Norio Ishigami

Lack of Interleukin-1 Receptor Antagonist Modulates Plaque Composition in Apolipoprotein E–Deficient Mice

Objective—Interleukin (IL)-1 plays an important role in atherosclerosis. IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor of IL-1. However, the role of IL-1Ra in the development of atherosclerosis is poorly understood. Methods and Results—Mice that lacked IL-1Ra (IL-1Ra−/−) were crossed with apolipoprotein E-deficient (E−/−) mice and formation of atherosclerotic lesions was analyzed after 16 weeks or 32 weeks consumption of a normal chow diet. This study focused on the comparison of atherosclerotic lesion between IL-1Ra+/+/apoE−/− (n=12) and IL-1Ra+/−/apoE−/− mice (n=12), because of the significantly leaner phenotype in IL-1Ra−/−/apoE−/− mice compared with the others. Interestingly, atherosclerotic lesion size in IL-1Ra+/−/apoE−/− mice at age 16 weeks was significantly increased (30%) compared with IL-1Ra+/+/apoE−/− mice (P< 0.05). At 32 weeks, the differences of lesion size between these mice failed to achieve statistical significance. However, immunostaining demonstrated an 86% (P< 0.0001) increase in the MOMA-2–stained lesion area of IL-1Ra+/−/apoE−/− mice. In addition, α-actin staining in these lesions was significantly decreased (−15%) compared with those in IL-1Ra+/+/apoE−/− mice (P< 0.05). Conclusions—These results suggest an important role of IL-1Ra in the suppression of lesion development during early atherogenesis and furthermore indicate its role in the modulation of plaque composition.

Deficiency of Interleukin-1 Receptor Antagonist Promotes Neointimal Formation After Injury

Background—The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via the IL-1 receptor antagonist (IL-1Ra). The role of IL-1Ra in neointima formation after injury, however, is poorly understood. Methods and Results—Using IL-1Ra–deficient (IL-1Ra−/−; backcrossed 8 generations into the C57BL/6J background) and wild-type (IL-1Ra+/+) mice, we investigated neointimal formation 3 weeks after femoral artery injury induced by an external vascular cuff model. Intima and media thicknesses were measured, and the intima/media ratio was calculated. The mean intimal thickness and the intima/media ratio of IL-1Ra−/− mice increased by 249% (31.8±2.9 &mgr;m [n=10] versus 9.1±0.7 &mgr;m [n=10]; P <0.0001) and 257% (2.5±0.2 versus 0.7±0.1; P <0.0001), respectively, compared with IL-1Ra+/+ mice. No significant differences were observed in the medial thickness. Control immunostaining for IL-1Ra in injured vessels localized IL-1&bgr; and the endogenous inhibitor in the endothelium and inflammatory cells of the adventitia in IL-1Ra+/+ but not IL-1Ra−/− mice. Conclusions—The absence of IL-1Ra promotes neointimal formation in mice after injury. These results suggest that endogenous IL-1Ra may suppress other occlusive vascular responses to injury, such as atherosclerosis and restenosis after angioplasty.

IκBNS regulates interleukin-6 production and inhibits neointimal formation after vascular injury in mice

