Atherosclerotic Plaque Destabilization Research Articles

The effects of non-surgical periodontal therapy on neutrophil elastase and elastase alpha-1 proteinase inhibitor levels in GCF in periodontitis patients with or without acute coronary syndrome.

Periodontitis may contribute to vascular damage, resulting in the destabilization of atherosclerotic plaque leading to acute coronary syndrome (ACS). In this study, we explored the effect of non-surgical periodontal treatment (NSPT) on cardiovascular blood biomarkers and gingival crevicular fluid (GCF) neutrophil elastase (NE) and α1-proteinase inhibitor (α-1PI) levels in periodontitis (P) participants with and without ACS. Medical and dental examinations were performed to diagnose ACS and periodontitis, respectively. Seventeen patients with diagnosis of ACS and periodontitis were included in this study, as a test group (group ACS). Twenty-six age and sex-matched control patients with periodontitis (group P) were otherwise systemically healthy. Both groups received NSPT. Plasma levels of cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), C-reactive protein (CRP), GCF NE activity, GCF α1-PI levels, and GCF NE/α1-PI rates were measured at baseline, at1st and 3rd months after NSPT. GCF NE activity/time (μU/30s) decreased significantly at 3rd month compared to baseline values in the Group P after NSPT. First and 3rd months after NSPT, in the Group P GCF α1-PI activity/time (pg/30s) was significantly higher than the Group ACS. Moreover GCF NE/α1-PI rates decreased significantly compared to baseline values at 1st and 3rd months after NSPT in the group P. NSPT yields decrease in NE/α1-PI rates. NE and its possible interactions with α1-PI may play a crucial role in both periodontitis and ACS. GCF α1PI activity/time (U/30s) can be a potential biomarker in management of periodontitis associated with ACS. The GCF α1-PI reduction may alter the immune-inflammatory response in patients with periodontitis and thus increase the risk of ACS. Thai Clinical Trials.gov (NCT04785235).

Therapeutic Implications of NLRP3-Mediated Inflammation in Coronary Artery Disease.

Atherosclerosis is considered a chronic, inflammatory disease responsible for more than 15% of all global deaths, secondary to its complications of myocardial infarction, vascular disease, and stroke. Current treatment regimens consist of lipid-lowering pharmaceuticals, control of risk factors, and prevention of plaque rupture and thrombosis with antiplatelet agents. However, a significant burden on society remains due to the morbidity and mortality of coronary artery disease despite our best practices. In addition to dyslipidemia and hemostasis, inflammation has now moved to the proverbial forefront as the remaining obstacle to appropriate management of atherosclerosis. A complex dance of endothelial dysfunction, complement activation, and immune cell-mediated cytokine release underlie the pathogenesis of atherosclerotic plaque development, destabilization, and rupture. Cholesterol-induced sterile inflammation is thought to be central to this process via activation of a protein complex called the nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome. The focus of this review article will be to examine the NLRP3 inflammasome, which directs the release of interleukin-1, leading to downstream pro-inflammatory effects, and its potential for therapeutic targeting using currently available and future tools in our pharmacologic arsenal. In particular, we focus on the results of several large, recently concluded clinical trials including the Canakinumab Antiinflammatory Thrombosis Outcome Study, Colchicine Cardiovascular Outcomes Trial, and the Low-Dose Colchicine Study, examining the efficacy of direct inhibition of interleukin-1 with canakinumab or a multimodal approach to inhibiting the NLRP3 inflammasome using colchicine, as well as an overview of novel small molecule inhibitors that are still in development.

