Feasibility of Intravascular Lithotripsy for the Treatment of Calcified Supra-Aortic Vessels: A Case Report and Literature Review.

PURPOSE: To report a case of coronary-subclavian steal syndrome (CSSS) due to a history of a left internal mammary artery (LIMA) to left anterior descending (LAD) artery coronary bypass (CABG) and a heavily calcified ostial left subclavian artery (LSA) occlusion, that was treated with intravascular lithotripsy (IVL) technique and to summarize the current trends of IVL treatment for supra-aortic vessels. CASE REPORT: A 64-year-old woman with progressive intermittent angina pectoris and a history of LIMA to LAD bypass underwent coronary angiography which demonstrated complete ostial occlusion of the LSA. Via brachial access, the patient underwent Shockwave IVL balloon treatment of the LSA and stent-graft implantation. At 9 months follow-up, the patient showed symptoms resolution, and duplex ultrasound (DUS) demonstrated a patent LSA. CONCLUSIONS: The Shockwave IVL system was demonstrated to be a feasible treatment and justified for selective cases of highly calcified lesions in supra-aortic vessels. The present case report and the literature review, in a total of 47 patients resulted in a high technical procedural success rate, with a low rate of complications. Future studies with larger cohorts are warranted to confirm these findings and standardize this technology in this particular vascular field. CLINICAL IMPACT: The present study exemplifies a case of recanalization of the left subclavian artery in a patient with coronary-subclavian steal syndrome with a heavily calcified ostial lesion treated with intravascular lithotripsy (IVL). In this paper, for the first time, a review of the contemporary literature on the use of IVL in supra-aortic vessels is reported, elucidating the feasibility of this technique in this vascular territory. Despite the heterogeneous features of the reported cases and the lack of a standardized protocol for the use of IVL in the management of highly calcified lesions of supra-aortic vessels, it was demonstrated to be a feasible technique, with a high technical success rate, being an advantageous tool for heavily calcified supra-aortic lesions.

Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia.

Critical limb ischemia (CLI) is the most severe presentation of peripheral arterial disease. We developed cell-based therapy entailing intra-arterial injection of autologous venous endothelial cells (ECs) modified to express angiopoietin 1, combined with autologous venous smooth muscle cells (SMCs) modified to express vascular endothelial growth factor. This combination promoted arteriogenesis in animal models and was safe in patients with limiting claudication. In an open-label, phase Ib study, we assessed the safety and efficacy of this therapy in CLI patients who failed or were unsuitable for surgery or intravascular intervention. Of 23 patients enrolled, 18 with rest pain or non-healing ulcers (Rutherford categories 4 and 5) were treated according to protocol, and 5 with significant tissue loss (Rutherford 6) were treated under compassionate treatment. Patients were assigned randomly to receive 1 × 107 or 5 × 107 (EC-to-SMC ratio, 1:1) of the cell combination. One-year amputation-free survival rate was 72% (13/18) for Rutherford 4 and 5 patients; all 5 patients with Rutherford 6 underwent amputation. Of the 12 with unhealing ulcers at dosing, 6 had complete healing and 2 others had >66% reduction in ulcer size. Outcomes did not differ between the dose groups. No severe adverse events were observed related to the therapy.

Characterizing Cathepsin Activity and Macrophage Subtypes in Excised Human Carotid Plaques.

BACKGROUND AND PURPOSE: Atherosclerosis is a leading cause of mortality worldwide, contributing to both strokes and heart attacks. Macrophages are key players in atherogenesis, promoting vascular inflammation and arterial remodeling through cysteine cathepsin proteases. We used a cathepsin-targeted activity-based probe in human carotid plaque to assess its diagnostic potential and evaluate macrophage subtypes ex vivo. METHODS: Carotid plaque specimens surgically removed during endarterectomy from 62 patients (age range, 38% female, 28% symptomatic) were graded pathologically as either stable (Grade 1) or unstable (Grade 2 or 3). A cathepsin activity-based probe was used to quantify individual cathepsins in plaque tissue and macrophage subtypes. RESULTS: Cathepsin B and S activities were increased in unstable carotid plaques. They were quantified using the probe to biochemically investigate individual cathepsins (Cathepsin B and S: 0.97 and 0.90 for grade 3 versus 0.51 and 0.59 for grade 1; P=0.006 and P=0.03 arbitrary units (AU), respectively). Higher cathepsin activity was observed in carotid plaques from symptomatic patients (Cathepsin B and S: 0.65 and 0.77 for asymptomatic, 0.99 and 1.17 for symptomatic; P=0.008 and P=0.005 AU, respectively). Additionally, it was demonstrated that M2 macrophages from unstable plaques express cathepsin activity 5-fold higher than M2 macrophages from stable plaques (25.52 versus 5.22; P=0.008 AU). CONCLUSIONS: Targeting cathepsin activity in human carotid plaques may present a novel diagnostic tool for characterizing high-risk plaques. Novel cathepsin activity patterns within plaques and macrophage subpopulations suggest their involvement in the transition to active disease.

