Gale L. Tang

Low levels of a natural IgM antibody are associated with vein graft stenosis and failure.

BACKGROUND All humans have natural, protective antibodies directed against phosphorylcholine (PC) epitopes, a common inflammatory danger signal appearing at sites of cell injury, oxidative stress, and on bacterial capsules. In large human cohorts, low levels of anti-PC IgM were associated with a significantly increased risk of stroke or myocardial infarction. However, it is not known if these antibodies protect against the premature closure of arterial reconstructions. METHODS A prospective, observational study of patients undergoing elective, infrainguinal, autogenous vein bypasses for atherosclerotic occlusive disease of the legs was conducted. Clinical data were recorded prospectively, and preoperative levels of anti-PC IgM measured with the CVDefine kit from Athera Biotechnologies (Solna, Sweden). The principal clinical end point was the loss of primary patency (loss of graft flow, or any intervention for stenosis). Patients were followed regularly by duplex ultrasound at 1, 3, 6, 12, 18 months, and yearly thereafter. RESULTS Fifty-six patients were studied, for an average of 1.3 years. Indications for surgery were claudication (33.9%), ischemic rest pain (17.9%), and ischemia with ulceration or gangrene (48.2%). Seventeen (30.4%) patients experienced loss of primary patency (10 graft occlusions, seven surgical or endovascular revisions of graft stenoses). Kaplan-Meier survival analysis showed that the quartile of patients with the lowest anti-PC IgM levels had significantly worse primary graft patency (log-rank test, P = .0085). Uni- and multivariate Cox proportional hazards analysis revealed that the preoperative anti-PC IgM level was an important predictor of graft failure. Patients with IgM values in the lowest quartile had a 3.6-fold increased risk of graft failure (95% confidence interval: 1.1-12.1), even after accounting for other significant clinical or technical factors such as indication for surgery, site of distal anastomosis, or vein graft diameter. CONCLUSIONS A naturally occurring IgM antibody directed against the proinflammatory epitope PC may be protective against vein graft stenosis and failure, through anti-inflammatory mechanisms. Measurement of this antibody may be a useful prognostic indicator, although larger studies of more diverse populations will be needed to confirm these results. The biological actions of anti-PC IgM suggest it may be useful in developing immunotherapies to improve bypass longevity.

Outcomes after stent graft therapy for dissection-related aneurysmal degeneration in the descending thoracic aorta

OBJECTIVE Stent graft therapy has emerged as an alternative to open surgery in the management of chronic dissection-related aneurysmal degeneration (DRAD) in the descending thoracic aorta (DTA). The incidence of perioperative complications, need for secondary aortic intervention (SAI), and rate of aneurysmal false-lumen thrombosis have not been thoroughly described. METHODS Perioperative and midterm outcomes in patients who underwent stent graft therapy for chronic DRAD DTA at a single institution between January 2006 and September 2013 were retrospectively analyzed. Preoperative anatomic factors, including the number of visceral and renal side branches off the false lumen, and false lumen volume, were analyzed for their ability to predict treatment failure. Treatment failure was defined as death, need for a SAI, and failure to achieve thrombosis of the DRAD DTA. Treatment success was defined as thrombosis of the false lumen in the area of the DRAD DTA with stability or a decrease in the maximum diameter of the DRAD DTA. RESULTS During the study period, 47 patients underwent stent graft therapy for chronic DRAD DTA. Patients were a mean age of 58.3 ± 11.7 years, 74.5% (n = 35) were male, and 14.9% (n = 7) had a history of connective tissue disease. The left subclavian artery was covered in 48.9% (n = 23), and revascularization was performed in 87.0% (n = 20). Spinal drains were used in 74.5% (n = 35). Spinal cord ischemia developed in 6.4% (n = 3), which resolved in two and improved in one. No retrograde aortic dissections occurred. The 30-day mortality was 4.3% (n = 2); one death was in a patient with rupture. Mean clinical follow-up was 35.1 ± 20.9 months. The 5-year Kaplan-Meier survival was 89% ± 5%. Treatment failure occurred in 18 patients (38.3%): 9 required SAIs, 6 did not have thrombosis of the false lumen in the area of the DRAD DTA, and 4 died, with 1 patient dying during a SAI. No preoperative anatomic factor predicted treatment failure. The 5-year freedom from treatment failure was 54% ± 9%. Including the nine patients who underwent SAI, treatment success was achieved in 85.2% of patients. CONCLUSIONS In this single-center experience of stent graft therapy for chronic DRAD DTA, treatment success was achieved in 85% of patients after a SAI rate of 20%. No preoperative anatomic factor predicted treatment failure, which occurred in almost 40% of the patients. Identifying predictors of treatment failure may improve future outcomes.

