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

Dirk Westermann, Björn C. Knollmann, Paul Steendijk, Susanne Rutschow, Alexander Riad, Matthias Pauschinger, James D. Potter, Heinz Peter Schultheiss, Carsten Tschöpe

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68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)115-121
Number of pages7
JournalEuropean Journal of Heart Failure
Volume8
Issue number2
DOIs
StatePublished - Mar 1 2006

Keywords

  • Diastole
  • Heart failure
  • Sudden death
  • Troponin T mutation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Westermann, D., Knollmann, B. C., Steendijk, P., Rutschow, S., Riad, A., Pauschinger, M., Potter, J. D., Schultheiss, H. P., & Tschöpe, C. (2006). Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy. European Journal of Heart Failure, 8(2), 115-121. https://doi.org/10.1016/j.ejheart.2005.07.012