Elsevier

Heart Rhythm

Volume 1, Issue 2, July 2004, Pages 210-217
Heart Rhythm

Role of sodium and calcium channel block in unmasking the Brugada syndrome

https://doi.org/10.1016/j.hrthm.2004.03.061Get rights and content

Abstract

Objective

We hypothesized that a combination of INa and ICa blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS.

Background

The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium.

Methods

Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations.

Results

Terfenadine (5–10 μM)-induced block of ICa and INa caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (≤7.5 μM), ajmaline (≤20 μM), and procainamide (≤300 μM) failed to generate polymorphic VT in any preparation except when combined with a calcium channel blocker (verapamil, ≤20 μM). Terfenadine-induced ST segment elevation was normalized and arrhythmias suppressed following Ito block with 4-aminopyridine (0.5–2 mM).

Conclusion

Our data suggest that combined sodium and calcium channel block may be more effective than sodium channel block alone in unmasking the Brugada syndrome and that pharmacologic agents that inhibit Ito may be useful in preventing lethal arrhythmias in patients with the 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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