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Background Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI. Methods STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points. Results Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo. Conclusions Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes. Clinical Trial Registration: CT.gov NCT03470441 ; EudraCT 2017-000047-41

Contains fulltext : 286832.pdf (Publisher’s version ) (Open Access) BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [

Aims Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Methods and results Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.− production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. Conclusions We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin., Graphical Abstract Proposed mechanism of canagliflozin-induced improvement of myocardial redox state. Canagliflozin increases intracellular AMP/ATP ratio through inhibition of SGLT1, which can activate AMPK/NOS signalling and increase NO that suppresses pro-inflammatory signalling. AMPK activation also inhibits activation of Rac1 and membrane translocation of Rac1 and p47phox, which decrease NADPH oxidase activity and superoxide (O2.−) production, attenuates inflammatory and apoptotic pathways and increasing the bioavailability of tetrahydrobiopterin (BH4), a key factor for NOS coupling.

Introduction: Epicardial adipose tissue (EAT) is a visceral fat deposit within the pericardial sac. The automated quantification of EAT volume is possible from routine CCTA scans via deep-learning. The use of automated EAT quantification for the assessment of cardiovascular disease (CVD) risk in addition to standard measures of obesity like BMI has not been fully explored. Purpose: To use deep-learning for automated segmentation of EAT from routine CCTA scans to assess the long-term CVD risk conveyed by EAT. Methods: A deep-learning automated EAT segmentation tool using a 3D Residual-U-Net neural network architecture for 3D volumetric segmentation of CCTA data was created and trained on over 2500 consecutive CCTAs from within the Oxford Risk Factors And Non Invasive Imaging (ORFAN) Study. External validation in 817 patients demonstrated excellent correlation between machine and human expert (CCC = 0.972). The prognostic value of deep-learning derived EAT volume was assessed against 5 years outcomes from the SCOTHEART trial (n=1588), with adjustment for CVD risk factors. An optimal cutoff was selected by identifying the EAT value that maximized the Youden’s J index (sum of sensitivity and specificity) for the three outcomes of interest - high risk was deemed to be EAT ≥ 170.5cm 3 . Results: There were 35 deaths (all-cause mortality), 35 non-fatal myocardial infarctions and 8 non-fatal strokes during the 5 years follow up period. By using multi-variable cox-regression, EAT volume was predictive of all-cause mortality (Figure 1A), non-fatal MI (Figure 1B), and non-fatal stroke (Figure 1C) independently from CVD risk factors. Conclusions: Automatically segmented EAT volume measured using a deep learning network, predicts 5-year all-cause mortality, heart attacks and stroke independently of BMI and clinical risk profile of the patients. This suggests that measures of visceral obesity will be of value in the interpretation of cardiovascular computed tomography.

Background Epicardial adipose tissue (EAT) is a visceral fat deposit within the pericardial sac which surrounds the heart myocardium and coronary arteries. EAT volume has been demonstrated to be strongly associated with the development and prognosis of cardiovascular diseases, but its measurement is subjective and challenging in practice. Purpose To develop a deep-learning approach for automated segmentation of EAT from routine CCTA scans, that could assist clinical interpretation of CCTA. Methods A deep-learning method using a 3D Residual-U-Net neural network architecture for 3D volumetric segmentation of CCTA data was created. The network was trained on a diverse sample of 1900 CCTAs, each manually segmented by a single expert, drawn from the UK sites of the Oxford Risk Factors And Non-invasive imaging (ORFAN) Study. Three iterations of feedback learning were used to fine tune the algorithm for the segmentation of the whole heart within the bounds of the pericardium. In each iteration, the machine analysed sets of 100–250 unannotated CCTAs unseen by the machine which were then corrected by experts. EAT volumes were calculated by automated thresholding of adipose tissue (−190HU through −30HU) from within the bound of the pericardial segment (Figure 1). The network was then applied to 817 unseen CCTAs from US sites of the ORFAN Study. These scans were also segmented for ground truth by two experts blind to all other data. Comparisons between machine vs expert total pericardial volume and EAT volume were made using Lin's concordance correlation coefficient (CCC). The algorithm was then applied externally in 1588 CCTAs from the SCOTHEART trial (UK), and the EAT volume was automatically calculated for each case. Cross-sectional associations between standardised EAT volumes and prevalent AF and CAD were performed. Results Within both the internal (UK ORFAN sites) and external (USA ORFAN sites) validation cohorts correlation between human and machine segmented total pericardium and EAT was excellent, with CCC of 0.97 for both volumes (external validation cohort shown in Figure 2A). Utilising SCOTHEART CCTAs with automatically segmented EAT volumes, a multivariable-adjusted logistic regression model accounting for risk factors of age, sex, BMI, hypertension, diabetes mellitus, valvular disease, and previous heart surgery found that EAT volumes were significantly associated with prevalent AF, with odds ratio (OR) per 1 SD increase of EAT volume of 1.20 (95% CI, 1.06 to 1.44; P=0.03). A similar model for prevalent CAD, adjusted for age, sex, BMI, hypertension, non-HDL cholesterol, diabetes mellitus, and coronary artery calcium score resulted in an OR per 1 SD increase of EAT volume of 1.26 (95% CI, 1.10 to 1.45; P=0.001) (Figure 2B). Conclusion Highly accurate, reproducible, and instantaneous EAT volume quantification is possible utilising deep-learning detection of the whole human heart within the pericardial sac. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): British Heart FoundationNational Institute for Health Research - Oxford University Hospitals Biomedical Research Centre Figure 1Figure 2

