Background-Isolated cardiac conduction block is a relatively common condition in young and elderly populations. Genetic predisposing factors have long been suspected because of numerous familial case reports. Deciphering genetic predisposing factors of conduction blocks may give a hint at stratifying conduction block carriers in a more efficient way. Methods and Results-One Lebanese family and 2 French families with autosomal dominant isolated cardiac conduction blocks were used for linkage analysis. A maximum combined multipoint lod score of 10.5 was obtained on a genomic interval including more than 300 genes. After screening 12 genes of this interval for mutation, we found a heterozygous missense mutation of the TRPM4 gene in each family (p.Arg164Trp, p.Ala432Thr, and p.Gly844Asp). This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. All 3 mutations result in an increased current density. This gain of function is due to an elevated TRPM4 channel density at the cell surface secondary to impaired endocytosis and deregulation of Small Ubiquitin MOdifier conjugation (SUMOylation). Furthermore, we showed by immunohistochemistry that TRPM4 channel signal level is higher in atrial cardiomyocytes than in common ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles. Conclusions-the TRPM4 gene is a causative gene in isolated cardiac conduction disease with mutations resulting in a gain of function and TRPM4 channel being highly expressed in cardiac Purkinje fibers. (Circ Cardiovasc Genet. 2010;3:374-385.)Key Words: bundle-branch block Ⅲ heart block Ⅲ ion channel Ⅲ sudden death Ⅲ genetics C onduction block is a condition in which the depolarization wave initiated in the sinus node of the heart is slowed down or even blocked on the way to ventricular cardiomyocytes. The position of the block, its completeness (partial or complete), and the number of blocks are largely variable from one individual to the other. Conduction blocks are not rare in the general population either among young people or late in life. Right bundle-branch block (RBBB) has a prevalence of about 0.1% in normal children, with a male predominance. 1 Complete RBBB with normal left ejection fraction and no diagnoses of cardiac disease was observed in 0.3% of individuals in a population of adults with a median age of 64 years in a community-based study lead by Miller et al. 2 The natural evolution of isolated conduction blocks is unpredictable, and deciphering the genetic predisposing factors might help in unmasking those that are dangerous. Rare cases of familial conduction blocks are secondary to mutations in SCN5A 3 or NKX2.5. 4 In the latter gene, the conduction block is often associated with a congenital heart defect (typically an atrial septal defect). Recently, a South African family with cardiac conduction block was reported to carry a ...
The dilated coronary sinus (DCS) has only recently been clearly visualised in the fetus due to progress in prenatal echography. This is a retrospective study of 22 fetuses presenting with DCS revealed by prenatal echography. We report the circumstances leading to the detection of a DCS and the neonatal outcome of these fetuses. The coronary sinus was defined as dilated depending on its visualisation in cross-section from the '4 chamber' view, as well as a pseudo inter-atrial septal defect from a more posterior view. In each case the gestational age, circumstances of detection, associated anomalies and postnatal outcome are reported. The circumstances were: evaluation of a clearly identified DCS in four cases and during detailed fetal echocardiography because of suspected congenital heart disease in 18 cases. Five cases were associated with a cardiac anomaly, three with an extracardiac anomaly, six with both cardiac and extracardiac anomaly and eight were isolated. Postnatal outcome was related to the associated anomaly. In conclusion, it is important that the echography image be correctly interpreted, as a DCS often implies possible associated defects and therefore affects prognosis. When not associated with other anomalies this condition is not considered serious.
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