Vinit N. Varu

Basic Science Review: Nitric Oxide—Releasing Prosthetic Materials

Prosthetic devices that come into contact with blood ultimately fail secondary to thrombus formation. This limits the utility of a variety of materials used to surgically treat cardiovascular disease, including vascular grafts and stents, as well as sensors and catheters placed within the circulatory system. Moreover, systemic anticoagulation that is used to prevent malfunction of these devices has potential for serious complications. It is known that nitric oxide (NO) produced via the endothelium imparts thromboresistant properties to native blood vessels. Thus, if NO were delivered locally to the site of the prosthetic material, it has the potential to halt thrombus formation while limiting life-threatening side effects. This review serves to examine the variety of NO-releasing materials that have been created with the two different classes of NO donors, the diazeniumdiolates and S-nitrosothiols, and the clinical applications of these prosthetics for potential future use.

Outcome and clinical significance of delayed endoleaks after endovascular aneurysm repair

OBJECTIVE Endovascular aneurysm repair (EVAR) is considered the standard therapy for most patients with abdominal aortic aneurysm (AAA). Endoleak is a well-known EVAR-related complication that requires long-term follow-up. However, patient follow-up is often challenging outside clinical trials. We sought to evaluate the incidence and the effect of delayed endoleaks in a Veterans Administration (VA) health care system where long-term follow-up is ensured. METHODS We retrospectively evaluated 213 consecutive patients who underwent EVAR at a referral Veterans Administration medical center. Age, aneurysm size, patency of lumbar and inferior mesenteric arteries, and follow-up evaluations were recorded. Type of endoleak, date of detection, and intervention were also documented. Patients who had <1 year of follow-up were excluded. The χ(2) test, Student t-test, Mann-Whitney test, and Spearman correlation were used for data analysis. RESULTS The analysis included 183 patients with a mean follow-up of 53 months (range, 12-141 months); of these, 48 patients (26%) had endoleaks, and 31 (17%) had aneurysm progression. The mean diagnosis time for nontype II (n = 14) endoleaks was 45 months (range, 3-127 months), and 71% were diagnosed >1 year after EVAR. All except one nontype II endoleak received prompt secondary interventions, and the one without intervention presented with aneurysm rupture. An isolated type II endoleak was detected in 34 patients at an average of 14.4 months (range, 0-76 months) after EVAR, 41% of which were detected >1 year after EVAR. Patients without a documented endoleak had a significant decrease in aneurysm size at the latest computed tomography evaluation compared to the preoperative size (4.8 vs 5.7 cm; P < .001), whereas those with isolated type II endoleak had an increase at the latest computed tomography follow-up compared to preoperative size (5.8 vs 5.7 cm). Importantly, 59% of the patients with a type II endoleak had significant AAA enlargement (0.8 cm), and delayed type II endoleak was significantly associated with sac enlargement compared to type II endoleaks detected early. No significant correlation was seen between the diameter of inferior mesenteric artery or lumbar to AAA enlargement among the patients with a type II endoleak. Secondary interventions in 12 patients with isolated type II endoleak resulted in overall aneurysm stabilization or regression. CONCLUSIONS This long-term outcome study demonstrated that delayed endoleaks appearing >1 year after EVAR contributed to most of the overall endoleaks and were significantly associated with aneurysm sac growth. This study underscores that type II endoleak is not benign and that vigilant lifelong surveillance after EVAR is critical.

Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome

Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.

Anatomic Suitability of Aortoiliac Aneurysms for Next Generation Branched Systems

BACKGROUND Preservation of internal iliac flow is an important consideration to prevent ischemic complications during endovascular aneurysm repair. We sought to determine the suitability of aortoiliac aneurysms for off-the-shelf iliac branched systems currently in clinical trial. METHODS Patients undergoing abdominal aortic aneurysm repair from 2004 to 2013 at 2 institutions were reviewed. Centerline diameters and lengths of aortoiliac morphology were measured using three-dimensional workstations and compared with inclusion/exclusion criteria for both Cook and Gore iliac branch devices. RESULTS Of the nearly 2,400 aneurysm repairs performed during the study period, 99 patients had common iliac aneurysms suitable for imaging review. Eighteen of the 99 (18.2%) patients and 25/99 (25.3%) patients fit the inclusion criteria and would have been able to be treated using the Cook and Gore iliac branch devices, respectively. The most common reason for exclusion from Cook was internal iliac diameter of <6 or >9 mm (68/99, 68.7%). The most common reason for exclusion from Gore was proximal common iliac diameter of <17 mm (39/99, 39.4%) and inadequate internal iliac artery diameter of <6.5 or >13.5 mm (37/99, 37.3%). Comparing the included patients across both devices, a total of 35/99 (35.4%) of patients would be eligible for the treatment of aortoiliac aneurysms based on anatomic criteria. CONCLUSIONS Only 35% of the aneurysm repairs involving common iliac arteries would have been candidates for the 2 iliac branch devices currently in trial based on anatomic criteria. The major common reason for exclusion is the internal iliac landing zone for both devices. Design modifications for future generation iliac branch technology should focus on diameter accommodations for the hypogastric branch stent and proximal and distal sizes of the iliac branch components. Familiarity with alternate branch preserving techniques is still needed in the majority of cases.

