RECURRENTATHEROSCLEROTICDISEASEVikramS.pptVIP

Human Studies EDR measurement N 3 Arginase II How does thrombus cause endothelial dysfunction?Mechanistic insights Causes endothelial cell loss--No Scavenges NO--Perhaps Decreases NO secretion or diffusion--No Decreases NO production by affecting eNOS--No Affects L-arginine transport via the Y+ channel-- No Increases endogenous vasoconstrictor—No Decreases L-arginine availability—Yes Thrombin increases arginase activity The Fate of L-arginine Future Studies In vitro studies (endothelial cells) Thrombin, fibrin exposure with arginase blockade Activated neutrophil effects In vivo studies (rodent models) Arginase blockade in thrombosed infrarenal arterial segments Mouse model, knockouts Human studies Explanted human arteries—endothelial function RCT using thrombolysis and L-arginine supplementation Conclusions Endothelial cells exposed to thrombin have increased arginase enzymatic activity NO generation capability is unaffected Local administration of L-Arginine or arginase blockade may ameliorate endothelial dysfunction Targeted NO augmentation may prove to be an attractive therapeutic alternative Questions? L-精氨酸代谢途径 未来研究方向 体外试验 (内皮细胞) 凝血酶、纤维蛋白暴露于精氨酸酶阻断剂 活化中性粒细胞效应 体外试验 (啮齿动物模型) 在血栓形成的肾下腹主动脉使用精氨酸酶阻断剂 基因敲除鼠模型 人体试验 人动脉标本—内皮细胞功能 使用溶栓治疗与L-精氨酸行RCT研究 结 论 暴露于凝血酶的内皮细胞增加了精氨酸酶的活性 NO 产生能力不受影响 局部使用L-精氨酸和精氨酸酶阻断剂可以调整内皮细胞异常功能 目的性增加NO可能是一个有前途的治疗方法 Questions? Enhancing Endothelial Function After ThrombosisVikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular SurgeryThe Cleveland Clinic New Horizons in Cardiovascular Treatment (Angiogenesis and other) December 11, 2008 Case 53 y.o. female with acute R leg pain for 4 days. No R leg pulses, faint femoral Doppler signal (Rutherford Class IIA ischemia) PMH—Aortic reconstruction in the early 1990s, R iliac stent 2002 Previous L hip disarticulation secondary to ischemia/infection in the 1998 Heparin allergy—bivalirudin (Angiomax) used for this case Aortogra