Duplex Ultrasound Assessment and Outcomes of Renal Malperfusion Syndromes after Acute Aortic Dissection.

BACKGROUND: We investigated the feasibility of renal duplex ultrasound in the identification of renal malperfusion in acute aortic dissection and evaluated whether intervention for renal malperfusion improved outcomes over best medical management alone. METHODS: All patients with acute aortic dissections involving the renovisceral aorta who underwent a duplex ultrasound were included (2004-2016). We assessed duplex findings among patients who developed acute kidney injury (AKI; 50% increase in serum creatinine) and compared AKI, 30-day mortality, and overall survival among patients who underwent a procedure to treat malperfusion versus those who did not. RESULTS: Of 37 patients with acute dissection involving the renovisceral aorta (73% were male, 59% had type B dissection, mean follow-up 4.6 ± 0.6 years), 70% developed AKI, 11% required dialysis, and 5% developed permanent dialysis dependence. AKI was correlated with higher peak creatinine levels (4.2 vs. 2.2 mg/dL, P < 0.001), although 30-day mortality and overall survival were similar (both, P ≥ 0.24). Progression to AKI was associated with significantly lower end-diastolic velocity (EDV) measurements on renal duplex (17 vs. 27 cm/sec, P = 0.03); an EDV threshold of 23 cm/sec had a positive predictive value of 85% for AKI. Operative intervention (n = 10) was associated with lower follow-up creatinine (0.9 vs. 2.1 mg/dL, P = 0.002), although there was no difference in progression to dialysis dependence, 30-day mortality, or overall survival (all, P ≥ 0.34). CONCLUSIONS: Patients who developed AKI demonstrated characteristic renal duplex ultrasound findings with lower EDV measurements in the distal renal arteries bilaterally. Performing a renal malperfusion procedure was associated with normalization of postoperative creatinine without affecting 30-day mortality or overall survival.

Treatment of Aortic Graft Infection in the Endovascular Era.

PURPOSE OF REVIEW: This review provides an overview of the current literature surrounding the medical and surgical treatment of aortic graft infection with particular focus on the role of endovascular aortic grafts in the changing demographics and management of these infections. RECENT FINDINGS: Definitive therapy for aortic graft infection continues to include parenteral antibiotics and surgical explantation and revascularization procedures, which are historically vast operations and sources of significant operative stress. Surgical management has evolved to include more options for infection resistant in situ conduits, attempts at partial explantations, and use of endovascular therapy to temporize the urgent sequelae of these infections, such as aortoenteric fistula. Aortic graft infection continues to be a significant and morbid complication of graft placement even with the advent of endovascular therapy, and its treatment will only increase in difficulty as a more frail population has gained access to complex aortic repair. In the future, more flexible revascularization and partial explantation options are keys, along with long-term suppressive antibiotics where appropriate.

Use of Brilliant Blue FCF during vein graft preparation inhibits intimal hyperplasia.

BACKGROUND: Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia. METHODS: Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV. RESULTS: FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture. CONCLUSIONS: Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV.

MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.

Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.

Brilliant blue FCF as an alternative dye for saphenous vein graft marking: effect on conduit function.

IMPORTANCE: Surgical skin markers are used off-label to mark human saphenous veins (HSVs) to maintain orientation before implantation as aortocoronary or peripheral arterial bypass grafts. These surgical skin markers impair functional responses of the HSV tissue. OBJECTIVES: To investigate the effect of brilliant blue dye 1 (brilliant blue FCF [for food coloring]; hereinafter, FCF) as a nontoxic alternative marking dye and to determine whether FCF has pharmacological properties. DESIGN, SETTING, AND PARTICIPANTS: Segments of HSVs were collected in university hospitals from patients undergoing coronary artery bypass grafting procedures immediately after harvest (unmanipulated) or after typical intraoperative surgical graft preparation (after manipulation). Rat inferior venae cavae were used to determine the pharmacological properties and cellular targets of FCF. Endothelial and smooth muscle functional responses were determined in a muscle bath, and intimal thickening in HSVs was determined after 14 days in organ culture. MAIN OUTCOMES AND MEASURES: Contractile responses were measured in force and converted to stress. Smooth muscle function was expressed as maximal responses to potassium chloride depolarization contractions. Endothelial function was defined as the percentage of relaxation of maximal agonist-induced contraction. Neointimal thickness was measured by histomorphometric analysis. RESULTS: Human saphenous veins stored in the presence of FCF had no loss of endothelial or smooth muscle function. Unmanipulated HSVs preserved in the presence of FCF demonstrated a significant increase in endothelial-dependent relaxation (mean [SEM], 25.2% [6.4%] vs 30.2% [6.7%]; P = .02). Application of FCF to functionally nonviable tissue significantly enhanced the smooth muscle responses (mean [SEM], 0.018 [0.004] × 105 N/m² vs 0.057 [0.016] × 105 N/m²; P = .05). Treatment with FCF reduced intimal thickness in organ culture (mean [SEM], -17.5% [2.1%] for unmanipulated HSVs vs -27.9% [3.7%] for HSVs after manipulation; P < .001). In rat inferior venae cavae, FCF inhibited the contraction induced by the P2X7 receptor agonist 2'(3')-O-(4-benzoyl)benzoyl-adenosine-5'-triphosphate (mean [SEM], 14.8% [2.2%] vs 6.5% [1.8%]; P = .02) to an extent similar to the P2X7 receptor antagonist oxidized adenosine triphosphate (mean [SEM], 5.0% [0.9%]; P < .02 vs control) or the pannexin hemichannel inhibitor probenecid (mean [SEM], 7.3% [1.6%] and 4.7% [0.9%] for 0.5mM and 2mM, respectively; P < .05). CONCLUSIONS AND RELEVANCE: Treatment with FCF did not impair endothelial or smooth muscle function in HSVs. Brilliant blue FCF enhanced endothelial-dependent relaxation, restored smooth muscle function, and prevented intimal hyperplasia in HSVs in organ culture. These pharmacological properties of FCF may be due to P2X7 receptor or pannexin channel inhibition. Brilliant blue FCF is an alternative, nontoxic marking dye that may improve HSV conduit function and decrease intimal hyperplasia.

