Proarrhythmic Lipid Inflammatory Mediators: Mechanisms in Obesity Arrhythmias

Figures

• 

  Figure 1. Hypothetical cellular proarrhythmic mechanisms of heightened LTB4 signaling in obesity. High‐fat diet feeding (compared to low fat diet) or excessive caloric intake predisposes to obesity and associated metabolic conditions. We speculate that heightened LTB4 cellular activity in obesity contribute to life threatening arrhythmogenesis, however, precise mechanisms are yet to be identified. LTB4 is generated from arachidonic acid (AA), through cytosolic phospholipase A2 (cPLA2), and the 5‐lipoxygenase (5‐LO) pathway. FLAP (5‐lipoxygenase activating protein) enables the interaction of 5‐LO with the cell membrane and the conversion of AA into leukotriene A4 (LTA4), which is then further converted into LTB4 (the organic structure is shown in red) by the enzyme LTA4 hydrolase. The 5‐LO pathway is expressed in myocardial tissue, cardiomyocytes, adipose tissue, macrophages, liver, muscle, neutrophils, and leukocytes. There is evidence that chronically overactive LTB4 directly promotes systemic inflammation and triggers IR, in the liver, muscle, adipose tissue, and cardiomyocytes. LTB4 exerts its effects through the interaction with the G‐protein‐coupled receptor LTB4R1/2 (BLT1/2‐Gαi and…

• 

  Figure 2. Overview of LTB4 biosynthesis and regulation. High‐fat diet feeding and an increase in adipose tissue promote LTB4 production. LTB4 originates from arachidonic acid (AA) which is an omega‐6 poly‐unsaturated fatty acid. Although AA is not an essential FA and is produced by desaturation and elongation of linoleic acid, it can be considered one if there are insufficient amounts of linoleic acid or the body is not able to convert linoleic acid to AA. AA is also provided through dietary intake of foods rich in omega‐6 like meat and dairy products, fish, and eggs. AA is found in the phospholipid membrane of various cells throughout the body and is released from the phospholipid membranes by cytosolic phospholipase A2 (cPLA2), a calcium (Ca) sensitive enzyme that also serves as a substrate for the mitogen‐activated protein kinase (MAPK). Interestingly, phosphorylation of cPLA2 by MAPK can be inhibited by dapagliflozin, in turn curbing the release of AA and reducing associated downstream pathways. Even though AA plays a significant role in maintaining cellular function and energy, excessive amounts of AA may promote a reduced Ca influx through l‐type Ca channels leading to enhanced…

• 

  Figure 3. Arrhythmogenic changes in EAT and therapeutic interventions. Epicardial adipose tissue (EAT) is mostly composed of white adipose tissue, however, under physiological conditions, EAT maintains characteristics of brown adipose tissue by regulating thermogenesis and thus providing cardioprotection through creating thermal and energy balance. In contrast, pathologic conditions like obesity and diabetes disrupt this balance which leads to the formation of potentially arrhythmogenic white adipose features, and heightened infiltration/accumulation of proinflammatory macrophages. Subsequently, EAT becomes an inflammatory substrate secreting an excessive amount of proinflammatory cytokines including IL‐6, IL‐1ꞵ, and TNF‐α, and overactivating cytokine signaling thus increasing the susceptibility to cardiac arrhythmias manifested as cellular proarrhythmic mechanisms including pathological action potential duration prolongation, leading to QT prolongation that increases sudden cardiac death risks. Advances have been made to reduce the pathologic effects of EAT. SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, luseogliflozin) have shown promising outcomes in reducing EAT volume.…