Frontiers in Myocardia

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.

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.

Genetic testing over the years has grown to be a crucial aspect in medical practice for inheritable forms of cardiomyopathies. However, though a great deal of progress in understanding the genetic basis of dilated cardiomyopathy has been made, issues of rare variants, prevalence, penetrance, mismatch, noncausal options, the burden of heart failure, and the more-complex genomics that underlie dilated cardiomyopathy still exist in cardiovascular genetics today. The challenging aspect of identifying common and rare genetic variants contributing to systolic heart failure is made difficult due to its diverse and multiple etiology. Improving our understanding of the genetic basis of both systolic heart failure and dilated cardiomyopathies, would lead to the discovery of rare novel variant(s), identify malignant phenotypes, help optimize treatment and clarify the diagnosis. Hence, this chapter aims to provide a detailed and concise overview of dilated cardiomyopathy genetic etiology, discuss the latest phenomic and genomic available data which are vital to understanding the emerging complexity of familial dilated cardiomyopathy as well as the clinical utilities and limitations of genetic testing. The chapter will also, examine the genetic underpinnings of heart failure syndromes, advances in the common and rare variant discovery and the interpretation in dilated cardiomyopathy and systolic heart failure. With this in mind, this chapter will further aim to define the diagnostic criteria(s) of familial dilated cardiomyopathy, current clinical management options/strategies and the implications, these findings hold for patient care and future research.

One of Cardiology's “great masqueraders” and the most common heritable cardiovascular disease with a heterogeneous clinical presentation, hypertrophic cardiomyopathy (HCM) has been investigated extensively over the past two decades affecting approximately 1 in 500 individuals. HCM is one of the primary causes of sudden death in young people and a significant cause of heart failure at any age. Once considered deadly, untreatable, and relentless as delays and mistakes in diagnosis abound, it has become a highly treatable disease, though contemporary with the help of genomic medicine. The continuous research and discovery of new HCM susceptibility genes, recent advances in the diagnosis and treatment of HCM, a growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM have been crucial in decreasing the frequency of adverse clinical events. However, complete elimination of sudden cardiac death remains an elusive gain. Therefore, it is essential that a modern-day basic or clinical physician, cardiologist, cardiac surgeons, and cardiovascular geneticist understand the diagnostic, prognostic, and therapeutic implications of HCM. This chapter aims to evaluate the new development and the novel achievements made compared to previous eras of the disease across published European registries. It also analyses the prevalent issues and misconceptions regarding HCM that persist among practicing physicians today. The chapter further focuses on the risk assessment, the various diagnosis and treatment therapies in children, adolescent, adults, and athletes in contrast to the current European set guidelines for the diagnosis and management of HCM patients.

Restrictive cardiomyopathy is an uncommon heart muscle disorder characterized by reduced diastolic volume and an impaired ventricular filling in the presence of a normal systolic function and normal or near normal myocardial thickness (progressive symptoms of heart failure) with various gene mutations having been identified in cardiac genes (desmin, α-actin, troponin I and troponin T). It is a clinically challenging type of cardiomyopathy due to it is diverse etiopathogenesis, and a heterogeneous group of myocardial diseases which usually result from an increased myocardial stiffness leading to impaired ventricular filling with an often-poor prognosis in infants, and children. Despite advances in resynchronization and pharmacological therapy, many patients progress to end-stage heart failure as congestive heart failure continue to remain a severe burden even in the Western World with patients been either candidate for a heart transplant or a left ventricular assist device therapy. This chapter will focus primarily on clinical practice for primary care physicians and pediatric heart failure cardiologist. It will also go further to highlight the clinical and functional characteristics of restrictive cardiomyopathy linked mutations within the troponin complex, as well as address both clinical and reported functional studies for known troponin mutations associated with restrictive cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease that primarily affects the right ventricle where the right ventricular free wall is partially or almost entirely replaced by fatty or fibrofatty tissue, providing a substrate for lifethreatening ventricular arrhythmias in young, apparently healthy individuals and athletes. However, whether fatty or fibrofatty infiltration of the right ventricle has been considered to be a sufficient morphologic hallmark of arrhythmogenic right ventricular cardiomyopathy is still a source of controversy as it is crucial that arrhythmogenic right ventricular cardiomyopathy is kept distinct from both fatty infiltrations of the right ventricle and Adipositas cordis. The autosomal dominant inheritance pattern is typical of this myocardial disease, and the identification of causative mutations in cell adhesion proteins has shed new light on its pathogenesis with familiar studies highlighting the need to broaden the diagnostic criteria, which are highly specific but lacking in sensitivity. This chapter will provide a detailed insight into arrhythmogenic right ventricular cardiomyopathies pathology, pathophysiology, clinical presentations, diagnosis, and management. It will however also highlight the genetic basis of arrhythmogenic right ventricular cardiomyopathy, risk stratification, phenotypic manifestations, and arrhythmia mechanisms with an analytical review of the evolving role of cardiac magnetic resonance and late gadolinium enhancement with contrastenhanced imaging in the diagnostic workup of arrhythmogenic right ventricular cardiomyopathy.

