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Outcomes from vein graft bypass are limited by graft failure, leading causes of which include intimal hyperplasia and vasospasm. Intimal hyperplasia remains the most common cause of graft failure, but no therapeutic modalities have been shown to prevent intimal hyperplasia in humans. The small heat shock proteins are a class of naturally occurring proteins in vascular smooth muscle. These proteins have an integral role in maintenance of vascular tone and in cellular defense against various stressors. Transduction domains have enabled intracellular therapeutic delivery of peptide analogs of heat shock proteins, as well as peptide inhibitors of the kinases that phosphorylate these proteins. These cell-permeant peptides have been shown to prevent vasospasm and intimal hyperplasia in vitro. Since vascular bypass using vein grafts is analogous to autologous organ transplantation, ex vivo treatment of the vein graft with cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia prior to implantation provides a unique opportunity for targeted treatment of the graft to improve patency.
Thrombosis is the leading cause of arteriovenous (AV) access failure for hemodialysis patients requiring frequent interventions. We describe a novel approach to the lyse-and-wait technique in thrombosed AV access using nurse-administered thrombolytics in a hospital-based hemodialysis unit. All patients at a single-center, large, urban, tertiary care hospital, who underwent in-center thrombolysis via alteplase instilled directly into a thrombosed AV access by inpatient hemodialysis unit staff between January 1, 2003 and December 31, 2007, were eligible. Included subjects were at least 18 years old and did not have known or suspected infection or trauma to the AV access site. Primary outcome measure was successful thrombolysis defined as hemodialysis performed immediately or after the interventional radiology (IR) procedure. Adverse events related to the procedure were collected. A total of 321 procedures, performed on 145 subjects (77 (53%) male, 68 (47%) female) remained for analysis. Successful instillation occurred in 317 of 321 procedures (98.8%). Successful thrombolysis occurred in 237 of 321 procedures (73.8%). Adverse events (8 major and 10 minor) occurred in 18 procedures, yielding a complication rate of 5.6%. In-center thrombolysis with alteplase administration by hemodialysis unit nursing staff under physician supervision is safe and effective with an adverse outcome rate similar to the literature. Thus, this modified lyse-and-wait protocol can be adopted with appropriate IR and surgical backup in place.
© 2012 Wiley Periodicals, Inc.
The saphenous vein remains the most widely used conduit for peripheral and coronary revascularization despite a high rate of vein graft failure. The most common cause of vein graft failure is intimal hyperplasia. No agents have been proven to be successful for the prevention of intimal hyperplasia in human subjects. The renin-angiotensin system is essential in the regulation of vascular tone and blood pressure in physiologic conditions. However, this system mediates cardiovascular remodeling in pathophysiologic states. Angiotensin II is becoming increasingly recognized as a potential mediator of intimal hyperplasia. Drugs modulating the renin-angiotensin system include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These drugs are powerful inhibitors of atherosclerosis and cardiovascular remodeling, and they are first-line agents for management of several medical conditions based on class I evidence that they delay progression of cardiovascular disease and improve survival. Several experimental models have demonstrated that these agents are capable of inhibiting intimal hyperplasia. However, there are no data supporting their role in prevention of intimal hyperplasia in patients with vein grafts. This review summarizes the physiology of the renin-angiotensin system, the role of angiotensin II in the pathogenesis of cardiovascular remodeling, the medical indications for these agents, and the experimental data supporting an important role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia.
Copyright © 2012 Annals of Vascular Surgery Inc. All rights reserved.
Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeant peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.
Published by Elsevier Inc.
BACKGROUND AND OBJECTIVES - Referring hemodialysis patients for elective access angiography and percutaneous transluminal angioplasty (PTA) is commonly done to prevent access failure, yet the effectiveness of this procedure remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASURES: An observational matched cohort analysis among 40,132 Medicare beneficiaries receiving hemodialysis with a fistula or graft was performed. Cox regression was used to determine whether access intervention was associated with improved 1-year access survival.
RESULTS - Nonsurgical access intervention was found to be frequent at a rate of 20.9 procedures per 100 access years. In the 1-year period after intervention using angiography and PTA, the overall access failure rate was 53.7 per 100 access years in the intervention group and 49.6 in the nonintervention group (HR = 1.02; 95% CI, 0.96 to 1.08). Similar findings were also seen when the analysis was repeated in only fistulas (HR = 1.06; 95% CI, 0.98 to 1.15) and grafts (HR = 0.95; 95% CI, 0.86 to 1.05). In patients with a low intra-access flow rate (HR = 0.86; 95% CI, 0.75 to 0.99) or a new access (HR = 0.79; 95% CI, 0.71 to 0.89), angiography and PTA significantly increased access survival when compared with nonintervention (P for interaction was <0.0001). Angiography-PTA-related upper-extremity hematoma, vessel injury, or embolism-thrombosis occurred in 1.1% of all patients.
CONCLUSIONS - Access characteristics significantly modify the survival benefits of angiography and PTA intervention where the benefits of these interventions are most seen in newer accesses or accesses with insufficient flow.
BACKGROUND - Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity.
METHODS - We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates.
RESULTS - At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups.
CONCLUSIONS - Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)
2009 Massachusetts Medical Society
CONTEXT - The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas.
OBJECTIVE - To determine whether clopidogrel reduces early failure of hemodialysis fistulas.
DESIGN, SETTING, AND PARTICIPANTS - Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later.
INTERVENTION - Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation.
MAIN OUTCOME MEASURES - The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions.
