Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death.

BACKGROUND: The majority of sudden cardiac deaths (SCDs) occur in low-risk populations often as the first manifestation of cardiovascular disease (CVD). Biomarkers are screening tools that may identify subclinical cardiovascular disease and those at elevated risk for SCD. We aimed to determine whether the total to high-density lipoprotein cholesterol ratio, high-sensitivity cardiac troponin I, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity C-reactive protein individually or in combination could identify individuals at higher SCD risk in large, free-living populations with and without cardiovascular disease. METHODS: We performed a nested case-control study within 6 prospective cohort studies using 565 SCD cases matched to 1090 controls (1:2) by age, sex, ethnicity, smoking status, and presence of cardiovascular disease. RESULTS: The median study follow-up time until SCD was 11.3 years. When examined as quartiles or continuous variables in conditional logistic regression models, each of the biomarkers was significantly and independently associated with SCD risk after mutually controlling for cardiac risk factors and other biomarkers. The mutually adjusted odds ratios for the top compared with the bottom quartile were 1.90 (95% CI, 1.30-2.76) for total to high-density lipoprotein cholesterol ratio, 2.59 (95% CI, 1.76-3.83) for high-sensitivity cardiac troponin I, 1.65 (95% CI, 1.12-2.44) for NT-proBNP, and 1.65 (95% CI, 1.13-2.41) for high-sensitivity C-reactive protein. A biomarker score that awarded 1 point when the concentration of any of those 4 biomarkers was in the top quartile (score range, 0-4) was strongly associated with SCD, with an adjusted odds ratio of 1.56 (95% CI, 1.37-1.77) per 1-unit increase in the score. CONCLUSIONS: Widely available measures of lipids, subclinical myocardial injury, myocardial strain, and vascular inflammation show significant independent associations with SCD risk in apparently low-risk populations. In combination, these measures may have utility to identify individuals at risk for SCD.

Association between plasma adiponectin levels and colorectal cancer risk in women.

BACKGROUND: Adiponectin, an adipocyte-secreted hormone, has insulin-sensitizing characteristics. It remains unclear whether adiponectin may influence colorectal cancer development. METHODS: To determine whether prediagnostic levels of adiponectin were associated with risk of incident colorectal cancer in the Women's Health Study, we conducted a nested case-control study of 275 colorectal cancer cases and 275 matched controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Multivariable logistic regression with adjustment for colorectal cancer risk factors was used to estimate the odds ratio (OR) and 95 % confidence interval (CI) for risk of colorectal cancer incidence and mortality by adiponectin quartiles based on the control distribution. RESULTS: Median plasma adiponectin level was similar in cases versus controls (6.00 vs. 6.24 µg/mL). In multivariable-adjusted logistic regression models, high plasma adiponectin levels were not significantly associated with risk of colorectal cancer [quartile 4 (Q4) vs. quartile 1 (Q1): OR (95 % CI) 0.86 (0.48-1.56), p trend = 0.63]. CONCLUSIONS: These results suggest no appreciable association between plasma adiponectin and risk of colorectal cancer in women. Confirmation of these observations in larger studies is needed.

Identifying an Optimal Cutpoint for the Diagnosis of Hypertriglyceridemia in the Nonfasting State.

BACKGROUND: Nonfasting triglycerides are similar or superior to fasting triglycerides at predicting cardiovascular events. However, diagnostic cutpoints are based on fasting triglycerides. We examined the optimal cutpoint for increased nonfasting triglycerides. METHODS: We obtained baseline nonfasting (<8 h since last meal) samples from 6391 participants in the Women's Health Study who were followed prospectively for ≤17 years. The optimal diagnostic threshold for nonfasting triglycerides, determined by logistic regression models by use of c-statistics and the Youden index (sum of sensitivity and specificity minus 1), was used to calculate hazard ratios (HRs) for incident cardiovascular events. Performance was compared to thresholds recommended by the American Heart Association (AHA) and European guidelines. RESULTS: The optimal threshold was 175 mg/dL (1.98 mmol/L), with a c-statistic of 0.656, statistically better than the AHA cutpoint of 200 mg/dL (c-statistic 0.628). For nonfasting triglycerides above and below 175 mg/dL, after adjusting for age, hypertension, smoking, hormone use, and menopausal status, the HR for cardiovascular events was 1.88 (95% CI 1.52-2.33, P < 0.001), and for triglycerides measured at 0-4 and 4-8 h since the last meal, 2.05 (1.54- 2.74) and 1.68 (1.21-2.32), respectively. We validated performance of this optimal cutpoint by use of 10-fold cross-validation and bootstrapping of multivariable models that included standard risk factors plus total and HDL cholesterol, diabetes, body mass index, and C-reactive protein. CONCLUSIONS: In this study of middle-aged and older apparently healthy women, we identified a diagnostic threshold for nonfasting hypertriglyceridemia of 175 mg/dL (1.98 mmol/L), with the potential to more accurately identify cases than the currently recommended AHA cutpoint.