AIMS IκBNS regulates a subset of Toll-like receptor (TLR)-dependent genes including interleukin-6 (IL-6) by inhibiting nuclear factor-κB (NF-κB). IL-6 is an inflammatory biomarker for cardiovascular diseases. The aim of this study was to determine whether IκBNS changes arterial inflammation and intimal hyperplasia after vascular injury. METHODS AND RESULTS We investigated neointimal formation in IκBNS-deficient (IκBNS(-/-); C57BL/6 background) and wild-type (IκBNS(+/+)) mice 2 weeks after cuff injury. The mean intimal area and the intima/media ratio of IκBNS(-/-) mice increased 89% (8066 ± 1141 vs. 4267 ± 1095 μm(2); P = 0.027) and 100% (0.72 ± 0.13 vs. 0.36 ± 0.09; P = 0.032) compared with IκBNS(+/+) mice. We observed significant up-regulation of TLR4 in injured arteries of IκBNS(-/-) mice. NF-κB activity in the intima of IκBNS(-/-) mice was 5.1-fold higher (P = 0.008) compared with IκBNS(+/+) mice at 7 days post-injury. IL-6 mRNA levels in injured arteries of IκBNS(-/-) mice were 1.8-fold higher (P = 0.002) compared with those of IκBNS(+/+) mice at 3 days post-injury. Vascular smooth muscle cells from IκBNS(-/-) mice showed a significant increase in cell migration compared with those from IκBNS(+/+) mice after IL-6 stimulation in the scratch-wound healing assay. Furthermore, anti-mouse IL-6 receptor antibody (MR16-1) significantly reduced intimal hyperplasia compared with control IgG injection in IκBNS(-/-) mice. These findings suggest that IL-6 participates in the development of neointimal hyperplasia after vascular injury in IκBNS(-/-) mice. CONCLUSION IκBNS down-regulates TLR4 expression, NF-κB activity, and IL-6 production after vascular injury. IκBNS might suppress intimal hyperplasia caused by vascular inflammation such as atherosclerosis, and restenosis after angioplasty.

Successful diagnosis of an atypical prosthetic vascular graft infection without perivascular abscess: luminal vegetation as the hidden septic source.

A 62-year-old woman with a vascular prosthesis for a common hepatic artery aneurysm (3 years ago) was hospitalized because of a 2-week history of lumbago and fever. Six months previously, she was hospitalized at another medical facility for 1 month because of a fever of unknown pathogenesis. Laboratory examination revealed moderate inflammation with an elevated C-reactive protein level of 6.5 mg/dL and a white blood cell count of 7070/mm3. Initial 8-row multi-detector computed tomography (CT) with contrast agent in the emergency department did not show any focus for the origin of the fever. She was referred to the orthopedic surgery department, and MRI of the pelvis revealed inflammation of the left sacroiliac joint (Figure 1). Her first 2 sets of blood cultures were positive for Streptococcus anginosus . Intravenous administration of ampicillin/cloxacillin sodium was started. She was then transferred to the cardiology department for the evaluation of septicemia, which could have been caused by infectious endocarditis. A transthoracic echocardiogram showed severe aortic regurgitation, which was not seen at the time of previous surgery for the vascular prosthesis (Figure 2A). However, a transesophageal echocardiogram only detected a small degenerative change in the right coronary cusp of the aortic valve, which could be healed …

Cardiac Asystole Triggered by Temporal Lobe Epilepsy with Amygdala Enlargement

A 25-year-old previously healthy man was hospitalized for syncope. While standing, he suddenly lost consciousness, followed by a generalized tonic clonic seizure. An electrocardiogram demonstrated asystole. No cardiac abnormalities were detected on the echocardiogram, cardiac magnetic resonance imaging (MRI), positron emission tomography, or a coronary angiogram. An electrophysiological study showed normal sinus node and atrioventricular node function. An electroencephalogram revealed small spike waves in the fronto-temporal region. Brain MRI demonstrated a left-sided amygdala enlargement. To the best of our knowledge, this is the first case of temporal lobe epilepsy with an amygdala enlargement that induced cardiac asystole.

Successful Endovascular Removal of a Perforated Inferior Vena Cava Filter Complicated by a Large Retroperitoneal Hematoma: Pitfall of Catheter-Directed Thrombolysis

Symptomatic caval perforation is rare complication after inferior vena cava (IVC) filter insertion. A 44-year-old woman developed back pain after the placement of retrieval IVC filter during catheter-directed thrombolysis (CDT). Her computed tomography showed a large right-sided retroperitoneal hematoma. After 2 weeks, endovascular removal of the perforated filter was successfully performed without complication. Because thrombolytic agents can accelerate bleeding caused by endovascular procedures, the bleeding rate of the IVC filter deployment during CDT might be higher than expected.