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We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03–1.09, P  = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30–6.26, P  < 0.01) were the only independent predictors of the primary outcome. The TG/HDL-C ratio and the CTA risk score progressed over time despite increased use of lipid-lowering drugs and reduction in LDL-C. In patients with stable angina, high TG and low HDL-C levels are associated with CAD related outcomes independently of LDL-C and treatments. Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.

Atherosclerosis is becoming the number one cause of death worldwide. In this study, three-dimensional computer model of plaque formation and development for human carotid artery is developed. The three-dimensional blood flow is described by the Navier–Stokes equation, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection–diffusion equation. The low-density lipoproteins transports in lumen of the vessel and through the vessel tissue are coupled by Kedem–Katchalsky equations. The inflammatory process is modeled using three additional reaction–diffusion partial differential equations. Fluid–structure interaction is used to estimate effective wall stress analysis. Plaque growth functions for volume progression are correlated with shear stress and effective wall stress distribution. We choose two specific patients from MRI study with significant plaque progression. Plaque volume progression using three time points for baseline, 3- and 12-month follow up is fitted. Our results for plaque localization correspond to low shear stress zone and we fitted parameters from our model using nonlinear least-square method. Determination of plaque location and composition, and computer simulation of progression in time for a specific patient shows a potential benefit for the prediction of disease progression. The proof of validity of three-dimensional computer modeling in the evaluation of atherosclerotic plaque burden may shift the clinical information of MRI from morphological assessment toward a functional tool. Understanding and prediction of the evolution of atherosclerotic plaques either into vulnerable or stable plaques are major tasks for the medical community.

Supplementation of glutathione (GSH) may be a positive strategy to improve the endogenous antioxidant defense required to counteract many acute and chronic diseases. However, the efficacy of GSH treatment seems to be closely related to type of administration, degree of absorption, and increase of its concentrations. The aim of this study was to test a new sublingual formulation of L-GSH, which enters directly the systemic circulation, to assess its efficacy on circulating biochemical markers of hepatic metabolism, lipid profile, and oxidative stress and on peripheral vascular function compared with placebo in patients with cardiovascular risk factors (CVRF). We enrolled 16 healthy men with CVRF in a double-blinded, randomized placebo-controlled crossover study. At each visit, blood samples were collected for biochemistry analyses and peripheral endothelial function (reactive hyperemia index [RHI]) and stiffness were measured by Endo-PAT2000. In the overall population, a decrease in total and low-density lipoprotein cholesterol was highlighted after L-GSH supplementation compared with placebo (P = 0.023 and P = 0.04, respectively). On the contrary, no difference was observed in RHI and oxidative stress markers between L-GSH and placebo in the study population. However, seven participants with baseline abnormal RHI (≤1.67) compared with those with normal RHI showed a significant reduction of arterial stiffness after L-GSH administration, (P = 0.007 and P = 0.037, respectively). Supplementation of L-GSH compared with placebo influences the lipid profile of patients with CVRF. Sublingual L-GSH may represent a valid prevention of vascular damage in patients with CVRF and endothelial dysfunction. •The presented study tested a sublingual formulation of l-glutathione (L-GSH) in men with cardiovascular risk factors.•We evaluated vascular function and biochemical markers.•L-GSH improved vascular elasticity in men with abnormal vasodilation.•L-GSH decreased total and low-density lipoprotein cholesterol in study participants.

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (β -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.)

The immune response is crucial in the development of multi-organ failure (MOF) and complications in end-stage heart failure patients supported by left ventricular assist device (LVAD). However, at pre-implant, the association between inflammatory state and post-LVAD outcome is not yet clarified. Aim of the study was to assess the relationship among pre-implant levels of immune-related cytokines, postoperative inflammatory response and 3-month outcome in LVAD-patients. In 41 patients undergoing LVAD implantation, plasma levels of interleukin (IL)-6, IL-8, crucial for monocyte modulation, and urine neopterin/creatinine ratio (Neo/Cr), marker of monocyte activation, were assessed preoperatively, at 3 days, 1 and 4 weeks post-LVAD. MOF was evaluated by total sequential organ failure assessment (tSOFA) score. Intensive care unit (ICU)-death and/or post-LVAD tSOFA ≥11 was considered as main adverse outcome. Length of ICU-stay, 1 week-tSOFA score, hospitalisation and 3-month survival were considered additional end-points. During ICU-stay, 8 patients died of MOF, while 8 of the survivors experienced severe MOF with postoperative tSOFA score ≥11. Pre-implant level of IL-6 ≥ 8.3 pg/mL was identified as significant marker of discrimination between patients with or without adverse outcome (OR 6.642, 95% CI 1.201-36.509, p = 0.030). Patients were divided according to pre-implant IL-6 cutoff of 8.3 pg/ml in A [3.5 (1.2-6.1) pg/mL] and B [24.6 (16.4-38.0) pg/mL] groups. Among pre-implant variables, only white blood cells count was independently associated with pre-implant IL-6 levels higher than 8.3 pg/ml (OR 1.491, 95% CI 1.004-2.217, p = 0.048). The ICU-stay and hospitalisation resulted longer in B-group (p = 0.001 and p = 0.030, respectively). Postoperatively, 1 week-tSOFA score, IL-8 and Neo/Cr levels were higher in B-group. LVAD-candidates with elevated pre-implant levels of IL-6 are associated, after intervention, to higher release of monocyte activation related-markers, a clue for the development of MOF, longer clinical course and poor outcome.

