Background Suicide is the third-leading cause of death among adolescents and nonsuicidal self-harm occurs in 13%–45% of individuals within this age group, making these phenomena major public health ...concerns. Lesbian, gay, bisexual, and transgender (LGBT) youth particularly are at risk for engaging in these behaviors. Nevertheless, relatively little is known about the specific risk factors associated with suicidal ideation and self-harm behaviors in the population. Purpose This study provides a longitudinal evaluation of the relative contributions of general and LGBT-specific risk factors as well as protective factors to the occurrence of suicidal ideation and self-harm in an ethnically diverse sample of LGBT youth. Methods A community sample of 246 LGBT youth (aged 16–20 years) was followed prospectively over five time points at regular 6-month intervals. Participants completed a baseline structured interview assessing suicide attempt history and questionnaires measuring gender nonconformity, impulsivity, and sensation-seeking. At follow-up assessments, participants completed a structured interview assessing self-harm and questionnaires for suicidal ideation, hopelessness, social support, and LGBT victimization. Data were collected from 2007 to 2011, and HLM analyses were conducted in 2011. Results A history of attempted suicide ( p =0.05); impulsivity ( p =0.01); and prospective LGBT victimization ( p =0.03) and low social support ( p =0.02) were associated with increased risk for suicidal ideation. Suicide attempt history ( p <0.01); sensation-seeking ( p =0.04); female gender ( p <0.01); childhood gender nonconformity ( p <0.01); and prospective hopelessness ( p <0.01) and victimization ( p <0.01) were associated with greater self-harm. Conclusions General and LGBT-specific risk factors both uniquely contribute to likelihood of suicidal ideation and self-harm in LGBT youth, which may, in part, account for the higher risk of these phenomena observed in this population.
Introduction Hydrogen sulfide is produced endogenously in response to myocardial ischemia and thought to be cardioprotective. The mechanism underlying this protection has yet to be fully elucidated, ...but it may be related to sulfide's ability to limit inflammation. This study investigates the cardioprotection provided by exogenous hydrogen sulfide and its potential anti-inflammatory mechanism of action. Methods The mid left anterior descending coronary artery in 14 Yorkshire swine was acutely occluded for 60 minutes, followed by reperfusion for 120 minutes. Controls (n = 7) received placebo, and treatment animals (n = 7) received sulfide 10 minutes before and throughout reperfusion. Hemodynamic and functional measurements were obtained. Evans blue and triphenyl tetrazolium chloride staining identified the area at risk and infarction. Coronary microvascular reactivity was assessed. Tissue was assayed for myeloperoxidase activity and proinflammatory cytokines. Results Pre-ischemia/reperfusion hemodynamics were similar between groups, whereas post-ischemia/reperfusion mean arterial pressure was reduced by 28.7 ± 5.0 mm Hg in controls versus 6.7 ± 6.2 mm Hg in treatment animals ( P = .03). Positive first derivative of left ventricular pressure over time was reduced by 1325 ± 455 mm Hg/s in controls versys 416 ± 207 mm Hg/s in treatment animals ( P = .002). Segmental shortening in the area at risk was better in treatment animals. Infarct size (percent of area at risk) in controls was 41.0% ± 7.8% versus 21.2% ± 2.5% in the treated group ( P = .036). Tissue levels of interleukin 6, interleukin 8, tumor necrosis factor-alpha, and myeloperoxidase activity decreased in the treatment group. Treated animals demonstrated improved microvascular reactivity. Conclusions Therapeutic sulfide provides protection in response to ischemia/reperfusion injury, improving myocardial function, reducing infarct size, and improving coronary microvascular reactivity, potentially through its anti-inflammatory properties. Exogenous sulfide may have therapeutic utility in clinical settings in which ischemia/reperfusion injury is encountered.
