This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.
Background-Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in Ϸ50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-One hundred forty-nine ARVD/C index patients (111 male patients; age, 49Ϯ13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44Ϯ13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligationdependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V 1 to V 3 , especially in mutation-carrying relatives Ͻ20 years of age. In 45% of screened families, Ն1 affected relatives were identified (90% with mutations). Conclusions-Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives. A rrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is histopathologically characterized by progressive fibrofatty replacement of myocardium, primarily of the right ventricle (RV). 1-3 Although familial occurrence was recognized in the first report, only in the last decade has the genetic substrate been identified in genes encoding desmosomal proteins. 1,4 -9 Desmosomes are protein complexes in the intercalated disk, among others responsible for mechanical coupling of cardiac myocytes. Their impairment leads to both mechanical and electric uncoupling of cardiomyocytes, followed by cell death with fibrofatty replacement. 10 -13 Both uncoupling and altered architecture result in activation delay, which is the pivotal mechanism for reentry and thus ventricular tachycardia (VT). 14 -16 Editorial see p 2661 Clinical Perspective on p 2700Arrhythmogenic right ventricular dysplasia/cardiomyopathy usually shows an autosomal dominant inheritance pattern, w...
BACKGROUND Patients with long QT syndrome (LQTS) have inadequate shortening of the QT interval in response to the sudden heart rate accelerations provoked by standing—a phenomenon of diagnostic value. We now validate our original observations in a cohort twice as large. We also describe that this abnormal QT-interval response persists as the heart rate acceleration returns to baseline. OBJECTIVES To describe a novel observation, termed “QT stunning” and to validate previous observations regarding the “QT-stretching” phenomenon in patients with LQTS by using our recently described “standing test.” METHODS The electrocardiograms of 108 patients with LQTS and 112 healthy subjects were recorded in the supine position. Subjects were then instructed to stand up quickly and remain standing for 5 minutes during continuous electrocardiographic recording. The corrected QT interval was measured at baseline (QTcbase), when heart rate acceleration without appropriate QT-interval shortening leads to maximal QT stretching (QTcstretch) and upon return of heart rate to baseline (QTcreturn). RESULTS QTcstretch lengthened significantly more in patients with LQTS (103 ± 80 ms vs 66 ± 40 ms in controls; P <.001) and so did QTcreturn (28 ± 48 ms for patients with LQTS vs −3 ± 32 ms for controls; P <.001). Using a sensitivity cutoff of 90%, the specificity for diagnosing LQTS was 74% for QTcbase, 84% for QTcreturn, and 87% for QTcstretch. CONCLUSIONS The present study extends our previous findings on the abnormal response of the QT interval in response to standing in patients with LQTS. Our study also shows that this abnormal response persists even after the heart rate slows back to baseline.
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