David Conen

Meta-analysis identifies six new susceptibility loci for atrial fibrillation

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the WHS (women's health study).

OBJECTIVES The purpose of this study was to characterize the relationship between changes in body mass index (BMI) and incident atrial fibrillation (AF) in a large cohort of women. BACKGROUND Obesity and AF are increasing public health problems. The importance of dynamic obesity-associated AF risk is uncertain, and mediators are not well characterized. METHODS Cases of AF were confirmed by medical record review in 34,309 participants in the Womens Health Study. Baseline and updated measures of BMI were obtained from periodic questionnaires. RESULTS During 12.9 +/- 1.9 years of follow-up, 834 AF events were confirmed. BMI was linearly associated with AF risk, with a 4.7% (95% confidence interval [CI]: 3.4 to 6.1, p < 0.0001) increase in risk with each kilogram per square meter. Adjustment for inflammatory markers minimally attenuated this risk. When updated measures of BMI were used to estimate dynamic risk, overweight (hazard ratio [HR]: 1.22; 95% CI: 1.02 to 1.45, p = 0.03), and obesity (HR: 1.65; 95% CI: 1.36 to 2.00; p < 0.0001) were associated with adjusted short-term increases in AF risk. Participants becoming obese during the first 60 months had a 41% adjusted increase in risk of the development of AF (p = 0.02) compared with those maintaining BMI <30 kg/m(2). The prevalence of overweight and obesity increased over time. The adjusted proportion of incident AF attributable to short-term elevations in BMI was substantial (18.3%). CONCLUSIONS In this population of apparently healthy women, BMI was associated with short- and long-term increases in AF risk, accounting for a large proportion of incident AF independent of traditional risk factors. A strategy of weight control may reduce the increasing incidence of AF. (Womens Health Study [WHS]: A Randomized Trial of Low-Dose Aspirin and Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer; NCT00000479).

Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation

CONTEXT The risks associated with new-onset atrial fibrillation (AF) among middle-aged women and populations with a low comorbidity burden are poorly defined. OBJECTIVES To examine the association between incident AF and mortality in initially healthy women and to evaluate the influence of associated cardiovascular comorbidities on risk. DESIGN, SETTING, AND PARTICIPANTS Between 1993 and March 16, 2010, 34,722 women participating in the Womens Health Study underwent prospective follow-up. Participants were 95% white, older than 45 years (median, 53 [interquartile range {IQR}, 49-59] years), and free of AF and cardiovascular disease at baseline. Cox proportional hazards models with time-varying covariates were used to determine the risk of events among women with incident AF. Secondary analyses were performed among women with paroxysmal AF. MAIN OUTCOME MEASURES Primary outcomes included all-cause, cardiovascular, and noncardiovascular mortality. Secondary outcomes included stroke, congestive heart failure, and myocardial infarction. RESULTS During a median follow-up of 15.4 (IQR, 14.7-15.8) years, 1011 women developed AF. Incidence rates per 1000 person-years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1-13.5) and 3.1 (95% CI, 2.9-3.2) for all-cause mortality, 4.3 (95% CI, 2.6-6.0) and 0.57 (95% CI, 0.5-0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4-8.6) and 2.5 (95% CI, 2.4-2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all-cause: HR, 1.70 [95% CI, 1.30-2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63-4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02-1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55-5.59). CONCLUSION Among a group of healthy women, new-onset AF was independently associated with all-cause, cardiovascular, and noncardiovascular mortality, with some of the risk potentially explained by nonfatal cardiovascular events.

Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country

BackgroundThe prevalence of hyperuricemia has rarely been investigated in developing countries. The purpose of the present study was to investigate the prevalence of hyperuricemia and the association between uric acid levels and the various cardiovascular risk factors in a developing country with high average blood pressures (the Seychelles, Indian Ocean, population mainly of African origin).MethodsThis cross-sectional health examination survey was based on a population random sample from the Seychelles. It included 1011 subjects aged 25 to 64 years. Blood pressure (BP), body mass index (BMI), waist circumference, waist-to-hip ratio, total and HDL cholesterol, serum triglycerides and serum uric acid were measured. Data were analyzed using scatterplot smoothing techniques and gender-specific linear regression models.ResultsThe prevalence of a serum uric acid level >420 μmol/L in men was 35.2% and the prevalence of a serum uric acid level >360 μmol/L was 8.7% in women. Serum uric acid was strongly related to serum triglycerides in men as well as in women (r = 0.73 in men and r = 0.59 in women, p < 0.001). Uric acid levels were also significantly associated but to a lesser degree with age, BMI, blood pressure, alcohol and the use of antihypertensive therapy. In a regression model, triglycerides, age, BMI, antihypertensive therapy and alcohol consumption accounted for about 50% (R2) of the serum uric acid variations in men as well as in women.ConclusionsThis study shows that the prevalence of hyperuricemia can be high in a developing country such as the Seychelles. Besides alcohol consumption and the use of antihypertensive therapy, mainly diuretics, serum uric acid is markedly associated with parameters of the metabolic syndrome, in particular serum triglycerides. Considering the growing incidence of obesity and metabolic syndrome worldwide and the potential link between hyperuricemia and cardiovascular complications, more emphasis should be put on the evolving prevalence of hyperuricemia in developing countries.