Background: coronary computed tomography angiography (CCTA) is a first line non-invasive imaging modality for detection of coronary atherosclerosis. Computational modeling with lipidomics analysis can be used for prediction of coronary atherosclerotic plaque progression. Methods: 187 patients (480 vessels) with stable coronary artery disease (CAD) undergoing CCTA scan at baseline and after 6.2 ± 1.4 years were selected from the SMARTool clinical study cohort (Clinicaltrial.gov Identifiers NCT04448691) according to a computed tomography (CT) scan image quality suitable for three-dimensional (3D) reconstruction of coronary arteries and the absence of implanted coronary stents. Clinical and biohumoral data were collected, and plasma lipidomics analysis was performed. Blood flow and low-density lipoprotein (LDL) transport were modeled using patient-specific data to estimate endothelial shear stress (ESS) and LDL accumulation based on a previously developed methodology. Additionally, non-invasive Fractional Flow Reserve (FFR) was calculated (SmartFFR). Plaque progression was defined as significant change of at least two of the morphological metrics: lumen area, plaque area, plaque burden. Results: a multi-parametric predictive model, including traditional risk factors, plasma lipids, 3D imaging parameters, and computational data demonstrated 88% accuracy to predict site-specific plaque progression, outperforming current computational models. Conclusions: Low ESS and LDL accumulation, estimated by computational modeling of CCTA imaging, can be used to predict site-specific progression of coronary atherosclerotic plaques.

Background and Aims: Coronary atherosclerosis is a chronic non-resolving inflammatory process wherein the interaction of innate immune cells and platelets plays a major role. Circulating neutrophils, in particular, adhere to the activated endothelium and migrate into the vascular wall, promoting monocyte recruitment and influencing plaque phenotype and stability at all stages of its evolution. We aimed to evaluate, by flow cytometry, if blood neutrophil number and phenotype—including their phenotypic relationships with platelets, monocytes and lymphocytes—have an association with lipid-rich necrotic core volume (LRNCV), a generic index of coronary plaque vulnerability, in a group of stable patients with chronic coronary syndrome (CCS). Methods: In 55 patients, (68.53 ± 1.07 years of age, mean ± SEM; 71% male), the total LRNCV in each subject was assessed by a quantitative analysis of all coronary plaques detected by computed tomography coronary angiography (CTCA) and was normalized to the total plaque volume. The expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1, CXCR4 and CD41a cell surface markers was quantified by flow cytometry. Adhesion molecules, cytokines and chemokines, as well as MMP9 plasma levels, were measured by ELISA. Results: On a per-patient basis, LRNCV values were positively associated, by a multiple regression analysis, with the neutrophil count (n°/µL) (p = 0.02), neutrophil/lymphocyte ratio (p = 0.007), neutrophil/platelet ratio (p = 0.01), neutrophil RFI CD11b expression (p = 0.02) and neutrophil–platelet adhesion index (p = 0.01). Significantly positive multiple regression associations of LRNCV values with phenotypic ratios between neutrophil RFI CD11b expression and several lymphocyte and monocyte surface markers were also observed. In the bivariate correlation analysis, a significantly positive association was found between RFI values of neutrophil–CD41a+ complexes and neutrophil RFI CD11b expression (p < 0.0001). Conclusions: These preliminary findings suggest that a sustained increase in circulating neutrophils, together with the up-regulation of the integrin/activation membrane neutrophil marker CD11b may contribute, through the progressive intra-plaque accumulation of necrotic/apoptotic cells exceeding the efferocytosis/anti-inflammatory capacity of infiltrating macrophages and lymphocytes, to the relative enlargement of the lipid-rich necrotic core volume of coronary plaques in stable CAD patients, thus increasing their individual risk of acute complication.

