Shih Yuan Fang

Rosuvastatin improves vascular function of arteriovenous fistula in a diabetic rat model.

OBJECTIVE This study investigates the pathogenesis of arteriovenous (AV) fistula failure in patients with diabetes mellitus (DM) and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. METHODS DM was induced in rats by a single injection of streptozotocin. One week later, a fistula was created in the descending aorta and the adjacent inferior vena cava (aortocaval [AC] fistula). Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. Blood flow in the aortic segments of the fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined 2 weeks after creation of the AC fistulas using flow cytometry. Vascular function of the AC fistulas was assessed by isometric force testing. The expression of proinflammatory genes and generation of superoxide anions in the fistulas were examined. RESULTS The number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased the number of circulating EPCs. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated after treatment with rosuvastatin. Rosuvastatin also attenuated the expression of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase and generation of superoxide anions in the fistula tissues isolated from diabetic rats. CONCLUSIONS We provide the first evidence demonstrating that rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with DM by attenuating the activity of proinflammatory genes and generation of superoxide anions in the remodeled vasculature. CLINICAL RELEVANCE Arteriovenous (AV) fistula is the most common vascular access for hemodialysis in patients with end-stage renal disease. Studies have shown that blood flow in the AV fistula is significantly reduced in patients with diabetes and the period for maturation of an AV fistula is longer in these patients. The underlying mechanisms of AV fistula failure in diabetes are still poorly understood and there are limited therapeutic approaches that can increase the lifespan of these fistulas. The present study demonstrates that oral administration rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with diabetes, which results from attenuating the activity of proinflammatory genes in the remodeled vasculature, thereby reducing the generation of tissue superoxide anions. Our results may thus enhance our ability to prevent and manage vascular access failure in patients with diabetes with chronic renal disease.

Spinal cord injury enhances arterial expression and reactivity of α1-adrenergic receptors—mechanistic investigation into autonomic dysreflexia

BACKGROUND CONTEXT Autonomic dysreflexia (AD) usually presents with a significant increase in blood pressure, and uncontrollable autonomic response to stimuli below the level of spinal cord injury (SCI). PURPOSE This study analyzed the vasomotor function and molecular changes in the peripheral arteries below the lesion of SCI to characterize the mechanism of autonomic dysreflexia. STUDY DESIGN This was a randomized experimental study in rats. METHODS Contusive SCI was induced using a force-calibrated weight-drop device at the T10 level in anesthetized rats. Two weeks after severe SCI, blood flow in the femoral arteries was measured, and the vasomotor function and expression of α1-adrenergic receptors were analyzed. RESULTS Blood flow in the femoral artery was significantly reduced in rats with SCI (8.0±2 vs. 17.5±4 mL/min, SCI vs. control, respectively; p=.016). The contraction responses of femoral artery segments to cumulative addition of α1-adrenergic agonist phenylephrine were significantly enhanced in rats with SCI. Expression of α1-adrenergic receptor was upregulated in the medial layer of femoral artery vascular homogenates of these rats. CONCLUSION Our study provides evidence demonstrating that prolonged denervation below the lesion level following SCI results in a compensatory increased expression of α1-adrenergic receptors in the arterial smooth muscle layer, thereby enhancing the responsiveness to α1-adrenergic agonist and potentiating the development of AD.

Rosuvastatin Suppresses the Oxidative Response in the Venous Limb of an Arteriovenous Fistula and Enhances the Fistula Blood Flow in Diabetic Rats

Objective: The blood flow in the arteriovenous (AV) fistula is significantly reduced in diabetic patients. Statins are known to mediate pleiotropic effects in the vascular endothelium and attenuate inflammatory responses. This study tested the vascular protective effect of rosuvastatin in an experimental model of AV fistula. Methods: One week after the induction of diabetes mellitus (DM) in rats, a fistula was created in the abdominal aorta and inferior vena cava. Rats received placebo or rosuvastatin (15 mg/kg/day) in chow for 2 weeks. The blood flow in the venous segments of the fistula was measured. The expression of proinflammatory genes and the generation of superoxide in the venous fistula were examined. Results: The blood flow and luminal diameter of the AV fistula was significantly enhanced in animals treated with rosuvastatin. Rosuvastatin attenuated the expression of inducible nitric oxide synthase, NADPH oxidase, and monocyte chemotactic protein-1 in the fistula. The levels of superoxide anions and proinflammatory cytokines were also suppressed in rosuvastatin-treated animals. Neointimal formation in the AV fistula was not affected following treatment with rosuvastatin. Conclusions: We demonstrated that rosuvastatin improves luminal dilatation and blood flow in the AV fistula of subjects with DM. These vascular protective effects of rosuvastatin are most likely mediated by the attenuation of proinflammatory activities in the remodeled vasculature.

SUBCUTANEOUS EMPHYSEMA, PNEUMOTHORAX, PNEUMOMEDIASTINUM, AND PNEUMOPERITONEUM DURING COLONOSCOPIC BALLOON DILATION: A CASE REPORT

A 77‐year‐old woman underwent colonoscopic balloon dilatation for colonic stricture 1 year after laparoscopic anterior resection of sigmoid colon cancer. During the balloon dilatation, panfacial swelling and apnea were noted. Emergency endotracheal intubation was undertaken. Chest X‐ray revealed diffuse subcutaneous emphysema and bilateral pneumothorax. We discuss the possible mechanism and management of this uncommon complication during therapeutic colonoscopy.

Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension

Objectives: Systemic left‐to‐right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon‐like peptide, exendin‐4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. Methods: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin‐4 (1 &mgr;g/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. Results: Exendin‐4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin‐1&bgr; levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin‐4. Smooth muscle‐myosin heavy chain‐II and &agr;‐smooth muscle actin protein levels increased in the pulmonary arteries of exendin‐4‐treated rats. Histology showed that exendin‐4 decreased the main and intra‐acinar pulmonary artery medial thickness. Conclusions: Exendin‐4 treatment improved pulmonary artery function in flow‐induced PH via its direct vasoactive properties, anti‐inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin‐1&bgr; and its downstream signaling molecules. Glucagon‐like peptide analogs may possess pleiotropic therapeutic potential in flow‐induced PH.

Autologous endothelial progenitor cells improve allograft survival in porcine lung transplantation with prolonged ischemia

BACKGROUND As endothelial progenitor cells (EPCs) attenuated acute lung injury (ALI) in rabbit model, we hypothesized that autologous EPCs preserved lung graft function during the acute reperfusion period of lung transplantation and tested the therapeutic potential of EPCs in a porcine model of lung transplantation with prolonged graft ischemia. METHODS Day-7 EPCs isolated from the recipient subjects or plain culture media were administered into the left pulmonary artery immediately before restoration of pulmonary blood flow in a porcine lung allotransplantation model, with the transplantation surgeons blinded to the content of injection. Hemodynamics and arterial blood gas were recorded, and the right pulmonary artery was occluded 30 min after reperfusion to evaluate the lung graft function. The lung grafts were sectioned for histological examination at the end of experiments. The total ischemic time for lung graft was approximately 14 h. RESULTS All animals receiving plain medium died within 40 min after reperfusion, but 3 out of 5 (60%) piglets receiving EPCs survived up to 4 h after diversion of the entire cardiac output into the lung graft (P<0.01). The donor body weight, recipient body weight, cold ischemic time, and time for anastomosis were comparable between the EPC and control group (P=0.989, 0.822, 0.843, and 0.452, respectively). The mean aortic pressure decreased, and the cardiac output and mean pulmonary artery pressure elevated after right pulmonary artery occlusion. All these parameters were gradually compensated in the EPC group but decompensated in the control group. Better preservation of gas exchange function, reduced thrombi formation in the terminal pulmonary arterioles, and attenuated interstitial hemorrhage of the lung graft were observed in the EPC group. CONCLUSIONS We concluded autologous EPCs significantly enhanced the function of lung allograft and improved survival in a porcine model of lung transplantation with prolonged ischemia.

Isoflurane Impairs Motor Function Recovery by Increasing Neuroapoptosis and Degeneration during Spinal Ischemia-Reperfusion Injury in Rats

BACKGROUND: Spinal cord ischemia (SCI) leads to variable degrees of neurologic deficit in patients undergoing major cardiovascular surgery. The effect of intraoperative neuroprotection against SCI and the subsequent ischemia–reperfusion injury is still limited. Because isoflurane is a commonly used anesthetic agent during major operation, and its neuroprotective and neurotoxicity effects have both been discussed, this study aimed to investigate the effect of isoflurane on the spinal cord’s functional recovery in a rat model of cord ischemia. METHODS: Rats were randomly anesthetized by parenteral anesthetic (Zoletil®) and isoflurane (0% and 1.5% v/v in oxygen). Cord ischemia was induced by cross-clamping of thoracic aorta at the level of T5, and cord perfusion was resumed after 25 minutes. The motor function was assessed independently up to 48 hours after reperfusion. Spinal cords were harvested and analyzed for molecular and histologic changes. RESULTS: The locomotor rating scale was significantly reduced in rats that received isoflurane treatment during SCI at 12 to 48 hours after reperfusion. Isoflurane enhanced the expression of heme oxygenase-1, glial fibrillary acidic protein, cleaved caspase-3, and Iba-1 in the spinal cord. Increased apoptotic cells and the presence of axonal damage were also observed in the histologic sections. CONCLUSION: Our results demonstrate that the administration of inhaled isoflurane in spinal cord ischemia–reperfusion injury impairs the recovery of motor function. This response is associated with the neuronal apoptosis and degeneration. This study highlights the potential adverse effect of isoflurane on the functional recovery of ischemic spinal cord during major aortic surgery.

Giant adenoma arising in the lower esophagus with adenocarcinoma

Gastrointestinal adenomas are neoplasms of glandular epithelium containing dysplasia of varying degrees. Villous adenomas of the lower esophagus are extremely rare [1]. Most have developed in Barrett’s epithelium and some have been associated with either high-grade dysplasia or carcinoma [2, 3]. Like adenomatous colon polyps, they have been associated with malignancy. We presented an adult patient who had a solitary tumor obstructing the thoracic esophagus. Initial histological diagnosis was adenocarcinoma, but finally, the base of the tumor was tubulovillous adenoma.