Sodium‐Glucose Co‐Transporter 2 (SGLT2) Inhibitor Dapagliflozin Stabilizes Diabetes‐Induced Atherosclerotic Plaque Instability

Background Diabetes is known to accelerate atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis mouse model, which reflects plaque instability/rupture as seen in patients, can be applied to study the effects of diabetes and respective therapeutics on plaque instability/rupture. Methods and Results ApoE −/− mice at 7 weeks of age were rendered diabetic with streptozotocin and 5 weeks later were surgically subjected to tandem stenosis in the right carotid artery and fed with a high‐fat diet for 7 weeks. As a promising new antidiabetic drug class, a sodium glucose co‐transporter 2 inhibitor was tested in this new model. Diabetic mice showed an increase in the size of unstable atherosclerotic plaques and in the plaque instability markers MCP‐1, CD68, and necrotic core size. Mice treated with dapagliflozin demonstrated attenuated glucose and triglyceride levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap‐to‐lesion height ratios, and significant upregulation of the vasculoprotective NADPH oxidase 4 expression. Conclusions The tandem stenosis mouse model in combination with the application of streptozotocin represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque‐stabilizing effects of sodium‐glucose co‐transporter 2 inhibitor. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing antidiabetic drugs for the highly sought‐after potential to stabilize atherosclerotic plaques.

Abstract 1122‐000088: Vertebral Origin Stenting Appears Safe and is Associated with Improved Functional Outcome at 3 Months

Introduction : Stenosis of the vertebral artery origin (VAOS), while under‐diagnosed, is common and may cause up to 25% of posterior circulation infarctions. Stenting is widely employed as a secondary prevention strategy, but clinical studies of safety and efficacy are limited compared to carotid interventions. Methods : This is a retrospective observational cohort study of subjects who underwent vertebral origin stenting at two large academic centers. The demographic profile of the subjects, medical comorbidities, and radiological parameters were all collected. Primary safety outcome was defined as 30‐day post‐procedure complications. Secondary safety outcomes included periprocedural complications and change in the pre‐procedure Modified Rankin score (mRS) at 3 months of follow‐up. Results : There were 80 subjects who underwent vertebral artery stenting in this cohort. Mean age was 66.6 +10.2 years, 72.5% (n = 58) were male, 70% (n = 56) were Caucasian. 53.8% (n = 43) were treated for the right VA, 72.5% (n = 58) received second‐generation drug‐eluting stents (DES). Hypertension 67.5% (n = 54) and hyperlipidemia 65% (n = 52) were the most prevalent vascular risk factors. 76.3% (m = 61) of subjects were symptomatic at presentation. There were 8 adverse events identified at 30 days (10%): 3 strokes in the same vascular territory (2 minor and without permanent disability), 1 stroke in a different vascular territory, 2 subjects with worsening of symptoms attributable to the posterior circulation, 1 GI bleed, and 1 femoral thrombosis. 3 of these subjects were found to have ipsilateral tandem stenosis and 1 patient died due to distal occlusion and large cerebellar infarction. There were 4 (5%) adverse events identified in the immediate periprocedural period: 1 vertebral dissection, 1 in‐stent thrombosis, 1 SCA embolism, and 1 stent migration. mRS of these patients remained the same at 30 days and 3 months of follow‐up. Overall, the Modified Rankin score was significantly lower at 3 months versus the pre‐procedure (Z = ‐2.45, p = 0.01). Conclusions : This large cohort of subjects undergoing vertebral origin stenting demonstrates a low incidence of procedural complications and adverse outcomes at 30 days. mRS was significantly lower at 3 months. While disability seemed to decrease in this population, longer prospective efficacy endpoints are needed to better evaluate this therapy.

Pharmacological inhibition of Factor XIIa attenuates abdominal aortic aneurysm, reduces atherosclerosis, and stabilizes atherosclerotic plaques

Background: 3F7 is a monoclonal antibody targeting the enzymatic pocket of FXIIa, thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thrombo-inflammation, along with its apparent redundancy for haemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases. Methods: The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease - angiotensin II-induced abdominal aortic aneurysm (AAA), an ApoE-/- model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability. 3F7 or its isotype control, BM4, were administered to mice (10 mg/kg) on alternate days for 4 to 8 weeks, depending on the experimental model. Mice were examined for the development and size of AAAs, or the burden and instability of atherosclerosis and associated markers of inflammation. Results: Inhibition of FXIIa resulted in a reduced incidence of larger AAAs, with less acute aortic ruptures and an associated fibro-protective phenotype. FXIIa inhibition also decreased stable atherosclerotic plaque burden and achieved plaque stabilization associated with increased deposition of fibrous structures, a >2-fold thicker fibrous cap, increased cap-to-core ratio, and reduction in localized and systemic inflammatory markers. Conclusions: Inhibition of FXIIa attenuates disease severity across three mouse models of thromboinflammation-driven cardiovascular diseases. Specifically, the FXIIa-inhibiting monoclonal antibody 3F7 reduces AAA severity, inhibits the development of atherosclerosis, and stabilizes vulnerable plaques. Ultimately, clinical trials in patients with cardiovascular diseases such as AAA and atherosclerosis are warranted to demonstrate the therapeutic potential of FXIIa inhibition.

