Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy

被引:68
作者
Westermann, D
Knollmann, BC
Steendijk, P
Rutschow, S
Riad, A
Pauschinger, M
Potter, JD
Schultheiss, HP
Tschöpe, C
机构
[1] Charite Univ Med Berlin, Dept Cardiol & Oneumol, D-12220 Berlin, Germany
[2] George Washington Univ, Med Ctr, Dept Pharmacol, Washington, DC USA
[3] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands
[4] Univ Miami, Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL USA
关键词
troponin T mutation; diastole; sudden death; heart failure;
D O I
10.1016/j.ejheart.2005.07.012
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
`Background: The cardiac troponin T 179N mutation, linked to familial hypertrophic cardiomyopathy, carries a high risk of sudden cardiac death even in the absence of significant cardiac hypertrophy. The pathology underlying this mechanism has not yet been identified. Aims: To study the underlying mechanism of this phenomenon we characterized the left ventricular (LV) performance of transgenic mice carrying the human troponin T mutation 179N under basal and isoproterenol-induced stress conditions. Methods and results: LV function was analyzed by recording pressure-volume loops using a microconductance catheter. Despite a hypercontractile systolic function under basal conditions TnT-179N mice showed a diastolic dysfunction indicated by an increase in end-diastolic pressure-volume relationship (EDPVR), a load-independent factor of LV stiffiness (0.06 +/- 0.01 vs. 0.02 +/- 0.01; P < 0.05). when compared to mice expressing human wild-type troponin T (TnT-W7). TnT-179N mutants developed severe diastolic heart failure and cardiac sudden death under isoproterenol stress. This was prevented after pretreatment with the L-type Ca2+ channel inhibitor diltiazem. Conclusions: Diastolic dysfunction due to increased LV stiffness in TnT-179N mice leads to severe primary diastolic heart failure and finally to cardiac sudden death, which can be prevented by diltiazem. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:115 / 121
页数:7
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