Electrophysiologic Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes

Tan, Hanno L.; Hou, Charles Jia Yin; Lauer, Michael R.; Sung, Ruey J.

doi:10.7326/0003-4819-122-9-199505010-00009

Cited by 231 publications

(130 citation statements)

References 147 publications

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“…Torsades de pointes tachycardia is often associated with hypokalaemia and possibly concomitant hypomagnesaemia [5,6]. We found no indication of other underlying perturbations in our patient, e.g.…”

Section: Discussionmentioning

confidence: 59%

Life‐threatening ventricular tachycardia due to liquorice‐induced hypokalaemia

Eriksson

Carlberg

Hillörn

1999

Journal of Internal Medicine

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Abstract. Eriksson JW, Carlberg B, Hillo Èrn V (Umea Ê University Hospital, Umea Ê, Sweden). Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia (Case Report). J Intern Med 1999; 245: 307]10.We report on a patient with hypokalaemia and severe ventricular tachycardia of torsades de pointes type which turned out to be caused by an apparent mineralocorticoid excess syndrome associated with liquorice consumption. The patient, a 44-year-old woman, attended the hospital because of irregular heart rhythm and she displayed repeated episodes of life-threatening torsades de pointes ventricular tachycardia. The initial serum potassium was low: mmol L 21. The patient was treated with potassium and magnesium infusions, and the dysrhythmias eventually ceased. Endocrinological investigations showed no indication of Cushing's syndrome or hyperaldosteronism. After some time it became clear that the patient had ingested moderately large amounts of liquorice every day for 4 months. After the patient stopped this habit the hypokalaemia and dysrhythmias did not recur and after more than 1 year there are no signs of cardiac illness.

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Section: Discussionmentioning

confidence: 59%

Life‐threatening ventricular tachycardia due to liquorice‐induced hypokalaemia

Eriksson

Carlberg

Hillörn

1999

Journal of Internal Medicine

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“…16,17) EADs typically occur at slow heart rates. 18) Increasing the cycle length from 2 to 5 seconds resulted in AP prolongation, along with a significantly higher incidence of EAD formation in females. EADs were observed in 80% of the female VMs (n = 5) tested, but in none of the male VMs (n = 5).…”

Section: Resultsmentioning

confidence: 99%

Gender Disparities in Cardiac Cellular Electrophysiology and Arrhythmia Susceptibility in Human Failing Ventricular Myocytes

et al. 2005

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SUMMARYGender disparities in ECG variables and susceptibility to arrhythmia exist. The basis of these sex-related distinctions in cardiac electrophysiology has been extensively studied in various species, but is virtually unexplored in humans. The aim of this study was to clarify the cellular basis of electrophysiological gender disparities in human cardiac myocytes.Human midmyocardial left ventricular myocytes were isolated from explanted hearts of male and female patients in end-stage heart failure at the time of cardiac transplantation. The action potentials, sarcolemmal ion currents, and susceptibility to the generation of early afterdepolarizations were studied using whole-cell patch-clamp methodology. The functional effects of gender disparities in sarcolemmal ion currents were assessed by computer simulations using the Priebe-Beuckelmann or the ten Tusscher-Noble-Noble-Panfilov human ventricular cell models.Female myocytes had significantly longer action potentials and greater susceptibility to early afterdepolarizations than male myocytes. All other action potential parameters (resting membrane potential, amplitude, plateau level, upstroke velocity, maximal velocity of phase-1 and phase-3 repolarization) had similar values for both genders. In female myocytes, the transient outward potassium current (I to1 ) tended to be smaller, while the Ltype calcium current (I Ca,L ) and quasi-steady state current (I QSS ) tended to be larger. Computer simulations showed that these subtle differences in sarcolemmal ion currents may conspire to cause the observed gender disparities in action potential properties.Female failing myocytes have longer action potentials and a greater susceptibility to early afterdepolarizations than male failing myocytes. These gender disparities may be due to slightly larger depolarizing I Ca,L in conjunction with slightly smaller repolarizing I QSS and I to1 in female myocytes. (Int Heart J 2005; 46: 1105-1118

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“…Numerous classes of drugs have been shown to prolong the QT interval, which reflects a slowing of repolarization of the ventricular myocardium (12,13), where excessive prolongation can lead to the potentially life-threatening ventricular tachyarrhythmia, torsade de pointes. In cardiac tissue, inhibition of potassium channels is associated with QT interval prolongation (14,15).…”

Section: Introductionmentioning

confidence: 99%

Shape Signatures: New Descriptors for Predicting Cardiotoxicity In Silico

Chekmarev

Kholodovych

Balakin

et al. 2008

Chem. Res. Toxicol.

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Shape Signatures is a new computational tool that is being evaluated for applications in computational toxicology and drug discovery. The method employs a customized ray-tracing algorithm to explore the volume enclosed by the surface of a molecule and then uses the output to construct compact histograms (i.e., signatures) that encode for molecular shape and polarity. In the present study, we extend the application of the Shape Signatures methodology to the domain of computational models for cardiotoxicity. The Shape Signatures method is used to generate molecular descriptors that are then utilized with widely used classification techniques such as k nearest neighbors (k-NN), support vector machines (SVM), and Kohonen self-organizing maps (SOM). The performances of these approaches were assessed by applying them to a data set of compounds with varying affinity toward the 5-HT 2B receptor as well as a set of human ether-a-go-go-related gene (hERG) potassium channel inhibitors. Our classification models for 5-HT 2B represented the first attempt at global computational models for this receptor and exhibited average accuracies in the range of 73−83%. This level of performance is comparable to using commercially available molecular descriptors. The overall accuracy of the hERG Shape Signatures-SVM models was 69−73%, in line with other computational models published to date. Our data indicate that Shape Signatures descriptors can be used with SVM and Kohonen SOM and perform better in classification problems related to the analysis of highly clustered and heterogeneous property spaces. Such models may have utility for predicting the potential for cardiotoxicity in drug discovery mediated by the 5-HT 2B receptor and hERG.

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Electrophysiologic Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes

Abstract: The long QT interval syndromes and torsade de pointes are potentially life-threatening conditions caused by various agents, conditions, and genetic defects. The mechanisms responsible for these conditions and available treatment options for them are reviewed.

Cited by 231 publications

References 147 publications

Life‐threatening ventricular tachycardia due to liquorice‐induced hypokalaemia

Life‐threatening ventricular tachycardia due to liquorice‐induced hypokalaemia

Gender Disparities in Cardiac Cellular Electrophysiology and Arrhythmia Susceptibility in Human Failing Ventricular Myocytes

Shape Signatures: New Descriptors for Predicting Cardiotoxicity In Silico

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