Myocardial Steatosis and Necrosis in Atria and Ventricles of Rats Given Pyruvate Dehydrogenase Kinase Inhibitors

Abstract

Pharmaceutical therapies for non-insulin-dependent diabetes mellitus (NIDDM) include plasma glucose lowering by enhancing glucose utilization. The mitochondrial pyruvate dehydrogenase (PDH) complex is important in controlling the balance between glucose and fatty acid substrate oxidation. Administration of pyruvate dehydrogenase kinase inhibitors (PDHKIs) to rats effectively lowers plasma glucose but results in myocardial steatosis that in some instances is associated primarily with atrial and to a lesser degree with ventricular pathology. Induction of myocardial steatosis is not dose-dependent, varies from minimal to moderate severity, and is either of multifocal or diffuse distribution. Ventricular histopathology was restricted to few myocardial degenerative fibers, while that in the atrium/atria was of either acute or chronic appearance with the former showing myocardial degeneration/necrosis, acute myocarditis, edema, endothelial activation (rounding up), endocarditis, and thrombosis associated with moderate myocardial steatosis and the latter with myocardial loss, replacement fibrosis, and no apparent or minimal association with steatosis. The evidence from these evaluations indicate that excessive intramyocardial accumulation of lipid may be either primarily adverse or represents an indicator of other adversely affected cellular processes.

A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity

“…However, the potency of DCA is low and clinical translation is unlikely because DCA causes a peripheral neuropathy (16) along with carcinogenic effects (17). Treatment with another class of PDK inhibitors, AZD7545 (18), in normal rats caused cardiac steatosis and myocardial degeneration (19). The pathogenic effects of AZD7545 may be because of activation of PDK4 (13,20).…”

Selective Phosphorylation Inhibitor of Delta Protein Kinase C–Pyruvate Dehydrogenase Kinase Protein–Protein Interactions: Application for Myocardial Injury in Vivo

“…However, although small molecule PDK inhibitors can increase the recovery rate of cardiac function following simulated myocardial infarction in vitro , 61,62 these PDK inhibitors cause myocardial steatosis and sometimes death within a few days of treatment in vivo . 63 In contrast, ψPDK1 peptide selectively inhibited only excessive activation of PDK by δPKC, but not basal PDK activity. Therefore, ψPDK1 peptide will likely have a therapeutic advantage over other inhibitors of PDK activity.…”

Microvesicular Steatosis and Severe Cardiac Allograft Dysfunction

“…4 Animal models have shown that cardiac-restricted long-chain acyl CoA synthase overexpression, administration of pyruvate kinase inhibitors, and inactivation of pituitary adenylate cyclase-activating polypeptide can all disrupt mitochondrial fatty acid metabolism and lead to lipid vacuolization in multiple tissues, including the heart, liver, and skeletal muscle. [5][6][7] Microvesicular fat accumulation in multiple organs is a hallmark of Reye syndrome. [8][9][10] This disorder is characterized by rapidly progressive encephalopathy, usually occurring after recovery from a viral illness, such as influenza and varicella, and is strongly associated with salicylate use.…”