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


OBJECTIVE
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.


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.
Westermann
Dirk
D
Department of Cardiology and Pneumonology, Charite-Universiätsmedizin Berlin, Campus Benjamin-Franklin, Hindenburgdamm 30 12220, Berlin, Germany.
Knollmann
Björn C
BC
Steendijk
Paul
P
Rutschow
Susanne
S
Riad
Alexander
A
Pauschinger
Matthias
M
Potter
James D
JD
Schultheiss
Heinz-Peter
HP
Tschöpe
Carsten
C
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D003094:Collagen / Q000032:analysis / Q000187:drug effects; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D054144:Heart Failure, Diastolic / Q000209:etiology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000737:chemistry; D011897:Random Allocation; D016896:Treatment Outcome; D020107:Troponin T / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects
D002121:Calcium Channel Blockers; D020107:Troponin T; D003094:Collagen; D004110:Diltiazem