Katsuyuki Hoshina

Flow Loading Induces Macrophage Antioxidative Gene Expression in Experimental Aneurysms

Objective—Reactive oxygen species may act as proinflammatory mediators in abdominal aortic aneurysm (AAA) disease. Flow loading increases antioxidative enzyme expression and limits reactive oxygen species production in vascular smooth muscle cells in vitro, limits experimental AAA enlargement in rodent models, and is indirectly associated with reduced clinical AAA risk. We attempted to determine the mechanism or mechanisms by which flow loading limits AAA enlargement. Methods and Results—Rodent AAAs were flow loaded via femoral arteriovenous fistula creation. Aortic wall shear stress and relative wall strain were significantly higher in flow-loaded rodents. Flow loading reduced AAA diameter by 26% despite evidence of flow-mediated aortic enlargement proximal to the aneurysmal segment. Messenger RNA from AAA tissue was harvested for cDNA labeling and hybridization to a 384-clone DNA microarray. Twenty-nine genes were differentially expressed (relative intensity/relative intensity of control ratio >1.5 and <0.67) in flow-loaded compared with normal flow AAA tissue, including heme oxygenase 1 (HO-1). Increased HO-1 expression was confirmed via reverse transcriptase–polymerase chain reaction. Immunohistochemistry localized HO-1 expression to infiltrative macrophages. &agr;-Tocopherol was found to be as effective as flow loading in limiting AAA enlargement. Flow loading and &agr;-tocopherol therapy reduced AAA reactive oxygen species production. Conclusions—Flow loading may attenuate AAA enlargement via wall shear or strain-related reductions in oxidative stress.

A Retrospective Study of Intravascular Ultrasound use in Patients Undergoing Endovascular Aneurysm Repair: Its Usefulness and a Description of the Procedure

OBJECTIVES To verify the usefulness and limitation of intravascular ultrasound (IVUS) in endovascular aneurysm repair (EVAR). METHODS A total of 112 consecutive patients, who underwent EVAR to treat abdominal aortic aneurysms, were examined retrospectively. Of these, 33 patients were assigned to the IVUS group because of renal failure, a suspected allergy to contrast agents or anatomical difficulties; the remaining 79 patients were assigned to the non-IVUS group. RESULTS Patients in the IVUS group required fewer intra-arterial contrast agents (IACAs) than those in the non-IVUS group (67±34ml vs. 123±50ml; p<0.01). Blood loss and operation time were comparable between the two groups. No patients died within 30 days of the operation. Three major renal complications occurred in the non-IVUS group. Renal deterioration evaluated by chronic kidney disease (CKD) stage was found to a greater extent in the non-IVUS group. CONCLUSIONS IVUS is a powerful auxiliary method in EVAR for reducing the required volume of contrast agents. The combination of IVUS and IACA usage showed good overall performance; thus, we propose the routine use of IVUS in EVAR procedures.

Family history of aortic aneurysm is an independent risk factor for more rapid growth of small abdominal aortic aneurysms in Japan

OBJECTIVE We aimed to investigate risk factors associated with more rapid growth of abdominal aortic aneurysms (AAA) <50 mm (small AAAs) in Japan. METHODS We retrospectively investigated the clinical data of 374 patients with small AAAs (maximum diameter, ≤50 mm) who were referred to The University of Tokyo Hospital, Tokyo Medical University Hospital, or Saitama Medical Center, between 1995 and 2008. RESULTS A total of 374 patients (321 men and 53 women) were followed up for a median of 66 months. The median diameter on initial examination was 40 mm, and the median growth rate of the AAAs was 2.1 mm/y. The growth rate of AAAs with an initial diameter ≥45 mm was significantly greater than those with an initial diameter <45 mm (3.3 mm/y vs 2.0 mm/y, respectively; P = .007). The growth rate of AAAs was significantly greater in patients with hypertension than in those without (2.3 mm/y vs 1.7 mm/y, respectively; P = .006) and in patients with a family history of aortic aneurysm than in those without (4.2 mm/y vs 2.0 mm/y, respectively; P = .009). Logistic regression analysis revealed that a large initial diameter and family history of aortic aneurysm were independent predictors of accelerated growth rate of small AAAs in Japan. CONCLUSIONS In the present study, a large initial diameter and family history of aortic aneurysm were independent risk factors for more rapid growth of small AAAs. Although few studies have reported similar findings thus far, family history of aortic aneurysm should be carefully considered during follow-up of patients with small AAAs.

