Marc E. Mitchell

Bone Formation in Carotid Plaques A Clinicopathological Study

Background and Purpose— Bone formation and dystrophic calcification are present in carotid endarterectomy plaques. The clinical significance of these findings is unknown. The purpose of this study was to determine whether bone formation and extensive dystrophic calcification are associated with stable plaques and protective against ischemic vascular events. Methods— Carotid endarterectomy plaques were collected from 142 patients (94 men) with carotid stenosis. The specimens were evaluated for lamellar bone formation, dystrophic calcifications, inflammatory infiltrates, neovascularization, and histological type or grade of plaque according to a standard AHA grading system. Immunohistochemical staining was performed to identify vascular endothelial cells in neovascularization (factor VIII) and lymphocytes. Clinical data, including history of cerebrovascular and cardiovascular events, were recorded at the time of surgery. Results— Patients with calcification of carotid plaques had fewer symptoms of stroke and transient ischemic attack (P =0.042) than those without calcification. Stroke and transient ischemic attack occurred less frequently in patients with plaques with large calcific granules (P =0.021). Of the patients, 13% had lamellar bone formation, which directly correlated with the presence of sheetlike calcifications (P =0.0001) and inversely correlated with ulcerated lesions (P =0.048). The presence of bone also correlated with diabetes (P <0.01) and coronary artery disease (P <0.01). Of the 20 patients with bone, 6 had a history of stoke and transient ischemic attack (P =0.5). Conclusions— The results indicate that bone formation tends to occur in heavily calcified carotid lesions devoid of ulceration and hemorrhage. Patients with extensive calcification of the carotid plaques are less likely to have symptomatic disease.

Anti-Neutrophil-Elastase Defenses of the Lower Respiratory Tract in α1-Antitrypsin Deficiency Directly Augmented with an Aerosol of α1-Antitrypsin

STUDY OBJECTIVE: To determine if aerosolization of purified human plasma alpha 1-antitrypsin is an effective means for increasing lower respiratory anti-neutrophil-elastase defenses in alpha 1-antitrypsin deficiency. DESIGN: Nonrandomized, before-and-after trial with a 7-day treatment period. Companion studies in animals to determine lung epithelial permeability to alpha 1-antitrypsin. PATIENTS: Twelve patients with homozygous Z-type alpha 1-antitrypsin deficiency and mild to moderate emphysema. INTERVENTIONS: Aerosol administration of human plasma alpha 1-antitrypsin, 100 mg every 12 hours for 7 days. Single, 100-mg aerosol dose to anesthetized sheep with indwelling thoracic lymph duct catheters for direct assessment of lung permeability. MEASUREMENTS AND MAIN RESULTS: Treatment resulted in increased alpha 1-antitrypsin levels in the lung epithelial lining fluid (0.28 +/- 0.07 microM before therapy to 5.86 +/- 1.03 microM after therapy) and increased anti-neutrophil-elastase capacity (0.78 +/- 0.38 microM before therapy to 4.16 +/- 0.95 microM after therapy). Aerosolized alpha 1-antitrypsin diffused across the respiratory epithelium and entered lung interstitial lymph (in sheep) and reached the systemic circulation (in sheep and humans). No side effects were noted. CONCLUSION: Short-term aerosol administration of human plasma alpha 1-antitrypsin to patients with alpha 1-antitrypsin deficiency is safe and feasible, resulting in a return to normal of anti-neutrophil-elastase defenses in the lower respiratory tract. The aerosol approach, therefore, merits serious long-term evaluation as an alternative to other parenteral forms of administering therapeutic proteins.

Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters

Emerging evidence supports a role for platelets in the progression of atherosclerosis in addition to an involvement in thrombotic vascular occlusion. Platelet Factor 4 (PF4), a chemokine released by activated platelets, stimulates several pro-atherogenic processes. Therefore, we examined the localization of PF4 and the homologous protein, Neutrophil Activating Protein-2 (NAP-2) in lesions representing the evolution of human atherosclerotic plaques. Carotid plaques from 132 patients with critical carotid stenosis and 6 autopsy specimens were studied. Clinical, histologic and immunohistochemical data were analyzed using a chi(2)-test. PF4 was detected in the cytoplasm of luminal and neovascular endothelium, in macrophages and in regions of plaque calcification. The presence of PF4 in macrophages and neovascular endothelium correlated with lesion grade (p = 0.004; p = 0.044). Staining of macrophages for PF4 correlated with the presence of symptomatic atherosclerotic disease (p = 0.028). In early lesions, PF4 was commonly found in macrophages of early lesions (Grade I/II), whereas NAP-2 was rarely present. In conclusion, correlation between PF4 deposition, lesion severity and symptomatic atherosclerosis suggests that persistent platelet activation may contribute to the evolution of atherosclerotic vascular lesions. These studies support the rationale for the chronic use of anti-platelet therapy in patients at risk for developing symptomatic atherosclerosis.

