170 Chapter 7 carriers with preserved LV systolic function, suggesting that fibrosis is an early feature of PLN-R14del cardiomyopathy.193 They hypothesized that the inferolateral wall could be more vulnerable due to regional molecular changes caused by the mutation or that the regional susceptibility could result from exposure to higher mechanical stress.194 This finding could suggest that cardiac fibrosis is an early feature of PLN-R14del cardiomyopathy before LV function decreases. In fact, recent data show that total collagen turnover correlates weakly to moderately with clinical parameters in PLN-R14del patients.88 The occurrence of fibrosis is then speculated to be a primary process triggered by the PLN-R14del mutation, which eventually leads to ventricular arrhythmias and heart failure. Additionally, an independent association between the presence of fibrosis and the occurrence of ventricular arrhythmias has been demonstrated.195 Hence, the heterogeneity of fibrosis depends on both the spatial size and the degree of heterogeneity: a larger size and larger degree of heterogeneity make the formation of arrhythmias more probable.196 Recent data show that total collagen turnover correlates weakly to moderately with clinical parameters in PLN-R14del patients.197 These findings may help to understand the disease onset and to improve the identification and diagnosis of PLN-R14del patients. Inflammation Inflammation is a hallmark of heart failure and plays a crucial role in the progression of cardiac dysfunction in both DCM and ACM.198,199 However, very little is known about the role of inflammation in DCM/ACM associated with PLN-R14del mutation. Recently, an unbiased approach of combined transcriptomics and proteomics revealed a progressive increase of myocardial inflammation in the hearts of homozygous PLN-R14del mice.200 Interestingly, a strong infiltration of immune cells was observed in the sub-epicardial region of the heart in a knock-in PLN-R14del zebrafish model.201 Together the results of these studies suggest that inflammation might impact PLN-R14del disease progression and emphasize the clinical relevance of inflammation in the severity of PLN-R14del-induced cardiomyopathy. Further investigation is needed to understand the specific mechanisms by which inflammation contributes to disease progression in PLN-R14del-associated cardiomyopathy. This could involve studying the interactions between immune cells, cytokines, and other signalling molecules in the heart. In addition, it would be important to investigate whether the extent of inflammation correlates with disease severity in PLN-R14del-associated cardiomyopathy patients. This could involve analyzing patient samples and medical records to identify potential biomarkers of inflammation and disease progression. A recent study used a label-free whole myocardium multi-omics analysis in homozygous PLN-R14del (PLN-R14Δ/Δ) mice and identified four biomarkers associated with all-cause mortality; proline and arginine-rich end leucine-rich repeat protein (PRELP), cytoskeleton-associated protein 4 (CKAP4), S100 calciumbinding protein A11 (S100A11) and annexin A1 (ANXA1).98 These biomarkers play roles in disease progression (cell death and tissue repair pathways) and the regulation of the inflammatory
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