Arrest of progression of pre-induced abdominal aortic aneurysm in apolipoprotein E-deficient mice by low level laser phototherapy.

BACKGROUND AND OBJECTIVES: Using non-invasive, high-frequency ultrasonography (HF-u/s), we showed that low-level laser phototherapy (LLL) inhibits de-novo formation of abdominal aortic aneurysms (AAA) in apolipoprotein-E-deficient (Apo-E(-/-)) mice. The current study tests the effect of LLL on the progression of pre-induced AAA. STUDY DESIGN/MATERIAL AND METHODS: AAA was induced in Apo-E(-/-) mice (age 16-20 weeks) by subcutaneous infusion of angiotensin-II using osmotic minipumps (1000 ng/kg/minutes, 4 weeks). HF-u/s (40 MHz, 0.01 mm resolution, Vevo-770, VisualSonics) was used to measure the maximum cross-sectional-diameter (MCD) of the suprarenal abdominal aorta, the anterior wall displacement (AWD), and radial wall velocity (RWV). The aortas of mice that developed >35% dilatation at 2 weeks over baseline were exposed retroperitoneally and treated with LLL (780 nm, 2.2 J/cm(2), 9 minutes) or sham-operated. HF-u/s was repeated at 4 weeks, the mice sacrificed by perfusion fixation, and the aortas excised for histopathology. RESULTS: Of all mice with >35% MCD expansion of the suprarenal aorta at 2 weeks, 7(58%) of 12 non-treated, but only 1(7%) of 14 LLL, had increased MCD(> 1 SD) at 4 weeks (P < 0.009 by Fisher's Exact Test [FET]). The mean change in MCD from 2-4 weeks was also markedly reduced in the LLL-treated mice (control vs. LLL, 0.24 ± 0.25 vs. -0.06 ± 0.39 mm, P = 0.029 by unpaired t-test). Similar results were obtained when limiting the analysis to animals with ≥ 50% expansion at 2 weeks. The deterioration in AWD from 2-4 weeks in non-treated controls was not observed in LLL-treated animals (ΔAWD: control, 0.03 ± 0.05 mm, P < 0.036 vs. LLL, 0.00 ± 0.05, P = 0.91 by paired t-test). By the modified Daugherty classification, we found significantly fewer severe aneurysms at 4 weeks in the LLL-treated animals versus control (3 of 10 vs. 9 of 11, P = 0.03 by FET). CONCLUSIONS: LLL not only prevents de novo development of AAA, but, from this study, also arrests further progression of pre-induced AAA and its associated deterioration in the biomechanical integrity of the aortic wall in Apo-E(-/-) mice.

Intraoperative blood transfusion of one or two units of packed red blood cells is associated with a fivefold risk of stroke in patients undergoing elective carotid endarterectomy.

OBJECTIVE: Transfused blood can disrupt the coagulation cascade. We postulated that packed red blood cell (PRBC) transfusion may be associated with thromboembolic phenomena. We used propensity matching to examine the relationship between intraoperative PRBC transfusion and stroke during carotid endarterectomy (CEA). METHODS: We selected CEA procedures from the American College of Surgeons National Surgical Quality Improvement Program database from 2005-2009. We excluded bilateral, redo, and emergent procedures. We used multivariate logistic regression to identify independent risk factors for stroke. We then calculated a transfusion propensity score to match patients who received one or two units of transfused PRBC intraoperatively with patients of similar risk profiles who had not been transfused. RESULTS: Our criteria resulted in 12,786 elective CEA patients. Of these, 82 (0.6%) received a one- to two-unit intraoperative transfusion. Thirty-day stroke rates were 1.4% (179/12,704) in the nontransfused group and 6.1% (5/82) in the transfused group (Fisher exact test, P = .007). In forward stepwise multivariable regression of risk factors, only hemiplegia, stroke history, and transient ischemic attacks were predictive of 30-day stroke. We used these same variables to calculate transfusion propensity. We matched 80 transfused patients with 160 controls, thus, creating two groups with very similar risk profiles differing only by their transfusion status. In the matched groups, there was a fivefold increase in the risk of stroke in transfused patients (Fisher exact test, P = .043) CONCLUSIONS: Intraoperative transfusion of one to two units of PRBCs is associated with a fivefold increase in stroke risk. This holds true after consideration of stroke risk variables and operative duration as a surrogate for technical difficulty. The increased risk may be related to several effects of transfused blood on the coagulation inflammation cascade.