AimsCoronary computed tomography angiography (CCTA) is a first-line modality in the investigation of suspected coronary artery disease (CAD). Mapping of perivascular fat attenuation index (FAI) on routine CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which integrates standardized FAI mapping together with clinical risk factors and plaque metrics to provide individualized cardiovascular risk prediction.Methods and resultsThe study included 3912 consecutive patients undergoing CCTA as part of clinical care in the USA (n = 2040) and Europe (n = 1872). These cohorts were used to generate age-specific nomograms and percentile curves as reference maps for the standardized interpretation of FAI. The first output of CaRi-Heart® is the FAI-Score of each coronary artery, which provides a measure of coronary inflammation adjusted for technical, biological, and anatomical characteristics. FAI-Score is then incorporated into a risk prediction algorithm together with clinical risk factors and CCTA-derived coronary plaque metrics to generate the CaRi-Heart® Risk that predicts the likelihood of a fatal cardiac event at 8 years. CaRi-Heart® Risk was trained in the US population and its performance was validated externally in the European population. It improved risk discrimination over a clinical risk factor-based model [Δ(C-statistic) of 0.085, P = 0.01 in the US Cohort and 0.149, P < 0.001 in the European cohort] and had a consistent net clinical benefit on decision curve analysis above a baseline traditional risk factor-based model across the spectrum of cardiac risk.ConclusionMapping of perivascular FAI on CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which allows standardized measurement of coronary inflammation by calculating the FAI-Score of each coronary artery. The CaRi-Heart® device provides a reliable prediction of the patient's absolute risk for a fatal cardiac event by incorporating traditional cardiovascular risk factors along with comprehensive CCTA coronary plaque and perivascular adipose tissue phenotyping. This integration advances the prognostic utility of CCTA for individual patients and paves the way for its use as a dual diagnostic and prognostic tool among patients referred for CCTA.

Background Recent clinical trials have demonstrated a role for sodium glucose cotransporter 2 (SGLT2) inhibitors in improving cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We investigated the direct effects of canagliflozin, a non-selective SGLT1/SGLT2 inhibitor on myocardial redox signalling in humans. Methods Study 1 included 364 patients undergoing cardiac surgery. Human right atrial appendage biopsies, obtained during surgery, were used to quantify the sources of superoxide (O2.-) and the gene expression of inflammation, fibrosis and myocardial stretch markers. In Study 2, myocardial biopsies from 51 patients were used ex vivo to study the direct effects of canagliflozin on O2.- generation and understand its role in controlling the activity of NADPH-oxidases and uncoupled nitric oxide synthase (NOS). Finally, we used differentiated H9C2 and human primary cardiomyocytes (hCM) to further characterise the key regulatory mechanisms (Study 3). Results SGLT1 was abundantly expressed in the human myocardial biopsies and hCM whilst SGLT2 was barely detectable. SGLT1 expression levels were positively correlated with basal O2.- production and the expression of natriuretic peptides, proinflammatory cytokines and pro-fibrotic markers in human myocardial biopsies from study 1. Incubation of human myocardium with canagliflozin significantly reduced basal and NADPH-oxidase-derived O2.- via AMP kinase (AMPK)-mediated suppression of GTP-activation and consequent reduction of membrane translocation of Rac1, an NADPH-oxidase subunit. This resulted in reduced oxidation and increased bioavailability of tetrahydrobiopterin, the nitric oxide synthase (NOS) co-factor essential for enzymatic coupling, leading to improved NOS coupling. These findings were replicated in hCM, where canagliflozin was shown to regulate AMP/ATP ratio, which could be upstream of AMPK activation. The effects of canagliflozin were significantly attenuated by knocking-down SGLT1 in hCM. Transcriptional profiling of hCM treated with canagliflozin revealed that canagliflozin had striking effects on myocardial redox signalling, causing suppression of apoptotic and inflammatory pathways in the human heart. Conclusions We demonstrate for the first time in humans that canagliflozin suppresses myocardial NADPH-oxidase activity and improves NOS coupling through an SGLT1/AMPK/Rac1-mediated pathway, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings provide a mechanistic basis for the beneficial effects of SGLT1/2 inhibitors in patients with heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): 1. British Heart Foundation (FS/16/15/32047 and PG/13/56/30383 to CA, CH/16/1/32013 to KC, and Centre of Research Excellence award RG/13/1/30181), 2. The Japanese Heart Rhythm Society-European Heart Rhythm Association fellowship grant sponsored by Biotronik.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): UKRI, British Heart Foundation Background Inflammation in the coronaries induces macroscopic changes in perivascular adipose tissue composition, detectable by the pericoronary Fat Radiomic Profile (FRP) on coronary computed tomography angiography (CCTA). Purpose To assess the ability of FRP to stratify cardiac risk in patients with Coronary Artery Calcium (CAC) score below 100 following routine CCTA. Methods 1,575 participants from the CCTA arm of the SCOT-HEART trial (NCT01149590) eligible for image analysis were included. Pericoronary FRP mapping was performed in perivascular adipose tissue segmentations around the proximal sites of the right and left coronary arteries, as previously validated. We first tested the prognostic value of FRP in the sub-cohort of patients with CAC Results In total, 1,032 patients (53.9% female sex) were found with low CAC score (CAC Conclusion In individuals with low CAC scores the Fat Radiomic Profile biormarker significantly improves risk prediction for adverse clinical events beyond the current state-of-the-art. Non-invasive profiling of pericoronary adipose tissue using CCTA-derived FRP captures irreversible changes in perivascular adipose tissue composition associated with chronic vascular inflammation and atherosclerotic disease, and can supplement the traditional anatomical assessment of the coronary vasculature with a functional marker of disease activity.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation OnBehalf the CRISP-CT study investigators Introduction Non-invasive detection of coronary inflammation has the potential to improve targeting of cardiovascular prevention strategies. Coronary computed tomography angiography (CCTA)-based fat attenuation indexing (FAI) is a novel, validated measure of coronary inflammation that captures spatial changes in perivascular fat composition induced by coronary inflammation. However, to ensure accuracy, FAI values must be carefully standardized for technical, anatomical and biological factors before they are introduced for risk stratification in clinical practice. Purpose To validate the prognostic value of FAI-Score, the output of a new, artificial intelligence (AI)-powered algorithm, that harmonizes the FAI values of each coronary artery to generate a standardized metric of coronary inflammation for clinical use. Methods The study included 3912 individuals from the CRISP-CT study (2040 from the United States and 1872 from Europe) with a mean age of 55.7 (± standard deviation 13.7 years), 1608 (41.1%) of whom were women; all underwent clinically indicated CCTA. FAI-Score was measured at baseline in the proximal right coronary (RCA), left anterior descending (LAD) and left circumflex arteries (LCX) using the CaRi-Heart V1.1 platform (panel A). Percentile curves were created for the FAI-score of the RCA, LAD and LCX across different age and sex strata. Their prognostic value was further assessed in Cox models adjusted for hypertension, hyperlipidemia, diabetes mellitus, smoking, high-risk plaque features and the modified Duke prognostic coronary artery disease index. Results Over a median follow-up period of 5.6 years there were a total of 74 cardiac deaths. FAI-Score percentile curves were created to provide a population reference map for FAI-Score phenotyping of the three main coronary territories; LAD (panels B, C), RCA and LCX. There was a stepwise association between higher FAI-Score percentiles and the prospective risk of cardiac mortality across all three vessels analysed. When compared to individuals below the 50th percentile, those in the 90th percentile or higher had a 3.5-fold (LAD, panel D), 5.5-fold (RCA, panel E) and 2-fold (LCX, panel F) higher adjusted risk of cardiac mortality. Conclusion Coronary FAI-Score percentile curves provide a reference map for coronary inflammatory burden and enable standardized interpretation of perivascular FAI mapping on CCTA. Individuals in the top percentile curves have an increased cardiovascular risk independent of traditional risk factors and existing atherosclerotic changes. Abstract Figure.

