Mechanisms of pro-arrhythmic abnormalities in ventricular repolarisation and anti-arrhythmic therapies in human hypertrophic cardiomyopathy
Passini, Elisa ; Mincholé, Ana ; Coppini, Raffaele ; Cerbai, Elisabetta ; Rodriguez, Blanca ; Severi, Stefano ; Bueno-Orovio, Alfonso
Resumen: Introduction
Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.
Methods
Experimental ionic current, action potential (AP) and Ca2 +-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.
Results
Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca2 + current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca2 +, but compromised CaT amplitude. Late Na+ current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na+/Ca2 + exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block.
Conclusions
Experimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.
Idioma: Inglés
DOI: 10.1016/j.yjmcc.2015.09.003
Año: 2016
Publicado en: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 96 (2016), 72-81
ISSN: 0022-2828
Factor impacto JCR: 5.68 (2016)
Categ. JCR: CELL BIOLOGY rank: 42 / 189 = 0.222 (2016) - Q1 - T1
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 20 / 126 = 0.159 (2016) - Q1 - T1
Factor impacto SCIMAGO: 2.536 - Molecular Biology (Q1) - Cardiology and Cardiovascular Medicine (Q1)
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
Exportado de SIDERAL (2021-05-07-08:16:16)
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Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalities remains unknown. The goal of this study is to identify key ionic mechanisms driving repolarisation abnormalities in human HCM, and to evaluate anti-arrhythmic effects of single and multichannel inward current blocks.
Methods
Experimental ionic current, action potential (AP) and Ca2 +-transient (CaT) recordings were used to construct populations of human non-diseased and HCM AP models (n = 9118), accounting for inter-subject variability. Simulations were conducted for several degrees of selective and combined inward current block.
Results
Simulated HCM cardiomyocytes exhibited prolonged AP and CaT, diastolic Ca2 + overload and decreased CaT amplitude, in agreement with experiments. Repolarisation abnormalities in HCM models were consistently driven by L-type Ca2 + current (ICaL) re-activation, and ICaL block was the most effective intervention to normalise repolarisation and diastolic Ca2 +, but compromised CaT amplitude. Late Na+ current (INaL) block partially abolished repolarisation abnormalities, with small impact on CaT. Na+/Ca2 + exchanger (INCX) block effectively restored repolarisation and CaT amplitude, but increased Ca2 + overload. Multichannel block increased efficacy in normalising repolarisation, AP biomarkers and CaT amplitude compared to selective block.
Conclusions
Experimentally-calibrated populations of human AP models identify ICaL re-activation as the key mechanism for repolarisation abnormalities in HCM, and combined INCX, INaL and ICaL block as effective anti-arrhythmic therapies also able to partially reverse the HCM electrophysiological phenotype.
Idioma: Inglés
DOI: 10.1016/j.yjmcc.2015.09.003
Año: 2016
Publicado en: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 96 (2016), 72-81
ISSN: 0022-2828
Factor impacto JCR: 5.68 (2016)
Categ. JCR: CELL BIOLOGY rank: 42 / 189 = 0.222 (2016) - Q1 - T1
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 20 / 126 = 0.159 (2016) - Q1 - T1
Factor impacto SCIMAGO: 2.536 - Molecular Biology (Q1) - Cardiology and Cardiovascular Medicine (Q1)
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. Exportado de SIDERAL (2021-05-07-08:16:16)
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