Abstract Background Research in the USA and in west European countries has shown that long-term exposure to fine particles (PM2.5) is associated with an increased risk of mortality from ...cardiovascular disease, but no such studies have been done in China to date. We have estimated the association between long-term exposure to PM2·5 and cardiovascular mortality from cardiovascular disease in a cohort of Chinese men. Methods For this prospective cohort study, we monitored men aged 40–79 years from 44 counties or cities in China since 1990–91. Annual average PM2·5 levels for the years 2000 and 2005 were estimated for each of the 44 cohort locations using a combination of satellite-based estimates, chemical transport models, and ground-level measurements developed for the Global Burden of Disease study. We used a Cox proportionate hazards regression model to estimate hazard ratios (HR) for cardiovascular mortality during 15 years of follow-up, adjusting for age, urbanicity (ie, urban vs rural), smoking status, alcohol consumption, and body-mass index (BMI). This study was approved by the ethics committee of Chinese Center for Disease Control and Prevention. Findings 186 399 men were included in the cohort. 52 000 deaths were reported during the 15 years of follow-up, of which 18 773 (36%) were due to cardiovascular disease, which included 3726 deaths from ischaemic heart disease, 6765 deaths from haemorrhagic stroke, and 2688 deaths from ischaemic stroke. The mean PM2·5 concentration between year 2000 and 2005 was 43·7 μg/m3 and ranged from 4·2 μg/m3 to 83·8 μg/m3 . An increase in PM2·5 of 10 μg/m3 was associated with a 9·7% increase in the risk of mortality from ischaemic heart disease (HR 1·097, 95% CI 1·079–1·116), a 4·4% increase in the risk of mortality from haemorrhagic stroke (HR 1·044, 95% CI 1·031–1·057), and a 13·5% increase in the risk of mortality from ischaemic stroke (HR 1·135, 95% CI 1·113–1·158). Interpretation This study estimated cardiovascular mortality risk associated with exposure to ambient PM2·5 over a broader range than in previous studies, including the high levels currently observed in China and other low-income and middle-income countries. Long-term exposure to PM2·5 was associated with cause-specific cardiovascular mortality in Chinese men. Relative risks were comparable to those reported in studies in high-income Western countries. As limitations of the study, we only included men in our cohort, and we were not able to assess the effect of within-city air pollution contrasts on mortality because personal exposure measurements were not available during the period of follow-up. Funding This study was supported by the National Basic Research Program of China (“973 Program”, number 2012CB955500) and Gong-Yi Program of China Ministry of Environmental Protection (201402022).
Background We investigated the contractile response of human coronary microvasculature to thromboxane A-2 (TXA-2), with and without the blockade of TXA-2 receptors or the inhibition of ...phospholipase-C (PLC) or of protein kinase C-α (PKC-α) in the human coronary microvasculature before and after cardioplegia, followed by reperfusion (CP/Rep). Protein/gene expression and localization of TXA-2 receptors, TXA-2 synthase, PLC, and other TXA-2–related proteins was also examined. Methods Right atrial tissue was harvested before and after cold blood cardioplegia, followed by about 10 minutes of reperfusion, from 28 patients undergoing cardiac operations. Coronary arterioles (90 to 170 μm in diameter) were dissected from the harvested tissue. Results The post-CP/Rep contractile response of coronary arterioles to TXA-2 analog U-46619 was significantly impaired vs pre-CP/Rep ( p < 0.05). The TXA-2 receptor antagonist SQ-29548 (10–6 M) prevented the contractile response to U-46619 ( p < 0.05). Pretreatment with the PLC inhibitor U73122 (10–6 M) significantly inhibited the U-46619–induced contractile response ( p < 0.05). Administration of the PKC-α inhibitor safingol failed to affect U-46619–induced contraction. Total protein levels and gene expression of TXA-2 receptors, TXA-2 synthase, PLC-β3, phospho–PLC-β3, PLC-γ1, and phospho–PLC-γ1 were not altered after CP/Rep. Confocal microscopy showed no significant differences in the expression of TXA-2 receptors or PLC-β3 in the microcirculation. TXA-2 receptors and PLC-β3 were both present in smooth muscle and endothelium. Conclusions Cardioplegia/Rep decreases the contractile response of human coronary arterioles to TXA-2 soon after cardiac operations. The contractile response to the TXA-2 analog U-46619 is through activation of TXA-2 receptors and PLC.
