Spatial Inhomogeneity of Sympathetic Nerve Function in

Background—Although humans and swine with hibernating myocardium have an increased risk of sudden death, the contribution of chronic alterations in sympathetic nerve function is unknown. Acute transmural ischemia causes inhomoge-neity in sympathetic innervation that may lead to lethal arrhythmias, but it is unclear whether similar abnormalities develop in response to chronic reversible ischemia. Methods and Results—Swine were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis that produced hibernating myocardium after 3 months. Resting subendocardial flow (LAD 0.750.14 versus 1.190.14 mL · min1 · g1, P0.05) and wall thickening (LAD 153 % versus 402%, P0.05) were reduced compared with normal remote regions, without triphenyltetrazolium chloride evidence of necrosis. 131I-meta-iodobenzylguanidine (MIBG) was used to assess integrity of the norepinephrine uptake-1 mechanism, and the spatial and transmural distributions were quantified by ex vivo counting. In hibernating myocardium, MIBG deposition was decreased in each layer, with the greatest reduction in the subendocardium (LAD subendocardium 0.280.02 versus 0.420.04 mL · g1 · min1 in normal, P0.05; LAD subepicardium 0.310.03 versus 0.380.04 mL · g1 · min1 in normal, P0.05). In contrast, there were no spatial alterations of MIBG deposition in sham-instrumented animals. Conclusions—The sympathetic norepinephrine uptake-1 mechanism is impaired in hibernating myocardium. These findings raise the possibility that chronic alterations in sympathetic innervation contribute to the excess mortality see