Raul J. Guzman

Matrix Metalloproteinase Inhibition Attenuates Aortic Calcification

Objective—Arterial calcification has been associated with matrix metalloproteinase (MMP)–mediated elastin degradation. In this study, we investigated whether inhibiting MMP activity could reduce calcium accumulation in rodent models of aortic calcification. Methods and Results—Aortic calcification was first induced in male Sprague-Dawley rats by administration of vitamin D3. Treatment with doxycycline decreased aortic calcium and phosphorus accumulation, and it reduced aortic gelatinase levels; however, it also prevented the bone resorption associated with high doses of vitamin D3. Using an in vivo model of localized aortic calcification, systemic doxycycline treatment reduced aortic calcium accumulation without affecting serum calcium levels, suggesting a more specific effect of doxycycline in the arterial wall. In organ culture, doxycycline limited aortic calcification caused by exposure to alkaline phosphatase and inorganic phosphate. When GM6001, a synthetic and specific inhibitor of MMPs, was used instead of doxycycline, it had a similar effect. In vivo, periadventitial delivery of GM6001 to calcifying arteries significantly reduced calcification compared with controls. Conclusions—These results suggest that MMPs are involved in aortic calcification, and inhibiting MMP activity could reduce calcium accumulation in the arterial wall.

Cellular Therapy With Ixmyelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-blind, Placebo-controlled RESTORE-CLI Trial

Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option.

Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

OBJECTIVES Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs). METHODS A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10(6) total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing. RESULTS There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, P = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, P = .038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls (P = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months. CONCLUSIONS Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options.

Tibial Artery Calcification as a Marker of Amputation Risk in Patients With Peripheral Arterial Disease

OBJECTIVES The purpose of this study was to evaluate the relationship between calcification in tibial arteries, the degree of limb ischemia, and the near-term risk of amputation. BACKGROUND Determining the amputation risk in patients with peripheral arterial disease (PAD) remains difficult. Developing new measures to identify patients who are at high risk for amputation would allow for targeted interventions and focused trials aimed at limb preservation. METHODS Two hundred twenty-nine patients underwent evaluation by history, arterial Doppler, and multislice computed tomography of the lower extremities. We then explored the relationship between a tibial artery calcification (TAC), traditional risk factors for PAD, limb status at presentation, and near-term amputation risk. RESULTS Increased age and traditional atherosclerosis risk factors were associated with higher TAC scores. Patients with critical limb ischemia had the highest TAC scores, and increasing TAC scores were associated with worsening levels of limb ischemia in ordinal regression analysis. Receiver-operator characteristic analysis suggested that the TAC score predicted amputation better than the ankle-brachial index (ABI). Symptomatic patients with a TAC score greater than 400 had a significantly increased risk of amputation. In Cox regression analysis, there was a strong association between the TAC score and the risk of major amputation that remained after adjustment for traditional risk factors and the ABI. CONCLUSIONS In patients presenting with PAD, the TAC score is associated with the stage of disease and it identifies those who are at high risk for amputation better than traditional risk factors and an abnormal ABI.

Risk factors for readmission after lower extremity bypass in the American College of Surgeons National Surgery Quality Improvement Program

