At baseline, the mean (±SD) age was 74.1 (±5.2) years, and 60% of participants were women. The mean total n-3 PUFA concentration was 4.5 (±1.3) percent of plasma phospholipid fatty acids, including DHA (3.0±1.0%), DPA (0.83±0.17%), and EPA (0.58±0.36%). Characteristics at baseline according to quartiles of n-3 PUFA are shown in . Consumption of tuna or other broiled or baked fish was positively associated with EPA and DHA, but not DPA levels. Each individual n-3 PUFA was inversely associated with smoking and total fat consumption. Interestingly, the individual n-3 PUFA had varying patterns of associations with most other demographic, medical, and dietary variables, suggesting that there may not be one single or set of major confounders of their associations with incident AF.
Baseline Characteristics According to Plasma Phospholipid EPA, DPA, and DHA Among 3326 US Adults.
During 31,169 person-years of follow up, 789 incident cases of AF occurred, an incidence rate of 25.3 per 1000 person-years. After adjusting for age and sex, total n-3 PUFA levels were inversely associated with incident AF, with 36% lower risk (RR=0.64, 95% CI=0.52-0.79, P-trend<0.001) among participants in the highest compared with the lowest quartile (
). After further multivariate adjustment for demographic, cardiovascular, and lifestyle risk factors, total n-3 PUFA levels remained inversely associated with incident AF, with 29% lower risk (RR=0.71, 95% CI=0.57-0.89, P-trend=0.004) in the highest quartile. When evaluated continuously as percent of total fatty acids, each 1 percent higher total n-3 PUFA was associated with 9% (RR=0.91, 95% CI=0.85-0.97) lower risk of AF. Further adjustment for potential intermediate risk factors including systolic and diastolic blood pressure, left ventricular systolic function, plasma C-reactive protein and fibrinogen did not greatly alter the observed associations (not shown). As the risk estimates were based on a single baseline fatty acid measurement and therefore subject to regression dilution,35, 36
we carried out sensitivity analysis to correct for this potential bias. After correction for regression dilution bias, the RR associated with the highest quartile of total n-3 PUFA was 0.57 (95% CI=0.39-0.82), compared to the lowest quartile.
Relative Risk of Incident Atrial Fibrillation According to Plasma Phospholipid Long-Chain n-3 Polyunsaturated Fatty Acids in 3,326 US Adults
When each individual n-3 PUFA was examined separately, DHA was associated with lower risk of AF, with 23% lower risk associated with the highest quartile compared to the lowest (RR=0.77, 95% CI=0.62-0.96, P-trend=0.01) (). When evaluated continuously as percent of total fatty acids, each 0.5 percent higher DHA was associated with 6% (RR=0.94, 95% CI=0.90-0.98) lower risk of AF. In sensitivity analysis adjusting for regression dilution, higher DHA levels were associated with 35% lower risk (RR=0.65, 95% CI=0.45-0.93) among participants in the highest versus lowest quartile. EPA and DPA were not significantly associated with AF risk in multivariate-adjusted analyses. Results were not appreciably altered following adjustment for potential intermediate risk factors (not shown).
Semi-parametric analyses using restricted cubic splines suggested relatively linear inverse associations of both total n-3 PUFA and DHA with incidence of AF (). EPA and DPA were not associated with risk of incident AF across the range of their plasma phospholipid levels in this study (). Visual inspection of the splines also suggested a trend towards lower RR in participants with higher EPA or DPA, but these findings were not statistically significant.
Figure 1 Semi-parametric multivariable-adjusted relationship of plasma phospholipid EPA, DPA, DHA, and total long-chain n-3 PUFA with incident AF, evaluated using restricted cubic splines after excluding participants with values below the 1st or above the 99th (more ...)
Results were not appreciably altered in several sensitivity analyses, including analyses with additional adjustment for other covariates including income; consumption of processed meat or dietary fiber; presence of asthma or emphysema; use of aspirin, estrogen, non-steroidal anti-inflammatory agents, antihypertensive medications, or lipid-lowering medications; fasting plasma LDL, HDL, triglycerides, glucose, insulin, or resting heart rate; or timing of fatty acid measurements (recent measures vs. prior measures from the nested study of myocardial infarction) (data not shown). Results were also similar after exclusion of current smokers (n=317) (data not shown). We did not find evidence that the observed inverse associations of total n-3 PUFA and DHA with incident AF were mediated by effects on MI or CHF. After additional adjustment for MI or CHF as time-varying covariates, those in the highest vs. lowest quartile of total n-3 PUFA and DHA had 27% (RR=0.73, 95% CI=0.59-0.91) and 23% (RR=0.77, 95% CI=0.62-0.96) lower risk of AF, respectively.
There was also little evidence that age, gender or ethnicity modified the associations between n-3 PUFA levels and incident AF (8 comparisons; P for interaction>0.15 for each). For example, total n-3 PUFA was significantly associated with lower AF risk in both whites (n=2,897, extreme quartile RR=0.72, 95% CI=0.57-0.91), and African-Americans (n=429, extreme quartile RR=0.41, 95% CI=0.17-0.98).
In secondary analysis, we assessed the extent to which phospholipid n-3 PUFA levels might explain the previously observed lower risk of AF seen with higher consumption of tuna/other broiled or baked fish (Supplemental Table 1
In a multivariable model, additional adjustment for plasma phospholipid total n-3 PUFA led to appreciable attenuation of the relationship between fish consumption and incident AF, including 82% attenuation among those consuming 1-4 fish servings/week and 43% attenuation among those consuming 5+ fish servings/week (Supplemental Table 1
). When n-3 PUFA were examined individually, attenuation of the association between fish consumption and incident AF was observed after adjustment for EPA and especially DHA. In contrast, the inverse association between higher plasma phospholipid n-3 PUFA and incident AF was minimally affected by additional adjustment for fish consumption, with extreme-quartile multivariable-adjusted RRs of 0.71 (95% CI=0.56-0.89) and 0.77 (95% CI=0.61-0.97) for total n-3 PUFA and DHA, respectively.