Common femoral adventitial cystic disease in a young female patient.

Adventitial cystic disease (ACD) is a rare condition that typically presents in young healthy men with symptoms of claudication. ACD is characterized by formation of a mucinous cyst within the adventitia of a blood vessel, usually in the popliteal artery, causing compression of the vessel's lumen and leading to reduced flow and symptoms of claudication. We have presented a rare case of ACD of the common femoral artery in a young female patient that was treated successfully with resection and femoral vein graft interposition reconstruction.

An out of the box treatment for an infected pseudoaneurysm: Deep to superficial femoral artery transposition.

An infected pseudoaneurysm is a condition that has become more common in recent years, with the proliferation of endovascular intervention and the use of intravenous drugs. If left untreated, an infected pseudoaneurysm can progress to rupture, which can lead to life-threatening hemorrhage. No clear consensus has been reached among vascular surgeons regarding the management of infected pseudoaneurysms, and the literature describes a wide range of treatment techniques. In the present report, we describe an "out of the box" approach to infected pseudoaneurysms: a superficial femoral artery to deep femoral artery transposition, as an alternative to ligation with or without bypass reconstruction. We also describe our experience with six patients who underwent this procedure with 100% technical success and limb salvage rates. Although we implemented this technique for cases of infected pseudoaneurysms, we believe it can also be applied to other cases of femoral pseudoaneurysms when angioplasty or graft reconstruction is not feasible. However, further research with larger cohorts is warranted.

Low level laser arrests abdominal aortic aneurysm by collagen matrix reinforcement in apolipoprotein E-deficient mice.

BACKGROUND AND OBJECTIVES: Recent in vitro studies by our group indicated that low level laser irradiation (LLLI) modifies cellular processes essential to the progression of abdominal aortic aneurysm (AAA). Using high-frequency ultrasonography (HF-u/s) in the angiotensin-II (Ang-II)-infused, apolipoprotein-E-deficient (Apo-E(-/-) ) mouse model of AAA, we found that LLLI markedly inhibited aneurysm formation and preserved arterial wall elasticity. We now report, using quantitative histopathology, the likely mechanism underlying the preventative effect of LLLI on aneurysm formation in this model. STUDY DESIGN/MATERIALS AND METHODS: This study was performed on 32 Apo-E(-/-) mice of which 10 were Ang-II-infused and LLL-irradiated (780 nm, 2 J/cm(2) , 9-minutes), 12 were Ang-II-infused but not irradiated, and 10 were saline infused. The aortas were excised at 28d, sectioned at 250 µm intervals, and stained with H + E, Movat-pentachrome and picrosirius-red for histomorphometry, and immunostained with Mac-2 and α-actin for detection of macrophages and SMCs, respectively. RESULTS: Transmural disruptions of the aorta occurred with distinct predilection for branch orifices. In the LLLI-treated animals, the frequency of these disruptions was lower (#branches with break points: 17 of 40 vs. 32 of 48, P = 0.023 by Chi-squared), their size smaller (length [mm]: 0.48 ± 0.26 vs. 0.98 ± 1.42, P = 0.044 by ANOVA with FPLSD), and the number of Mac-2-positive macrophages in the intramural areas of these disruptions lower than in the non-treated control (#Macrophages/0.01 mm(2) at break points: 11.6 ± 7.2 vs. 26.0 ± 15.7, P = 0.016 by Kruskal-Wallis). The average size of the medial SMCs was larger reflecting a heightened synthetic state (SMC size [µm(2) ]: 463.9 ± 61.4 vs. 354.9 ± 71.7, P = 0.001 by ANOVA with FPLSD). Furthermore, at sites of transmural disruption, the %area occupied by collagen of the overall area of attempted repair (%Col/WO) was significantly greater in the LLLI-treated animals versus control (%Col/WO: 41 ± 13 vs. 32 ± 16, P = 0.009 by ANOVA with FPLSD). CONCLUSION: Enhanced matrix reinforcement and modification of the inflammatory response at sites of transmural injury are prominent mechanisms by which LLLI reduces AAA progression in this model.

A novel endovascular treatment for transcatheter aortic valve embolization.