Background Coronary computed tomography angiography (CCTA) provides useful information regarding cardiovascular risk assessment. Key aspects of coronary biology induce changes in perivascular adipose tissue composition, detectable by the pericoronary Fat Radiomic Profile (FRP) index. Purpose We assessed the ability of FRP to further stratify cardiac risk in patients with Coronary Artery Calcium (CAC) scoring below 100 following routine CCTA. Methods The study population consisted of 1,575 participants from the CCTA arm of the SCOT-HEART trial (NCT01149590) with images available and eligible for analysis. Pericoronary FRP mapping was performed in perivascular adipose tissue segmentations around the proximal sites of the right and left coronary arteries, as previously validated. The prognostic potential of FRP was initially tested in a sub-cohort, consisting of patients with Coronary Artery Calcium (CAC) score lower than 100. Further analysis was performed after sub-grouping based on the absence of high risk plaque (HRP) features and obstructive coronary artery disease (CAD). The association with future incidence of major adverse cardiac events (MACE: cardiac mortality or non-fatal myocardial infarction) or a composite endpoint of MACE ± late revascularization (MACE-ReVasc) was assessed using adjusted Cox regression models [adjusted for age, sex, systolic blood pressure (SBP), diabetes mellitus (DM), body mass index (BMI), smoking, CAD (≥50% stenosis), total cholesterol, high-density lipoprotein (HDL), and HRP features]. Results Two-thirds (66%) of the study population were at low-risk according to the CAC score (CAC Conclusion The Fat Radiomic Profile biormarker significantly improves risk prediction for adverse clinical events beyond the current state-of-the-art in individuals with low CAC scores. Non-invasive profiling of pericoronary adipose tissue using CCTA-derived FRP captures irreversible changes in perivascular adipose tissue composition associated with chronic vascular inflammation and atherosclerotic disease, and can improve risk stratification and clinical decision making in low-risk populations. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, National Institute of Health Research, Oxford Biomedical Research Centre

Although the short- and long-term clinical outcomes of patients with ST-segment elevation myocardial infarction (STEMI) has improved substantially over the last 2 decades the risk of future cardiovascular events, in particular heart failure, remains high [ 1 ]. The most important determinant of long-term clinical outcomes after STEMI is infarct size (IS). In a recent meta-analysis, IS measured within 1 month after primary percutaneous intervention (pPCI) was strongly associated with all-cause mortality and hospitalization for heart failure within 1 year [ 2 ]. There are currently no established therapies to reduce IS, with the exception of timely reperfusion by pPCI. Furthermore, ischemia-reperfusion injury (IRI) remains a major clinical problem in patients with STEMI, leading to greater IS, ventricular arrhythmias and heart failure, despite early reperfusion by pPCI. There are no effective therapies to prevent or limit IRI, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species. Contemporary research focus is on new therapeutic interventions to reduce IRI and subsequent IS, with the ultimate aim of improving event-free survival in STEMI patients.

Introduction Coronary inflammation induces spatial changes in perivascular adipose tissue (PVAT) composition, which can now be detected as spatial changes in PVAT attenuation quantified by the perivascular Fat Attenuation Index (FAI) on coronary computed tomography angiography (CCTA). We assessed the ability of perivascular FAI mapping around the right and left coronary territories to independently stratify future cardiac risk. Methods This was a post-hoc analysis of the CRISP-CT (Cardiovascular RISk Prediction using Computed Tomography) study that included 3912 patients with an average age of 55.7 years (standard deviation [SD]: 13.7 years). Perivascular FAI mapping was performed around the proximal right (RCA) and left anterior descending (LAD) coronary arteries. FAI was calculated based on the weighted average attenuation of PVAT using the CaRi-HEART algorithm, as previously described. The independent association with future incidence of cardiac death was assessed in adjusted Cox regression models. Results Over a median follow-up period of 5.6 years, 74 cardiac deaths were recorded. The cross-sectional association between perivascular FAI around the RCA and LAD at baseline was found to be moderate (R2=0.36, P Conclusion Perivascular FAI around the coronary arteries is characterised by anatomical/regional variability, and its values are affected by the coronary segment interrogated. Non-invasive characterization of coronary inflammation using CCTA-derived FAI should include a comprehensive assessment of both coronary arteries in order to better characterize the inflammatory residual risk of each patient.