Up-regulation of PCSK6 by lipid oxidation products: A possible role in atherosclerosis

Atherosclerosis is a degenerative disease characterized by lesions that develop in the wall of large- and medium-sized arteries due to the accumulation of low-density lipoproteins (LDLs) in the intima. A growing bulk of evidence suggests that cholesterol oxidation products, known as oxysterols, and the aldehyde 4-hydroxy-2-nonenal (HNE), the major pro-atherogenic components of oxidized LDLs, significantly contribute to atherosclerotic plaque progression and destabilization, with eventual plaque rupture. The involvement of certain members of the protein convertase subtilisin/kexin proteases (PCSKs) in atherosclerosis has been recently hypothesized. Among them, PCSK6 has been associated with plaque instability, mainly thanks to its ability to stimulate the activity of matrix metalloproteinases (MMPs) involved in extracellular matrix remodeling and to enhance inflammation. In U937 promonocytic cells and in human umbilical vein endothelial cells, an oxysterol mixture and HNE were able to up-regulate the level and activity of PCSK6, resulting in MMP-9 activation as demonstrated by PCSK6 silencing. Inflammation, enhanced by these lipid oxidation products, plays a key role in the up-regulation of PCSK6 activity as demonstrated by cell pretreatment with NS-398, with epigallocatechin gallate or with acetylsalicylic acid, all with anti-inflammatory effects.For the first time, we demonstrated that both oxysterols and HNE, which substantially accumulate in the atherosclerotic plaque, up-regulate the activity of PCSK6. Of note, we also suggest a potential association between PCSK6 activity and MMP-9 activation, pointing out that PCSK6 could contribute to atherosclerotic plaque development.

Колхицин у пациентов с ишемической болезнью сердца: новые возможности снижения остаточного воспалительного риска

Inflammation plays an important role in atherosclerotic plaque destabilisation and the development of cardiovascular complications. Suppression of its activity in order to reduce residual inflammatory risk in atherosclerotic cardiovascular diseases remains an urgent and unresolved problem to the date. Over the recent years, evidence of the effectiveness of such an approach in secondary prevention of coronary heart disease has been obtained. The purpose of this review was to analyse modern literature on the effect of anti-inflammatory therapy with colchicine on the prognosis of patients with coronary heart disease. The review was carried out using the search for papers published in the PubMed and ClinicalTrials databases within the period from 2007 to 2021. The search was carried out using the keywords «colchicine», «inflammation», «atherosclerosis», «coronary heart disease» and «acute coronary syndrome». The anti-inflammatory and antiatherogenic effects of colchicine are discussed. The paper presents results of studies devoted to the use of colchicine in chronic and acute coronary syndrome, including the key ones LoDoCo2 (2020) and COLCOT (2019) which provided evidence of the effect of the drug on the disease outcome. The issues of safety and prospects of colchicine application in clinical practice for reduction of the residual inflammatory risk in patients with coronary heart disease are addressed.

Complement component-7 is a long-term predictor of all-cause mortality in chest-pain patients with suspected acute coronary syndrome

Abstract Introduction The complement cascade is an important component of the innate immune system. Complement activation plays a major role in chronic inflammation and has been associated with atherosclerosis, atherosclerotic plaque destabilization and increased risk of cardiovascular events. Complement component 7 (C7) binds C5bC6 complex being part of the terminal complement complex (TCC/C5b-9). Purpose To investigate the prognostic utility of complement C7 for long-term outcome in patients with suspected acute coronary syndrome (ACS). Methods Complement C7 plasma-levels were measured by enzyme immunoassay in admission samples from 1823 patients included in a transatlantic prospective cohort study, which consecutively included hospital admitted chest-pain patients with clinically suspected ACS from South-Western Norway and Northern Argentina. Data were pooled for analysis. Univariable- and multivariable Cox proportional-hazards models were fitted for the analysis of all-cause mortality, cardiac death and sudden cardiac death (SCD) within 24 months, applying both quartiles (Q1–4) and loge-transformed continuous values of complement C7. Results There were 253 (13.9%) deaths, of which 150 (8.2%) were categorized as cardiac death and 76 (4.2%) as SCD. Complement C7 levels were significantly higher in patients who died as compared to long-term survivors [176.9 (142.1–228.7) μg/mL versus 139.8 (110.6–179.7) μg/mL (median, 25 and 75% percentile), p<0.001], and were significantly associated with 24-month survival [log rank p<0.001 for all-cause mortality and cardiac death, log rank p=0.035 for SCD]. In univariable analysis, patients with complement C7-concentrations in the highest quartiles had significantly increased risk of all-cause mortality (Figure 1), cardiac death [Q4: Hazard Ratio (HR) 4.58 (95% confidence interval (CI): 2.65–7.92), p<0.001, Q3: HR 2.69 (95% CI: 1.51–4.80), p=0.001] and SCD [Q4: HR 2.83 (95% CI: 1.36–5.90), p=0.005, Q3: HR 2.33 (95% CI: 1.10–4.92), p=0.027] compared to patients in the lowest quartile (Q1). After adjusting for conventional clinical risk factors for coronary heart disease, complement C7-concentrations in Q4 [HR 2.09 (95% CI: 1.23–3.57), p=0.007] and Q3 [HR 2.21 (95% CI: 1.29–3.81), p=0.004] remained significantly associated with all-cause mortality, reproduced using loge-transformed continuous values. Conclusion High levels of complement C7 were found to independently predict long-term all-cause mortality in chest-pain patients with clinically suspected ACS. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Western Norway Regional Health Authority

