Anti-inflammatory Strategies in Atherosclerosis

Atherosclerotic vascular disease and its related complications are the major cause of mortality in Western societies. Atherosclerosis is a chronic inflammatory disease of the arterial wall triggered by traditional and nontraditional risk factors and mediated by inflammatory and immune responses. Recent clinical trials provided compelling evidence corroborating that atherosclerosis is an inflammatory disease and demonstrated efficacy of anti-inflammatory interventions in reducing cardiovascular events and mortality. Traditional risk factors drive vascular inflammation, further justifying the instrumental role of intensified risk factor management in attenuating and preventing atherosclerotic disease and complications. Promising therapeutic approaches specifically related to inhibition of inflammation span traditional anti-inflammatory drugs, specific immunomodulation, and development of vaccination against atherosclerotic disease. Here, we review the inflammatory component in atherogenesis, the available evidence from clinical trials evaluating efficacy of therapeutic anti-inflammatory interventions in patients with high cardiovascular risk, and discuss potential future targets for anti-inflammatory or immune modulatory treatment in atherosclerotic cardiovascular disease.

Abstract 17117: Hyperhomocysteinemia Associated St Elevation Myocardial Infarction In A Young Male

Case Presentation: A 24-year-old male with a medical history of Crohn’s on mesalamine presented to the emergency room with crushing substernal chest pain at rest. Electrocardiogram revealed ST elevations in Lead V2-V5 (Figure-1a). He was taken emergently to the catheterization laboratory and had 100% thrombotic occlusion of his proximal left anterior descending coronary artery (LAD) (Figure-1b). Intravascular ultrasound (IVUS) confirmed the presence of soft atheromatous lipid-rich plaque in the proximal LAD with heavy thrombus burden (Figure-1c/d). He underwent aspiration thrombectomy and IVUS guided percutaneous coronary intervention with a 4.5 mm x 32 mm drug-eluting stent. Echocardiogram revealed an akinetic anterior wall with an ejection fraction of 35% without a patent foramen ovale. Hypercoagulable workup was initiated and showed a significantly elevated homocysteine level of 84.4 umol/L (normal:3.5-10.4). Family history, drug screen, hemoglobin A1C, and lipid profile were unremarkable. Discussion: The differential diagnosis in a young male presenting with a STEMI includes thromboembolism versus plaque rupture. IVUS showed clear evidence of a lipid-rich plaque demonstrating premature atherosclerotic vascular disease rather than a thromboembolic event. His most striking risk factor was hyperhomocysteinemia with a level of 84.4 umol/L. Elevations in homocysteine plasma concentration has been identified as an independent risk factor for atherosclerosis due to its atherogenic and prothrombotic properties. To date lowering homocysteine levels with folate and additional therapies have not shown to reduce the risk of coronary disease. Our case stresses the importance of intravascular imaging, especially in atypical cases such as a young male presenting with a STEMI to differentiate plaque rupture versus thromboembolism. Further studies are needed to identify risk modifying therapies for hyperhomocysteinemia associated vascular disease.

Ruptured Left Gastric Artery Aneurysm Associated with Fibromuscular Dysplasia

Background: Fibromuscular dysplasia is a non-inflammatory, non-atherosclerotic vascular disease that commonly affects renal and carotid arteries but involvement of virtually any vascular territory has been observed. Research Design/ Study sample: This is a case report of a ruptured left gastric artery aneurysm as the first presentation of fibromuscular dysplasia. Data collection: After written consent from the patient, relevant clinical notes and imaging were retrospectively reviewed and critically analysed. Purpose: This case reiterates the importance of considering fibromuscular dysplasia as an uncommon cause of visceral artery aneurysms. In addition, this case shows that the impact of visceral artery vasospasm on endovascular access should not be underestimated and subsequent attempts can be successful after a period of resuscitation. Results: After initial difficulty in endovascular treatment due to visceral vasospasm, the case was successfully managed with with staged open ligation and endovascular embolization after a period of resuscitation. Conclusions: FMD is an important differential diagnosis to consider in cases of visceral aneurysms.

Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.

Impact of adverse events on quality of life and hospital costs in secondary cardiovascular disease prevention

