Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia

Abstract

Background Several metabolic conditions can cause the Brugada ECG pattern, also called Brugada phenotype (BrPh). We aimed to define the clinical characteristics and outcome of BrPh patients and elucidate the mechanisms underlying BrPh attributed to hyperkalemia. Methods and Results We prospectively identified patients hospitalized with severe hyperkalemia and ECG diagnosis of BrPh and compared their clinical characteristics and outcome with patients with hyperkalemia but no BrPh ECG. Computer simulations investigated the roles of extracellular potassium increase, fibrosis at the right ventricular outflow tract, and epicardial/endocardial gradients in transient outward current. Over a 6-year period, 15 patients presented severe hyperkalemia with BrPh ECG that was transient and disappeared after normalization of their serum potassium. Most patients were admitted because of various severe medical conditions causing hyperkalemia. Six (40%) patients presented malignant arrhythmias and 6 died during admission. Multiple logistic regression analysis revealed that higher serum potassium levels (odds ratio, 15.8; 95% CI, 3.1-79; P=0.001) and male sex (odds ratio, 17; 95% CI, 1.05-286; P=0.045) were risk factors for developing BrPh ECG in patients with severe hyperkalemia. In simulations, hyperkalemia yielded BrPh by promoting delayed and heterogeneous right ventricular outflow tract activation attributed to elevation of resting potential, reduced availability of inward sodium channel conductance, and increased right ventricular outflow tract fibrosis. An elevated transient outward current gradient contributed to, but was not essential for, the BrPh phenotype. Conclusions In patients with severe hyperkalemia, a BrPh ECG is associated with malignant arrhythmias and all-cause mortality secondary to resting potential depolarization, reduced sodium current availability, and fibrosis at the right ventricular outflow tract.

Keywords: Brugada syndrome; Sudden cardiac death; hyperkalemia.

Figure 1

ECG recordings of patients displaying brugada ECG pattern at the time of peak hyperkalemia (precordial and aVR leads).

Figure 2

Brugada pattern uncovered by hyperkalemia in a patient with Brugada syndrome. A, Patient previously asymptomatic, admitted because of diabetic ketoacidosis, displaying an ECG Brugada pattern. B, ECG normalized after correction of the electrolyte disturbances. C, Baseline ECG and following infusion of Flecainide.

Figure 3

Computer simulations testing the role of fibrosis of the right ventricular outflow tract (RVOT) at different levels of hyperkalemia. A, Activation isochrones maps of the anterior wall with healthy (upper) and fibrotic RVOT (bottom), under basal conditions with extracellular potassium concentration ([K⁺]_o)=5.4 mmol/L and hyperkalemic conditions with [K⁺]_o=7.5 mmol/L, [K⁺]_o=10.0 mmol/L, and [K⁺]_o=10.5 mmol/L. Pseudo‐ECGs of V1, V2, and V3 leads are shown in each case. B, Action potential duration (APD) maps and corresponding action potential signals of sites a, b, and c are shown in each case.

Figure 4

Computer simulations testing the role of incremental transient outward current (I_to) conductance. A, Activation isochrones maps of the anterior right ventricular outflow tract (RVOT) wall with increasing the maximal conductance of I_to in the RVOT epicardium, from its basal level to a characteristic value in BrS modeling (from 0.08 to 1.50 mS/μF, showing 0.30 and 0.70 mS/μF), under severe hyperkalemia (extracellular potassium concentration [K⁺]_o=10.5 mmol/L). Pseudo‐ECGs of V1, V2, and V3 leads are shown in each case. B, Action potential duration (APD) maps and corresponding action potential signals of sites a, b, and c are shown in each case. BrS indicates Brugada syndrome.

Figure 5

Computer simulations testing the role of incremental fibrosis, transient outward current (I_to) conductance, and extracellular potassium concentration ([K⁺]_o) conditions. A, Activation isochrones maps of the anterior right ventricular outflow tract (RVOT) wall with different degrees of fibrosis (55, 65, and 75%), at baseline and severe [K⁺]_o concentrations (5.4 and 10.5 mmol/L, respectively), combined with 2 values of maximal conductance of I_to: basal (0.08 mS/μF) or increased (0.50 mS/μF). Pseudo‐ECGs of V1, V2, and V3 leads are shown in each case. B, Action potential duration (APD) maps and corresponding action potential signals of sites a, b, and c are shown in each case.

Figure 6

Computer simulations testing the role of gradient of I_to conductance over the entire epicardial surface at different levels of extracellular potassium concentration ([K⁺]_o). A, Activation isochrones maps with I_to maximal conductance in the whole epicardium to a characteristic value in BrS modeling (1.50 mS/μF), under basal conditions ([K⁺]_o=5.4 mmol/L) and hyperkalemic conditions ([K⁺]_o=10.5 mmol/L). Pseudo‐ECGs of V1, V2, and V3 leads are shown in each case. B, Action potential duration (APD) maps and corresponding action potential signals of sites a, b, and c are shown in each case. BrS indicates Brugada syndrome; I_to, transient outward current.

Figure 7

Computer simulations testing the role of fibrosis over the entire epicardial surface at different levels of extracellular potassium concentration ([K⁺]_o). A, Activation isochrones maps with fibrosis in the whole (65%), under basal conditions ([K⁺]_o=5.4 mmol/L) and hyperkalemic conditions ([K⁺]_o=10.5 mmol/L). Pseudo‐ECGs of V1, V2, and V3 leads are shown in each case. B, Action potential duration (APD) maps and corresponding action potential signals of sites a, b, and c are shown in each case.

Figure 8

Wide complex tachycardia response to adenosine in a patient with severe hyperkalemia. A, Wide complex tachycardia upon arrival (serum potassium [K]=9.1 mmol/L). B, ECG recording during peak adenosine effect showing sinus arrest and significant QRS narrowing, followed by accelerated ventricular rhythm with progressive QRS widening later after disappearance of the adenosine effect. C, One hour later, after the initial treatment of hyperkalemia ([K] = 8.1 mmol/L).

Figure 9

Monomorphic ventricular tachycardia induction during burst stimulation train followed by an extrastimuli at 400 ms allowed a stable reentry formation at the right ventricular outflow tract (RVOT) fibrotic site in a model with hyperkalemic conditions and extracellular potassium concentration of 10.0 mmol/L.