Angiopoietin-2 is a long-term predictor of all-cause mortality, cardiac death and sudden cardiac death in chest-pain patients with suspected acute coronary syndrome

Abstract Background Angiopoietin-2 (ANGPT2) is an important regulator of angiogenesis. Higher levels of ANGPT2 have been found to be associated with an adverse cardiovascular risk factor profile potentially reflecting maladaptive vascular remodelling including atherosclerotic plaque destabilization. Purpose To evaluate the prognostic utility of ANGPT2 added to conventional clinical risk factors for coronary heart disease, including B-type natriuretic peptide (BNP), troponin T (TnT) and C-reactive protein (CRP), in patients with suspected acute coronary syndrome (ACS). Methods 871 chest-pain patients with clinically suspected ACS from South-Western Norway and 982 patients from Northern Argentina were consecutively included in a prospective transatlantic cohort study. We measured plasma-concentrations of ANGPT2 in admission-samples from 1815 patients by enzyme immunoassay. Univariable- and multivariable Cox proportional-hazards models, applying both loge-transformed continuous values and quartiles (Q1–4), were fitted for the analysis of all-cause mortality, cardiac death and sudden cardiac death (SCD) within 24-month follow-up. Of the patients with suspected ACS, 838 patients had TnT release above the detection-limit of 0.01 ng/mL. We performed subgroup analysis for all-cause mortality in patients with and without TnT release. Results Median age in the total population was 66.0 (Q1-Q3; 55.0–76.8) years and 60.4% were males. At 24-month follow-up, 254 patients (14%) had died, of which 150 (8.3%) suffered cardiac death and 76 (4.2%) SCD. ANGPT2 levels were significantly higher in patients who died compared to long-term survivors [3.87 (2.40–7.54) ng/mL versus 2.11 (1.48–3.22) ng/mL (median, 25 and 75% percentiles), p<0.001]. In multivariable analysis, ANGPT2 concentrations in the highest quartile (Q4) as compared to the lowest (Q1) were significantly associated with all-cause mortality [Hazard Ratio (HR) 1.96 (95% confidence interval (CI); 1.12–3.42), p=0.018) and cardiac death [HR 2.23 (95% CI; 1.01–4.92), p=0.047] at 24-month follow-up. For SCD, ANGPT2 concentrations in both Q3 [HR 3.59 (95% CI; 1.05–12.3), p=0.041] and Q4 [HR 3.81 (95% CI; 1.12–12.9), p=0.032] as compared to Q1 were significantly related to outcome. These results were confirmed using loge-transformed continuous values of ANGPT2. ANGPT2 was also an independent predictor of all-cause mortality in both patients with and without TnT release. For patients with TnT >0.01 ng/mL, HR for ANGPT2 in Q4 as compared to Q1 was 2.77 (95% CI: 1.41–5.44), p=0.003. For patients with TnT ≤0.01, HR for ANGPT2-Q4 was 2.67 (95% CI: 1.08–6.62), p=0.034. Conclusion High levels of ANGPT2 were found to independently predict all-cause mortality, cardiac death and sudden cardiac death in chest-pain patients with suspected ACS, irrespective of clinical demographics, troponin-release, CRP and BNP. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Western Norway Regional Health Authority

