Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling

Cardiac hypertrophy and remodeling are pathological features of many cardiac diseases, with underlying causes including hypertension, cardiomyopathy, valvular dysfunction, and myocardial infarction. In these diseases, ventricular hypertrophy occurs in response to pathological stimuli such as pressure and volume overload, sarcomere gene mutations, and neurohumoral activation, and a major consequence of prolonged and uncontrolled hypertrophic remodeling is cardiac dysfunction, which can lead to heart failure or cardiac arrest resulting from arrhythmia. Despite the various pathological stimuli, there are many common features in the hypertrophic response in different cardiac diseases. In addition to increased cardiomyocyte mass, sarcomere rearrangement, and extracellular matrix deposition, other common features have recently been appreciated, including inflammatory signaling and immune cell activation. Numerous cell types are involved in orchestrating this complex pathological response. The heart consists of a heterogeneous population of cells, including cardiomyocytes and noncardiomyocytes, and it is now clear that intercellular signaling and communication between these cell types are critical in the pathophysiology of ventricular hypertrophy and remodeling (Figure 1). Figure 1. Overview of cardiomyocyte and noncardiomyocyte interactions during cardiac hypertrophy and remodeling. Cardiomyocytes respond to pathogenic stimuli by secreting inflammatory cytokines, chemokines, and damage-associated molecular pattern molecules (DAMPs), which are recognized by local noncardiomyocyte cells. This induces activation and expansion of resident macrophages and fibroblasts and recruits bone marrow–derived immune cells from the circulation. Activated immune cells and fibroblasts secrete both prohypertrophic and profibrotic cytokines, which induce cardiomyocyte hypertrophy and promote fibroblast differentiation, matrix deposition, and interstitial fibrosis. ECM indicates extracellular matrix. Noncardiomyocytes display phenotypic changes during the development of cardiac hypertrophy. There is still much to be revealed about the specific roles of these cell types and their overall contribution to the hypertrophic response. Inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) and neurohumoral factors such as …