Altered β-Adrenergic System, Cardiac Dysfunction, and Lethal Arrhythmia in a Rat Model of Metabolic Syndrome

Metabolic syndrome (MetS) is a worldwide problem affecting at least one-third of the population. MetS patients have increased cardiovascular risk associated with an abnormal β-adrenergic response; however, it is not clear how MetS affects the cardiac β-adrenergic system. We analyzed cardiac function and the β-adrenergic response in an experimental model of MetS in rats by recording pressure-volume (PV) loops via an open-chest approach and performed a biochemical characterization of the cardiac β-adrenergic system through ELISA, radioligand binding assays, and Western blotting. Microscopy was employed to evaluate cardiac hypertrophy, fibrosis, and ultrastructure. MetS rats exhibited cardiac dysfunction, evidenced by a reduced cardiac output and ejection fraction, not explained by heart hypertrophy or fibrosis. MetS rats also had an elevated susceptibility to lethal arrhythmia following intra-cardiac administration of the non-selective β-adrenergic agonist isoproterenol, suggesting alterations in the β-adrenergic system. The total serum adrenaline and noradrenaline levels were higher in the MetS animals than those in the control group. The radioligand binding assays indicated no change in the βAR density; however, the Western blot analyses revealed decreased levels of Gα_s proteins and β-arrestin 1, but increased β₂AR and Gα_i protein levels. This study contributes to our understanding of how MetS can alter cardiac function, raising the risk of lethal arrhythmia induced by the β-adrenergic (fight or flight) response and underscores the relevance of therapeutically targeting MetS before its pathological progression toward cardiomyopathy.