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.
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-I79Nmice 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-I79Nmice leads to severe primary diastolic heart failure and finally to cardiac sudden death, which can be prevented by diltiazem.
Authors: D Westermann; S Rutschow; S Van Linthout; A Linderer; C Bücker-Gärtner; M Sobirey; A Riad; M Pauschinger; H-P Schultheiss; C Tschöpe Journal: Diabetologia Date: 2006-08-26 Impact factor: 10.122
Authors: Gad A Silberman; Tai-Hwang M Fan; Hong Liu; Zhe Jiao; Hong D Xiao; Joshua D Lovelock; Beth M Boulden; Julian Widder; Scott Fredd; Kenneth E Bernstein; Beata M Wolska; Sergey Dikalov; David G Harrison; Samuel C Dudley Journal: Circulation Date: 2010-01-18 Impact factor: 29.690
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