RESULTS - Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40).
CONCLUSION - Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.
Complications of liver transplantation are not limited to acute and chronic rejection, and recurrence of original disease, but include surgical complications, most commonly hepatic artery occlusion, infections, and development of de novo malignancies. In the early posttransplantation period, procurement/preservation injury, non-immunologic injury to the graft during harvesting and implantation, is manifested by centrilobular hepatocyte pallor and cholestasis but rarely leads to significant graft dysfunction. Ischemic complications, such as hepatic artery thrombosis, are more serious complications and may lead to early graft loss or biliary stricture. Infectious complications generally occur in the mid-to-late period after transplantation; cytomegalovirus (CMV) remains a common pathogen. Human herpes 6 virus infection has been implicated in allograft dysfunction, but is usually seen in the setting of co-infection with CMV. De novo malignancies are emerging as a significant cause of mortality after liver transplantation; risk is cumulative, and increases with time posttransplantation. Development of such malignancies in the setting of solid organ transplantation is multifactorial, and is related to individual and regional predispositions to malignancy, pre-transplantation disease states, recipient viral status, and use and intensity of immunosuppression regimens.
BACKGROUND - This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors potentiate activation of the kallikrein-kinin system during cardiopulmonary bypass (CPB).
METHODS - The effects of CPB on concentrations of bradykinin and its metabolite bradykinin 1-5 (BK1-5) were determined in 31 patients taking an ACE inhibitor who were randomized to continue ACE inhibitors until coronary artery bypass surgery (ACE inhibitor group, N = 19) or to discontinue them 48 hours before surgery (no ACE inhibitor group, N = 12). Arterial and venous blood was sampled before CPB, at 30 minutes of CPB, at 60 minutes of CPB, after separation from CPB, and on postoperative day 1.
RESULTS - Arterial bradykinin ( P < .001 [from 22.4 +/- 24.1 fmol/mL to 86.2 +/- 98.7 fmol/mL in the no ACE inhibitor group]) and arterial ( P < .001) and venous ( P = .016) BK1-5 concentrations increased significantly during CPB. Arterial bradykinin concentrations were significantly higher ( P = .017), whereas BK1-5 concentrations ( P = .024) and the molar ratio of BK1-5/bradykinin ( P = .008) were significantly lower in the ACE inhibitor group compared with the no ACE inhibitor group. In addition, arterial bradykinin concentrations were significantly increased in smokers compared with nonsmokers ( P = .015), when we controlled for the ACE inhibitor group. There was no effect of smoking on ACE activity ( P = .597 overall). There was a significant inverse correlation between arterial bradykinin and mean arterial pressure ( r 2 = 0.2137, P = .010) and a significant correlation between arterial bradykinin and tissue-type plasminogen activator antigen concentrations ( r 2 = 0.174, P = .022) during CPB. Tissue-type plasminogen activator antigen was significantly higher in the ACE inhibitor group than in the no ACE inhibitor group (18.0 +/- 7.8 ng/mL versus 12.4 +/- 4.5 ng/mL, P = .016) but not in smokers compared with nonsmokers ( P = .451).
CONCLUSION - Preoperative ACE inhibitors and smoking potentiate the kinin response to CPB and may contribute to the hemodynamic and fibrinolytic response observed during CPB.
BACKGROUND - The long-term clinical advantages of using routine multiple internal mammary artery (IMA) grafts for coronary artery bypass (CAB) are not clear. This study was designed to test the hypothesis that multiple IMA grafts would provide better 15-year outcomes when compared with single IMA and vein grafts.
METHODS AND RESULTS - Between 1984 and 1987, 1067 consecutive patients undergoing isolated CAB were referred to 1 surgeon practicing primarily single and another surgeon maximizing multiple IMA grafts (clinical practice trial). A 207-patient subset with multiple IMAs underwent postoperative graft angiography at 1 to 32 weeks to define initial IMA patency. Patients were followed-up yearly, and the groups were analyzed as (I) surgical strategy (surgeon operating) (single=413 versus multiple=654), (II) ultimate operation performed (single=418 versus multiple=449), or (III) single versus multiple coronary systems revascularized with IMAs (single=490 versus multiple=377). Advantages of this study design were that an entire referral population was examined, multiple IMAs were applied to the entire spectrum of baseline patient risk, 15-year follow-up provided a complete prognostic picture, and the subgroups were potentially comparable at baseline. In all 3 analyses, single and multiple groups were statistically similar with respect to baseline, operative, and immediate postoperative variables. Early IMA patency was 98.5% (333/338 grafts patent), validating the quality of IMA procedures. Unadjusted and adjusted 15-year outcome analyses for I, II, and III for death, myocardial infarction, percutaneous coronary intervention, redo coronary bypass, and the composite of all events identified multiple versus single as a significant predictor of outcome for the composite end point in adjusted analysis III (hazard ratio=0.808; 95% CI, 0.689 to 0.948; P=0.009), because of a 5% to 10% absolute reduction in each of the outcome variables at 15 years. Moreover, >50% reduction in reoperation rate was observed at 15 years in every analysis.
CONCLUSIONS - At 15-year follow-up, multiple IMA grafting was associated with a 19.2% adjusted risk reduction in death and cardiac events, caused by decreases in all adverse end points and fewer reoperations. These data indicate that the clinical advantages of maximizing IMA conduits are significant. Based on this information, it is suggested that multiple IMA grafting to 2 coronary systems should be applied liberally to patients with noncardiac risk profiles predictive of long-term survival.