Introduction High-risk plaque (HRP) features on coronary computed tomography angiography (CCTA) are indicators of increased cardiac risk. Coronary inflammation induces spatial changes in perivascular adipose tissue (PVAT) composition, which can be quantified with the perivascular Fat Attenuation Index (FAI). We hypothesized that perivascular FAI mapping can further stratify the cardiac risk associated with HRP on CCTA. Methods Individuals from the CRISP-CT (Cardiovascular RISk Prediction using Computed Tomography) study were included (n=3,912, mean age 55.7±13.7 years, 41.1% females). Perivascular FAI mapping was performed around the proximal right coronary artery and was calculated based on the weighted average attenuation of PVAT using the CaRi-HEART algorithm, as previously described. HRP features were defined as the presence of either positive remodelling, low-attenuation plaque, spotty calcification or napkin-ring sign. The association with future incidence of major adverse cardiac events (cardiac mortality or non-fatal myocardial infarction) was assessed using Cox regression models (adjusted for age, sex, epicardial fat volume and coronary artery disease [≥50% stenosis]). Results The prevalence of HRP and high FAI (≥-70.1 Hounsfield Units, as previously validated) was 23.6% (n=923) and 24.3% (n=952), respectively. Over a median follow-up of 5.6 years (25th-75th percentile: 4.0–7.0 years) 91 MACE were recorded. Patients with both HRP features and high FAI (FAI+/HRP+) had a 6.3-fold higher adjusted risk of MACE compared to those with neither of these risk features (HRP-/FAI-). Furthermore, patients without HRP features but with high FAI (HRP-/FAI+) had a 4.9-fold higher adjusted risk of MACE compared to the reference (HRP-/FAI-) group. Conclusion FAI is a stronger predictor of cardiac mortality than high-risk plaques, and there is additive predictive value between plaque morphology and coronary inflammatory burden. There is need for tools to provide comprehensive risk assessment based on CCTA, by extracting, weighting and interpreting all available information from these scans.

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.

Psoriasis is a chronic inflammatory skin disease associated with increased coronary plaque burden and cardiovascular events. Biologic therapy for psoriasis has been found to be favorably associated with luminal coronary plaque, but it is unclear whether these associations are attributable to direct anti-inflammatory effects on the coronary arteries.To investigate the association of biologic therapy with coronary inflammation in patients with psoriasis using the perivascular fat attenuation index (FAI), a novel imaging biomarker that assesses coronary inflammation by mapping spatial changes of perivascular fat composition via coronary computed tomography angiography (CCTA).This prospective cohort study performed from January 1, 2013, through March 31, 2019, analyzed changes in FAI in patients with moderate to severe psoriasis who underwent CCTA at baseline and at 1 year and were not receiving biologic psoriasis therapy at baseline.Biologic therapy for psoriasis.Perivascular FAI mapping was performed based on an established method by a reader blinded to patient demographics, visit, and treatment status.Of the 134 patients (mean [SD] age, 51.1 [12.1] years; 84 [62.5%] male), most had low cardiovascular risk by traditional risk scores (median 10-year Framingham Risk Score, 3% [interquartile range, 1%-7%]) and moderate to severe skin disease. Of these patients, 82 received biologic psoriasis therapy (anti-tumor necrosis factor α, anti-interleukin [IL] 12/23, or anti-IL-17) for 1 year, and 52 did not receive any biologic therapy and were given topical or light therapy (control group). At baseline, 46 patients (27 in the treated group and 19 in the untreated group) had a focal coronary atherosclerotic plaque. Biologic therapy was associated with a significant decrease in FAI at 1 year (median FAI -71.22 HU [interquartile range (IQR), -75.85 to -68.11 HU] at baseline vs -76.09 HU [IQR, -80.08 to -70.37 HU] at 1 year; P .001) concurrent with skin disease improvement (median PASI, 7.7 [IQR, 3.2-12.5] at baseline vs 3.2 [IQR, 1.8-5.7] at 1 year; P .001), whereas no change in FAI was noted in those not receiving biologic therapy (median FAI, -71.98 [IQR, -77.36 to -65.64] at baseline vs -72.66 [IQR, -78.21 to -67.44] at 1 year; P = .39). The associations with FAI were independent of the presence of coronary plaque and were consistent among patients receiving different biologic agents, including anti-tumor necrosis factor α (median FAI, -71.25 [IQR, -75.86 to -66.89] at baseline vs -75.49 [IQR, -79.12 to -68.58] at 1 year; P .001) and anti-IL-12/23 or anti-IL-17 therapy (median FAI, -71.18 [IQR, -75.85 to -68.80] at baseline vs -76.92 [IQR, -81.16 to -71.67] at 1 year; P .001).In this study, biologic therapy for moderate to severe psoriasis was associated with reduced coronary inflammation assessed by perivascular FAI. This finding suggests that perivascular FAI measured by CCTA may be used to track response to interventions for coronary artery disease.

OBJECTIVES: In stable patients with high-risk coronary plaques on coronary CT angiography (CTA), we aimed to assess the association between increased lesion pericoronary adipose tissue (PCAT) density and coronary (18)F- sodium fluoride ((18)F-NaF) uptake on positron emission tomography (PET). BACKGROUND: Coronary (18)F-NaF uptake reflects coronary microcalcification. Increased PCAT density is associated with vascular inflammation. To date the relationship between increased PCAT density and ¹⁸F-NaF uptake in stable patients with high risk plaques on coronary CTA has not been characterized. METHODS: Patients undergoing coronary CTA were screened for HRP defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP, 100mm(3). Patients with HRPs were recruited for (18)F-NaF PET/CT. In lesions with stenosis ≥25%, quantitative plaque analysis, mean PCAT density, maximal coronary motion-corrected (18)F-NaF standard uptake values (SUVmax) and target to background ratios (TBR) were measured. RESULTS: Forty-one patients (age 65±6 years, 68% male) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronary (18)F-NaF activity. Lesions with (18)F-NaF uptake had higher surrounding PCAT density than those without (−73 [interquartile range −79 to −68] vs. −86 [−94 to −80] HU, p

This chapter discusses endocarditis and acute rheumatic fever, including definitions of the disease, etiology, typical symptoms, uncommon symptoms, demographics, natural history, complications, diagnostic approaches, other diagnoses that should be considered, prognosis, and treatment.

