Abstract
Metabolic syndrome is associated with hypercholesterolemia, cardiac remodeling, and increased susceptibility to ventricular arrhythmias. Effects of diet-induced hypercholesterolemia on susceptibility to torsades de pointes arrhythmias (TdP) together with potential indicators of arrhythmic risk were investigated in three experimental groups of Carlsson’s rabbit model: (1) young rabbits (YC, young control, age 12–16 weeks), older rabbits (AC, adult control, age 20–24 weeks), and older age-matched cholesterol-fed rabbits (CH, cholesterol, age 20–24 weeks). TdP was induced by α-adrenergic stimulation by methoxamine and IKr block in 83% of YC rabbits, 18% of AC rabbits, and 21% of CH rabbits. High incidence of TdP was associated with high incidence of single (SEB) and multiple ectopic beats (MEB), but the QTc prolongation and short-term variability (STV) were similar in all three groups. In TdP-susceptible rabbits, STV was significantly higher compared with arrhythmia-free rabbits but not with rabbits with other than TdP arrhythmias (SEB, MEB). Amplitude-aware permutation entropy analysis of baseline ECG could identify arrhythmia-resistant animals with high sensitivity and specificity. The data indicate that the TdP susceptibility in methoxamine-sensitized rabbits is affected by the age of rabbits but probably not by hypercholesterolemia. Entropy analysis could potentially stratify the arrhythmic risk and identify the low-risk individuals.
Highlights
Torsades de pointes arrhythmia (TdP) is a potentially life-threatening polymorphic ventricular tachycardia arising on the basis of QT interval prolongation
Most published results concerning hypercholesterolemia and arrhythmogenicity came from models combining high cholesterol and high triglyceride plasma levels, and arrhythmia models were limited to rapid pacing-induced ventricular fibrillations or arrhythmias due to myocardial ischemia/reperfusion injury
Female rabbits were used in order to avoid gender variability and because higher susceptibility to torsades de pointes arrhythmias (TdP) arrhythmias was reported for both female patients and rabbits (e.g., Ebert et al, 1998). 37 female New Zealand white rabbits were divided into three groups: (1) young control rabbits fed standard chow (YC; n = 12; age 12– 16 weeks, and mean weight 2.4 kg), (2) adult control rabbits fed standard chow (AC; n = 11; age 20–24 weeks, and mean weight 4.1 kg), and (3) adult hypercholesterolemic rabbits fed standard chow supplemented with 1% cholesterol for 8– 12 weeks (CH; n = 14; age 20–24 weeks, and mean weight 4 kg)
Summary
Torsades de pointes arrhythmia (TdP) is a potentially life-threatening polymorphic ventricular tachycardia arising on the basis of QT interval prolongation. QT interval prolongation is a manifestation of decreased repolarization reserve, which comprises a substrate for TdP arrhythmia (Roden, 1998). Metabolic syndrome is associated with abnormal electrical activities in the myocardium characterized by prolonged QT interval in the ECG, QT interval dispersion, and ventricular arrhythmias (Soydinc et al, 2006; Li et al, 2009; Karaagac et al, 2014; Park and Lee, 2018). Hyperlipidemia has a direct prolonging effect on action potential duration (Liu et al, 2009) and QT/QTc interval (Szabó et al, 2005). Treatment with statins lowers cardiovascular risk by reduction of QTc dispersion and ventricular premature complexes (Gualdiero et al, 2002; Vedre et al, 2009) and prevents prolongation of action potential duration (Liu et al, 2009). To investigate the effects of hypercholesterolemia on long-QT arrhythmia inducibility, the Carlsson’s methoxamine sensitized rabbit model of TdP arrhythmias (Carlsson et al, 1990) was combined with diet-induced hypercholesterolemia
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