Abstract
BackgroundPrevious cross-sectional studies have suggested that biomarkers of extracellular matrix remodelling are associated with atrial fibrillation (AF), but no prospective data have yet been published. Hence, we examine whether plasma matrix metalloproteinases (MMP) and their inhibitors are related to increased risk of incident AF.MethodsWe used a case-cohort design in the context of the prospective Atherosclerosis Risk in Communities (ARIC) study. From 13718 eligible men and women free from AF in 1990-92, we selected a stratified random sample of 500 individuals without and 580 with incident AF over a mean follow-up of 11.8 years. Using a weighted proportional hazards regression model, the relationships between MMP-1, MMP-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2 and C-terminal propeptide of collagen type-I with incident AF were examined after adjusting for confounders.ResultsIn models adjusted for age, sex and race, all biomarkers were associated with AF, but only the relationship between plasma MMP-9 remained significant in the fully-adjusted model: each one standard deviation increase in MMP-9 was associated with 27% (95% Confidence Interval: 7% to 50%) increase in risk of AF with no evidence of an interaction with race or sex. Individuals with above mean levels of MMP-9 were more likely to be male, white and current smokers.ConclusionsThe findings suggest that elevated levels of MMP-9 are independently associated with increased risk of AF. However, given the lack of specificity of MMP-9 to atrial tissue, it remains to be determined whether the observed relationship reflects the impact of atrial fibrosis or more generalized fibrosis on risk of incident AF.
Highlights
The precise etiology of atrial fibrillation (AF) is unknown but typically it is initiated by ectopic electrical activity that requires the presence of an appropriate substrate, both structural and electrical, to persist
Atrial fibrosis is considered to be a key element of the AF substrate [1], with extracellular matrix (ECM) remodeling playing a major role in this process
But not all [5], prospective studies have suggested that raised levels of matrix metalloproteinases (MMP) may be modestly associated with greater risk of coronary heart disease (CHD) while other studies have suggested that MMPs and tissue inhibitor of matrix metalloproteinase (TIMP) are only correlates of inflammatory status and are not independently associated with coronary risk [6]
Summary
The precise etiology of atrial fibrillation (AF) is unknown but typically it is initiated by ectopic electrical activity that requires the presence of an appropriate substrate, both structural and electrical, to persist. The MMPs are a relatively large family of twenty zincdependent enzymes that together with TIMPs precisely regulate the degradation of collagen and other ECM molecules in the atria. Dysfunction in this finely regulated mechanism is postulated to contribute to atherosclerotic plaque rupture and myocardial infarction [3,4]. Most of the evidence suggesting a potential role of fibrosis and ECM remodelling in the etiology of AF has come from animal or cross-sectional clinical studies. Previous cross-sectional studies have suggested that biomarkers of extracellular matrix remodelling are associated with atrial fibrillation (AF), but no prospective data have yet been published. We examine whether plasma matrix metalloproteinases (MMP) and their inhibitors are related to increased risk of incident AF
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