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Am J Nucl Med Mol Imaging 2012;2(3):314-334
Review Article
Altered sympathetic nervous system signaling in the diabetic heart: emerging
targets for molecular imaging
James T Thackeray, Rob S Beanlands, Jean N DaSilva
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute; Department of Cellular &
Molecular Medicine, Faculty of Graduate and Postdoctoral Studies, University of Ottawa
Received June 1, 2012; accepted June 29, 2012; Epub July 20, 2012; Published July 30, 2012
Abstract: Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in
sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and
free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance
and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered
expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal
contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and
impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes
enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second
messenger sites of signal transduction, providing mechanistic insights on cardiac pathology. This review will examine the evidence
for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from
basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be
paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in
diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or
123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and post-synaptic β-adrenoceptor density measurements using CGP12177
derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes
research and clinical care. (ajnmmi1205004)
Keywords: Sympathetic neuronal imaging, SNS signaling, norepinephrine, β-adrenoceptor, norepinephrine reuptake transporter
Address all correspondence to:
Dr. Jean DaSilva
National Cardiac PET Centre
University of Ottawa Heart Institute
40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7.
Tel: 613-798-5555 x 19704; Fax: 613-761-5406
E-mail: JDasilva@ottawaheart.ca
Review Article
Altered sympathetic nervous system signaling in the diabetic heart: emerging
targets for molecular imaging
James T Thackeray, Rob S Beanlands, Jean N DaSilva
Molecular Function & Imaging Program, National Cardiac PET Centre, University of Ottawa Heart Institute; Department of Cellular &
Molecular Medicine, Faculty of Graduate and Postdoctoral Studies, University of Ottawa
Received June 1, 2012; accepted June 29, 2012; Epub July 20, 2012; Published July 30, 2012
Abstract: Diabetes is commonly associated with increased risk of cardiovascular morbidity and mortality. Perturbations in
sympathetic nervous system (SNS) signaling have been linked to the progression of diabetic heart disease. Glucose, insulin, and
free fatty acids contribute to elevated sympathetic nervous activity and norepinephrine release. Reduced left ventricular compliance
and impaired cardiac function lead to further SNS activation. Chronic elevation of cardiac norepinephrine culminates in altered
expression of pre- and post-synaptic sympathetic signaling elements, changes in calcium regulatory proteins, and abnormal
contraction-excitation coupling. Clinically, these factors manifest as altered resting heart rate, depressed heart rate variability, and
impaired cardiac autonomic reflex, which may contribute to elevated cardiovascular risk. Development of molecular imaging probes
enable a comprehensive evaluation of cardiac SNS signaling at the neuron, postsynaptic receptor, and intracellular second
messenger sites of signal transduction, providing mechanistic insights on cardiac pathology. This review will examine the evidence
for abnormal SNS signaling in the diabetic heart and establish the physiological consequences of these changes, drawing from
basic biological research in isolated heart and rodent models of diabetes, as well as from clinical reports. Particular attention will be
paid to the use of molecular imaging approaches to non-invasively characterize and evaluate sympathetic signal transduction in
diabetes, including pre-synaptic norepinephrine reuptake assessment using 11C-meta-hydroxyephedrine (11C-HED) with PET or
123I-metaiodobenzylguanidine (123I-MIBG) with SPECT, and post-synaptic β-adrenoceptor density measurements using CGP12177
derivatives. Finally, the review will attempt to define the future role of these non-invasive nuclear imaging techniques in diabetes
research and clinical care. (ajnmmi1205004)
Keywords: Sympathetic neuronal imaging, SNS signaling, norepinephrine, β-adrenoceptor, norepinephrine reuptake transporter
Address all correspondence to:
Dr. Jean DaSilva
National Cardiac PET Centre
University of Ottawa Heart Institute
40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7.
Tel: 613-798-5555 x 19704; Fax: 613-761-5406
E-mail: JDasilva@ottawaheart.ca
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