Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million residents of the United States and 4.5 million residents of the European Union. It is unclear whether plasma free fatty acids (FFAs) influence the risk of AF in older adults. The aim of this study was to prospectively examine the association between plasma FFAs and incident AF in a prospective cohort of 4,175 men and women ≥65 years old from the Cardiovascular Health Study. Plasma concentrations of FFAs were measured 2 times during the 1992 to 1993 examination. Incident AF was ascertained based on study electrocardiographic and hospitalization records during follow-up. We used Cox regression to estimate relative risks of AF. Average age at baseline was 74.6 ± 5.1 years. During a mean follow-up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFAs. There was a positive association between plasma FFAs and risk of AF. Multivariable adjusted hazard ratios (95% confidence intervals) for incident AF were 1.00 (referent), 1.02 (0.85 to 1.21), 1.05 (0.88 to 1.26), and 1.29 (1.08 to 1.55) from the lowest to highest quartiles of FFAs, respectively. In a secondary analysis restricted to the first 5 years of follow-up, this association persisted. In conclusion, our data show an increased risk of AF with higher plasma FFAs in community-dwelling older adults.
Previous data from the Cardiovascular Health Study (CHS) have demonstrated beneficial effects of light to moderate physical activity on atrial fibrillation (AF) risk, no association between moderate alcohol consumption and AF risk, and a positive association between N-terminal pro–B-type natriuretic peptide (NT–pro-BNP) and AF. Other investigators have reported an increased risk of AF with type 2 diabetes (T2D), hypertension (HTN), obesity, and inflammation. However, the common link among adiposity, T2D, HTN, and sedentary lifestyle and a higher propensity for developing AF is unclear. Increased levels of plasma free fatty acids (FFAs) have been associated with increased insulin resistance and T2D, HTN, physical inactivity, and inflammation, suggesting that FFAs may play an important role in the development of AF. However, the association between plasma FFA and incident AF has not been investigated in the general population including older adults, a group extremely vulnerable to AF. Therefore, the present study sought to prospectively assess whether plasma FFA concentration measured late in life was associated with a higher risk of incident AF in community-living older adults.
Methods
Detailed descriptions of the CHS have been published elsewhere. Briefly, the CHS is a prospective population-based cohort study of cardiovascular disease in older adults. From 1989 through 1990, 5,201 ambulatory noninstitutionalized men and women ≥65 years of age were recruited from a random sample of Medicare-eligible residents from 4 United States communities (Forsyth County, North Carolina [Wake Forest University School of Medicine, Winston-Salem]; Sacramento County, California [University of California, Davis]; Washington County, Maryland [Johns Hopkins University, Hagerstown]; and Allegheny County, Pennsylvania [University of Pittsburgh, Pittsburgh]). From 1992 through 1993, a supplemental cohort of 687 predominantly African-American men and women was recruited using the same sampling and recruitment methods. The 1992 to 1993 visit was considered the baseline examination for the present study. Of the 5,265 participants who completed the baseline examination, we excluded subjects without data on FFAs (n = 550), prevalent AF during the 1992 to 1993 examination (n = 265), and missing data on covariates (n = 275). Thus, a final sample of 4,175 participants was used for the present analyses. Each participant gave written informed consent and the institutional review board at each participating institution approved the study protocol.
Comprehensive information on health-related variables was collected at baseline and annually thereafter from CHS participants. Clinic examinations including electrocardiography were performed annually from 1989/1990 and to 1998/1999 and clinical examination without electrocardiography was performed from 2005 to 2006. Standardized questionnaires were administered at a baseline home interview, at annual clinic visits, and during telephone contacts.
Plasma samples collected at the 1992 to 1993 examination were stored at −70°C until FFA measurements at the central laboratory at the University of Vermont. FFA concentrations in plasma were measured 2 times by the Wako (Wako Diagnostics, Richmond, Virginia) enzymatic method and the average of the 2 measurements was used for the present analyses.
