access MDE according to Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Stroke events were ascertained through death certificates, medical records, and health insurance data. Results— Past year MDE was marginally associated with a 15% increased risk of stroke (adjusted hazard ratio, 1.15; 95% confidence interval, 0.99–1.33) in the fully adjusted model, and the association was steeper and statistically significant in individuals aged 〈50 years, smokers, drinkers, those with higher education degree, body mass index 〈24.0 kg/m 2 , and no history of diabetes mellitus. Moreover, there was a positive dose–response relationship between the number of depression symptoms and increased stroke risk ( P trend =0.011). In addition, smoking status significantly interacted with MDE on stroke onset ( P for multiplicative interaction=0.025). Conclusions— Findings from this large prospective study suggest that the presence of MDE is a risk factor for stroke, especially in smokers.

Description: Background Irisin is a newly discovered myokine that has been considered a promising candidate for the treatment of cardiovascular disease through improving endothelial function. However, little is known about the role of irisin in the progression of atherosclerosis. Methods and Results We used a carotid partial ligation model of apolipoprotein E–deficient mice fed on a high-cholesterol diet to test the anti-atherosclerosis effect of irisin. Irisin treatment significantly suppressed carotid neointima formation. It was associated with increased endothelial cell proliferation. In addition, irisin promoted human umbilical vein endothelial cell survival via upregulating microRNA126-5p expression through the ERK signaling pathway. Inhibition of microRNA126-5p using the microRNA126-5p inhibitor abolished the prosurvival effect. The same results were demonstrated in vivo as the expression of microRNA126-5p noticeably increased in ligated carotid artery after irisin treatment. Furthermore, in vivo blockade of microRNA126-5p expression using the antagomir abolished the inhibitory effects of irisin on neointima formation, lesional lipid deposition, macrophage area, and the pro-proliferation effects on endothelial cells. Conclusions Taken together, our study demonstrates that irisin significantly reduces atherosclerosis in apolipoprotein E–deficient mice via promoting endothelial cell proliferation through microRNA126-5p, which may have a direct therapeutic effect on atherosclerotic diseases.

Description: Rationale: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. Objective: To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR). Methods and Results: Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca 2+ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P 〈0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-β, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation ( P 〈0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P 〈0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV ( P 〈0.01), and reversed atrial hypertrophy ( P 〈0.05). Independent of antifibrotic actions, RLX (0.1 µmol/L) increased Na + current density, I Na (2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P 〈0.01). Conclusions: RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing I Na . The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents.

Description: Background In-hospital cardiac arrest (IHCA) is common and often fatal. However, the extent to which hospitals vary in survival outcomes and the degree to which this variation is explained by patient and hospital factors is unknown. Methods and Results Within Get with the Guidelines-Resuscitation, we identified 135 896 index IHCA events at 468 hospitals. Using hierarchical models, we adjusted for demographics comorbidities and arrest characteristics (eg, initial rhythm, etiology, arrest location) to generate risk-adjusted rates of in-hospital survival. To quantify the extent of hospital-level variation in risk-adjusted rates, we calculated the median odds ratio (OR). Among study hospitals, there was significant variation in unadjusted survival rates. The median unadjusted rate for the bottom decile was 8.3% (range: 0% to 10.7%) and for the top decile was 31.4% (28.6% to 51.7%). After adjusting for 36 predictors of in-hospital survival, there remained substantial variation in rates of in-hospital survival across sites: bottom decile (median rate, 12.4% [0% to 15.6%]) versus top decile (median rate, 22.7% [21.0% to 36.2%]). The median OR for risk-adjusted survival was 1.42 (95% CI: 1.37 to 1.46), which suggests a substantial 42% difference in the odds of survival for patients with similar case-mix at similar hospitals. Further, significant variation persisted within hospital subgroups (eg, bed size, academic). Conclusion Significant variability in IHCA survival exists across hospitals, and this variation persists despite adjustment for measured patient factors and within hospital subgroups. These findings suggest that other hospital factors may account for the observed site-level variations in IHCA survival.

Description: Background and Purpose— Sex differences in secular trends of stroke incidence are rarely reported. We aimed to explore sex differences in incidence and mortality of stroke in rural China from 1992 to 2012. Methods— In 1992, 14 920 residents were recruited to participate in the Tianjin Brain Study, a population-based study on stroke surveillance. Stroke events and all deaths were annually registered. Results— We observed 908 incident strokes (366 in women) from 1992 to 2012. Women were significantly younger than men (64±12 versus 68±11 years) in 1992 to 1998 ( P =0.024). The incidence of first-ever stroke per 100 000 person-years for men was 166 in 1992 to 1998, 227 in 1999 to 2005, and 376 in 2006 to 2012; for women, the rates were 86 (1992–1998), 148 (1999–2005), and 264 (2006–2012). From 1992 to 2012, the incidence grew annually by 5.8% in men and 8.0% in women. The male/female incidence ratio declined significantly: 1.9 in 1992 to 1998, 1.5 in 1999 to 2005, and 1.4 in 2006 to 2012. There were no significant sex differences in mortality. The prevalence of obesity and diabetes mellitus, the levels of total cholesterol and triglycerides, and the age of menopause and reproductive years in women concurrently increased in 2011. Conclusions— There was a significant increase in the incidence of first-ever stroke in women annually and a declining trend in the male/female rate ratio in rural China during the past 21 years. These results suggest that stroke will become one of the major diseases affecting women in future decades in China.

Description: Rationale: Sympathetic nervous system triggered activation of protein kinase A, which phosphorylates several targets within cardiomyocytes, augments inotropy, chronotropy, and lusitropy. An important target of β-adrenergic stimulation is the sarcolemmal L-type Ca 2+ channel, Ca V 1.2, which plays a key role in cardiac excitation–contraction coupling. The molecular mechanisms of β-adrenergic regulation of Ca V 1.2 in cardiomyocytes, however, are incompletely known. Recently, it has been postulated that proteolytic cleavage at Ala 1800 and protein kinase A phosphorylation of Ser 1700 are required for β-adrenergic modulation of Ca V 1.2. Objective: To assess the role of Ala 1800 in the cleavage of α 1C and the role of Ser 1700 and Thr 1704 in mediating the adrenergic regulation of Ca V 1.2 in the heart. Methods and Results: Using a transgenic approach that enables selective and inducible expression in mice of FLAG-epitope–tagged, dihydropyridine-resistant Ca V 1.2 channels harboring mutations at key regulatory sites, we show that adrenergic regulation of Ca V 1.2 current and fractional shortening of cardiomyocytes do not require phosphorylation of either Ser 1700 or Thr 1704 of the α 1C subunit. The presence of Ala 1800 and the 1798 NNAN 1801 motif in α 1C is not required for proteolytic cleavage of the α 1C C-terminus, and deletion of these residues did not perturb adrenergic modulation of Ca V 1.2 current. Conclusions: These results show that protein kinase A phosphorylation of α 1C Ser 1700 does not have a major role in the sympathetic stimulation of Ca 2+ current and contraction in the adult murine heart. Moreover, this new transgenic approach enables functional and reproducible screening of α 1C mutants in freshly isolated adult cardiomyocytes in a reliable, timely, cost-effective manner.