Yasunori Iida

RGD-conjugated human ferritin nanoparticles for imaging vascular inflammation and angiogenesis in experimental carotid and aortic disease

PurposeInflammation and angiogenesis are important contributors to vascular disease. We evaluated imaging both of these biological processes, using Arg–Gly–Asp (RGD)-conjugated human ferritin nanoparticles (HFn), in experimental carotid and abdominal aortic aneurysm (AAA) disease.ProceduresMacrophage-rich carotid lesions were induced by ligation in hyperlipidemic and diabetic FVB mice (n = 16). AAAs were induced by angiotensin II infusion in apoE−/− mice (n=10). HFn, with or without RGD peptide, was labeled with Cy5.5 and injected intravenously for near-infrared fluorescence imaging.ResultsRGD-HFn showed significantly higher signal than HFn in diseased carotids and AAAs relative to non-diseased regions, both in situ (carotid: 1.88 ± 0.30 vs. 1.17 ± 0.10, p = 0.04; AAA: 2.59 ± 0.24 vs. 1.82 ± 0.16, p = 0.03) and ex vivo. Histology showed RGD-HFn colocalized with macrophages in carotids and both macrophages and neoangiogenesis in AAA lesions.ConclusionsRGD-HFn enhances vascular molecular imaging by targeting both vascular inflammation and angiogenesis, and allows more comprehensive detection of high-risk atherosclerotic and aneurysmal vascular diseases.

Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression

Objective—Macrophages are critical contributors to abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4–CCL5 interaction, to influence AAA progression in murine models. Approach and Results—AAAs were created in 10-week-old male C57BL/6J mice by transient infrarenal aortic porcine pancreatic elastase infusion. Mice were treated with MKEY via intravenous injection either (1) before porcine pancreatic elastase infusion or (2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited migration of adaptively transferred leukocytes into aneurysmal aortae in recipient mice. Although all vehicle-pretreated mice developed AAAs, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg/kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic metalloproteinase 2 and 9 expression after porcine pancreatic elastase infusion. MKEY initiated after porcine pancreatic elastase infusion also stabilized or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation after angiotensin II infusion in apolipoprotein E–deficient mice. Conclusion—MKEY suppresses AAA formation and progression in 2 complementary experimental models. Peptide inhibition of CXCL4–CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.

Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.

Background Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. Methodology/Principal Findings AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. Conclusion/Significance Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

Successful coil embolization for rupture of the subclavian artery associated with Ehlers-Danlos syndrome type IV

Ehlers-Danlos syndrome is a rare inherited disease of connective tissue. Patients with type IV Ehlers-Danlos syndrome are likely to present with arterial disorders such as aneurysm or dissection. We report a 20-year-old man with type IV Ehlers-Danlos syndrome in whom a subclavian arterial rupture was successfully treated with transcatheter coil embolization.

A modified infarct exclusion technique: Triple-patch technique for postinfarction ventricular septal perforation

Postinfarction ventricular septal perforation (VSP) remains an important complication of myocardial infarction. The prevalence is approximately 1% to 2% among patients withacutemyocardialinfarction,anditisoftenfatalunless surgical treatment is performed. Despite numerous improvements in surgical technique, the mortality remains about 19% to 40%. 1 Perioperative low-output syndrome and residual shunt are associated with a poor outcome. We operated on 4 patients with our simple technique that minimizes residual shunting. Materials and Methods OPERATIVE TECHNIQUE. Cardiopulmonary bypass was established, and myocardial revascularization if necessary was performed on the beating heart before repair of the VSP. The heart was then arrested with a cardioplegic solution, and repair was done through a longitudinal left ventriculotomy in the infarcted area, about 1 to 2 cm away from the left anterior descending coronary artery. First, a tailored small bovine pericardial patch was used to close the VSP directly with a running 3-0 polypropylene suture. Then two bovine pericardial patches were cut into rectangular shapes. One pericardial patch was sutured to the noninfarcted endocardium around the ventricular septal side, and the other patch was sutured to the noninfarcted endocardium of the anterolateral ventricular wall, both with running 3-0 polypropylene sutures. These two patches were then cut and sewn to determine the ideal size and shape of the pouch fitting the left ventricular cavity to make an infarct exclusion. After the VSP patch and endoventricular pouch were sutured, fibrin glue was applied to fill the cavity between the patches. The ventriculotomy was closed in two layers with two polytetrafluoroethylene felt strips and 2-0 polypropylene sutures (Figure 1). PATIENTS. Between 1996 and 2006, a total of 10 patients underwent VSP repair. Through 2003, we performed VSP repair by the David‐Komeda method in 6 patients. Since 2004, the new triplepatch technique has been used for all patients. STATISTICAL ANALYSIS. Preoperative and postoperative variables were compared between the two operative groups with the Mann‐Whitney U test.