The Role of MicroRNA-146a in the Pathogenesis of the Diabetic Wound-Healing Impairment: Correction With Mesenchymal Stem Cell Treatment

The impairment in diabetic wound healing represents a significant clinical problem. Chronic inflammation is thought to play a central role in the pathogenesis of this impairment. We have previously shown that treatment of diabetic murine wounds with mesenchymal stem cells (MSCs) can improve healing, but the mechanisms are not completely defined. MicroRNA-146a (miR-146a) has been implicated in regulation of the immune and inflammatory responses. We hypothesized that abnormal miRNA-146a expression may contribute to the chronic inflammation. To test this hypothesis, we examined the expression of miRNA-146a and its target genes in diabetic and nondiabetic mice at baseline and after injury. MiR-146a expression was significantly downregulated in diabetic mouse wounds. Decreased miR-146a levels also closely correlated with increased gene expression of its proinflammatory target genes. Furthermore, the correction of the diabetic wound-healing impairment with MSC treatment was associated with a significant increase in the miR-146a expression level and decreased gene expression of its proinflammatory target genes. These results provide the first evidence that decreased expression of miR-146a in diabetic wounds in response to injury may, in part, be responsible for the abnormal inflammatory response seen in diabetic wounds and may contribute to wound-healing impairment.

Time of day is associated with postoperative morbidity: an analysis of the national surgical quality improvement program data.

Objective:To examine the association between surgical start time and morbidity and mortality for nonemergent procedures. Summary Background Data:Patients require medical services 24 hours a day. Several studies have demonstrated a difference in outcomes over the course of the day for anesthetic adverse events, death in the ICU, and dialysis care. The relationship between operation start time and patient outcomes is yet undefined. Methods:We performed a retrospective cohort study of 144,740 nonemergent general and vascular surgical procedures performed within the VA Medical System 2000–2004 and entered into the National Surgical Quality Improvement Program Database. Operation start time was the independent variable of interest. Logistic regression was used to adjust for patient and procedural characteristics and to determine the association between start time and, in 2 independent models, mortality and morbidity. Results:Unadjusted later start time was significantly associated with higher surgical morbidity and mortality. After adjustment for patient and procedure characteristics, mortality was not significantly associated with start time. However, after appropriate adjustment, operations starting between 4 pm and 6 pm were associated with an elevated risk of morbidity (OR = 1.25, P ≤ 0.005) over those starting between 7 am and 4 pm as were operations starting between 6 pm and 11 pm (OR = 1.60, P ≤ 0.005). Conclusions:When considering a nonemergent procedure, surgeons must bear in mind that cases that start after routine “business” hours within the VA System may face an elevated risk of complications that warrants further evaluation.

Insulin action enhancement normalizes brachial artery vasoactivity in patients with peripheral vascular disease and occult diabetes

