Surprise, surprise: idiopathic, isolated complete atrioventricular block may be heritable.

Congenital complete AV block (CAVB) affects 1 in 20 000 live-born infants2 and is commonly associated with an immune-related cause associated with maternal collagen vascular disease or structural cardiac disease.3 Other causes of CAVB have been described, including infections, myopathies, and genetic disorders such as the Hunter and Hurler syndromes. Still, the specific cause of CAVB remains elusive for a significant number of patients, raising the possibility that a portion of idiopathic CAVB stems from CAVBsusceptibility genes. Currently, mutations in transcription factors and cardiac channels yield electrocardiographic phenotypes that include cardiac conduction abnormalities. For example, patients with NKX2.5 mutations can have cardiac conduction defects, cardiomyopathy, and atrial septal defects.4 Long-QT syndrome has also been associated with both 2:1 AV block ad CAVB, but this is usually in the presence of overt QT prolongation on the ECG.5 Mutations in the SCN5A-encoded Nav1.5 sodium channel have an everexpansive breadth of channelopathic/cardiomyopathic phenotypes, including type 3 long-QT syndrome, type 1 Brugada syndrome, dilated cardiomyopathy, and atrial standstill and conduction disturbances.6 Among patients with idiopathic CAVB, the electrophysiological phenotype may extend beyond the AV node. In the Baruteau et al cohort, a wide QRS complex was noted in almost 10% of patients with childhood AV block and in nearly one third of patients with congenital CAVB, which is extremely high compared with patients with immunemediated CAVB in which a wide QRS complex is relatively rare and is a Class I indication for a pacemaker.7 This high percentage of wide QRS complexes suggests a more diffuse disease of the conduction system rather than an effect on just the AV node. In addition, this defect may affect conduction velocity, as is evidenced by a prolonged P wave and QRS complex seen in the parents of affected individuals compared with control subjects. Although the QT and corrected QT intervals measured within normal limits, both intervals were statistically longer in parents compared with the control population. Although there is an effect on conduction velocity, there did not seem to be an effect on spontaneous depolarization because the heart rates were almost identical in the 2 groups. It is interesting that more than two thirds of their patients with incomplete AV block progressed to having CAVB, suggesting a progressive mode of damage to the AV node, not just an underlying static channelopathy. However, this progression seems to involve the conduction system exclusively because no patient died or developed dilated cardiomyopathy during a median follow-up of 11 years. There is likely a complex interaction between multiple genes in genetically mediated CAVB because the ECG phenotypes were different in children and their parents. Because virtually all cardiac channelopathies and cardiomyopathies are underscored by marked genetic and phenotypic heterogeneity, incomplete penetrance, and variable expressivity, we can anticipate the same story line for genetically mediated CAVB, not to mention the likely contribution of modifier genes in the patients who progress from incomplete to complete AV block. Furthermore, compound heterozygosity and the 2-hit phenomenon may underlie some CAVB, because we can infer from their observation that cardiac conduction impairment (but not complete AV block) was noted in both parents in 30% of the cohort. However, before proceeding with genetic testing of known channelopathyor cardiomyopathy-associated genes as intimated by the authors, caution and restraint are probably the words of the day. The recent 2011 guidelines suggested a “may be considered” recommendation concerning genetic testing for isolated/familial cardiac conduction disease and urged careful interpretation of the genetic test results.8 Currently, the anticipated yield of bona fide SCN5A defects for otherwise idiopathic CAVB is unknown, whereas the potential false-positive rate is 2% in whites and 4% to 5% in nonwhites. In addition, a major point lacking in this study is the evaluation of siblings. If there is truly a familial process, it would stand to reason that many of the siblings would be affected with conduction system disturbances or even unrecognized CAVB. Because there are many causes of conduction system disturbances in adults, including acquired coronary The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Pediatrics/Division of Pediatric Cardiology (B.C.C., M.J.A.) and Departments of Medicine/Division of Cardiovascular Diseases and Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (M.J.A.), Mayo Clinic, Rochester, MN. Correspondence to Michael J. Ackerman, MD, PhD, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN 55905. E-mail [email protected] (Circulation. 2012;126:1434-1435.) © 2012 American Heart Association, Inc.