Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice.
BACKGROUND
Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation.


OBJECTIVE
To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Δ/Δ)) mouse model of CPVT2.


METHODS
A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy.


RESULTS
Adult CASQ2(Δ/Δ) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Δ/Δ) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice (P < .05).


CONCLUSIONS
We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.
Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Efrat
E
Kurtzwald-Josefson
Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Edith
E
Hochhauser
Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Katia
K
Bogachenko
Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Shiraz
S
Harun-Khun
Pinchas Borenstein Talpiot Medical Leadership Program, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Guy
G
Katz
Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dan
D
Aravot
Department of Genetics, Harvard Medical School, Boston, Massachusetts.
Jonathan G
JG
Seidman
Department of Genetics, Harvard Medical School, Boston, Massachusetts.
Christine E
CE
Seidman
Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Michael
M
Eldar
Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Asher
A
Shainberg
Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: michael.arad@sheba.health.gov.il.
Michael
M
Arad
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D002155:Calsequestrin / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011942:Receptors, Adrenergic, alpha / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
D000317:Adrenergic alpha-Antagonists; D002155:Calsequestrin; D011942:Receptors, Adrenergic, alpha
Arrhythmia; CPVT; Calcium; Calsequestrin; Mouse model; Sympathetic; α-Adrenergic receptor