PURPOSE Brachial artery vasoactivity (BAVA) evaluation is a reliable, noninvasive method of assessing arterial endothelial function in vivo. We previously have shown that patients with peripheral vascular disease (PVD) and occult diabetes have abnormal BAVA results when fasting and after oral glucose intake during oral glucose tolerance test (OGTT). Troglitazone is an oral hypoglycemic agent that enhances the action of insulin. The effect of troglitazone on BAVA in patients with occult diabetes and PVD is not known. METHODS Patients with PVD, normal fasting glucose levels, and abnormal OGTT results were identified. With a duplex ultrasound scan, BAVA was evaluated by measuring the brachial artery (BA) flow (in millimeters per minute) before and after 5 minutes of BA occlusion during fasting and at 30 minutes, 1 hour, and 2 hours after the administration of 75 g of glucose during OGTT. Troglitazone therapy (400 mg/day) was begun, and the BAVA evaluation was repeated after 2 and 4 months. These results were compared with the results of the control group who had normal fasting glucose levels, normal OGTT results, and no evidence of PVD. A paired t test was used to compare the BA flow before and after BA occlusion, with a P value of less than.05 considered significant. RESULTS The control group had a normal hyperemic response with a significantly increased BA flow after 5 minutes of BA occlusion during fasting and at all stages of the OGTT. The occult diabetic group had an abnormal response to hyperemia before the treatment with troglitazone and showed little change in flow after BA occlusion. After 2 months of troglitazone therapy, BAVA results improved after oral glucose intake but not during fasting. After 4 months, BAVA results normalized both while fasting and after oral glucose intake during the OGTT. CONCLUSION Patients with occult diabetes and PVD have impaired BAVA, which normalizes after treatment with troglitazone. Insulin-action enhancers may slow the progression of PVD in patients with diabetes by improving endothelial cell function. Agents that are aimed at enhancing the action of insulin may have an advantage over the other traditional therapies for diabetes.

Therapeutic thrombin injection of pseudoaneurysms: a multicenter experience

The standard non-invasive treatment of pseudoaneurysms has been ultrasound-guided compression (UGC). Problems with UGC include pain at the site of compression, long compression times and incomplete closure. Each of these difficulties is exacerbated with large pseudoaneurysms. Recently, ultrasound-guided injection of pseudoaneurysms with thrombin has gained popularity. The goal of this study was to report a multicenter registry using this technique and in so doing detail the clinical utility and safety of this emerging procedure. The medical records of all patients diagnosed with pseudoaneurysm in the vascular laboratory who underwent thrombin injection over the past year were reviewed for patient characteristics and clinical outcome. There were 91 patients (55 male) with a mean age of 69 years. Three patients also had an arteriovenous fistula. The majority of patients were receiving one or more antiplatelet agents and/or anticoagulants. All patients underwent pseudoaneurysm injection with bovine thrombin. The mean aneurysm diameter was 3.3 cm, with a range of 1.5-6.3 cm. Successful thrombosis of the pseudoaneurysm was achieved in 89/91 (98%) of cases. Anticoagulation with heparin was used in one of the unsuccessful cases. In two cases, UGC was used to close a small active region that did not completely thrombose after thrombin injection. There were two patients who had recurrence of pseudoaneurysm the day after successful injection and thrombosis of the pseudoaneurysm. There were no local complications after injection; however, one patient suffered a pulmonary embolus that was thought to be unrelated to the procedure. In conclusion, thrombin injection for the treatment of pseudoaneurysms is safe and effective, even in patients receiving anticoagulation. This procedure should be considered as the initial therapeutic approach for peripheral pseudoaneurysms.

Barriers to Endovascular Aortic Aneurysm Repair: Past Experience and Implications for Future Device Development:

Despite improvements in endovascular aortic aneurysm repair (EVAR) devices and techniques, significant anatomic constraints still preclude successful EVAR in a large number of patients. The authors sought to identify the current barriers to EVAR and examine their evolution over time. Patients were evaluated for potential endovascular repair by computed tomography angiography (CTA) with or without supplemental conventional arteriograms. The patient population was separated into 2 groups (A and B) based on early and late time periods in the experience with EVAR, corresponding to the availability of various devices. Group A (early) consisted of the Guidant Ancure, Medtronic Talent, and AneuRx devices and comprised patients presenting between April 1997 through June 2000. Group B (late) consisted of the Medtronic AneuRx, Cook Zenith, Edwards Lifepath, Gore Excluder, and Endologix PowerLink devices and comprised patients presenting between July 2000 and December 2003. Patient demographics and anatomic reasons for rejection were recorded in a database for statistical analysis. In total, 547 patients were evaluated (463 men, 84 women). Of these, 346 patients (63%; 312 men, 34 women) were deemed suitable candidates for EVAR and 201 (37%; 151 men, 50 women) were rejected. There was no significant difference in the overall rate of rejection in the early vs the late time period (34% A, 41% B, p= 0.08), but the number of exclusion criteria per patient decreased over time; patients rejected for EVAR had an overall average of 1.6 exclusion criteria (Group A, 1.9; Group B, 1.2). The reasons for rejection did significantly change over time. Specifically, rejection on the basis of inadequate arterial access, presence of extensive iliac artery aneurysms, or an inadequate proximal neck decreased. A disproportionate number of women were excluded throughout the study: Group A, 56% of women compared to 30% of men (p= 0.0003); Group B, 63% of women compared to 36% of men (p= 0.0022). Women were more likely than men to have inadequate arterial access routes. In addition, patients with high operative risk were also more likely to be excluded from EVAR, a finding that persisted over time. Anatomic constraints continue to pose significant challenges to aortic endografting. Progress has been made in that technological advances have conquered some of the previous anatomic challenges, chiefly those of arterial access and treatment of concomitant iliac aneurysm disease. However, the overall rate of rejection for EVAR remains the same. The chief anatomic barriers continue to be the difficult aortic neck and management of branched vascular segments.

