Factors That Modulate ECG and Arrhythmic Manifestations of the Brugada Syndrome

ST segment elevation in the Brugada syndrome is often dynamic. The Brugada ECG is often concealed and can be unmasked or modulated by sodium channel blockers, a febrile state, vagotonic agents, a-adrenergic agonists, ^-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and by alcohol and cocaine toxicity (Brugada et al. 2000bc; Miyazaki et al. 1996; Babaliaros and Hurst 2002; Goldgran-Toledano et al. 2002; Tada et al. 2001; Pastor et al. 2001; Ortega-Carnicer et al. 2001; Nogami et al. 2003; Araki et al. 2003). These agents may also induce acquired forms of the Brugada syndrome (Table 1). Until a definitive list of drugs to avoid in the Brugada syndrome is formulated, the list of agents in Table 1 may provide some guidance.

Acute ischemia or myocardial infarction due to vasospasm involving the RVOT mimics ST segment elevation similar to that in Brugada syndrome. This effect is secondary to the depression of ICa and the activation of Ik-atp during ischemia, and suggests that patients with congenital and possibly acquired forms of Brugada syndrome may be at a higher risk for ischemia-related SCD (Noda et al. 2002).

VF and sudden death in the Brugada syndrome usually occur at rest and at night. Circadian variation of sympatho-vagal balance, hormones, and other metabolic factors likely contribute this circadian pattern. Bradycardia, due to altered symaptho-vagal balance or other factors, may contribute to arrhythmia initiation (Kasanuki et al. 1997; Proclemer et al. 1993; Mizumaki et al. 2004). Abnormal 123I-MIBG uptake in 8 (17%) of the 17 Brugada syndrome patients but none in the control group was demonstrated by Wichter et al. (2002). There was segmental reduction of 123I-MIBG in the inferior and the septal left ventricular wall, indicating presynaptic sympathetic dysfunction. Of note, imaging of the right ventricle, particularly the RVOT, is difficult with this technique, so insufficient information is available concerning sympathetic function in the regions known to harbor the arrhythmogenic substrate. Moreover, it remains

Table 1 Drug-induced Brugada-like ECG patterns

I. Antiarrhythmic drugs

1. Na+ channel blockers

Class IC drugs [Flecainide (Krishnan and Josephson 1998; Fujiki et al. 1999; Shimizu et al. 2000a; Brugada et al. 2000c; Gasparini et al. 2003), Pilsicainide (Takenaka et al. 1999; Shimizu et al. 2001), Propafenone (Matana et al. 2000)] Class IA drugs [Ajmaline (Brugada et al. 2000c; Rolf et al. 2003), Procainamide (Miyazaki et al. 1996; Brugada et al. 2000c), Disopyramide (Miyazaki et al. 1996; Wilde et al. 2002a), Cibenzoline (Tada et al. 2000)]

2. Ca2+ channel blockers Verapamil

II. Antianginal drugs

1. Ca2+ channel blockers Nifedipine, diltiazem

2. Nitrate

Isosorbide dinitrate, nitroglycerine (Matsuo et al. 1998)

3. K+ channel openers Nicorandil

III. Psychotropic drugs

1. Tricyclic antidepressants

Amitriptyline (Bolognesi et al. 1997; Rouleau et al. 2001), Nortriptyline (Tada et al. 2001), desipramine (Babaliaros and Hurst 2002), clomipramine (Goldgran-Toledano et al. 2002)

2. Tetracyclic antidepressants Maprotiline (Bolognesi et al. 1997)

3. Phenothiazine

Perphenazine (Bolognesi et al. 1997), cyamemazine

4. Selective serotonin reuptake inhibitors Fluoxetine (Rouleau et al. 2001)

IV. Other drugs

1. Histaminic H1 receptor antagonists Dimenhydrinate (Pastor et al. 2001)

2. Cocaine intoxication (Ortega-Carnicer et al. 2001; Littmann et al. 2000)

3. Alcohol intoxication

Modified from Shimizu (2004) with permission unclear what role the reduced uptake function plays in the arrhy thmogenesis of the Brugada syndrome. If indeed the RVOT is similarly affected, this defect may alter the symaptho-vagal balance in favor of the development of an arrhythmo-genic substrate (Litovsky and Antzelevitch 1990; Yan and Antzelevitch 1999).

More recently, Kies and coworkers (Kies et al. 2004) assessed autonomic nervous system function noninvasively in patients with the Brugada syndrome, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analog 11C-Hydroxyephedrine (11C-HED) and the nonselective ^-blocker 11C-CGP 12177 (11C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11C-HED, was found to be globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects, whereas postsynaptic ^-adrenoceptor density, assessed by 11C-CGP, was similar in patients and controls. This study provides further evidence in support of an autonomic dysfunction in Brugada syndrome.

Hypokalemia has been implicated as a contributing cause for the high prevalence of SUDS in the northeastern region of Thailand, where potassium deficiency is endemic (Nimmannit et al. 1991; Araki et al. 2003). Serum potassium in the northeastern population is significantly lower than that of the population in Bangkok, which lies in the central part of Thailand, where potassium is abundant in the food. A recent case report highlights the ability of hypokalemia to induce VF in a 60-year-old man who had asymptomatic Brugada syndrome, without a family history of sudden cardiac death (Araki et al. 2003). This patient was initially treated for asthma by steroids, which lowered serum potassium from 3.8 mmol/l on admission to 3.4 and 2.9 mmol/l on the seventh day and eighth day of admission, respectively. Both were associated with unconsciousness. VF was documented during the last episode, which reverted spontaneously to sinus rhythm.

Accelerated inactivation of the sodium channel in SCN5A mutations associated with the Brugada syndrome has been shown to be accentuated at higher temperatures (Dumaine et al. 1999), suggesting that a febrile state may unmask the Brugada syndrome by causing loss of function secondary to premature inactivation of INa. Indeed, numerous case reports have emerged since 1999 demonstrating that febrile illness could reveal the Brugada ECG and precipitate VF (Gonzalez Rebollo et al. 2000; Madle et al. 2002; Saura et al. 2002; Porres et al. 2002; Kum et al. 2002; Antzelevitch and Brugada 2002; Ortega-Carnicer et al. 2003; Dzielinska et al. 2004). Anecdotal reports point to hot baths as a possible precipitating factor. Of note, the northeastern part of Thailand, where the Brugada syndrome is most prevalent, is known for its very hot climate.

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