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.

COVID-19 and Cardiovascular Complications: An Updated Review

COVID-19 has become a global pandemic. Patients with pre-existing comorbidities such as hypertension, diabetes, and cardiovascular disease (CVD) are associated with greater severity and higher mortality. COVID-19 can cause cardiovascular complications, including myocardial injury, myocarditis, heart failure, acute coronary syndrome, and coagulation abnormalities. Possible pathophysiology and molecular pathways driving these disease processes are cytokine release syndrome, RAAS system dysregulation, plaque destabilization and coagulation disorders Myocarditis is one concern among persons who received mRNA-Based COVID-19 vaccines. There are several cardiovascular complications that are possibly caused by COVID-19 treatments, such as QT interval prolongation, arrhythmia, and hypotension. Due to increasingly recognized CVD damage in COVID-19, we need to understand about COVID-19 related to cardiovascular complications and treatment strategies.

Features of atherosclerosis in carotid and coronary arteries

Atherothrombosis is a leading cause of myocardial infarction and ischemic atherothrombotic stroke. It represents a stage of atherosclerosis which is a pathologic process throughout the circulatory system. However, atherosclerosis has specific development characteristics in different vascular beds. Multiple factors contribute to atherosclerosis formation and progression such as genetic factors, vessel hemodynamics, and vessel anatomy. A better understanding of differences in vessels would improve prevention and treatment of atherosclerosis and its complication. In this article we review features of atherosclerosis in carotid and coronary vessels. We discuss specific conditions of local hemodynamics in the areas of bifurcation which promote atherosclerotic plaque progression, and review characteristics of unstable plaques in carotid and coronary vessels. We analyze immunologic and inflammatory processes, extracellular matrix degradation and remodeling, cellular apoptosis and autophagy occurring during atherosclerotic plaque destabilization as well as the possibility of diffuse plaque instability in systemic atherosclerosis. We review association and interaction of atherosclerotic processes in coronary and carotid arteries, and its significance for a patient. Improvement in understanding of atherosclerosis pathogenesis can lead to advances in atherosclerosis prevention. Timely and effective interventions would promote prevention of myocardial infarction and ischemic stroke which is highly important taking into account high mortality and morbidity rates.

Comprehensive analysis of dysregulated genes associated with atherosclerotic plaque destabilization

Atherosclerotic plaque destabilization is a dominating cause of acute cardiovascular events such as myocardial infarction and stroke. This study aims to identify genetic biomarkers related to atherosclerotic plaque destabilization using bioinformatics. Three transcriptome datasets of human carotid atherosclerotic plaque samples were downloaded from ArrayExpress and Gene Expression Omnibus databases, including E-MATB-2055, E-TABM-190, and GSE120521. With Robust Rank Aggregation analysis, we documented 46 differentially expressed genes between stable and unstable/ruptured plaques. Functional enrichment analysis using DAVID tool demonstrated that these genes were mainly related to biological functions such as extracellular matrix disassembly, collagen catabolic process, response to mechanical stimulus, and PPAR signaling pathway. A protein–protein interaction network for the differentially expressed genes was constructed, and eight pivotal genes ( ITGAM, MMP9, PLAUR, CCR1, CD163, CD36, ADAM8, and IL1RN) were obtained from the network with a connective degree > 5. The expression patterns of these hub differentially expressed genes could be verified in atherosclerotic plaque samples with intraplaque hemorrhage. Using gene set variation analysis, the eight genes were integrated to generate an atherosclerotic plaque destabilization score, which showed a high performance in not only discriminating individuals with myocardial infarction from those with stable coronary illness, but also in predicting future acute cardiovascular events in atherosclerotic patients. In conclusion, the findings of this study will enhance our knowledge on the pathological mechanisms involved in atherosclerotic plaque destabilization, and provide potential gene biomarkers for risk stratification of patients with atherosclerotic cardiovascular disease.

Circulating Biomarkers Reflecting Destabilization Mechanisms of Coronary Artery Plaques: Are We Looking for the Impossible?

