Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia |
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Authors: | James T Thackeray Jerry Radziuk Mary-Ellen Harper Erik J Suuronen Kathryn J Ascah Rob S Beanlands Jean N DaSilva |
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Affiliation: | 1. Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, K1Y 4W7, Canada 4. Department of Cellular & Molecular Medicine, Faculty of Graduate & Postdoctoral Studies, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada 3. Ottawa Hospital Research Institute, 725 Parkdale Avenue, Ottawa, K1Y 4E9, Canada 5. Department of Biochemistry, Microbiology, and Immunology, Faculty of Graduate & Postdoctoral Studies, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada 2. Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, K1Y 4W7, Canada
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Abstract: | Background Diabetes mellitus is strongly associated with cardiovascular dysfunction, derived in part from impairment of sympathetic nervous system signaling. Glucose, insulin, and non-esterified fatty acids are potent stimulants of sympathetic activity and norepinephrine (NE) release. We hypothesized that sustained hyperglycemia in the high fat diet-fed streptozotocin (STZ) rat model of sustained hyperglycemia with insulin resistance would exhibit progressive sympathetic nervous dysfunction in parallel with deteriorating myocardial systolic and/or diastolic function. Methods Cardiac sympathetic nervous integrity was investigated in vivo via biodistribution of the positron emission tomography radiotracer and NE analogue [11C]meta-hydroxyephedrine ([11C]HED). Cardiac systolic and diastolic function was evaluated by echocardiography. Plasma and cardiac NE levels and NE reuptake transporter (NET) expression were evaluated as correlative measurements. Results The animal model displays insulin resistance, sustained hyperglycemia, and progressive hypoinsulinemia. After 8 weeks of persistent hyperglycemia, there was a significant 13-25% reduction in [11C]HED retention in myocardium of STZ-treated hyperglycemic but not euglycemic rats as compared to controls. There was a parallel 17% reduction in immunoblot density for NE reuptake transporter, a 1.2 fold and 2.5 fold elevation of cardiac and plasma NE respectively, and no change in sympathetic nerve density. No change in ejection fraction or fractional area change was detected by echocardiography. Reduced heart rate, prolonged mitral valve deceleration time, and elevated transmitral early to atrial flow velocity ratio measured by pulse-wave Doppler in hyperglycemic rats suggest diastolic impairment of the left ventricle. Conclusions Taken together, these data suggest that sustained hyperglycemia is associated with elevated myocardial NE content and dysregulation of sympathetic nervous system signaling in the absence of systolic impairment. |
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