Etiology of recurrent large vessel occlusions treated with repeated thrombectomy

Background Repeated mechanical thrombectomy for acute stroke treatment in individual patients has been proven feasible. However, less is known about the etiology of recurrent vessel occlusions after prior thrombectomy. We aimed to understand if the etiology of such recurrent events differs from the first stroke. Methods Retrospectively, we identified all patients at our center who received a repeated mechanical thrombectomy between 2007 and 2019. Clinical data were retrieved from medical records. Etiology of stroke was evaluated retrospectively, and angiographic studies were revisited. Results Twenty-three patients (1.5%) were identified. Median age was 68 years (IQR 56–77). Median NIHSS at first admission was 11 points (IQR 5–15). In nine cases (39.1%), the recurrent vessel occlusion was located exactly at the same position as the prior occlusion. Overall, five (21.7%) patients had a remarkable extracranial pathology as likely cause of stroke recurrence. In 16 patients (69.6%), the etiology of the first stroke and its recurrence was considered as likely being the same, mostly of cardioembolic or unknown origin. In the seven remaining patients (30.4%), the cause of stroke possibly differed from the first event, with five patients (21.7%) having a postinterventional intracranial intimal lesion as possible cause of stroke. Conclusion Incidence of repeated thrombectomy was low. However, the high number of patients with known origin of stroke etiology raises the question how their monitoring may be optimized. The number of patients with remarkable extracranial pathologies or intracranial endothelial lesions supports current clinical practice to pay attention to final angiographic series.

Insulin treatment attenuates diabetes-increased atherosclerotic intimal lesions and matrix metalloproteinase 9 expression in apolipoprotein E-deficient mice

Patients with diabetes mellitus have increased mortality and morbidity of cardiovascular diseases compared with nondiabetic patients. Although clinical studies have shown that effective glycemic control with insulin treatment in patients with type 1 diabetes is associated with reduced cardiovascular events, the underlying mechanisms have not been well understood. In this study, we treated diabetic apolipoprotein E-deficient (apoE−/−) mice with insulin for 20 weeks and studied the effect of insulin treatment on intimal lesion size and matrix metalloproteinase (MMP) 9 expression known to be involved in plaque destabilization. Results showed that insulin treatment, which effectively reduced plasma glucose level in diabetic mice, attenuated diabetes-increased intimal lesion size and significantly inhibited diabetes-increased MMP9 expression, but had no effect on tissue inhibitor of metalloproteinase 1 in atherosclerotic plaques. Furthermore, we observed that insulin treatment did not reduce diabetes-increased macrophage content but inhibited interleukin 6 expression, a stimulator for MMP expression. Taken together, this study has shown for the first time that insulin treatment in diabetic apoE−/− mice changes atherosclerotic lesions and gene expression to a state that favors plaque stability.

Abstract 5543: The P2Y 2 Nucleotide Receptor Contributes To Intimal Lesion Growth And Regulates Lymphotoxin-α Secretion

Inflammatory processes play a crucial role in atherosclerotic lesion growth. A number of pro-inflammatory molecules have been implicated in the pathogenesis of atherosclerosis, including lymphotoxin-α (LTA). Our research has shown that activation of a G protein-coupled P2Y 2 nucleotide receptor (P2Y 2 R) expressed in vascular cells mediates inflammatory responses. To examine the role of the P2Y 2 R in lesion growth, we developed P2Y 2 R over-expressing transgenic rats. Collar-induced injury to the carotid artery of P2Y 2 R transgenic rats caused a dramatic increase in intimal lesion growth and significant macrophage accumulation, which nearly blocked the arterial lumen. Immunohistochemical staining showed that LTA and galectin-2 (gal-2) were abundantly expressed in smooth muscle cells (SMC) and macrophages in carotid lesions of P2Y 2 R transgenic rats. We also identified galectin-2 as a P2Y 2 R binding partner using the yeast two-hybrid system and a co-immunoprecipitation assay. P2Y 2 R agonist, UTP, stimulated gal-2 mRNA expression in rat carotid SMC. Transient transfection of SMC with a genomic fragment including the rat galectin (LGALS2) promoter incorporated into a luciferase (pGL-3) reporter vector showed that UTP markedly increased LGALS2 promoter activity in a dose-dependent manner. Moreover, UTP induced LTA secretion in cultured aortic SMC from wild type, but not P2Y 2 R −/− mice. Adenoviral expression of the full length P2Y 2 R in SMC from P2Y 2 R −/− mice fully restored UTP-induced LTA secretion. However, expression of a mutant P2Y 2 R that does not bind filamin A, an actin-binding protein that interacts with the P2Y 2 R, only partially restored UTP-induced LTA secretion in P2Y 2 R −/− SMC. Gal-2 siRNA partially inhibited LTA release into medium of cultured SMC expressing the P2Y 2 R. In contrast, gal-2 siRNA abolished UTP-induced LTA secretion in SMC isolated from P2Y 2 R −/− mice expressing the filamin A binding mutant P2Y 2 R. These results indicate that P2Y 2 Rs regulate gal-2-dependent LTA secretion in SMC via a filamin A-dependent mechanism that likely contributes to vascular inflammation.

α1-Adrenoceptor stimulation directly induces growth of vascular wall in vivo

Previous studies suggesting that norepinephrine is directly trophic for the vascular wall have been confounded by concomitant hemodynamic disturbances. Herein, a microcatheter connected to an osmotic minipump was implanted adjacent to the rat carotid for 2-wk perivascular suffusion of agents at systemic levels ∼1,000 times below the threshold for altering arterial pressure. Norepinephrine decreased lumen and adventitial areas and circumference by 10, 14, and 5%, respectively (all P < 0.05); a nonsubtype-specific α1-adrenoceptor (AR) antagonist had no effect. When begun at the time of balloon injury, 2-wk norepinephrine increased lumen loss by 45%, increased neointimal area by 64% and collagen content by 33%, and reduced vessel circumference by 5% (all P < 0.05). α1-AR antagonists decreased neointimal area by 33% (all P < 0.05). α1A-AR antagonist reduced lumen loss by 70%, neointimal area by 54%, circumference decline by 84%, and adventitial thickening by 87% (all P < 0.05), whereas α1B-, α1D-, α2- and β-AR antagonists were without effect. These are the first in vivo studies demonstrating that norepinephrine is directly trophic for the vascular wall and augments injury-induced intimal lesion growth.