Mycotic aortic aneurysm caused by haemophilus influenzae group F.

BACKGROUND Haemophilus influenzae is a rare cause of mycotic aortic aneurysm. We present a case of H. influenzae mycotic aortic aneurysm, which was complicated by prior endovascular stent-graft placement at another facility. METHODS A 58 year-old man was treated by endograft placement for a presumed penetrating aortic ulcer after having symptoms of abdominal pain and malaise for one month. He presented to our institution 11 days after endograft placement with septic physiology. Repeat computed tomography angiogram demonstrated an inflammatory mass around the distal aorta and right common iliac artery, which had an associated contained rupture. RESULTS The patient was treated using intravenous antibiotics, axillo-bifemoral bypass followed by endograft explantation and aortic and iliac ligation. Intraoperative cultures grew Haemophilus influenzae, serotype f. CONCLUSIONS Aortic endografts have been successfully used for treatment of selected mycotic aneurysms, generally after adequate treatment of the primary infection with intravenous antibiotics. This case demonstrates the unfavorable natural history of endograft placement in an unsuspected mycotic aneurysm. A high index of suspicion for possible aortic infection should be maintained for patients with systemic symptoms and unusual aortic pathology prior to choosing endovascular repair.

The impact of chronic renal insufficiency on vascular surgery patient outcomes

Renal insufficiency is associated with an increased incidence of poor outcomes, including cardiovascular events and death, in the general population. Renal dysfunction appears to have a particularly negative impact in patients undergoing vascular surgery and endovascular therapy. Although the exact mechanism is unknown, increased levels of inflammatory and biochemical modulators associated with adverse cardiovascular outcomes, as well as endothelial dysfunction, appear to play a role in the association between renal insufficiency and adverse outcomes. Outcomes after the surgical and endovascular treatment of abdominal aortic aneurysms, carotid disease, and peripheral arterial disease are all negatively affected by renal insufficiency. Patients with renal dysfunction may warrant intervention for the treatment of critical limb ischemia and symptomatic carotid stenosis, given the comparatively worse outcomes associated with medical management. Open repair of aortic aneurysms and carotid intervention for asymptomatic disease in patients with severe renal dysfunction should be performed with significant caution, as the risks of repair may outweigh the benefits in this population. Further study is needed to better delineate the risks of medical management for these conditions in patients with coexisting severe renal dysfunction. Lastly, current guidelines for the management of vascular diseases, including objective performance goals for critical limb ischemia, are likely not applicable in patients with severe renal insufficiency.

A single nucleotide polymorphism of cyclin-dependent kinase inhibitor 1B (p27Kip1) associated with human vein graft failure affects growth of human venous adventitial cells but not smooth muscle cells

