Obesity Arrhythmias: Role of IL-6 Trans-Signaling

Figures

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  Figure 1. Cartoon illustration highlighting the well-established IL-6 trans-signaling pro-inflammatory pathway [45] leading to the activation of downstream JAK-STAT [43,46,47,48]. The potential therapeutic benefits and efficacy of selectively targeting IL-6 trans-signaling for the prevention of dangerous ventricular arrhythmias in obesity are unknown. STATs, upon phosphorylation, dimerize and translocate to the nucleus, where they can induce the expression of genes involved in proliferation and differentiation [51,52,53,54].

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  Figure 2. Cartoon representation of major ventricular depolarizing and repolarizing mechanisms that are prime candidates for modulation by individual and/or multiple combinations of pro-inflammatory cytokines pathologically elevated in obesity and associated pathologies (diabetes, inflammation, and hyperlipidemia). However, little work has been completed to date on mechanisms by which overexuberant inflammation and pro-inflammatory cytokine production can exacerbate pathologic ventricular electrical remodeling in obesity-linked ventricular arrhythmias. We suspect that overactivated cytokine-mediated remodeling processes may occur through the altered gene and protein expression of ion channel subunits and biophysical defects (subunit trafficking and/or gating defects). We hypothesize that understanding the contribution of distinct cellular arrhythmia triggers sensitive to cytokine mechanisms is important in interpreting the mechanistic bases of how cytokine channelopathies promote arrhythmia/SCD risk and informing on targeted anti-arrhythmia therapy in patients.

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  Figure 3. Cartoon illustration shows the hypothesized pro-inflammatory cytokine-linked channelopathies leading to pathological APD prolongation and ventricular arrhythmias. Obesity or excessive eating is associated with enlarged adipose tissue, leading to increased levels of a heightened pro-inflammatory response defined by a cytokine storm of overactivation of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, and IL-18), all of which are likely to play crucial roles in adverse remodeling of the relative functional expression of major ventricular repolarizing (IKr and IKs) and depolarizing (ICa and INa) macroscopic currents leading to delayed repolarization, which increases the risk for fatal malignant ventricular arrhythmias with obesity. Furthermore, macrophages and adipocytes infiltrate the heart at the onset of metabolic and inflammatory disorders and contribute to cardiac dysfunction, possibly through pathological local levels of individual and multiple combinations of pro-inflammatory cytokines.