Associations of Lipoprotein(a) Levels With Incident Atrial Fibrillation and Ischemic Stroke: The ARIC (Atherosclerosis Risk in Communities) Study

Abstract

Background: Lipoprotein(a) (Lp[a]) is proatherosclerotic and prothrombotic, causally related to coronary disease, and associated with other cardiovascular diseases. The association of Lp(a) with incident atrial fibrillation (AF) and with ischemic stroke among individuals with AF remains to be elucidated.

Methods and results: In the community-based ARIC (Atherosclerosis Risk in Communities) study cohort, Lp(a) levels were measured by a Denka Seiken assay at visit 4 (1996-1998). We used multivariable-adjusted Cox models to compare AF and ischemic stroke risk across Lp(a) levels. First, we evaluated incident AF in 9908 participants free of AF at baseline. AF was ascertained by electrocardiography at study visits, hospital International Statistical Classification of Diseases, 9th Revision (ICD-9) codes, and death certificates. We then evaluated incident ischemic stroke in 10 127 participants free of stroke at baseline. Stroke was identified by annual phone calls, hospital ICD-9 Revision codes, and death certificates. The baseline age was 62.7±5.6 years. Median Lp(a) levels were 13.3 mg/dL (interquartile range, 5.2-39.7 mg/dL). Median follow-up was 13.9 and 15.8 years for AF and stroke, respectively. Lp(a) was not associated with incident AF (hazard ratio, 0.98; 95% confidence interval, 0.82-1.17), comparing those with Lp(a) ≥50 with those with Lp(a) <10 mg/dL. High Lp(a) was associated with a 42% relative increase in stroke risk among participants without AF (hazard ratio, 1.42; 95% confidence interval, 1.07-1.90) but not in those with AF (hazard ratio, 1.06; 95% confidence interval, 0.70-1.61 [P interaction for AF=0.25]). There were no interactions by race or sex. No association was found for cardioembolic stroke subtype.

Conclusions: High Lp(a) levels were not associated with incident AF. Lp(a) levels were associated with increased ischemic stroke risk, primarily among individuals without AF but not in those with AF.

Keywords: atrial fibrillation; cardioembolic stroke; epidemiology; lipoprotein; lipoprotein (a); risk factor; stroke.

Figure 1

Participant flow diagram for aim 1 (incident atrial fibrillation [AF]). ARIC indicates Atherosclerosis Risk in Communities study; Lp(a), lipoprotein(a).

Figure 2

Participant flow diagram for aim 2 (incident stroke, stratified by history of atrial fibrillation vs no history of atrial fibrillation. ARIC indicates Atherosclerosis Risk in Communities study; Lp(a), lipoprotein(a).

Figure 3

Atrial fibrillation (AF) risk across lipoprotein(a) (Lp[a]) levels. Multivariable‐adjusted restricted cubic spline model showing the hazard ratios of AF (95% confidence intervals) by Lp(a) levels at visit 4. The solid line represents hazard ratios and the dashed lines represent 95% confidence intervals. Knots at 5th, 35th, 65th, and 95th percentiles (corresponding to 1.3, 7.7, 23.9, and 83.1 mg/L). The spline is centered at the 10th percentile. The histogram shows the distribution of Lp(a) levels. Restricted cubic spline is truncated at the 1st and 99th percentiles of Lp(a). The model is adjusted for age, sex, race‐center groups, smoking, systolic and diastolic blood pressure, treatment for hypertension, heart rate, height, body mass index, ECG left ventricular hypertrophy, PR interval, prevalent heart failure, coronary artery disease, diabetes mellitus, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, lipid‐lowering medication, and log‐transformed N‐terminal pro–B type natriuretic peptide.

Figure 4

Ischemic stroke risk across lipoprotein(a) (Lp[a]) levels stratified by atrial fibrillation (AF) status. Multivariable‐adjusted restricted cubic spline models showing the hazard ratio of ischemic stroke (95% confidence intervals) by Lp(a) levels at visit 4. The solid line represents the hazard ratio and the dashed lines represent the 95% confidence intervals. Knots at 5th, 35th, 65th, and 95th percentiles (corresponding to 1.3, 7.7, 23.9, and 83.1 mg/L). The splines are centered at the 10th percentile. The histograms show the distribution of Lp(a) levels. Restricted cubic splines are truncated at the 1st and 99th percentiles of Lp(a). The models are adjusted for age, sex, race‐center groups, smoking, systolic and diastolic blood pressure, treatment for hypertension, heart rate, height, body mass index, ECG left ventricular hypertrophy, PR interval, prevalent heart failure, coronary artery disease, and diabetes mellitus. hx indicates history.