Incident AF was defined based on electrocardiographic and hospitalization records until year 11 (1998 to 1999) and then based on hospitalization records without electrocardiographic review thereafter. Electrocardiograms obtained were reviewed and diagnosis of AF or atrial flutter was verified at the CHS centralized electrocardiographic reading center. When AF or atrial flutter was a discharge diagnosis, AF was believed to be present from day of admission to the hospital. AF or atrial flutter cases that occurred during the same hospitalization for coronary artery bypass graft surgery or valve replacement surgery were excluded from the present analysis. The positive predictive value of hospital discharge diagnosis for AF has been noted to be 98.6% in the CHS. In another Holter monitoring substudy, only 0.1% of patients having intermittent or persistent AF were not captured by this method.
Data on demographics, anthropometric measurements, HTN, T2D, coronary heart disease, congestive heart failure, lipid profile, renal function, smoking, and alcohol consumption were recorded at the 1992 to 1993 examination. NT–pro-BNP and C-reactive protein were measured using samples from the 1992 to 1993 examination. Age, body mass index, and systolic blood pressure were analyzed as continuous variables. Physical activity (kilocalories per day) was determined using a modified Minnesota Leisure-Time Activities questionnaire and analyzed as a continuous variable (after logarithmic transformation). Alcohol consumption was classified as 0, <7, 7 to 14, and >14 drinks/week. Smoking status was classified as never, former, and current. HTN was defined as present if average seated systolic blood pressure was >140 mm Hg, diastolic blood pressure was >90 mm Hg, or use of antihypertensive medications by participants who reported a HTN diagnosis. T2D was present if any of the following conditions was met: fasting glucose ≥126 mg/dl, nonfasting glucose ≥200 mg/dl, or use of insulin/hypoglycemic agents. Plasma levels of total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and C-reactive protein were analyzed as continuous variables.
Baseline characteristics of the study participants were summarized according to quartiles of FFA. Continuous variables were presented as mean ± SD or median (interquartile range) if the distribution was skewed. Categorical variables were presented as number (percentage) and incidence rate of AF (per 1,000 person-years) was calculated within each quartile of FFAs.
Cox proportional hazard regression was used to estimate the association of FFA with incident AF. FFAs were modeled as a continuous variable (per SD of FFAs) and quartiles. Cubic splines were used to assess the linearity of the association between FFAs (continuous variable) and incident AF. We computed person-time of follow-up from FFA assessment until the first occurrence of (1) AF/atrial flutter, (2) death, or (3) censoring date (i.e., last available follow-up). After crude analysis, we adjusted for demographic variables (age [continuous], race [African-American or other], and gender [model 1]). Model 2 also controlled for physical activity, alcohol intake, smoking, body mass index, coronary heart disease, congestive heart failure, T2D, HTN, and C-reactive protein.
NT–pro-BNP measurements were available in 3,709 subjects (88.8%). Within this subset, we repeated the final analysis with additional adjustment for log NT–pro-BNP. In a secondary analysis, we restricted the follow-up time to the first 5 years of follow-up. We also tested for effect modification by gender, adiposity, and T2D status. We used Schoenfeld residuals and plots of residuals over time to examine proportional hazard assumptions and no violations were found. All analyses were conducted using STATA 11.2 (STATA Corp. LP, College Station, Texas). The significance level was set at 0.05.
Results
Table 1 presents baseline characteristics of study participants according to quartiles of plasma FFAs. Mean age of study participants was 74.6 ± 5.1 years. During an average follow-up of 10.0 years, 1,041 new cases of AF/atrial flutter were reported. Subjects in the highest FFA quartile were older, more likely to be women, and had higher measurements of adiposity, triglycerides, low-density lipoprotein, high-density lipoprotein, NT–pro-BNP, and C-reactive protein. Higher FFA levels were also associated with prevalent HTN and T2D.