Diabetes and Risk of Sudden Death in Coronary Artery Disease Patients Without Severe Systolic Dysfunction.

OBJECTIVES: This study sought to determine the absolute and relative associations of diabetes mellitus (DM) and hemoglobin A1c (HbA1c) with sudden and/or arrhythmic death (SAD) versus other modes of death in patients with coronary artery disease (CAD) who do not qualify for implantable cardioverter-defibrillators. BACKGROUND: Patients with CAD and DM are at elevated risk for SAD; however, it is unclear whether these patients would benefit from implantable cardioverter-defibrillators given competing causes of death and/or whether HbA1c might augment SAD risk stratification. METHODS: In the PRE-DETERMINE study of 5,764 patients with CAD with left ventricular ejection fraction (LVEF) of >30% to 35%, competing risk analyses were used to compare the absolute and relative risks of SAD versus non-SAD by DM status and HbA1c level and to identify risk factors for SAD among 1,782 patients with DM. RESULTS: Over a median follow-up of 6.8 years, DM and HbA1c were significantly associated with SAD and non-SAD (P < 0.05 for all comparisons); however, the cumulative incidence of non-SAD (19.2%; 95% CI: 17.3%-21.2%) was almost 4 times higher than SAD (4.8%; 95% CI: 3.8%-5.9%) in DM patients. A similar pattern of absolute risk was observed across categories of HbA1c. In analyses limited to patients with DM, HbA1c was not associated with SAD, whereas low LVEF, atrial fibrillation, and electrocardiogram measurements were associated with higher SAD risk. CONCLUSIONS: In patients with CAD and LVEF of >30% to 35%, patients with DM and/or elevated HbA1c are at much higher absolute risk of dying from non-SAD than SAD. Clinical risk markers, and not HbA1c, were associated with SAD risk in patients with DM. (PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study; NCT01114269).

Amino-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein as predictors of sudden cardiac death among women.

BACKGROUND: Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been found to predict risk of sudden cardiac death (SCD) in patients with known cardiac disease, and C-reactive protein levels have been found to predict risk among apparently healthy men. However, there are no data on SCD risk prediction for either of these markers in a population of women unselected on the basis of cardiovascular disease. METHODS AND RESULTS: In a prospective, nested, case-control analysis within the 121,700-participant Nurses' Health Study, 99 cases of definite or probable SCD were identified and matched to 294 controls. In multivariable models that adjusted for coronary heart disease risk factors, glomerular filtration rate, and other biomarkers, the trend across quartiles approached significance for NT-proBNP (rate ratio=2.37 for comparison of the highest and lowest quartile; P for trend=0.05) but not for high-sensitivity C-reactive protein (P for trend=0.60). When examined continuously, both NT-proBNP and high-sensitivity C-reactive protein were significantly associated with SCD risk in age- and fasting-adjusted models (P for linear trend=0.04 and 0.03). Adjustment for coronary heart disease risk factors and other biomarkers strengthened the relationship with NT-proBNP and SCD (relative risk for 1-SD increment=1.49; 95% confidence interval, 1.09 to 2.05; P=0.01) but eliminated the relationship with high-sensitivity C-reactive protein (P=0.34). Women with NT-proBNP levels above the prespecified cut point of 389 pg/mL were at a markedly increased risk of SCD in both models (rate ratio=5.68; 95% confidence interval, 1.78 to 18.2; P=0.003). CONCLUSIONS: In this population of women, baseline levels of NT-proBNP were associated with subsequent risk of SCD. If this association is confirmed in larger prospectively studied populations, these findings might provide another useful marker contributing to efforts to screen and prevent SCD among women.