Background Cyclin‐dependent kinase inhibitor 1B (p27Kip1) is a cell‐cycle inhibitor whose ‐838C>A single nucleotide polymorphism (rs36228499; hereafter called p27 SNP) has been associated with the clinical failure of peripheral vein grafts, but the functional effects of this SNP have not been demonstrated. Methods Human saphenous vein adventitial cells and intimal/medial smooth muscle cells (SMCs) were derived from explants obtained at the time of lower extremity bypass operations. We determined the following in adventitial cells and SMCs as a function of the p27 SNP genotype: (1) p27 promoter activity, (2) p27 messenger (m)RNA and protein levels, and (3) growth and collagen gel contraction. Deoxyribonuclease I footprinting was also performed in adventitial cells and SMCs. Results p27 promoter activity, deoxyribonuclease I footprinting, p27 mRNA levels, and p27 protein levels demonstrated that the p27 SNP is functional in adventitial cells and SMCs. Both cell types with the graft failure protective AA genotype had more p27 mRNA and protein. As predicted because of higher levels of p27 protein, adventitial cells with the AA genotype grew slower than those of the CC genotype. Unexpectedly, SMCs did not show this genotype‐dependent growth response. Conclusions These results support the functionality of the p27 SNP in venous SMCs and adventitial cells, but an effect of the SNP on cell proliferation is limited to only adventitial cells. These data point to a potential role for adventitial cells in human vein graft failure and also suggest that SMCs express factors that interfere with the activity of p27. Clinical Relevance Approximately 400,000 vein grafts are used each year to bypass coronary and peripheral arterial occlusive disease, and ˜30% of the grafts fail in the first year because of intimal hyperplasia and pathologic remodeling. This high rate of failure has not changed in 40 years. Animal models of vein grafts have put the spotlight on the smooth muscle cells of the inner vein wall, but animal models may not accurately reflect this human disease. The current study implicates the adventitial cells of the outer wall in graft failure.

Clinical factors that influence the cellular responses of saphenous veins used for arterial bypass

Objective: When an autogenous vein is harvested and used for arterial bypass, it suffers physical and biologic injuries that may set in motion the cellular processes that lead to wall thickening, fibrosis, stenosis, and ultimately graft failure. Whereas the injurious effects of surgical preparation of the vein conduit have been extensively studied, little is known about the influence of the clinical environment of the donor leg from which the vein is obtained. Methods: We studied the cellular responses of fresh saphenous vein samples obtained before implantation in 46 patients undergoing elective lower extremity bypass surgery. Using an ex vivo model of response to injury, we quantified the outgrowth of cells from explants of the adventitial and medial layers of the vein. We correlated this cellular outgrowth with the clinical characteristics of the patients, including the Wound, Ischemia, and foot Infection classification of the donor leg for ischemia, wounds, and infection as well as smoking and diabetes. Results: Cellular outgrowth was significantly faster and more robust from the adventitial layer than from the medial layer. The factors of leg ischemia (P < .001), smoking (P = .042), and leg infection (P = .045) were associated with impaired overall outgrowth from the adventitial tissue on multivariable analysis. Only ischemia (P = .046) was associated with impaired outgrowth of smooth muscle cells (SMCs) from the medial tissue. Co‐culture of adventitial cells and SMCs propagated from vein explants revealed that adventitial cells significantly inhibited the growth of SMCs, whereas SMCs promoted the growth of adventitial cells. The AA genotype of the −838C>A p27 polymorphism (previously associated with superior graft patency) enhanced these effects, whereas the factor of smoking attenuated adventitial cell inhibition of SMC growth. Comparing gene expression, the cells cultured from the media overexpress Kyoto Encyclopedia of Genes and Genomes pathways associated with inflammation and infection, whereas those from the adventitia overexpress gene families associated with development and stem/progenitor cell maintenance. Conclusions: The adverse clinical environment of the leg may influence the biologic behavior of the cells in the vein wall, especially the adventitial cells. Chronic ischemia was the most significant factor that retards adventitial cell outgrowth. The cells arising from the vein adventitia may be key players in determining a healthy adaptive or a pathologic response to the injuries associated with vein grafting. Clinical Relevance: We prospectively studied saphenous veins from 46 infrainguinal bypasses and found that ex vivo cellular outgrowth was significantly impaired by the deleterious clinical factors of leg ischemia, smoking, and infection—especially for the adventitial layer of the vein. The adventitial cells may play an important role in the healthy remodeling of a successful vein graft.

