An Unusual Case of Flecainide‐induced <scp>QT</scp> Prolongation Leading to Cardiac Arrest

Oguayo, Kevin N.; Oyetayo, Ola O.; Costa, Steven M.; Mixon, Timothy A.

doi:10.1002/phar.1403

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…These agents prolong the QRS complex with minimal effect on the QT interval [61] . However, there are case reports where flecainide was shown to prolong the QT interval and lead to TdP [64] . Importantly, class IC agents have been implicated with proarrhythmia leading to SCD in patients with underlying structural heart disease [65] .…”

Section: Interactions Of Antiarrhythmic Drugs With Covid-19 Pharmacotmentioning

confidence: 99%

COVID-19 infection and cardiac arrhythmias

Manolis¹,

Manolis

et al. 2020

Trends in Cardiovascular Medicine

112

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Highlights Serious cardiac arrhythmias may be the consequence of direct effects of COVID-19 infection, but also the outcome of the deleterious effects of systemic illness and the adverse proarrhythmic reactions to drugs employed in the treatment of this pandemic Drug combinations, especially of QT-prolonging agents, can lead to higher arrhythmogenicity, compared with single drug therapies Furthermore, critically ill COVID-19 patients often have comorbidities that can trigger life-threatening ventricular arrhythmias, while acute myocardial injury increases the prevalence of arrhythmias ECG and QTc monitoring and taking appropriate measures are of critical importance to prevent, detect and manage cardiac arrhythmias in COVID-19 patients Contactless monitoring and telemetry for inpatients, especially those admitted to the ICU, as well as for outpatients needing continued management, has recently been facilitated by implementing digital health monitoring tools

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Section: Interactions Of Antiarrhythmic Drugs With Covid-19 Pharmacotmentioning

confidence: 99%

COVID-19 infection and cardiac arrhythmias

Manolis¹,

Manolis

et al. 2020

Trends in Cardiovascular Medicine

112

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“…Flecainide, nevertheless, remains one of the first‐line treatments for symptomatic atrial fibrillation in patients with structurally normal hearts . This practice, however, is increasingly challenged by clinical observations indicating that flecainide can induce VT, often in the form of torsade de pointes, in patients without coronary artery disease or severe heart failure . The Pediatric Electrophysiology Group reported on the relatively high incidence of flecainide‐induced proarrhythmia in young cardiac patients, presumably in the absence of advanced coronary atherosclerosis which is commonly seen in the elderly .…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 99%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

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“…Although rarely associated with Torsades de Pointes (TdP) arrhythmia or QT interval prolongation, some cases have been reported in which rate-corrected QT interval prolongation was not fully accounted for by widening of the QRS complex, and/or that exhibited a reverse-rate/bradycardia dependence that is consistent with a role for I Kr inhibition (e.g. [25–28] ).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide

Melgari

Zhang

Harchi

et al. 2015

Journal of Molecular and Cellular Cardiology

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The class Ic antiarrhythmic drug flecainide inhibits KCNH2-encoded “hERG” potassium channels at clinically relevant concentrations. The aim of this study was to elucidate the underlying molecular basis of this action. Patch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37 °C. Wild-type (WT) IhERG was inhibited with an IC50 of 1.49 μM and this was not significantly altered by reversing the direction of K+ flux or raising external [K+]. The use of charged and uncharged flecainide analogues showed that the charged form of the drug accesses the channel from the cell interior to produce block. Promotion of WT IhERG inactivation slowed recovery from inhibition, whilst the N588K and S631A attenuated-inactivation mutants exhibited IC50 values 4–5 fold that of WT IhERG. The use of pore-helix/selectivity filter (T623A, S624A V625A) and S6 helix (G648A, Y652A, F656A) mutations showed < 10-fold shifts in IC50 for all but V625A and F656A, which respectively exhibited IC50s 27-fold and 142-fold their WT controls. Docking simulations using a MthK-based homology model suggested an allosteric effect of V625A, since in low energy conformations flecainide lay too low in the pore to interact directly with that residue. On the other hand, the molecule could readily form π–π stacking interactions with aromatic residues and particularly with F656. We conclude that flecainide accesses the hERG channel from the cell interior on channel gating, binding low in the inner cavity, with the S6 F656 residue acting as a principal binding determinant.

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An Unusual Case of Flecainide‐induced QT Prolongation Leading to Cardiac Arrest

Cited by 10 publications

References 24 publications

COVID-19 infection and cardiac arrhythmias

COVID-19 infection and cardiac arrhythmias

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide

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