Catheter Ablation -> Ventricular Arrhythmias -> Electrocardiography D-PO01 - Featured Poster Session (ID 11) Poster

D-PO01-127 - A Whole-heart Model Of Brugada Syndrome (ID 929)

 J.M. Di Diego: Nothing relevant to disclose.


Background: The pathophysiology of the Brugada syndrome (BrS) is still debated. The repolarization hypothesis maintains that an outward shift in the balance of currents during the early phases of the epicardial (Epi) action potential (AP) in the right ventricular outflow tract (RVOT) underlies the J waves observed in leads V1-V3, and that these repolarization abnormalities lead to phase 2-reentry capable of triggering VT/VF. The depolarization hypothesis maintains that delayed conduction in the RVOT plays a primary role in BrS.
Objective: To perform a test of these hypotheses using a whole-heart model of BrS.
Methods: Canine hearts were isolated from adult mongrel dogs and perfused in Langendorff mode. The atria were removed and the hearts, allowed to beat spontaneously or paced from the His bundle, were immersed in a chamber with preset electrodes to record a 12 lead ECG. Epicardial unipolar electrograms were simultaneously recorded from RVOT, RV apex, LV base and LV apex. Transmembrane APs were recorded from the Epi RVOT using floating glass microelectrodes. The Ito agonist NS5806 (5-15 µM, NS; n= 16), ajmaline (10 µM; n= 10), verapamil (200 nM; n=4) or hypothermia (320C; n=6) were used to elicit J waves. 4-aminopyridine (0.5-1 mM, 4-AP; n= 6) or acacetin (5 µM; n= 10) were used to inhibit Ito.
Results: Increasing Ito with NS, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of RVOT Epi AP notch and ECG J waves, resulting in a characteristic BrS phenotype. Loss of the AP dome at some RVOT sites but not others resulted in development of phase 2-reentrant extrasystoles originating from the RVOT, capable of triggering VT/VF. Inhibition of Ito using 4-AP or acacetin led to a corresponding decrease of RVOT Epi AP notch and J wave amplitudes and suppressed arrhythmogenesis. The J waves in leads V1 or V2 were never associated with a delay of RVOT activation and always mirrored the appearance of the AP notch in the Epi AP recorded from the RVOT.
Conclusion: We provide the first whole heart model of BrS capable of recapitulating all of the ECG and arrhythmic manifestations of BrS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed for the manifestation of the BrS phenotype.