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Objective: To make a prospective assessment of the clinical and prognostic correlates of angiographically diffuse non-obstructive coronary lesions.Design: Angiographic vessel and extent scores were calculated in 228 clinically stable patients (mean (SD) age, 60 (11) years; 43 women, 185 men) undergoing prospective follow up for the composite end point of death and myocardial infarction. The effect on outcome of clinical variables (age, sex, previous myocardial infarction, diabetes mellitus, smoking habit, systemic hypertension, hypercholesterolaemia, ejection fraction) and angiographic variables (vessel and extent score) was evaluated by Cox's proportion hazard model.Results: The vessel score was 3 in 34 patients (15%), 2 in 78 (34%), 1 in 87 (38%), and 0 in 29 (13%). Median extent score was 60 (range 6-110; first quartile 40, third quartile 70). Forty one events (nine deaths and 32 myocardial infarcts) occurred over a median follow up period of 30 months. Age and extent score were the only multivariate predictors of outcome, but the latter provided 28% additional prognostic information after adjustment for the most predictive variables (gain in chi2 = 7, p < 0.01). A vessel score of 3 was associated with worse survival, while no significant discrimination was possible among the other groups. However, assignment of patients to two groups according to an ROC curve derived cut off value for the extent score made it possible to obtain significant discrimination of survival even in cases with vessel scores of 0 to 2. Age and diabetes were clinical markers of a higher extent score.Conclusions: The angiographic extent score is a powerful marker of adverse outcome independent of severity and the number of flow limiting coronary lesions, and may reflect the link between clinical risk profile and diffusion of coronary atherosclerosis. Thus it should be of clinical value for targeting aggressive preventive measures. [ABSTRACT FROM AUTHOR]

