The anti-inflammatory effects of exercise training promote atherosclerotic plaque stabilization in apolipoprotein E knockout mice with diabetic atherosclerosis

Physical exercise is the cornerstone of cardiovascular disease treatment. The present study investigated whether exercise training affects atherosclerotic plaque composition through the modification of inflammatory-related pathways in apolipoprotein E knockout (apoE-/-) mice with diabetic atherosclerosis. Forty-five male apoE-/- mice were randomized into three equivalent (n=15) groups: control (CO), sedentary (SED), and exercise (EX). Diabetes was induced by streptozotocin administration. High-fat diet was administered to all groups for 12 weeks. Afterwards, CO mice were euthanatized, while the sedentary and exercise groups continued high-fat diet for 6 additional weeks. Exercising mice followed an exercise program on motorized-treadmill (5 times/week, 60 min/session). Then, blood samples and atherosclerotic plaques in the aortic root were examined. A considerable (P<0.001) regression of the atherosclerotic lesions was observed in the exercise group (180.339±75.613 x103μm2) compared to the control (325.485±72.302 x103μm2) and sedentary (340.188±159.108 x103μm2) groups. We found decreased macrophages, matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-8 and interleukin-6 (IL-6) concentrations (P<0.05) in the atherosclerotic plaques of the exercise group. Compared to both control and sedentary groups, exercise training significantly increased collagen (P<0.05), elastin (P<0.001), and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) (P<0.001) content in the atherosclerotic plaques. Those effects paralleled with increased fibrous cap thickness and less internal elastic lamina ruptures after exercise training (P<0.05), while body-weight and lipid parameters did not significantly change. Plasma MMP-2 and MMP-3 concentrations in atherosclerotic tissues followed a similar trend. From our study we can conclude that exercise training reduces and stabilizes atherosclerotic lesions in apoE-/- mice with diabetic atherosclerosis. A favorable modification of the inflammatory regulators seems to explain those beneficial effects

Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: a randomised remote conditioning study

Aims: Remote ischemic conditioning (RIC) alleviates ischemia–reperfusion injury via several pathways, including micro-RNAs (miRs) expression and oxidative stress modulation. We investigated the effects of RIC on endothelial glycocalyx, arterial stiffness, LV remodelling, and the underlying mediators within the vasculature as a target for protection. Methods and results: We block-randomised 270 patients within 48 h of STEMI post-PCI to either one or two cycles of bilateral brachial cuff inflation, and a control group without RIC. We measured: (a) the perfusion boundary region (PBR) of the sublingual arterial microvessels to assess glycocalyx integrity; (b) the carotid-femoral pulse wave velocity (PWV); (c) miR-144,-150,-21,-208, nitrate-nitrite (NOx) and malondialdehyde (MDA) plasma levels at baseline (T0) and 40 min after RIC onset (T3); and (d) LV volumes at baseline and after one year. Compared to baseline, there was a greater PBR and PWV decrease, miR-144 and NOx levels increase (p  15% (odds-ratio of 3.75, p = 0.029). MiR-144 and PWV changes post-RIC were interrelated and associated with LVESV reduction at follow-up (r = 0.40 and 0.37, p < 0.05), in the single-cycle RIC. Conclusion: RIC evokes “vascular conditioning” likely by upregulation of cardio-protective microRNAs, NOx production, and oxidative stress reduction, facilitating reverse LV remodelling

The impact of type 2 diabetes and atorvastatin treatment on serum levels of MMP-7 and MMP-8

