Akihiro Hosaka

Gelatin Hydrogel Microspheres Enable Pinpoint Delivery of Basic Fibroblast Growth Factor for the Development of Functional Collateral Vessels

Background—Various growth factors promote collateral vessel development and are regarded as promising for the treatment of vascular occlusive diseases. However, an efficacious delivery system for them has yet to be established. We devised a strategy to augment functional collateral vessels by using acidic gelatin hydrogel microspheres (AGHMs) incorporating basic fibroblast growth factor (bFGF). The aim of the present study was to investigate the hypothesis that by intra-arterial (IA) administration of bFGF-impregnated AGHMs, bFGF could be delivered from AGHMs trapped in distal small-diameter vessels and thereby induce functional collateral vessels with an assured blood supply through the process of arteriogenesis. Methods and Results—Various sizes of AGHMs (3 mg) incorporating 125I-labeled bFGF were injected into the left internal iliac artery of a rabbit model of hindlimb ischemia. Less than 50% of radioactivity accumulated in the ischemic hindlimb after injection of AGHMs that were 10 &mgr;m in diameter, whereas ≈80% of radioactivity was counted in the ischemic limb after administration of 29- or 59-&mgr;m-diameter AGHMs. Calf blood pressure ratio and the ratio of regional blood flow of the bilateral hindlimbs immediately before and after IA administration of 29-&mgr;m–diameter AGHMs showed no significant change. Then we evaluated the function of the developed collateral vessels 28 days after IA administration of bFGF-impregnated, 29-&mgr;m-diameter AGHMs. IA administration of bFGF-impregnated AGHMs induced marked collateral vessel improvement compared with IA administration of phosphate buffered saline–treated AGHMs and intramuscular administration of bFGF-impregnated AGHMs. Conclusions—IA administration of bFGF-impregnated, 29-&mgr;m-diameter AGHMs strongly induced functional collateral vessels without worsening ischemia, indicating the possible therapeutic usefulness of this approach.

Selective and Sustained Delivery of Basic Fibroblast Growth Factor (bFGF) for Treatment of Peripheral Arterial Disease: Results of a Phase I Trial

OBJECTIVES The aim of this study was to evaluate the safety of selective and sustained delivery of basic fibroblast growth factor (bFGF) using acidic gelatine hydrogel microspheres (AGHMs) for the treatment of peripheral arterial disease (PAD). MATERIALS AND METHODS We conducted a non-randomised and uncontrolled trial involving prospective observation of eight patients (eight limbs) with PAD - five limbs with arteriosclerosis obliterans and three limbs with thromboangiitis obliterans, five limbs (three arms and two legs) with critical limb ischaemia (CLI) and three limbs with intermittent claudication (IC) - who were followed up for 6 months or more. AGHM suspension containing 100 microg bFGF was infused into the artery of the affected limb. Besides evaluation of safety and changes in symptoms, resting ankle-brachial pressure index measurement and transcutaneous PO(2) (tcPO(2)), angiography were conducted at baseline and then at various time points. Skin perfusion pressure as an index of CLI and claudication distance as an index of IC were also used to assess clinical improvement and limb perfusion. RESULTS No serious adverse events were observed. All cases showed improvement in symptoms, although this was temporary in some patients. CONCLUSION Selective delivery of bFGF using AGHMs was suggested to be safe and well-tolerated in patients with PAD.

Efficacy of Revascularization for Critical Limb Ischemia in Patients with End-stage Renal Disease

OBJECTIVE To evaluate the outcomes of surgical revascularization for critical limb ischemia in patients with end-stage renal disease (ESRD). PATIENTS AND METHODS From 2004 to 2010, 184 patients with 213 critically ischaemic limbs caused by arteriosclerosis were admitted to The University of Tokyo Hospital. The outcomes of primarily surgical revascularization-based treatments were retrospectively compared in patients with ESRD (ESRD group: 79 patients, 101 limbs) and without ESRD (non-ESRD group: 105 patients, 112 limbs) during the same period. RESULTS Arterial reconstruction was performed on 56 limbs in 46 patients in the ESRD group and 78 limbs in 73 patients in the non-ESRD group (55% vs. 70%; p = .03). Major amputation was performed in 6 of 48 limbs with patent grafts in the ESRD group because of uncontrolled infection or progression of necrosis. The limb salvage rate after arterial reconstruction was significantly lower in the ESRD group than in the non-ESRD group (p = .0019). The postoperative survival rate was lower in the ESRD group than in the non-ESRD group, although this difference was not significant (p = .052). Associated cardiovascular disease and systemic infection were the most frequent causes of death in the ESRD group. There was no significant difference in graft patency between the two groups after distal bypass surgery; however, the limb salvage rate was significantly lower in the ESRD group than in the non-ESRD group (p = .03). CONCLUSIONS Critical limb ischemia associated with ESRD has a poor prognosis. Infection control is particularly important for achievement of good treatment outcomes.

Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population.