In the present report, we have described the case of an 82-year-old obese man who had required transcatheter aortic valve replacement to treat severe symptomatic aortic stenosis. During implantation, the balloon-mounted valve became dislodged and embolized to the ascending aorta. A second valve was successfully implanted after several failed attempts to reposition the first one into the aortic annulus. The dislodged valve became further embolized and landed in the distal descending aorta, partially obstructing the splanchnic, renal, and lower extremity blood flow. It was rotated with flexible forceps and permanently secured in the distal thoracic aorta using a thoracic endoprosthesis, rendering it harmless.

Cardiac tamponade and coronary artery pseudoaneurysm after brachial arterial embolectomy, possible role for an aberrant origin of the right coronary artery.

A patient developed hemopericardium shortly after left brachial arterial embolectomy using an embolectomy catheter. Evaluation disclosed evolving pseudoaneurysm of the right coronary artery that was successfully managed by stenting. Misplacement of the embolectomy catheter within the coronary vessel was facilitated by an anomalous origin of the right coronary artery. This complication highlights the importance of correct insertion of the embolectomy catheter using the markers to avoid maladvancement and damage to central vessels.

Acute mesenteric ischemia: guidelines of the World Society of Emergency Surgery.

Acute mesenteric ischemia (AMI) is typically defined as a group of diseases characterized by an interruption of the blood supply to varying portions of the small intestine, leading to ischemia and secondary inflammatory changes. If untreated, this process will eventuate in life threatening intestinal necrosis. The incidence is low, estimated at 0.09-0.2% of all acute surgical admissions. Therefore, although the entity is an uncommon cause of abdominal pain, diligence is always required because if untreated, mortality has consistently been reported in the range of 50%. Early diagnosis and timely surgical intervention are the cornerstones of modern treatment and are essential to reduce the high mortality associated with this entity. The advent of endovascular approaches in parallel with modern imaging techniques may provide new options. Thus, we believe that a current position paper from World Society of Emergency Surgery (WSES) is warranted, in order to put forth the most recent and practical recommendations for diagnosis and treatment of AMI. This review will address the concepts of AMI with the aim of focusing on specific areas where early diagnosis and management hold the strongest potential for improving outcomes in this disease process. Some of the key points include the prompt use of CT angiography to establish the diagnosis, evaluation of the potential for revascularization to re-establish blood flow to ischemic bowel, resection of necrotic intestine, and use of damage control techniques when appropriate to allow for re-assessment of bowel viability prior to definitive anastomosis and abdominal closure.

Cathepsin Activity-Based Probes and Inhibitor for Preclinical Atherosclerosis Imaging and Macrophage Depletion.

BACKGROUND AND PURPOSE: Cardiovascular disease is the leading cause of death worldwide, mainly due to an increasing prevalence of atherosclerosis characterized by inflammatory plaques. Plaques with high levels of macrophage infiltration are considered "vulnerable" while those that do not have significant inflammation are considered stable; cathepsin protease activity is highly elevated in macrophages of vulnerable plaques and contributes to plaque instability. Establishing novel tools for non-invasive molecular imaging of macrophages in plaques could aid in preclinical studies and evaluation of therapeutics. Furthermore, compounds that reduce the macrophage content within plaques should ultimately impact care for this disease. METHODS: We have applied quenched fluorescent cathepsin activity-based probes (ABPs) to a murine atherosclerosis model and evaluated their use for in vivo imaging using fluorescent molecular tomography (FMT), as well as ex vivo fluorescence imaging and fluorescent microscopy. Additionally, freshly dissected human carotid plaques were treated with our potent cathepsin inhibitor and macrophage apoptosis was evaluated by fluorescent microscopy. RESULTS: We demonstrate that our ABPs accurately detect murine atherosclerotic plaques non-invasively, identifying cathepsin activity within plaque macrophages. In addition, our cathepsin inhibitor selectively induced cell apoptosis of 55%±10% of the macrophage within excised human atherosclerotic plaques. CONCLUSIONS: Cathepsin ABPs present a rapid diagnostic tool for macrophage detection in atherosclerotic plaque. Our inhibitor confirms cathepsin-targeting as a promising approach to treat atherosclerotic plaque inflammation.

Acute Type B Aortic Pathology Mimicking Acute Type A Intramural Hematoma with Organ Malperfusion.

The management of acute Stanford Type A intramural hematoma (IMH) of the aorta remains controversial. Most surgeons advocate emergency surgery in a manner similar to frank acute Type A dissection. Others recommend a conservative approach to this distinct clinicopathological entity. We describe a case of acute aortic pathology initially diagnosed as Type A IMH with organ malperfusion, subsequently identified as acute Type B pathology with retrograde and antegrade extension. An endovascular approach was successfully used to exclude the site of origin.