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Commission in the H2020 program: Project SMARTool, "Simulation Modeling of coronary ARTery disease: a tool for clinical decision support—SMARTool" Background and aims The coexistence of elevated plasma triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) may contribute to the residual cardiometabolic risk of coronary artery disease (CAD) independently of total cholesterol and low-density lipoprotein cholesterol (LDL-C) absolute plasma levels [1]. Aim of this study is to assess whether a high TG/HDL-C ratio is characterized by a specific lipidomics signature in statin users and its relationship with the coronary risk score defined by coronary computed tomography angiography (CTA). Methods TG/HDL-C ratio was calculated in 132 patients (68.8±7.7 years, 85 males) with suspected or known CAD referred to coronary CTA and receiving statins treatment in the last 6.3 ± 1.4 years before enrolment. Patients were grouped according to TG/HDL-C ratio quartiles: IQ (≤1.694), IIQ (1.695-2.399), IIIQ (2.400-3.281), and IVQ (>3.282). Coronary CTA exams were analysed according to the modified 17-segment American Heart Association classification [2] and interpretable segments were visually assessed for degree of stenosis and plaque composition. A comprehensive coronary risk score (CTA score) [3], previously validated as predictor of adverse outcome, was calculated in each patient. Except for subjects with normal arteries (CTA score = 0), all patients were classified into 3 groups of CTA score severity:  low (score < 5), intermediate (score 5-20) and high (score > 20) risk [4]. Patient-specific plasma targeted lipidomics was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach allowed to quantify 69 circulating lipids encompassing six lipid classes (triacylglycerol [TG], phosphatidylcholine [PC], phosphatidylethanolamine [PE], ceramide [Cer], sphingomyelin [SM], cholesterol ester [CE]). Differential analysis was performed using TG/HDL-C and CTA score annotation. Results 18 altered lipid species in the group with higher TG/HDL-C ratio were also altered in the group with higher CTA risk score. This common set of lipids is composed of CE(16:0), CE(18:0), PC(38:2), 8 SM [SM(34:2), SM(38:2), SM(41:2), SM(41:1), SM(42:4), SM(42:3), SM(42:1), SM(43:3)], TG(52:1) and 6 PE [PE(34:0), PE(34:1), PE(34:2), PE(36:1), PE(36:2), PE(36:3)], and represents the lipidomics signature associating elevated plasma TG/HDL-C ratio with high CTA risk score in statin users. Conclusion In patients with stable CAD under statin treatment, a specific pattern of altered lipids, characterized by reduced plasma levels of cholesterol esters and sphingomyelins and increased levels of triacylglicerols and phosphatidylethanolamines, is associated with high TG/HDL-C ratio and high CTA score. This specific lipidomic signature identifies patients with higher residual cardiometabolic and coronary risk, not tackled by current lipid lowering therapy, unveiling possible new molecular targets of treatment. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Background. Inflammation is a critical process contributing to heart failure (HF).We hypothesized that IL-33/ST2 pathway, a new mechanism regulated during cardiac stress, may be involved in the functional worsening of end-stage HF patients, candidates for left ventricular assist device (LVAD) implantation, and potentially responsible for their outcome. Methods. IL-33, ST2, and conventional cytokines (IL-6, IL-8, and TNF-α) were determined in cardiac biopsies and plasma of 22 patients submitted to LVAD implantation (pre-LVAD) and compared with (1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior circulatory support (HT); (2) patients supported by LVAD at the moment of LVAD weaning (post- LVAD). Results. Cardiac expression of ST2/IL-33 and cytokines was lower in the pre-LVADthan in theHT group. LVADdetermined an increase of inflammatory mediators comparable to levels of the HT group. Only ST2 correlated with outcome indices after LVAD implantation. Conclusions. IL-33/ST2 and traditional cytokines were involved in decline of cardiac function of ESHF patients as well as in hemodynamic recovery induced by LVAD. IL-33/ST2 pathway was also associated to severity of clinical course.Thus, a better understanding of inflammation is the key to achieving more favorable outcome by new specific therapies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Neopterin, a marker of inflammation and monocyte activation, is found increased in patients with heart failure (HF). This study investigates whether neopterin levels correlate with left ventricular (LV) remodeling and brain natriuretic peptide (BNP), a marker of cardiac stress, in chronic HF (CHF) patients with different severity of disease. Design and methods: The relationship between neopterin and LV dimensions, NT-proBNP, and pro-inflammatory cytokines were studied in 98 CHF patients, while nineteen healthy subjects were enrolled as controls. Nineteen (19%) patients were in NYHA class I, 38 (39%) in NYHA class II, 27 (28%) in NYHA class III, and 14 (14%) in NYHA class IV. Results: Neopterin levels were higher in CHF patients than in age- and gender-matched healthy controls, and related with indexed LV end-diastolic volume (LVEDVi). Prospectively CHF patients were separated into tertiles of low, medium and high neopterin levels. Among patients, male gender, LVEDVi, diuretic treatment, NYHA class I, NT-proBNP and IL-8 levels were significant determinants of urine neopterin levels by bivariate analysis. Neopterin levels were associated only to LV remodeling, as assessed by LVEDVi, and IL-8 levels, a crucial monocyte chemoattractant, by multivariate ordinal regression analysis. Conclusions: The relationship between elevated neopterin levels and LV enlargement in CHF patients suggests a crucial role of monocyte activation in the development of cardiac dysfunction in CHF patients. Assessment of neopterin levels is a potential biomarker to evaluate the progression of LV remodeling in CHF patients. [Copyright &y& Elsevier]

