Electrical and Structural Insights into Right Ventricular Outflow Tract Arrhythmogenesis

Figures

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  Figure 1. Distinctive electrophysiological features of right ventricular outflow tract (RVOT) myocytes relative to right ventricular (RV) apex myocytes. RVOT myocytes had longer action potential duration (APD) at 90% and 50% repolarization (APD90 and APD50) than RV apex myocytes. RVOT myocytes were characterized by a larger late sodium current (INa-Late), transient outward potassium current (Ito), and smaller the rapid component of the delayed rectifier potassium current (IKr-tail), L-type calcium current (ICa-L) and nickel-sensitive Na+-Ca2+ exchanger (NCX). The differences in the properties of the INa-Late, the Ito, the IKr-tail, the ICa-L and the NCX current might contribute to the differences in APD between RVOT myocytes and RV apex myocytes. (Adapted with permission from [14]).

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  Figure 2. Effects of KN93 (a CaMKII inhibitor) and ranolazine (a late sodium current inhibitor) on ouabain (a cardiac glycoside)-induced ventricular tachycardia (VT). (A) Ouabain induces sustained VT in the right ventricular outflow tract (RVOT) and non-sustained VT in the right ventricular (RV) apex. (B) KN93 or ranolazine can terminate ouabain-induced sustained VT in RVOT preparations. Arrows (↑) indicate electrical stimuli. (Adapted with permission from [14]).

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  Figure 3. Electrical ventricular remodeling in pathological conditions, such as heart failure, chronic kidney disease and obesity/epicardial adipose tissue (EAT) accumulation, contributes to right ventricular outflow tract (RVOT) arrhythmogenesis. In heart failure, RVOT myocytes have a smaller L-type calcium (Ca2+) current (ICa-L) and a rapid component of delayed rectifier potassium current (IKr-tail) and a larger late sodium (Na+) current (INa-Late) than RV apex myocytes, which prolongs action potential duration (APD). Moreover, an increase in intracellular Na+ by INa-Late may drive the Ca2+ inside by the reverse mode of Na+-Ca2+ exchanger current (NCX), which increases intracellular Ca2+ ([Ca2+]i) and induces delayed afterdepolarization (DAD). In chronic kidney disease, RVOT myocytes have a larger transient outward potassium current (Ito), which causes APD dispersion and phase 2 reentry. CKD RVOT myocytes have a larger ICa-L and NCX than RV apex myocytes that increase Ca2+ load and Ca2+ leak, resulting in Ca2+ calmodulin-dependent protein kinase II (CaMKII) activation and inducing triggered activity. Moreover, chronic kidney disease increases oxidative stress and causes autonomic…

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  Figure 4. Schematic illustration of the intrinsic and extrinsic factors and possible mechanisms resulting in right ventricular outflow tract (RVOT) arrhythmogenesis due to electrical and structural remodeling. The idiopathic (autonomic, gender, genetic, embryonic, anatomical, and histological) and pathological conditions (obesity/epicardial adipose tissue (EAT) accumulation, heart failure (HF), and chronic kidney disease (CKD)) cause RVOT electrical and structural remodeling and are prone to induce triggered activity and reentry, resulting in RVOT arrhythmogenesis. APD, action potential duration; Ca2+, calcium; CV, conduction velocity.