Silibinin augments the effect of clopidogrel on atherosclerosis in diabetic ApoE deficiency mice

BACKGROUND: Diabetes mellitus (DM) abolishes the antithrombotic effect of Clopidogrel. Here, we investigated the synergistic effect of Silibinin on Clopidogrel-mediated atherosclerosis treatment in diabetic mice. METHODS: ApoE–/– mice were fed with high-fat diet (HFD) to establish the atherosclerotic model with diabetes. Animals were treated with Clopidogrel, Silibinin, or the combined to evaluate the protective effects on atherosclerosis and diabetes through Oil-red-O staining, qRT-PCR, Western blot, and metabolic measurements. Platelet activation and aggregation ex vivo assays were performed to detect the anti-thrombotic effect of different administrations. RESULTS: Silibinin significantly enhanced the inhibitory effect of Clopidogrel on atherosclerosis in DM mice. Co-administration of Silibinin with Clopidogrel remarkedly reduced the aortic lesion, inflammation, and endothelial dysfunction in aorta roots, and diabetic symptoms were significantly improved by the Silibinin-Clopidogrel treatment in HFD-fed ApoE–/– mice. Interestingly, the anti-thrombotic effect of Clopidogrel was further augmented by the Silibinin treatment in atherosclerotic mice. CONCLUSION: In atherosclerotic mouse model, Silibinin significantly improves the effect of Clopidogrel on atherosclerosis.

Abstract P473: Obstructive Sleep Apnea Results In Microbial Bile Acid Biotransformations To Promote Atherosclerosis

Obstructive sleep apnea (OSA) is an independent exacerbator of cardiovascular disease (CVD). However, it is unclear how OSA or it’s characteristic components, intermittent hypoxia and hypercapnia (IHC), increase CVD risk. Our previous work has shown that IHC reproducibly changes the gut microbiome dynamics in murine models of atherosclerosis and that these changes could affect host cardiovascular physiology through bile acids and phosphocholines. In our initial targeted metabolomics approach, changes in particular bile acids, such as taurocholic acid, taurodeoxycholic acid, and muricholic acid, were associated with and were predictive of IHC exposure in atherosclerotic Ldlr-/- mice. In a more recent study, we identified the formation of novel, microbially-synthesized conjugated bile acids by the gut microbiome that are more potent farnesoid X receptor agonists than other previously described bile acids, and thus, potentially can affect atherosclerosis formation. To determine whether these novel bile acids are associated with IHC-induced atherosclerosis, we characterized luminal bile acid changes in Ldlr-/- mice in an OSA model. We hypothesize that IHC alters the amount of microbially-synthesized novel bile acids and that these bile acids are associated with IHC-induced atherosclerosis. To test this hypothesis, we subjected atherogenic diet-fed Ldlr-/- mice to either room-air (control) or IHC conditions (n=10/condition) and assessed atherosclerotic lesion formation after 12 weeks post-diet. Mice under IHC conditions had significantly higher aortic lesion formation compared to controls. Assessment of fecal bile acid metabolites indicated changes in novel bile acid levels under IHC conditions. Moreover, correlational analysis showed that these novel bile acid changes were positively correlated with atherosclerotic lesion amounts, mainly driven by IHC conditions. Our results demonstrate that bile acid changes through microbial biotransformations occur under IHC conditions and could be the mechanistic link between OSA-induced microbiome changes and atherosclerosis.

The effects of olive oil and cholesterol enriched diets on aortic fatty streak development and lipid peroxidation in rabbits

Background and aim: High plasma cholesterol levels, mainly low-density lipoprotein-cholesterol (LDL) is a widely recognized major risk factor for coronary heart disease (CHD). According to epidemiologic studies’ findings, people from the Mediterranean countries have lower CHD rates than other countries; in these countries the usual diet is high in olive oil. The present study compares the effects of a cholesterol-enriched diet with or without adding olive oil on serum lipoproteins, lipid peroxidation, and atherosclerosis development. Methods: Twenty Dutch male rabbits were categorized into four groups (one group as control, and others as experimental). They received one of control (CON), olive oil-rich (OIL), cholesterol-rich (CHOL), and cholesterol + olive oil (COIL) diet for 12 weeks. Fasting blood samples from the heart were collected at the beginning and the end of the experimental period. Results: Means of serum lipids were not significantly different at the beginning of the experimental period. After the intervention, significant differences were shown in total cholesterol (TC) (CON: 27.75 ± 4.83, OIL: 19.75 ± 2.62, CHOL: 1757.20 ± 149.62, COIL: 2906.40 ± 421.01; P < 0.001), high-density lipoprotein-cholesterol (HDL-C) (CON: 16 ± 1.47, OIL: 10.25 ± 1.70, CHOL: 22.2 ± 3.83, COIL: 28.60 ± 6.27; P = 0.04), triglyceride (CON: 65 ± 12.21, OIL: 71.75 ± 6.23, CHOL: 244.2 ± 44.45, COIL: 775.6 ± 105.07; P < 0.001), and MDA between groups (CON: 0.57 ± 0.10, OIL: 0.63 ± 0.15, CHOL: 5.62 ± 0.18, COIL: 2.06 ± 0.64; P < 0.001). The comparison of CHOL and the COIL groups showed a higher mean of malondialdehyde (MDA) in group CHOL (4.47 ± 0.28 vs 1.1 ± 0.6; P < 0.001). Aortic lesion was not observed in CON and OIL groups. Aortic lesion degree was significantly lower in the COIL group compared to the CHOL (2.4 ± 0.6 vs 3.66 ± 0.33; P = 0.02). Conclusions: These findings showed the preventive effect of olive oil on atherosclerosis development. However, it is independent of the plasma lipoprotein effect, and olive oil probably acts on arteries directly.

