Background Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling through the activity of protein kinase C-β (PKCβ) and nuclear factor κB (NFκB) reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results We measured protein expression and insulin response in freshly isolated endothelial cells from patients with Type 2 diabetes mellitus (n=40) and non-diabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in non-diabetic subjects but not in diabetic patients (P=0.003) consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541, P=0.02) Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes. Endothelial NFκB activation was higher in diabetes and was reduced with PKCβ inhibition. Conclusions We provide evidence for the presence of altered eNOS activation, reduced insulin action and inflammatory activation in the endothelium of patients with diabetes. Our findings implicate PKCβ activity in endothelial insulin resistance.
Background Recent studies have suggested that endoscopic vein harvest (EVH) compromises graft patency. To test whether the learning curve for EVH alters conduit integrity owing to increased trauma compared with an open harvest, we analyzed the quality and early patency of conduits procured by technicians with varying EVH experience. Methods During coronary artery bypass grafting, veins were harvested open (n = 10) or by EVH (n = 85) performed by experienced (>900 cases, >30/month) versus novice <100 cases, <3/month) technicians. Harvested conduits were imaged intraoperatively using optical coherence tomography and on day 5 to assess graft patency using computed tomographic angiography. Results Conduits from experienced (n = 55) versus novice (n = 30) harvesters had similar lengths (33 versus 34 cm) and harvest times (32.4 versus 31.8 minutes). Conduit injury was noted in both EVH groups with similar distribution among disruption of the adventitia (62%), intimal tears at branch points (23%), and intimal or medial dissections (15%), but the incidence of these injuries was less with experienced harvesters and rare in veins procured with an open technique. Overall, the rate of graft attrition was similar between the two EVH groups (6.45% versus 4.34% of grafts; p = 0.552). However, vein grafts with at least 4 intimal or medial dissections showed significantly worse patency (67% versus 96% patency; p = 0.05). Conclusions High-resolution imaging confirmed that technicians inexperienced with EVH are more likely to cause intimal and deep vessel injury to the saphenous vein graft, which increases graft failure risk. Endoscopic vein harvest remains the most common technique for conduit harvest, making efforts to better monitor the learning curve an important public health issue.
Background - Stereotactic body radiation therapy (SBRT) is a novel treatment for refractory ventricular tachycardia (VT). While outcomes have been described in small studies, histological findings after SBRT for VT are unknown. Methods - We identified four explanted hearts in the context of transplant who received prior SBRT as part of an 11-patient compassionate use series at our institution. Clinical VTs and CT-defined target volume areas of SBRT were correlated to the anatomic specimens. Gross pathologic, histologic and ultrastructural examination of tissue in the target area of SBRT were performed. Results - All four patients had NICM, and three had left ventricular assist devices. In all cases, patients had recurrent sustained VT and had failed multiple antiarrhythmics and radiofrequency ablations. Four patients underwent 5 total SBRT therapy session with 25 Gy single fraction dose delivered to the area of culprit scar. The time from SBRT to explant ranged from 12-250 days. Histopathologic features following radiation were comparable in all patients and were characterized by areas of subendocardial necrosis surrounded by a rim of fibrosis. In one patient, the surrounding myocardium showed cytoplasmic vacuolization in myocytes and in another patchy interstitial fibrosis. Vascular changes consisted of myointimal thickening with prominence of endothelial cells. Electron microscopy (EM) of myocardium showed irregular, convoluted intercalated disc regions, loss of contractile elements with disrupted and haphazardly arranged myofibrils and edematous mitochondria with loss of cisternae. Conclusions - Here, we report the first series of findings in human tissue in four patients after SBRT. Histopathologic features were consistent across all four patients, and were indicative of cell injury, death, and to a lesser extent, fibrosis. EM demonstrated features consistent with acute injury. These specimens provide radiobiological mechanisms of acute cellular injury during SBRT for VT which may have an antiarrhythmic effect prior to the onset of fibrosis.
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