Sudden death is always an unexpected and devastating occurrence. The normal electrophysiological behavior of the human heart is determined by an ordered propagation of excitatory stimuli that result in slow repolarization and a rapid depolarization, thereby, generating action potential in each myocyte. Hence, mutations in or involving cardiac ion channels result in an abnormal propagation or action potential formation, leading to cardiac arrhythmias. Despite the worrisome impact of sudden cardiac death, and sudden infant death syndrome in the society resulting from such arrhythmias, knowledge of the underlying cellular mechanism is poor, and treatment is consequently and continuously limited. This chapter aims to focus on the role of basic science (current diagnostic and therapeutic options) in investigating primary electrical cardiac diseases as a paradigm for cardiac arrhythmias, concentrating on the long-QT syndrome, Brugada syndrome, and catecholaminergic polymorphous ventricular tachycardia. Also, the underlying pathology and physiology of ion channel diseases are described associated with sudden infant death syndrome to provide a clinical perspective of cardiac channelopathies about sudden infant death syndrome. The learning objectives of the chapter would enable practicing physicians/clinicians in the field to:

I. Recognize risk factors, signs, and symptoms that should prompt suspicion of a congenital arrhythmia syndrome,

II. Explain the treatment options, list measures to prevent sudden cardiac death and sudden infant death syndrome, and

III. Finally, describe what can be achieved with molecular genetic diagnostic tests and thereby, comfortably list the difficulties and limitations of interpreting genetic results.

Congenital Chagas disease known as a neglected tropical disease can, however, be considered as an ecological model of multiple and complex interactions between parasites, the pregnant woman, placenta, and the unborn child. Indeed, congenital infection is a rather rare event, it can, however, occur and be found in any part of the world and the lack of a well-established surveillance program means that the diagnosis can probably be easily missed putting both the pregnant mother and the fetus, with the newborn at risk. In this era of globalization with the ongoing European immigration policies, Congenital Chagas disease would no longer become confined to only poor rural areas and endemic countries, eventually becoming a significant public health concern. Bearing this in mind, the possibility of Chagasic disease, in general, becoming the new human immunodeficiency virus in third world African countries and developing African nations in the foreseeable future is inevitable. The simple fact that both the policymakers, and the health care providers are ignorant of the disease and also lack both the technical knowledge and understanding of the disease modes of transmission, progression, pathology, and its pathophysiology make it futuristically possible. This chapter aims to discuss the presenting global challenge of this neglected tropical disease, its ecological interactions and also try to better understand the mechanisms sequentially associated with the transmission of live parasites from maternal blood and the development of congenital infection (asymptomatic) or congenital Chagas disease (symptomatic) in the fetus and newborns (in both endemic and non-endemic areas).