Abstract: This study aimed to evaluate left ventricular assist device (LVAD) effects on natriuretic peptide (NP) prohormone plasma levels in end-stage heart failure (HF) patients, especially NT-proCNP, in order to better characterize the NP system during hemodynamic recovery by LVAD. HF patients (n =17, NYHA III-IV) undergoing LVAD were studied: 6 died of multi-organ failure syndrome (NS) and 11 survived (S). Total sequential organ failure assessment (t-SOFA) score and blood samples were obtained at admission (T1) and at 24, 72h and 1, 2, 4 weeks (T2–T6) after LVAD. In S, NT-proANP and NT-proCNP significantly increased at 24h after implantation, reaching a reduction to basal levels at 4 weeks following LVAD [NT-proANP: T1 vs. T2 p =0.017, NT-proCNP: T1 vs. T2 p =0.028, T1 vs. T3 p =0.043]. Elevated NT-proBNP plasma levels were observed at all times. In NS, NP plasma levels sustained higher with respect to S. No statistical variation was observed for NT-proCNP and NT-proANP in S and NS while NT-proBNP reached significant differences at T4 in NS. Considering S+NS, only NT-proCNP strongly correlated with t-SOFA score at T1 (rho=0.554, p =0.04) while subdividing patients NT-proCNP positively correlated in NS with t-SOFA score (rho=0.988, p =0.002) only at T4. In NS a correlation between NT-proCNP and NT-proBNP at T1 was observed (rho=−0.900, p =0.037). Both IL-6 and TNF-alpha sustained higher in NS patients than in S; in particular, statistical significance was observed for IL-6. The study of new peptides, such as NT-proCNP, would provide additional information for identifying patients who are more likely to recover. [Copyright &y& Elsevier]

In this work, we present a platform for the development of multiscale patient-specific artery and atherogenesis models. The platform, called ARTool, integrates technologies of 3-D image reconstruction from various image modalities, blood flow and biological models of mass transfer, plaque characterization, and plaque growth. Patient images are acquired for the development of the 3-D model of the patient specific arteries. Then, blood flow is modeled within the arterial models for the calculation of the wall shear stress distribution (WSS). WSS is combined with other patient-specific parameters for the development of the plaque progression models. Real-time simulation can be performed for same cases in grid environment. The platform is evaluated using both animal and human data. [ABSTRACT FROM AUTHOR]

Objectisves: To assess the value of the European system For cardiac operative risk evaluation (EuroSCORE), a validated model for prediction of in-hospital mortality after cardiac surgery, in predicting long term event-free survival. Design and setting: Single institution observational cohort study. Patients: Adult patients (n = 1230) who underwent cardiac surgery between January 2000 and August 2002. Results: Mean age was 65(11) years and 32% were women. Type of surgery was isolated coronary artery bypass grafting in 62%, valve surgery in 23%, surgery on the thoracic aorta in 4%, and combined or other procedures in 11%. Mean EuroSCORE was 4.53 (3.16) (range 0-21); 366 were in the low (0-2), 442 in the medium (3-5), 288 in the high (6-8), and 134 in the very high risk group (⩾ 9). Information on deaths or events leading to hospital admission after the index discharge was obtained from the Regional Health Database. Out of hospital deaths were identified through the National Death Index. In-hospital 30 day mortality was 2.8% (n = 34). During 2024 person-years of follow up, 44 of 1196 patients discharged alive (3.7%) died. By Cox multivariate analysis, EuroSCORE was the single best independent predictor of long term all cause mortality (hazard ratio (HR) 1.55, 95% confidence interval (CI) 1.03 to 2.34, p < 0.0001). In the time to first event analysis, 227 either died without previous events (n = 20, 9%) or were admitted to hospital for an event (n = 207, 91%). EuroSCORE (HR 1.60, 95% CI 1.36 to 1.89, p < 0.0001), the presence of ⩾ 2 co-morbidities versus one (HR 1.49, 95% Cl 1.09 to 2.02, p < 0.0001), and < 96 hour? stay in the intensive care unit after surgery (HR 2.04, 95% Cl 1.42 to 2.95, p = 0.0001) were independently associated with the combined end point of death or hospital admission after the index discharge. Conclusions: EuroSCORE and a prolonged intensive care stay after surgery are associated with long term event-free survival and can be used to tailor long term postoperative follow up and plan resource allocation for the cardiac surgical patient. [ABSTRACT FROM AUTHOR]

