Compendium on Cardiomyopathies - Basics, Therapeutics, and Perspectives

The Dynamics and the Continual Pursuit for an In-Depth Understanding of the Genetics of Cardiomyopathies

Iroegbu Chukwuemeka Daniel*

Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, 410011 Changsha, China

Abstract

Cardiomyopathies are a complex and essential group of heart muscle diseases with diverse etiologies and heterogenous phenotypic expressions, often leading to progressive heart failure (muscular or electrical dysfunction) of the heart with significant morbidity and mortality. In some cases, cardiomyopathies can be asymptomatic in the early stages of the disease with symptoms (fatigue, shortness of breath, paroxysmal nocturnal dyspnea, orthopnea, edema, and cough) characteristically similar to any heart failure. Estimated to occur in 3% of the general population worldwide, knowledge and the understanding of these diseases in both the general public and the medical communities have historically been impaired by periodic confusion surrounding definitions and terminologies. Cardiomyopathies may be primary (i.e., genetic, acquired, or mixed) or secondary (e.g., toxic inflammatory, and infiltrative). Major types include hypertrophic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. Relieving symptoms of heart failure and decreasing hospitalization rates of cardiac failure are therapeutic aims of cardiomyopathy.

Keywords: Arrhythmia, Arrhythmogenic cardiomyopathy, Cardiomyopathy, Classification, Dilated cardiomyopathy, Heart failure, Heart transplantation, Hypertrophic cardiomyopathy, Implantable cardioverter defibrillator, Myocardial diseases, Restrictive cardiomyopathy, Sudden death.

* Corresponding author Iroegbu Chukwuemeka Daniel: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, 410011 Changsha, China; E-mails: [email protected] and [email protected]

INTRODUCTION

Cardiomyopathy is a complex and a multifactorial pathogenetic group of disease which affects function, structure, ventricular filling and the ejection of blood as they are either circumscribed to the heart or being part of a generalized systemic disorder affecting the heart muscles. Cardiomyopathies have a high morbidity and mortality rate, frequently leading to progressive heart failure-related disability in the absence of coronary artery disease, hypertension, valvular disease, or congenital heart diseases [1]. As the condition worsens, it damages muscle tone of the heart and reduces its ability to pump blood to the rest of the body and maintain a normal electrical rhythm as a result can either be heart failure or irregular heartbeats. Compared to other cardiac-related issues, it is remarkably seen in young individuals as a weakened heart and may also cause other complications, such as heart valve problems. For the heart to properly function, it requires the synchronous electrical and mechanical activity of each cardiomyocyte to ensure the coordinated excitation and contractile performance of the heart, like an organ. The heart’s proper function is supported by a unique membrane structure (intercalated disk) forming at the edges of mammalian cardiomyocytes [2] which allows the secure transmission of both electrical and mechanical activities between neighboring cells [3, 4].

Being one of the essential heterogeneous group of diseases, its all-around insight which also includes its knowledge, awareness, and its related pathologies to the public and as well the medical community is impaired by the persistent confusion surrounding its nomenclature, definition(s), therapeutics and diagnosis. This heart muscle disease is so dangerous, and most often goes untreated as many adults are affected and may not even know they have the condition as it is a well-known cause of heart failure and also the most common reason for the need of a heart transplant. Over the years, significant progress has been achieved in getting explicit knowledge about the physiological, molecular, and genetic aspect of cardiomyopathies with novel discoveries being made. The tremendous achievements made in molecular genetics of inherited cardiomyopathies allowed the establishment of hypertrophic-restrictive cardiomyopathies (as sarcomeric, force generation disease) dilated cardiomyopathies (as the cytoskeleton, force transmission disease), and arrhythmogenic cardiomyopathy (as desmosome, cell junction disease). Channelopathies (Brugada, short and long QT,) are also additions considered cardiomyopathies because of electric myocyte dysfunction.