Despite significant strides to mitigate the complications of acute coronary syndrome (ACS), this clinical entity still represents a major global health burden. It has so far been well-established that most of the plaques leading to ACS are not a result of gradual narrowing of the vessel lumen, but rather a result of sudden disruption of vulnerable atherosclerotic plaques. As most of the developed imaging modalities for vulnerable plaque detection are invasive, multiple biomarkers were proposed to identify their presence. Owing to the pivotal role of lipids and inflammation in the pathophysiology of atherosclerosis, most of the biomarkers originated from one of those processes, whereas recent advancements in molecular sciences shed light on the use of microRNAs. Yet, at present there are no clinically implemented biomarkers or any other method for that matter that could non-invasively, yet reliably, diagnose the vulnerable plaque. Hence, in this review we summarized the available knowledge regarding the pathophysiology of plaque instability, the current evidence on potential biomarkers associated with plaque destabilization and finally, we discussed if search for biomarkers could one day bring us to non-invasive, cost-effective, yet valid way of diagnosing the vulnerable, rupture-prone coronary artery plaques.

Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression

Background and Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors. Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured. Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P <0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P <0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels ( P =0.010, r =−0.30) and directly with circulating uric acid levels ( P <0.001, r =0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P <0.001). Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.

The role of cytomegalovirus and interleukin-8 in destabilization of atherosclerotic lesions in humans

Relevance. Currently, the role of persistent infections in the atherogenesis development mechanism is not fully understood. Therefore, its important to analyze the role of viral infection against the background of the pro-inflammatory cytokines expression in atherosclerotic plaque destabilization. The aim of the work was a comparative immunohistochemical study of cytomegalovirus (CMV) and IL-8 in different types of human atherosclerotic lesions during their destabilization. Materials and methods. The study was carried out on 130 autopsy samples of human aorta. CMV was detected by direct immunofluorescent antibody staining. IL-8 was detected by two-stage streptavidin-biotin antibody staining. Results. It has been shown that active detection of both CMV and IL-8 is characteristic of atherogenesis foci of the arterial intima with the most intense immune-inflammatory changes. The obtained results indicate the synergism of the cellular response to CMV and IL-8 in the vascular wall during the destabilization atherosclerotic lesions process. Conclusion. According to the results of the work, it can be concluded that both the presence of CMV in atherosclerotic lesions and the high production of IL-8 play a significant role in the formation of unstable atherosclerotic plaques in the vascular wall.

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.

Elevation of CD40/CD40L Inflammatory Pathway Molecules in Carotid Plaques from Moderate-and-Severe Obstructive Sleep Apnea Patients

A chronic inflammatory process characteristic of obstructive sleep apnea promotes vascular endothelial dysfunction and atherogenesis. This process can lead to destabilization and rupture of cardiovascular plaques, which clinically manifests as an acute coronary syndrome or stroke. The aim of this study was to investigate the inflammatory pathway leading to plaque destabilization in non-to-mild and moderate-to-severe groups of OSA patients. This prospective study involved enrollment of patients scheduled for endarterectomy. A sleep study was performed prior to surgery. Immunohistochemistry was performed on atherosclerotic plaques from carotid arteries obtained during standard open endarterectomy to determine levels of CD40, CD40L receptors, MCP-1, and MMP-9. The 46 patients included 14 controls, 13 with mild, 11 with moderate, and 8 with severe OSA. Increased expression of CD40, CD40L receptors, MCP-1, and MMP-9 were found to be proportionate with OSA severity. However, significant differences among groups were observed only for MCP-1 (p = 0.014). Increased expression of inflammatory markers (CD40, CD40L, MCP-1, MMP-9) is associated with increasing OSA severity. This suggests the CD40-CD4-L inflammatory pathway may contribute to plaque instability and rupture in OSA patients.

Regulation of Long Non-Coding RNAs by Statins in Atherosclerosis

Despite increased public health awareness, atherosclerosis remains a leading cause of mortality worldwide. Significant variations in response to statin treatment have been noted among different populations suggesting that the efficacy of statins may be altered by both genetic and environmental factors. The existing literature suggests that certain long noncoding RNAs (lncRNAs) might be up- or downregulated among patients with atherosclerosis. LncRNA may act on multiple levels (cholesterol homeostasis, vascular inflammation, and plaque destabilization) and exert atheroprotective or atherogenic effects. To date, only a few studies have investigated the interplay between statins and lncRNAs known to be implicated in atherosclerosis. The current review characterizes the role of lncRNAs in atherosclerosis and summarizes the available evidence related to the effect of statins in regulating lncRNAs.