Alcohol consumption and risk of incident atrial fibrillation in women.

CONTEXT: Previous studies suggest that consuming moderate to high amounts of alcohol on a regular basis might increase the risk of developing atrial fibrillation in men but not in women. However, these studies were not powered to investigate the association of alcohol consumption and atrial fibrillation among women. OBJECTIVE: To prospectively assess the association between regular alcohol consumption and incident atrial fibrillation among women. DESIGN, SETTING, AND PARTICIPANTS: Participants were 34 715 initially healthy women participating in the Women's Health Study, a completed randomized controlled trial conducted in the United States. Participants were older than 45 years and free of atrial fibrillation at baseline and underwent prospective follow-up from 1993 to October 31, 2006. Alcohol consumption was assessed via questionnaires at baseline and at 48 months of follow-up and was grouped into 4 categories (0, > 0 and < 1, > or = 1 and < 2, and > or = 2 drinks per day). Atrial fibrillation was self-reported on the yearly questionnaires and subsequently confirmed by electrocardiogram and medical record review. MAIN OUTCOME MEASURE: Time to first episode of atrial fibrillation. RESULTS: Over a median follow-up of 12.4 years, 653 cases of incident atrial fibrillation were confirmed. Age-adjusted incidences among women consuming 0 (n = 15,370), more than 0 and less than 1 (n = 15,758), 1 or more and less than 2 (n = 2228), and 2 or more (n = 1359) drinks per day were 1.59, 1.55, 1.27, and 2.25 events/1000 person-years of follow-up. Thus, compared with nondrinking women, women consuming 2 or more drinks per day had an absolute risk increase of 0.66 events/1000 person-years. The corresponding multivariate-adjusted hazard ratios (HRs) for incident atrial fibrillation were 1, 1.05 (95% CI, 0.88-1.25), 0.84 (95% CI, 0.58-1.22), and 1.60 (95% CI, 1.13-2.25), respectively. The increased hazard in the small group of women consuming 2 or more drinks per day persisted when alcohol intake was updated at 48 months (HR, 1.49; 95% CI, 1.05-2.11) or when women were censored at their first cardiovascular event (HR, 1.68; 95% CI, 1.18-2.39). CONCLUSIONS: Among healthy middle-aged women, consumption of up to 2 alcoholic beverages per day was not associated with an increased risk of incident atrial fibrillation. Heavier consumption of 2 or more drinks per day, however, was associated with a small but statistically significant increased risk of atrial fibrillation.

Hemoglobin A1c levels and risk of sudden cardiac death: A nested case-control study.

BACKGROUND: Sudden cardiac death (SCD) is often the first manifestation of cardiovascular disease (CVD), and preventive strategies within this broad population are lacking. Patients with diabetes represent a high-risk subgroup, but few data exist regarding whether measures of glycemia mediate risk and/or add to SCD risk stratification. OBJECTIVE: The purpose of this study was to examine the association between hemoglobin A1c (HbA1c) and SCD. METHODS: We performed a case-control analysis among individuals enrolled in 6 prospective cohort studies. HbA1c levels were determined for 482 cases of SCD and 914 matched controls. Conditional logistic regression with fixed effects meta-analysis was used for analysis. RESULTS: In multivariable models, HbA1c levels were linearly associated with SCD risk over follow-up of 11.3 years (P <.001). Each 1% increment in HbA1c was associated with a hazard ratio (HR) of 1.32 (95% confidence interval [CI] 1.16-1.50). The magnitude of the association was greater in subjects without vs those with known CVD [HR per 1% increment 1.64 (95% CI 1.31-2.06) vs 1.15 (95% CI 0.99-1.33), P interaction = .009]. In models simultaneously controlling for diabetes status and HbA1c, the association between HbA1c and SCD remained significant (HR 1.29, 95% CI 1.07-1.55, P = .01), whereas the association between diabetes and SCD was attenuated (relative risk 1.21, 95% CI 0.64-2.27, P = .56). CONCLUSION: In these prospective cohorts, HbA1c levels associated with SCD risk, particularly among those without known CVD, even after controlling for diabetes status. These data support the hypothesis that hyperglycemia mediates SCD risk among patients with diabetes.

