12 Chapter 1 GENERAL INTRODUCTION This chapter describes the scientific content that incited the hypotheses and ideas investigated in this thesis. Firstly, it introduced the clinical significance of a genetic variation in cardiomyopathies, especially the dilated cardiomyopathy and arrhythmogenic cardiomyopathy, caused by a deleterious mutation of the arginine 14 codon in the phospholamban (PLN) gene (p.Arg14del). Secondly, it describes the knowledge derived from cardiogenesis and reproducible methods for the efficient generation of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs). Lastly, it discusses the use of hiPSC-CMs for disease modeling and contemporary challenges encountered in drug research and postulates methodological alternatives. 1.1 Clinical relevance In the past 30 years, the importance of cardiomyopathies as causes of morbidity and mortality, particularly in sudden cardiac death and heart failure, has been highlighted by the recognition of disease-causing genetic variants.1 Genetic cardiomyopathies affect families following a Mendelian inheritance pattern with variable phenotype expression. They typically affect young patients and are important causes of sudden cardiac death in individuals who might otherwise be asymptomatic. The individual genetic makeup and environmental circumstances are responsible for a highly variable disease onset and progression. Despite major efforts to improve their condition with lifestyle alterations and medication, the natural course of cardiomyopathies cannot be halted, and gradual progress towards severely impaired cardiac function and death is generally inevitable. Progress has also been made in the management of several types of cardiomyopathies. However, advances in understanding these diseases show that cardiomyopathies represent complex genotypic and phenotypic entities.2 Therefore, in the past decade, major progress has been made in detecting and, understanding the molecular and genetic basis of disease, pathophysiology, and clinical and radiological assessment of genetic cardiomyopathies.3,4 These insights can potentially fuel enormous improvements for the early detection and novel therapeutic strategies of the future to prevent the detrimental effects of genetic cardiomyopathies. 1.2 PLN-R14del cardiomyopathy The major inherited cardiomyopathies, dilated cardiomyopathy (DCM), arrhythmogenic cardiomyopathy (ACM), and hypertrophic cardiomyopathy (HCM), are characterized by arrhythmias and/or cardiac dysfunction often leading to progressive heart failure and sudden cardiac death.5 In 40-60% of the patients with DCM and HCM, underlying pathogenic variants can be found, mainly located in genes encoding sarcomeric proteins6,7. In contrast, ACM is mainly caused in 60% of the patients by pathogenic variants in desmosomal genes.8 Interestingly, one of the pathogenic mutations in both 10% of the DCM and 15% of
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