Abstract
Introduction: Myocardial fibrosis is a key feature of heart failure, and its mechanisms are incompletely understood. It has been postulated that advanced glycation end-products (AGEs) form an etiologic link between diabetes and its vascular complications. Binding of AGEs to the cellular receptor for AGEs (RAGE) induces a state of increased oxidative stress, inflammation and fibrosis. Circulating soluble RAGEs (sRAGE) compete with cellular RAGE for the binding of AGEs which reduces the activation of the AGE-RAGE mediated pro-inflammatory and pro-fibrotic signaling pathways. We hypothesize that low levels of sRAGE will be associated with higher risk of heart failure. Methods: We conducted a prospective analysis of a random subsample of 1,157 participants from the ARIC Study who attended visit 2 (1990-1992). We included participants without a history of heart disease or heart failure, and with measured plasma sRAGE levels. Incident heart failure was defined as death from health failure or hospitalization due to heart failure. Results: In this community-based population (mean age 63 years, 60% women, 78% white), there were 132 incident cases of heart failure during approximately 20 years of follow up. Lower levels of sRAGE were significantly and independently associated with an increased risk of heart failure (Table). Analyses stratified by diabetes status at baseline showed that the risk of heart failure among those in the lowest quartile, compared to those in the upper quartile, was consistent but stronger among persons with diabetes compared to those without diabetes with HR=5.31 (95%CI 1.05-26.76) versus HR=2.50 (95%CI, 1.22-5.13), respectively. We did not observe any significant interactions by race or obesity status. Conclusions: Lower circulating levels of sRAGE are independently associated with the development of heart failure in older adults. These results highlight the pathophysiological role of the AGE-RAGE-sRAGE axis even among persons without diabetes.
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