Intracranial Hemorrhage in the TST Trial

Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of <70 mg/dL or 100±10 mg/dL, using statin or ezetimibe. Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of <70 mg/dL compared with 100±10 mg/dL in patients with atherosclerotic ischemic stroke nonsignificantly increased the risk of ICH. Incident ICHs were not associated with low LDL cholesterol. Uncontrolled hypertension and anticoagulant therapy were associated with ICH which has important clinical implications. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Associations of Antioxidant Enzymes with the Concentration of Fatty Acids in the Blood of Men with Coronary Artery Atherosclerosis

Objective: To identify associations of fatty acids (FAs) with the antioxidant enzymes in the blood of men with coronary atherosclerosis and ischemic heart disease (IHD). Methods: The study included 80 patients: control group—20 men without IHD, the core group—60 men with IHD. The core group was divided into subgroups: subgroup A—with the presence of vulnerable atherosclerotic plaques, subgroup B—with the absence of vulnerable atherosclerotic plaques. We analyzed the levels of FAs, free radicals, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the blood. Results. Patients with IHD, compared with the control group: (1) had higher levels of SOD, CAT, myristic, palmitic, palmitoleic, and octadecenoic FAs; (2) had lower levels of GPx, α-linolenic, docosapentaenoic, docosahexaenoic, and arachidonic FAs. In subgroup A there were found: (1) negative associations of SOD—with linoleic, eicosatrienoic, arachidonic, eicosapentaenoic, docosapentaenoic and docosahexaenoic FAs, positive associations—with palmitic acid; (2) positive correlations of CAT level with palmitoleic and stearic acids; (3) negative associations between of GPx and palmitic, palmitoleic, stearic and octadecenoic FAs. Conclusions: Changes in the levels of antioxidant enzymes, and a disbalance of the FAs profile, probably indicate active oxidative processes in the body and may indicate the presence of atherosclerotic changes in the vessels.

Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis

Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.

Circulating ANGPTL3 and ANGPTL4 levels predict coronary artery atherosclerosis severity

Background We investigated the role of ANGPTL3 and ANGPTL4 in atherosclerosis development and determined whether plasma concentrations of ANGPTL3 and ANGPTL4 are related to the degree of coronary stenosis. Methods A total of 305 consecutive patients with angina who underwent diagnostic coronary angiography were enrolled in the study between August 2017 and August 2018. The levels of ANGPTL3 and ANGPTL4 were measured by using competitive ELISA kits. Results According to the degree of coronary artery stenosis, patients were classified into four types: coronary artery stenosis of < 10%, 10-50%, 50-75, and > 75%. The plasma ANGPTL3 level was higher (51.71 ± 52.67 vs. 24.65 ± 10.32 ng/mL, P < 0.001) and that of ANGPTL4 was lower (454.66 ± 269.05 vs. 875.49 ± 961.15 ng/mL, P < 0.001) in the coronary artery stenosis ≥ 10% group than in the < 10% group. ANGPTL3 and ANGPTL4 levels were significantly associated with the severity of coronary vascular stenosis. ROC curve analyses indicated that ANGPTL3 concentrations above 30.5 ng/mL can predict atherosclerosis with a sensitivity of 71.2% and specificity of 75.3%, and that ANGPTL4 levels below 497.5 ng/mL can predict atherosclerosis with a sensitivity of 63.9% and specificity of 74.5%. ANGPTL3 and ANGPTL4 were determined to be independent risk factors for coronary atherosclerosis with odds ratios (ORs) of 0.189 (95% CI 0.097-0.368, P < 0.001) and 3.625 (95% CI 1.873-7.016, P < 0.001), respectively. Conclusions Increased ANGPTL3 or decreased ANGPTL4 shows an association with coronary atherosclerosis and, may become a predictor of coronary atherosclerosis in the future.