| FFA Quartiles (mEq/L) | ||||
|---|---|---|---|---|
| 1 (≤0.348) | 2 (>0.348–0.469) | 3 (>0.469–0.610) | 4 (>0.610) | |
| (n = 1,044) | (n = 1,047) | (n = 1,044) | (n = 1,040) | |
| Age (years) | 74 ± 4.6 | 75 ± 5.2 | 75 ± 5.3 | 75 ± 5.3 |
| African-American | 160 (15%) | 188 (18%) | 184 (18%) | 196 (19%) |
| Men | 628 (60%) | 477 (46%) | 348 (33%) | 251 (24%) |
| Body mass index (kg/m 2 ) | 26 ± 4.0 | 27 ± 4.6 | 27 ± 5.0 | 28 ± 5.3 |
| Physical activity (kcal), median (interquartile range) | 1,022 (405–2,173) | 908 (304–1,951) | 769 (263–1,768) | 735 (234–1,646) |
| Coronary heart disease | 269 (26%) | 202 (19%) | 198 (19%) | 201 (19%) |
| Heart failure | 51 (4.9%) | 46 (4.4%) | 45 (4.2%) | 56 (5.4%) |
| Diabetes mellitus | 122 (12%) | 134 (13%) | 145 (14%) | 225 (22%) |
| Hypertension | 517 (50%) | 553 (53%) | 615 (59%) | 706 (68%) |
| Low-density lipoprotein (mg/dl) | 127 ± 32 | 129 ± 33 | 130 ± 35 | 127 ± 36 |
| High-density lipoprotein (mg/dl) | 50 ± 13 | 52 ± 14 | 55 ± 14 | 57 ± 16 |
| Triglycerides (mg/dl) | 115 (84–159) | 123 (90–170) | 127 (91–175) | 133 (96–192) |
| Smoking status | ||||
| Never | 399 (38%) | 460 (44%) | 511 (49%) | 549 (53%) |
| Former | 528 (51%) | 473 (45%) | 428 (41%) | 401 (39%) |
| Current | 117 (11%) | 114 (11%) | 105 (10%) | 90 (9%) |
| Alcohol consumption (drinks/week) | ||||
| 0 | 531 (51%) | 577 (55%) | 579 (56%) | 615 (59%) |
| <7 | 379 (36%) | 338 (32%) | 352 (34%) | 281 (27%) |
| 7–14 | 73 (7%) | 76 (7%) | 68 (7%) | 72 (7%) |
| >14 | 61 (6%) | 56 (5%) | 45 (4%) | 72 (7%) |
| N-terminal pro–B-type natriuretic peptide, median (interquartile range) | 125 (63–259) | 130 (63–268) | 135 (72–247) | 146 (74–262) |
| C-reactive protein, median (interquartile range) | 2.2 (1.0–5.0) | 2.5 (1.3–5.9) | 2.8 (1.4–6.1) | 3.1 (1.3–6.5) |
Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years from lowest to highest quartile of FFAs ( Table 2 ). Compared to the lowest quartile, there was a positive and statistically significant association between highest quartile of plasma FFAs and incident AF, with a hazard ratio (HR) of 1.29 (95% confidence interval [CI] 1.08 to 1.55) in the fully adjusted analysis ( Table 2 ). Each SD (SD =0.20 mEq/L) of increased FFAs was associated with an 11% higher risk of AF (95% CI 4 to 18) in the fully adjusted model ( Table 2 ). Evaluation of cubic splines also suggested a linear relation between plasma FFA levels and incident AF ( Figure 1 ) . At additional adjustment for NT–pro-BNP (available in 3,704 subjects), the final adjusted HR of AF per SD of increased FFA was 1.11 (95% CI 1.03 to 1.18).
| FFA Quartiles (mEq/L) | Continuous | ||||
|---|---|---|---|---|---|
| 1 (≤0.348) | 2 (>0.348–0.469) | 3 (>0.469–0.610) | 4 (>0.610) | Per SD (0.20 mEq/L) Increase | |
| HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| Events/number at risk | 257/1,044 | 248/1,047 | 245/1,044 | 291/1,040 | |
| Cases/1,000 person-years | 23.7 | 23.3 | 23.9 | 29.7 | |
| Unadjusted | 1.00 (ref) | 0.98 (0.82–1.17) | 1.01 (0.85–1.21) | 1.26 (1.07–1.49) | 1.09 (1.03–1.16) |
| Model 1 ⁎ | 1.00 (ref) | 1.02 (0.85–1.21) | 1.08 (0.91–1.30) | 1.43 (1.20–1.70) | 1.15 (1.08–1.22) |
| Model 2 † | 1.00 (ref) | 1.02 (0.85–1.21) | 1.05 (0.88–1.26) | 1.29 (1.08–1.55) | 1.11 (1.04–1.18) |
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