Knocking Out Viral Myocarditis

Abstract

Viral myocarditis (VM) is an inflammatory disease of the myocardium initiated by common viral infections, such as the enterovirus coxsackie group B, parovovirus B19, and human herpes virus 6, and sustained by postviral immune-mediated responses. While acute myocarditis is typically self-limited in most individuals, the development of severe heart muscle injury may lead to dilated cardiomyopathy, heart failure, or even death in others. The mechanisms underlying why some individuals are more susceptible to cardiotropic viruses than others are not well established. Furthermore, therapies for VM are generally directed at supportive care of heart failure (eg, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, or β-blockers) rather than specific early pathophysiological targets involved in innate or adaptive immunity that are thought to contribute to deleterious events in susceptible individuals. Article, see p 415 The majority of information about the pathogenesis of myocarditis has been derived from experimental models in rodents. Using mouse models of enteroviral myocarditis, the course of VM has been characterized into 3 phases: (1) viral entry; (2) innate and adaptive immune activation; and (3) chronic/resolution (Figure, A).1 First, the virus may proliferate in a variety of tissues in the susceptible host and eventually reach the myocardium through hematogenous or lymphangitic spread. During the first few days of viral exposure, the virus gains entry into cells, including cardiomyocytes, using viral specific receptors and replication proceeds which itself can cause direct myocardial tissue injury (Figure, A, left panel). However, viral infectivity also strongly activates the innate immune system by inducing proinflammatory Toll-like receptors (TLRs), the inflammasome, and the release of cytokines such as TNF-α or IL-1β (Figure, A, middle panel). Indeed, cardiac TLR4 mRNA expression and signaling is higher in human subjects with myocarditis than control subjects and has been associated with the presence of active viral proliferation and …