Objectives: To assess the link between perfusion, metabolism, and function in viable myocardium before and early after surgical revascularisation. Design: Myocardial blood flow (MBF, thermodilution technique), metabolism (lactate, glucose, and free fatty acid extraction and fluxes), and function (transoesophageal echocardiography) were assessed in patients with critical stenosis of the left anterior descending coronary artery (LAD) before and 30 minutes after surgical revascularisation. Setting: Tertiary cardiac centre. Patients: 23 patients (mean (SEM) age 57 (1.7) years with LAD stenosis: 17 had dysfunctional viable myocardium in the LAD territory, as shown by thallium-201 rest redistribution and dobulamine stress echocardiography (group 1), and six had normally contracting myocordium (9roup 2). Results: LAD MBF was lower in group 1 than in group 2 (58 (7) v 113 (21) mI/mm, p < 0.001) before revascularisation and improved postoperatively in group 1 (129 (133) mI/mm, p < 0.001) but not in group 2 (105 (20) mI/mm, p = 0.26). Group I also hod functional improvement in the LAD territory at intraoperative echocardiography (mean regional wall motion score from 2.6 (0.85) to 1.5 (0.98), p < 0.01). Oxidative metabolism, with lactate and free fatty acid extraction, was found preoperatively and postoperatively in both groups; however, lactate and free fatty acid uptake increased after revascularisation only in group 1. Conclusions: MBF is reduced and oxidative metabolism is preserved at rest in dysfunctional but viable myocardium. Surgical revascularisation yields immediate perfusion and functional improvement, and increases the uptake of lactate and free fatty acids. [ABSTRACT FROM AUTHOR]

The aim of this report was to assess the relation between heart rate response to dipyridamole infusion and perfusion defects at quantitative sestamibi single-photon emission computed tomographic imaging. We demonstrated in 166 heart transplant recipients that chronotropic incompetence to dipyridamole is the only significant and independent predictor of perfusion defects. [ABSTRACT FROM AUTHOR]

Purpose: De-differentiation and phenotype changes in vascular smooth muscle cells (VSMCs) are hallmarks of vascular disorders such as atherosclerosis (ATS). High fat diet pigs were exploited as model of accelerated coronary ATS. In the present study, a gel-free proteomics approach was proposed to highlight protein markers modulated during atherogenesis and plaque growth in cultured VSMCs obtained from coronary and femoral arteries.Methods: Protein extracts from cultured VSMCs obtained from coronary and femoral arteries of pigs that had been fed with standard (CTRL) and high fat (HF) diet were digested with trypsin. Peptide mixtures were fractioned by HPLC and collected for ESI QTOF analyses. Protein expression variations amongst different cell specimens were examined and the correlation between stage of ATS development and protein modulations were immunohistologically assessed. Confocal microscopy was used to characterise cell morphology.Results: Histological analysis showed intact coronary wall in CTRL (arteries from healthy pigs), early ATS changes in femoral arteries and fibrofatty atheromas in coronary segments (cross-sectional lesion area of 0,05-0,1 mm2, and 0,3- 3,0 mm2 respectively) of HF pig. Comparing the proteomes of VSMCs isolated from healthy coronaries, pre-lesional femoral arteries and atherosclerotic coronaries allowed the highlighting, among the 264 identified proteins, of four functional protein classes. In particular, redox enzymes (i.e. catalase, superoxide dismutase, peroxiredoxin), related to energetic metabolism mitochondrial proteins (i.e. cytochrome c oxidase, succinyl trasferase), annexins (i.e. the anti-inflammatory Annexin-A1) and focal adhesion molecules (i.e. moesin, thymosin, integrin beta 1) showed differential expressions depending on the ATS stage.Conclusion: In overt atherosclerosis, VSMCs acquire a distinct protein "signature" that suggests an increase of redox events and mitochondrial damage. Focal adhesion pathways seem to have a pivotal role in the onset of VSMC pathological phenotype and this study may suggest possible targets for therapeutic treatment in proliferative disorders. [ABSTRACT FROM PUBLISHER]