Multiple predictors of in-stent restenosis after stent implantation in symptomatic intracranial atherosclerotic stenosis

OBJECTIVE This study aimed to identify predictors of intracranial in-stent restenosis (ISR) after stent placement in symptomatic intracranial atherosclerotic stenosis (ICAS). METHODS The authors retrospectively collected data from consecutive patients who suffered from symptomatic ICAS and underwent successful stent placement in Beijing Tiantan hospital. Eligible patients were classified into “ISR,” “indeterminate ISR,” or “no-ISR” groups by follow-up digital subtraction angiography or CT angiography. A multivariate logistic regression model was used to explore the predictors of intracranial ISR after adjustments for age and sex. In addition, ISR and no-ISR patients were divided into two groups based on the strongest predictor, and the incidence of ISR, recurrent stroke, and symptomatic ISR was compared between the two groups. RESULTS A total of 511 eligible patients were included in the study: 80 ISR, 232 indeterminate ISR, and 199 no-ISR patients. Elevated high-sensitivity C-reactive protein (hs-CRP; odds ratio [OR] 4.747, 95% confidence interval [CI] 2.253–10.01, p < 0.001), Mori type B and C (Mori type B vs Mori type A, OR 3.119, 95% CI 1.093–8.896, p = 0.033; Mori type C vs Mori type A, OR 4.780, 95% CI 1.244–18.37, p = 0.023), coronary artery disease (CAD; OR 2.721, 95% CI 1.192–6.212, p = 0.017), neutrophil/lymphocyte ratio (NLR; OR 1.474 95% CI 1.064–2.042, p = 0.020), residual stenosis (OR 1.050, 95% CI 1.022–1.080, p = 0.001) and concurrent intracranial tandem stenosis (OR 2.276, 95% CI 1.039–4.986, p = 0.040) synergistically contributed to the occurrence of intracranial ISR. Elevated hs-CRP (hs-CRP ≥ 3 mg/L) was the strongest predictor for ISR, and the incidence of ISR in the elevated hs-CRP group and normal hs-CRP group (hs-CRP < 3 mg/L) was 57.14% versus 21.52%, respectively, with recurrent stroke 44.64% versus 16.59%, and symptomatic ISR 41.07% versus 8.52%. CONCLUSIONS Elevated hs-CRP level, NLR, residual stenosis, Mori type B and C, CAD, and concurrent intracranial tandem stenosis are the main predictors of intracranial ISR, and elevated hs-CRP is crucially associated with recurrent stroke in patients with symptomatic ICAS after intracranial stent implantation.

Surgical treatment of tandem stenosis of the internal carotid artery

<p>This review article presents an analysis of the world literature devoted to treating patients with tandem stenosis of the intra- and extra-cranial parts of the internal carotid artery. We indicate the frequency of tandem lesion occurrence and describe the applied instrumental methods of its diagnosis. The review demonstrates the results of tandem stenosis surgical treatment in both early and more modern studies and describes the possibilities of endovascular correction of extra- and intra-cranial stenosis of the internal carotid artery. The authors emphasise the lack of large-scale studies — including randomised studies — regarding combined, tandem carotid stenosis and the need for further studies.</p><p>Received 30 March 2021. Revised 8 May 2021. Accepted 11 May 2021.</p><p><strong>Funding:</strong> The study did not have sponsorship.</p><p><strong>Conflict of interest:</strong> The authors declare no conflicts of interests.</p><p><strong>Contribution of the authors:</strong> The authors contributed equally to this article.</p>

First-Pass Reperfusion by Mechanical Thrombectomy in Acute M1 Occlusion: The Size of Retriever Matters

Introduction: Single-pass complete reperfusion using stent retrievers has been shown to improve functional outcome in patients with large vessel occlusion strokes. The aim of this study was to investigate the optimal size of stent retrievers to achieve one-pass complete reperfusion by mechanical thrombectomy.Methods: The study evaluated the results of aspiration-assisted mechanical thrombectomy of acute isolated occlusion of the middle cerebral artery in the M1 segment with a novel 5 × 40-mm stent retriever compared to the usual 4 × 20-mm device. Reperfusion status was quantified using the Thrombolysis In Cerebral Infarction (TICI) scale. We hypothesized that thrombectomy of M1 occlusions with 5 × 40-mm stent retriever yields higher rates of complete first-pass reperfusion (FP) (TICI ≥2c after one pass) and successful or modified FP (mFP) (TICI ≥2b after one pass) than thrombectomy with 4 × 20. We included isolated M1 occlusions treated with pRESET 5 × 40 (phenox) as first-choice device for thrombectomy and compared with M1 occlusions treated with pRESET 4 × 20. We excluded patients with additional occlusions or tandem stenosis or who received an intracranial stent or angioplasty as a part of the endovascular treatment.Results: One hundred thirteen patients were included in the 4 × 20 group and 57 patients in the 5 × 40 group. The 5 × 40 group achieved higher FP compared to 4 × 20 group [61.4% (35 of 57 patients) vs. 40.7% (46 of 113), respectively; adjusted odds ratio (OR) and 95% confidence interval (95% CI) = 2.20 (1.08–4.48), p = 0.030] and a higher mFP [68.4%, 39 of 57 patients vs. 48.7%, 55 of 113; adjusted OR (95% CI) = 2.11 (1.04–4.28), p = 0.037]. Frequency of successful reperfusion (TICI ≥2b) was similar in both groups (100 vs. 97.3%), but frequency of complete reperfusion (TICI ≥2c) was higher in the 5 × 40 group [82.5 vs. 61.9%, adjusted OR (95% CI) = 2.47 (1.01–6.04), p = 0.047]. Number of passes to achieve reperfusion was lower in the 5 × 40 group than in the 4 × 20 group [1.6 ± 1.1 vs. 2 ± 1.4, p = 0.033; adjusted incidence rate ratio (95% CI) = 0.84 (0.69–1.03), p = 0.096]. Modified Rankin scale at 90 days was similar in 5 × 40 and 4 × 20 groups.Conclusions: The size of stent retriever matters in acute M1 occlusions treated with aspiration-assisted mechanical thrombectomy. A longer stent retriever with a larger nominal diameter achieves a higher complete and successful FP and higher successful reperfusion compared to a shorter stent retriever.

Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor Dapagliflozinstabilizes Diabetes-Induced Atherosclerotic Plaque Instability

Aims/hypothesis: Diabetes is known to accelerate the progression of atherosclerosis and increase plaque instability. However, there has been a lack of suitable animal models to study the effect of diabetes on plaque instability. We hypothesized that the tandem stenosis (TS) mouse model, which reflects plaque instability and rupture as seen in patients, can be applied to study the effects of diabetes and its respective therapeutic approaches on plaque instability/rupture. Methods: ApoE -/- mice at 7 weeks of age were injected with streptozotocin (STZ) for 5 consecutive days. 5 weeks after STZ injection, mice were surgically subjected to TS in the right carotid artery and fed with a high-fat diet for an additional 7 weeks. To validate this newly developed animal model, administration of the interventional drug dapagliflozin was provided via drinking water (25 mg/kg) 3 days after TS surgery. Results: Diabetic mice showed an increase in the size of unstable atherosclerotic plaques in the TS model. Plaque instability markers such as MCP-1, CD68, and necrotic core (NC) size were significantly increased. Mice treated with the sodium glucose co-transporter 2i (SGLT2i) dapagliflozin demonstrated attenuated glucose levels. Importantly, these mice demonstrated plaque stabilization with enhanced collagen accumulation, increased fibrosis, increased cap-to-lesion ratios, and significant upregulation of plaque NADPH oxidase 4 (NOX4) expression. Conclusions/interpretation: The TS mouse model in combination with the application of STZ represents a highly suitable and unique mouse model for studying plaque destabilization under diabetic conditions. Furthermore, for the first time, we provide evidence of plaque-stabilizing effects of SGLT2i. Our data also suggest that this newly developed mouse model is an attractive preclinical tool for testing anti-diabetic drugs for their highly sought-after potential to stabilize atherosclerotic plaques.

Case Report: Evaluating Biomechanical Risk Factors in Carotid Stenosis by Patient-Specific Fluid-Structural Interaction Biomechanical Analysis

Background: Carotid atherosclerosis is one of the main underlying inducements of stroke, which is a leading cause of disability. The morphological feature and biomechanical environment have been found to play important roles in atherosclerotic plaque progression. However, the biomechanics in each patient’s blood vessel is complicated and unique. Method: To analyse the biomechanical risk of the patient-specific carotid stenosis, this study used the fluid-structure interaction (FSI) computational biomechanical model. This model coupled both structural and hemodynamic analysis. Two patients with carotid stenosis planned for carotid endarterectomy were included in this study. The 3D models of carotid bifurcation were reconstructed using our in-house-developed protocol based on multisequence magnetic resonance imaging (MRI) data. Patient-specific flow and pressure waveforms were used in the computational analysis. Multiple biomechanical risk factors including structural and hemodynamic stresses were employed in post-processing to assess the plaque vulnerability. Results: Significant difference in morphological and biomechanical conditions between 2 patients was observed. Patient I had a large lipid core and serve stenosis at carotid bulb. The stenosis changed the cross-sectional shape of the lumen. The blood flow pattern changed consequently and led to a complex biomechanical environment. The FSI results suggested a potential plaque progression may lead to a high-risk plaque, if no proper treatment was performed. The patient II had significant tandem stenosis at both common and internal carotid artery (CCA and ICA). From the results of biomechanical factors, both stenoses had a high potential of plaque progression. Especially for the plaque at ICA branch, the current 2 small plaques might further enlarge and merge as a large vulnerable plaque. The risk of plaque rupture would also increase. Conclusions: Computational biomechanical analysis is a useful tool to provide the biomechanical risk factors to help clinicians assess and predict the patient-specific plaque vulnerability. The FSI computational model coupling the structural and hemodynamic computational analysis, better replicates the in vivo biomechanical condition, which can provide multiple structural and flow-based risk factors to assess plaque vulnerability.