Cellular and molecular mechanisms of the enhanced survival benefits of the βI-adrenoceptor biased agonist, carvedilol, in diabetic cardiomyopathy with heart failure: a case report and literature review

Abstract

S. E. Oriaifo, N. Oriaifo, M. Oriaifo, C. Iruolagbe, E. O. Okogbenin, E. K. I. Omogbai

The incidence of diabetic cardiomyopathy, the leading cause of heart failure amongst diabetic patients, is on the increase in the same proportion with the ageing of the population. Reactive oxygen species (ROS) and mitochondrial dysfunction are front runners in the mechanisms of the pathobiology of diabetic cardiomyopathy. Carvedilol reverses mitochondria to nucleus stress signalling and the retrograde response to offer survival advantages over other beta adrenoceptor antagonists due to its peculiar mechanisms of action, especially its anti-oxidant effect which is tenfold above that of vitamin E. The nitric oxide and hydrogen sulphide dependent vasodilator carvedilol is a biased agonist at βI-adrenoceptors involving βI-arrestin-mediated downstream transactivation of the epidermal growth factor receptor (EGFR) and extra-cellular signal-regulated kinase (ERK) which signals to increase Akt-mediated cardioprotection, anti-apoptosis, mitochondrial biogenesis and insulin sensitivity. Upregulation of Transforming growth factor beta (TGF-β) activity and increased central sympathetic outflow by central neurons may be a sequel of increased superoxide generation from free fatty acids (FFA) and shear stress mediated uncoupling of endothelial nitric oxide synthase (eNOS), hyperglycaemic stress, ET-I activation and AT IA-R upregulation. The anti-oxidant carvedilol reduces cardiac catecholamine toxicity by inhibition of ROS-mediated upregulation of central RhoA and ROCK II kinase to decrease central sympathetic activation and baroreceptor imbalance while attenuating eNOS mRNA destabilisation. It thus successfully redresses the sympatho-cholinergic imbalance, chronotropic incompetence and enhanced arrhythmogenesis in heart failure. Carvedilol also blocks transforming growth factor-beta (TGF-β)-mediated calcineurin phosphatase activity and thus decreases extracellular matrix (ECM) accumulation and cardiac hypertrophy. This case report is of an elderly Nigerian male patient with diabetes induced dilated cardiomyopathy who responded well to active management with adjunctive carvedilol after the apparent non-response to adjunctive metoprolol. After 3 months on carvedilol treatment, ejection fraction rose from 39±2% to 45± 4% and there was also improvement in well-being as reflected in the Geriatric Depression Scale which fell from 14.20 ± 5 to 8.50 ± 4. Carvedilol may thus be the ideal beta-blocker for patients with diabetes mellitus with cardiomyopathy and deserves regular deployment.

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