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Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy.
Coleman, James A; Doste, Ruben; Beltrami, Matteo; Argirò, Alessia; Coppini, Raffaele; Olivotto, Iacopo; Raman, Betty; Bueno-Orovio, Alfonso.
Afiliación
  • Coleman JA; Department of Computer Science, University of Oxford, Oxford, United Kingdom.
  • Doste R; Department of Computer Science, University of Oxford, Oxford, United Kingdom.
  • Beltrami M; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
  • Argirò A; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
  • Coppini R; Department of NeuroFarBa, University of Florence, Florence, Italy.
  • Olivotto I; Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
  • Raman B; Meyer Children's Hospital IRCCS, Florence, Italy.
  • Bueno-Orovio A; Oxford Centre for Clinical Magnetic Resonance Research (OCMR), Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.
Front Pharmacol ; 15: 1379236, 2024.
Article en En | MEDLINE | ID: mdl-38659580
ABSTRACT

Introduction:

Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na+ block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM.

Methods:

Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against in vitro and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects.

Results:

10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JTc interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment.

Conclusion:

Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Suiza