The term ‘acute coronary syndrome’ includes unstable angina, ST-elevation myocardial infarction (STEMI), and non-ST-elevation myocardial infarction (NSTEMI). The difference between these three syndromes is as follows. In STEMI and NSTEMI, there is evidence of myocardial necrosis, as evidenced by raised cardiac enzymes, specifically, the very sensitive cardiac biomarker troponin. STEMI is diagnosed when the ECG shows persisting ST elevation in an appropriate territory consistent with STEMI whereas, in NSTEMI, there can be any or no ECG changes, or very transient, self-limiting ST elevation. In unstable angina, there is no myocardial necrosis, and troponins are normal. The ECG is as for NSTEMI and often shows no change, ST depression, or T-wave inversion. The prognoses in STEMI and NSTEMI are identical; unstable angina has a better prognosis than either STEMI or NSTEMI.

Chronic stable angina is a condition where patients experience symptoms of chest pain of a particular character (e.g. angina pectoris) on effort only, due to atherosclerotic coronary artery disease. The hallmarks of stable angina are as follows. First, there must be stable atherosclerotic coronary artery disease, resulting in luminal narrowing(s) in one or more of the major epicardial coronary arteries. Atheroma can be detected by using appropriate technology. Not all angina chest discomfort is due to atherosclerotic coronary disease—some is due to aortic stenosis, and some to hypertrophic cardiomyopathy; rarely, pulmonary hypertension is the cause. Second, symptoms must have been present for some time, say, arbitrarily, 2–3 months, as opposed to the case for angina of acute coronary syndromes, where symptoms are present only for a few weeks at most (see Chapter 90). This time limit is important, as it allows the differentiation of symptoms from coronary obstruction due to coronary atheroma (generally a stable pathology, with a lower risk of infarction) from symptoms of coronary obstruction due to atheroma with superadded thrombus, which can be quite unstable and lead suddenly to total coronary obstruction with all its attendant risks. Third, symptoms must be stable, that is to say, from day to day, roughly similar levels of effort must be required for provocation. The pathological translation of this is that the degree of coronary obstruction is stable, as opposed to that of the rapidly changing coronary obstruction found in acute coronary syndromes.

Cardiac catheterization is a procedure by which information is obtained from the heart by passing fine plastic tubes (occasionally other instruments) either near to or within the heart, to introduce contrast to cardiac structures to understand their anatomy and function better, to measure pressures, and/or to measure oxygen saturations in different cardiac chambers. It is an extraordinarily useful diagnostic procedure. Percutaneous coronary intervention (PCI) is the modern term for an intervention on a coronary artery that relieves narrowing. It includes balloon angioplasty and stent insertion. PCI is a therapeutic procedure.

Background Coronary artery inflammation inhibits adipogenesis in adjacent perivascular fat. A novel imaging biomarker—the perivascular fat attenuation index (FAI)—captures coronary inflammation by mapping spatial changes of perivascular fat attenuation on coronary computed tomography angiography (CTA). However, the ability of the perivascular FAI to predict clinical outcomes is unknown. Methods In the Cardiovascular RISk Prediction using Computed Tomography (CRISP-CT) study, we did a post-hoc analysis of outcome data gathered prospectively from two independent cohorts of consecutive patients undergoing coronary CTA in Erlangen, Germany (derivation cohort) and Cleveland, OH, USA (validation cohort). Perivascular fat attenuation mapping was done around the three major coronary arteries—the proximal right coronary artery, the left anterior descending artery, and the left circumflex artery. We assessed the prognostic value of perivascular fat attenuation mapping for all-cause and cardiac mortality in Cox regression models, adjusted for age, sex, cardiovascular risk factors, tube voltage, modified Duke coronary artery disease index, and number of coronary CTA-derived high-risk plaque features. Findings Between 2005 and 2009, 1872 participants in the derivation cohort underwent coronary CTA (median age 62 years [range 17–89]). Between 2008 and 2016, 2040 patients in the validation cohort had coronary CTA (median age 53 years [range 19–87]). Median follow-up was 72 months (range 51–109) in the derivation cohort and 54 months (range 4–105) in the validation cohort. In both cohorts, high perivascular FAI values around the proximal right coronary artery and left anterior descending artery (but not around the left circumflex artery) were predictive of all-cause and cardiac mortality and correlated strongly with each other. Therefore, the perivascular FAI measured around the right coronary artery was used as a representative biomarker of global coronary inflammation (for prediction of cardiac mortality, hazard ratio [HR] 2·15, 95% CI 1·33–3·48; p=0·0017 in the derivation cohort, and 2·06, 1·50–2·83; p Interpretation The perivascular FAI enhances cardiac risk prediction and restratification over and above current state-of-the-art assessment in coronary CTA by providing a quantitative measure of coronary inflammation. High perivascular FAI values (cutoff ≥–70·1 HU) are an indicator of increased cardiac mortality and, therefore, could guide early targeted primary prevention and intensive secondary prevention in patients.