Aim: Novel members of matrix metalloproteinases (MMPs), MMP-7 and MMP-8, have emerged as predictors of cardiovascular events. Our study aimed to evaluate serum MMP-7 and MMP-8 concentrations in patients with type 2 diabetes mellitus (T2DM) and the effects of atorvastatin on them. Methods: We enrolled 85 statin-free subjects with concomitant T2DM and hypercholesterolemia, but without overt micro-/macro-vascular complications (diabetic group - DG). 42 age- and gender-matched healthy subjects without chronic diseases or therapy served as healthy group (HG). All diabetic patients received fix dose of atorvastatin (20 mg/day). Clinical and anthropometrical parameters, lipids, fasting plasma glucose (FPG), serum MMP-7, MMP-8, their inhibitor (TIMP-1), IL-18, hsCRP and insulin resistance (HOMA-IR) were assayed at baseline in all participants and after 3 months in the DG. Results: At baseline, DG showed higher levels of BMI, systolic blood pressure, insulin resistance and FPG compared to HG (p&amp;lt;0.05). Similarly, DG appeared with elevated concentrations of MMP-7 (4.28±1.01 ng/ml vs 2.63±1.11 ng/ml, p&amp;lt;0.001), MMP-8 (73.07±21.96 ng/ml vs. 21.27±10.49 ng/ml, p&amp;lt;0.001) and inflammatory markers (WBC, hsCRP, IL-18, p&amp;lt;0.010). Importantly, atorvastatin treatment improved lipid profile, significantly reduced the concentrations of MMP-7, MMP-8 and inflammatory markers (p&amp;lt;0.01). Moreover, there was considerable suppression of both MMP-7/TIMP-1 and MMP-8/TIMP-1 ratios (p&amp;lt;0.01). In standard multiple regression analysis, the atorvastatin-induced reduction in MMP-7 was independently associated with LDL and IL-18 downregulation (R2=0.648, p=0.017). Similarly, IL-18 changes emerged as an independent determinant of MMP-8 alterations (R2=0.678, p=0.007). Conclusions: Hypercholesterolemic patients with T2DM showed elevated MMP-7 and MMP-8 serum concentrations. Atorvastatin reduced the latter concentrations and their ratio with TIMP-1. Those effects seemed mediated by the atorvastatin-induced suppression of inflammatory mediators. ClinicalTrials.gov Identifier: NCT00636766 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York

Surgery for metachronic metastasized esophageal cancer

Esophageal cancer (EC) is an aggressive type of malignancy which is nowadays responsible for 16,000 deaths solely in the USA region and 400,200 deaths in Western countries. Despite the fact that there have been significant improvements in multimodality therapies, operative and perioperative management, the overall 5-year survival rate ranges from 25–50%, and a significant proportion (30–50%) of patients will develop recurrence within months or few years after esophagectomy. The aim of this article is to review the current evidence on the role of surgical treatment for metachronous oligometastases from EC. A literature search about surgical management of metachronous EC metastases was conducted and the results from the most relevant studies are presented. The types and locations of recurrence considerably differ among individual patients mainly categorized as locoregional at the site of anastomosis, lymphatic and hematogenic metastasis, or a combination of these. The standard treatment for EC patients experiencing recurrence is currently based on systemic chemotherapy and/or radiotherapy. Recent literature shows that in highly selected individuals, surgical resection of oligometastatic disease might lead to improved outcomes as far as survival rates are concerned over medical management alone. Nowadays, only few retrospective studies with small number of patients report the results of surgical treatment in oligometastatic disease. Thus, the low quality of existing scientific data is not yet possible to define the role of surgery as a part of multimodality treatment in patients with isolated distant recurrence in solid organs. However, a well-selected group of patients, especially those with a disease-free interval of more than 12 months with isolated one-field lymph node (LN) metastasis or solitary lesions in organs, might benefit from surgical management. © Annals of Esophagus. All rights reserved

The differential anti-inflammatory effects of exercise modalities and their association with early carotid atherosclerosis progression in patients with Type 2 diabetes