Association between rs2228014 Polymorphism of CXCR4 and Coronary Artery Atherosclerosis: A Case-Control Study

Introduction: Atherosclerosis is an inflammatory disease and is one of the leading causes of cardiovascular disease. Vascular plaques are formed on the inner surface of hardened arteries and gradually develop, reducing the diameter of the arteries. CXCR4 is one of the most important chemokine receptors, whose presence has been confirmed in cardiac plaques. Our aim was to determine the relationship between genetic diversity of CXCR4 gene (rs2228014) and atherosclerosis among the population of patients. Methods: The present study included 254 participants who referred to the Cardiac Angiography Department of Afshar Hospital in Yazd City. The main criteria for admission to the case group were coronary artery stenosis with angiography testing, and in the control group, the clients did not have coronary artery disease. The age and sex matching of the two groups were considered. Blood specimens were taken, and after DNA extraction, the SNP genotype of the CXCR4 gene was determined using ARMS-PCR. Statistical analysis of the data carried out using SPSS software version 19 and Chi-square test. Results: Genetic models of rs2228014 variant were evaluated in patients with atherosclerosis in comparison with the control group and a significant difference between allelic (P = 0.333), homozygous (P = 0.087), heterozygous (P = 849.0), dominant (P = 0.570) and recessive (P = 0.086) genetic models of rs2228014 polymorphism was not observed. Conclusion: In the current study, no significant difference was observed between genetic models of rs222801 polymorphism in patients with atherosclerosis and healthy individuals. Based on our findings, the rs222801 polymorphism of the CXCR4 gene might not be considered as a predisposing factor for atherosclerosis.

Late Cardiac Pathology in Severe Covid-19. A Postmortem Series of 30 Patients

The role of SARS-CoV-2 as a direct cause in the cardiac lesions in patients with severe COVID-19 remains to be established. Our objective is to report the pathological findings in cardiac samples of 30 patients who died after a prolonged hospital stay due to Sars-Cov-2 infection. We performed macroscopic, histological and immunohistochemical analysis of the hearts of 30 patients; and detected Sars-Cov-2 RNA by RT-PCR in the cardiac tissue samples. The median age of our cohort was 69.5 years and 76.6% were male. The median time between symptoms onset and death was 36.5 days. The main comorbidities were arterial hypertension (13 patients, 43.3%), dyslipidemia (11 patients, 36.7%), cardiovascular conditions (8 patients, 26.7%), and obesity (8 patients, 26.7%). Cardiovascular conditions included ischemic cardiopathy in 4 patients (13.3%), hypertrophic cardiomyopathy in 2 patients (6.7%) and valve replacement and chronic heart failure in one patient each (3.3%). At autopsy, the most frequent histopathological findings were coronary artery atherosclerosis (8 patients, 26.7%), left ventricular hypertrophy (4 patients, 13.3%), chronic epicardial inflammation (3 patients, 10%) and adipose metaplasia (2 patients, 6.7%). Two patients showed focal myocarditis, one due to invasive aspergillosis. One additional patient showed senile amyloidosis. Sars-Cov-2 RNA was detected in the heart of only one out of 30 patients, who had the shortest disease evolution of the series (9 days). However, no relevant cardiac histological alterations were identified. In present series, cardiac pathology was only modest in most patients with severe COVID-19. At present, the contribution of a direct effect of SARS-CoV-2 on cardiac lesions remains to be established.

Biological markers of endothelial dysfunction and fibrosis, macro- and microcirculation alterations in patients with obstructive and nonobstructive coronary artery disease and diabetes mellitus