Atherosclerotic plaque vulnerability is increased in mouse model of lupus

Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe−/− mice resulting in Apoe−/−Nba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although Apoe−/−Nba2.Yaa and Apoe−/− mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in Apoe−/−Nba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though Apoe−/−Nba2.Yaa mice and Apoe−/− mice had similar lipid levels, Apoe−/−Nba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. Apoe−/−Nba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of Apoe−/−Nba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone Apoe−/−Nba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.

Impact of Short-Term Air Pollution Exposure on Acute Coronary Syndrome in Two Cohorts of Industrial and Non-Industrial Areas: A Time Series Regression with 6,000,000 Person-Years of Follow-Up (ACS - Air Pollution Study)

Background: There is a lack of data on the effect of air pollution on acute coronary syndrome (ACS) in industrial and non-industrial areas. Objectives: A comparison of association of air pollution exposure with ACS in two cohorts of industrially different areas. Materials and Methods: The study covered 6,000,000 person-years of follow-up and five types of air pollution between 2008 and 2017. A time series regression analysis with 7-lag was used to assess the effects air pollution on ACS. Results: The daily concentrations of PM2.5, PM10, NO2, SO2, CO were higher in industrial than in non-industrial area(P<0.001). In non-industrial area, an increase of 10 µg/m3 of NO2 concentration (Relative Risk (RR)=1.126, 95%CI=1.009–1.257;P=0.034, lag-0) and an increase of 1 mg/m3 in CO concentration (RR=1.055, 95%CI=1.010–1.103;P=0.017, lag-0) were associated with an increase in the number of hospitalization due to Non-ST segment elevation myocardial infarction (NSTEMI) (for industrial area increase of 10 µg/m3 in NO2 (RR=1.062, 95%CI=1.020–1.094;P=0.005, lag-0), SO2 (RR=1.061, 95%CI=1.010–1.116;P=0.018, lag-4), PM10 (RR=1.010, 95%CI=1.001–1.030;P=0.047, lag-6). In ST-segment elevation myocardial infarction (STEMI) patients in industrial area, an increased hospitalization was found to be associated with an increase of 10 µg/m3 in SO2 (RR=1.094, 95%CI=1.030–1.162;P=0.002, lag-1), PM2.5 (RR=1.041, 95%CI=1.020–1.073;P<0.001, lag-1), PM10 (RR=1.030, 95%CI=1.010–1.051;P<0.001, lag-1). No effects of air pollution on the number of hospitalization due to STEMI were noted from non-industrial area. Conclusion: The effect of NO2 on the incidence of NSTEMI was observed in both areas. In industrial area, the effect of PMs and SO2 on NSTEMI and STEMI were also observed. A negative clinical effect was more delayed in patients with NSTEMI, especially after exposure to PM10 . Chronic exposure to air pollution causes destabilization of atheroscleroticplaque and may underlie the differences in the short-term effect between particulate air pollution impact on the incidence of STEMI. Trial Registration: This study was registered at ClinicalTrials.gov (NCT04539925). Funding Statement: No external funding. Declaration of Interests: Not declared. Ethics Approval Statement: The study was approved by the bioethics committee of the Medical University of Bialystok (Approval No.: R-1-002/18/2019).

Cardiovascular Complications Associated with COVID-19 and Potential Therapeutic~Strategies.

