Role of sodium and calcium channel block in unmasking the Brugada syndrome
Section snippets
Methods
The detailed methods employed for isolation, perfusion, and recording of transmembrane activity from the arterially perfused canine right ventricular (anterior wall) wedge preparation, as well as the viability and electrical stability of the preparation, have been previously reported. Experiments demonstrating that activity recorded from the cut surface of the perfused wedge preparation is representative of cells within the respective layers of the wall throughout the wedge have also been
Results
The ability of combined INa and ICa block to cause loss of the epicardial action potential dome and phase 2 reentry in the canine right ventricular wedge preparation is illustrated in Figure 1. High concentrations of terfenadine, in this case 5 μM, produced an accentuation of the epicardial action potential notch following acceleration of the rate from a BCL of 800 ms to 400 ms. The dramatic accentuation of the notch was due to the effect of the drug to depress phase 0, augment the magnitude
Discussion
Mutations in SCN5A associated with a loss of function of the sodium channel have been shown to underlie some forms of the Brugada syndrome. Linkage to SCN5A is consistent with the clinical finding that potent sodium channel blockers, including Class IC antiarrhythmic agents such as flecainide, ajmaline, or pilsicainide, or Class IA agents such as procainamide and disopyramide, can unmask the Brugada syndrome when the electrocardiographic phenotype is concealed.3, 4, 18 These findings prompted
Clinical implications
Our data demonstrate that terfenadine can induce loss of the epicardial action potential dome, phase 2 reentry, and resulting polymorphic ventricular tachycardia and fibrillation in the canine right ventricular wedge, highlighting the potential adverse effects of agents with combined sodium and calcium channel blocking effects. Whether terfenadine itself may be useful as a diagnostic tool is questionable because of its actions to block the rapidly activating delayed rectifier current, IKr, at
Study limitation
As with all basic studies involving animal experimentation, we must exercise caution in extrapolating these findings to the clinic. Although inhibition of INa and ICa by terfenadine generates electrocardiographic characteristics and arrhythmic manifestations very similar to those observed clinically, to what extent this model mimics the various forms of congenital and acquired Brugada syndrome remains to be established.
Acknowledgements
Supported by grant HL47678 from NHLBI (CA) and grants from the American Heart Association (JF and CA) and NYS and Florida Grand Lodges F. & A.M.
We gratefully acknowledge the expert technical assistance of Judy Hefferon, Robert Goodrow, Di Hou, and Andrew Pitoniak.
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