Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome

Mazzanti, Andrea; Maragna, Riccardo; Vacanti, Gaetano; Κωστοπούλου, Άννα; Marino, Maira; Monteforte, Nicola; Bloise, Raffaella; Underwood, Katherine; Tibollo, Valentina; Pagan, Eleonora; Napolitano, Carlo; Bellazzi, Riccardo; Bagnardi, Vincenzo; Priori, Silvia G.

doi:10.1016/j.jacc.2017.10.025

Cited by 75 publications

(41 citation statements)

References 13 publications

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“…Importantly, (hydro)quinidine has recently also been confirmed to be associated with prevention of life‐threatening arrhythmic events in SQTS patients (Mazzanti et al. ). For the N558K mutation at least, simulation data suggest that the beneficial actions of quinidine on effective refractory period result from both I hERG / I Kr inhibition and the drug's Na channel inhibitory action (Whittaker et al.…”

Section: Discussionmentioning

confidence: 99%

“…Issues with (hydro)quinidine availability in some countries (Mazzanti et al. ) may be problematic for its use, however. In relation to this, it is worth highlighting that conventional voltage clamp experiments have shown that the Class Ia agent disopyramide also retains effectiveness against the S631A mutation (Paul et al.…”

Section: Discussionmentioning

confidence: 99%

“…The N588K SQT1 hERG mutation has previously been demonstrated to have quantitatively similar effects on potency of quinidine inhibition of I hERG under conventional voltage clamp (with IC 50 values 3.5-to 5.8fold those for WT I hERG ; (Wolpert et al 2005;McPate et al 2008)) and (hydro)quinidine is effective in prolonging the QT interval in that form of SQT1 (Wolpert et al 2005;Giustetto et al 2011;Villafane et al 2013). Importantly, (hydro)quinidine has recently also been confirmed to be associated with prevention of life-threatening arrhythmic events in SQTS patients (Mazzanti et al 2017). For the N558K mutation at least, simulation data suggest that the beneficial actions of quinidine on effective refractory period result from both I hERG /I Kr inhibition and the drug's Na channel inhibitory action (Whittaker al.…”

Section: Effectiveness Of Quinidinementioning

confidence: 99%

“…However, the similarity between the effects of the N588K and S631A mutations on potency of I hERG inhibition by quinidine in a direct comparison ) and the known effectiveness of the drug in N588K hERG linked SQT1 strongly suggest that quinidine is likely to be effective at delaying repolarization in the setting of S631A-linked SQT1. Issues with (hydro)quinidine availability in some countries (Mazzanti et al 2017) may be problematic for its use, however. In relation to this, it is worth highlighting that conventional voltage clamp experiments have shown that the Class Ia agent disopyramide also retains effectiveness against the S631A mutation (Paul et al 2001;McPate et al 2008) and so disopyramide might provide a viable alternative where quinidine is unavailable.…”

Section: Effectiveness Of Quinidinementioning

confidence: 99%

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Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Butler¹,

Zhang²,

Stuart

et al. 2018

Physiol Rep

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The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss‐ and gain‐of‐function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (I h ERG) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on I h ERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current–voltage (I–V) relation for I h ERG exhibited a marked right‐ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented I h ERG, which also peaked much earlier during the AP plateau than did wild‐type (WT) I h ERG. Instantaneous I–V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance‐voltage relation showed an earlier and more sustained rise in S631A compared to WT I h ERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted I h ERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 μmol/L) against S631A I h ERG. Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effectiveness Of Quinidinementioning

confidence: 99%

Section: Effectiveness Of Quinidinementioning

confidence: 99%

See 2 more Smart Citations

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Butler¹,

Zhang²,

Stuart

et al. 2018

Physiol Rep

View full text Add to dashboard Cite

show abstract

“…Therefore, an indication should be evaluated by a referral centre with good experience in SQTS (El-Battrawy et al, 2019). In addition, recently published data have shown that hydroquinidine prevent arrhythmias (Giustetto et al, 2011;Mazzanti et al, 2017). Other antiarrhythmics such as carvediol, metoprolol, and sotalol do not have the same effect as hydroquinidine (El-Battrawy et al, 2018a).…”

Section: Introductionmentioning

confidence: 99%

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

El‐Battrawy

Schlentrich

et al. 2020

Front. Genet.

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Background: Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse. Methods: We conducted a pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl). Results: 67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%). Conclusions: The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).

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Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

Zhao

El‐Battrawy

et al. 2019

Clin Pharma and Therapeutics

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Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug—quinidine—has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single‐cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC‐CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD‐prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC‐CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine‐induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.

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Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome

Cited by 75 publications

References 13 publications

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome

Differences in Short QT Syndrome Subtypes: A Systematic Literature Review and Pooled Analysis

Drug Testing in Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

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