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Eur J Heart Fail. 2006 Mar;8(2):115-21. Epub 2005 Oct 7.

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

Author information

1
Department of Cardiology and Pneumonology, Charite-Universiätsmedizin Berlin, Campus Benjamin-Franklin, Hindenburgdamm 30 12220, Berlin, Germany.

Abstract

BACKGROUND:

The cardiac troponin T I79N 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 I79N 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-I79N mice showed a diastolic dysfunction indicated by an increase in end-diastolic pressure-volume relationship (EDPVR), a load-independent factor of LV stiffness (0.06+/-0.01 vs. 0.02+/-0.01; P<0.05), when compared to mice expressing human wild-type troponin T (TnT-WT). TnT-I79N 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-I79N mice leads to severe primary diastolic heart failure and finally to cardiac sudden death, which can be prevented by diltiazem.

PMID:
16214409
DOI:
10.1016/j.ejheart.2005.07.012
[Indexed for MEDLINE]
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