Abstract
Obesity mechanisms that make atrial tissue vulnerable to arrhythmia are poorly understood. Voltage-dependent potassium (IK, IKur, and IK1) and L-type calcium currents (ICa,L) are electrically relevant and represent key substrates for modulation in obesity. We investigated whether electrical remodeling produced by high-fat diet (HFD) alone or in concert with acute atrial stimulation were different. Electrophysiology was used to assess atrial electrical function after short-term HFD-feeding in guinea pigs. HFD atria displayed spontaneous beats, increased IK (IKr + IKs) and decreased ICa,L densities. Only with pacing did a reduction in IKur and increased IK1 phenotype emerge, leading to a further shortening of action potential duration. Computer modeling studies further indicate that the measured changes in potassium and calcium current densities contribute prominently to shortened atrial action potential duration in human heart. Our data are the first to show that multiple mechanisms (shortened action potential duration, early afterdepolarizations and increased incidence of spontaneous beats) may underlie initiation of supraventricular arrhythmias in obese guinea pig hearts. These results offer different mechanistic insights with implications for obese patients harboring supraventricular arrhythmias.
Highlights
High-fat diet (HFD)-induced obesity is associated with insulin resistance, Type 2 diabetes mellitus (T2DM), and dyslipidemias (Schulze et al, 2016)
In the initial set of experiments, we investigated the effects of HFD on Delayed rectifier potassium current (IK) current measured in atrial myocytes isolated from HFD-fed guinea pigs compared to Low-fat diet (LFD)-fed controls using whole-cell patch clamp (Figure 1)
The data is in line with our previous finding that atrial IK density is significantly increased by HFD feeding in guinea pigs (Aromolaran et al, 2016)
Summary
High-fat diet (HFD)-induced obesity is associated with insulin resistance, Type 2 diabetes mellitus (T2DM), and dyslipidemias (Schulze et al, 2016). A recent estimation by the National Institutes of Health (NIH) shows that obesity and its co-morbidities, affects 17% of children and young adults in the United States, while over one-third of adults are overweight and/or obese (Jensen et al, 2014). Obesity is an independent and key contributor to the expanding prevalence of atrial fibrillation (AF) (Michael et al, 2009; Lau et al, 2012; Abed and Wittert, 2013), a serious condition affecting approximately 2.7 million people in the United States (www.heart.org/en/health-topics/atrial-fibrillation). Nord-Trøndelag Health prospective cohort study (HUNT3), demonstrated that being overweight or obese increased the AF risk by 18 and 59% (Garnvik et al, 2018); while epidemiological studies revealed a 4–5% increased risk of AF for each one unit increase in body mass index (BMI) (De Sensi et al, 2018). Despite the growing knowledge that obesity and AF are serious conditions with significant implications for public health, the molecular mechanisms that underlie atrial remodeling in obesity are poorly understood
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