Palliative pharmacological and invasive therapies have been the gold standard for treatments of cardiomyopathies. However, curative treatment made it possible to target critical mechanisms responsible for the onset and progression of cardiomyopathies with a clinical understanding of the involved molecular pathogenesis. The advances made by researchers and clinicians to interpret this disease only goes to show how vital and intricate cardiomyopathy as a complex entity is. Knowledge of the genotype, etiology, pathophysiology and the clinical course is pivotal to diagnosis and prevention of cardiomyopathies as new approaches for its clinical and prognostic assessment are based on contemporary knowledge of its mechanism and the gene-phenotypic complex clinical evaluation and management strategies which invariably improves its clinical evaluation.

The translations and interpretations of cardiomyopathies discussed here are in line with the current concept of cardiomyopathies and have direct clinical applications and implications for cardiac diagnosis. Furthermore, presented classifications of cardiomyopathies herein are not intended to provide precise methodologies or strategies for clinical diagnosis. Instead, its classification rather serves as a scientific and an objective demonstration that offers new insights, aiding in the understanding of this complex and heterogeneous group of diseases, and the underlying disease mechanisms.

DEFINITIONS

The term cardiomyopathy was used in 1957 for the first time. In the original World Health Organization (WHO) 1980 classification, cardiomyopathies were defined only as heart muscle diseases of unknown cause, reflecting a general lack of available information about underlying disease mechanisms [5]. WHO in 1968, defined cardiomyopathies as diseases of different and often unknown etiology in which the dominant feature is cardiomegaly and heart failure [5]. The final WHO classification published in 1995 proposed diseases of the myocardium associated with cardiac dysfunction and included for the first time arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as primary restrictive cardiomyopathy (RCM) [5].

However, the American Heart Association (AHA) expert consensus panel proposed definition of cardiomyopathies is as follows: Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction, which usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation, due to a variety of etiologies that frequently are genetic. Cardiomyopathies are either confined to the heart or are part of generalized systemic disorders, and often lead to cardiovascular death or progressive heart failure-related disability [6]. This definition of cardiomyopathies, similar to that reported by the European Society of Cardiology (ESC), under the auspices of the Working Group on Myocardial and Pericardial Diseases, excludes myocardial involvement secondary to coronary artery disease, systemic hypertension, and valvular and congenital heart disease [1].

CLASSIFICATION OF CARDIOMYOPATHIES

In general, the proper distinction of cardiac diseases is an important and essential one to make, as cardiac diseases with similar phenotypes can have a diverse origin and may need different types of management. However, as for cardiomyopathies, its classification is difficult, as the background or its pathophysiology is not always understood. The classification of these cardiac diseases has been based on morphofunctional phenotypes, but it has been changed according to molecular genetics in recent years. As we know, the traditional classification proposed by the WHO (Table 1) is easy to differentiate between various cardiomyopathies in a couple of functional and structural phenotypes, which help us to define common treatment strategies [5]. New classification-orientated genomic and molecular science also help us understand the heterogeneity and complexity of these diseases [6]. To promote a consistent terminology and well-defined clinical patient groups, new knowledge on underlying causes and pathophysiology of cardiomyopathies has been implemented in a cardiomyopathy classification system both on behalf of the AHA and of the ESC (Table 2). The AHA divided cardiomyopathies into two major groups based on predominant organ involvement. Primary cardiomyopathies (genetic, nongenetic, acquired) are those solely or predominantly confined to the heart muscle and are relatively few [6].

Table 1 Classification of cardiomyopathies by World Health Organization (WHO).

Secondary cardiomyopathies show pathological myocardial involvement as part of a large number and variety of generalized systemic (multiorgan) disorders [6]. According to the ESC guidelines, cardiomyopathies are grouped into specific morphological and functional phenotypes; each phenotype is then sub-classified into familial and non-familial forms [6]. The last classification system (MOGES) proposed by the World Heart Federation (WHF) (Table 3) includes all characteristics: morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance (G), etiology (E), and functional status (S) [7]. From the clinical perspective, the essential objective is the diagnosis of the mechanism of heart failure and delivery of the appropriate, effective treatment.

Table 2 American Heart Association (AHA) Classification for Cardiomyopathies.