Comparison of outcomes in women and men following carotid interventions in the Washington state's Vascular Interventional Surgical Care and Outcomes Assessment Program

Background The benefit for carotid endarterectomy (CEA) to prevent a potential stroke has been shown to be less beneficial for women compared with men and the risk of carotid stenting (CAS) is higher in women than men. We hypothesized that a community‐based Washington state registry data would also reveal increased morbidity and mortality for women undergoing carotid interventions. Methods Deidentified data for CEA and CAS between 2010 and 2015 were obtained from 19 hospitals participating in the Washington State Vascular‐Interventional Surgical Care and Outcomes Assessment Program. Data analysis compared in‐hospital composite outcome of stroke and mortality from CEA and CAS between women and men. Results Over the study period, 3704 individuals underwent CEA (n = 2759; 49.5% symptomatic) and CAS (n = 945; 60.9% symptomatic). Women accounted for 39.5% of the cohort. Women were slightly younger than men (70.0 ± 10.2 vs 71.0 ± 9.6 years respectively; P < .01), less likely to be smokers (70.1% vs 75.6%; P < .01), and less likely to have a diagnosis of coronary artery disease (32.9% vs 46.5%; P < .01). Fewer women underwent CEA for symptomatic carotid disease (46.1% vs 51.8%; P < .01). There were no statistically significant differences in the postoperative in‐hospital stroke and mortality among women and men undergoing CEA (asymptomatic, 0.8% vs 1.4% [P = .36]; symptomatic, 1.8% vs 2.2% [P = .58]) and CAS (asymptomatic, 1.4% vs 2.2% [P = .56]; symptomatic, 4.6% vs 2.5% [P = .18]). Hospital duration of stay and discharge disposition were similar for women and men. A subanalysis of the octogenarian cohort undergoing CAS demonstrated a substantial increase in‐hospital stroke and mortality among women and men (11.6% [CAS] vs 2.2% [CEA]; P = .024). Conclusions In the Washington state Vascular‐Interventional Surgical Care and Outcomes Assessment Program registry, hospital composite outcome of stroke and mortality following carotid interventions from 2010 to 2015 were noted to be similar for women and men. The notable exception to this finding was observed in subcohort of women undergoing CAS for symptomatic carotid disease at age 80 years or older. These findings should be taken into account when risk stratifying patients for carotid interventions.

Decreased Apoptosis and Increased Proangiogenic Gene Expression in p27Kip1-Deficient Mouse Collaterals After Hindlimb Ischemia

variables but retaining the frailty domains (nutrition, social, physical function) performed just as well (AUC 1⁄4 0.76; Fig). Addition of procedure-specific mortality risk further improved model performance (AUC 1⁄4 0.77). The final model showed that open aortic procedures, thoracic endovascular aortic repair, and renal insufficiency carried the greatest risk for 9-month mortality. A nomogram summing points for each frailty element and procedure-based risk allows estimation of 9-month mortality (Fig). Conclusions: A model using only seven VQI frailty-related data elements and procedure-based risk estimates 9-month mortality after arterial reconstruction. Frailty assessment may improve preoperative decision-making, especially in considering risk/benefit of procedures for claudication or asymptomatic disease.

