Electrophysiological and Contractile Effects of Disopyramide in Patients With Obstructive Hypertrophic Cardiomyopathy: A Translational Study
| Autor: | Raffaele, Coppini, Cecilia, Ferrantini, Josè Manuel, Pioner, Lorenzo, Santini, Zhinuo J, Wang, Chiara, Palandri, Marina, Scardigli, Giulia, Vitale, Leonardo, Sacconi, Pierluigi, Stefàno, Laura, Flink, Katherine, Riedy, Francesco Saverio, Pavone, Elisabetta, Cerbai, Corrado, Poggesi, Alessandro, Mugelli, Alfonso, Bueno-Orovio, Iacopo, Olivotto, Mark V, Sherrid |
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| Rok vydání: | 2019 |
| Předmět: |
QT interval
safety HCM hypertrophic cardiomyopathy pCa Ca activation level SR sarcoplasmic reticulum hERG human ether-à-go-go-related gene hypertrophic cardiomyopathy RyR ryanodine receptor EAD early afterdepolarization PRECLINICAL RESEARCH ECG electrocardiography ICa-L L-type Ca current NCX Na+/Ca2+ exchanger IK delayed-rectifier K current LVOT left ventricular outflow tract diastolic dysfunction AP action potential DAD delayed afterdepolarization arrhythmias INaL late Na current action potentials |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • In patients with HCM and symptomatic LVOT-obstruction, first treatment with disopyramide leads to a marked reduction of LVOT gradients, with a slight decrease of resting ejection fraction and a modest increase of corrected QT interval, highlighting high efficacy and safety. • In single cardiomyocytes and intact trabeculae from surgical samples of patients with obstructive HCM, in vitro treatment with 5 μmol/l disopyramide lowered force and Ca2+ transients while reducing action potential duration and the rate of arrhythmic afterdepolarizations. • These effects are mediated by the combined inhibition of peak and late Na+ currents, L-type Ca2+ current, delayed-rectifier K+ current, and ryanodine receptors. • In addition to the negative inotropic effect of disopyramide, in vitro results suggest additional antiarrhythmic actions. Summary Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We tested disopyramide in cardiomyocytes from the septum of surgical myectomy patients: disopyramide inhibits multiple ion channels, leading to lower Ca transients and force, and shortens action potentials, thus reducing cellular arrhythmias. The electrophysiological profile of disopyramide explains the efficient reduction of outflow gradients but also the limited prolongation of the QT interval and the absence of arrhythmic side effects observed in 39 disopyramide-treated patients. In conclusion, our results support the idea that disopyramide is safe for outpatient use in obstructive patients. |
| Databáze: | OpenAIRE |
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