161 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 were considerably reduced in the RV of PLN-R14del cardiomyocytes.99 Moreover, myofilament calcium sensitivity increased in both ventricles of these mutant mice. These findings indicate that myofilament calcium function in disturbed in both ventricles, but abnormal myocyte calcium cycling and contractility are primarily limited to the RV over the long term. In another recent study, RNA-Sequencing splicing analysis revealed more than 200 different alternative splicing events and profiles in the LV and RV of PLN-R14del versus healthy mouse hearts.97 Interestingly, in the RV, the most affected biological process was associated with "cardiac cell action potential". Furthermore, the splicing of two key genes, TRPM4 and CAMK2D, which encode proteins that regulate calcium homeostasis in the heart, was altered in PLN-R14del mouse hearts and hiPSC-CMs. This suggests that abnormal splicing may influence calcium homeostasis in the heart, potentially contributing to the increased risk of arrhythmogenesis in PLN-R14del arrhythmogenic cardiomyopathy. These findings collectively present, for the first time, distinct differences in calcium cycling and contractility within specific heart compartments affected by PLN-R14del disease. The reason why the PLN-R14del mutation affects the right ventricle, specifically in this mouse model, is not fully understood. However, it is known that there are intrinsic differences in the physiology and metabolism between the left and right ventricles. Additionally, compensatory mechanisms in the LV may mask any effects of the PLN-R14del mutation in this compartment. Further studies are needed to fully elucidate the mechanisms underlying the compartmentspecific effects of PLN-R14del mutation in the heart. Ventricular tachycardia One of the most concerning clinical features of PLN-R14del mutation is the risk of malignant ventricular tachycardia (VT), which can be life-threatening. This risk appears to be agedependent, with the incidence of VT increasing over time.11,74 Even if an individual does not exhibit any symptoms, they may still be at risk for developing complications associated with the mutation. Therefore, early identification of high-risk individuals who carry the PLN-R14del mutation is crucial. This allows for close monitoring and timely intervention, which can help prevent life-threatening ventricular arrhythmias and/or slow down the progression of heart failure. In a recent study using artificial intelligence, echocardiographic deformation imaging was employed to predict the risk of VT in pre-symptomatic mutation carriers.106 This technique allows for the assessment of both regional and global myocardial deformation patterns, offering valuable insights into the heart’s mechanical function. The study identified significant alterations in mechanical function, particularly in the apical region, among pre-symptomatic PLN-R14del mutation carriers, indicating an increased risk of VT.116 These findings suggest that deformation imaging could be a valuable tool for identifying individuals at a heightened risk
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