Dietary Avian Proteins Are Comparable to Soybean Proteins on the Atherosclerosis Development and Fatty Liver Disease in Apoe-Deficient Mice

Background and aim: The type and amount of dietary protein has become a topic of renewed interest in light of their involvement in metabolic diseases, atherosclerosis and thrombosis. However, little attention has been devoted to the effect of avian proteins despite their wide human consumption. The aim was to investigate the influence of chicken and turkey as sources of protein compared with that of soybean on atherosclerosis and fatty liver disease. Methods and results: To this purpose, male and female Apoe-deficient were fed purified Western diets differing in their protein sources for 12 weeks. After this period, blood, liver, aortic tree and heart base samples were taken for analyses of plasma lipids and atherosclerosis. Plasma triglycerides, non-esterified fatty acids, esterified cholesterol levels and radical oxygen species in lipoproteins changed depending on the diet and sex. Females consuming the turkey protein-containing diet showed decreased atherosclerotic foci, as evidenced by the en face atherosclerosis analyses. The presence of macrophages and smooth muscle cells in plaques were not modified, and no changes were observed in hepatic lipid droplets in the studied groups either. Paraoxonase activity was higher in the group consuming turkey protein without sex differences, but only in females, it was significantly associated with aortic lesion areas. Conclusions: Compared to soybean protein, the consumption of avian proteins depending on sex resulted in similar or lower atherosclerosis development and comparable hepatic steatosis.

Efficacy of Levosimendan vs. Dobutamine in the Treatment of Ventricular Dysfunction in Patients Subjected to Aortic Valve Replacement

Introduction: The ischaemic lesion due to coarctation of the aorta, inadequate myocardial protection, cardioplegic solutions, hypothermia and other factors can contribute to alterations in the myocardial contractility in the postsurgical period of valve replacement. Objective: To determine the efficacy of Levosimendan vs. Dobutamine in the treatment of ventricular dysfunction in patients subjected to aortic valve replacement. Materials and Methods: Quasi-experimental research was carried out on 60 patients diagnosed with stenosis, insufficiency or double aortic lesion subjected to aortic valve replacement under general anaesthesia. Cohorts were randomly assigned, group I (n=30) Dobutamine at 7.5 μg/kg/min, and group II (n=30) Levosimendan infusion of 0.2 μg/kg/min. The following criteria were monitored in both groups arterial tension, heart rate, oxygen saturation, and the hemodynamic variables with central venous catheter 7 Fr Arrow and Swan Ganz catheter 7Fr Edwards via internal jugular. For the statistical analysis, the variables were analysed using the student’s t-test P<0.05. Results: The average age was 57.02±13 years. The average dose was 3-5 gammas for Dobutamine and 0.1-0.2 gammas for Levosimendan. The left ventricular ejection fractions were 56.2±11% and 56.4±10%, respectively. In the postsurgical setting, significant differences were observed only in the capillary pressure (17.03±5.8 vs. 13.87±2.9 cmH2O, p<0.01). The Levosimendan group (64.1±13.6 vs. 57.6±12.9%, p=0.06). Conclusion: The administration of Levosimendan during the perioperative aortic valve replacement was associated with a tendency of deterioration of the ejection fraction in the left ventricle compared to the use of Dobutamine.

PROSE – Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation (EDIT – March 21,2021& April 16,2021)Part 1 – Preoperative Demographics and Preoperative and Operative Risk Factors

ObjectivesThe PROSE trial purpose is to investigate whether the incidence of thromboembolic – related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc. – On-X) compared with a previous generation mechanical prosthesis (St Jude Medical – SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. MethodsThe PROSE study was conducted in 29 worldwide centres and incorporated 854 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors.ResultsThe total patient population (854) incorporated On-X population (461) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic & mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. ConclusionsThe preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations.