Predictors of mortality after emergency or elective repair of abdominal aortic aneurysm in a Japanese population

In Japan, there has been virtually no study in a population large enough to definitively demonstrate a relationship between the preoperative clinical features and postoperative outcomes in patients undergoing abdominal aortic aneurysm (AAA) repair. The aim of this study was to determine the preoperative variables that significantly predict postoperative mortality after emergency or elective repair in Japanese patients with infrarenal AAA. In this retrospective cohort study, we assessed significant predictors of postoperative mortality in 1055 consecutive patients undergoing emergency (n = 186) or elective repair (n = 869) of an infrarenal AAA at the University of Tokyo Hospital or Sakakibara Heart Institute (Tokyo, Japan). Using logistic regression analysis, anemia (hemoglobin <9 g/dl), shock (systolic blood pressure <80 mmHg), and hypocholesterolemia (total cholesterol <120 mg/dl) were found to be independent preoperative predictors of 30-day mortality after emergency repair for ruptured AAA. The hazard ratio (HR) (95 % confidence interval) for these three predictors was 5.96 (1.70–20.84), 8.48 (1.47–49.02), and 7.31 (1.96–27.35), respectively. In the elective repair cases, no significant preoperative predictor of postoperative mortality could be identified either within or beyond 30 days of surgery. Hypocholesterolemia, anemia, and shock were found to be independent preoperative predictors of a postoperative high mortality rate in Japanese patients undergoing emergency repair for ruptured infrarenal AAA.

Inverse association between the existence of coronary artery disease and progression of abdominal aortic aneurysm.

OBJECTIVES A strong degree of co-existence between coronary artery disease (CAD) and abdominal aortic aneurysm (AAA) is widely acknowledged, however, it remains to be elucidated whether the existence of CAD is associated with an accelerated expansion rate of AAA. Also, the relationship between preoperative CAD and postoperative major adverse cardiovascular events (MACE) has not been examined in Japanese patients. The aim of this study was to investigate the deleterious effects of CAD on the progression of AAA and the onset of postoperative MACE after elective AAA repair. METHODS AND RESULTS A retrospective cohort study of 665 consecutive Japanese patients who underwent elective surgical repair for infrarenal AAA at 2 high-volume Tokyo hospitals from 2003 through 2010 was performed. Preoperative CAD was shown to be a significant determinant of postoperative MACE (HR 2.29; 95%CI, 1.12-4.66; p=0.02). In the analysis of 510 patients for whom there were at least 2 follow-up CT scans of the size of their AAA before repair, the existence of CAD was shown to be inversely associated with the accelerated expansion rate of AAA. CONCLUSION This study on the patients undergone elective repair for infrarenal AAA identified an inverse association between the existence of CAD and progression of AAA as well as the significant impact of preoperative CAD on the occurrence of postoperative MACE after elective AAA repair.

Long-term outcomes of surgical treatment in patients with popliteal artery entrapment syndrome.