Background: Non-invasive detection of vascular inflammation remains an unmet goal. We hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation can be quantified using a new computed tomography angiography (CTA) methodology. Methods: In Arm 1, human PVAT adipocytes were cultured +/- inflammatory cytokines (n=7) or co-cultured with vascular tissue (+/-Angiotensin-II, n=6) to assess the effects of vascular inflammation on PVAT differentiation. In Arm 2, AT explants (epicardial, subcutaneous and thoracic AT) from 453 cardiac surgery patients were used in histology and gene expression studies to relate the ex vivo images with in vivo CT scan information (n=105) on the biology of the explants. In Arm 3, in 267 patients undergoing diagnostic CTA, PVAT attenuation (Fat Attenuation Index (FAI) defined as the average CT attenuation of AT), was analysed around the proximal right coronary artery. In Arm 4, PVAT FAI around unstable (culprit) and stable coronary plaques was calculated in 22 CAD patients undergoing CTA. Results: In Arm 1, Angiotensin-II (A) and proinflammatory cytokines (B) prevented lipid accumulation and adipocyte differentiation in cultured PVAT. In Arm 2, adipocyte size by histology was inversely correlated with FAI in vivo (C). Both FAI of AT explants (not shown) and FAI in-vivo (n=105) were negatively associated with epicardial AT differentiation as assessed by FABP4 expression (D). In Arm 3, PVAT FAI change over distance from RCA wall was significantly different in CAD compared to no CAD patients (E). In Arm 4, PVAT FAI was significantly increased around unstable plaques (F). Conclusions: Human vessels exert paracrine effects on surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can then be monitored using a CT imaging approach. This novel methodology can be implemented in clinical practice to detect unstable plaques in the human coronary vasculature.

Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase–derived superoxide anions (O2˙−). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase–derived O2˙−. However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase–derived O2˙−. Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22phox through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator–activated receptor-γ–mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT “senses” the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.

Early detection of vascular inflammation is a long-standing goal that would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Since vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography angiography (CTA) methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo and in vivo. We developed a 3D PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We have developed a new imaging biomarker, CT Fat attenuation index (FAI), that describes adipocyte lipid content and size. FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18FFDG in positron emission tomography (PET). In a validation cohort of 273 subjects, the FAI gradient around the human coronary arteries identified early subclinical coronary artery disease in vivo, and detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can then be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to allow the non-invasive detection of unstable plaques in the human coronary vasculature.

Perivascular fat attenuation index (FAI) is a novel imaging biomarker that assesses coronary inflammation by mapping spatial changes of perivascular fat composition on computed tomography angiography (CCTA). Psoriasis is a chronic inflammatory skin disease associated with increased vascular

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 (O 2 − ) 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 O 2 − 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 O 2 − 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.

Nitric oxide has a pivotal role in vascular homeostasis. It has a protective role because it suppresses abnormal proliferation of vascular smooth muscle after various diseases, including atherosclerosis and restenosis after vascular interventions (e.g. balloon angioplasty, stent deployment, bypass grafting). A reduction in the generation and bioavailability of nitric oxide is a critical step in the development of atherosclerosis, a disease of the arterial wall that underlies vascular disease. With cardiovascular diseases postulated to be the main cause of death globally within the next 15 years, increasing the understanding of the biology of atherosclerosis and the process of endothelial function may aid development of therapeutic strategies to reduce risk. © 2007 Elsevier Ltd. All rights reserved.

Background Intramural coronary haematoma following percutaneous coronary intervention in the absence of coronary dissection is a rare phenomenon. Case presentation A 69 year old lady with previous prosthetic aortic valve replacement underwent percutaneous coronary intervention (PCI) from the left mainstem to the left anterior descending artery (LAD) and kissing balloon inflations to the LAD and circumflex (Cx) arteries. Although intravascular ultrasound examination (IVUS) of both the LAD and Cx showed both vessels to be widely patent at the end of the procedure, she developed ischaemic chest pain six hours later. Repeat coronary angiography revealed a significant stenosis in the proximal Cx vessel, which was confirmed on IVUS to be intramural haematoma. Conclusion In patients taking warfarin in addition to standard antiplatelet therapy, kissing balloon inflations should be carried out with caution.

Recent advances in cardiovascular medicine include further evidence supporting the role of primary angiopiasty, advances in stent technology, and new pharmacological approaches to the treatment of ischaemic heart disease. © 2004 The Medicine Publishing Company Ltd.

Vascular magnetic resonance imaging (MRI) is emerging as a powerful research tool. We studied 18 patients with type 2 diabetes mellitus and 20 controls (all with coronary artery disease). MRI measured distensibility, pulse wave velocity (PWV) and atherosclerosis in the aorta, and brachial artery flow-mediated dilatation (FMD). Patients with diabetes showed lower aortic distensibility (2.1 × 10-3 vs. 3.5 × 10-3 mmHg-1, p

Drug-eluting stents (DESs) may represent a simple, effective treatment for in-stent restenosis (ISR); however, the underexpansion of stents is a significant cause of target vessel failure. It was hypothesized that high-pressure postdilatation would be necessary to optimize DES expansion and minimize the risk for restenosis when treating patients with ISR. Fifteen patients with diffuse ISR were treated by predilatation (including cutting balloons), DES deployment, and high-pressure postdilatation, with the measurement of luminal and stent dimensions by intravascular ultrasound after each intervention. After initial deployment, DES underexpansion was present in 10 of 15 patients (66%); after high-pressure postdilatation, there was a significant increase in luminal dimensions, including minimum luminal area (4.3 +/- 0.3 to 5.6 +/- 0.4 mm(2), p

Background Tetrahydrobiopterin (BH4), a critical endothelial nitric oxide synthase (eNOS) cofactor, is an important determinant of endothelial function. Oral BH4 therapy has been proposed as a treatment for vascular disease. We investigated the pharmacokinetics and pharmacodynamics of oral BH4 in both plasma and vascular tissue to determine whether oral BH4 therapy would improve vascular function in patients with established atherosclerosis and oxidative stress. Methods In a double-blind, randomised trial, 49 patients with coronary artery disease (CAD) awaiting coronary artery bypass graft surgery received oral BH4 700 mg/d (n=16) or 400 mg/d (n=14), or placebo (n=19), for a mean duration of 30 days prior to surgery. Biopterin levels were measured in plasma at baseline and after the treatment period, and in saphenous vein (SV) and internal mammary artery (IMA) tissue collected at the time of surgery. Vascular superoxide and endothelial function were measured ex vivo. Cardiovascular MRI was used to determine brachial artery flow-mediated dilatation and indices of arterial stiffness before and after treatment. Results Plasma BH4 levels were elevated threefold by both low- and high-dose BH4 treatment compared to placebo (p ex vivo , or in MRI indices of vascular function. Conclusion Although absolute BH4 levels in plasma and SV are increased, chronic oral BH4 therapy does not alter biopterin redox status (BH4:BH2 ratio) in either plasma or vascular tissue. Accordingly, oral BH4 does not improve vascular function or oxidative stress in patients with established CAD.

BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered to be a risk factor for atherosclerosis. However, the mechanisms relating ADMA with vascular function have been evaluated in vitro and in animal models, but its effect in human vasculature is unclear. AIMS: We examined the impact of serum ADMA on endothelial nitric oxide (NO) bioavailability and vascular superoxide radical (O2-) production in patients with advanced atherosclerosis. METHODS AND RESULTS: Paired samples of saphenous veins (SVs) and internal mammary arteries (IMAs) were collected from 201 patients undergoing coronary bypass surgery, and serum ADMA was measured pre-operatively. The vasomotor responses of SV segments to acetylcholine (ACh) and bradykinin (Bk) were evaluated ex vivo. Vascular O2- was measured in paired SV and IMA by lucigenin-enhanced chemiluminescence. The l-NAME-inhibitable as well as the NADPH-stimulated vascular O2- generation was also determined by chemiluminescence. High serum ADMA levels were associated with decreased vasorelaxation of SV to ACh (P < 0.05) and Bk (P < 0.05). Similarly, high serum ADMA was associated with higher total O2- production in both SVs and IMAs (P < 0.05) and greater L-NAME-inhibitable vascular O2- (P < 0.05). However, serum ADMA was not associated with NADPH-stimulated vascular O2-. In multivariable linear regression, serum ADMA was independently associated with vascular O2- in both SVs [beta (SE): 0.987 (0.412), P = 0.019] and IMAs [beta (SE): 1.905 (0.541), P = 0.001]. Asymmetrical dimethylarginine was also independently associated with maximum vasorelaxation in response to both ACh [beta (SE): 14.252 (3.976), P = 0.001] and Bk [beta (SE): 9.564 (3.762), P = 0.013]. CONCLUSION: This is the first study that demonstrates an association between ADMA and important measures of vascular function, such as vascular O2- production and NO bioavailability directly in human vessels. Although serum ADMA has no effect on NADPH-stimulated superoxide in intact vessels, it is associated with greater eNOS uncoupling in the human vascular endothelium of patients with coronary artery disease.

Background— The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. Methods and Results— Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. Conclusions— Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00423280.

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).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 (ρ = -0.49, P = 0.004) and SV (ρ = -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 P22ph°x alleles (P = 0.007).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.

SummaryVascular oxidative stress is a key feature of atherogenesis, and targeting vascular redox signalling is a rational therapeutic goal in vascular disease pathogenesis. 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors or statins are potent lipid-lowering drugs that improve cardiovascular outcomes. It is now widely accepted that cardiovascular disease prevention by statins is dependent not only on their lipid lowering effects, but also on their beneficial effects on vascular redox signalling. Cell culture and animal models have provided important findings on the effects of statins on vascular redox and nitric oxide bioavailability. Recent evidence from studies on human vessels has further enhanced our understanding of the “pleiotropic” effects of statins on vascular wall. Reversal of endothelial dysfunction in human vessels by statins is dependent on the mevalonate pathway and Rac1 inhibition. These critical steps are responsible for reducing NADPH-oxidase activity and improving tetrahydrobiopterin bioavailability and nitric oxide synthase (NOS) coupling in human vessels. However, mevalonate pathway inhibition has been also held responsible for some of the side effects observed after statin treatment. In this review we summarise the existing knowledge on the effects of statins on vascular biology by discussing key findings from basic science as well as recent evidence from translational studies in humans. Finally, we discuss emerging aspects of statin pleiotropy, such as their effects on adipose tissue biology and adipokine synthesis that may light additional mechanistic links between statin treatment and improvement of clinical outcome in primary and secondary prevention.

Objectives: Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function.Background: NA raises high-density lipopr...

Bright blood cine images acquired using magnetic resonance imaging contain simple contrast that is tractable to automated analysis, which can be used to derive a measure of arterial compliance that is known to correlate with disease severity. The purpose of this work was to evaluate whether automated methods could be used reliably on a clinically relevant population, and to assess the precision of these measurements so that it could be compared with expert manual assessment. In this paper we apply an algorithm similar to that used by Krug et al., and the exact processing steps are described in detail to allowing easy reproduction of our methods. Phantoms of different sizes have been assessed and the MRI measurements are found to correlate well (r = 0.9998) with physical measurement. Reproducibility assessment was performed on 33 CAD subjects in three anatomical locations along the aorta. Six normal volunteers and ten patients with more severe aortic plaques were investigated to assess reproducibility and sensitivity to pathological changes, respectively. The performance was also assessed on carotid vessels in 40 patients with known arterial plaques. In the human aorta the method is found to be robust (failing in only 7% of cases, all due to clear errors with image acquisition), and to be quantifiably consistent with expert clinical measurement, but showing smaller errors than that approach [

GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease: Effects on Vascular Superoxide Production and Endothelial FunctionCharalambos Antoniades, Cheerag Sh...

