Diltiazem prevents stress-induced contractile deficits in cardiomyocytes, but does not reverse the cardiomyopathy phenotype in Mybpc3 -knock-in mice
| Autor: | Felix W. Friedrich, Silke Reischmann-Düsener, Frederik Flenner, Florian Weinberger, Lucie Carrier, Birgit Geertz, Thomas Eschenhagen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Inotrope medicine.medical_specialty Physiology business.industry Diastole Cardiomyopathy Hypertrophic cardiomyopathy 030204 cardiovascular system & hematology medicine.disease Left ventricular hypertrophy Muscle hypertrophy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology Internal medicine Isoprenaline cardiovascular system Cardiology Medicine Diltiazem business medicine.drug |
| Zdroj: | The Journal of Physiology. 595:3987-3999 |
| ISSN: | 0022-3751 |
| Popis: | Left ventricular hypertrophy, diastolic dysfunction and fibrosis are main features of hypertrophic cardiomyopathy (HCM). Guidelines recommend β-adrenoceptor or Ca2+ channel antagonists as pharmacological treatment. The Ca2+ channel blocker diltiazem recently showed promising beneficial effects in pre-clinical HCM, particularly in patients carrying MYBPC3 mutations. In the present study we evaluated whether diltiazem could ameliorate or reverse the disease phenotype in cells and in vivo in Mybpc3-targeted knock-in (KI) mouse model of HCM. Sarcomere shortening and Ca2+ transient were measured in KI and wild-type (WT) cardiomyocytes in basal condition (1-Hz pacing) and under stress conditions (30 nm isoprenaline, 5-Hz pacing) with or without pre-treatment with 1 μm diltiazem. KI cardiomyocytes exhibited lower diastolic sarcomere length (dSL) at baseline, a tendency to a higher positive inotropic response to isoprenaline than WT, and a marked reduction of dSL and a tendency towards arrhythmias under stress conditions. Pre-treatment of cardiomyocytes with 1 μm diltiazem reduced the drop in dSL and arrhythmia frequency in KI, and attenuated the positive inotropic effect of isoprenaline. Furthermore, diltiazem reduced the contraction amplitude at 5 Hz but did not affect diastolic Ca2+ load and Ca2+ transient amplitude. Six-month diltiazem treatment of KI mice did not reverse cardiac hypertrophy and dysfunction, activation of the fetal gene program or fibrosis. In conclusion, diltiazem blunted the response to isoprenaline in WT and KI and improved diastolic relaxation under stress conditions in KI cardiomyocytes. This beneficial effect of diltiazem in cells did not translate in therapeutic efficacy when applied chronically in KI mice. This article is protected by copyright. All rights reserved |
| Databáze: | OpenAIRE |
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