Accepted as an unclassified cardiomyopathy by the American Heart Association or a genetic cardiomyopathy by the European Society of Cardiology, left ventricular non-compaction is an intriguing, but poorly understood condition characterized by the presence of a non-compacted extensive myocardial layer lining the cavity of the left ventricle which potentially leads to malignant arrhythmias, cardiac failure, and thromboembolism. Whether it is distinct cardiomyopathy or a morphological heterogeneous clinical condition with phenotypic morphologic traits often overlapping other types of cardiomyopathies remains very much debated. Ventricular trabeculation and compaction are two of the many essential steps for generating a functionally competent ventricular wall whereas, hyper trabeculation and the lack of ventricular wall compaction (non-compaction) are also one of the significant cardio-embryogenic defects associated with left ventricular noncompaction. This chapter aims to discuss in detail the current knowledge on embryology, epidemiology, clinical spectrum, genetics as both an isolated trait, and as part of other cardiac diseases or complex syndromes. It also explains the physiology, and the present pathophysiological concepts of non-compaction cardiomyopathy, provide an up-to-date view on imaging and also reevaluate the current diagnostic criteria and its impact on overdiagnosis of left ventricular non-compaction as well as the available data on prognosis, and therapy. The chapter will even go further to describe the challenges, and uncertainties facing the medical community, and the future directions in diagnosing left ventricular non-compaction.

Takotsubo syndrome is one of the few heart conditions that have witnessed an increasing incidence in modern clinical practice. It is an acute syndrome that presents with various clinical symptoms and etiological factors. Since its first description in the early 1990s, much progress has been made in many aspects of the condition including its treatment approaches, clinical investigations, prognosis, clinical presentation, complications, pathophysiology, epidemiology, triggers, anatomical variants, primary and secondary clinical subtypes, diagnosis, definition, and terminology. In addition to clinical studies, many pre-clinical and basic research platforms and technologies have been developed to help advance our understanding of this syndrome. This chapter presents a comprehensive discussion on what is the current state of knowledge concerning this disease. By so doing, we provide the clinical and non-clinical scientists as well as general readers with new diagnostic approaches, subtypes classification, and management tools for Takotsubo. New algorithms to facilitate decision-making by a cardiologist are provided as well as grey areas for further research.

The sex preference of Takotsubo and the role of estrogen and catecholamines are brought to focus on providing the future research outlook of this condition. The available treatments and proposed mechanisms are also summarized. Although Takotsubo is generally considered to have a good prognosis, some complications of severe nature may occur in a subset of patients, e.g., dangerous ventricular arrhythmias, cardiogenic shock, pulmonary edema, which can cause damage to the myocardium which transcends the recovery phase of the left ventricular ballooning.

Endomyocardial fibrosis is a neglected tropical heart disease of poverty which carries a poor prognosis with no specific treatment, and the most common restrictive cardiomyopathy worldwide, affecting mainly children and young adults. Since the first description(s) in Uganda in 1948, high-frequency areas for EMF have included Africa, Asia, and South America and more recently, developed eastern European countries. Although, its etiology, pathogenesis and natural history remain unclear, its natural history includes both an active and chronic phase with recurrent flare-ups of inflammation characterized by an impaired diastolic filling of either one or both ventricles as a result of the fibrous tissue deposition on the endocardial surface, variable degree of systolic dysfunction, atrioventricular valve dysfunction, and associated intra-cavitary thrombi. This chapter aims to discuss the current knowledge so far in clinical practice about the etiology, mechanism(s) and natural history of the disease which would improve public awareness in rural endemic areas, leading to early detection and diagnosis of the disease, enhancing therapeutic strategies/treatment, biomolecular and other innovative technologies. The chapter would further go on to explore and highlight critical potential gray areas for future translational research which would enable both basic and clinical researchers, physicians and surgeons recognize and address the many gaps, inconsistencies, flaws, and setbacks encountered with this neglected cardiovascular disease.