Patients with systemic sclerosis (SSc) are at risk for developing pulmonary hypertension, which is associated with a poor prognosis. Exercise Doppler echocardiography enables the identification of exercise-induced increase in pulmonary artery systolic pressure (PASP) and may provide a thorough noninvasive hemodynamic evaluation. The aim of this study was to evaluate the clinical and echocardiographic determinants of exercise-induced increase in PASP in a large population of patients with SSc. We selected 164 patients with SSc (age 58 ± 13 years, 91% female) with normal resting PASP (<40 mm Hg) who underwent a comprehensive 2-dimensional and Doppler echocardiography and graded bicycle semisupine exercise Doppler echocardiography. Pulmonary artery systolic pressure, cardiac output, and pulmonary vascular resistance (PVR) were estimated noninvasively. Cutoff values of PASP ≥50 mm Hg and PVR ≥3.0 Wood Units at peak exercise were considered a significant exercise-induced increase in PASP and PVR, respectively. Sixty-nine (42%) patients showed a significant exercise-induced increase in PASP. Among them, peak PVR ≥3 Wood Units was present only in 11% of patients, about 5% of the total population. Univariate analysis showed that age, presence of interstitial lung disease, and both right and left diastolic dysfunction are predictors of peak PASP ≥50 mm Hg, but none of these parameters predict elevated peak PVR. Exercise-induced increase in PASP occurs in almost one-half of patients with SSc with normal resting PASP. Peak exercise PASP is affected by age, interstitial lung disease, and right and left ventricular diastolic dysfunction and, only in 5% of the patients, is associated with an increase in PVR during exercise, suggesting heterogeneity of the mechanisms underlying exercise-induced pulmonary hypertension in SSc.

Background. In acute coronary syndrome (ACS), inflammation and redox response are associated with increased residual platelet reactivity (RPR) on clopidogrel therapy. We investigated whether clopidogrel interaction affects platelet function and modulates factors related to inflammation and oxidation in ACS patients differently responding to clopidogrel. Material and Methods. Platelet aggregation was measured in 29 ACS patients on dual (aspirin/clopidogrel) antiplatelet therapy. Nonresponders (NR) were defined as RPR ≥70% by ADP. Several inflammatory and redox parameters were assayed and platelet proteome was determined. Results. Eight (28%) out of 29 ACS patients resulted NR to clopidogrel. At 24 hours, the levels of Th2-type cytokines IL-4, IFNγ, and MCP-1 were higher in NR, while blood GSH (r-GSHbl) levels were lower in NR than responders (R). Proteomic analysis evidenced an upregulated level of platelet adhesion molecule, CD226, and a downregulation of the antioxidant peroxiredoxin-4. In R patients the proinflammatory cytokine IL-6 decreased, while the anti-inflammatory cytokine IL-1Ra increased. Conclusions. In patients with high RPR on clopidogrel therapy, an unbalance of inflammatory factors, platelet adhesion molecules, and circulatory and platelet antioxidant molecules was observed during the acute phase. Proinflammatory milieu persists in nonresponders for a long time after the acute event while antioxidant blood factors tend to conform to normal responsiveness.

Background: Atherosclerosis is a chronic inflammatory disease. The balance between pro- and anti-inflammatory factors, acting on the arterial wall, promotes less or more coronary plaque macro-calcification, respectively. We investigated the association between monocyte phenotypic polarization and CTCA-assessed plaque dense-calcium volume (DCV) in patients with stable coronary artery disease (CAD). Methods: In 55 patients, individual DCV component was assessed by quantitative CTCA and normalized to total plaque volume. Flow cytometry expression of CD14, CD16, CD18, CD11b, HLA-DR, CD163, CCR2, CCR5, CX3CR1 and CXCR4 was quantified. Adhesion molecules and cytokines were measured by ELISA. Results: DCV values were significantly associated, by multiple regression analysis, with the expression (RFI) of CCR5 (p = 0.04), CX3CR1 (p = 0.03), CCR2 (p = 0.02), CD163 (p = 0.005) on all monocytes, and with the phenotypic M2-like polarization ratio, RFI CCR5/CD11b (p = 0.01). A positive correlation with the increased expression of chemokines receptors CCR2, CCR5 and CX3CR1 on subsets Mon1 was also present. Among cytokines, the ratio between IL-10 and IL-6 was found to be strongly associated with DCV (p = 0.009). Conclusions: The association between DCV and M2-like phenotypic polarization of circulating monocytes indicates that plaque macro-calcification in stable CAD may be partly modulated by an anti-inflammatory monocyte functional state, as evidenced by cell membrane receptor patterns.