CE: Tripti; HCO/330310; Total nos of Pages: 6; HCO 330310 REVIEW CURRENT OPINION Myocarditis and cardiomyopathy Jonathan Buggey and Chantal A. ElAmm Purpose of review The aim of this study is to summarize the literature describing the pathogenesis, diagnosis and management of cardiomyopathy related to myocarditis. Recent findings Myocarditis has a variety of causes and a heterogeneous clinical presentation with potentially life- threatening complications. About one-third of patients will develop a dilated cardiomyopathy and the pathogenesis is a multiphase, mutlicompartment process that involves immune activation, including innate immune system triggered proinflammatory cytokines and autoantibodies. In recent years, diagnosis has been aided by advancements in cardiac MRI, and in particular T1 and T2 mapping sequences. In certain clinical situations, endomyocardial biopsy (EMB) should be performed, with consideration of left ventricular sampling, for an accurate diagnosis that may aid treatment and prognostication. Summary Although overall myocarditis accounts for a minority of cardiomyopathy and heart failure presentations, the clinical presentation is variable and the pathophysiology of myocardial damage is unique. Cardiac MRI has significantly improved diagnostic abilities, but endomyocardial biopsy remains the gold standard. However, current treatment strategies are still focused on routine heart failure pharmacotherapies and supportive care or cardiac transplantation/mechanical support for those with end-stage heart failure. Keywords cardiac MRI, cardiomyopathy, endomyocardial biopsy, myocarditis INTRODUCTION prevalence seen in children and young adults aged Myocarditis refers to inflammation of the myocar- 20–30 years [1]. dium and may be caused by infectious agents, systemic diseases, drugs and toxins, with viral infec- CAUSE tions remaining the most common cause in the developed countries [1]. The clinical symptoms Viral infections are the most common cause of myo- associated with myocarditis are highly variable carditis in Europe and the United States with a tem- and may range from chest pain, palpitations and poral variation in the most prevalent causative heart failure to cardiogenic shock and death [2&]. pathogens. From the 1950s through the 1990s, the Myocarditis may progress to a dilated cardiomyopa- most frequently identified virus was coxsackievirus thy (DCM) in nearly 30% of cases, and accounts for [4]. In the late 1990s, adenovirus was the most com- 9–16% of all nonischemic DCM among adult monly detected virus in endomyocardial biopsy patients [3]. This review will focus on the recom- (EMB)s, and more recently parvovirus B19 and Human mended criteria for diagnosis, understanding the Herpesvirus 6 are the most common viruses identified. pathophysiology, treatment options and clinical In areas of Asia, such as Japan, the hepatitis C outcomes. virus is a common cause of myocarditis and DCM, while Central and South America literature describe EPIDEMIOLOGY University Hospitals Cleveland Medical Center, Harrington Heart and Myocarditis will result in heart failure in around 12– Vascular Institute, Cleveland, Ohio, USA 17% of adults with a death rate of approximately 8.4 Correspondence to Jonathan Buggey, MD, UH Cleveland Medical per 100 000. There are regional and temporal varia- Center, 11100 Euclid Avenue, Cleveland, OH 44106, United States. tions in myocarditis with a noted increased mortal- Tel: +1 216 983 4989; e-mail: [email protected] ity from 1980 to 1995 that then declined. Men are Curr Opin Cardiol 2018, 33:000–000 more often affected than women with the peaks in DOI:10.1097/HCO.0000000000000514 0268-4705 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-cardiology.com Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: Tripti; HCO/330310; Total nos of Pages: 6; HCO 330310 Cardiac failure virus, the innate immune system via Toll-like recep- KEY POINTS tors (TLRs) [7] and subsequent release of proinflam- Myocarditis has variable clinical presentations, but may matory cytokines. The second part of the immune have deadly consequences. system response is the activation of T and B-cells. The innate immune system will in turn result in the The most common viral causes for myocarditis are likely activation of the acquired immunity with the parvovirus B19 and HHV6. expansion of T and B-cells resulting in inflammation Cardiac MRI with contemporary T1 and T2 imaging is along with necrosis, fibrosis and remodelling that a well tolerated, accurate and noninvasive method for involves different cellular compartments: the bone diagnosing myocarditis. marrow derived compartment, the endothelial com- When clinically indicated, endomyocardial