The object of the study is to determine the long-term outcomes of surgical treatment of patients with popliteal artery entrapment syndrome at a single institute. We retrospectively reviewed 19 limbs of 16 consecutive patients who underwent surgery for popliteal artery entrapment syndrome at our hospital over the past 36 years. The popliteal artery was stenotic in 11 limbs, occlusive in 7 limbs, and compressed and deviated by the medial head of the gastrocnemius muscle but not damaged in 1 limb. Six limbs were treated with autologous saphenous vein bypass, 10 with bypass or venous patch graft concomitant with musculotendinous section, and 3 limbs underwent musculotendinous section alone. The 10-year cumulative patency of the 13 limbs treated with bypass was 100%, although two of them showed occlusion at 23 and 12 years after surgery. One patient who received a venous patch graft showed occlusion 15 years after surgery. Additionally, one asymptomatic patient with an apparently non-damaged popliteal artery who received preventive musculotendinous section alone showed stenosis of the artery 2 years after musculotendinous section. In conclusion, the bypass patency observed in this study was excellent in the long term. Careful examination of popliteal artery anatomy using imaging studies is essential for selecting the appropriate surgical procedure for popliteal artery entrapment syndrome.

Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats.

Several drugs targeting the pathogenesis of aortic aneurysm have shown efficacy in model systems but not in clinical trials, potentially owing to the lack of targeted drug delivery. Here, we designed a novel drug delivery system using nanoparticles to target the disrupted aortic aneurysm micro-structure. We generated poly(ethylene glycol)-shelled nanoparticles incorporating rapamycin that exhibited uniform diameter and long-term stability. When injected intravenously into a rat model in which abdominal aortic aneurysm (AAA) had been induced by infusing elastase, labeled rapamycin nanoparticles specifically accumulated in the AAA. Microscopic analysis revealed that rapamycin nanoparticles were mainly distributed in the media and adventitia where the wall structures were damaged. Co-localization of rapamycin nanoparticles with macrophages was also noted. Rapamycin nanoparticles injected during the process of AAA formation evinced significant suppression of AAA formation and mural inflammation at 7 days after elastase infusion, as compared with rapamycin treatment alone. Correspondingly, the activities of matrix metalloproteinases and the expression of inflammatory cytokines were significantly suppressed by rapamycin nanoparticle treatment. Our findings suggest that the nanoparticle-based delivery system achieves specific delivery of rapamycin to the rat AAA and might contribute to establishing a drug therapy approach targeting aortic aneurysm.

Favorable outcomes of very elderly patients with critical limb ischemia who undergo distal bypass surgery

OBJECTIVE To determine the midterm outcomes of distal bypass surgery for very elderly patients, and to determine the ideal candidates for this procedure. METHODS Of 268 consecutive patients (328 limbs) with critical limb ischemia who were treated between 2006 and 2013, 106 (126 limbs) underwent distal bypass and were retrospectively reviewed. Nineteen patients (22 limbs) were aged ≥80 years (very elderly group) and 87 patients (104 limbs) were aged <80 years (control group). RESULTS The baseline characteristics differed between the 2 groups in terms of regular hemodialysis rate (very elderly group, 4 [21%] vs control group, 60 [69%]; P = .0002) and the Charlson comorbidity index (very elderly group, 3.2 ± 1.7 vs control group, 5.0 ± 2.0; P = .0005). According to the Rutherford category of limb ischemia (4/5/6), the very elderly and control groups were classified as 5/17/0 and 11/87/6, respectively (P = .18). Before the surgery, 17 patients (77%) and 67 patients (64%) were ambulatory in the very elderly and control groups, respectively. At follow-up at 29 ± 22 months, the rates of primary (P = .33) and secondary patency (P = .14), limb salvage (P = .50), survival (P = .26), amputation-free survival (P = .42), major adverse limb event and also perioperative death (P = .11), and major adverse cardiovascular events (P = .36) did not significantly differ between the groups. In multivariate analysis, a history of coronary artery disease (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.3-5.9; P = .005), preoperative nonambulatory status (HR, 4.2; 95% CI, 2.1-8.1; P < .0001), and serum albumin levels <3 g/dL (HR, 2.7; 95% CI, 1.3-5.4; P = .01) were significantly related to poor amputation-free survival. Thirteen patients (59%) remained ambulatory at the latest follow-up. In 91 patients (110 limbs) with tissue loss, the Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on Wound, Ischemia, and foot Infection classification stages 3 and 4 negatively affected complete wound healing, according to multivariate analysis (HR, 0.34; 95% CI, 0.20-0.61; P = .0005). CONCLUSIONS A very elderly age should not preclude a patient from undergoing distal bypass surgery. A history of coronary artery disease, a nonambulatory status, and hypoalbuminemia, along with the Wound, Ischemia, and foot Infection classification for patients with tissue loss, should be carefully considered to obtain the most benefit from distal bypass surgery.