Objective: Adipokines, visfatin, apelin, vaspin and ghrelin have emerged as novel cardiovascular risk factors. We aimed to evaluate the effects of different exercise modalities on the aforementioned novel adipokines and carotid intima-media thickness in patients with Type 2 diabetes mellitus. Methods: One hundred patients with Type 2 diabetes were equivalently (n = 25) randomized into four groups: (1) a control group with patients encouraged to perform self-controlled exercise; (2) a supervised aerobic exercise group (exercise four times/week, 60 min/session, 60-75% of maximum heart rate); (3) a resistance training group (60-80% baseline maximum load achieved in one repetition); and (4) a combined aerobic exercise plus resistance training group, as in groups 2 and 3. All participants had HbA1c levels ≥ 48 mmol/mol (≥ 6.5%), without overt diabetic vascular complications. Blood samples, clinical characteristics, peak oxygen uptake and carotid intima-media thickness measurements were obtained at baseline and at the end of the study, after 6 months. Results: At baseline, there were non-significant differences between groups. All active groups significantly ameliorated glycaemic profile, insulin sensitivity and triglycerides levels compared with the control group (P &amp;lt; 0.05). Aerobic training further improved lipids, systolic blood pressure and exercise capacity compared with the resistance training and the control groups (P &amp;lt; 0.05). Moreover, high-sensitivity C-reactive protein and visfatin decreased, while vaspin and apelin circulating levels increased within the aerobic exercise group and the aerobic exercise plus resistance training group, and compared with the other groups (P &amp;lt; 0.05). Within- and between-group comparisons showed negligible alterations in ghrelin serum levels and body weight after all exercise modalities. Finally, aerobic training attenuated the carotid intima-media thickness progression (0.017 ± 0.006 mm) compared with the control subjects (0.129 ± 0.042 mm, P &amp;lt; 0.001). That effect was independently associated with visfatin and amelioration of peak oxygen uptake. Conclusions: In subjects with Type 2 diabetes, all exercise training modalities improved metabolic profile. Importantly, aerobic training predominantly ameliorated adipokines concentrations and carotid intima-media thickness progression. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK

Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization

Objective: Atherosclerotic plaque stabilization is a promising strategy to prevent cerebrovascular events in patients with carotid atherosclerosis. Vascular calcification inhibitors, known osteopontin (OPN) and osteoprotegerin (OPG), have emerged as novel cardiovascular biomarkers. This open-label, prospective study aimed to examine whether aggressive lipid-lowering therapy with atorvastatin is more effective than moderate lipid-lowering in increasing carotid plaque echogenicity, assessed by Gray-Scale Median (GSM) score and suppressing serum OPN and OPG levels in patients with moderate carotid stenosis. Methods: One hundred forty patients (64 males, 76 females), aged 50 to 75 years, with carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET]: 30%-60% for symptomatic and 30%-70% for asymptomatic), but without indications for surgical intervention, were enrolled. Patients with coronary heart disease, renal failure, hypothyroidism, osteoporosis, and ongoing use of statins were excluded. Patients were randomly assigned to: Group A (N = 70): Moderate lipid-lowering therapy with low-dose of atorvastatin (10 mg-20 mg) to target LDL-C &amp;lt;100 mg/dL. Group B (N = 70): Aggressive lipid-lowering therapy with high-dose of atorvastatin (80 mg) to target LDL-C &amp;lt;70 mg/dL. Blood pressure, lipid and glycemic indexes, hsCRP, serum OPN, and OPG were measured at baseline and after 12 months as well as the GSM score. Independent samples t test, paired samples t test, Pearson correlation, and multiple regression analysis were used (P &amp;lt; .05). Results: There were no significant differences between groups at baseline. Three patients in group A experienced either cerebrovascular or cardiac ischemic attacks, while two patients in group B underwent coronary angioplasty during follow-up. Group B showed a more pronounced improvement in total cholesterol and LDL-cholesterol compared with group A (P &amp;lt; .05). Moreover, atorvastatin treatment suppressed serum hsCRP, OPN, and OPG levels from baseline in both groups (P &amp;lt; .001). Notably, aggressive treatment decreased OPN (P = .012) and OPG (P = .025) levels to a greater degree compared with moderate treatment. Similarly, GSM score was remarkably increased in both groups, but that augmentation was greater in group B (from 66.39 ± 23.66 to 100.4 ± 25.31) than in group A (from 64.4 ± 23.62 to 85.39 ± 20.21) (P = .024). No change in the degree of carotid stenosis was noted in both treatment arms. Importantly, the aforementioned reduction in OPN (r = -0.517, P = .024) and OPG (r = -0.312, P = .008) levels was inversely associated with GSM score changes in univariate and standard multiple regression analysis (R2 = 0.411, P = .021). Conclusions: Among patients with moderate carotid stenosis, an aggressive atorvastatin regimen enhanced carotid plaque echogenicity and reduced serum OPN and OPG levels to a greater extent than respective moderate atorvastatin therapy. Most importantly, those atorvastatin-induced effects were associated with OPN and OPG suppression in a dose-dependent manner. © 2010 Society for Vascular Surgery