Effective LDL-cholesterol (LDL-C) reduction improves vascular function and can bring about regression of atherosclerosis. Alterations in endothelial function can occur rapidly, but changes in atherosclerosis are generally considered to occur more slowly. Vascular magnetic resonance imaging (MRI) is a powerful technique for accurate non-invasive assessment of central and peripheral arteries at multiple anatomical sites. We report the changes in atherosclerosis burden and arterial function in response to open label statin treatment, in 24 statin-naïve newly diagnosed stable coronary artery disease patients. Patients underwent MRI before, and 3 and 12 months after commencing treatment. Mean LDL-C fell by 37% to 70.8 mg/dL (P

Background— Tetrahydrobiopterin (BH 4 ) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH 4 levels are altered in human atherosclerosis and the importance of BH 4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH 4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. Methods and Results— Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor N G -nitro- l -arginine methyl ester. High vascular BH 4 was associated with greater vasorelaxations to acetylcholine ( P 4 was associated with lower vasorelaxations in response to acetylcholine ( P P 4 was associated with reduced total and N G -nitro- l -arginine methyl ester–inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels ( P Conclusions— An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH 4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

Introduction: Myocardial redox state is a strong determinant of heart biology. Epicardial adipose tissue (EpAT) is in close contact with the human heart and it is likely that by secreting a wide range of adipokines it may affect the biology of the underlying myocardium. Hypothesis: We hypothesised that EpAT volume may predict myocardial redox state and consequently myocardial function in ischaemic heart disease (IHD). Methods: We recruited 38 patients undergoing coronary artery bypass grafting surgery. Patients underwent transthoracic echocardiography to assess cardiac function and cardiac computerised tomography to determine the volume of EpAT, pericardial (PerAT) and subcutaneous (ScAT) AT, by using a strictly pre-defined protocol. Samples of right atrium appendage were collected during surgery and myocardial NADPH oxidase activity was assessed by lucigenin-enhanced chemiluminescence (using its substrate -NAPDH 100uM +/- its specific inhibitor VAS2870 40uM). Results: Increased EpAT volume index (EpAT volume/body surface area), but not PerAT or ScAT, was strongly associated with increased myocardial NADPH oxidase activity (Figure). EpAT volume index was not related with left ventricle (LV) mass index or LV systolic/diastolic function (p=NS for all). EpAT volume index was also unrelated to risk factors or body mass index (p=NS for all). Conclusions: These findings introduce the concept of a local cross-talk between EpAT and the underlying myocardium in humans. EpAT volume can be used as a surrogate of myocardial redox state, and this may have direct implications in risk stratification of patients undergoing coronary bypass surgery.

Background Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. Design This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non–high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. Summary ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

The role of B vitamins in the prevention of cardiovascular disease has been extensively investigated during the last decade. Folic acid supplemented with B12 and B6 vitamins has been used in randomized clinical trials to lower plasma homocysteine, a biomarker closely related with increased cardiovascular risk. In this chapter we discuss the existing basic and clinical data on the role of B vitamins in cardiovascular disease. We focus on the homocysteine lowering B vitamins (folic acid, B6 and B12). We review the beneficial cardiovascular effects of B vitamins per se at a molecular level as well as the lessons learned from clinical trials. We discuss recent concerns over B vitamin administration at pharmacological doses and the issue of folate fortification in the context of cardiovascular disease prevention. Clinical trials have failed to provide any strong evidence in favour of the use of B vitamins in cardiovascular disease prevention. However, the positive mechanistic data mandate closer investigation of the role of B vitamins in cardiovascular physiology.

Background Cardiovascular magnetic resonance (CMR) of the vessel wall is highly reproducible and can evaluate both changes in plaque burden and composition. It can also measure aortic compliance and endothelial function in a single integrated examination. Previous studies have focused on patients with pre-identified carotid atheroma. We define these vascular parameters in patients presenting with coronary artery disease and test their relations to its extent and severity. Methods and Results 100 patients with CAD [single-vessel (16%); two-vessel (39%); and three-vessel (42%) non-obstructed coronary arteries (3%)] were studied. CAD severity and extent was expressed as modified Gensini score (mean modified score 12.38 ± 5.3). A majority of carotid plaque was located in the carotid bulb (CB). Atherosclerosis in this most diseased segment correlated modestly with the severity and extent of CAD, as expressed by the modified Gensini score (R = 0.251, P < 0.05). Using the AHA plaque classification, atheroma class also associated with CAD severity (rho = 0.26, P < 0.05). The distal descending aorta contained the greatest plaque, which correlated with the degree of CAD (R = 0.222; P < 0.05), but with no correlation with the proximal descending aorta, which was relatively spared (R = 0.106; P = n. s.). Aortic distensibility varied along its length with the ascending aorta the least distensible segment. Brachial artery FMD was inversely correlated with modified Gensini score (R = -0.278; P < 0.05). In multivariate analysis, distal descending aorta atheroma burden, distensibility of the ascending aorta, carotid atheroma class and FMD were independent predictors of modified Gensini score. Conclusions Multimodal vascular CMR shows regional abnormalities of vascular structure and function that correlate modestly with the degree and extent of CAD.

Coronary atherosclerosis is the largest cause of mortality and morbidity in industrialised countries. Despite recent advances in medical therapies, the prevention and treatment of atherosclerosis remain suboptimal. Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall, involving the accumulation of macrophages and excess low density lipoproteins (LDL), the formation of foam cells which create the atheromatous plaque, resulting in stenosis, aneurysm and plaque rupture leading to acute coronary events. Every step in the atherogenesis process is a potential therapeutic target for both the prevention and regression of atherosclerosis. A novel approach is the use of nanoparticles containing drugs, providing new perspectives in targeted modification of these pathways. Nanoparticles are ultrafine particles sized between 1-100 nm. By using specific methods, nanoparticles can be filled with drugs and achieve targeted drug delivery near the diseased area. In this review article we describe the basic actions of nanoparticles, and we discuss their potential applications in atherosclerosis. We also discuss their advantages and we expose the existing toxicity issues, making it clear however, that the use of nanoparticles is one of the most promising therapeutic strategies against atherosclerosis.

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.