Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes

Hartmann, Nico; Pabel, Steffen; Herting, Jonas; Schatter, Felix; Renner, André; Gummert, Jan; Schotola, Hanna; Danner, Bernhard C.; Maier, Lars S.; Frey, Norbert; Hasenfuß, Gerd; Fischer, Thomas; Sossalla, Samuel

doi:10.1016/j.hrthm.2016.09.014

Cited by 57 publications

(67 citation statements)

References 35 publications

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“…Interestingly, and in accordance with this mechanism, reduced I Ks density, impaired repolarization reserve, and increased risk for sudden cardiac death were described in diabetic dogs (28). Although there is no doubt that RyR2 channel dysfunction is directly linked to heart failure (41), cardiac arrhythmia development (42, 43), IGT, and reduced insulin release (36, 44), however, further clinical studies are needed to determine whether RYR2 mutations leading to leaky RyR2 channels are frequently present in patients diagnosed with IGT in general.…”

Section: Discussionmentioning

confidence: 99%

Increased Short-Term Beat-to-Beat QT Interval Variability in Patients with Impaired Glucose Tolerance

et al. 2017

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Prediabetic states and diabetes are important risk factors for cardiovascular morbidity and mortality. Determination of short-term QT interval variability (STVQT) is a non-invasive method for assessment of proarrhythmic risk. The aim of the study was to evaluate the STVQT in patients with impaired glucose tolerance (IGT). 18 IGT patients [age: 63 ± 11 years, body mass index (BMI): 31 ± 6 kg/m2, fasting glucose: 6.0 ± 0.4 mmol/l, 120 min postload glucose: 9.0 ± 1.0 mmol/l, hemoglobin A1c (HbA1c): 5.9 ± 0.4%; mean ± SD] and 18 healthy controls (age: 56 ± 9 years, BMI: 27 ± 5 kg/m2, fasting glucose: 5.2 ± 0.4 mmol/l, 120 min postload glucose: 5.5 ± 1.3 mmol/l, HbA1c: 5.4 ± 0.3%) were enrolled into the study. ECGs were recorded, processed, and analyzed off-line. The RR and QT intervals were expressed as the average of 30 consecutive beats, the temporal instability of beat-to-beat repolarization was characterized by calculating STVQT as follows: STVQT = Σ|QTn + 1 − QTn| (30x√2)−1. Autonomic function was assessed by means of standard cardiovascular reflex tests. There were no differences between IGT and control groups in QT (411 ± 43 vs 402 ± 39 ms) and QTc (431 ± 25 vs 424 ± 19 ms) intervals or QT dispersion (44 ± 13 vs 42 ± 17 ms). However, STVQT was significantly higher in IGT patients (5.0 ± 0.7 vs 3.7 ± 0.7, P < 0.0001). The elevated temporal STVQT in patients with IGT may be an early indicator of increased instability of cardiac repolarization during prediabetic conditions.

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Section: Discussionmentioning

confidence: 99%

Increased Short-Term Beat-to-Beat QT Interval Variability in Patients with Impaired Glucose Tolerance

et al. 2017

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“…In addition to these molecules, other classes of RyR2 inhibitors with anti-arrhythmic effects have been described, including dantrolene, 295 carvedilol analogues, 296 and tetracaine derivatives. 297 In addition to LTCC and RyR2, other Ca 2+ channels, Ca 2+ transporters, and Ca 2+ -dependent signaling molecules (such as CaM, CaMKII) are potential therapeutic targets.…”

Section: Therapeutic Approaches To Correcting Calcium Mishandlingmentioning

confidence: 99%

Calcium Signaling and Cardiac Arrhythmias

Landstrom

Dobrev

Wehrens

2017

Circulation Research

388

331

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There has been significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function - in particular, excitation-contraction coupling and normal electrical rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes.

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“…Our group and others have demonstrated that the RyR stabilizer dantrolene has an antiarrhythmic effect . A recent study demonstrated that dantrolene produced similar outcomes to those of amiodarone with respect to the return of spontaneous circulation rates in a porcine model of prolonged VF .…”

Section: Introductionmentioning

confidence: 80%

“…Our group and others have demonstrated that the RyR stabilizer dantrolene has an antiarrhythmic effect. 3,6 A recent study demonstrated that dantrolene produced similar outcomes to those of amiodarone with respect to the return of spontaneous circulation rates in a porcine model of prolonged VF. 7 Nevertheless, it is not clear whether RyR2 modulators, comprising a class of drugs, would be beneficial in the treatment of VF or if the effect is specific to dantrolene alone.…”

Section: Introductionmentioning

confidence: 98%