The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerability

Objective: Osteopontin (OPN) and osteoprotegerin (OPG) are well-known vascular calcification inhibitors, which have been recently demonstrated to correlate with inflammation and cardiovascular events incidence. The aim of this cross-sectional study is to survey whether OPN and OPG are involved in carotid plaque vulnerability. For this reason, we assessed serum OPN and OPG levels in patients with carotid stenosis, and we explored their relationship with carotid plaque echogenicity and subsequent cerebrovascular ischemic events. Methods: A total of 164 Whites were selected from a large cohort of 297 subjects to participate. In particular, 114 patients (61 men, 53 women), aged 55 to 80, had recently-diagnosed ICA stenosis higher than 50%. A group of 50 age-, sex-, and body mass index (BMI)-matched healthy individuals served as healthy controls. Patients with renal failure, hypothyroidism, osteoporosis, and lipid-lowering therapy were excluded. Images of both carotids were obtained from all participants using a high-resolution color duplex ultrasound and the gray-scale median (GSM) score was calculated. Brain computed tomography (CT), and magnetic resonance imaging (MRI) scans when CT was questionable, were performed on all patients with carotid stenosis. Clinical parameters, lipid and glycemic indexes, hsCRP, fibrinogen, white blood cells (WBC) count, OPN, and OPG were measured. Independent t test, one-way ANOVA, Pearson correlation, and multiple regression analysis were used for statistical analysis. Results: Among patients with carotid stenosis, 60 had history of ipsilateral stroke or TIA and positive CT or MRI findings (group A), while 54 had no neurological symptoms and negative CT and MRI scan (group B). Overall, patients with carotid stenosis showed worse lipid profile and increased waist circumference, blood pressure, hsCRP, fibrinogen, WBC count, OPN, and OPG levels compared with healthy subjects (group C) (P &amp;lt;.05). Statistical analysis revealed that group A had significantly lower levels of GSM than group B (57.41 ± 38.19 vs 76.32 ± 36.72; P = .008) and higher levels of hsCRP, OPN, and OPG than groups B and C (P &amp;lt; .05). Concerning the latter, biochemical markers group B showed only elevated OPG levels compared with group C (P = .038). Notably, GSM was considerably associated with serum OPN and OPG and waist circumference in patients with carotid atherosclerosis in univariate (r = -0.333; P = .032, r = -0.575; P &amp;lt; .001, r = -0.590; P =.006, respectively) and multiple regression analysis (R2 = 0.445; P =.006). Conclusions: The present study demonstrated elevated serum OPN and OPG levels in patients with carotid stenosis and documented an independent association between these biochemical markers, GSM and carotid-induced symptomatology. Therefore bone-matrix proteins combined with GSM could be potential markers for vulnerable carotid plaques. © 2008 The Society for Vascular Surgery

Effects of rosiglitazone/metformin fixed-dose combination therapy and metformin monotherapy on serum vaspin, adiponectin and IL-6 levels in drug-naïve patients with type 2 diabetes

