title: T-type Ca2+ channel blockade prevents sudden death in mice with heart failure.
abstract: BACKGROUND
  Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.
  
  
  RESULTS
  We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.
  
  
  CONCLUSIONS
  T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduated School of Medicine, Kyoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Takano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Michio
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Masaki
authors.initials: M
authors.lastname: Harada
authors.forename: Masataka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Masao
authors.initials: M
authors.lastname: Murakami
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000401:mortality / Q000517:prevention & control; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure; D001835:Body Weight; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000401:mortality; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000401:mortality; D032383:Myocytes, Cardiac / Q000502:physiology; D009568:Nitrendipine / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D020748:Mibefradil; C066425:efonidipine; D009568:Nitrendipine