Prevention Of Aneurysm Formation Research Articles

Blockade of the Platelet-Driven CXCL7-CXCR1/2 Pathway Prevents Cerebral Aneurysm Formation

Abstract INTRODUCTION Platelet aggregation is intimately associated with vascular inflammation and is commonly seen on routine histology studies of cerebral aneurysms. Platelets, when activated, have been shown to augment neutrophil response and the proinflammatory cascade. Antiplatelet therapy, especially via ADP-GPIIb/IIIa antagonism, has inherent anti-inflammatory actions that could be of therapeutic interest in prevention of aneurysm formation, but could also interfere with healing of coiled aneurysms. Platelet-neutrophil complexes have been found to aggravate atherosclerosis through a positive feedback loop involving CXCL1, CXCR1/2, and CXCL7. We propose that treatment with GPIIb/IIIa antagonists or anti-CXCR1/2 receptor blockers could be used to prevent aneurysm formation. METHODS First, we induced cerebral aneurysm formation in a previously described intracranial aneurysm model via carotid artery ligation, hypertension, and stereotactic elastase injection in C57BL/6 mice, and analyzed vessels for lesion and thrombus formation. Raybiotech cytokines arrays were used to analyze 96 cytokines in induced aneurysms. Cerebral aneurysm formation was then studied in animals treated with 1:3 DMSO:PBS (control), clopidogrel, or anti-CXCR1/2 small molecule inhibitor. RESULTS CD31 + platelet aggregates are a common feature in human and mouse cerebral aneurysm specimens. Mice treated with 1 mg/kg clopidogrel develop significantly less aneurysms than controls (0% vs 57%, n = 6 and 7 respectively, P = .049). Semi-quantitative analysis of 96 different cytokines using Raybiotech arrays shows increased protein expression of CXCL7 in murine cerebral aneurysms when compared to controls. Treatment with clopidogrel results in reciprocal decrease in detected CXCL7. Targeting CXCL7-CXCR1/2 axis with 10 mg/kg reparixin (CXCR1/2 antagonist) tends decrease aneurysm formation. (14% vs 57%, n = 6 and 7, P = .13). CONCLUSION Small molecule inhibitors targeting platelet CXCL7-CXCR1/2 inflammatory axis can be used to prevent murine cerebral aneurysm formation.

Response to Sympathoinhibitory Effect of Diltiazem and Prevention of Aneurysm Formation

We thank Dr Tsuda1 for the important remark and his interest in our work. Unfortunately, we did not perform measurements on the effect of diltiazem on sympathetic nerve activity in our study and as mechanism of action of the drug we …

Sympathoinhibitory Effect of Diltiazem and Prevention of Aneurysm Formation

We read with great interest the article by Mieth and colleagues1 dealing with the effect of the benzothiazepine-type calcium channel blocker, diltiazem, on aortic aneurysm formation in a mouse model. The results of their study demonstrated that diltiazem significantly prevented abdominal aneurysm formation in a blood pressure–independent manner in male apolipoprotein E–deficient mice infused with angiotensin II. In addition, the authors showed that diltiazem inhibited the interleukin-6 (IL-6)–induced mRNA expression of IL-1β and the monocyte chemoattractant protein …

Abstract 483: Prevention of Aneurysm Formation using Ribbon-type Decoy Oligodeoxynucleotides against NFκB and Ets in a Rat Model

Current therapy to treat abdominal aortic aneurysm (AAA) is limited to elective surgical repair. Especially, there is no well-defined treatment strategy for small AAAs. Therefore, the development of a novel therapeutic approach to treat AAA is awaited. We focused on the simultaneous inhibition of the transcription factors, NFκB and ets. Indeed, we previously reported the preventive and regressive effects of chimeric decoy oligodeoxynucleotides (ODN) against NFκB and ets. However, local application of ODN is necessary due to easily degradation. To overcome this limitation, we developed novel chimeric decoy ODN with a ribbon-shaped circular structure (ribbon-type chimeric decoy ODN, RC-ODN) to stabilize decoy ODN against nucleases. First, we examined the stability of RC-ODN. RC-ODN was more stable than the conventional phosphorothioated chimeric decoy ODN (PC-ODN) after incubation in the presence of exonuclease or serum. In addition, the inhibitory effect of RC-ODN on MMP-9 expression in cultured THP-1 cells was more potent than that of PC-ODN (n=8, P<0.005). To achieve a minimally invasive molecular therapy, intra-peritoneal application of RC-ODN was performed in a rat AAA model. One week after injection of FITC-labeled RC-ODN, FITC-positive macrophages, migrated from peritoneal space, could be detected in the aneurismal wall. In addition, EMSA showed that both NFκB and ets activity were inhibited by RC-ODN. 4 weeks after treatment, transfection of RC-ODN inhibited the aortic dilatation as compared to control or ribbon-type scrambled decoy ODN transfer (n=6 per group, RC-ODN 5.66±1.08 mm 2 , Scrambled 13.89±3.55 mm 2 , P<0.05). Interestingly, a significant preservation of elastic fibers was observed with RC-ODN treatment, accompanied by a reduction of MMP-9 activity (P<0.0005) and MMP-12 expression (P<0.0005), while the recruitment of macrophages was not inhibited. The expression of cysteine proteases, cathepsin B and K, was also suppressed by RC-ODN treatment (P<0.05). Here, the present study provided a novel strategy to treat AAA by the simultaneous inhibition of NFκB and ets using intra-peritoneal application of RC-ODN in a rat model. Minimally invasive molecular therapy using this strategy is expected to be useful for treating AAA.

Genetics of intracranial aneurysm

Subarachnoid hemorrhage (SAH) secondary to ruptured saccular intracranial aneurysm (IA) is a complex trait, with both genetic and environmental risk factors playing an important part. The 30-day mortality rate of patients with SAH is 40% to 44%, with many survivors suffering from major disability. Because most of the mortality after SAH is caused by rapid and massive brain injury from the initial bleeding, primary prevention of aneurysm formation and rupture is of paramount importance. This article reviews the evidence supporting a genetic predisposition to SAH from saccular IA, the conditions commonly associated with saccular IA, and the search for genetic risk factors.

Thoracoabdominal Endaortectomy in Case of Type B Aortic Dissection

Despite remarkable progress in both, diagnostic and therapeutic development in treating aortic dissections, this continues to be one of the most severe vascular disorders and is subject to high mortality rates. While aortic dissections of Type A can be treated surgically today, in the majority of patients with Type B dissections hypotensive treatment is the method of choice, providing a better chance of survival and the effective prevention of aneurysm formation and rupture at the site of the intimal tear. However in certain cases, Type B dissection generates either isthmic aneurysm formation, or, with distal progression, may result in long segmental thoracic, thoraco-abdominal or abdominal deterioration of the aorta and its side branches.The spinal, visceral, renal and lower limb ischemia threatens the viability of these organs and hypotensive medication may enhance this risk. Emergency diagnostic work-up and selective surgical reconstruction could lead to reduced mortality. In our department we have undertaken 33 thoracoabdominal endoaortectomies with meticulous reconstruction of renal and visceral orifices. The mortality rate in this subgroup of patients was 6%. Based on our experience with Type B aortic dissections we recommend open 舢endoaortectomy” in selected cases in order to improve the long-term outcome.