Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a common cardiac condition caused primarily by sarcomeric protein mutations with several distinct phenotypes, ranging from asymmetric septal hypertrophy, either with or without left ventricular outflow tract obstruction, to moderate left ventricular dilation with or without apical aneurysm formation and marked, end-stage dilation with refractory heart failure. Sudden cardiac death can occur at any stage. The phenotypic variability observed in HCM is the end-result of many factors, including pre-load, after-load, wall stress and myocardial ischemia stemming from microvascular dysfunction and thrombosis; however, tissue level inflammation to include leukocyte-derived extracellular traps consisting of chromatin and histones, apoptosis, proliferation of matrix proteins and impaired or dysfunctional regulatory pathways contribute as well. Our current understanding of the pathobiology, developmental stages, transition from hypertrophy to dilation and natural history of HCM with emphasis on the role of tissue-level inflammation in myocardial fibrosis and ventricular remodeling is summarized.

Keywords: Extracellular traps; Hypertrophic cardiomyopathy; Inflammation; Thrombosis.

Figure 1:

Proposed staged and general mechanistic events in the metamorphosis of hypertrophic cardiomyopathy to heterogeneous phenotypes, to include in some cases dilated, end-stage heart failure with heart failure and clinical events.

Figure 2:

The attachment of neutrophil extracellular traps (NETs) to areas of cardiomyocyte injury, vascular injury and tissue inflammation is mediated by Von Willebrand Factor (see text).

Figure 3:

Stages of hypertrophic cardiomyopathy that include an early phase characterized by tissue-level inflammation and neutrophil extracellular traps or NETs; an intermediate phase with platelet activation, microvascular thrombosis and transforming growth factor (TGF) β1 signaling and a late phase of myocardial fibrosis, ventricular remodeling and ultimately heart failure.