169 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 deposition of excess fibrous connective tissue is the result of a disturbed balance between the synthesis and degradation of extracellular matrix proteins due to myofibroblast activation.177 Interestingly, PLN-R14del hearts were compared with hearts with desmosomal, lamin A/C, sarcomeric, and desmin mutations and presented the highest amount of myocardial fibrosis which is found in a distinct pattern in the posterolateral left ventricular wall.178 Further studies in Dutch patient populations have demonstrated a more detailed analysis using digital quantification and identified a distinct pattern of interstitial fibrosis, most prominently located in the subepicardial layer of the posterolateral wall of the left ventricle in PLN-R14del patients compared to controls and other hereditary cardiomyopathies.179–182 Fibrosis is associated with low R amplitudes and inverted T waves found on ECGs of PLN-R14del patients.183,184 Using a novel method of high-resolution systematic digital histological quantification of fibrosis and fatty infiltration in transversal cardiac slides, Gho et al. determined the exact patterns of fatty changes in PLN-R14del hearts.185 They found that fatty changes in the myocardial tissue were observed in the entire right ventricular (RV) wall and partially in the epicardial layer of the left ventricle (LV) posterolateral wall. Overall, the amount of adipose tissue infiltration was more pronounced in the RV than in the LV. The observations share this conclusion in several other studies, where fibrofatty replacement was mainly observed in the epicardial layer of the RV wall and limited fibrofatty alterations were seen in the LV wall.186–189 Fibrofatty replacement could be induced by increased sensitivity to wall stress and metabolic demand in the RV.190 Additionally, a recent preprint has revealed increased lipid droplet accumulation in both the hearts and stem cell-derived cardiomyocytes of PLN-R14del patients. Here, the authors identified key transcription factors involved in the affected (lipid) metabolism, even before the onset of RV wall stress.95 Another recent study has linked lipid droplet accumulation in PLN-R14del to the impairment of the ER/mitochondria compartment.72 Nonetheless, the exact pathophysiological mechanism and metabolic changes behind the source of adipose structures in PLN-R14del cardiomyopathy remain to be investigated. Still, the exact pathophysiological mechanism responsible for the segregated and distinct pattern of fibrosis in PLN-R14del hearts remains to be elucidated. Onset of pathological myofibroblast activation and fibrosis Despite fibrosis being a crucial process in the repair of damaged tissue, progressive fibrosis can lead to myocardial stiffness, dysfunction, and arrhythmias.191,192 Sepehrkhouy et al.178 speculated that the pattern of predominantly posterolateral epicardial fibrosis is induced by increased sensitivity to wall stress on the heart. This wall stress could be induced when cardiomyocytes are more vulnerable to mechanical forces. For example, the aggregation of remnant PLN protein found in cardiomyocytes81 or disturbed calcium handling can result in the maladaptive remodeling of the macromolecular protein complexes, leading to enhanced mechanical force within the cardiomyocyte.52 Interestingly, te Rijdt et al. have observed a specific predominance of fibrosis in the inferolateral wall of the left ventricle in PLN-R14del
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