Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III

Molecular Cardiology and Electrophysiology Laboratory, Fondazione S. Maugeri, IRCCS, Pavia, Italy.
Circulation (Impact Factor: 14.43). 03/1999; 99(4):518-28. DOI: 10.1161/01.CIR.99.5.674
Source: PubMed


Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.

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Available from: Jeffrey A Towbin, Jan 21, 2014
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    • "It is characterized primarily by abnormal prolongation of the QT interval (QTc) due to delayed ventricular repolarization, and the occurrence of ventricular tachyarrhythmias, particularly torsade de pointes, leading to recurrent syncope (transient loss of consciousness), seizures and sudden death [Moss et al., 1991; Towbin et al., 2001; Tristani-Firouzi and Sanguinetti, 2001]. Symptoms often occur during high adrenergic activity in association with physical exercise or emotional stress [Nakajima et al., 1995; Ackerman, 1998; Priori et al., 1999] but can occur during rest or sleep [Shimizu, 2005]. Untreated patients with cardiac symptoms may have a 10-year mortality rate as high as 50% [Moss et al., 1991]. "
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    ABSTRACT: A large Australian family affected with long QT syndrome (LQTS) was studied. The medical characteristics of the 16 clinically affected members were consistent with LQT1. A previously identified mutation in KCNQ1 was found in 12 affected individuals and 1 unaffected infant but absent in 4 affected family members. A haplotype consisting of specific alleles for microsatellites flanking in KCNQ1 was associated with the mutation. This was absent from the four affected individuals without the mutation, who had three different haplotypes in this region, indicating that LQTS is unlikely to be segregating with KCNQ1 in these anomalous family members. A genome scan revealed 12 regions where all four of these individuals shared alleles. One region on chromosome 21 contained the KCNE1, KCNE2, KCNJ6, and KCNJ15 genes. A common variant of KCNE1 was segregating in the family but did not explain the anomalous cases. A candidate region on chromosome 7 contained the AKAP9 and KCND2 genes. A previously reported mutation in the N-terminal Yotiao region of AKAP9 was absent from the family. No evidence was found implicating any other known or suspected LQTS gene. This family shows that there remain unidentified genetic causes of LQTS which are clinically significant and highlights the difficulties associated with genetic testing in LQTS, since we cannot rule out risk in individuals who are negative for the known mutation in KCNQ1 without knowing the second disease locus.
    American Journal of Medical Genetics Part A 03/2010; 152A(3):613-21. DOI:10.1002/ajmg.a.33274 · 2.16 Impact Factor
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    • "pathophysiological roles of cardiac delayed rectifiers . Subsequent genetic studies in the late 1990s showed that even subtle derangements in delayed - rectifier currents can cause life - threatening arrhythmia syndromes ( Priori et al . 1999 ) , implying that delayed - rectifier function is finely tuned to ensure electrophysiological integrity . The notion that APD - prolonging drugs act by mimicking potentially lethal congenital arrhythmia syndromes provided sober food for thought ( Nattel , 2000 ) , and disease - induced delayed - rectifier channel subunit down - regulati"
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    ABSTRACT: Delayed rectifier potassium currents and the control of cardiac repolarization: Noble and Tsien forty years after.
    The Journal of Physiology 11/2008; 586(Pt 24):5849-52. DOI:10.1113/jphysiol.2008.163089 · 5.04 Impact Factor
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    • "Whether such interplay may consist of a simple summation or have a more complex nature is largely unknown. There are diverse conditions under which adrenergic activation is not accompanied by the expected (quantitatively appropriate) increase in ventricular activation rate; they are all characterized by an abnormal susceptibility to ventricular arrhythmias, mostly attributed to repolarization abnormalities (Zlotikamien et al. 1990; Swan et al. 1999; Priori et al. 1999). Whilst in some conditions the mismatch between neural activity and rate response stands out as the causative abnormality (Ueda et al. 2004), in others it can enhance the arrhythmogenic effect of primary (Gladman et al. 1996) and drug-induced repolarization defects (Pinski et al. 2002). "
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    ABSTRACT: Beta-adrenergic stimulation modulates ventricular currents and sinus cycle length (CL). We investigated how changes in CL affect the current induced by isoprenaline (Iso) during the action potential (AP) of guinea-pig ventricular myocytes. Action-potential clamp was applied at CLs of 250 and 1000 ms to measure: (1) the net current induced by 0.1 microm Iso (I(Iso)); (2) the L-type Ca2+ current I(CaL) and slow delayed rectifier current I(Ks) components of I(Iso) (I(IsoCa) and I(IsoK)), identified as the Iso-induced current sensitive to nifedipine and HMR1556, respectively; and (3) I(Iso) persisting after inhibition of both I(Ca) and I(Ks) (I(isoR)). The pause dependency of I(Ks) and its modulation were evaluated in voltage-clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD90) and its modulation by isoprenaline were tested in current-clamp experiments. At a CL of 250 ms I(Iso) was inward during initial repolarization and reversed at 59% of APD90. At a CL of 1000 ms I(Iso) became mostly inward in all cells. Switching to shorter CL did not change I(IsoCa) and I(IsoK) amplitudes, but moved their peak amplitudes to earlier repolarization; I(IsoR) was independent of CL. Acceleration of I(IsoK) at shorter CL was based on faster pause dependency of I(Ks) activation rate. The 'restitution' of activation rates was modulated by isoprenaline. The APD90-CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min(-1)). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL-dependent I(Ca) and I(Ks) modulation; (2) the effect of isoprenaline on APD90 was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.
    The Journal of Physiology 08/2006; 574(Pt 1):183-93. DOI:10.1113/jphysiol.2006.105015 · 5.04 Impact Factor
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