SPATIOTEMPORAL DISTRIBUTION OF INTERCALATED DISK COMPONENTS

During maturation and the developmental stages of cardiomyocytes, significant changes occur in the structures associated with the intercalated disk. During the early developmental periods in human myocardium, adherens junction, and desmosomal organization follow that of gap junctions [8]. However, at the postnatal developmental phase, proteins of the adherens and gap junctions appear to orient themselves at the intercalated disk simultaneously [9].

Table 3 World Heart Federation (WHF) MOGE(S) classification for cardiomyopathies.

ORGANIZATION OF THE INTERCALATED DISK

The direct communication between neighboring cardiomyocytic cells for the transmission of signals and an electrical current is mediated by Gap junctions (hexagonal arrays) (Fig. 1) due to the low resistance pathways formed [10]. A gap junction is composed of twelve connexin proteins, with connexin-43 being the most prominent, along with lesser amounts of connexin-45 and 40 [11, 12] (Figs. 2 A, B, C & D). Each cardiomyocyte contributes six connexin molecules to form a hemichannel or a connexion; two connexons join to form a pore or gap junction channel, which is isolated from the extracellular space and connects the cytosol of two neighboring cells [13].

Fig. (1))

Gap junctions in ventricular cardiomyocytes are composed of two homo-hexameric hemichannels.

Consequently, in the absence of connexin-43 channels, normal propagation of contraction is disrupted, and lethal arrhythmias develop [14, 15].

On the other hand, Adherens junctions composed of mainly transmembrane cadherins and cytosolic catenin’s [16], helps in facilitating the transmission of contractile forces between cardiac cells and is also crucial in maintaining a uniform mechanical strength across the heart [17]. Adherens junctions serve as anchors between the extracellular space and the actin cytoskeleton [18] (Figs. 3 A & B).

Desmosomes provide structural support to cardiomyocytes [19]. They are similar to adherens junctions and are composed of intercellular (desmosomal cadherins, desmocollin, and desmoglein) [20], and intracellular components (proteins of the armadillo/catenin- plakoglobin and plakophilin), and plakin (desmoplakin) families [21] (Fig. 4).

Fig. (2A, B, C & D))

Schematic representation of the domain structure of major intercalated disk proteins. Grey ovals denote protein specific domains.

Fig. (3 A & B))

Adherens Junctions connect neighboring cardiomyocytes through homophilic dimers of N-cadherin. Connections within the intracellular space link N-cadherin to the actin cytoskeleton (depicted in grey), via additional adherens junction proteins (shown in hues of teal). Adherens junctions did not consider proteins components traditionally but localizing to the intercalated disk are shown in grey. Proteins of other intercalated disk structures, ZO-1 (gap junctions) and.-catenin (desmosomes), are depicted in light purple and gold, respectively.

Fig. (4))

Desmosomes connect neighboring cardiomyocytes through heterophilic dimers of desmocollin-2 and desmoglein-2 (shown in hues of orange) forming within the extracellular space. Interactions with plakophilin-2, plakoglobin, and desmoplakin-1 (depicted in shades of gold and orange) link the desmosomal complex to the intermediate filament protein desmin (shown in gray) in cardiomyocytes.

Both echocardiography and cardiovascular magnetic resonance imaging are complementary imaging modalities and powerful tools used in the diagnosis of cardiomyopathies. However, echocardiography is superior in the assessment of diastolic function and dynamic outflow tract obstruction while cardiovascular magnetic resonance imaging has several advantages over the former such as excellent resolution, demonstration of relationships between the heart and thoracic structures, three-dimensional visualization, can be repeated safely, tissue characterization (scar or infiltration), and the quantification of cardiac volumes and function [22]. Therapeutic options include pharmacotherapy, implantable cardioverter-defibrillators, cardiac resynchronization therapy, and heart transplantation alongside lifestyle changes.

