Atrial fibrillation associated with elevated serum IL-6

December 15, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

San Francisco New data from the Heart and Soul study links elevated levels of serum IL-6 with atrial fibrillation in patients with stable coronary artery disease.

The role of inflammation in the pathogenesis of atrial fibrillation is a focus of current research (see ref. 2 for review). IL-6 is a key inflammatory cytokine that regulates expression of the acute phase reactants, including C-reactive protein. Atrial myxomas can secrete IL-6 and are associate with atrial fibrillation, IL-6 levels correlate with left atrial size, and IL-6 promoter polymorphisms have been correlated with risk of atrial fibrillation post-operatively.

971 patients with stable coronary artery disease were included, 46 of whom had atrial fibrillation, and ECG and blood samples were provided. A cross-sectional analysis was performed, comparing those with and without atrial fibrillation. Patients with atrial fibrillation were older (mean age 74 vs. 66), were more likely male (95% vs. 81%; much of data was from VA hospital), white (87% vs. 59%), took ace inhibitors (63% vs. 51%), and drank alcohol (38% vs. 29%), while fewer had hypertension (60% vs. 71%), took statins (54% vs. 65%), and smoked (9% vs. 21%). As expected, left atrial size was larger in patients with atrial fibrillation (101 vs. 62 mL). Patients with and without atrial fibrillation were similar with regard to heart failure history and left ventricular mass. Data were adjusted for covariates including age, sex, race, hypertension, ejection fraction were included in the logistic regression model.

Biomarkers measured included IL-6, C-reactive protein, TNF-alpha, MCP-1, soluble CD40-ligand (sCD40L), and fibrinogen. The only statistically significance was observed for IL-6, levels of which were elevated in patients with atrial fibrillation (3.76 vs. 2.52 pg/mL, p=0.0005). High serum levels of IL-6 were associated with covariates including age, atrial volume, left ventricular mass index, and left ventricular ejection fraction (p<0.0001 for all).

871 patients had the IL-6 promoter regions sequenced, including 40 patients with atrial fibrillation. In the unadjusted analysis no genotype was significantly associated with atrial fibrillation. After adjustment for covariates, however, the -174CC genotype was statistically associated with atrial fibrillation (p=0.04).

This study is a large cross-sectional analysis demonstrating a statistically significant association between atrial fibrillation and elevated levels of IL-6. As is the case with this methodology, no causal relationship between the IL-6 and atrial fibrillation can be determined. A few specific concerns should be noted, including the small sample size of patients with atrial fibrillation combined with the large number of variables included in the regression model. Measurement of sCD40L in serum rather than plasma can introduce significant assay variability, likely secondary to the release of CD40L from platelets ex vivo. The promoter polymorphism data is intriguing, but requires further validation.

1. Gregory M. Marcus, Mary A. Whooley, David V. Glidden, Ludmila Pawlikowska, Jonathan G. Zaroff and Jeffrey E. Olgin. Interleukin-6 and atrial fibrillation in patients with coronary artery disease: Data from the Heart and Soul Study. In Press, Corrected Proof, Available online 25 October 2007

2. Issac TT, Dokainish H, Lakkis NM. Role of inflammation in initiation and perpetuation of atrial fibrillation: a systematic review of the published data. J Am Coll Cardiol. 2007 Nov 20;50(21):2021-8. Epub 2007 Nov 5.