Original Article: PDF OnlyMetformin Prevents Low-dose Isoproterenol-induced Cardiac Dilatation and Systolic Dysfunction in Male Sprague-Dawley Rats.Peterson, Vernice R PhD1; Norton, Gavin R MD, PhD1; Madziva, MT PhD2; Makaula, S PhD1 Author Information 1Cardiovascular Pathophysiology and Genomics Research Unit, (VRP, GRN and SM) 2Endocrine and Metabolism Research Laboratory (MTM) in the School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Correspondence and reprint requests: Vernice R Peterson, Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, 2193, Johannesburg, South Africa. Tel + 27 11 717 2363, e-mail: [email protected] Conflict of Interest/Disclosures: None VRP, GRN and SM contributed equally to this work. This work was supported by the Faculty of Health Sciences Research Council of the University of the Witwatersrand and the South African National Research Foundation. Journal of Cardiovascular Pharmacology: November 03, 2021 - Volume - Issue - doi: 10.1097/FJC.0000000000001172 Buy PAP Metrics Abstract Myocardial metabolic abnormalities are well recognized alterations in chronic heart failure, effects that may contribute to progressive cardiac dysfunction. However, whether metabolic alterations in-part mediate their deleterious effects by modifying the chronic impact of excess low dose sympathetic stimulation on cardiac chamber dilatation, is uncertain. We therefore aimed to determine the effect of metformin administration on cardiac function and mitochondrial architectural changes in a rat model of chronic sympathetic-induced left ventricular (LV) remodeling and systolic dysfunction (daily subcutaneous isoproterenol [ISO] injection at a low-dose of 0.02 mg/kg for 7 months). Echocardiography was used to assess in vivo LV dimensions and function, and mitochondrial and myofibril arrangement was assessed using transmission electron microscopy. 7 months of low-dose ISO administration increased left ventricular diastolic diameter (in mm) (CONT: 7.29±0.19 vs. ISO: 8.76±0.21; p=0.001), an effect that was attenuated by metformin (ISO+MET: 7.63±0.29 vs ISO: p=0.001) administration. Similarly, ISO increased LV end systolic diameter (CONT: 4.43±0.16 vs ISO: 5.49±0.16: p<0.0001) an effect prevented by metformin (ISO+MET: 4.04±0.25 vs. ISO: p<0.0001). Moreover, chronic ISO administration reduced LV endocardial fractional shortening (p=0.0001), midwall fractional shortening (p=0.0001) and ejection fraction (p=0.0001), effects similarly prevented by metformin administration. Furthermore, changes in mitochondrial arrangement and relative mitochondrial area (CONT: 37.7±2.2 vs. ISO: 28.1±2.9; p=0.05) were produced by ISO administration, effects prevented by metformin. In conclusion, metformin offers cardiac protection against chronic sympathetic-induced LV dilatation and systolic dysfunction. These data support a role for myocardial metabolic changes in mediating LV dilatation and LV dysfunction produced by chronic neurohumoral activation in cardiac disease. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.