OBJECTIVE Readmission is associated with high mortality, morbidity, and cost. We used the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) to determine risk factors for readmission after lower extremity bypass (LEB). METHODS We identified all patients who received LEB in the 2011 ACS-NSQIP database. Multivariable logistic regression was used to assess independent predictors of 30-day readmission. We also identified our institutional contribution of LEB patients to the ACS-NSQIP from 2005 to 2011 to determine our institutions rate of readmission and readmission indications. RESULTS Among 5018 patients undergoing LEB, ACS-NSQIP readmission analysis was performed on 4512, excluding those whose readmission data were unavailable, who suffered a death on index admission, or who remained in the hospital at 30 days. Overall readmission rate was 18%, and readmission rate of those with NSQIP-captured complications was 8%. Multivariable predictors of readmission were dependent functional status (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.08-1.79), dyspnea (OR, 1.28; 95% CI, 1.02-1.60), cardiac comorbidity (OR, 1.46; 95% CI, 1.16-1.84), dialysis dependence (OR, 1.44; 95% CI, 1.05-1.97), obesity (OR, 1.28; 95% CI, 1.07-1.53), malnutrition (OR, 1.42; 95% CI, 1.12-1.79), critical limb ischemia operative indication (OR, 1.40; 95% CI, 1.10-1.79), and return to the operating room on index admission (OR, 8.0; 95% CI, 6.68-9.60). The most common postdischarge complications occurring in readmitted patients included wound complications (55%), multiple complications (22%), and graft failure (5%). Our institutional data contributed 465 LEB patients to the ACS-NSQIP from 2005 to 2012, with an overall readmission rate of 14%. Unplanned readmissions related to the original LEB (related unplanned) made up 75% of cases. The remainder 25% included readmissions that were planned staged procedures related to the original LEB (related planned, 11%) and admissions for a completely unrelated reason (unrelated unplanned, 14%). The most common readmission indications included wound infection (37%) and graft failure (10%). Readmissions were attributable to NSQIP-captured postdischarge complications in 44% of cases, an additional 44% had a non-NSQIP-defined reason for readmission, and the remainder (12%) included patients admitted for complications described in NSQIP but not meeting strict NSQIP criteria. CONCLUSIONS Readmissions are common after LEB. Optimization of select chronic conditions, closer follow-up of patients in poor health and those who required return to the operating room, and early detection of surgical site infections may improve readmission rates. Our finding that 25% of readmissions after LEB are not procedure related informs the broader discussion of how a readmission penalty affects vascular surgery in particular.

Endoleak Following Endovascular Abdominal Aortic Aneurysm Repair: Implications for Duration of Screening

Objective:Endovascular abdominal aortic aneurysm repair (EAR) requires long-term surveillance for endoleak or increase in aneurysm diameter. We analyzed the natural history of and risk factors for endoleak development. Summary Background Data:Endoleak is a common complication of EAR that can lead to aneurysm enlargement and even rupture. Following EAR, imaging studies are used to identify leaks since patients with endoleak may require additional endovascular interventions or conversion to open repair. No criteria currently exist for cessation or reduction in frequency of screening imaging studies. Methods:Data on 220 patients undergoing EAR were retrospectively reviewed. Kaplan-Meier survival analysis and Cox proportional hazards regression were used with the end point being new endoleak development. Potential risk factors included preoperative aneurysm diameter, number of negative surveillance studies, and postoperative increase in diameter. Results:A total of 52 patients (24%) who underwent EAR had endoleak detected during postoperative follow-up, which averaged 19 months (range, 0.4–101 months). One, 6-, 12-, and 24- month endoleak-free survival was 90%, 80%, 77%, and 73%, respectively. Three leaks occurred after year 2, at postoperative months 24, 48, and 85. Increasing number of negative screening studies was negatively associated with risk for endoleak development (B = −3.122, P < 0.001), while increase in aneurysm diameter was positively associated with risk for endoleak (B = 0.072, P = 0.04). Conclusion:Risk for endoleak declines as the number of negative postoperative scans increases, but new endoleaks are identified as late as 7 years following EAR. Reduction in screening frequency cannot be uniformly recommended at this time. Patients with documented aneurysm expansion should be monitored carefully and endoleak should be suspected.

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.

Biomechanical stress induces novel arterial intima-enriched genes: implications for vascular adaptation to stress

