Pharmacological Modulation of Cardiac Remodeling after Myocardial Infarction

Abstract

Cardiac remodeling describes a series of structural and functional changes in the heart after myocardial infarction (MI). Adverse post-MI cardiac remodeling directly jeopardizes the recovery of cardiac functions and the survival rate in MI patients. Several classes of drugs are proven to be useful to reduce the mortality of MI patients. However, it is an ongoing challenge to prevent the adverse effects of cardiac remodeling. The present review aims to identify the pharmacological therapies from the existing clinical drugs for the treatment of adverse post-MI cardiac remodeling. Post-MI cardiac remodeling is a complex process involving ischemia/reperfusion, inflammation, cell death, and deposition of extracellular matrix (ECM). Thus, the present review included two parts: (1) to examine the basic pathophysiology in the cardiovascular system and the molecular basis of cardiac remodeling and (2) to identify the pathological aspects of cardiac remodeling and the potential of the existing pharmacotherapies. Ultimately, the present review highlights drug repositioning as a strategy to discover effective therapies from the existing drugs against post-MI cardiac remodeling.

Figure 1

The phases and the main pathological changes in post-MI cardiac remodeling. The early remodeling includes ischemia, cell death, and inflammation within hours to days after the acute myocardial insult. The late remodeling is characterized by ECM deposition and causes reactive cardiac hypertrophy, cardiac fibrosis, and ventricular dilatation.

Figure 2

Macrophage M1/M2 polarization and the inflammatory response in MI. MI-induced inflammatory response includes the initial proinflammatory and the subsequent anti-inflammatory reparative phase. In the proinflammatory phase, macrophages undergo M1 polarization while activation of the NLRP3 inflammasome increases the release of proinflammatory cytokines (such as IL-1β, IL-18, IL-1α, CCL21). In the subsequent anti-inflammatory reparative phase, macrophages undergo M2 polarization while anti-inflammatory factors (such as IL-10, IL6, TGF-β) are produced to execute the resolution of cardiac inflammation.

Figure 3

MI-induced activation and pharmacologic inhibition of the renin-angiotensin-aldosterone system. Renin-angiotensin-aldosterone system regulates the functions of multiorgans. AMI causes a decrease in cardiac output, reduces tissue perfusion in the kidney and liver, and stimulates renin and angiotensinogen production. Consequently, angiotensin production is increased to stimulate ventricular remodeling. Meanwhile, aldosterone has similar effects on cardiac remodeling.