Effect of Nitric Oxide on Neointimal Hyperplasia based on Sex and Hormone Status

Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone-replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G₀/G₁ cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent.

Insulin enhances the effect of nitric oxide at inhibiting neointimal hyperplasia in a rat model of type 1 diabetes

Diabetes confers greater restenosis from neointimal hyperplasia following vascular interventions. While localized administration of nitric oxide (NO) is known to inhibit neointimal hyperplasia, the effect of NO in type 1 diabetes is unknown. Thus the aim of this study was to determine the efficacy of NO following arterial injury, with and without exogenous insulin administration. Vascular smooth muscle cells (VSMC) from lean Zucker (LZ) rats were exposed to the NO donor, DETA/NO, following treatment with different glucose and/or insulin concentrations. DETA/NO inhibited VSMC proliferation in a concentration-dependent manner to a greater extent in VSMC exposed to normal-glucose vs. high-glucose environments, and even more effectively in normal-glucose/high-insulin and high-glucose/high-insulin environments. G(0)/G(1) cell cycle arrest and cell death were not responsible for the enhanced efficacy of NO in these environments. Next, type 1 diabetes was induced in LZ rats with streptozotocin. The rat carotid artery injury model was performed. Type 1 diabetic rats experienced no significant reduction in neointimal hyperplasia following arterial injury and treatment with the NO donor PROLI/NO. However, daily administration of insulin to type 1 diabetic rats restored the efficacy of NO at inhibiting neointimal hyperplasia (60% reduction, P < 0.05). In conclusion, these data demonstrate that NO is ineffective at inhibiting neointimal hyperplasia in an uncontrolled rat model of type 1 diabetes; however, insulin administration restores the efficacy of NO at inhibiting neointimal hyperplasia. Thus insulin may play a role in regulating the downstream beneficial effects of NO in the vasculature.

Nitric Oxide: What a Vascular Surgeon Needs to Know

Atherosclerosis in the form of peripheral arterial disease results in significant morbidity and mortality. Surgical treatment options for peripheral arterial disease include angioplasty with and without stenting, endarterectomy, and bypass grafting. Unfortunately, all of these procedures injure the vascular endothelium, which impairs its ability to produce nitric oxide (NO) and ultimately leads to neointimal hyperplasia and restenosis. To improve on current patency rates after vascular procedures, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. This article reviews some of the previous research that has aimed to improve NO bioavailability after vascular procedures whether through systemic or local delivery, as well as to describe some of the NO-releasing products that are currently undergoing study for use in clinical practice.

A prospective evaluation of using IVUS during percutaneous superficial femoral artery interventions.

BACKGROUND The outcomes of endovascular interventions of the superficial femoral artery (SFA) are variable. Completion angiography is typically performed to confirm satisfactory outcomes after SFA angioplasty and/or stenting. However, two-dimensional angiography may not accurately reflect the extent of residual stenosis. We sought to determine whether intravascular ultrasound (IVUS) can help with residual disease assessment and procedure outcome. METHODS Patients with anticipated SFA disease were prospectively recruited to the study. Patients with primary SFA disease on diagnostic angiography were included. After SFA endovascular intervention with angioplasty and/or stenting, a completion angiogram was performed to confirm satisfactory results before IVUS evaluation. IVUS-detected maximal residual stenosis, maximal residual lesion volume, and number of nonconsecutive posttreatment SFA segments with >50% residual stenosis were evaluated. Periprocedural ankle-brachial indexes (ABIs), Short Form 36 (SF-36) surveys, and Walking Impairment Questionnaires were also collected. RESULTS Fifty-nine patients were prospectively enrolled. Thirty-three received angioplasty only, and 26 received angioplasty and stenting. All patients were men, mean age was 67 years, and major comorbidities included coronary artery disease (53%), active smoking (56%), hypertension (88%), and diabetes (68%). The angioplasty-only cohort had more nonconsecutive areas of >50% residual stenosis (P = 0.004), greater residual stenosis (P = 0.03), and smaller minimal lumen diameters after treatment (P = 0.01) than the angioplasty and stenting cohort. However, there was no significant difference in ABI between the 2 groups and no difference in ABI improvement after intervention. Sixty-four percent of all patients demonstrated a >0.2 increase in postintervention ABI. Improvement in ABI at 1 month after procedure significantly correlated with postintervention SF-36 survey physical scores (r = 0.435, P = 0.007). CONCLUSIONS IVUS evaluation provides more-accurate intraprocedural insight on the extent of residual stenosis after SFA interventions. Future studies are warranted to determine whether IVUS-guided postangioplasty and/or stenting can impact long-term interventional outcome.

