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European Journal of Heart Failure 2006 8(2):115-121; doi:10.1016/j.ejheart.2005.07.012
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© 2006 European Society of Cardiology

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

Dirk Westermanna, Björn C. Knollmannb, Paul Steendijkc, Susanne Rutschowa, Alexander Riada, Matthias Pauschingera, James D. Potterd, Heinz-Peter Schultheissa and Carsten Tschöpea,*

a Department of Cardiology and Pneumonology, Charite-Universiätsmedizin Berlin Campus Benjamin-Franklin, Hindenburgdamm 30 12220, Berlin, Germany
b Department of Pharmacology, Georgetown University Medical Center Washington, DC, U.S.A.
c Department of Cardiology, Leiden University Medical Center Leiden, The Netherlands
d Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine Miami, FL, U.S.A.

* Corresponding author. Tel: +49 30 8445 2349; fax: +49 30 78717823. E-mail address: ctschoepe{at}yahoo.com


  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.

Key Words: Troponin T mutation • Diastole • Sudden death • Heart failure

Received January 28, 2005; Revised May 30, 2005; Accepted July 19, 2005

{star} This work was in part supported by funds from the National Institutes of Health (HL071670-01 to B.C.K., HL42325 and HL67415 to J.D.P.).


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