Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression.
BACKGROUND
According to clinical-pathological correlation studies, the natural history of arrhythmogenic right ventricular dysplasia/cardiomyopathy is purported to progress from localized to global right ventricular dysfunction, followed by left ventricular (LV) involvement and biventricular pump failure. The inevitable focus on sudden death victims and transplant recipients may, however, have created a skewed perspective of a genetic disease. We hypothesized that unbiased representation of the spectrum of disease expression in arrhythmogenic right ventricular dysplasia/cardiomyopathy would require in vivo assessment of families in a genetically heterogeneous population.


RESULTS
A cohort of 200 probands and relatives satisfying task force or modified diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy underwent comprehensive clinical evaluation. Desmosomal mutations were identified in 39 individuals from 20 different families. Indices of structural severity correlated with advancing age and were increased in long-term endurance athletes. Fulfillment of modified criteria indicated phenotypically mild disease, whereas asymptomatic status did not. In >80%, ECG, rhythm monitoring, and/or gadolinium-enhanced cardiovascular magnetic resonance were suggestive of LV involvement, the extent of which often was marked among individuals with chain-termination mutations and/or desmoplakin disease. Three patterns of disease expression were identified: (1) classic, with isolated right ventricular disease or LV involvement in association with significant right ventricular impairment; (2) left dominant, with early and prominent LV manifestations and relatively mild right-sided disease; and (3) biventricular, characterized by parallel involvement of both ventricles.


CONCLUSIONS
LV involvement in arrhythmogenic right ventricular dysplasia/cardiomyopathy may precede the onset of significant right ventricular dysfunction. Recognition of disease variants with early and/or predominant LV involvement supports adoption of the broader term arrhythmogenic cardiomyopathy.
Sen-Chowdhry
Srijita
S
The Heart Hospital, University College London, United Kingdom.
Syrris
Petros
P
Ward
Deirdre
D
Asimaki
Angeliki
A
Sevdalis
Elias
E
McKenna
William J
WJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000453:epidemiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002648:Child; D018389:Codon, Nonsense; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D051187:Desmocollins / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000473:pathology; D018450:Disease Progression; D004562:Electrocardiography; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006334:Heart Function Tests; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D010807:Physical Endurance; D051191:Plakophilins / Q000235:genetics; D013177:Sports; D051185:gamma Catenin
D018389:Codon, Nonsense; C081561:DSC2 protein, human; C495314:DSG2 protein, human; C495294:DSP protein, human; D051187:Desmocollins; D051301:Desmoglein 2; D051180:Desmoplakins; C495292:JUP protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D051185:gamma Catenin