Understanding of the molecular and ionic mechanisms underlying cardiac electrophysiology is essential for the appreciation of the pathogenesis of conduction abnormalities in structurally normal and altered hearts. These fundamental principles and concepts are necessary for the diagnosis and treatment of patients with cardiac electrophysiological disease processes. Based on the increasing knowledge of pathophysiology of conduction system disease, alternative diagnostic methods and new therapeutic strategies can be targeted. The gene therapy approach is an expanding research field as a promising, albeit futuristic, alternative to pacemaker devices. Currently electronic pacemakers are the mainstay of therapy for heart block and other electrophysiological abnormalities, but particularly in the pediatric population they are suboptimal regarding patient's size, continued growth and activity, limited battery and lead longevity, and a lack of biological responsiveness of native tissue. Thus, several gene therapy approaches have been explored as potential alternatives, including over-expression of β2-adrenergic receptors, the use of a dominant-negative construct to suppress inward rectifier current when expressed together with the wild-type gene Kir2.1, and the implantation of vectors carrying the pacemaker gene HCN2 into atrium or bundle branches. A common problem inherent in these approaches is the use of viruses to deliver the necessary genes. Although the vectors are replication-deficient adenoviruses that have little infectious potential, there is concern related to the possibility of only a transient improvement in pacemaker function as well as potential inflammatory responses and proarrhythmia.
In summary, inherited conduction system disease is not a single entity caused by a single-gene mutation. There are a myriad of inherited CCS diseases, ranging from isolated sinoatrial or AV nodal defects to diffuse conduction system diseases associated with congenital heart diseases, neuromuscular disorders, and cardiomyopathies. Somatic factors and environmental influences may modulate the disease severity, making genotype–phenotype correlation challenging. The genetic bases of these inherited conduction system diseases range from early developmental transcription factor mutations, ion channelopathies, to mutations in genes regulating energy metabolism, gap junctions, and other structural proteins.
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The authors are very grateful to Emily McIntosh, Emily Harris, and Bill McIntosh for excellent graphical design of the figures.Reprint Address
Charles I. Berul, M.D., Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Fax: (617) 566-5671; E-mail: email@example.com
J Cardiovasc Electrophysiol. 2006;17(4):446-455. © 2006 Blackwell Publishing
Cite this: Inherited Conduction System Abnormalities -- One Group of Diseases, Many Genes - Medscape - Apr 01, 2006.