Thoracic endovascular aortic repair with aortic arch vessel revascularization

BACKGROUND Revascularization of aortic arch vessels was performed with thoracic endovascular aortic repair (TEVAR) to preserve the endoprosthesis landing zone in 19 high-risk patients. METHODS The operative procedure used was a bypass or transposition involving the common carotid and subclavian arteries. Homemade fenestrated stent-grafts, deployed in landing zone 0, were used for TEVAR. RESULTS All lesions resolved without endoleaks. No perioperative deaths occurred; seven patients had postoperative complications. One patient with acute respiratory distress syndrome required reoperation to change the bypass route and permit tracheostomy. One patient died of pneumonia 2 months after treatment, after an anastomotic pseudoaneurysm and cerebral infarction developed and an operation was performed to obtain hemostasis. The procedure-related mortality was 5.3%. CONCLUSION Aortic arch vessel revascularization before TEVAR may permit less invasive surgery, although careful patient selection is essential.

Hybrid procedures combining conventional and thoracic endovascular aortic repair for thoracic aortic aneurysms

PurposeTo minimize surgical invasiveness for extensive aortic aneurysms and expand the indications for thoracic endovascular aortic repair (TEVAR), we evaluated outcomes of hybrid procedures combining conventional surgical aortic repair and TEVAR for thoracic aortic aneurysms.MethodsThe following hybrid procedures were performed: second-stage TEVAR after total aortic arch replacement using the elephant trunk as the landing zone in 17 patients; and for multiple aortic aneurysms, vascular graft replacement and TEVAR in 13 patients, vascular graft replacement and TEVAR with bypass in 2 patients, and TEVAR with bypass in 23 patients.ResultsThere were three (5.3%) hospital deaths, from serious complications including stroke, paraplegia, paraparesis, and aspiration pneumonia; and eight late deaths. There was only one aneurysm-related death, of a patient who underwent emergency surgery for an esophageal fistula resulting from enlargement of a residual false lumen of a thoracoabdominal aorta after second-stage TEVAR.ConclusionHybrid procedures minimize surgical invasiveness in thoracic aortic aneurysm repair, but further evaluation of a larger number of patients is necessary.

Long-term results of second-stage thoracic endovascular aortic repair following total aortic arch replacement

PurposeWe investigated the surgical results of secondary thoracic endovascular aneurysm repair (TEVAR) using the elephant trunk graft after total aortic arch replacement (TAR) for extensive thoracic aortic lesions.MethodsThe subjects comprised 16 patients who underwent TEVAR as a staged procedure following TAR at our institution between 1997 and 2007. Long-term results were retrospectively surveyed (mean observation period 68.4 months). We performed TEVAR with the elephant trunk graft as a proximal landing zone for the descending thoracic repair, the mean duration between TAR and TEVAR was 4.7 weeks for the staged operations and 18.3 months for the nonstaged operations.ResultsEarly results were good in all cases, with no deaths and no noteworthy complications. For the seven patients without dissection, long-term results were also good. Among the nine patients with dissection, the false lumen in the thoracoabdominal area enlarged in three during follow-up. We performed thoracoabdominal repair in two, but one died of an aneurysm-esophageal fistula. There was only one long-term aneurysm-related death.ConclusionSecond-stage TEVAR using the elephant trunk graft after TAR allows less invasive surgery for extensive aortic lesions and achieves good long-term results. However, enlargement of the false lumen was a long-term concern in patients with aortic dissection, and careful follow-up is essential.

RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm

To evaluate Arg‐Gly‐Asp (RGD)‐conjugated human ferritin (HFn) iron oxide nanoparticles for in vivo magnetic resonance imaging (MRI) of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm (AAA).

Diagnostic accuracy of CT for the detection of left ventricular myocardial fibrosis in various myocardial diseases

PURPOSE To evaluate the diagnostic accuracy of computed tomography (CT) for the detection of myocardial fibrosis, we compared the frequency of abnormal late enhancement (LE) in left ventricular myocardium (LVM) on CT with that on gadolinium-enhanced cardiac magnetic resonance (CMR) in patients with various myocardial diseases. METHODS Fifty-six patients with suspected various myocardial diseases (19 with hypertrophic cardiomyopathy, 3 with cardiac amyloidosis, 3 with post myocarditis, 2 with dilated cardiomyopathy, 2 with cardiac sarcoidosis, 2 with cardiac tumor, 2 with previous myocardial infarction, 2 with hypertensive heart disease) underwent 1.5-T CMR and cardiac CT within 2months without clinical accidents. RESULTS LE on LVM was detected in 31 and 31 patients on CT and CMR, respectively, and in 192 and 197 LVM segments on CT and CMR, respectively, among a total of 952 LVM segments. The sensitivity, specificity, positive and negative predictive values, and consistency for detection of LE on CT in comparison with CMR were 90, 89, 90, 89 and 89%, respectively, on patient-based analysis, and 67, 92, 68, 91 and 87%, respectively, on segment-based analysis. Inter-observer agreement for detection of LE on CT was 0.71 (kappa coefficient), and it was significantly lower than that on CMR (0.82) on segment-based analysis (P<0.05). CONCLUSIONS Compared with CMR, diagnostic accuracy of CT for the evaluation of LE in LVM in patients with myocardial diseases was relatively higher on patient-based analysis, but was limited on segment-based analysis, and the inter-observer agreement on CT was significantly lower than that on CMR.