CONCLUDING REMARKS

Cardiomyopathies represent an ideal translational model of integration between basic and clinical sciences. A multidisciplinary approach is, therefore, essential to ensure their correct diagnosis and management. Rather than affecting mostly the elderly like other heart diseases, it is now commonly found among young adults, directly damaging cardiac muscles, and hence impairing the heart's ability to pump blood to other parts of the body. However, the exact frequency of cardiomyopathy is still currently challenging to ascertain. Although, about five thousand new cases develop each year in the States with an estimated 3% in the general population worldwide. At present, and in the foreseeable future, clinical classifications of cardiomyopathies based on clinical presentation and morphological criteria would prove vital and serve as an essential tool for clinicians involved with these complex disease(s) while calling for a constant improvement and update in the light of the advances provided by imaging genetics and basic sciences.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The author confirms that this chapter contents have no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

The Relationship Between Myocarditis (Viral, Autoimmune) and Cardiomyopathy (Infective, Inflammatory)

Iroegbu Chukwuemeka Daniel¹, Jiarong Li¹, Xiaoming Wu¹, Zhou Zhongxin², Jinfu Yang¹, *

¹ Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, 410011 Changsha, China

² Department of Thoracic and Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 99 Huaihai Road West Xuzhou, Jiangsu Province 221000, China

Abstract

Myocarditis, an inflammatory disease of the heart muscle, most often caused by an autoimmune process or viral infection is an essential cause of dilated cardiomyopathy worldwide and also, one of the most challenging diagnosis in cardiology today. Myocarditis of either viral or an autoimmune cause can lead to fatal, life-threatening arrhythmias and/or cardiogenic shock which in some patients, may progress to chronic myocarditis and dilated cardiomyopathy affecting both short- and long-term prognostic outcomes where rapid elimination of the infectious agent and rapid withholding changes of the inflammatory process in the myocardium are too small. Conceptually, the pathogenesis of myocarditis can be sub-divided into three stages: an initial viral proliferation phase, immunologic response and inflammation phase, and finally, a myocardial remodeling and fibrotic phase. Due to the long-term consequences, and the broad spectrum of factors (infectious, immunologic, toxic, among others) causing/leading inflammatory heart muscle diseases, it is imperative that diagnosis and appropriate treatments are done early. At present, due to the insensitivity of traditional diagnostic tests, no diagnostic gold standard is generally accepted, leading to the search for new diagnostic approaches/methods, resulting in the emergence of new molecular diagnostic techniques, and a more detailed immunohistochemical analysis of endomyocardial biopsies. Be it as it may, this chapter aims to discuss the unresolved issues faced with myocarditis (viral and autoimmune) and cardiomyopathy (Infective inflammatory), their relationship as single entities, associated autoimmune processes, old and new treatment options available for patients, recently proposed new general diagnostic approaches, diagnostic gold standard, setbacks, and pitfalls.

Keywords: Autoimmune mechanism, Biopsy, Cytokine, Consensus, Cardiomyopathy, Contrast media, Cardiovascular magnetic resonance imaging, Diagnosis, Endomyocardial fibrosis, Heart failure, Inflammation, Infective heart disease, Immunosuppression, Immunomodulation, Immunoadsorption, Myocarditis, Management, Polymerase chain reaction, Pediatric Cardiology, Therapy, Virus.

* Corresponding author Jinfu Yang: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, 410011 Changsha, China; E-mails: [email protected], [email protected], [email protected]

INTRODUCTION

Myocarditis as a term was first coined and introduced by a German physician Joseph Friedrich Sobernheim in 1837 [1] although, individual cases of myocarditis were documented as early as the 1600s [2]. Pathologically and clinically defined clearly as inflammation of the myocardium. the term has since been a center of controversy over the past decades as it has continuously been confused with other cardiovascular conditions such as ischemic heart diseases and hypertension [3]. Acute myocarditis is a potentially lethal disease and in most cases it leads to sudden death and usually progresses to dilated cardiomyopathy (DCM) in 10 to 15% of patients either by a progressive autoimmune myocardial injury or as a result of a persistent viral infection. Also, issues of sudden cardiac death prevalence in young people reported in some autopsy studies are highly variable, ranging from 2 to 40% [4].

