Daisuke Akagi

Biocompatible micellar nanovectors achieve efficient gene transfer to vascular lesions without cytotoxicity and thrombus formation.

Gene therapy, a promising treatment for vascular disease, requires appropriate gene vectors with high gene transfer efficiency, good biocompatibility and low cytotoxicity. To satisfy these requirements from the approach of nonviral vectors, a novel block copolymer, poly(ethylene glycol) (PEG)-block-polycation, carrying ethylenediamine units in the side chain (PEG-b-P[Asp(DET)]) was prepared. PEG-b-P[Asp(DET)] formed a polyplex micelle through polyion complex formation with plasmid DNA (pDNA). The PEG-b-P[Asp(DET)] polyplex micelle showed efficient gene expression with low cytotoxicity against vascular smooth muscle cells in vitro. It also showed reduced interactions with blood components, offering its feasibility of gene delivery via the vessel lumen. To evaluate in vivo gene transfer efficiency for vascular lesions, PEG-b-P[Asp(DET)] micelle was instilled into rabbit carotid artery with neointima by an intravascular method, and expression of the reporter gene in vascular lesions was assessed. Polyplexes from homopolymer P[Asp(DET)] and branched polyethyleneimine (BPEI) were used as controls. Ultimately, only the polyplex micelle showed appreciable gene transfer into vascular lesions without any vessel occlusion by thrombus, which was in strong contrast to BPEI and P[Asp(DET)] polyplexes which frequently showed occlusion with thrombus. These findings suggest that the PEG-b-P[Asp(DET)] polyplex micelle may have promising potential as a nonviral vector for the treatment of vascular diseases.

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.

Increase in skin perfusion pressure predicts amputation-free survival after lower extremity bypass surgery for critical limb ischemia:

The objective of this study was to determine how postoperative skin perfusion pressure (SPP) as a measure of blood flow after revascularization affects limb prognosis in patients with critical limb ischemia (CLI). We retrospectively reviewed 223 consecutive bypass surgery cases performed in 192 patients with CLI during a 10-year period. SPP was measured 1–2 weeks before and after the procedure. An SPP of 40 mmHg was set as the cut-off value for revascularization. Patients were grouped according to their postoperative SPPs, and amputation-free survival (AFS) was analyzed. An SPP of ≥ 40 mmHg was recovered in 75% of the patients, but no significant difference was found between this group and the group that did not reach 40 mmHg. On the other hand, the values increased by ≥ 20 mmHg from the preoperative values in 70% of the patients. This group had a significantly better AFS than the group that did not increase by 20 mmHg. Logistic regression analysis revealed that (1) a preoperative SPP of < 20 mmHg and (2) a high serum albumin level (> 3.0 g/dL) were significant factors in increasing SPP by 20 mmHg. These results showed that an increase in SPP of ≥ 20 mmHg after bypass surgery was associated with better limb prognosis.

Targeting ability of self-assembled nanomedicines in rat acute limb ischemia model is affected by size

ABSTRACT Peripheral artery disease (PAD) is one of the most spreading diseases all over the world. The treatment strategies are limited to surgical or endovascular procedures for final stage chronic PAD or acute limb ischemia, and no pharmacological approaches have been achieved to prevent the worsening of chronic PAD or to regenerate the tissues of acute limb ischemia. Therefore, the improvement of therapeutic strategy is strongly demanded in clinics. Here, we adopted an acute hindlimb ischemia model in rats, which provides concomitant inflammatory response, to evaluate the application of drug delivery system against PAD. Through comparative experiments by using different‐sized nanomedicine analogues, polyion complex (PIC) micelles with 30 nm diameter and PIC vesicles with 100‐ and 200‐nm diameter (PICs‐30, −100, −200 respectively), we found the size‐dependent accumulation and retention in the collateral arteries. In contrast to PICs‐30 and ‐200, histological analysis showed that PICs‐100 were around the arterioles and co‐localized with macrophages, which indicates that the PICs‐100 can achieve moderate interaction with phagocytes. Our data suggests that controlling the size of nanomedicines has promise for developing novel angiogenic treatments toward the effective management of collateral arteries. Graphical abstract Figure. No caption available.