Influence of Systolic and Diastolic Blood Pressure on the Risk of Incident Atrial Fibrillation in Women

Background— The influence of systolic and diastolic blood pressure (BP) on incident atrial fibrillation (AF) is not well studied among initially healthy, middle-aged women. Methods and Results— A total of 34 221 women participating in the Womens Health Study were prospectively followed up for incident AF. The risk of AF across categories of systolic and diastolic BP was compared by use of Cox proportional-hazards models. During 12.4 years of follow-up, 644 incident AF events occurred. Using BP measurements at baseline, we discovered that the long-term risk of AF was significantly increased across categories of systolic and diastolic BP. Multivariable-adjusted hazard ratios for systolic BP categories (<120, 120 to 129, 130 to 139, 140 to 159, and ≥160 mm Hg) were 1.0, 1.00 (95% CI, 0.78 to 1.28), 1.28 (95% CI, 1.00 to 1.63), 1.56 (95% CI, 1.22 to 2.01), and 2.74 (95% CI, 1.77 to 4.22) (P for trend <0.0001). Adjusted hazard ratios across baseline diastolic BP categories (<65, 65 to 74, 75 to 84, 85 to 89, 90 to 94, and ≥95 mm Hg) were 1.0, 1.17 (95% CI, 0.81 to 1.69), 1.18 (95% CI, 0.84 to 1.65), 1.53 (95% CI, 1.05 to 2.23), 1.35 (95% CI, 0.82 to 2.22), and 2.15 (95% CI, 1.21 to 3.84) (P for trend=0.004). When BP changes over time were accounted for in updated models, multivariable-adjusted hazard ratios were 1.0, 1.14 (95% CI, 0.89 to 1.46), 1.37 (95% CI, 1.07 to 1.76), 1.71 (95% CI, 1.33 to 2.21), and 2.21 (95% CI, 1.45 to 3.36) (P for trend <0.0001) for systolic BP categories and 1.0, 1.12 (95% CI, 0.82 to 1.52), 1.13 (95% CI, 0.83 to 1.52), 1.30 (95% CI, 0.89 to 1.88), 1.50 (95% CI, 1.01 to 1.88), and 1.54 (95% CI, 0.75 to 3.14) (P for trend=0.026) for diastolic BP categories. Conclusions— In this large cohort of initially healthy women, BP was strongly associated with incident AF, and systolic BP was a better predictor than diastolic BP. Systolic BP levels within the nonhypertensive range were independently associated with incident AF even after BP changes over time were taken into account.

Meta-Analysis and Systematic Review of the Long-Term Predictive Value of Assessment of Coronary Atherosclerosis by Contrast-Enhanced Coronary Computed Tomography Angiography

OBJECTIVES We conducted a systematic review and meta-analysis to determine the predictive value of findings of coronary computed tomography angiography for incident cardiovascular events. BACKGROUND Initial studies indicate a prognostic value of the technique; however, the level of evidence as well as exact independent risk estimates remain unclear. METHODS We searched PubMed, EMBASE, and the Cochrane Library through January 2010 for studies that followed up ≥ 100 subjects for ≥ 1 year and reported at ≥ 1 hazard ratio (HR) of interest. Risk estimates for the presence of significant coronary stenosis (primary endpoint; ≥ 50% diameter stenosis), left main coronary artery stenosis, each coronary stenosis, 3-vessel disease, any plaque, per coronary segment containing plaque, and noncalcified plaque were derived in random effect regression analysis, and causes of heterogeneity were determined in meta-regression analysis. RESULTS We identified 11 eligible articles including 7,335 participants (age 59.1 ± 2.6 years, 62.8% male) with suspected coronary artery disease. The presence of ≥ 1 significant coronary stenosis (9 studies, 3,670 participants, and 252 outcome events [6.8%] with 62% revascularizations) was associated with an annualized event rate of 11.9% (6.4% in studies excluding revascularization). The corresponding HR was 10.74 (98% confidence interval [CI]: 6.37 to 18.11) and 6.15 (95% CI: 3.22 to 11.74) in studies excluding revascularization. Adjustment for coronary calcification did not attenuate the prognostic significance (p = 0.79). The estimated HRs for left main stenosis, presence of plaque, and each coronary segment containing plaque were 6.64 (95% CI: 2.6 to 17.3), 4.51 (95% CI: 2.2 to 9.3), and 1.23 (95% CI: 1.17 to 1.29), respectively. CONCLUSIONS Presence and extent of coronary artery disease on coronary computed tomography angiography are strong, independent predictors of cardiovascular events despite heterogeneity in endpoints, categorization of computed tomography findings, and study population.

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 Womens 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.