biopsies partment that regulates the access of bone marrow are generally well tolerated and may help with derived cells to the heart, the interstitial compart- accurate diagnosis, cause and management in patients ment and the cardiomyocyte compartment, which with myocarditis. interacts with the local milieu to shape the inflam- matory response [8,9&]. Contemporary data have provided further sup- port for the role of B-cell mediated antiheart auto- causes such as Chagas disease, caused by the proto- antibodies in the development of myocarditis via zoa Trypanosoma cruzi [1]. In Africa, HIV is com- passive antibody transfer in mouse models and monly associated with myocarditis and DCM, ensuing histopathologic examination [10]. Further- although coinfections with other viruses may also more, when compared with healthy controls, exist [1] (Table 1). patients with inflammatory DCM were found to have higher levels of T helper (Th) 17 cells [11&], PATHOPHYSIOLOGY an established mediator of myocarditis-associated cardiomyopathy in murine models [12]. The inves- The pathogenesis of myocarditis depends on the tigators provide evidence for a myosin-associated specific pathogen. However, much of our under- TLR-2 ligand mechanism that triggers Th17 cyto- standing into the pathogenesis and progression to kine formation, and potentially contributes to the an inflammatory DCM stems from animal models & development of DCM in myocarditis [11 ]. infected with coxsackievirus. The pathogenesis is The progression of acute myocarditis to an believed to be a multiphase process that involves inflammatory DCM, which only occurs in a subset multiple compartments and begins with entry of the of patients, is characterized by myocyte hypertro- virus into myocardial cells via viral-specific recep- phy, apopotosis and fibrosis [13]. It has been shown tors (coxsackiadenovirus receptor or CAR) [5,6] and that proinflammatory cytokines such as tumour subsequent direct inflammatory injury to the myo- necrosis factor (TNF) a, interleukin (IL) 1b and IL- cardium. This inflammation and damage to the 6 are elevated in mice with myocarditis [14], and cardiac muscle leads to the exposure of myosin that TNFa and IL1b will depress human myocyte func- induces the body’s first line of defense against the tion in vitro [15]. In support of this mechanism, adult patients with DCM in fact have elevated levels of Table 1. Causes of myocarditis myocardial IL1b expression with concomitant myo- cardial hypertrophy and fibrosis [16&]. Murine mod- Infectious Noninfectious els of viral myocarditis have also shown that Coxsackie virus Giant cell myocarditis activation of Th2 cells and the subsequent produc- tion of IL-33 are protective from the development of Parvovirus-B19 Drug-induced hypersensitivity DCM [17], further suggesting that patients who Epstein–Barr virus Sarcoidosis progress to a DCM may have genetic susceptibilities Human herpes virus 6 Systemic lupus erythematosus that lead to variations in the immune system Adenovirus Eosinophilic myocarditis response to myocardial viral infections. Other inves- Streptococcus Idiopathic tigators have found that the persistence of virus in Borrelia burgdorferi the myocardium is an important predictor of myo- Trypanosoma cruzi cardial dysfunction [18]. Using EMB in 172 patients, HIV they found that the continued presence of at least Influenza one of four common cardiovirulent viruses was Cytomegalovirus associated with worse left ventricular ejection frac- Hepatitis C tion (LVEF), and in contrast eradication of the virus was associated with a nearly 8% increase in LVEF 2 www.co-cardiology.com Volume 33 Number 00 Month 2018 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: Tripti; HCO/330310; Total nos of Pages: 6; HCO 330310 Myocarditis and cardiomyopathy Buggey et al. [18]. Although the primary mechanism for the important diagnostic and prognostic information, development of a DCM, persistent viral infection clinicians should not purposefully avoid the proce- versus autoimmune-mediated, remains debated, it is dure in the appropriate clinical scenario [9&,24]. The obvious that patient outcomes depend, at least in sensitivity of the EMB increases when immunoper- part, on host genetic susceptibility, the type of oxidase stains are used to detect CD3-stained T pathogen and degree of molecular mimicry [9&]. lymphocytes and/or CD68-stained macrophages along with human leukocyte antigen class II anti- bodies and viral stains [25]. DIAGNOSIS In recent years, cardiac magnetic resonance Due to the nonspecific symptoms associated with (CMR) has become a widely used modality in the acute myocarditis, providers must maintain a high diagnosis of myocarditis,