The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways

Role of human epicardial adipose tissue–derived miR-92a-3p in myocardial redox state

Background Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. Objectives This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. Methods This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years. Results EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase–derived superoxide (O2.–) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events. Conclusions EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease

Open tension free repair of inguinal hernias; the Lichtenstein technique

BACKGROUND: Recurrences have been a significant problem following hernia repair. Prosthetic materials have been increasingly used in hernia repair to prevent recurrences. Their use has been associated with several advantages, such as less postoperative pain, rapid recovery, low recurrence rates. METHODS: In this retrospective study, 540 tension-free inguinal hernia repairs were performed between August 1994 and December 1999 in 510 patients, using a polypropylene mesh (Lichtenstein technique). The main outcome measure was early and late morbidity and especially recurrence. RESULTS: Inguinal hernia was indirect in 55 % of cases (297 patients), direct in 30 % (162 patients) and of the pantaloon (mixed) type in 15 % (81 patients). Mean patient age was 53.7 years (range, 18 – 85). Follow-up was completed in 407 patients (80 %) by clinical examination or phone call. The median follow-up period was 3.8 years (range, 1 – 6 years). Seroma and hematoma formation requiring drainage was observed in 6 and 2 patients, respectively, while transient testicular swelling occurred in 5 patients. We have not observed acute infection or abscess formation related to the presence of the foreign body (mesh). In two patients, however, a delayed rejection of the mesh occurred 10 months and 4 years following surgery. There was one recurrence of the hernia (in one of these patients with late mesh rejection) (recurrence rate = 0.2 %). Postoperative neuralgia was observed in 5 patients (1 %). CONCLUSION: Lichtenstein tension-free mesh inguinal hernia repair is a simple, safe, comfortable, effective method, with extremely low early and late morbidity and remarkably low recurrence rate and therefore it is our preferred method for hernia repair since 1994

Development of a risk score for early saphenous vein graft failure: An individual patient data meta-analysis.

OBJECTIVES: Early saphenous vein graft (SVG) occlusion is typically attributed to technical factors. We aimed at exploring clinical, anatomical, and operative factors associated with the risk of early SVG occlusion (within 12 months postsurgery). METHODS: Published literature in MEDLINE was searched for studies reporting the incidence of early SVG occlusion. Individual patient data (IPD) on early SVG occlusion were used from the SAFINOUS-CABG Consortium. A derivation (n = 1492 patients) and validation (n = 372 patients) cohort were used for model training (with 10-fold cross-validation) and external validation respectively. RESULTS: In aggregate data meta-analysis (48 studies, 41,530 SVGs) the pooled estimate for early SVG occlusion was 11%. The developed IPD model for early SVG occlusion, which included clinical, anatomical, and operative characteristics (age, sex, dyslipidemia, diabetes mellitus, smoking, serum creatinine, endoscopic vein harvesting, use of complex grafts, grafted target vessel, and number of SVGs), had good performance in the derivation (c-index = 0.744; 95% confidence interval [CI], 0.701-0.774) and validation cohort (c-index = 0.734; 95% CI, 0.659-0.809). Based on this model. we constructed a simplified 12-variable risk score system (SAFINOUS score) with good performance for early SVG occlusion (c-index = 0.700, 95% CI, 0.684-0.716). CONCLUSIONS: From a large international IPD collaboration, we developed a novel risk score to assess the individualized risk for early SVG occlusion. The SAFINOUS risk score could be used to identify patients that are more likely to benefit from aggressive treatment strategies

A novel machine learning-derived radiotranscriptomic signature of perivascular fat improves cardiac risk prediction using coronary CT angiography

Background: Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. Methods and results: We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62–0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P  Conclusion: The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art. </p

Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study

Background: Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. Methods: This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4–5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4–9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. Findings: In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9–63·9], p<0·001) or MACE (12·6 [8·5–18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17–8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93–5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. Interpretation: The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators

Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17//RAC1-mediated activation of NADPH oxidases

Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2–mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans

The impact of G276T and T45G single nucleotide polymorphisms of adiponectin gene on patients with coronary artery disease: effects on inflammation, endothelial function and hemostasis