Background We compared the contractile responses to endothelin-1 (ET-1) with and without the inhibition of ET-A receptors and protein kinase C-alpha (PKC-α) in the human peripheral microvasculature ...of diabetic and case-matched, nondiabetic patients. Methods Chest wall skeletal muscle was harvested from patients with and without diabetics undergoing cardiac surgery. Peripheral arterioles (90–180 μm in diameter) were dissected from the harvested tissue. Microvascular constriction was assessed by videomicroscopy in response to ET-1 with and without an endothelin-A (ET-A) receptor antagonist, an endothelin B (ET-B) antagonist, or a PKC-α inhibitor. Results ET-1 induced a dose-dependent contractile response of skeletal muscle arterioles from diabetic and nondiabetic patients. The contractile response of diabetic arterioles from both prebypass and postbypass to ET-1 (10−9 mol/L) was decreased compared with those of nondiabetic patients ( P < .05). The contractile responses of microvessels of both diabetics and nondiabetics to ET-1 were inhibited in the presence of either ET-A receptor antagonist BQ123 (10−7 mol/L) or the PKC-α inhibitor safingol (2 × 10−5 mol/L, P < .05, respectively). In contrast, the ET-1–induced vasoconstriction was not affected by the administration of the ET-B receptor antagonist BQ788 (10−7 mol/L). There were no differences in skeletal muscle levels of the ET-A and ET-B receptors between diabetic and nondiabetic groups. Conclusion Diabetic patients demonstrated a decreased contractile response to ET-1 in human peripheral microvasculature. The contractile response of diabetic vessels to ET-1 occurs via activation of ET-A receptors and PKC-α. These results provide novel mechanisms of ET-1–induced contraction in vasomotor dysfunction in patients with diabetes.
Background We investigated the role of calcium-activated potassium (KCa ) channel activity in human skeletal muscle microvascular function in the setting of cardiopulmonary bypass (CPB). Methods and ...Results Human skeletal muscle arterioles (80- to 180 μm in diameter) were dissected from tissue harvested before and after CPB. In vitro relaxation responses of precontracted arterioles in a pressurized no-flow state were examined in the presence of KCa channel activators/blockers and several other vasodilators. Post-CPB responses to the activator of intermediate (IKCa ) and small conductance (SKCa ) KCa channels, NS309, to the endothelium-dependent vasodilator adenosine 5′-diphosphate (ADP), and to substance P were reduced compared with pre-CPB responses ( P < .05), respectively, whereas responses to the activator of large conductance (BKCa ) KCa channels, NS1619, and to the endothelium-independent vasodilator, sodium nitroprusside (SNP) were unchanged. Endothelial denudation decreased NS309-induced relaxation and abolished that induced by ADP or substance P ( P < .05), but had no effect on relaxation induced by either NS1619 or SNP. Polypeptide levels of BKCa , IKCa , and SK3Ca were not altered post-CPB. Conclusion IK/SK-mediated relaxation is predominantly endothelium dependent, whereas BK-mediated relaxation seems to be largely independent of endothelial function in human skeletal muscle microvasculature. CPB-associated microvascular dysfunction likely arises in part from impaired function of endothelial SK and IK channels in the peripheral microvasculature.
Background Myocardial ischemia-reperfusion injury may lead to cardiac dysfunction or death. This study investigates the potential efficacy of a novel thrombin fragment (TP508) on myocardial ...ischemia-reperfusion injury. Methods Fourteen male Yucatan pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either saline vehicle (control, n = 7) or thrombin fragment TP508 (n = 7) as a bolus (0.5 mg/kg) 50 minutes into the ischemic period, followed by continuous intravenous infusion (1.25 mg · kg−1 · h−1 ) during reperfusion. Myocardial function was monitored throughout the experiments. Monastryl blue/triphenyl tetrazolium chloride staining was utilized to measure the area at risk and infarcted tissue. Apoptosis was assessed by Western blotting and dUTP nick-end labeling (TUNEL) staining. Coronary microvascular reactivity to endothelium-dependent factors (adenosine diphosphate, substance P, A23187) and endothelium-independent factor (sodium nitroprusside) was examined. Results Global and regional left ventricular function was not significantly different between groups. Endothelium-dependent coronary microvascular relaxation was greater in the TP508 group and associated with higher endothelial nitric oxide synthase phosphorylation. Both infarct size and TUNEL staining was significantly decreased in the TP508 group compared with the control group ( p < 0.05). Expression of the cell survival proteins B-cell lymphoma 2 (2.2-fold, p < 0.05) and heat shock protein-73 (1.6-fold, p < 0.05) was higher in the TP508 group. Expression of the cell-death–signaling proteins poly adenosine diphosphate-ribose polymerase (1.6-fold, p < 0.05), cleaved poly adenosine diphosphate-ribose polymerase (6.4-fold, p < 0.05), and B-cell lymphoma 2/adenovirus E1B 19 kDa-interacting protein 3 (3.8-fold, p < 0.05) was significantly higher in the TP508 group in the ischemic territory. Conclusions This study demonstrates that TP508 decreases infarct size, improves endothelial microvascular function, and induces cell-survival signaling in the setting of ischemia-reperfusion injury. Thus, TP508 may be a useful agent to attenuate myocardial reperfusion injury.