Similarly, biopsy-proven myocarditis is reported in 10–18% of adult patients with unexplained non-ischemic DCM and in 48% of children with an identifiable cause [5]. However, in 20% of biopsy-proven cases, myocarditis can progress to DCM [6, 7]. Excess amount of cytokine-induced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. However, various published studies have shown that cytokines generated by activated immune cells cause an increase in nitric oxide (NO) via induction of NO synthase, which eventually results in a direct negative inotropic effect and a modulation of inotropic responsiveness [8-10]. Myocarditis is a challenging heart disease to diagnosis due to its heterogenic clinical presentations. In the pursuit for a global standardized diagnostic criterion for myocarditis, the Dallas classification [11] was introduced in 1987 although, the designation had several pitfalls, being susceptible to variation in pathological interpretation, sampling errors, and not considering the exact cause of pathological findings.

The actual incidence of myocarditis is also challenging to determine due to the infrequent use of endomyocardial biopsy (EMB) as the gold standard for diagnosis [12, 13]. With this in mind, EMBs is, however, no longer recommended for the determination of autoimmune or viral myocarditis, mainly due to its lack of additional immunostaining for inflammation and polymerase chain reaction (PCR) for viral diagnosis. Viral myocarditis presents with various symptoms, ranging from minimally symptomatic cases to fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis [14]. However, efforts made to redefine viral and autoimmune heart disease may eventually lead to the abolishment of the Dallas criteria as a diagnostic criterion for myocarditis [15]. Experimental Investigations in mouse models carried out described complicated relationship between myocarditis (viral) and cardiomyopathies (infective). The pathological cardiac changes that occurred as a result of the direct cell damage are caused by the virus which was evidently no longer detected (disappeared) in the myocardium as events other than direct myocardial cell damage and inflammatory processes. However, the concept supported by the ongoing damage occurs on an immunologic basis. Whereas in humans, the elevation of cardiotropic viral antibody titers in patients with cardiomyopathy provides evidence of the relationship between the two conditions since lymphocytic myocarditis, in most cases, are related to a preceding viral infection.

Furthermore, histological examination provides further links between myocarditis and cardiomyopathies, documenting definite acute inflammation in patients suffering from cardiomyopathies. Although, the exact prevalence of inflammatory changes in cardiomyopathy is still not apparent. Jean Nicolas Corvisart in 1806, further described a cardiac inflammatory disorder that could result in progressive abnormalities of cardiac function after all the evidence of the infective agent had disappeared [16]. These various infective agents cause functional and structural heart disorders with vast variety form of symptoms such as hypertrophy and dilatation of heart chambers, making a diagnosis of infective inflammatory cardiomyopathies (ICM) steep [17].

Myocarditis onset is often clinically challenging to recognize. Even when the diagnosis is made, the diagnostic procedures suffer from various limitations [18, 19], resulting in many cases diagnosed after congestive heart failure has occurred or only at autopsies [20]. Therefore, strategies to diagnose and depict small areas of myocardial damage in patients with suspected myocarditis is essential as postmortem studies show active myocarditis which causes small areas of myocardial necrosis [21]. Active myocarditis is characterized by inflammatory cellular infiltrate with evidence of myocyte necrosis. As a result of the various clinical features of the disease, Lieberman et al. [22] proposed a broader clinicopathological classification to incorporate these features. The classification divided myocarditis into fulminant, subacute, active chronic, and persistent subtypes. However, Borderline myocarditis demonstrates an inflammatory cellular infiltrate without any evidence of myocyte injury, unlike active myocarditis. The inflammation could be mild, moderate, or severe, and its distribution can also be focal, confluent, or diffuse, respectively. The extreme diversity of clinical manifestations has led to the development of molecular techniques to facilitate new insights into autoimmune inflammatory processes that affect the myocardium. Despite the well-established associated myocarditis morbidity and mortality rate, clinical practice guidelines about its evaluation and treatment are lacking caused as a result of the variety of etiologies and its various clinical presentations [23, 24].

Sampling error with EMB has remained a significant limitation to myocarditis diagnostic accuracy. Although three to six biopsy samples are performed routinely during diagnostic procedures, postmortem investigations proved that above ten samples were necessary to clinically and correctly give a definite diagnosis for myocarditis which is not feasible in clinical practice [25]. Intra-observer variability is also another significant limitation in the diagnosis of myocarditis. However, the treatment of many forms of myocarditis is symptomatic, but biological molecular analysis of EMB, autoantibody serum testing, and immunohistochemical analysis is essential in identifying patients for whom specific therapy is appropriate [18, 22, 26-28]. Myocarditis and cardiomyopathies are one of the most difficult and challenging diagnosis in cardiology as it is difficult to recognize, misdiagnosed, and its pathophysiology defectively understood.