Strength Training and the Risk of Type 2 Diabetes and Cardiovascular Disease.

PURPOSE: This study aimed to examine the association of strength training with incident type 2 diabetes and cardiovascular disease risk. METHODS: We followed 35,754 healthy women (mean age = 62.6 yr, range = 47.0-97.8) from the Women's Health Study, who responded to a health questionnaire that included physical activity questions in 2000, assessing health outcomes through annual health questionnaire through 2014 (mean ± SD follow-up = 10.7 ± 3.7 yr). Incident type 2 diabetes (N cases = 2120) and cardiovascular disease (N cases = 1742) were confirmed on medical record review. Cases of cardiovascular disease were defined as confirmed cases of myocardial infarction, stroke, coronary artery bypass graft, angioplasty, or cardiovascular disease death. RESULTS: Compared with women who reported no strength training, women engaging in any strength training experienced a reduced rate of type 2 diabetes of 30% (hazard ratio = 0.70, 95% confidence interval = 0.61-0.80) when controlling for time spent in other activities and other confounders. A risk reduction of 17% was observed for cardiovascular disease among women engaging in strength training (hazard ratio = 0.83, 95% confidence interval = 0.72, 0.96). Participation in both strength training and aerobic activity was associated with additional risk reductions for both type 2 diabetes and cardiovascular disease compared with participation in aerobic activity only. CONCLUSIONS: These data support the inclusion of muscle-strengthening exercises in physical activity regimens for reduced risk of type 2 diabetes and cardiovascular disease, independent of aerobic exercise. Further research is needed to determine the optimum dose and intensity of muscle-strengthening exercises.

Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women.

Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case-control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25-0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17-0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women.

Analysis of sister chromatid exchange, micronucleus and chromosomal aberration frequencies in rodents exposed to mosquito coil smoke by inhalation route.

Mosquito coil smoke emitting from a mosquito repellent, was tested for its mutagenic effect in bone marrow cells from mouse and rat after 4 h acute inhalation exposure. Coil smoke with suspended particulate concentrations of 99-129 mg/m3, significantly elevated the frequencies of sister chromatid exchanges in bone marrow cells and micronuclei in polychromatic erythrocytes. Analysis of chromosomal aberrations in metaphases also revealed a significantly higher incidence of chromosomal aberration frequency in exposed rats and mice.

Do moderate-intensity and vigorous-intensity physical activities reduce mortality rates to the same extent?

BACKGROUND: Limited data exist directly comparing the relative benefits of moderate- and vigorous-intensity activities with all-cause and cardiovascular (CV) disease mortality rates when controlling for physical activity volume. METHODS AND RESULTS: We followed 7979 men (Harvard Alumni Health Study, 1988-2008) and 38 671 women (Women's Health Study, 1992-2012), assessing their physical activity and health habits through repeated questionnaires. Over a mean follow-up of 17.3 years in men and 16.4 years in women, there were 3551 deaths (1077 from CV disease) among men and 3170 deaths (620 from CV disease) among women. Those who met or exceeded an equivalent of the federal guidelines recommendation of at least 150 minutes of moderate-intensity activity, 75 minutes of vigorous-intensity activity, or a combination of the 2 that expended similar energy experienced significantly lower all-cause and CV disease-related mortality rates (men, 28% to 36% and 31% to 34%, respectively; women: 38% to 55% and 22% to 44%, respectively). When comparing different combinations of moderate- and vigorous-intensity activity and all-cause mortality rates, we observed sex-related differences. Holding constant the volume of moderate- to vigorous-intensity physical activity, men experienced a modest additional benefit when expending a greater proportion of moderate- to vigorous-intensity physical activity in vigorous-intensity activities (Ptrend=0.04), but women did not (Ptrend<0.001). Moderate- to vigorous-intensity physical activity composition was not associated with further cardiovascular mortality rate reductions in either men or women. CONCLUSIONS: The present data support guidelines recommending 150 minutes of moderate-intensity activity per week, 75 minutes of vigorous-intensity activity per week, or an equivalent combination for mortality benefits. Among men, but not women, additional modest reductions in all-cause mortality rates are associated with a greater proportion of moderate- to vigorous-intensity physical activity performed at a vigorous intensity.