Natural history of grade I-II blunt traumatic aortic injury.

BACKGROUND: Endovascular aortic repair has revolutionized the management of traumatic blunt aortic injury (BAI). However, debate continues about the extent of injury requiring endovascular repair, particularly with regard to minimal aortic injury. Therefore, we conducted a retrospective observational analysis of our experience with these patients. METHODS: We retrospectively reviewed all BAI presenting to an academic level I trauma center over a 10-year period (2000-2010). Images were reviewed by a radiologist and graded according to Society for Vascular Surgery guidelines (grade I-IV). Demographics, injury severity, and outcomes were recorded. RESULTS: We identified 204 patients with BAI of the thoracic or abdominal aorta. Of these, 155 were deemed operative injuries at presentation, had grade III-IV injuries or aortic dissection, and were excluded from this analysis. The remaining 49 patients had 50 grade I-II injuries. We managed 46 grade I injuries (intimal tear or flap, 95%), and four grade II injuries (intramural hematoma, 5%) nonoperatively. Of these, 41 patients had follow-up imaging at a mean of 86 days postinjury and constitute our study cohort. Mean age was 41 years, and mean length of stay was 14 days. The majority (48 of 50, 96%) were thoracic aortic injuries and the remaining two (4%) were abdominal. On follow-up imaging, 23 of 43 (55%) had complete resolution of injury, 17 (40%) had no change in aortic injury, and two (5%) had progression of injury. Of the two patients with progression, one progressed from grade I to grade II and the other progressed from grade I to grade III (pseudoaneurysm). Mean time to progression was 16 days. Neither of the patients with injury progression required operative intervention or died during follow-up. CONCLUSIONS: Injury progression in grade I-II BAI is rare (~5%) and did not cause death in our study cohort. Given that progression to grade III injury is possible, follow-up with repeat aortic imaging is reasonable.

Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein.

INTRODUCTION: Human saphenous vein (HSV) is the most widely used bypass conduit for peripheral and coronary vascular reconstructions. However, outcomes are limited by a high rate of intimal hyperplasia (IH). HSV undergoes a series of ex vivo surgical manipulations prior to implantation, including hydrostatic distension, marking, and warm ischemia in solution. We investigated the impact of surgical preparation on HSV cellular function and development of IH in organ culture. We hypothesized that oxidative stress is a mediator of HSV dysfunction. METHODS: HSV was collected from patients undergoing vascular bypass before and after surgical preparation. Smooth muscle and endothelial function were measured using a muscle bath. Endothelial preservation was assessed with immunohistochemical staining. An organ culture model was used to investigate the influence of surgical preparation injury on the development of IH. Superoxide levels were measured using a high-performance liquid chromatography-based assay. The influence of oxidative stress on HSV physiologic responses was investigated by exposing HSV to hydrogen peroxide (H2O2). RESULTS: Surgical vein graft preparation resulted in smooth muscle and endothelial dysfunction, endothelial denudation, diminished endothelial nitric oxide synthase staining, development of increased IH, and increased levels of reactive oxygen species. Experimental induction of oxidative stress in unmanipulated HSV by treatment with H2O2 promoted endothelial dysfunction. Duration of storage time in solution did not contribute to smooth muscle or endothelial dysfunction. CONCLUSIONS: Surgical vein graft preparation causes dysfunction of the smooth muscle and endothelium, endothelial denudation, reduced endothelial nitric oxide synthase expression, and promotes IH in organ culture. Moreover, increased levels of reactive oxygen species are produced and may promote further vein graft dysfunction. These results argue for less injurious means of preparing HSV prior to autologous transplantation into the arterial circulation.