Bicuspid Aortic Valve: Morphology, Clinic, Diagnosis, Complications

Bicuspid aortic valve refers to common (0.5-2% of the population) congenital heart defects that are asymptomatic throughout life, with valve dysfunction and/or aortopathy (pathia- from Greek pathos disease), manifested by expansion, aneurysm or dissection of the vessel. The pathogenesis of the formation of a bicuspid valve is unknown, a genetic component is noted, since the defect develops as sporadic, familial, in combination with other congenital heart defects and with hereditary connective tissue disorders. Morphogenetic studies suggest that different phenotypes of bicuspid aortic valve can be considered as etiologically different diseases, with valve dysfunction or valve dysfunction and aortopathy. Aortic lesion is characterized by phenotypic heterogeneity due to genetic or hemodynamic features. Researchers are discussing the relationship between the phenotype of the bicuspid aortic valve and aortopathy to predict the course of the disease and select the optimal surgical treatment technique. Diagnosis of heart disease is based on the results of an echocardiographic study, magnetic resonance imaging. Surgical treatment is performed for significant hemodynamic disturbances resulting from insufficiency or stenosis of the aortic valve, in cases of infective endocarditis, the risk of which is high, with aneurysm or aortic dissection.

Endovascular repair of ascending aortic diseases with custom-made endografts

OBJECTIVES The aim of this article is to report the mid-term results of ascending thoracic endovascular aortic repair using a custom-made device (CMD). METHODS This was a retrospective study performed at tertiary centres. Nine patients considered unfit for open surgery received elective total endovascular repair of the ascending aorta with a Relay® (Terumo Aortic, Sunrise; FL, USA) CMD: pseudoaneurysn (n = 5), localized dissection (n =3) and contained rupture (n = 1). RESULTS Primary clinical success was achieved in all patients with no major complications and no early conversion to open surgery. All patients were discharged home and independent: median length of stay was 7 days (interquartile range, 6–18). No patient was lost to follow-up at a median 26 months (interquartile range, 12–36). Three patients died 2, 6 and 24 months after intervention; 1 was aorta related (late aorto-atrial fistula due to infection that required open surgery). At the last follow-up available, no endoleaks, migrations, fractures or ruptures were observed in the remaining 6 patients. CONCLUSIONS Ascending thoracic endovascular aortic repair with Terumo Aortic CMDs was technically feasible, effective and safe in very selected lesions. CMDs showed good ascending aorta conformability with different configurations and diameters, and satisfactory mid-term durability as shown by both structural integrity and aortic lesion exclusion.

Para-aortic haemangioma mimics paraganglioma on MRI

Here, we report a case of a 70-year-old man referred for an incidentally discovered left renal lesion with peri-aortic lymphadenopathy following a CT scan for back pain. A follow-up MRI scan demonstrated a Bosniak IIF left renal cyst and a T2-hyperintense para-aortic lesion concerning for extra-adrenal paraganglioma (EAP). [131I] Metaiodobenzylguanidine scintigraphy of the para-aortic lesion and urine catecholamines were equivocal. The mass was resected via a robotic approach. Histological examination revealed a haemangioma. Haemangiomas are benign vascular tumours frequently identified on imaging of the liver. Intra-abdominal haemangiomas outside of the liver, however, are rare and may have imaging characteristics that mimic EAP.

Regional Variation in Genetic Control of Atherosclerosis in Hyperlipidemic Mice

Atherosclerosis is a polygenic disorder that often affects multiple arteries. Carotid arteries are common sites for evaluating subclinical atherosclerosis, and aortic root is the standard site for quantifying atherosclerosis in mice. We compared genetic control of atherosclerosis between the two sites in the same cohort derived from two phenotypically divergent Apoe-null (Apoe−/−) mouse strains. Female F2 mice were generated from C57BL/6 (B6) and C3H/He (C3H) Apoe−/− mice and fed 12 weeks of Western diet. Atherosclerotic lesions in carotid bifurcation and aortic root and plasma levels of fasting lipids and glucose were measured. 153 genetic markers across the genome were typed. All F2 mice developed aortic atherosclerosis, while 1/5 formed no or little carotid lesions. Genome-wide scans revealed 3 significant loci on chromosome (Chr) 1, Chr15, 6 suggestive loci for aortic atherosclerosis, 2 significant loci on Chr6, Chr12, and 6 suggestive loci for carotid atherosclerosis. Only 2 loci for aortic lesions showed colocalization with loci for carotid lesions. Carotid lesion sizes were moderately correlated with aortic lesion sizes (r = 0.303; P = 4.6E-6), but they showed slight or no association with plasma HDL, non-HDL cholesterol, triglyceride, or glucose levels among F2 mice. Bioinformatics analyses prioritized Cryge as a likely causal gene for Ath30, Cdh6 and Dnah5 as causal genes for Ath22. Our data demonstrate vascular site-specific effects of genetic factors on atherosclerosis in the same animals and highlight the need to extend studies of atherosclerosis to sites beyond aortas of mice.