Inadequate reinforcement of transmedial disruptions at branch points subtends aortic aneurysm formation in apolipoprotein-E-deficient mice.

INTRODUCTION: Infusion of angiotensin-II (Ang-II) in apolipoprotein-E-deficient mice (Apo-E(-/-)) results in suprarenal abdominal aortic aneurysm (AAA) in 30-85% of cases. This study identifies the apparent mechanism by which some animals do, but others do not, develop AAA in this model. METHODS: Male Apo-E(-/-) mice were infused with Ang-II (n=21) or saline (n=6) and sacrificed at 4 weeks. Aortas were excised, embedded in paraffin, sectioned (250 µm intervals), and stained. Sites of transmedial disruption (TMD) were identified and characterized, and their relationship to the 4 major aortic side branches (celiac, superior mesenteric, and renals) were determined. RESULTS: The frequency of TMDs in Ang-II-infused mice that formed AAA (n=9) was similar to those that did not (n=12) (AAA vs. no-AAA: 25 of 36[69%] vs. 28 of 48[58%] branches, P=.3 by chi-square). All TMDs were at branch points. However, in animals with AAA, the mean maximum length of the TMDs was significantly larger (1.94±1.6 vs. 0.65±0.5mm, P=.007 by Mann Whitney U test), the #mac-2(+) macrophages per 0.01mm(2) of defect area was greater (32±10 vs. 19±11, P<.02 by Kruskal-Wallis with Conover-Inman post hoc), the % area of attempted repair occupied by collagen was less (17±13% vs. 44±15%, P=.0009 by Mann Whitney U test), and the density of collagen per unit length of media missing was also markedly less (0.13±0.2 vs. 1.14±1.0, P=.0001 by Mann Whitney U test). CONCLUSIONS: Reinforcement of transmedial defects at branch points by wall matrix is a key intrinsic player in limiting AAA formation in the Ang-II-infused, Apo E(-/-) mouse and a potentially important mechanism-based therapeutic target for management of small, slowly progressing aneurysms.

Lessons from Animal Models of Arterial Aneurysm.

We review the results from the most common animal models of arterial aneurysm, including recent findings from our novel, laparoscopy-based pig model of abdominal aortic aneurysm, that contribute important insights into early pathogenesis. We emphasize the relevance of these findings for evaluation of treatment protocols and novel device prototypes for mechanism-based prevention of progression and rupture.

Thrombin injection for the treatment of mycotic gluteal aneurysm.

Gluteal aneurysms are rare entity, whose surgical or endovascular management is traditionally challenging. Infectious source being increasingly more common as the underlying etiology. We herein describe successful implementation of direct thrombin injection as another therapeutic option for these patients.

Low-level laser irradiation inhibits abdominal aortic aneurysm progression in apolipoprotein E-deficient mice.

AIMS: Increased early detection of abdominal aortic aneurysm (AAA) and the severe complications of its current treatment have emphasized the need for alternative therapeutic strategies that target pathogenetic mechanisms of progression and rupture. Recent in vitro studies from our laboratory have shown that low-level laser irradiation (LLLI) (780 nm) modifies cellular processes fundamental to aneurysm progression. The present study was designed to determine whether LLLI retards the progression of suprarenal AAA in vivo. METHODS AND RESULTS: High-frequency ultrasonography (0.01 mm resolution) was used to quantify the effect of LLLI on aneurysmatic aortic dilatation from baseline to 4 weeks after subcutaneous infusion of angiotensin II by osmotic minipumps in the apolipoprotein E-deficient mouse. At 4 weeks, seven of 15 non-irradiated, but none of the 13 LLLI, mice had aneurysmal dilatation in the suprarenal aneurysm-prone segments that had progressed to >or=50% increase in maximal cross-sectional diameter (CSD) over baseline (P = 0.005 by Fisher's exact test). The mean CSD of the suprarenal segments (normalized individually to inter-renal control segments) was also significantly lower in irradiated animals (LLLI vs. non-irradiated: 1.32 +/- 0.14 vs. 1.82 +/- 0.39, P = 0.0002 by unpaired, two-tailed t-test) with a 94% reduction in CSD at 4 weeks compared with baseline. M-mode ultrasound data showed that reduced radial wall velocity seen in non-treated was significantly attenuated in the LLLI mice, suggesting a substantial effect on arterial wall elasticity. CONCLUSION: These in vivo studies, together with previous in vitro studies from this laboratory, appear to provide strong evidence in support of a role for LLLI in the attenuation of aneurysm progression. Further studies in large animals would appear to be the next step towards testing the applicability of this technology to the human interventional setting.