186 | Chapter 9 Introduction In this thesis, arrhythmogenic right ventricular cardiomyopathy (ARVC) was used as a disease model to demonstrate the added clinical value of echocardiographic deformation imaging in early diagnosis and risk prediction of genetic cardiomyopathies in general. The chapters of this thesis all contribute to the process of wider clinical implementation in their own way. Besides studies of added clinical value, validation of the technique as well as pathophysiological background of our findings are addressed. Based on the research presented in this thesis, the following chapter will discuss several important aspects and future perspectives in the field. First, the role of genotypic basis in disease definition is discussed. Second, the role of computer modelling and a multimodality approach are addressed. Third, vulnerable arrhythmogenic spots of the heart and the influence of exercise on disease progression will be discussed. Finally, the future steps towards wider clinical implementation of deformation imaging will be addressed. Genotype vs Phenotype The classical approach of inherited heart muscle diseases, or cardiomyopathies, is based on phenotype. Based on morphological and functional features, a distinction is made between hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), right-sided cardiomyopathy (ARVC) and restrictive cardiomyopathy.1 While the first two are characterized by mainly structural abnormalities with hypertrophy and dilatation of the left ventricle (LV), respectively, ARVC patients may experience life-threatening arrhythmias before the occurrence of clear structural abnormalities, hence the addition “arrhythmogenic”. The problem with this phenotypic approach is that not all cardiomyopathies can be classified within one of these three categories. Not all left-sided cardiomyopathies show clear dilatation before functional impairment or arrhythmia occur, and not all cardiomyopathies evolve into isolated left- or right-dominant involvement. The problems with this phenotypic approach are well reflected in the changing terminology in the field of ARVC over the past decades, as addressed in the introduction of this thesis. Due to the diverse phenotypic manifestations observed among patients sharing a similar genetic background, the term “ARVC” had become insufficiently comprehensive. Not only the right ventricle (RV) was affected, but also the LV could be involved. Sometimes predominant or even isolated LV disease was observed. This led to the broader term arrhythmogenic cardiomyopathy (AC), which was also used in some chapters of this thesis. Since myriad unrelated diseases which can cause ventricular dysfunction and arrhythmias (including DCM) could now be classified as AC2, the field moved back to ARVC to address that one disease and a distinct arrhythmogenic left ventricular cardiomyopathy (ALVC). However, phenotypic expression may be dynamic and often progresses over time. Besides, this approach complicates familial screening, since phenotypic expression may differ within families carrying the same genetic basis for a disease. In the most recent 2023 guideline for the management of cardiomyopathies3, the category of non-dilated left ventricular cardiomyopathy (NDLVC) is added to the existing four phenotype-based categories. Besides, the guideline proposes to start the diagnostic process by integrating symptoms, incidental findings like ECG abnormalities and arrhythmia, and family history to the imaging findings in a so-called clinical scenario, which should lead to a phenotype-based diagnosis. Based on advances in medical technology, clinicians do no longer have to rely on merely phenotypical expression of disease. In the era of increasing availability of genetic testing, disease-causing genetic variants can be identified in many familial (cardiomyopathy) cases.
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