Endovascular AAA Repair in Patients with Renal Insufficiency: Strategies for Reducing Adverse Renal Events

Vascular imaging, usually employing nephrotoxic contrast agents is relied upon for all aspects of endovascular AAA repair causing some to consider renal insufficiency a relative contraindication. We sought to determine if endovascular AAA evaluation and repair could be successfully accomplished by minimally or non-nephrotoxic modalities. Records and results for 98 consecutive patients undergoing endovascular AAA repair were reviewed. Patients requiring dialysis preoperatively were excluded (N=3). The average volume of iodinated contrast agent employed for intraoperative imaging was 152 cc (35-420 cc). Twenty patients (20%) had baseline renal insufficiency (serum creatinine > or =1.3 mg/dl). A rise in serum creatinine above baseline was observed in 23 (24%) patients following repair; for 15 (16%) this was permanent. Creatinine rise occurred in patients with both normal (15) and abnormal (8) baseline values (P=0.09). Rise in creatinine was independent of contrast volume employed and of the use of infrarenal vs suprarenal device fixation (P>0.05). Two (2%) patients required permanent dialysis, one of which had a normal baseline creatinine and unclear etiology for renal failure, the other had a baseline creatinine of 2 and required device placement over an accessory renal artery. Strategies to minimize the use of nephrotoxic contrast for patients with renal insufficiency included the use of MRA, rather than contrast-CT for pre and postoperative imaging (7, 35%) and use of Gadolinium rather than iodinated contrast for performance of intraoperative arteriography (5, 25%). Endovascular grafts were successfully designed and implanted based upon MRA as the sole preoperative imaging modality in every case in which it was attempted (7). Mortality was not significantly different between those with and without abnormal baseline renal function (P>0.05). Adverse events (access failures, arterial injuries, blood loss, endoleaks) were not significantly correlated with baseline renal insufficiency, rise in creatinine from baseline, use of MRA or intraoperative Gadolinium angiography (P>0.05).Pre- and postoperative evaluation and performance of endovascular AAA repair can be accomplished in patients with renal insufficiency without increasing the rate of mortality or adverse events employing a strategy which minimizes the use of nephrotoxic contrast agents, relying upon Gadolinium arteriography and MRA. Endovascular grafts can be successfully planned and followed employing MRA as the sole imaging modality.

Surgical approach of choice for penetrating cardiac wounds.

One hundred nineteen patients suffered penetrating cardiac trauma over a 15-year period: 59 had gunshot wounds, 49 had stab wounds, and 11 had shotgun wounds. The overall survival rate was 58%. The most commonly injured structures were the ventricles. Twenty-seven patients had injuries to more than one cardiac chamber. Thirty patients had associated pulmonary injuries. Emergency thoracotomy was performed in 47 patients with 15% survival. Median sternotomy was used in 30 patients with 90% survival. Seventeen of the 83 patients with thoracotomies required extension across the sternum for improved cardiac exposure or access to the contralateral hemithorax. Only one patient with sternotomy also required a thoracotomy. All pulmonary injuries were easily managed when sternotomy was used. We conclude that sternotomy provides superior exposure for cardiac repair in patients with penetrating anterior chest trauma. We feel it is the incision of choice in hemodynamically stable patients. Thoracotomy should be reserved for unstable patients requiring aortic cross-clamping, or when posterior mediastinal injury is highly suspected.