BACKGROUND The arterial vasculature is subjected to considerably greater biomechanical stress than the venous circulation. This is reflected in the difference in morphology between large arteries and veins, however little is known about the molecular differences that arise as a consequence of biomechanical stress. Previously, we identified a group of arterial intima-enriched (AIE) genes: sciellin, periplakin, SPRR3, envoplakin, galectin 7, and plakoglobin that are functionally related in that they contribute to the stress properties of stratified epithelium. We sought to test our hypothesis that these genes were regulated by biomechanical stress in vascular smooth muscle cells (VSMCs). METHODS Immunofluorescence was employed to determine the expression of the AIE genes in saphenous vein coronary artery bypass grafts. Furthermore, we used a model of cyclic stress to determine if the AIE genes were regulated by biomechanical stress in VSMCs in vitro. RESULTS Sciellin and periplakin were upregulated in saphenous vein coronary artery bypass grafts after arterialization, but were absent in non-arterialized saphenous veins. Sciellin, SPRR3, and periplakin transcripts were all upregulated (4.67-, 4.95-, 2.77-fold, respectively) by prolonged exposure to cyclic strain (24-72 h), but not at earlier time points. CONCLUSIONS These findings suggest a novel role for several human AIE genes in the VSMC response to arterialization and extended cyclic strain. SUMMARY Biomechanical stress has long been implicated in vascular pathologies. We report the novel finding of a group of genes, previously studied in stratified epithelium, that were regulated by prolonged cyclic stress in vascular smooth muscle cells. This may have important implications to vascular disease.

Combined endovenous ablation and transilluminated powered phlebectomy : Is less invasive better?

This study was undertaken to evaluate the evolution of operative vein approaches from combined “open” saphenous stripping-stab avulsion phlebectomy to combined “minimally invasive” endovenous ablation-transilluminated powered phlebectomy with a focus on comparing clinical outcomes. All patients undergoing a combined operative approach for concomitant saphenous vein insufficiency and associated varicose tributary veins between January 1, 1998 and December 31, 2005 were identified. Patients were stratified by operative approach into 3 groups: combined saphenous vein stripping-stab avulsion phlebectomy (STRIP-PHLEB); combined saphenous vein stripping-transilluminated phlebectomy (STRIP-TPP); and combined endovenous ablation-transilluminated phlebectomy (EVAB-TPP). Clinical volume, indications, technical details, and complications were retrospectively reviewed. Over the 8-year period, there were 72 limbs in 59 patients treated with STRIP-PHLEB, 92 limbs in 81 patients with STRIP-TPP, and 99 limbs in 76 patients with EVAB-TPP, with a time-dependent transition in operative techniques noted. There was no difference in distribution of CEAP clinical classification between groups, overall with most limbs in the C2-C4 categories (93.1%) and fewer in the C5-C6 categories (6.9%). There was no difference in overall complication rates between STRIP-PHLEB and EVAB-TPP, although the distribution of complications did shift with a trend toward more wound problems noted in procedures involving saphenous stripping (STRIP-PHLEB 5.6%, STRIP-TPP 6.5%, EVAB-TPP 2.0%; P = NS), and more hematomas in procedures involving transilluminated powered phlebectomy (STRIP-PHLEB 5.6%, STRIP-TPP 16.3%, EVAB-TPP 6.9%; P < .05; see Table 2). Complications associated with the endovenous ablation portion were low including technical inability to cannulate 1.6%, saphenous re-cannulation 2.4%, hematoma 2.4%, severe phlebitis 3.1%, venous thromboembolism 0.8%, and no wound or thermal injury problems. With the shift of combined operative vein approaches for concomitant saphenous vein insufficiency and varicose tributary veins towards “minimally invasive” techniques the overall complication rate has remained unchanged. While combined endovenous ablation-transilluminated phlebectomy offers some advantage of “less” invasiveness, this perceived benefit should be balanced against unchanged overall risk over traditional operative approaches.

Durability of Percutaneous Angioplasty and Stent Implantation for the Treatment of Abdominal Aortic Coarctation A Case Report

Abdominal aortic coarctation (AAC) is an uncommon vascular lesion with serious sequelae related to uncontrolled hypertension. Balloon-expandable stents have recently been utilized in the treatment of AAC as an alternative to surgical intervention. A 17-year-old female presented with hypertension uncontrolled by beta blockade. She underwent angiography, which revealed an isolated supraceliac aortic coarctation without visceral or renal artery involvement. Balloon angioplasty with stent placement was performed. At 2-year follow-up, a restenosis was identified and was treated with repeat balloon-expandable stent placement. Implantation of balloon-expandable stents is a safe and technically feasible treatment modality for abdominal aortic coarctation not involving the renal and mesenteric arteries. However, it is currently unknown whether the long-term durability of this approach may limit its effectiveness when compared to traditional surgical interventions.