Drug Therapy for Abdominal Aortic Aneurysms Utilizing Omega-3 Unsaturated Fatty Acids and Their Derivatives

BACKGROUND Abdominal aortic aneurysms (AAA) are life-threatening because of the potential for rupture, resulting in death. The current standard treatment for AAA is surgery, comprising laparotomic graft replacement and endovascular repair. However, because surgery carries the risk of major complications and re-intervention, drug therapies are desirable because they may reduce the occurrence of enlargement and rupture. OBJECTIVE Recent research shows that the progression of AAA is related to inflammatory reactions, especially those in the NF-κB pathway. Omega-3 polyunsaturated fatty acids (PUFA) show antiinflammatory effects. Some derivatives of omega-3 PUFA are known as specialized pro-resolving lipid mediators (SPM) such as resolvins. They play an important role in resolving inflammation. CONCLUSION Omega-3 PUFA and SPM may show promised effects for drug treatment of AAA.

Stenotic lesion level did not affect outcomes of carotid endarterectomy

Background Carotid endarterectomy is the established treatment for carotid artery stenosis, and remains the primary surgical option due to its superior outcomes compared to carotid arterial stenting. However, Japanese patients are known to have unfavorable anatomical conditions for carotid endarterectomy, with a relatively higher level of the carotid artery bifurcation than in the Western population. We investigated the outcomes of carotid endarterectomy in our institute and evaluated the procedural quality by comparing patients based on higher or lower lesion levels. Methods The clinical data of 65 patients who underwent carotid endarterectomy were collected retrospectively. The outcomes reviewed included stroke-free survival and stroke-free rate. The patients were divided into a higher group (n = 25) and a lower group (n = 40), based on lesion location in respect of the 2nd cervical vertebral level. Results There was no perioperative death and only one case of stroke in the higher group within 30 days after carotid endarterectomy. At 5 years after carotid endarterectomy, the stroke-free survival rates were 83.4% in the higher group and 87.8% in the lower group, while the stroke-free rates were 96.0% and 94.0%, respectively; there were no significant differences between groups. Conclusions Stenotic lesion level did not affect the outcome or procedural quality of carotid endarterectomy.

Pulse volume recordings to identify falsely elevated ankle brachial index.

Background Ankle brachial index can be falsely elevated in cases of medial arterial calcification, and its clinical use should be limited, especially in patients with diabetes. The aim of this study was to evaluate the potential role of pulse volume recording in detecting falsely elevated ankle brachial index. Methods Two parameters of the pulse waveform were automatically calculated: upstroke time and percentage mean artery pressure. Pulse volume recordings were retrospectively evaluated in 171 consecutive patients (342 limbs); 73 (43%) had a diagnosis of diabetes. Results On multivariate analysis, diabetes (hazard ratio = 1.7), ankle brachial index ≤ 0.90 (hazard ratio = 4.4), upstroke time ≥ 180 ms (hazard ratio = 2.1), and percentage mean artery pressure ≥ 45% (hazard ratio = 2.8) were significantly related to toe brachial index < 0.60. Further analysis for falsely elevated ankle brachial index was performed in 196 limbs (146 patients) with ankle brachial index > 0.90. The difference between ankle brachial index and toe brachial index differentiated the limbs of diabetic patients, with percentage mean artery pressure ≥ 45%, from controls (0.45 ± 0.17 vs. 0.35 ± 0.16, p = 0.03); upstroke time was not found to be a discriminating factor. Conclusions Although measurement of ankle brachial index remains the gold standard for diagnosing peripheral arterial disease, percentage mean artery pressure, automatically obtained in ankle brachial index measurement, may be useful to detect falsely elevated ankle brachial index, especially in patients with diabetes.