Be it as it may, this scientific chapter aims to discuss the unresolved issues faced with myocarditis (viral and autoimmune) and cardiomyopathy (Infective inflammatory), their relationship as single entities, associated autoimmune processes, old and new treatment options available for patients, recently proposed new general diagnostic approaches, diagnostic gold standard (EMB’s), setbacks and pitfalls.

NATURAL HISTORY

Myocarditis natural history is as varied (fulminant, acute, viral, bacterial, autoimmune, etc.) to its various clinical presentations (fever, fatigue, chest pain, clinical heart failure, dyspnea on exertion, palpitations, and subsequent viral prodromes), complete recovery, and long-term evolution to DCM [29]. Due to its asymptomatic course and its difficult diagnosis, D’ Ambrosio et al. [29] reviewed the history of histology-proven acute myocarditis. Once patients with acute fulminant myocarditis survive the severe illness, they tend to have a favorable long-term prognosis of 90-94% at an average of eight to eleven years with a one-year mortality rate of 20% [30] as compared to patients presenting with acute non-fulminant myocarditis [23]. Patients with a previous history of myocarditis, Kuhl et al. [31] showed that viral persistence in the myocardium leads to left ventricular deterioration (LV), whereas clearance of the viral genomes resulted in a significant improvement of LV function. Myocarditis masquerading as myocardial infarction usually results in a full recovery of cardiovascular function in previously healthy adults [32]. Patients with clinical features of heart failure may have a mildly compromised left ventricular ejection fraction [LVEF] of 42% to 50% which typically improves within weeks to months. Moderate to severe cases lead to a more advanced left ventricular dysfunction (LVEF 30-35%, left ventricular end-diastolic dimension 60 mm). Alternatively, patients with chronic ventricular dysfunction will need planned surgical heart transplantation, or will eventually lead to sudden death [33]. Patients follow-up of two to three years suffering from myocarditis is pivotal as reoccurrence even after years of its first episode is highly possible. However, the natural course of history in patients with newly diagnosed cardiomyopathy due to myocarditis remains unclear and problematic.

INCIDENCE AND ETIOLOGY

Myocarditis is reported to be one of the leading courses of the sudden death of young adults [34-37] and is also a primary underlying etiology of other myocardial diseases such as DCM and infective inflammatory cardiomyopathy [38, 39]. Infective ICM, however, may also be triggered by reversible and irreversible toxic, mechanical injury, ischemic or drug-related inflammation, transplant rejection or other immune reactions as the case of autoimmune myocarditis. The incidence of the infectious disease accounts for the majority of cases, in previously healthy patients typically due to either a direct viral infection or post-viral immune-mediated reaction. Viral myocarditis still remains the prototype for the disease study. Although, a broad array of etiologies is implicated as causes of myocarditis as a single disease entity and its evolution. The extensive testing of myocardial tissues for potential viral etiologies are facilitated by the use of polymerase chain reaction (PCR) [40]. The etiologies of myocarditis, infective inflammatory cardiomyopathies are manifold and include viral, bacterial, helminthic, fungal, rickettsial, and protozoal infections as well as other noninfectious causes (Table 1). The histology of inflammation in the myocardium is nowadays characterized quantitatively by an infiltrate of ≥14 cells/mm². The respective subpopulations named as B- (CD 21-positive) and T-cells, whereby CD3 labels all, CD4 only helper, CD8 suppressor, CD45R0 activated T-cells and CD 68 macrophages and monocytes. The interplay between the myocardial injury by microbial agents and the different components of the patient’s immune system determine the histological and clinical phenotype of the individual patient.

Table 1 Etiologies of Myocarditis, human infectious and non-infectious inflammatory cardiomyopathy.

MYOCARDITIS

The term myocarditis inflammation of the myocardium describes acute inflammatory disorders of