Cardiac mast cells: the centrepiece in adverse myocardial remodelling

Abstract

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Figure 1

In response to elevations in myocardial stress such as volume or pressure overload, or injury such as lesions of the vasculature or myocardial infarction, a variety of factors are released that have the potential to activate cardiac mast cells. Upon activation, cardiac mast cells release numerous products that may include histamine, chymase, tryptase and TNF-α as well as others that are as yet undetermined. These products can act directly on cardiac fibroblasts, endothelial cells, smooth muscle cells or cardiac myocytes, depending on the pathology involved. In addition to this, cardiac mast cells may also interact with other inflammatory cells such as T cells and macrophages to amplify their effects on remodelling. Oestrogen may protect females from the same degree of adverse cardiovascular remodelling as males by altering the phenotype of cardiac mast cells or by inhibiting their activation.