The outbreak of coronavirus disease 2019 (COVID-19), an infectious disease with severe acute respiratory syndrome, has now become a worldwide pandemic. Despite the respiratory complication, COVID-19 is also associated with significant multiple organ dysfunction, including severe cardiac impairment. Emerging evidence reveals a direct interplay between COVID-19 and dire cardiovascular complications, including myocardial injury, heart failure, heart attack, myocarditis, arrhythmias as well as blood clots, which are accompanied with elevated risk and adverse outcome among infected patients, even sudden death. The proposed pathophysiological mechanisms of myocardial impairment include invasion of SARS-CoV-2 virus via angiotensin-converting enzyme 2 to cardiovascular cells/tissue, which leads to endothelial inflammation and dysfunction, de-stabilization of vulnerable atherosclerotic plaques, stent thrombosis, cardiac stress due to diminish oxygen supply and cardiac muscle damage, and myocardial infarction. Several promising therapeutics are under investigation to the overall prognosis of COVID-19 patients with high risk of cardiovascular impairment, nevertheless to date, none have shown proven clinical efficacy. In this comprehensive review, we aimed to highlight the current integrated therapeutic approaches for COVID-19 and we summarized the potential therapeutic options, currently under clinical trials, with their mechanisms of action and associated adverse cardiac events in highly infectious COVID-19 patients.

Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti–Interleukin 12/23p40 Antibody Ustekinumab

Ustekinumab, a monoclonal antibody targeting interleukin 12/23p40 (IL-12/23p40), is effective in the treatment of moderate to severe psoriasis, psoriatic arthritis, and Crohn disease. In 2011, a meta-analysis of randomized clinical trials reported a potential risk of severe cardiovascular events (SCEs) within the first few months after the initiation of anti-IL-12/23p40 antibodies. To assess whether the initiation of ustekinumab treatment is associated with increased risk of SCEs. This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018. The initiation of ustekinumab treatment was screened during the risk and reference periods. Odds ratios for the risk of SCE after the initiation of ustekinumab treatment were calculated. Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke). Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59). Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13). This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk. In line with the current mechanistic models for atherosclerotic disease, the period after the initiation of anti-IL-12/23p40 may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17. Although the study interpretation is limited by its observational design, these results suggest that caution may be needed in the prescription of ustekinumab to patients at high cardiovascular risk.

DIAGNOSTIC CRITERIA FOR UNDIFFERENTIATED CONNECTIVE TISSUE DYSPLASIA IN PATIENTS WITH ARTERIAL HYPERTENSION

The aim – to improve the diagnosis efficiency of patients with arterial hypertension (AH) combined with undifferentiated connective tissue dysplasia (UCTD) based on the study of clinical course, the severity of UCTD external and internal symptoms with determining the levels of IL-1, IL-6, TNF-a, free and general blood oxyproline.&#x0D; Material and Methods. The study implied examination of 90 patients (52 women and 38 men) with AH of stage 2 from first to third degrees with manifestations of UCTD, who were on inpatient treatment in the Cardiology Department of the Lviv City Communal Clinical Emergency Hospital. The mean age of patients was (61.14±2.58) years. Patients were divided into 3 groups depending on the stage and degree of hypertension. Group I (n=16) included patients with hypertension of the first degree, group II (n=35) – with AH of the second degree, group III (n=39) – with AH of the third degree. The control group consisted of 20 patients with hypertension without manifestations of CTD.&#x0D; Patients underwent clinical (checkup, palpation, percussion, auscultation), laboratory (determination of IL-1, IL-6, TNF-a, free and general oxyprolin blood levels) and instrumental studies (ECG, echocardiography, DBPM, ultrasound examination of internal organs and vessels of the lower extremities, ultrasound duplex examination of the carotid and vertebral arteries, radiological examination of the osteoarticular system), consultations of an ophthalmologist, neurologist, traumatologist and dentist.&#x0D; Results. As a result of the study, in the group I of patients (n=16) UCTD of slight degree of severity was revealed in 13 (81 %), of medium degree – in 3 (19 %) persons. In the group II of patients (n=35), UCTD of moderate severity was found in 30 (86 %), severe – in 5 patients (14 %). In the group III of patients (n=39), UCTD of moderate severity was found in 32 patients (82 %), severe – in 7 (18 %). In the study of the level of TNF-a, an increase compared to the control group was detected, particularly, in the group I of patients its level exceeded in 37.4 times, in the group II – in 39.6 times, in the group III – in 46.2 times (p&lt;0.001). IL-1b increased by 2.6-fold (р&lt;0.05) in the group I of patients compared to the control group, 3.1-fold (р&lt;0.01) – in the group II, and by 3.7-fold, that was the foremost (р&lt;0.001), in patients of the group III. In turn, IL-6 in the group I of patients exceeded the indicators of the control group by 4.3 times (p&lt;0.001), in the group II – 4.8 times (p&lt;0.001), in the group III – 5.7 times (р&lt;0.001). The study of the level of free oxyproline revealed its increase in comparison with the control group, namely in the group I of patients exceeded in 6.12 times, in the group II – in 6.81 times, in the group III – by 7.56 times (р&lt;0.01). The study of the general of bound oxyproline revealed its increase in comparison with the control group, namely in the group I of patients exceeded by 6.98 times, in the group II – by 7.79 times, in the group III – by 9.42 times (p&lt;0.01), which indicates an increase in fibrillogenesis and more pronounced destructive and inflammatory processes in connective tissue.&#x0D; Conclusions. Patients with AH of the stage 2 from first to third degrees with manifestations of UCTD have increased levels of IL-1, IL-6 and TNF-a, which are not only sensitive markers of inflammation, but also play an important role in the pathogenesis and progression of vascular lesions, occurrence and destabilization of atherosclerotic plaques and thrombotic vessels occlusion. The determination of blood oxyprolin in patients with hypertension combined with UCTD confirms the presence of CTD, namely the decay of collagen is more pronounced in patients with severe dysplasia.