Inflammation, Endoleaks, and Aortic Remodeling—The Chicken or the Egg

Shalaby and colleagues1have taken a fresh look at inflammationandaortic aneurysmsbyexamining thecontinued remodeling of the residual aneurysmal sac after endovascular repair of infrarenal aortic aneurysms (endovascular aneurysm repair [EVAR]). Two long-term pitfalls for EVAR areendoleaksandcontinuedexpansionof the residual sac.The rate of type II endoleaks may be as low as 15%2 or as high as 27%.3Type II endoleaksusually involve continued flowwithin the aneurysm sac. Approximately 60% resolve within 6 months, but persistence of a type II endoleak after the first 6 months is associatedwith higher rates (55%) of aneurysm sac enlargement.2 The search for risk factors for type II endoleaks and sac expansion have primarily focused on anatomical factors (after all, it is a plumbingproblem): thenumber of patent lumbars, the sizeof the inferiormesenteric artery, theburden of laminated thrombus in the aneurysm, or the technical complexities of the endovascular procedure. Inflammation in the arterialwall has long been suspected as a causative factor for thedevelopment and expansionof an infrarenal aortic aneurysm, which is the most common type of sporadic, nonsyndromic aneurysm. An abundance of inflammatory cells can be found in the aneurysm wall, as well as increases in proteolytic activity and matrix protein degradation.4 This article1 suggests that increased systemic inflammationmay play a role in the failure of sac shrinkage and the development of endoleaks. In a retrospective group of 79 patients undergoingEVAR, 65%had some type of inflammatory condition (eg, allergic rhinitis, osteoarthritis, gout, or rheumatoid arthritis). The “inflammatory” group showed comparable long-termsurvival, experiencedmorepostoperativecomplications (no surprise), and had a significantly higher rate of type II endoleaks, as well as less sac shrinkage in the longterm. Their observations support the intuitive idea that excessive systemic inflammation leads to a failure of aorticwall fibrosis and contraction, resulting in retarded sac shrinkage. Why should this cause more endoleaks, primarily an anatomic problem? Instead of the conventional wisdom that endoleaks cause a failure of sac shrinkage, perhaps the reverse is true: does failure of sac shrinkage foster endoleaks? Themain caveat to their conclusions is that their classification of systemic inflammatory diseasewas based on a diagnosis proffered by others and lacked independent confirmation or, even better, some objective measurements of inflammation.Without confirmatorydata, itwouldbehard to understandhowallergic rhinitisandrheumatoidarthritismight confer a similar derangement of the systemic inflammatory state. This points to a key therapeutic question: what aspect(s) of systemic inflammationmightbeassociatedwith failure of aortic remodeling and which pathways are involved? Some directions for further study may be found in disorders in transforminggrowth factor–βsignalingandtheSMADgenes, bothofwhich share clinical associationswith aneurysmal diseases and osteoarthritis.4,5

Original Excluder component overlap from proximal or distal extension during initial repair not correlated with aneurysm sac shrinkage

OBJECTIVES The original abdominal Excluder (W.L. Gore & Associates, Flagstaff, Ariz) endoprosthesis has been associated with late aneurysm sac expansion over time from transgraft ultrafiltration of serous fluid. This has been treated by relining the graft with original or low-permeability components. We asked whether additional component overlap of the original graft material resulting from proximal or distal extensions placed at the time of initial repair would influence the rate of late aneurysm sac expansion in the absence of endoleak. METHODS Computed tomography (CT) scans from subjects (n = 120) receiving the original endoprosthesis from the Excluder pivotal trial were measured for total distance of original graft overlap (including contralateral gate, proximal extension, or distal extension overlap) based on reformatted CT scans. This was compared to change in aneurysm sac diameter and volume (as measured in independent laboratories) at the latest time point available. Patients were omitted if they were missing CT scan data (n = 10), their graft was explanted for endoleak (n = 2), they underwent an intervention for endoleak and did not have diameters available after their intervention (n = 3), or if they had a continued endoleak that could account for an increase in aneurysm sac diameter (n = 11). This left 27 patients with more overlapping components than the required contralateral limb/gate overlap (mean follow-up time 40.6 +/- 17.0 months) and 67 patients with required gate overlap (mean follow-up time 46.2 +/- 15.9 months). RESULTS Subjects with increased component overlap (mean overlap 87.1 mm +/- 57.4 mm) were not protected from aneurysm sac expansion when compared to those with the minimum required gate overlap (mean overlap 31.2 mm +/- 3.4 mm). There was no association of total distance of overlap with aneurysm sac size change by diameter or volume (r(2) = 0.00034, P = .86 for diameter and r(2) = 0.0019, P = .68 for volume). Increasing percentage of overlap within the aneurysm sac was likewise not associated with aneurysm sac decrease in diameter (r(2) = 0.0028, P = .61). Few patients had large percentages of original graft overlap (mean 26.2% +/- 14.1% for the increased overlap group and 18.6% +/- 5.5% for the required overlap group, P = .0097). CONCLUSION Partial graft overlap involving multiple original components from proximal and distal extensions is not protective against aneurysm sac expansion due to transgraft ultrafiltration. This suggests that transgraft ultrafiltration is not impeded by having partial double layers of original material. All patients who received the original Excluder and have late aneurysm sac expansion in the absence of endoleak should have as complete relining as feasible with low permeability components if sac shrinkage is the surrogate goal.