Intimal thickness associated with endothelial dysfunction in human vein grafts.

BACKGROUND: Intimal hyperplasia is a complex process thought to be initiated by injury and is the leading cause of vein graft failure. In the present investigation, we hypothesized that the basal intimal thickness in the human saphenous vein is a predictor of endothelial dysfunction and, potentially, intimal hyperplasia. METHODS: Human saphenous veins were obtained during coronary artery bypass surgery. The segments were contracted with phenylephrine and relaxed with carbachol to determine the endothelial-dependent relaxation. The vein segments were fixed in 10% buffered formalin and grown for 14 d in high-serum culture and then fixed in formalin. The fixed tissues were stained with Verhoeff-Van Gieson, and the average intimal and medial thicknesses were calculated using light microscopy and a computerized image analysis system. RESULTS: The human saphenous veins displayed varying amounts of basal intimal thickness (range 18.80-241.3 µm). The endothelial-dependent relaxation of the veins was highly variable, with values ranging from 0% to 27.59%. Human saphenous veins with a basal intimal thickness greater than 120 µm had significantly less endothelial-dependent relaxation (8.90% ± 6.32%) than those with a basal intimal thickness less than 120 µm (21.97% ± 10.64%). Endothelial dysfunction correlated with a basal intimal thickness greater than 120 µm (P = 0.02). The basal intimal thickness also correlated with increased intimal thickness after 14 d in organ culture (P = 0.0001). CONCLUSIONS: A basal intimal thickness greater than 120 µm is a predictor of endothelial dysfunction. Also, because a greater basal intimal thickness correlated with an increased intimal thickness after organ culture, the basal intimal thickness might predict vein graft failure owing to intimal hyperplasia.

Cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia.

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.

Role of the renin-angiotensin system in the pathogenesis of intimal hyperplasia: therapeutic potential for prevention of vein graft failure?

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.

Women in academic surgery: the pipeline is busted.

PURPOSE: This investigation examined the trends for gender-based advancement in academic surgery by performing a comparative analysis of the rate of change in the percentage of medical students, surgery residents, and full professors of surgery who are women. METHODS: All available Women in Medicine Annual Reports were obtained from the American Association of Medical Colleges (AAMC). The gender compositions of medical graduates, surgery residents, and full professors were plotted. Binomial and linear trendlines were calculated to estimate the year when 50% of surgery full professors would be women. Additionally, the percentage distribution of men and women at each professorial rank was determined from 1995 to 2009 using these reports to demonstrate the rate of academic advancement of each gender. RESULTS: The slope of the line of increase for women full professors is significantly less than for female medical students and for female general surgery residents (0.36, compared with 0.75 and 0.99, respectively). This predicts that the earliest time that females will account for 50% of full professors in surgery is the year 2096. When comparing women and men in academic ranks, we find that women are much less likely than men to be full professors. CONCLUSIONS: The percentage of full professors in surgery who are women is increasing at a rate disproportionately slower than the increases in female medical students and surgery residents. The rates of increase in female medical students and surgery residents are similar. The disproportionately slow rate of increase in the number of female full professors suggests that multiple factors may be responsible for this discrepancy.

MELD scores of liver transplant recipients according to size of waiting list: impact of organ allocation and patient outcomes.

CONTEXT: The Model for Endstage Liver Disease (MELD) score serves as the basis for the distribution of deceased-donor (DD) livers and was developed in response to "the final rule" mandate, whose stated principle is to allocate livers according to a patient's medical need, with less emphasis on keeping organs in the local procurement area. However, in selected areas of the United States, organs are kept in organ procurement organizations (OPOs) with small waiting lists and transplanted into less-sick patients instead of being allocated to sicker patients in nearby transplant centers in OPOs with large waiting lists. OBJECTIVE: To determine whether there is a difference in MELD scores for liver transplant recipients receiving transplants in small vs large OPOs. DESIGN AND SETTING: Retrospective review of the US Scientific Registry of Transplant Recipients between February 28, 2002, and March 31, 2003. Transplant recipients (N = 4798) had end-stage liver disease and received DD livers. MAIN OUTCOME MEASURES: MELD score distribution (range, 6-40), graft survival, and patient survival for liver transplant recipients in small (<100) and large (> or =100 on the waiting list) OPOs. RESULTS: The distribution of MELD scores was the same in large and small OPOs; 92% had a MELD score of 18 or less, 7% had a MELD score between 19 and 24, and only 2% of listed patients had a MELD score higher than 24 (P =.85). The proportion of patients receiving transplants in small OPOs and with a MELD score higher than 24 was significantly lower than that in large OPOs (19% vs 49%; P<.001). Patient survival rates at 1 year after transplantation for small OPOs (86.4%) and large OPOs (86.6%) were not statistically different (P =.59), and neither were graft survival rates in small OPOs (80.1%) and large OPOs (81.3%) (P =.80). CONCLUSIONS: There is a significant disparity in MELD scores in liver transplant recipients in small vs large OPOs; fewer transplant recipients in small OPOs have severe liver disease (MELD score >24). This disparity does not reflect the stated goals of the current allocation policy, which is to distribute livers according to a patient's medical need, with less emphasis on keeping organs in the local procurement area.

Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection.

We recently reported on a series of patients who experienced acute cellular rejection (ACR) during the treatment of hepatitis C virus (HCV) infection in our posttransplantation cohort. Our hypothesis is that HCV clearance improves hepatic microsomal function, which in turn results in lower trough cyclosporine (CyA) and tacrolimus (TAC) levels, predisposing the patient to ACR. Records of all patients receiving transplants for HCV infection at our center from 1993 to June 2002 were reviewed. Two hundred three patients were identified. Thirty-seven patients (18%) were treated with interferon-based therapies in combination with ribavirin. Twelve patients were selected for analysis because they became HCV RNA negative during therapy, and 18 patients with no antiviral response were selected as controls (7 other patients had incomplete data or had switched from one immunosuppression [IS] therapy to the other). Baseline IS levels were compared with the first available level after documented negative HCV RNA results in the study group and the last on-treatment IS level in the control group. We also compared frequency and percentage of change in IS levels during therapy. Mean decline in CyA trough levels in the study group was from 187.28 ng/mL at baseline to 118.14 ng/mL immediately after becoming HCV RNA negative (-36.92%; P =.018). Mean decline in TAC levels was from 7.34 ng/mL at baseline to 5.02 ng/mL immediately after becoming HCV RNA negative (-29.17%; P =.044). Overall, 6 of 12 patients who cleared HCV RNA during therapy experienced ACR; 1 patient died as a result of ACR. Using percentage of decrease from baseline IS level, we combined results for patients administered CyA and TAC and found a significant decrease from baseline IS levels in responders (-31.8% after HCV RNA clearance on treatment; P =.0001). Nonresponders experienced a 0.98% decline in IS levels while on treatment, and the difference was significant compared with the change in the responder group (P =.006). A greater proportion of antiviral therapy responders also experienced trough IS levels 20% less than baseline than nonresponder controls during therapy (P =.0006). In conclusion, IS levels decreased significantly in patients responding favorably to anti-HCV therapy. This decrease in IS levels may have a key role in predisposing these patients to ACR.

Different immunosuppressive regimens and recurrence of primary sclerosing cholangitis after liver transplantation.

Primary sclerosing cholangitis (PSC) is the fourth leading diagnosis in liver transplant recipients in the United States. The disease is known to recur in 15% to 30% of liver transplant recipients. We set out to investigate how different immunosuppression regimens affected natural history of PSC after liver transplantation at our center. We reviewed records of all patients who underwent a liver transplantation at our institution in between 1988 and 2000 and had a diagnosis of PSC at the time of liver transplantation. Primary sclerosing cholangitis recurred in 15 of 71 patients (21.1%) who had complete records and survived more than 30 days after liver transplantation. Although recurrence of primary sclerosing cholangitis was most often seen (but not statistically significantly so) in patients who received maintenance corticosteroids, the time to recurrence was not significantly different between those who were treated with maintenance, those who were not successfully weaned, and those who successfully weaned off corticosteroids within 3 months after liver transplantation. Orthoclone (OKT3) therapy (Ortho-Biotech, Inc., Raritan, NJ) was associated with a higher risk of primary sclerosing cholangitis recurrence (29% versus 10%, P <.05). Recurrence was not influenced by immunosuppression with either cyclosporine or tacrolimus. Coexistent inflammatory bowel disease was a cause of failure to wean off corticosteroids, was associated with a shorter time to recurrence of sclerosing cholangitis, and was responsible for significant comorbidity (colon cancer in 7.3%). Primary sclerosing cholangitis recurrence is commonly seen after liver transplantation. More immunosuppression seems to be detrimental to the outcome of our patients with sclerosing cholangitis: use of OKT3 was associated with a greater incidence of recurrence. Length of corticosteroid use did not affect timing or risk of recurrence, and because it has been proven that early corticosteroid withdrawal after liver transplantation is beneficial, we continue to recommend this practice.