CD36 in Atherosclerosis: Pathophysiological Mechanisms and Therapeutic Implications.

Atherosclerosis is a chronic disease characterized by lipid retention and inflammation in the artery wall. The retention and oxidation of low-density lipoprotein (LDL) in sub-endothelial space play a critical role in atherosclerotic plaque formation and destabilization. Oxidized LDL (ox-LDL) and other modified LDL particles are avidly taken up by endothelial cells, smooth muscle cells, and macrophages mainly through several scavenger receptors, including CD36 which is a class B scavenger receptor and membrane glycoprotein. Animal studies performed on CD36-deficient mice suggest that deficiency of CD36 prevents the development of atherosclerosis, though with some debate. CD36 serves as a signaling hub protein at the crossroad of inflammation, lipid metabolism, and fatty acid metabolism. In addition, the level of soluble CD36 (unattached to cells) in the circulating blood was elevated in patients with atherosclerosis and other metabolic disorders. We performed a state-of-the-art review on the structure, ligands, functions, and regulation of CD36 in the context of atherosclerosis by focusing on the pathological role of CD36 in the dysfunction of endothelial cells, smooth muscle cells, monocytes/macrophages, and platelets. Finally, we highlight therapeutic possibilities to target CD36 expression/activity in atherosclerosis.

Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis.

Purpose of ReviewThe COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications.Recent FindingsThe Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase–type increase in Lp(a) levels following a cytokine storm from COVID-19.SummaryThus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.

Fatal cerebral and cardiac infarction due to embolism of a mobile thrombus from aorta sinotubular junction atheroma in a 40-year-old female

Strokes in young adults present a challenging problem in terms of care and social impact. Most of cases in this cohort are classified as strokes of uncertain etiology. Application of multimodality diagnostic approach could help in the estimation of risk factors and underlying mechanisms. Simultaneous acute cardio-cerebral infarction is a rare manifestation, especially in young individuals. Large artery atherosclerosis should be excluded as a potential cause. Transesophageal echocardiography plays an important role in the diagnostic algorithm. The current article presents a clinical case of a fatal acute cardio-cerebral infarction in a 40-year old female without previous cardiovascular diseases and negative family history. Transesophageal echocardiography identified a large mobile thrombus at the sinotubular junction of ascending aorta. Transthoracic echocardiography revealed regional akinesia of the inferior wall, despite normal electrocardiogram. The autopsy findings confirmed co-occurrence of thromboembolic stroke in the right middle cerebral artery area and left ventricular inferior myocardial infarction due to thrombosis of the right coronary artery. This case documents an exceedingly rare phenomenon in this cohort of a cardio-cerebral thromboembolism due to single atherosclerotic plaque destabilization.

