'The Graduate School of the Humanities, Utrecht University'
Abstract
Background: Arrhythmogenic Cardiomyopathy (AC) is characterized by ventricular arrhythmias and structural and functional ventricular abnormalities. The genetic substrate is mostly found in genes encoding desmosomal proteins. However, pathogenic desmosomal genes mutations are identified in 60% of patients. In the remaining 40%, unclassified genetic variants or no genetic variation at all can be found. Moreover, the impact of the genotype on clinical course remains to be defined. The increased ventricular arrhythmia susceptibility is presumably due to activation delay. Therefore, detection of activation delay, preferably by non-invasive techniques, may improve risk management. Although AC is considered a progressive cardiomyopathy, information on outcomes during long-term follow-up is limited.
Objectives: 1) to evaluate the desmosomal and non-desmosomal genetic contribution, facilitate interpretation of genetic screening results, and to define the impact of genotype on disease course and 2) to evaluate invasive and non-invasive measurements of arrhythmic substrate and to define the long-term outcome of AC. The ultimate goal of this thesis was to support and improve early diagnosis and patient management in AC.
Results: The studies in this thesis showed that in 58% of Dutch AC index patients, a pathogenic desmosomal mutation was found. A non-desmosomal phospholamban (PLN) mutation was identified in 13% of patients, explaining 32% of the up-till-then genetically unexplained cases. PLN mutation carriers more often had low voltages and negative T waves in left precordial leads on their ECG and additional left ventricular abnormalities compared to desmosomal mutation carriers. An algorithm composed of in silico prediction program scores combined with the variant minor allele frequency and the in vitro mRNA analysis improved the prediction of pathogenicity of unclassified variants and facilitated interpretation of genetic screening results in AC. Genotype-phenotype correlation analysis showed that the genotype impacted the phenotype and clinical course. With invasive evaluation of arrhythmogenic substrate in AC patients, electrical abnormalities were mostly shown in the subtricuspid and RV outflow tract area. ECG criteria for non-invasive detection of activation delay mostly in the RV outflow tract already exist in the 2010 diagnostic Task Force Criteria. ECG criteria reflecting electrical abnormalities and activation delay mostly in the subtricuspid area might be: 1) late isolated potentials in inferior leads, 2) negative T waves in inferior leads, and 3) left axis deviation. Assessment of the clinical, genetic, and long-term follow-up data of 1001 individuals showed that long-term outcomes were favorable in diagnosed and appropriately treated index patients and family members. In index-patients, long-term outcome was determined by ICD implantation but remarkably not by mutation status and familial background of disease. In family members, long-term outcome was determined by symptoms at presentation and the presence of mutations.
Conclusions: The non-desmosomal PLN mutation is an important contributor to AC in The Netherlands and results in a specific phenotype. Genetic screening results interpretation can be improved by in silico and in vitro techniques. The genotype has important implications for the disease course. Non-invasive parameters of activation delay may improve early diagnosis and risk management. Long-term outcome of AC is favorable when diagnosed and appropriately treated