Background and purpose People with atherosclerotic vascular disease remain at high risk of cardiovascular (CVD) events despite effective risk factor management 1. There is little research on impacts of adverse events on quality of life (QoL) and hospital cost to inform evaluations of novel interventions in this population. We estimate QoL and annual hospital costs associated with a range of adverse events of interests using the individual participant data from the Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trial. Methods Data from the 30,449 participants with atherosclerotic vascular disease receiving effective statin therapy in REVEAL, were used to estimate regression models for participants' hospital costs and QoL using participants' characteristics at entry (socio-demographic, clinical, prior diseases and treatments) and time-updated adverse events. We estimate costs and QoL in the year of an event, and in subsequent years, using stepwise covariate selection (p-value <0.01). Standard errors were adjusted for clustering of participant annual costs. Hospital episodes were costed (2019 UK£) using the UK Healthcare Resource Groups reference costs 2. One- and two-part generalized linear regression models (GLMs) for annual hospital costs (part 1: logistic model for estimating probability of incurring cost, part 2: GLM with Gaussian, Poisson or Gamma distributions with identity or log links for estimating costs, conditional on incurring any) were compared. EQ-5D-5L questionnaires, completed by study participants at entry and final follow-up visits in the study, were mapped into QoL utility scores 3. QoL utility at final follow-up was used to estimate QoL decrements of adverse events using GLM linear model and adjusting for QoL at entry in addition to other participants characteristics. Results The two-part model with gamma distribution and identity link, indicated by specification tests and model fit statistics, was selected for modelling annual hospital costs (Figure 1). Non-haemorrhagic stroke, non-coronary revascularization, coronary revascularization and incident cancer were associated with highest hospital costs. The QoL model (Figure 2) indicated large QoL decrements associated with non-fatal non-haemorrhagic stroke, heart failure hospitalization, incident cancer and non-coronary revascularization, and comparatively small QoL decrement associated with experiencing non-fatal myocardial infarction. Conclusion These cost and QoL models in a well-managed contemporary high CVD risk patient population would assist in assessments of long-term net effects and cost-effectiveness of novel interventions to reduce cardiovascular risk. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Merck Sharp & Dohme and UK Medical Research Council Figure 1 Figure 2

CAV1 and VCL are Downregulated in Atherosclerotic Aortic Endothelial

Background: Atherosclerosis (AS) is a common atherosclerotic vascular disease, and is one of the important factors leading to cardiovascular and cerebrovascular diseases.So far, the specific etiology and pathogenesis of AS have not been clarified, and further research is needed.Methods: Bioinformatics methods were used to analyze the data set of GSE57691 and GSE137578 in normal and atherosclerotic arterial endothelial cells from Gene Expression Omnibus (GEO).Results: There are a total of 300 differentially expressed genes (DEGs) in the GSE57691 and GSE137578 datasets, which are mainly enriched in the focal adhesion signaling pathway (adj P<0.05).We identified 10 hub genes (ACTG2, CAV1, CALD1, CDC42, CCT2, CCT3, VCL, PPARG, POLR2F and TPM3) in the protein-protein interaction (PPI) network, of which 3 (CAV1, CDC42 and VCL) Significantly enriched in the adhesion signaling pathway.In addition, a search in the BIOGPS database found that CAV1 and VCL are highly expressed in coronary arteries.Conclusions: In conclusion, bioinformatics technology has proved to be useful for screening and identifying novel biomarkers of diseases.300 DEGs and 10 hub genes were significantly enriched in atherosclerotic aortic endothelial cells, especially CAV1 and VCL genes.

CAV1 and VCL are Downregulated in Atherosclerotic Aortic Endothelial

Background: Atherosclerosis (AS) is a common atherosclerotic vascular disease, and is one of the important factors leading to cardiovascular and cerebrovascular diseases.So far, the specific etiology and pathogenesis of AS have not been clarified, and further research is needed.Methods: Bioinformatics methods were used to analyze the data set of GSE57691 and GSE137578 in normal and atherosclerotic arterial endothelial cells from Gene Expression Omnibus (GEO).Results: There are a total of 300 differentially expressed genes (DEGs) in the GSE57691 and GSE137578 datasets, which are mainly enriched in the focal adhesion signaling pathway (adj P<0.05).We identified 10 hub genes (ACTG2, CAV1, CALD1, CDC42, CCT2, CCT3, VCL, PPARG, POLR2F and TPM3) in the protein-protein interaction (PPI) network, of which 3 ( CAV1, CDC42 and VCL) Significantly enriched in the adhesion signaling pathway.In addition, a search in the BIOGPS database found that CAV1 and VCL are highly expressed in coronary arteries.Conclusions: In conclusion, bioinformatics technology has proved to be useful for screening and identifying novel biomarkers of diseases.300 DEGs and 10 hub genes were significantly enriched in atherosclerotic aortic endothelial cells, especially CAV1 and VCL genes.

Gastric ischaemia: a rare cause of gastric ulcers

Gastric ulcers secondary to gastric ischaemia is rare because of the rich blood supply of the stomach. We present a case where a patient with history of atherosclerotic vascular disease (ASCVD) presented with unintentional weight loss and failure to thrive for several months. Initial imaging studies ruled out any active malignancy. Oesophagogastroduodenoscopy revealed multiple shallow gastric ulcers. CT angiography was performed in later course of the hospital stay, which demonstrated a high-grade stenosis at the origin of both the superior mesenteric artery and the coeliac trunk. This combination stenosis is a rare finding, which can lead to ischaemia of the stomach by blocking the stomach’s dual blood supply. Although the patient underwent revascularisation attempt with stent placement, she expired due to critical postoperative condition. This case signifies the importance of keeping a low threshold for suspicion for gastric ischaemia in patients with ASCVD risk factors and unexplained weight loss.