Drug induced shortening of the QT/QTc interval: An emerging safety issue warranting further modelling and evaluation in drug research and development?

Holbrook, Mark; Malik, Marek; Shah, Rajiv; Valentin, Jean‐Pierre

doi:10.1016/j.vascn.2008.09.001

Cited by 46 publications

(41 citation statements)

References 44 publications

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“…[24][25][26] Likewise, little is known about the significance of acquired, e.g., drug-induced shortening of QTc and therapeutic consequences are uncertain. 23,27,28 Primidone and rufinamide can both shorten QTc, 29,30 but these drugs were not used in our patients. Although the use of carbamazepine could have influenced our results, this drug is associated with bradyarrhythmias and has only minor effects on QT intervals.…”

Section: Methodsmentioning

confidence: 90%

“…Shortening of QT is substantially mediated by circulating catecholamines and can be enhanced by hyperkalemia and acidosis. 23,27,28,33 All these conditions occur particularly during or shortly after GTCS. 18,19,34 Furthermore, chronic epilepsy patients display altered autonomic function with a presumably increased sympathetic tone and enhanced QT dispersion (spatial heterogeneity of cardiac repolarization), which are both independent predictors of cardiac mortality.…”

Section: Methodsmentioning

confidence: 99%

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Enhanced QT shortening and persistent tachycardia after generalized seizures

Surges¹,

Scott²,

Walker³

2010

Neurology

139

111

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Objective: Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP). We investigated whether ictal/postictal cardiac features were dependent on seizure type within individual patients.Methods: ECG data from patients with medically refractory temporal lobe epilepsy (TLE) undergoing presurgical investigation who had both complex partial seizures and secondarily GTCS during video-EEG telemetry were retrospectively reviewed. Peri-ictal heart rate (HR), corrected QT interval (QTc), HR variability, and cardiac rhythm were assessed.Results: Twenty-five patients were included in this study. Secondarily GTCS led to higher ictal HR, persistent postictal tachycardia, and decreased postictal HR variability. Moreover, abnormal shortening of QTc occurred in 17 patients mainly during the early postictal phase and significantly more often in secondarily GTCS. Abnormal QTc prolongation occurred in 3 patients with no significant association with GTCS. Benign cardiac arrhythmias occurred in 14 patients and were independent of seizure type. Conclusions:Our data suggest a substantial disturbance of autonomic function following secondarily generalized tonic-clonic seizures (GTCS) in patients with medically refractory temporal lobe epilepsy. The observed alterations could potentially facilitate sudden cardiac death and might contribute to the association of sudden unexpected death in epilepsy with GTCS. Neurology ® 2010;74:421-426 GLOSSARY CI ϭ confidence interval; CPS ϭ complex partial seizure; GTCS ϭ generalized tonic-clonic seizures; HR ϭ heart rate; HRV ϭ HR variability; QTc ϭ corrected QT interval; SUDEP ϭ sudden unexpected death in epilepsy; TLE ϭ temporal lobe epilepsy.Sudden unexpected death in epilepsy (SUDEP) is the most frequent epilepsy-related cause of death and is particularly prevalent in patients with chronic epilepsy.1 In younger people with epilepsy (age 20 -40 years), the risk for sudden death is increased about 24-fold compared to the general population.2 Peri-ictal cardiorespiratory alterations are likely to be involved in the pathophysiology of SUDEP and include tachyarrhythmias and bradyarrhythmias as well as central or obstructive hypoventilation and neurogenic pulmonary edema.1 Since generalized tonic-clonic seizures (GTCS) are a major risk factor for SUDEP, 3,4 then determining the specific cardiac characteristics of GTCS may give us a considerable insight into the mechanisms underlying SUDEP. Abnormalities in cardiac repolarization, persistent elevations of heart rate (HR) after exercise, and a decreased HR variability (HRV) are established predictors for cardiac mortality and sudden cardiac death in other medical conditions or in healthy populations. [5][6][7] Previous studies have suggested a greater impact of GTCS on cardiac excitability than nongeneralized seizures with higher ictal heart rates in chronic epilepsy and SUDEP patients 4,[8][9][10][11] and possibly more cardiac arrhythmias following GTCS. 8,10 These studies, however, are confou...

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Section: Methodsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Enhanced QT shortening and persistent tachycardia after generalized seizures

Surges¹,

Scott²,

Walker³

2010

Neurology

139

111

View full text Add to dashboard Cite

show abstract

“…Moreover, evidence was provided that detection of delayed repolarization was not sufficient to determine proarrhythmic potentials. Lastly, preclinical safety pharmacology studies were suggested to include assessment of the potentials to shorten ventricular repolarization [4][5][6].…”

Section: Preclinical Models For Assessment Of Ion Channel-related Carmentioning

confidence: 99%

“…In addition to delayed ventricular repolarization, evidence was recently provided and discussed that shortening of ventricular repolarization is a risk factor for ventricular arrhythmias [4][5][6]. Only a few patients with congenital short QT syndrome (SQTS) have been described to date, but all suffer from an increased vulnerability to atrial and ventricular fibrillation and sudden cardiac death [7].…”

mentioning

confidence: 99%

Cardiac Toxicity

Kettenhofen¹,

Schwengberg²

2010

ADMET for Medicinal Chemists

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“…There has long been a need arising from within the industry as well as from global regulatory authorities for the implementation of a certification process to confirm expertise and identify quality standards for professionals involved in the practice of SP. In response to such needs, SPS has provided recommendations on best practices in a form of peer-reviewed publications, as well as discussions during annual meetings (Authier, Vargas, Curtis, Holbrook, & Pugsley, 2013;Cavero, 2013Cavero, , 2014Holbrook, Malik, Shah, & Valentin, 2009;Leishman et al, 2012;Vargas et al, 2008).…”

mentioning

confidence: 99%