Three-Dimensional Imaging of Intraplaque Neovascularization in a Mouse Model of Advanced Atherosclerosis

Multiple lines of evidence suggest that intraplaque (IP) neovascularization promotes atherosclerotic plaque growth, destabilization, and rupture. However, pharmacological inhibition of IP neovascularization remains largely unexplored due to the limited number of animal models that develop IP neovessels and the lack of reliable methods for visualizing IP angiogenesis. Here, we applied 3D confocal microscopy with an optimized tissue-clearing process, immunolabeling-enabled three-dimensional imaging of solvent-cleared organs, to visualize IP neovessels in apolipoprotein E-deficient (ApoE^−/−) mice carrying a heterozygous mutation (C1039+/−) in the fibrillin-1 gene. Unlike regular ApoE^−/− mice, this mouse model is characterized by the presence of advanced plaques with evident IP neovascularization. Plaques were stained with antibodies against endothelial marker CD31 for 3 days, followed by incubation with fluorescently labeled secondary antibodies. Subsequent tissue clearing with dichloromethane (DCM)/methanol, DCM, and dibenzyl ether allowed easy visualization and 3D reconstruction of the IP vascular network while plaque morphology remained intact.

Incidence and consequences of systemic arterial thrombotic events in COVID-19 patients.

A high incidence of thrombotic events, particularly deep vein thrombosis and pulmonary embolism, has been clearly documented in COVID-19 patients. In addition, small series of patients with coronary, cerebrovascular and peripheral arterial thrombotic events have also been reported, but their true incidence and consequences are not well described, and constitute the objective of this study. From February 1st to April 21st, 2020, 2115 COVID-19 patients were treated at Hospital Universitario Fundación Alcorcón (Madrid, Spain), and 1419 were eventually admitted. Patient characteristics and outcomes were collected by reviewing their electronic medical records. Fourteen patients had a systemic arterial thrombotic event, which represents a 1% incidence in relation to the total number of hospitalized patients. Three patients suffered an acute coronary syndrome, two with persistent ST-segment elevation, one of whom was treated invasively, and one with transient ST-segment elevation. Eight patients had a cerebrovascular event. Six suffered an acute ischemic stroke and two a transient ischemic attack, 50% of them had a Rankin score ≥ 3 at discharge. Three additional patients had a limb thrombotic event, all of them infrapopliteal, and were managed conservatively. All three cases developed necrosis of the toes, two of them with bilateral involvement. The hospitalization death rate of patients with an arterial event was 28.6%. Although COVID-19 may favor the occurrence of thrombotic events, the destabilization and thrombosis of arterial atherosclerotic plaques do not seem to be a frequent mechanism which warrants the need for specific systematic preventive measures.

Visfatin associated with major adverse cardiovascular events in patients with acute myocardial infarction

BackgroundVisfatin is an adipokine that related with the inflammation in atherosclerosis and the destabilization of atherosclerotic plaque. The aim of this study was to observe the relationship between visfatin and major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients.MethodsWe enrolled a total of 238 patients (183 AMI and 55 control) who underwent coronary angiography. Patients with AMI were followed for an average of 19.3 months and 159 patients were finally included in the study.ResultsIt was observed patients with AMI had higher serum visfatin levels than controls. The total incidence of MACEs was 11.32% (18/159) in AMI patients. After calculation of the Youden index, the best cut-off value of visfatin on the curve of receiver-operating characteristic was 8.799 ng/mL for predicting the occurrence of MACEs. The occurrence of MACEs was elevated in high-visfatin group (≥8.799 ng/mL) compared with low-visfatin group (≤8.799 ng/mL). The time to MACEs was correlated with visfatin (HR = 1.235, 95%CI 1.051–1.451, P = 0.01) and high-visfatin group had an earlier time to MACEs and a shorter time of cumulative survival.ConclusionsIncreased serum visfatin levels were observed in AMI patients, and correlated with an earlier onset and higher incidence of MACEs.

