Key result
Pretreatment with diltiazem prevented severe primary diastolic heart failure and cardiac sudden death under isoproterenol stress in mice with the troponin T I79N mutation.
Why the study?
Does diltiazem prevent diastolic heart failure and sudden cardiac death in a transgenic mouse model of familial hypertrophic cardiomyopathy (TnT-I79N mutation)?
Does diltiazem prevent diastolic heart failure and sudden cardiac death in a transgenic mouse model of familial hypertrophic cardiomyopathy (TnT-I79N mutation)?
In a mouse model of familial hypertrophic cardiomyopathy, diltiazem prevented isoproterenol-induced diastolic heart failure and sudden cardiac death.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for diltiazem in genetic diastolic HF; leaves open translation to human TnT-mutation carriers.
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.
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Westermann et al. (2005) studied Familial hypertrophic cardiomyopathy. Diltiazem vs. Human wild-type troponin T (TnT-WT) / No pretreatment was evaluated on End-diastolic pressure-volume relationship (EDPVR) (p=<0.05). Pretreatment with diltiazem prevented severe primary diastolic heart failure and cardiac sudden death under isoproterenol stress in mice with the troponin T I79N mutation.
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