Background: Adiponectin is an adipokine with an important role in cardiovascularsystem conferring anti-inflammatory and anti-atherogenic effects. Two commonsingle nucleotide polymorphisms (SNP) on adiponectin gene, rs2241766 andrs1501299, have been associated with insulin resistance and diabetes mellitus riskhowever their effects on cardiovascular risk remain unclear. We examined the impactof rs2241766 and rs1501299 on circulating adiponectin levels, endothelial functionand cardiovascular disease risk.Methods: We enrolled in total 594 subjects in the present study; 462 patients withangiographically confirmed coronary artery disease (CAD) and 132 controls matchedfor age and gender. rs2241766 and rs1501299 were genotyped by polymerase chainreaction and restriction endonuclease digestion. Serum adiponectin levels weredetermined by enzyme-linked immunosorbent assay. Endothelial function wasassessed by the flow mediated dilatation (FMD) of the brachial artery.Results: rs2241766 had no effects on circulating adiponectin levels or FMD. Insubjects without CAD, carriers of the T/T alleles at rs1501299 had lower adiponectinlevels (p=0.001) and impaired endothelial function (pG)και ο rs1501299 (+276G>T) έχουν συσχετισθεί με την ανάπτυξη αντίστασης στηνινσουλίνη και σακχαρώδη διαβήτη τὐπου 2. Ωστόσο οι επιδράσεις τους στονκαρδιαγγειακό κίνδυνο παραμένουν ασαφείς. Εξετάσαμε την επίπτωση τωνrs2241677 και rs1501299 πολυμορφισμών του γονιδίου της αδιπονεκτίνης στακυκλοφορούντα επίπεδα αδιπονεκτίνης, την ενδοθηλιακή λειτουργία και τονκαρδιαγγειακό κίνδυνο.Μέθοδοι: Στην εργασία συμπεριλήφθησαν συνολικά 594 συμμετέχοντες: 462ασθενείς με αγγειογραφικά τεκμηριωμένη στεφανιαία νόσο (ΣΝ) και 132 μάρτυρες,εξομοιωμένους κατά ηλικία και φύλο. Οι πολυμορφισμοί rs2241766 και rs1501299ταυτοποιήθηκαν με αλυσιδωτή αντίδραση πολυμεράσης και πέψη με περιοριστικέςενδονουκλεάσες. Τα επίπεδα αδιπονεκτίνης ορού μετρήθηκαν με την ενζυμικήμέθοδο ανοσοπροσρόφησης (ELISA). Η ενδοθήλιο-εξαρτώμενη αγγειοδιαστολή(ΕΕΑ) της βραχιονίου αρτηρίας αξιολογήθηκε με χρήση υπερήχων υψηλήςευκρίνειας.Αποτελέσματα: Ο rs2241766 δεν είχε καμία επίδραση στα επίπεδα αδιπονεκτίνηςορού ή την ΕΕΑ. Ο γονότυπος T/T στο rs1501299 συσχετίσθηκε με χαμηλότεραεπίπεδα αδιπονεκτίνης ορού (p=0.001) και μειωμένη ΕΕΑ (p<0.05) στα άτομα χωρίςΣΝ. Μετά από πολυπαραγοντική ανάλυση κανένας από τους πολυμορφισμούς δενείχε επίδραση στον κίνδυνο για ΣΝ. Ωστόσο, οι φορείς του Τ αλληλομόρφου στηθέση rs1501299 είχαν αυξημένο κίνδυνο για έμφραγμα του μυοκαρδίου, ανεξάρτητααπό κλασικούς παράγοντες κινδύνου (OR=2.558 [95%CI=1.587-4.123], p=0.0001). Οαριθμός των T αλληλομόρφων και στους δύο πολυμορφισμούς συσχετίσθηκε ισχυράμε το ιστορικό εμφράγματος μυοκαρδίου (p=0.0001).Συμπεράσματα: Ο πολυμορφισμός rs1501299 του γονιδίου της αδιπονεκτίνηςεπηρεάζει τα κυκλοφορούντα επίπεδα αδιπονεκτίνης ορού και την ενδοθηλιακήλειτουργία σε άτομα χωρίς ΣΝ. Η παρουσία του T αλληλομόρφου στη θέσηrs1501299 συσχετίζεται ανεξάρτητα με αυξημένο κίνδυνο εμφράγματος μυοκαρδίου