Applying the Lessons of Influenza to COVID-19 During a Time of Uncertainty.

Applying the Lessons of Influenza to COVID-19 During a Time of Uncertainty.

GYY4137 exhibits anti-atherosclerosis effect in apolipoprotein E (-/-) mice via PI3K/Akt and TLR4 signalling.

Hydrogen sulphide (H2 S) had been suggested to be involved in the pathogenesis of atherosclerosis, but the underlying molecular mechanisms are poorly understood. In this study, we aimed to investigate the anti-atherosclerosis effect of morpholin-4-ium-methoxyphenyl-morpholino-phosphinodithioate (GYY4137) in RAW264.7 cell-derived foam cells formation and in the atherosclerotic plaque of ApoE-/- mice fed with a high-fat diet, and study the underlying mechanisms of phosphatidylinositol 3-kinase (PI3K), serine/ threonine kinase (Akt) and Toll-like receptor 4 (TLR4) signalling pathway. In the ApoE-/- mice fed with a high-fat diet, daily GYY4137 administration for 8weeks effectively decreased carotid atherosclerotic plaque area and the volume of foam cells, regulated the lipid metabolism, down-regulated the pro-inflammatory cytokine levels and up-regulated the anti-inflammatory cytokines levels. Consistent with these findings, in the RAW264.7 cell-derived foam cells, GYY4137 ameliorated foam cell formation in vitro, and decreased the expression of pro-inflammatory cytokines. Furthermore, our studies showed that GYY4137 could activate the PI3K/Akt signalling pathway and consequently reduce the expression of TLR4 to be critical for foam cell formation, preventing atherosclerotic plaque formation and destabilization. LY294002, a PI3K inhibitor, could inhibit the phosphorylation of Akt and reduce the expression of TLR4, thus reduce the foam cell source and lipid volume in the unstable plaque tissue. Our results suggest that GYY4137 is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating the PI3K/Akt/TLR4 signalling pathway.

Sequential Surgical Procedures in Vascular Surgery Patients Are Associated With Perioperative Adverse Cardiac Events.

Patients at elevated cardiovascular risk are prone to perioperative cardiovascular complications, like myocardial injury after non-cardiac surgery (MINS). We have demonstrated in a mouse model of atherosclerosis that perioperative stress leads to an increase in plaque volume and higher plaque vulnerability. Regulatory T cells (Tregs) play a pivotal role in development and destabilization of atherosclerotic plaques. For this exploratory post-hoc analysis we identified 40 patients recruited into a prospective perioperative biomarker study, who within the inclusion period underwent sequential open vascular surgery. On the basis of protein markers measured in the biomarker study, we evaluated the perioperative inflammatory response in patients' plasma before and after index surgery as well as before and after a second surgical procedure. We also analyzed available immunohistochemistry samples to describe plaque vulnerability in patients who underwent bilateral carotid endarterectomy (CEA) in two subsequent surgical procedures. Finally, we assessed if MINS was associated with sequential surgery. The inflammatory response of both surgeries was characterized by postoperative increases of interleukin-6,−10, Pentraxin 3 and C-reactive protein with no clear-cut difference between the two time points of surgery. Plaques from CEA extracted during the second surgery contained less Tregs, as measured by Foxp3 staining, than plaques from the first intervention. The 2nd surgical procedure was associated with MINS. In conclusion, we provide descriptive evidence that sequential surgical procedures involve repeat inflammation, and we hypothesize that elevated rates of cardiovascular complications after the second procedure could be related to reduced levels of intraplaque Tregs, a finding that deserves confirmatory testing and mechanistic exploration in future populations.