Posttraumatic growth among men with histories of child sexual abuse.

Despite an increased risk of long-term mental health problems, many survivors of child sexual abuse (CSA) experience positive changes in areas such as appreciation for life, personal strength, and interpersonal relationships. Drawing on life course theory, this study examined factors related to posttraumatic growth among a sample of men with CSA histories (N = 487). Using multiple linear regression (i.e., ordinary least squares), we found that men who had a better understanding of the sexual abuse experience, who ascribed to less traditional masculine norms, and who experienced a turning point reported greater growth. To promote growth, practitioners can help survivors understand the meaning and impact of the abuse on their lives and deconstruct rigid gender norms. More research on growth is needed with male survivors, especially on the nature of turning points in the recovery process.

Vitamin E supplementation and the risk of heart failure in women.

BACKGROUND: Oxidative stress may contribute to the development of heart failure (HF); however, an increased risk of HF has been observed with antioxidant therapy in secondary prevention trials. No large clinical trials have addressed the role of antioxidant therapy in the primary prevention of HF. METHODS AND RESULTS: We examined the effect of vitamin E and HF risk in 39 815 initially healthy women, aged at least 45 years at baseline, who were enrolled in the Women's Health Study, a randomized, double-blind, placebo-controlled trial of vitamin E (600 IU every other day). Over a median follow-up of 10.2 years, there were 220 incident HF events. In proportional hazards models, adjusting for age and randomized aspirin and beta carotene treatment, vitamin E assignment did not significantly affect HF risk (hazards ratio [HR], 0.93; 95% CI, 0.71-1.21; P=0.59). These results did not change with multivariate adjustment for other risk factors, including interim myocardial infarction. In a prespecified subgroup analysis, vitamin E was inversely related to developing HF with normal ejection fraction (≥50%) with HR 0.59 (95% CI, 0.38-0.92; P=0.02), but there was no statistically significant effect on the risk of developing systolic HF (HR, 1.26; 95% CI, 0.84-1.89; P=0.26). CONCLUSIONS: In this population of apparently healthy women, vitamin E did not affect the overall risk of HF. The possible benefit on diastolic HF requires confirmation in larger populations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

Physical activity and the risk of incident atrial fibrillation in women.

BACKGROUND: Physical activity (PA) is well known to reduce the risk of cardiovascular disease. We hypothesized that regular PA, possibly acting through reductions in blood pressure and body mass index (BMI), would reduce the risk of incident atrial fibrillation (AF) in women. METHODS AND RESULTS: We prospectively followed 34 759 women who reported their leisure-time PA levels for the occurrence of AF. We estimated energy expenditure in metabolic equivalent (MET)-h/wk and validated self-reported AF with medical records. The mean (SD) age of the 34 759 participants was 54.6 (7.0) years, the mean BMI was 26.0 (5.0) kg/m(2), 26.5% had hypertension, and the median (IQR) PA was 8.4 (2.8, 20.4) MET-h/wk. After a median of 14.4 years of observation, 968 women had development of AF. In age-, cholesterol-, smoking-, alcohol-, diabetes-, and race-adjusted models, increasing quintiles of PA were associated with reduced risks of AF (hazard ratio for extreme quintiles, 0.82; 0.66 to 1.01; P trend=0.007 over quintiles). Although this association was not substantially different after adjusting for hypertension (0.87; 0.70 to 1.07; P trend 0.02), it was attenuated after adjustment for BMI (0.99; 0.80 to 1.23; P trend=0.22). Women who achieved the federal government's recommendation of 7.5 MET-h/wk of PA were at reduced risk of AF compared with those who did not (0.86; 0.75 to 0.98; P=0.03). This association was also attenuated by BMI (0.96; 0.84 to 1.10; P=0.57). CONCLUSIONS: In middle-aged women, physical activity was associated with a modestly reduced risk of AF. However, this relationship was no longer significant after controlling for body mass index.

Effect of thiamine hydrochloride on the blood level of 2-formyl 1-methyl pyridinium oxime chloride (2-PAM.C1) in rats.

The biological half-life of 2-PAM.C1 was found to increase in female rats pretreated with thiamine hydrochloride (10 mg/kg i.m.). No such effect was observed in the male rats.