Incremental value of blood-based markers of liver fibrosis in cardiovascular risk stratification.

AIMS: Non-alcoholic fatty liver disease (NAFLD) with advanced liver fibrosis is associated with cardiovascular disease (CVD). To examine if markers of vascular injury mediate the link between liver fibrosis non-invasive tests (LFNITs) and CVD events, and to compare the incremental predictive value of LFNITs over established CVD risk scores. METHODS: Consecutively recruited individuals (n=1,692) with or without clinically overt coronary artery disease (CAD) from the Athens Cardiometabolic Cohort, were analysed. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), and BARD score were evaluated for direct and indirect associations with indices of subclinical arterial injury including carotid maximal wall thickness (maxWT) and pulse wave velocity (PWV) and with a composite of major adverse cardiovascular events (MACE) that consisted of cardiac death, acute myocardial infarction, or coronary revascularization (39-month median follow-up). RESULTS: FIB-4 was the only LFNIT which consistently associated with multiple markers of vascular injury, irrespective of CAD presence and after controlling for traditional risk factors, surrogates of insulin resistance or obesity (adjusted p<0.05 for all). FIB-4 also independently associated with CAD presence (adjusted OR 6.55 (3.48-12.3), p<0.001). Increased FIB-4>2.67 was incrementally associated with increased risk for MACE (OR (95% CI) 2.00(1.12, 3.55), deltaAUC (95% CI) 0.014(0.002-0.026)). These associations were mediated by maxWT rather than PWV. Only FIB-4 (>3.25) was independently and incrementally associated with all-cause mortality (adjusted p<0.05). CONCLUSIONS: In a cardio-metabolically diverse population, the incremental associations of LFNITs with CVD outcomes were mediated by atherosclerotic burden rather than arterial stiffening. FIB-4 consistently demonstrated associations with all study endpoints. These findings provide mechanistic insights and support the clinical applicability of FIB-4 in CVD prevention.

Amyloid beta is associated with carotid wall echolucency and atherosclerotic plaque composition.

Circulating amyloid-beta 1-40 (Αb40) has pro-atherogenic properties and could serve as a biomarker in atherosclerotic cardiovascular disease (ASCVD). However, the association of Ab40 levels with morphological characteristics reflecting atherosclerotic plaque echolucency and composition is not available. Carotid atherosclerosis was assessed in consecutively recruited individuals without ASCVD (n = 342) by ultrasonography. The primary endpoint was grey scale median (GSM) of intima-media complex (IMC) and plaques, analysed using dedicated software. Vascular markers were assessed at two time-points (median follow-up 35.5 months). In n = 56 patients undergoing carotid endarterectomy, histological plaque features were analysed. Plasma Αb40 levels were measured at baseline. Ab40 was associated with lower IMC GSM and plaque GSM and higher plaque area at baseline after multivariable adjustment. Increased Ab40 levels were also longitudinally associated with decreasing or persistently low IMC and plaque GSM after multivariable adjustment (p < 0.05). In the histological analysis, Ab40 levels were associated with lower incidence of calcified plaques and plaques without high-risk features. Ab40 levels are associated with ultrasonographic and histological markers of carotid wall composition both in the non-stenotic arterial wall and in severely stenotic plaques. These findings support experimental evidence linking Ab40 with plaque vulnerability, possibly mediating its established association with major adverse cardiovascular events.

Investigation of Antihypertensive Properties of Chios Mastic via Monitoring microRNA-21 Expression Levels in the Plasma of Well-Controlled Hypertensive Patients.