Aim of the study To analyze the association of biological markers levels of endothelial dysfunction and fibrosis with macro- and microcirculation alterations in patients with obstructive and nonobstructive coronary artery disease (CAD) and type 2 diabetes mellitus (DM). Methods 52 patients with CAD were enrolled and divided into 4 groups: 19 patients with nonobstructive CAD (1–49% stenosis) without DM (1 group: 4 men, age 64.89±7.61, body mass index (BMI) 28.14±3.69 kg/m2); 13 patients with obstructive CAD (≥50% stenosis) without DM (2 group: 9 men, age 66.92±7.02, BMI 30.4±5.91 kg/m2); 10 patients with obstructive CAD (3 group: 4 men, age 63.4±10.37, BMI 31.7±4.81kg/m2) and 10 patients with nonobstructive CAD with DM (4 group: 3 men, age 64.6±5.32, BMI 33.74±3.25 kg/m2). Patients were matched for age, sex and BMI. All patients underwent coronary angiography or coronary computed tomography angiography. Biological markers levels (E-selectin, ng/ml; tissue inhibitor of metalloproteinase 1 (TIMP-1), ng/ml) were measured using ELISA. To determine arterial damage in both macro- and microcirculation, digital reactive hyperemia photoplethysmography were performed. Endothelial function of small (Occlusion Index, OI) and large vessels (Phase Shear, PS, ms) were analyzed. Vascular remodeling of aorta (Stiffness Index, aSI, m/s) and arterioles (Reflection Index, RI, %) were studied. Results The elevation of E-selectin (1 – 21.6 [18.7; 30.4]; 2 – 31.5 [20.1; 36.9]; 3 – 42.25 [29.9; 55.3]; 4 – 42.1 [33.1; 46.5]) and TIMP-1 (1 – 416 [376; 481]; 2 – 478 [381; 539]; 3 – 534 [490; 579]; 4 – 590 [520; 782]) levels were found in all groups. Statistical analysis revealed significant differences between TIMP-1 (p1–3=0.004; p1–4=0.003) and E-Selectin (p1–3=0.013; p1–4=0.01) levels. Remodeling of large vessels was detected only in patients with obstructive CAD without DM and nonobstructive CAD with DM (2 – aSI, 9.05 [7.08; 10.58]; 3 – aSI, 8.2 [7.6; 11]). Patients in all groups had endothelial dysfunction of large vessels (PS, 1 – 5.1 [1.75; 7.75]; 2 – 6.45 [5.53; 9.03]; 3 – 7.65 [13.4; 9.5]; 4 – 4.6 [0.7; 8.1] and arterioles (IO; 1 – 1.5 [1.38; 1.78]; 2 – 1.4 [1.26; 1.53]; 3 – 1.4 [1.2; 1.7]; 4 – 1.3 [1.2; 2.0]). Structural disorders of arterioles were found in all groups, except for patients with obstructive CAD without DM (RI, 1 – 36.95 [23.4; 52.65]; 2 – 28.25 [23.35; 53.75]; 3 – 41.15 [26.5; 55]; 4 – 44.7 [20; 54.5]. The data did not show significant differences between the study groups. Conclusions The data showed that biological markers levels of endothelial dysfunction and fibrosis were increased in all groups. Significant differences revealed between the levels of E-selectin and TIMP-1 in patients with nonobstructive CAD without DM and patients with CAD and DM, regardless of the degree of stenosis. All patients had functional changes of large vessels and arterioles regardless of the severity of coronary artery atherosclerosis and presence of DM. FUNDunding Acknowledgement Type of funding sources: None.

Is there association between epicardial obesity and the severity of coronary artery atherosclerosis?

Background To assess the diagnostic capabilities of the ultrasound method for estimation of the epicardial fat (EF) and evaluate the association of the thickness of EF and the severity of coronary atherosclerosis in coronary heart disease (CHD) patients. Methods 461 people (age Me 58 years, Q1=52; Q3=64) were examined: 182 patients with CHD (age Me 61 years, Q1=56; Q3=66; 72% men), 279 control patients without CHD, undergoing heart valve surgery (age Me 55 years, Q1=51; Q3=59; 51% men). The severity of coronary artery lesions was assessed according to the current 2013 ESC Guidelines (&gt;50% for the left main coronary artery and &gt;70% for other coronary arteries). Coronary angiography, heart computer tomography (CT), echocardiography (ECHO) were estimated. Statistical data analysis (SPSS, version 17.0, USA). Results In CHD patients the volume of EF (heart CT) was significantly higher than in patients without CHD (167.0 cm3 (128,9; 167,1) and 89.1 cm3 (62,7; 102,7), z=−7.060, p&lt;0.001). The thickness of EF in the area of atrioventricular sulcus (according to the ECHO) most closely corresponds to the volume of EF (according to heart CT), ρ=0.731, p&lt;0.001. According to multiple linear regression analysis, it was found that in patients with CHD, an increase in age by 1 year is associated with an increase in the volume of EF by 1.4 cm3 (95% CI from 1.0 to 1.9). The volume of EF in CHD patients is meen 56.7±3.1 cm3 (95% CI from 46.6 to 66.8) more than in patients without CHD. The correlation between the number of coronary arteries affected by atherosclerosis and the values of the parameters characterizing the EF was not revealed. Conclusion The volume of epicardial fat measured by cardiac CT in patients with CHD is greater than epicardial fat volume measured in subjects without ischemic heart disease. The volume of epicardial adipose tissue measured by heart CT in patients with CHD increases with age. The number of coronary arteries affected by atherosclerosis in CHD patients does not depend on the thickness and volume of epicardial adipose tissue. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): The study has been supported by the grant from the Ministry of Science and Higher Education of the Russian Federation