We sought to investigate prognostic implications of the relationships of estimated left ventricular (LV) myocardial energy expenditure (MEE) with LV systolic dysfunction, body composition, and ...inflammation in a population-based sample of adults without overt congestive heart failure.
Echocardiography was used to assess LV ejection fraction (EF) and MEE. Body composition was evaluated by bioelectric impedance. Dietary recall was used to assess 24-hour calorie intake. Participants in the Strong Heart Study without prior congestive heart failure and with all needed data available (n = 3087) were divided based on LV EF (>55%, 54%-45%, or <45%).
Participants with EF less than 45% were older and they had lower body mass index, adipose mass, fat-free mass, and 24-hour calorie intake than participants with normal EF (>/=55%), and had greatest reductions of body mass index and physical activity in a time interval of 3.5 years, on average, elapsed between an initial clinical assessment and the evaluation at the time of the echocardiographic examination (P < .01). Lower EF was associated with male sex, hypertension, diabetes, coronary heart disease, and higher fibrinogen, C-reactive protein, and plasma creatinine levels (all P < .01). MEE was higher with lower EF (all P < .001). In Cox regression models, during approximately 8 years of observation, MEE comprised between 97 and 123 cal/min and MEE greater than 123 cal/min were associated with 2.5-fold and additional 3.3-fold higher rates of cardiac death, respectively, compared with MEE less than 97 cal/min, independently of EF, body composition, and other covariates. However, lower adipose mass predicted increased risk of cardiac death independent of MEE and EF.
In a population-based sample of adults including ambulatory individuals with depressed LV systolic function but without overt congestive heart failure, depressed EF was associated independently with higher MEE, lower adipose mass, and higher fibrinogen. However, increased MEE and lower adipose mass predicted cardiac death independently of EF and other covariates.
As a result of rapid economic development in China, the lifestyles and dietary habits of its people have been changing, and the rates of obesity, diabetes, and other chronic conditions have increased ...substantially. We report the prevalence of type 2 diabetes and impaired fasting glucose (IFG) and the association between diabetes and overweight and obesity in Chinese adults. We also compare the results with those from the US National Health and Nutrition Examination Survey, 1999-2002.
Data were from adults aged 20 years or older who participated in the China National Nutrition and Health Survey, 2002 (n = 47,729). Diabetes and IFG were defined by the American Diabetes Association 2009 criteria. We assessed the prevalence of diabetes, IFG, and overweight and obesity by sex, age, region of residence, and ethnicity.
The prevalence of diabetes and IFG in Chinese adults was 2.7% and 4.9%, respectively. The prevalence of diabetes increased with age and body mass index. Men and women had a similar prevalence of diabetes, but men had a significantly higher prevalence of IFG. The prevalence of diabetes among Chinese who lived in urban areas was 2 to 3 times higher than the prevalence among those who lived in rural areas (3.9% for urban areas and 6.1% for large cities vs 1.9% for rural areas), and the prevalence of IFG was 1.5 to 2 times higher (6.1% and 8.1% vs 4.2%, respectively). The prevalence of diabetes among Chinese women and young (20-39 y) and middle-aged (40-59 y) adults who lived in large cities was similar to the prevalence of diabetes in the US population.
The prevalence of diabetes and IFG was much higher in urban than rural areas, particularly in the large cities of China. Prevention must be emphasized among adults to reduce the future social and economic burden of diabetes in China.
Abstract Background The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response ...to medical therapy would elucidate the genetic basis of cardiac function. Objectives This study sought to identify genetic variations associated with response to HF therapy. Methods This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography. Results Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 ( HCRTR2 ), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10−5 ). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2 -deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model. Conclusions A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.
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