mTOR inhibition prevents angiotensin II-induced aortic rupture and pseudoaneurysm but promotes dissection in Apoe-deficient mice.

Aortic dissection and rupture are triggered by decreased vascular wall strength and/or increased mechanical loads. We investigated the role of mTOR signaling in aortopathy using a well-described model of angiotensin II-induced dissection, aneurysm, or rupture of the suprarenal abdominal aorta in Apoe-deficient mice. Although not widely appreciated, nonlethal hemorrhagic lesions present as pseudoaneurysms without significant dissection in this model. Angiotensin II-induced aortic tears result in free rupture, contained rupture with subadventitial hematoma (forming pseudoaneurysms), dilatation, or healing, while the media invariably thickens regardless of mural tears. Medial thickening results from smooth muscle cell hypertrophy and extracellular matrix accumulation, including matricellular proteins. Angiotensin II activates mTOR signaling in vascular wall cells, and inhibition of mTOR signaling by rapamycin prevents aortic rupture but promotes dissection. Decreased aortic rupture correlates with decreased inflammation and metalloproteinase expression, whereas extensive dissection correlates with induction of matricellular proteins that modulate adhesion of vascular cells. Thus, mTOR activation in vascular wall cells determines whether aortic tears progress to dissection or rupture. Previous mechanistic studies of aortic aneurysm and dissection by angiotensin II in Apoe-deficient mice should be reinterpreted as clinically relevant to pseudoaneurysms, and mTOR inhibition for aortic disease should be explored with caution.

"Real time" angiographic evidence of "pseudoaneurysm" formation after aneurysm rebleeding.

BACKGROUND: Pseudoaneurysms occur at the rupture site of true aneurysms and appear as irregularly shaped and partially thrombosed outpouchings of the main sac. Recanalization of thrombi inside pseudoaneurysmal sac is one of the putative mechanisms of rebleeding of unsecured aneurysms and of coil migration after endovascular treatment. We document "real time" pseudoaneurysm formation after rerupture of an anterior communicating artery aneurysm. METHODS: Case report. RESULTS: A 55-year-old man with aneurysmal subarachnoid hemorrhage from an anterior communicating aneurysm underwent catheter angiography. After the diagnostic angiogram while awaiting for the anesthesia team to proceed with endotracheal general anesthesia, a seizure occurred. Rebleeding was suspected and confirmed by a dynamic CT in the angio suite. A repeat angiogram showed a pseudoaneurysm arising from the previously ruptured aneurysm which had not been present on the original angiogram a few minutes earlier. Uneventful coiling of the aneurysm was undertaken and the patient was discharged home a week later. CONCLUSIONS: We document angiographic formation of a "pseudoaneurysm" at the site of rupture of an anterior communicating artery aneurysm. "Pseudoaneurysm" formation occurs after rupture of an intracranial aneurysm. They represent a weak spot in the aneurysm sac at the site of rupture and probably the result of persistent flow within the clot forming at the site of rupture. Presence of a pseudoaneurysm with characteristic angiographic features like the one herein described represents an unstable area within the aneurysm. This case also highlights the observation that, in patient harboring unsecured ruptured aneurysms, seizures or seizures-like phenomena are the clinical expression of rebleeding unless proven otherwise.

TGF-[beta]1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilation in apolipoprotein E-null mice.

OBJECTIVE: Impairment of transforming growth factor (TGF)-beta1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-beta1 expression would retard atherosclerosis. The role of TGF-beta1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-beta1 in hyperlipidemic mice affects atherogenesis and aortic dilation. METHODS AND RESULTS: We generated apolipoprotein E-null mice with transgenes that allow regulated overexpression of active TGF-beta1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-beta1, less aortic root atherosclerosis (P< or =0.002), fewer lesions in the thoracic and abdominal aortae (P< or =0.01), less aortic root dilation (P<0.001), and fewer pseudoaneurysms (P=0.02). Mechanistic studies revealed no effect of TGF-beta1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-beta1-overexpressing mice had fewer T-lymphocytes, more collagen, less lipid, lower expression of inflammatory cytokines and matrix metalloproteinase-13, and higher expression of tissue inhibitor of metalloproteinase-2. CONCLUSIONS: When overexpressed in the heart and plasma, TGF-beta1 is an antiatherogenic, vasculoprotective cytokine that limits atherosclerosis and prevents aortic dilation. These actions are associated with significant changes in cellularity, collagen and lipid accumulation, and gene expression in the artery wall.

Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1.

BACKGROUND: The tissue inhibitor of metalloproteinases-1 (TIMP-1) is expressed in atherosclerotic lesions, where it may play a critical role in regulating the activity of matrix metalloproteinases (MMPs). Several MMPs are overexpressed in the atherosclerotic plaque, and they are believed to contribute to the expansion and rupture of the lesion. METHODS AND RESULTS: The Timp-1-knockout mouse model (Timp-1-/-) was crossed into the apolipoprotein E-knockout (apoE0) background. A study population of male apoE0 mice, half of them deficient in TIMP-1, was fed an atherogenic diet. After 10 weeks of the diet, the mean lesion sizes of the two groups of animals were not significantly different, and the average content of fibrillar collagen and macrophages in the lesions was similar. There was no sign of plaque hemorrhage, even after 22 weeks of high-fat diet, indicating that deficiency in TIMP-1 does not predispose to luminal rupture. However the atherosclerotic lesions of the Timp-1-/0 mice developed more aortic medial ruptures, in which all elastic lamellae of the media were degraded and infiltrated with macrophages, forming pseudo-microaneurysms. After 10 weeks of high-fat diet, the Timp-1-/0/apoE0 mice averaged 1.9+/-1.2 medial ruptures in the proximal aorta, compared with 0.5+/-0.7 for the apoE0 controls (P<0.003). At the site of degradation, in situ zymography revealed that the gelatinolytic activity, mainly associated with macrophages, could be abolished by the addition of MMP inhibitors. CONCLUSIONS: These data strongly suggest that TIMP-1 plays a key role in preventing medial degradation associated with atherosclerosis through its ability to inhibit the MMPs that are involved in the disruption of the media.

[Symptomatic dissection of the internal carotid artery. A rare manifestation of autosome dominant polycystic kidney disease?]. / Symptomatische Dissektion der Arteria carotis interna. Eine seltene Manifestation der autosomal-dominanten polyzystischen Nierenerkrankung?

Autosomal dominant polycystic kidney disease (ADPKD) is a frequent, genetically heterogenous disease with renal and extrarenal manifestations. Intracranial aneurysms are found in about 10% of cases. Other vascular manifestations of ADPKD have been described only in small case series. We report a 44-year-old ADPKD patient who developed acute large middle cerebral artery infarction secondary to subpetrous dissection of the internal carotid artery. Six months after the stroke, pseudoaneurysm was demonstrated on magnetic resonance angiography at the site of a previous dissection. Based on this case report, we review the spectrum of neurovascular manifestations and stroke associated with ADPKD and summarize current concepts of the pathogenesis of this disease. Finally, special aspects of the diagnostic evaluation and therapeutic management in patients with ADPKD and cervicocephalic dissection are discussed.

Familial occurrence of an arteriovenous fistula with a giant perimedullary pseudoaneurysm of the thoracic spinal cord in 2 young siblings.

Two siblings, a sister at age 3 years and a brother (15 years later) at 4 years of age, both presented with similar clinical pictures consisting of back pain, progressive gait difficulty, lower extremity weakness and hyperreflexia. Imaging studies in both cases showed the presence of a perimedullary mass with expansion of the bony spinal canal at T10-T12. Angiography demonstrated almost identical vascular lesions that in each case was being fed by a single left-sided T8 fistulous vessel that expanded into a giant perimedullary venous pseudoaneurysm. Each malformation was successfully obliterated using endovascular techniques, balloon occlusion of the feeding vessel in the first case and coil embolization of the pseudoaneurysm in the second. Following treatment the neurologic deficits resolved in both patients. These young siblings represent the first known case of familial occurrence of very similar giant perimedullary venous pseudoaneurysms of the thoracic spinal cord.

Peripheral aneurysms in Behçet's disease.

In this report, 14 patients with Behçet's disease with a total of 16 aneurysms are presented. The most common site of aneurysm formation was the femoral artery. Patients with Behçet's disease and aneurysm formation carry the highest morbidity and mortality rates among all those with the disease. The results of reconstructive surgery in the treatment of aneurysms are discouraging, with many anastomotic aneurysms and grafts occluding. In this study, it was possible to ligate major arteries such as the common iliac, superficial femoral and popliteal without limb loss. It is suggested that ligature either at initial surgery or reoperation should be performed to avoid complications of reconstructive surgery. Adjuvant immunotherapy is required to control relapses responsible for new aneurysm formation.