174 Chapter 7 DISCUSSION PLN-R14del-associated cardiomyopathy is a complex disease that encompasses a spectrum of phenotypes, including both autosomal-dominant DCM and the association with ventricular arrhythmias. The disease is causing global concern with now 10 countries describing many patients carrying the p.Arg14del variant (Figure 1). Notably, understanding the role of the PLN mutation in this disease provides critical insights into the broader context of heart failure pathophysiology, contributing to a comprehensive understanding of heart diseases.233 Here, we have systematically gathered the studies describing PLN cardiomyopathy and the potential molecular mechanisms underlying the disease pathophysiology (Table 1, Supplementary Table 1). Importantly, clinicians have observed variability in disease penetrance, which includes the diversity in disease onset, differing from young symptomatic patients and elderly asymptomatic mutation carriers.234 With this variability, a mosaic pattern of cardiomyocytes with and without PLN aggregates was observed.235–237 Multiple mechanisms such as allelic imbalance or environmental factors could play a role238, where (epi)genomic analysis may unravel key modifiers and risk factors affecting the disease development.239 A recent study by van der Voorn revealed that the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protei, previously described as a secondary hit in cardiomyopathies, was not associated with life-threatening arrhythmias or heart failure-related events of 848 PLN-R14del carriers.109 Allelic imbalance is a process where two alleles of a gene are transcribed differentially and thereby expressed at different levels in a cell. Allelic imbalance has been identified in 88% of genes in human tissues240, which can be either tissue-specific or genome-wide.240,241 Additionally, more research is required focusing on the development and progression of PLN-R14del disease before heart failure occurs. For this, a human heart biobank was recently established, in which heart tissues and medical data from deceased donors are stored and can be used for scientific research.242 The collection of heart tissue from pre-symptomatic individual carriers will allow to study of early-stage disease mechanisms. Moreover, animal models represent potential approaches to studying disease onset and progression. Indeed, the recent development of PLN-R14del mouse models, together with the PLN-R14del zebrafish model, has helped identify early-stage molecular mechanisms of PLN-R14del disease. In addition, a pig model of PLN-R14del disease has been generated60, which could offer advantages over mouse and zebrafish models, especially in terms of cardiovascular physiology and disease manifestation, as they have a cardiac system that is anatomically and functionally more similar to humans. Pig models will better facilitate the efforts to delineate the molecular and cellular mechanisms underlying the pathogenesis of the PLN-R14del clinical phenotype and evaluate potential therapeutic interventions. However, animal models could give different outcomes compared to humans, as seen with the Istaroxime study in zebrafish243 versus the Istaroxime (PST3093) analogue compound in
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