Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response

Abstract

It is believed that obesity has detrimental effects on the coronary circulation. These include immediate changes in coronary arterial vasomotor responsiveness and the development of occlusive large coronary artery disease. Despite its critical role in regulating myocardial perfusion, the altered behavior of coronary resistance arteries, which gives rise to coronary microvascular disease (CMD) is poorly understood in obesity. A chronic, low-grade vascular inflammation has been long considered as one of the main underlying pathology behind CMD. The expanded adipose tissue and the infiltrating macrophages are the major sources of pro-inflammatory mediators that have been implicated in causing inadequate myocardial perfusion and, in a long term, development of heart failure in obese patients. Much less is known the mechanisms regulating the release of these cytokines into the circulation that enable them to exert their remote effects in the coronary microcirculation. This mini review aims to examine recent studies describing alterations in the vasomotor function of coronary resistance arteries and the role of adipose tissue-derived pro-inflammatory cytokines and adipokines in contributing to CMD in obesity. We provide examples of regulatory mechanisms by which adipokines are released from adipose tissue to exert their remote inflammatory effects on coronary microvessels. We identify some of the important challenges and opportunities going forward.

Fig. (1). Adipose tissue-derived cytokines and coronary microvascular vasomotor dysfunction

In obesity, expansion of adipose tissue leads to tissue hypoxia, which via hypoxia inducible factor-1α (HIF-1) results in an increased production of leptin, resistin, TNF, and IL-6. Adipocytes also enhance monocyte chemotactic protein-1 (MCP-1) synthesis, which facilitates macrophage (mΦ) accumulation in adipose tissue. TNF is cleaved by TACE from the cell membrane of adipocytes and macrophages leading to substantial release of soluble form of TNF (sTNF). The secreted adipokines and pro-inflammatory cytokines then reach the coronary microcirculation to exert their remote effects, via inducing production of superoxide anion (O₂^−·) and hydrogen peroxide (H₂O₂) in the coronary arteriolar wall, which leads to reduced availability of NO, hence limited vasodilator function.