Nitric oxide affects UbcH10 levels differently in type 1 and type 2 diabetic rats

BACKGROUND Nitric oxide (NO) more effectively inhibits neointimal hyperplasia in type 2 diabetic versus nondiabetic and type 1 diabetic rodents. NO also decreases the ubiquitin-conjugating enzyme UbcH10, which is critical to cell-cycle regulation. This study seeks to determine whether UbcH10 levels in the vasculature of diabetic animal models account for the differential efficacy of NO at inhibiting neointimal hyperplasia. MATERIALS AND METHODS Vascular smooth muscle cells (VSMCs) harvested from nondiabetic lean Zucker (LZ) and type 2 diabetic Zucker diabetic fatty (ZDF) rats were exposed to high glucose (25 mM) and high insulin (24 nM) conditions to mimic the diabetic environment in vitro. LZ, streptozotocin-injected LZ (STZ, type 1 diabetic), and ZDF rats underwent carotid artery balloon injury (±10 mg PROLI/NO), and vessels were harvested at 3 and 14 d. UbcH10 was assessed by Western blotting and immunofluorescent staining. RESULTS NO more effectively reduced UbcH10 levels in LZ versus ZDF VSMCs; however, addition of insulin and glucose dramatically potentiated the inhibitory effect of NO on UbcH10 in ZDF VSMCs. Three days after balloon injury, Western blotting showed NO decreased free UbcH10 and increased polyubiquitinated UbcH10 levels by 35% in both STZ and ZDF animals. Fourteen days after injury, immunofluorescent staining showed increased UbcH10 levels throughout the arterial wall in all animal models. NO decreased UbcH10 levels in LZ and STZ rats but not in ZDF. CONCLUSIONS These data suggest a disconnect between UbcH10 levels and neointimal hyperplasia formation in type 2 diabetic models and contribute valuable insight regarding differential efficacy of NO in these models.

Reentry Device Aided Endovascular Aneurysm Repair in Patients with Abdominal Aortic Aneurysm and Unilateral Iliac Artery Occlusion

BACKGROUND We report 2 cases of patients undergoing endovascular aneurysm repair (EVAR) using reentry devices to recanalize unilateral iliac artery occlusions and complete a bifurcated endovascular repair. METHODS Patient 1 is a 70-year-old male with an enlarging 6.5-cm abdominal aortic aneurysm (AAA) and disabling left leg claudication with L external iliac occlusion with patent common and internal iliac arteries. Patient 2 is a 67-year-old male with an asymptomatic 4.0-cm AAA and L iliac chronic total occlusion (CTO) and disabling claudication. Both patients were poor operative candidates for open repair. RESULTS Both patients underwent elective percutaneous EVAR along with left iliac artery revascularization. Initial angiography in both cases showed a blind ending of the left common iliac artery. Retrograde subintimal dissection through the occluded iliac segment was attempted but in both cases the wire was unable to traverse back into the true aortic lumen. Using either the Outback LTD or Pioneer reentry catheter, direct visualization of the true aortic lumen was obtained to re-enter the true lumen. The subintimal iliac tract was then predilated to facilitate routine EVAR in both cases. Both patients were discharged the following day and 1-year and 6-month follow-up imaging revealed aneurysm exclusion, no endoleak, and patent bilateral common iliac arteries with resolution of claudication symptoms and normal ankle-brachial indexes. The previously patent internal iliac artery was preserved. CONCLUSIONS While not always technically possible, reentry device aided EVAR is safe, feasible, and durable in the mid-term and avoids the morbidity and mortality related to aortouniiliac/femoral-femoral bypass and open repair. This technique should be considered in patients with iliac artery CTO and concurrent AAA to allow total endovascular repair.