Noninvasive 24-h ambulatory blood pressure and cardiovascular disease: a systematic review and meta-analysis

Objective We systematically assessed the evidence regarding the association between noninvasive 24-h systolic blood pressure and incident cardiovascular events. Methods We searched PubMed, EMBASE, and the Cochrane Library through April 2007. Studies that prospectively followed at least 100 individuals for at least 1 year, and that reported at least one effect estimate of interest were included. Two independent investigators abstracted information on study design, subject characteristics, blood pressure measurements, outcome assessment, effect estimates, and adjustment for potential confounders. Results We identified 20 eligible articles based on 15 independent cohort studies. The association between 24-h systolic blood pressure and a combined cardiovascular endpoint was assessed in nine cohort studies, including 9299 participants who were followed up to 11.1 years and had 881 outcome events. The summary hazard ratio (95% confidence interval) per 10-mmHg increase of 24-h systolic blood pressure was 1.27 (1.18–1.38) (P < 0.001). Further adjustment for office blood pressure in four studies with 4975 participants and 499 outcome events provided a similar summary estimate [hazard ratio (95% confidence interval) per 10-mmHg increase of 24-systolic blood pressure 1.21 (1.10–1.33) (P < 0.001)]. Office blood pressure was usually assessed on a single occasion. We found no significant variability according to age, sex, population origin, baseline office blood pressure, follow-up time, diabetes, or study quality. There was a consistent association between 24-h systolic blood pressure and stroke, cardiovascular mortality, total mortality, and cardiac events with hazard ratio (95% confidence interval) per 10 mmHg increase of 24-h systolic blood pressure of 1.33 (1.22–1.44), 1.19 (1.13–1.26), 1.12 (1.07–1.17), and 1.17 (1.09–1.25), respectively. Conclusion 24-h systolic blood pressure is a strong predictor of cardiovascular events, providing prognostic information independent of conventional office blood pressure.

Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study

Objective To compare cardiovascular risk among women with high normal blood pressure (130-9/85-9 mm Hg) against those with normal blood pressure (120-9/75-84 mm Hg) and those with baseline hypertension. Design Prospective cohort study. Setting Womens health study, United States. Participants 39 322 initially healthy women classified into four categories according to self reported baseline blood pressure and followed for a median of 10.2 years. Main outcome measures Time to cardiovascular death, myocardial infarction, or stroke (major cardiovascular event—primary end point); progression to hypertension. Results 982 (2.5%) women developed a major cardiovascular event, and 8686 (30.1%) women without baseline hypertension progressed to hypertension. The age adjusted event rate for the primary end point was 1.6/1000 person years among women with normal blood pressure, 2.9/1000 person years among those with high normal blood pressure, and 4.3/1000 person years among those with baseline hypertension. Compared with women with high normal blood pressure (reference group), those with normal blood pressure had a lower risk of a major cardiovascular event (adjusted hazard ratio 0.61, 95% confidence interval 0.48 to 0.76) and of incident hypertension (0.42, 0.40 to 0.44). The hazard ratio for a major cardiovascular event in women with baseline hypertension was 1.30 (1.08 to 1.57). Women who progressed to hypertension (reference group) during the first 48 months of the study had a higher cardiovascular risk than those who remained normotensive (adjusted hazard ratio 0.64, 0.50 to 0.81). Women with high normal blood pressure at baseline who progressed to hypertension (reference group) had similar outcome rates to women with baseline hypertension (adjusted hazard ratio 1.17, 0.88 to 1.55). Conclusion The cardiovascular risk of women with high normal blood pressure is higher than that of women with normal blood pressure. The cardiovascular risk of women who progress to hypertension is increased shortly after a diagnosis of hypertension has been made. Trial registration Clinical trials NCT00000479.

A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women

AIMS To assess the joint influence of inflammatory biomarkers on the risk of incident atrial fibrillation (AF) in women. METHODS AND RESULTS We performed a prospective cohort study among women participating in the Womens Health Study. All women were free of AF at study entry and provided a baseline blood sample assayed for high-sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen. To evaluate the joint effect of these three biomarkers, an inflammation score was created that ranged from 0 to 3 and reflected the number of biomarkers in the highest tertile per individual. During a median follow-up of 14.4 years, 747 of 24,734 women (3.0%) experienced a first AF event. Assessed individually, all three biomarkers were associated with incident AF, even after adjustment for traditional risk factors. When combined into an inflammation score, a strong and independent relationship between inflammation and incident AF emerged. Across increasing inflammation score categories, there were 1.66, 2.22, 2.73, and 3.25 AF events per 1000 person-years of follow-up. The corresponding hazard ratios (95% confidence intervals) across inflammation score categories were 1.0, 1.22 (1.00-1.49), 1.32 (1.06-1.65), and 1.59 (1.22-2.06) (P for linear trend 0.0006) after multivariable adjustment. CONCLUSION In this large-scale prospective study among women without a history of cardiovascular disease, markers of systemic inflammation were significantly related to AF even after controlling for traditional risk factors.