Arrhythmogenic Right Ventricular Cardiomyopathy : Genetic and Electrocardiographic Aspects on Risk of Ventricular Arrhythmia and Diagnosis

Sammanfattning: Introduction: ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy) is a heritable rare disease of the heart muscle, primarily affecting the right ventricle, that may cause arrhythmias and heart failure.Aim: The overall aim of this thesis was to study various aspects of genetic information and electrocardiography (ECG), for their use in diagnosis and risk evaluation in ARVC.Material and methods: Paper I: The genotype-phenotype correlations in four unrelated families with a plakophilin 2 gene variant (PKP2 c.2146-1C>G) were studied, to determine 1) to what extent family members fulfil diagnostic criteria and 2) to assess whether these gene carriers had any specific clinical characteristics in common. Paper II: Patients with definite ARVC but one group with and one without diagnostic ECG criteria were compared to each other and a healthy control group. Vectorcardiographic parameters were assessed alongside QRS duration, corrected QT interval and an angle measuring the upslope and downslope of the S wave (S-wave angle). Paper III: Combined Annotation Dependent Depletion (CADD, a bioinformatic tool) scores were calculated for all pathogenic and likely pathogenic variants in PKP2 found in patients from two ARVC Registries, and the scores association with arrhythmic events and age at definite ARVC diagnosis were assessed. Paper IV: Digital ECGs (n=6871) from 353 patients with definite ARVC were analysed using Glasgow algorithm to describe the longitudinal development of different ECG characteristics, but also to assess the relationship between the ECG parameters and 1) structural abnormalities and 2) sustained ventricular tachycardia (VT) during a 10-year follow-up.Results: Paper I: In 41 family members evaluated, 23 were mutation carriers, and seven of them fulfilled diagnostic criteria. The clinical presentation was variable, and no specific genotype-phenotype correlation was found. Paper II: The vectorcardiographic parameters significantly differentiated the ARVC patients with normal ECGs from controls (p>0.004 to p<0.001). Paper III: In total, 33 unique genetic variants were reported in 179 patients. CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p=0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p=0.731). Paper IV: Progressive changes in depolarisation and repolarisation parameters before as well as after the diagnosis was established confirming the progressive nature of ARVC developing over the course of decades, possibly in parallel with structural changes in the ventricles. The presence of T wave inversion in leads V3 or aVF at first ECG was significantly associated with ventricular tachycardia during 10 years follow-up (for lead V3 [HRadj 2.11, 95%CI 1.28-3.49, p=0.003], lead aVF [HRadj 1.68, 95%CI 1.02-2.77, p=.041] both adjusted for age, sex and proband status).Conclusions: Our studies confirms previous results that, with our current knowledge, genetic variants in desmosomal genes are useful for diagnosis and cascade screening in family members but not for detailed risk stratification or prediction of diagnosis. Progressive changes in depolarisation and repolarisation ECG parameters before as well as after the diagnosis were established, confirming the progressive nature of ARVC developing over the course of decades, possibly in parallel with structural changes in the ventricles. Novel vectorcardiographic markers may aid in early detection of disease progression, possibly with biggest potential in cascade screening.