Purpose: Baseline low/oscillatory wall shear stress (WSS) is assumed to be a determinant of artery/site specificity of atherogenesis. However, different flow and plaque metrics, spatial resolution and imaging co-registration accuracy may lead to different results in correlating site-specific WSS values and lesion probability/size. In this study we compared, by high resolution histology-validated ex vivo microCT coronary profiling, baseline and end-diet maximal and mean WSS values averaged at 2 different axial thickness in a hypercholesterolemic swine model of atherogenesis.Methods: In pigs on high fat diet, an IVUS catheter (20 MHz,100, 200 μm axial resolution, 5 mm penetration) has been advanced in distal left anterior descending artery (LAD), coronary Doppler flow velocity measured, and resulting 2D tomographic sections used to obtain 3D reconstruction for WSS estimate. WSS coronary profiling was obtained before and after 4 wks hypercholesterolemic diet.En bloc formalin fixed LAD was analysed by micro-CT scanner at 57.4 μm3 voxel resolution (up to 1300 consecutive cross-sections) and then processed for histomorphometry. 3D curved multi-planar reformation (MPR), image segmentation and 3D volume rendering allowed registration between microCT and IVUS cross-sectional frames at 120-130 corresponding sites. Coronary profiling of slice-averaged maximal and mean values of baseline and end-diet WSS and microCT plaque area (LA) and maximal intimal thickness (IT), validated by histomorphometry, were compared.Results: Statistically significant relations were found between 1. Plaque location and baseline WSS mean values at low resolution 2. Baseline WSS values and LA and IT of developed plaque at corresponding sites at low resolution 3. Baseline and end-diet diet mean and maximal WSS and LA(or IT) of mild/minimal intima changes (ATS initiation) at high resolution 4. End-diet maximal WSS values and plaque LA (or IT) at sites corresponding to the upstream slope of atheroma at high resolution.Conclusions: These findings confirm the higher incidence of atherogenesis at lower WSS sites within a single artery also suggesting that in the hypercholesterolemic swine model of atherogenesis, at higher spatial resolution of co-registered sections, 1. the overall inverse correlation between baseline WSS and plaque location/size becomes weaker 2. significant opposite wall geometry-related correlations are evidenced at different stages of developed lesions. [ABSTRACT FROM PUBLISHER]

Purpose: A major drawback in atherogenesis research is the difficulty of investigating early phase of disease in the clinical context. A high-cholesterol diet animal model of coronary artery disease was exploited in order to characterized by histomorphometry early stages of disease and to identify plaque-related markers of accelerated atherogenesis. The comparison of the secretomes from atherosclerotic and healthy coronaries led to the identification of differentially released proteins. Histology and immunohistology validated the proteomics results, allowing the tissue localization of interesting factors and correlating the released proteins with the lesion stage.Methods: Histological characterization of segmented main coronary arteries was performed in high cholesterol (HCD) and standard diet treated (SD) farm pigs and histomorphometry indexes (intimal thickness and lesion area wall percent) of all lesions were estimated. Right coronary artery (RCA) segments from HCD and SD animals were incubated for 24 hrs in serum-free medium. Released proteins were digested with trypsin and analysed by HPLC coupled with mass spectrometry. Immunohistology was performed for the most relevant differentially expressed proteins.Results: Atherosclerotic lesions (from fatty streaks to fibrofatty atheromas) of all 3 main coronary arteries have been observed in HCD group, with intimal thickening of 0,52±0,38 mm and lesion area of 40 ± 26%. Proteomics analysis of secreted factors identified 200 actively secreted proteins, of which, 10 were up-released as compared to SD and 6 were significantly related to morphometric indexes of ATS severity and burden. Among these, Chitinase-3-like protein 1 was validated by immunostaining. This last co-localizes with alpha-SM actin showing a distinctive tissue distribution that resulted significantly correlated to secretome expression both in early (fatty streaks) and atheromatous lesions.Conclusions: In the accelerated coronary atherogenesis swine model, tissue factors related to ATS stages and overall burden have been identified. These factors are strictly linked to VSMC phenotype changes and cell activation, thus they may be regarded as specific lesion-related molecules and are exploitable as potential biomarkers of atherosclerosis progression. [ABSTRACT FROM AUTHOR]