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BACKGROUND: Epicardial adipose tissue volume (EAT) is a marker of visceral obesity that can be measured in coronary CT angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented. OBJECTIVE: To develop a deep-learning network (DLN) for automated quantification of EAT from CCTA, test it in technically challenging patients, and validate its prognostic value in routine clinical care. METHODS: The DLN was trained and validated to auto-segment EAT in 3720 CCTA scans from the Oxford Risk Factors And Non-invasive imaging cohort. The model was tested in patients with challenging anatomy and scan artefacts and applied to a longitudinal cohort of 253 post-cardiac surgery patients and 1558 patients from the SCOT-HEART trial, to investigate its prognostic value. RESULTS: External validation of the DLN yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT was associated with coronary artery disease (OR[95%CI] per SD increase in EAT 1.13[1.04-1.30] p=0.01), and atrial fibrillation (AF) (1.25[1.08-1.40], p=0.03), after correction for risk factors (including BMI). EAT predicted all-cause mortality (HR[95%CI] per SD = 1.28[1.10-1.37], p=0.02), myocardial infarction (1.26[1.09-1.38] p=0.001) and stroke (1.20[1.09-1.38] p=0.02) independently of risk factors in SCOT-HEART (5y follow-up). It also predicted in-hospital (HR[95%CI] = 2.67[1.26-3.73], p=< 0.01) and long-term post-cardiac surgery AF (7y follow-up; HR[95%CI] = 2.14[1.19-2.97], p=< 0.01). CONCLUSIONS: Automated assessment of EAT is possible in CCTA, including in challenging patients; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification.

Aims: Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular (VTL) TL as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI). Methods and Results: In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause (HR[95%CI]: 3.21[1.46-7.06], P=0.004) and cardiovascular mortality (HR[95%CI]: 3.96[1.65-9.53], P=0.002) 1 year after AMI (for comparisons of short versus long BTL, as defined by a T/S ratio cut-off of 0.916, calculated using ROC analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2 .- ) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2 .- were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22phox (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2 .- in PBMNC (P=0.04) but not in vessels, whereas VTL was related to O2 .- in IMA (rho=-0.49, P=0.004) and SV (rho=-0.52, P=0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPH-oxidases, increased O2 .- and reduced TL in carriers of the high-responsiveness P22phox alleles (P=0.007) Conclusion: BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI.

Aims Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular TL (VTL) as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI). Methods and results In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause [hazard ratio (HR) [95% confidence interval (CI)]: 3.21 [1.46-7.06], P = 0.004] and cardiovascular mortality (HR [95% CI]: 3.96 [1.65-9.53], P= 0.002) 1 year after AMI (for comparisons of short vs. long BTL, as defined by a T/ S ratio cut-off of 0.916, calculated using receiver operating characteristic analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2 .-) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2 .-were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22ph-x (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2 .-in PBMNC (P = 0.04) but not in vessels, whereas VTL was related to O2 .-in IMA (q =-0.49, P=0.004) and SV (q =-0.52, P= 0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPHoxidases, increased O2 .-and reduced TL in carriers of the high-responsiveness P22ph-x alleles (P=0.007). Conclusion BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI. © The Author 2017.

Background: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. Methods and Results: The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2-) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2-production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2- and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism. Conclusions: We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue. © 2013 American Heart Association, Inc.

Background - The risk of atrial fibrillation (AF) after coronary bypass surgery has been related to redox state, inflammation, and ischemia. Platelet activation is common to all of these pathways. We investigated the relation between AF and preoperative soluble CD40 ligand (sCD40L), a proinflammatory marker released by activated platelets. Furthermore, we studied the role of inflammation, endothelial function, and redox state in this relation. Methods and Results - sCD40L levels were measured in 144 patients in sinus rhythm the day before off-pump coronary artery surgery. Systemic inflammation was assessed from levels of C-reactive protein and soluble intercellular adhesion molecule-1, and endothelial function was assessed from the brachial artery flow-mediated dilatation response. Graft samples were collected during surgery to assess vascular redox state. AF occurred in 33% of patients after surgery, with 3% still in AF after 6 weeks. Preoperative sCD40L levels were significantly higher in those who developed in-hospital AF (odds ratio for a 1-SD increase in log[sCD40L]=1.97; 95% CI, 1.21 to 3.22; P=0.007; after adjustment for age, sex, Euroscore, and total duration of operation). sCD40L and vascular superoxide levels were higher in patients still in AF at 6 weeks, and endothelial function was lower, although the small number of events precluded statistical analysis in this group. Systemic endothelial function, redox state, and preoperative markers of systemic inflammation were not associated with in-hospital postoperative AF. Conclusions - Preoperative platelet activation, as assessed by sCD40L levels, is a novel predictor of postoperative AF, independent of systemic endothelial function, vascular redox state, and systemic inflammation. © 2009 American Heart Association, Inc.

OBJECTIVES: This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability, and vascular superoxide production in patients with coronary artery disease (CAD). BACKGROUND: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production. METHODS: Blood samples and segments of internal mammary arteries and saphenous veins were obtained from patients with CAD undergoing coronary artery bypass grafting (n = 347). The GCH1 haplotypes were defined by 3 polymorphisms: rs8007267G