Non-invasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart

Abstract

The role of cardiac sympathetic nerves in the regulation of myocardial metabolism is not well defined. Owing to the presence of incomplete reinnervation, heart transplant recipients provide a unique model to study the effects of efferent sympathetic innervation. Using this model, we sought to determine the influence of cardiac sympathetic signals on substrate utilisation and overall oxidative metabolism. In 21 transplant recipients, positron emission tomography was applied to determine sympathetic innervation with the noradrenaline analogue carbon11 hydroxyephedrine, oxidative metabolism with carbon11 acetate (n=14), and glucose utilisation with fluorine-18 fluorodeoxyglucose (n=7). The reinnervated area comprised 22% +/- 20% of the left ventricle. Oxidative metabolism was similar in denervated and reinnervated myocardium [0.06 +/- 0.01 vs 0.06 +/- 0.01/min for k(mono)], while glucose uptake was significantly higher in denervated myocardium (6.9 +/- 6.6 vs 6.0 +/- 6.2 micromol/min/100 g; P=0.03). Reinnervation mainly occurred in the territory of the left anterior descending artery, where retention of 11C-hydroxyephedrine (6.8 +/- 2.7%/min) was higher compared with territories of the left circumflex (4.1 +/- 1.7%/min; P<0.01) and right coronary (3.8 +/- 1.1%/min; P<0.01) arteries. Oxidative metabolism was similar in all three territories, but compared with the reinnervated territory of the left anterior descending artery (53% +/- 16% of maximum), relative FDG uptake was higher in territories of the left circumflex (76% +/- 6%, P<0.01) and right coronary (67% +/- 10%, P<0.05) arteries. Similar degrees of regional heterogeneity were not observed in normals. Thus, while overall energy production through oxidative metabolism remains unaffected, cardiac utilisation of glucose in the fasting state is increased in the absence of catecholamine uptake sites. Innervated myocardium, however, may preferentially utilise free fatty acids, suggesting a role for sympathetic tone in substrate utilisation.

Myocardial Efficiency and Sympathetic Reinnervation After Orthotopic Heart Transplantation

“…Previous work has shown that sympathetic reinnervation contributes to partial restoration of exercise capacity 29 and plays a role for regulation of myocardial blood flow and metabolism. 30,31 In the present study, however, cardiac work, oxygen consumption, and efficiency at rest were not different between reinnervated and denervated transplant recipients. Additionally, there was no regional difference for contractile performance or oxygen consumption in reinnervated and denervated territories.…”

Clinical Determinants of Ventricular Sympathetic Reinnervation After Orthotopic Heart Transplantation

“…Patients were prospectively selected from a large group of Ͼ500 patients who had undergone transplantation since 1981 at the Herzchirurgische Klinik der Ludwig-Maximilians-Universität München to participate in projects aiming at characterization of allograft reinnervation and its physiological relevance. 8,10,12 Selection was based on availability, willingness to participate, and absence of acute rejection, clinically significant transplant vasculopathy (defined by absence of significant coronary stenoses at angiography and/or normal dobutamine stress echocardiography), allograft dysfunction, diabetes mellitus, other symptomatic noncardiac diseases, and medication known to interfere with presynaptic catecholamine uptake. Twenty-three of the patients had undergone transplantation because of ischemic cardiomyopathy and the other 54 because of idiopathic cardiomyopathy.…”

“…The occurrence of subsequent partial reinnervation of the left ventricle has been demonstrated in various studies, [1][2][3][4][5][6] and the physiological importance of this phenomenon has been supported by description of beneficial effects on regulation of myocardial blood flow, 7 metabolism, 8,9 and exercise performance. 10,11 Because of the increasing evidence that restoration of sympathetic innervation is advantageous for transplant recipients, approaches to support reinnervation are of interest, and a more detailed understanding of clinical determinants of reinnervation is desirable.…”

Imaging cardiac neuronal function and dysfunction

“…Several groups studied the in reinnervation the transplanted heart as a model of regional denervation. They showed that the sympathetic innervation is associated with improvement of endothelial-dependent vascular reactivity regulation, response of heart rate, and ventricular function [45][46][47]. These results support the functional importance of reinnervation of transplanted hearts, and may guide further therapies employing neuronal growth factor or stem cells.…”