This is an important study evaluating the associative factors and natural history of atrial fibrillation. Until age 90, men are at higher risk of developing A.Fib compared to women. Tall women, and overweight and dyslipidemic men are more likely to experience it than their counterparts. Lifetime risk for Atrial fibrillation high, more than 30%. It increases the mortality rate by 3.5 fold in both genders. Subjects were followed for about 13 years.
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Circulation
Observational
October 2017
Background
Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood.
Methods
In N=79,793 individuals without AF diagnosis at baseline (median age, 49.6 years; 51.7% women) from 4 community-based European studies of the BiomarCaRE consortium, we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years.
Results
Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men.
Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18 in women versus 1.31in men; interaction P value of 0.001).
Total cholesterol was inversely associated with incident AF with a greater risk reduction in women. No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index.
Conclusions
Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.
More from the publication:
Atrial fibrillation (AF) is a common cardiac disease that increases the risk of morbidity and mortality in aging women and men. Considerable sex differences in prevalence, incidence, and mortality have been reported. AF prevalence in middle-aged and older community cohorts is almost twice as high in men as in women. The increasing prevalence of AF and subsequent public health and economic burden require research efforts to understand sex differences in disease distribution and risk factor associations. The onset of AF diminishes the survival advantage in women. Risk of adverse outcomes in AF also appears to differ by sex, eg, stroke risk is higher in women with AF. Consistently reported risk factors for AF such as obesity, arterial hypertension, blood lipid profile, diabetes mellitus, smoking, alcohol consumption, and prevalent cardiovascular diseases show differential distributions by sex and thus need to be considered as possible explanations for observed differences in AF epidemiology. Furthermore, biomarkers related to the disease such as C-reactive protein (CRP) and B-type natriuretic peptide (Nt-proBNP) are known to differ by sex, and may be differentially associated with AF risk.
In a pooled analysis of community cohorts across Europe, the cumulative risk of developing AF was higher in men than in women over most of the lifespan but became similar at older age with a comparable lifetime risk. Incident AF was associated with >3.5-fold increased mortality risk with no significant sex difference. Among the classical risk factors, higher BMI and lower total cholesterol were associated with a higher risk of AF in men than in women. PAR resulting from classical risk factors were largely comparable.
The age dependency of AF is well known. We confirmed an increase in incidence of AF with age in women and men. Cumulative incidence was low in middle age. Women lagged about a decade behind men, but reached the cumulative incidence of men by the age of 90 years. Overall, one-third of women and men were estimated to develop AF during their lifetime. A considerable lifetime risk of AF between one-fifth and one-fourth has been reported in studies with usually comparatively small numbers in the older age groups.
BMI and obesity are established risk factors for AF. Prior studies have found sex differences in the association of obesity with long-term incidence of AF. Although no statistically significant interactions were reached in the Framingham Heart Study, the effect estimates showed a higher magnitude of association in men. In the Danish Diet, Cancer, and Health Study, obese women had a 2-fold higher risk of AF than men (HR of 2.35 in multivariable-adjusted analyses). An Australian study in >4000 individuals reported a possible sex interaction of BMI with incident AF. Body fat distribution differs by sex, and additional adiposity measures may need to be examined. For example, in a subsample of our cohorts, waist-to-hip ratio showed a stronger association with AF in men than in women, but the interaction did not reach statistical significance. However, BMI has remained the strongest validated predictor of incident AF.
Further secondary analyses in our sample revealed differential associations of height with AF in women and men. That, in part, may help to explain the observed sex differences for BMI. Increased height is related to higher risk of AF. This may be linked to a greater susceptibility to the arrhythmia through larger cardiac dimensions and higher excitability of the conduction system. In our data, the association appears to be stronger in women, which requires further examination to clarify possible mechanisms.
Despite the role of height in our findings, BMI remains a central risk factor. Elevated BMI may be a sign of insufficient risk factor control, but the proportionality of weight gain and increased AF risk within short periods of follow-up and the close correlation of weight and weight fluctuations with AF patterns suggest a possible direct relationship with AF. Evidence suggests that the effects of obesity on cardiac structural remodeling and function differ by sex, which increases the predisposition to AF.
Women and men show well-established differences in plasma lipid profiles. The counterintuitive inverse association of total cholesterol and other proatherogenic lipoproteins has been reported previously. This observation has been explained by the membrane-stabilizing characteristics of cholesterol, although the exact pathophysiology remains unclear. It is important to note that this inverse association was observed in both sexes in our study, with a borderline higher effect size in women.
The inflammatory biomarker CRP was associated with AF in men, but did not reach statistical significance in women. The HRs were relatively small, as described in prior investigations. For the cardiac biomarker Nt-proBNP, an interaction by sex in age-adjusted models with a higher relative risk in women became nonsignificant after adjustment for clinical covariates. Sex and BMI are among the strongest correlates of Nt-proBNP concentrations. Female sex and obesity are correlated with higher natriuretic peptides. Thus, confounding the small sample size with available information on Nt-proBNP or more complex interactions may explain the observations, which need to be elucidated in further studies.
Sex differences for risk factor associations have consistently been reported for diabetes mellitus and smoking in relation to coronary heart disease and stroke, with a higher relative risk of developing disease in women. In contrast to coronary heart disease and stroke, diabetes mellitus was not associated with incident AF in our cohorts, and no interaction by sex was observed. Smoking usually carries a higher risk for cardiovascular disease in women. We could not extend this knowledge towards AF, where the association appeared to be similar in both sexes. Differences in sex for prior cardiovascular disease prevalence are well-established major risk factors for incident AF. Our study indicates that previous myocardial infarction and stroke are associated with a similar risk of developing AF in women and men and are therefore comparable risk indicators in both sexes.
In conclusion, our data provide evidence that differences in AF incidence observed by sex may be explained by the sex-specific distribution of risk factors and by differential associations of classical risk factors. A substantial proportion of the AF burden can be explained by classical cardiovascular disease risk factors in both sexes.
Although blood pressure, smoking, alcohol consumption, Nt-proBNP, and prevalent cardiovascular disease are largely similar predictors of incident AF in both sexes, total cholesterol concentrations may show sex differences. A higher BMI and obesity are stronger risk factors for the development of AF in men and require better awareness and targeted intervention.
Understanding sex differences in AF risk and risk factors is essential for developing long-term preventive measures to reduce mortality, public health burden, and healthcare costs related to AF in both women and men.