Signaling effectors underlying pathologic growth and remodeling of the heart

Abstract

Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

Figure 1. Overview of different types of cardiac hypertrophy.

The normal heart can develop different types of hypertrophic remodeling depending on the stress. Exercise and pregnancy result in physiologic hypertrophy, in which individual cardiomyocytes increase in length and width and the heart undergoes a balanced type of eccentric hypertrophy (chambers, walls, and septum enlarge in unison). Pathologic stress or hypertrophic cardiomyopathy activates neuroendocrine factors that stimulate cardiac hypertrophy, often resulting in concentric remodeling, in which cardiomyocytes mostly increase in width compared with length, resulting in wall and septal thickening and a loss of chamber area. Over time, this state can deteriorate into dilated and eccentric hypertrophy, in which individual cardiomyocytes reduce in width and lengthening becomes excessive, leading to extreme chamber enlargement with loss of wall and septal thickness, along with large increases in wall tension. Some disease states can lead directly to dilated cardiomyopathy without a prior concentric remodeling phase.

Figure 2. Signaling pathways underlying pathologic cardiac remodeling that have emerged as translational targets.

Diagram of selected signaling effectors or signaling pathways that underlie cardiac hypertrophy or the transition to heart failure, with a special emphasis on immediate translational potential given the pharmacologic agents in development or clinical trials for other disorders. The diagram is also segregated into compartments in the cardiomyocyte, from receptors to second messengers to effector kinases. Some pathways lead to alterations in contractility and/or gene expression. The individual signaling mediators are discussed in the text. The diagram also depicts different therapeutic options based on known pharmacologic agents or gene therapy approaches. Green indicates drugs that are FDA approved, although not necessarily for cardiovascular indications. Red indicates treatments that are currently in phase 1 and 2 clinical trials, but again, not necessarily for cardiovascular indications. Blue indicates targets that have been identified in animal models and might be translated into phase 1 and 2 clinical trials with investigational compounds. NFAT, MEF2, and GATA4 are well-known cardiac-acting transcription factors that affect cardiovascular stress responsiveness. GPCR-BA, G-protein coupled receptor biased agonist, biased toward G-protein signaling; β-arrestin-BA, β-arrestin biased agonist. AC, adenylyl cyclase; ACE, angiotensin-converting enzyme; β-AR, β-adrenergic receptor; ARB, angiotensin receptor blocker; GC, guanylate cyclase; β-ARK-CT, β-adrenergic receptor kinase carboxyl terminus; NPR, natriuretic peptide receptor; PLC, phospholipase C; PLN, phospholamban; I-1, PP1 inhibitor 1; RYR2, ryanodine receptor 2; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase. Dotted lines indicate indirect pathways.