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(Circulation. 2008;117:1778-1786.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation- Contraction Coupling

Barnabas Gellen, MD; María Fernández-Velasco, PhD^*; François Briec, MD^*; Laurent Vinet, MS^*; Khai LeQuang, MD; Patricia Rouet-Benzineb, PhD; Jean-Pierre Bénitah, PhD; Mylène Pezet, PhD; Gael Palais, MS; Noémie Pellegrin, MS; Andy Zhang, MS; Romain Perrier, MS; Brigitte Escoubet, MD, PhD; Xavier Marniquet, MS; Sylvain Richard, PhD; Fréderic Jaisser, MD, PhD; Ana María Gómez, PhD; Flavien Charpentier, PhD; Jean-Jacques Mercadier, MD, PhD

From Inserm, U698, Paris (B.G., L.V., P.R.-B., N.P., X.M., J.-J.M.); Inserm, U637, Montpellier (A.M.G., J.-P.B., M.F.-V., R.P., S.R.); Inserm, U915, Nantes (K.L., F.B., F.C.); Inserm, U772, Paris (G.P., A.Z., B.E., F.J.); CEFI-IFR02, Paris (M.P., B.E., J.-J.M.); and Université Paris Diderot and Assistance Publique–Hôpitaux de Paris, Paris (B.E., J-.J.M.), France.

Correspondence to Dr Jean-Jacques Mercadier, Inserm, U698, G.H. Bichat–Claude Bernard, 46 Rue Henri Huchard, 75018 Paris, France. E-mail mercadie{at}bichat.inserm.fr

Received March 22, 2007; accepted February 7, 2008.

Background— Ca²⁺ release from the sarcoplasmic reticulum via the ryanodine receptor (RyR2) activates cardiac myocyte contraction. An important regulator of RyR2 function is FKBP12.6, which stabilizes RyR2 in the closed state during diastole. β-Adrenergic stimulation has been suggested to dissociate FKBP12.6 from RyR2, leading to diastolic sarcoplasmic reticulum Ca²⁺ leakage and ventricular tachycardia (VT). We tested the hypothesis that FKBP12.6 overexpression in cardiac myocytes can reduce susceptibility to VT in stress conditions.

Methods and Results— We developed a mouse model with conditional cardiac-specific overexpression of FKBP12.6. Transgenic mouse hearts showed a marked increase in FKBP12.6 binding to RyR2 compared with controls both at baseline and on isoproterenol stimulation (0.2 mg/kg IP). After pretreatment with isoproterenol, burst pacing induced VT in 10 of 23 control mice but in only 1 of 14 transgenic mice (P<0.05). In isolated transgenic myocytes, Ca²⁺ spark frequency was reduced by 50% (P<0.01), a reduction that persisted under isoproterenol stimulation, whereas the sarcoplasmic reticulum Ca²⁺ load remained unchanged. In parallel, peak I_Ca,L density decreased by 15% (P<0.01), and the Ca²⁺ transient peak amplitude decreased by 30% (P<0.001). A 33.5% prolongation of the caffeine-evoked Ca²⁺ transient decay was associated with an 18% reduction in the Na⁺-Ca²⁺ exchanger protein level (P<0.05).

Conclusions— Increased FKBP12.6 binding to RyR2 prevents triggered VT in normal hearts in stress conditions, probably by reducing diastolic sarcoplasmic reticulum Ca²⁺ leak. This indicates that the FKBP12.6-RyR2 complex is an important candidate target for pharmacological prevention of VT.

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