Objective: Vaspin, adiponectin and interleukin-6 (IL-6) constitute novel adipose-tissue derivatives, known as adipokines, which mediate insulin resistance. The aim of the present study was to evaluate the effects of metformin and rosiglitazone on serum levels of those novel adipokines in drug-naïve patients with type 2 diabetes mellitus (T2DM). Methods: 140 patients with T2DM, already treated with diet, but without adequate glycemic control (HbA1c&amp;gt;7%), were randomly assigned to: RSG+MET group, (n=70): Combination therapy with fixed dose of 4 mg rosiglitazone plus 500 mg metformin. MET group, (n=70): Half-maximum dose of metformin monotherapy (1 700 mg/day). Before and after 6-month treatment, body-mass index (BMI), blood pressure (BP), fat-mass, fasting plasma glucose (FPG), HbA1c, insulin resistance indexes (HOMA-IR, insulin), lipids, high-sensitivity CRP (hsCRP), vaspin, adiponectin, and interleukin-6 (IL-6) were measured. Results: Glucose regulation and insulin resistance were equivalently improved from baseline within both groups (p&amp;lt;0.05). There was a considerable amelioration of hsCRP, WBC, adiponectin, IL-6, systolic and diastolic BP with rosiglitazone/metformin combined treatment as compared to baseline (p&amp;lt;0.05) and MET group (p&amp;lt;0.05). In contrast, metformin monotherapy significantly reduced BMI (p&amp;lt;0.001), total-cholesterol (p=0.012) and LDL (p=0.020) levels compared to RSG+MET group. Importantly, serum vaspin concentration was equivalently decreased from baseline in both RSG+MET (0.96±0.75 ng/ml, p&amp;lt;0.001) and MET (0.92±0.57 ng/ml, p=0.001) group. The aforementioned vaspin changes correlated with changes in WHR, HbA1c, FPG, HOMA-IR, insulin, IL-6 (only in the RSG+MET group) and fat-mass. In standard multiple regression analysis, FPG, HbA1c, HOMA-IR and insulin remained independent determinants of serum vaspin levels changes (R2=0.836, p=0.004). Conclusions: Both rosiglitazone/metformin combination therapy and metformin monotherapy decreased serum vaspin levels through glucose and insulin sensitivity regulation, while they exerted differential effects on adiponectin, IL-6 and other cardiovascular risk factors in drug-naïve patients with T2DM. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York

Differential expression patterns of Toll Like Receptors and Interleukin-37 between calcific aortic and mitral valve cusps in humans

Background: Significant differences are mentioned in the progress of calcification between aortic and mitral valve. Evidence of inflammation in calcific aortic and mitral valve disease suggests that pathways of Toll Like Receptors (TLR) and Interleukin (IL)-37 expression may contribute to this process. We sought to investigate the role of TLR-mediated inflammatory response and IL-37 pathway expression on aortic and mitral valve calcification. Material and methods: One-hundred twenty stenotic valve cusps/leaflets (60 aortic, 60 mitral) were excised during surgery and were collected for histological, immunohistochemistry and morphometric analysis at our department. After total RNA isolation from a second part of valve cusps/leaflets, cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) protocols were performed and relative mRNA levels of target genes were assessed. Results: By histological analysis, the anti-inflammatory IL-37 levels were increased in mitral valve leaflets (MVL) compared to aortic valve cusps (AVCu) while all other biomarkers, including TLR, presented a reverse pattern with decreased levels as compared to AVCu. In terms of calcification biomarkers, only osteopontin differed between AVCu and MVL. mRNA analysis confirmed increased expression of IL-37 and decreased levels of TLR in MVL compared to AVCu. Conclusions: Stenotic cusps of aortic valves express lower IL-37 and increased TLRs levels than stenotic mitral valve leaflets, suggesting a differential pro-calcification and pro-inflammatory profile between the two valves. This may explain the higher incidence of calcification of AVCu than MVL and offer therapeutic considerations. © 2019 Elsevier Lt