Hypertension is a chronic, multifactorial disease, leading to high cardiovascular morbidity and mortality globally. Despite the advantages of pharmaceutical treatments, natural products have gained scientific interest due to their emerging phytotherapeutic properties. Chios mastic is a natural Greek product, consisting of bioactive compounds which modify microRNAs' (small, expression-regulating molecules) expression. In this study, we investigated the antihypertensive properties of Chios mastic through the assessment of miR-21 levels. Herein, plasma samples of 57 individuals with hypertension, recruited for the purposes of the HYPER-MASTIC study, were analyzed. This was a clinical trial with Chios mastic supplements in which the patients were divided into groups receiving high and low mastic doses and placebo supplements, respectively. miR-21 was significantly upregulated in patients compared to normotensive individuals. Mean changes in miR-21 levels were statistically significant, after adjusting for sex and age, between the placebo and low-dose group and between the low- and high-dose group. Post-intervention miR-21 levels were positively associated with night-time systolic blood pressure, pulse pressure, and central systolic mean arterial pressure and negatively associated with night-time pulse wave velocity in the low-dose group. Our findings suggest a potential implication of miR-21 in the association of Chios mastic with night-time blood pressure measurements.

Remnant cholesterol in atherosclerotic cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Accumulating evidence suggests a substantial contribution of remnant cholesterol (RC) to residual risk for the development or relapse of atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the association of RC levels with ASCVD risk by different risk categories and methods of RC assessment. We also assessed available evidence of the effects of lipid-lowering therapies (LLTs) on RC levels. METHODS: English-language searches of Medline, PubMed, and Embase (inception to 31 January 2023); ClinicalTrials.gov (October 2022); and reference lists of studies and reviews. Studies reporting on the risk of the composite endpoint [all-cause mortality, cardiovascular mortality, and major adverse cardiac events (MACE)] by RC levels were included. Moreover, we searched for studies reporting differences in RC levels after the administration of LLT(s). RESULTS: Among n = 29 studies with 257,387 participants, we found a pooled linear (pooled HR: 1.27 per 1-SD increase, 95% CI: 1.12-1.43, P < 0.001, I2 = 95%, n = 15 studies) and non-linear association (pooled HR: 1.59 per quartile increase, 95% CI: 1.35-1.85, P < 0.001, I2 = 87.9%, n = 15 studies) of RC levels and the risk of M ACE both in patients with and without established ASCVD. Interestingly, the risk of MACE was higher in studies with directly measured vs. calculated RC levels. In a limited number of studies and participants, LLTs reduced RC levels. CONCLUSION: RC levels are associated with ASCVD risk both in primary and secondary prevention. Directly measured RC levels are associated with ASCVD risk more evidently. Available LLTs tend to decrease RC levels, although the clinical relevance of RC decrease merits further investigation. PROSPERO REGISTRATION: CRD42022371346.

Glycemia is associated with subclinical atherosclerosis through renal function in nondiabetic apparently healthy adults: a mediation analysis.

The causative associations between glycemia and early alterations in renal and vascular function remain unclear. To examine the interplay among glycemia, renal function, and markers of subclinical atherosclerosis in apparently healthy subjects. Nondiabetic (30-60 years old) individuals (n = 205) without chronic kidney disease or cardiovascular disease were consecutively recruited from a cardiovascular prevention clinic. All subjects underwent arterial stiffness assessment by measuring the carotid-femoral pulse wave velocity (cfPWV). Glomerular filtration rate (GFR) was estimated by CKD-EPI equation. Study procedures were identical in the two visits (median follow-up 66 months). We employed structural equation modeling (SEM) analysis to investigate the directionality of associations. Baseline fasting plasma glucose (FPG) was independently and inversely associated with GFR (p = 0.008). GFR was significantly associated with cfPWV (p < 0.001) at baseline. By SEM analysis decreasing baseline GFR directly correlated with increasing cfPWV (p = 0.003) whereas FPG correlated with cfPWV indirectly through GFR (mediation) (P = 0.032). FPG did not mediate the effect of GFR on cfPWV (P = 0.768). SEM analysis of longitudinal data revealed bidirectional correlations between changes in FPG and GFR (P < 0.001). Alterations in GFR were directly related to changes in cfPWV (p < 0.001) whereas FPG only indirectly correlated with cfPWV through GFR changes (P = 0.002). In apparently healthy nondiabetic subjects, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status. These findings provide the first clinical evidence supporting the directionality between kidney function and glycemia in nondiabetic subjects leading to vascular dysfunction. In apparently healthy nondiabetic subjects, without cardiovascular disease or chronic kidney disease, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status.