Metabolomics of Repetitive Myocardial Stunning in Chronic Multivessel Coronary Artery Stenosis: Effect of Non-Selective and Selective Β1-Receptor Blockers.

Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning-associated myocardial dysfunction are not clear. We used non-targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without beta-adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3 months of placebo, metoprolol or carvedilol. We compared these two beta-blockers with their different beta-adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator-activated receptor signalling, resulting in a decline in adenosine monophosphate-activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by beta-blockers, with the non-selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that beta-blockade-associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function. imageKey points The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated. In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non-selective beta-receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective beta 1-receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium/calmodulin-dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic-adenosine monophosphate signalling. Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. Both beta-blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism. These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning. Abstract figure legend Repetitive stunning induced by chronic multivessel coronary artery stenosis resulted in myocardial and mitochondrial dysfunction, which was ameliorated by carvedilol more than metoprolol. beta-blockers-mediated reversal of adverse metabolic remodelling was linked with nitric oxide and possibly hydrogen sulphide signalling and enhancement of adenosine monophosphate-activated protein kinase [AMPK] and calcium/calmodulin-dependent protein kinase [CaMKK] function.cAMP, cyclic adenosine monophosphate; GHB, 4-hydroxybutyrate; pAMPK alpha 1/2, phosphorylated adenosine monophosphate-activated alpha 1/2;CPTA1, carnitine palmitoyltransferase-1A; SDMA, symmetric dimethylarginine; ADMA, asymmetric dimethylarginine; OXPHOS, oxidative phosphorylation. Created with BioRender.com image