KCNH2 Splice Variants
Several N-terminal splice variants of the human and mouse KCNH2 genes have been identified Kupershmidt et al. 1998 Lees-Miller et al. 1997 London et al. 1997 . The full-length KNCH2 isoform has 396 amino acids in the N-terminus and is designated isoform 1a. The alternatively spliced isoform 1b has a much shorter and divergent N-terminus of 36 amino acids. Isoform 1b lacks the sequence of amino acids 2-16 and the Per-Arnt-Sim PAS motif, which are both important for the slow deactivation process...
Genetics 1
Torsades de pointes occurs in drug-induced and congenital LQTS, and less commonly in other settings. In addition, there are interesting similarities between the congenital and drug-associated forms of the syndrome, e.g., female preponderance, and exaggeration by clinical risk factors such as hy-pokalemia and bradycardia. These parallels, and the relatively unpredictable nature of the drug-induced form, suggest the hypothesis that susceptibility to the drug-induced form may be, in part,...
Na Channel Blockers Diagnosis and Treatment
Local anesthetic LA molecules such as lidocaine, mexiletine, and flecainide block Na channels and have been used therapeutically to manage cardiac arrhythmias Rosen and Wit 1983 Rosen et al. 1975 Wit and Rosen 1983 . Despite the prospective therapeutic value of the inherent voltage- and use-dependent properties of channel block by these drugs in the treatment of tachyarrhythmias, their potential has been overshadowed by toxic side effects Rosen and Wit 1987 Weissenburger et al. 1993 . There has...
Treatment Iut
VT due to sodium channel block may be difficult to treat because it may be resistant to cardioversion and frequently recurs within several beats after cardioversion. Clinical anecdotes and animal studies have suggested that infusion of sodium bicarbonate or sodium chloride may be beneficial in some cases Chouty et al. 1987 Bajaj et al. 1989 . Atrial flutter with rapid AV conduction is acutely managed by recognition and administration of AV nodal block agents, such as diltiazem and verapamil....
Atrial Fibrillation
Luderitz 2003 speculated that William Shakespeare may have been the discoverer of atrial fibrillation because he wrote in his 1611 play The Winter's Tale I have tremor cordis on me my heart dances But not for joy, not joy. An older description of paroxysmal atrial fibrillation may have been in the Bible in the book of Job it is stated that in thinking of God My heart trembleth and is moved out of its place. The first electrocardiograms of atrial fibrillation were recorded by Einthoven 1906,1908...
Ionic Currents and Action Potential Prolongation
IKr is generated by expression of the human ether a-go-go-related gene HERG, now termed KCNH2 . The electrophysiological characteristics of heterolo-gously expressed KCNH2 are very similar, but not identical to, IKr recorded from human cells one commonly observed difference is in the rates of deactivation. A commonly invoked explanation for this discrepancy is that KCNH2 associates with other protein s in at least some but perhaps not all human myocytes to generate IKr. Candidate...
Human Disease
There have been two recent reports of human HCN4 mutations associated with sinus node dysfunction SND . The first study investigated the HCN4 gene in ten patients with idiopathic SND, and found a 1-bp deletion in one patient, resulting in a C-terminal truncated HCN4 protein that lacked the CNBD, HCN4-573X Schulze-Bahr et al. 2003 . The patient exhibited sinus bradycardia with episodes of atrial fibrillation, and during exercise a maximal heart rate significantly less than that predicted for...
Animal Models
Neonatal rat ventricle cell cultures have been employed to demonstrate both the ability of HCN isoforms to enhance automaticity and the contribution of HCN channels to normal automaticity. Qu and colleagues first demonstrated that over-expressing HCN2 in these cultures significantly increased spontaneous rate Fig. 6 Qu et al. 2001 . Er and colleagues subsequently confirmed this observation and extended it to HCN4 over-expression. They also demonstrated that expression of a dominant negative...
The Electrocardiogram
In 1887, Waller was the first to record an electrocardiogram from the body surface of dog and man see Fig. 1 . He used Lippmann's capillary electrometer, an instrument in which in a mercury column borders on a weak solution of sulphuric acid in a narrow glass capillary. Whenever a potential difference between the mercury and the acid is applied, changed or removed, this boundary moves see Snellen 1995 . The capillary electrometer was sensitive, but slow. Einthoven constructed his string...
History of Arrhythmias
The Experimental and Molecular Cardiology Group, Academic Medical Center, M 051, University of Amsterdam, Meibergdreef 9,1105 AZ Amsterdam, The Netherlands m.j.janse amc.uva.nl 2 Center for Molecular Therapeutics, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168th Street, PH7West-321, New York NY, 10032, USA 2 Methods to Record the Electrical Activity of the Heart 4 2.1 The 2.2 The Interpretation of Extracellular Waveforms 6 2.3 The Recording of...