Characteristics of peripheral arterial disease (PAD) are the occlusion or stenosis of multiple vessel sites caused mainly by atherosclerosis and chronic lower limb ischemia. To identify PAD susceptible loci, we conducted a genome-wide association study (GWAS) with 785 cases and 3,383 controls in a Japanese population using 431,666 single nucleotide polymorphisms (SNP). After staged analyses including a total of 3,164 cases and 20,134 controls, we identified 3 novel PAD susceptibility loci at IPO5/RAP2A, EDNRA and HDAC9 with genome wide significance (combined P = 6.8 x 10−14, 5.3 x 10−9 and 8.8 x 10−8, respectively). Fine-mapping at the IPO5/RAP2A locus revealed that rs9584669 conferred risk of PAD. Luciferase assay showed that the risk allele at this locus reduced expression levels of IPO5. To our knowledge, these are the first genetic risk factors for PAD.

Outcome after concomitant unilateral embolization of the internal iliac artery and contralateral external-to-internal iliac artery bypass grafting during endovascular aneurysm repair

OBJECTIVE Despite improvement of devices, endovascular aneurysm repair (EVAR) is still challenging in cases with associated aneurysmal involvement of the iliac arteries. This study examined the safety and efficacy of EVAR with concomitant unilateral embolization of the internal iliac artery (IIA) and contralateral external-to-internal iliac artery bypass grafting, with bilateral endograft limbs extended into the external iliac arteries (EIAs). METHODS The study included 22 consecutive patients (mean age, 74 years) who underwent elective endovascular repair of aortoiliac or iliac aneurysms, with concomitant coil embolization of the unilateral IIA and contralateral EIA-to-IIA bypass in the same operative setting. Five patients had a unilateral IIA aneurysm, and eight had bilateral IIA aneurysms. EIA-to-IIA bypass grafting was performed through the retroperitoneal approach. The perioperative and midterm outcome of the procedure was assessed. RESULTS The procedure was successfully performed in all cases. Eleven patients underwent IIA embolization at the main trunk, and the other 11 cases required IIA occlusion at distal branches. There was no perioperative death or severe complication. The mean follow-up period was 15.7 ± 7.8 months, ranging from 2 to 32 months. The bypass remained patent in all cases, and there was no occurrence of graft-related complication. Enlargement of aneurysms or development of type I endoleak was not observed. Persistent mild buttock claudication occurred in two patients (9%) ipsilaterally to the occluded IIA; one patient after IIA occlusion at the main trunk and the other at distal branches. No other pelvic ischemic manifestation was observed. CONCLUSIONS EVAR with simultaneous unilateral IIA embolization and contralateral EIA-to-IIA bypass grafting is feasible, with a relatively low risk of complications. It can be a useful treatment option in cases with complex aortoiliac aneurysms, including those with bilateral IIA aneurysms.

Spontaneous mesenteric hemorrhage associated with Ehlers-Danlos syndrome.

The vascular type of Ehlers-Danlos syndrome is a genetic disorder of connective tissue and is frequently associated with catastrophic arterial complications. Its surgical treatment is extremely difficult because of the fragility of vessels. This article describes three patients with vascular type of Ehlers-Danlos syndrome who developed mesenteric hemorrhage due to spontaneous arterial rupture. The clinical and molecular characteristics of the disease are briefly reviewed.

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.

Outcomes of conservative management of spontaneous celiac artery dissection

Objective: Spontaneous celiac artery (CA) dissection without associated aortic dissection is a rare condition. Although this condition has been diagnosed more frequently with the advent of improved diagnostic imaging modalities, its pathogenesis and treatment strategy remain to be established. The present study examined the clinical features and outcomes of conservative management of this disease. Methods: The study included 12 patients (10 men and two women) in whom spontaneous CA dissection was diagnosed between 2007 and 2015. The medical records of each patient were retrospectively reviewed. Results: The mean age at diagnosis was 56.4 years (range, 42–77 years). Eight patients presented with abdominal or back pain, and the remaining four patients were asymptomatic and diagnosed incidentally. Four patients had a history of hypertension, and six had a history of smoking. Celiac trunk compression by the median arcuate ligament was found in two patients. The dissection extended into the common hepatic artery in five patients and into the splenic artery in four patients. Retroperitoneal hemorrhage was found in 2 patients, splenic infarction in 3, and transient mild liver dysfunction in 2. All patients were treated conservatively: two patients received short‐term anticoagulation and antiplatelet therapy, and antihypertensive treatment was initiated in three patients. The mean follow‐up period was 35.5 months (range, 5–101 months). Distal extension of the dissection occurred in one patient within a week of the initial symptom, which was also managed conservatively. Late aneurysmal degeneration was not observed in any of the patients, and none required endovascular or surgical treatment. Conclusions: If the general condition of the patient is stable, then CA dissection can be managed with careful conservative treatment, even in patients with associated retroperitoneal hemorrhage. Long‐term anticoagulation or antiplatelet medication may not be necessary in most patients with this condition.

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.

Bowel necrosis following endovascular revascularization for chronic mesenteric ischemia: a case report and review of the literature

BackgroundEndovascular revascularization has recently been established as a less invasive treatment method for chronic mesenteric ischemia. However, intestinal necrosis caused by distal embolization following this procedure has not been emphasized.Case presentationThe present report describes a 59-year-old man who was treated with endovascular revascularization for chronic mesenteric ischemia. After the procedure, he was diagnosed with intestinal necrosis caused by distal embolization. Despite emergent bowel resection, he died on postoperative day 109.ConclusionAlthough endovascular revascularization for chronic mesenteric ischemia is less invasive and may be suitable for high-risk patients, attention should be paid to avoid embolic complications that can cause intestinal infarction possibly leading to a fatal condition.