Viscoelastic Deterioration of the Carotid Artery Vascular Wall is a Possible Predictor of Coronary Artery Disease

AIM The viscoelastic properties of the artery are known to be altered in patients with vascular diseases. However, few studies have evaluated the viscoelasticity of the vascular wall in humans. We sought to investigate the degree of viscoelastic deterioration of the carotid artery and assess its clinical implications. METHODS Between January 2011 and June 2013, patients in whom the toe-brachial index was measured at the vascular laboratory were included in this single-institute retrospective observational study. I(＊), a parameter of viscoelastic deterioration, was computed using a non-invasive ultrasonic Doppler effect sensor on the carotid artery. I(＊) is a non-dimensional value, and I(＊)>0 is considered abnormal. Other patient characteristics were identified and tested for correlations with I(＊). RESULTS The study included 383 patients. The mean I(＊) value was 0.13 ± 0.22 with a normal distribution. Factors that increased the I(＊) value were a female sex (0.18 ± 0.23 vs. 0.10 ± 0.21, P<0.001), age ≥ 60 (0.14 ± 0.22 vs. 0.06 ± 0.23, P<0.05) and systolic blood pressure of >140 (0.15 ± 0.22 vs. 0.10 ± 0.22, P<0.05). I(＊) abnormality was a significant risk factor for coronary artery disease (OR 2.20, 95% CI 1.00-4.80, P<0.05) in a univariate analysis. In the multivariate analysis, I(＊) abnormality was also found to be an independent risk factor for coronary artery disease (OR 4.56, 95% CI 1.21-30.1, P<0.05). CONCLUSIONS I(＊) may reflect the degree of atherosclerotic changes in the arterial wall and could possibly be used to predict coronary artery disease.

Study Design of PROCEDURE Study. A Randomized Comparison of the Dose-Dependent Effects of Pitavastatin in Patients with Abdominal Aortic Aneurysm with Massive Aortic Atheroma: Prevention of Cholesterol Embolization during Endovascular and Open Aneurysm Repair with Pitavastatin (PROCEDURE) Study.

Outcomes of abdominal aortic aneurysm (AAA) repair have improved in the 2 decades since the emergence of endovascular aneurysm repair (EVAR). However, EVAR is considered a contraindication for shaggy aorta because of the high risk of shower embolization. Recently, statins have been implicated in preventing embolization in patients with shaggy aorta via its pleiotropic effects, including atheroma reduction and coronary artery stabilization. We selected pitavastatin, a statin with potent effects, discovered and developed by a Japanese company because it has shown excellent pleiotropic effects on atheromatous arteries in the Japanese population. A randomized comparison study of dose-dependent effects of pitavastatin in patients with AAA with massive atheromatous aortic thrombus (PROCEDURE study) has begun. PROCEDURE has an enrollment goal of up to 80 patients with AAA with massive aortic atheroma (excluding intrasac atheroma), randomly allocated into 2 groups receiving pitavastatin at a dose of 1 or 4 mg/day. The endpoints of the PROCEDURE study include change in atheroma volume, major adverse events related to shower embolization after aneurysm repair, and lipid-lowering effects. When complete, results of the PROCEDURE study should provide objective evidence to use statins preoperatively for AAA with massive aortic atheroma.