Bile Acids and Bilirubin Role in Oxidative Stress and Inflammation in Cardiovascular Diseases.

Bile acids (BAs) and bilirubin, primarily known for their role in lipid metabolism and as heme catabolite, respectively, have been found to have diverse effects on various physiological processes, including oxidative stress and inflammation. Indeed, accumulating evidence showed that the interplay between BAs and bilirubin in these processes involves intricate regulatory mechanisms mediated by specific receptors and signaling pathways under certain conditions and in specific contexts. Oxidative stress plays a significant role in the development and progression of cardiovascular diseases (CVDs) due to its role in inflammation, endothelial dysfunction, hypertension, and other risk factors. In the cardiovascular (CV) system, recent studies have suggested that BAs and bilirubin have some opposite effects related to oxidative and inflammatory mechanisms, but this area of research is still under investigation. This review aims to introduce BAs and bilirubin from a biochemical and physiological point of view, emphasizing their potential protective or detrimental effects on CVDs. Moreover, clinical studies that have assessed the association between BAs/bilirubin and CVD were examined in depth to better interpret the possible link between them.

Folic acid and plasma lipids: Interactions and effect of folate supplementation.

Dyslipidaemia and hyperhomocysteinemia are known risk factors for cardiovascular disease. While it is evident that optimization of plasma lipid is associated with low risk of cardiovascular disease in the general population, it is not yet fully clear whether reduction of homocysteinemia is associated with an improvement in risk in all subjects. The aim of our narrative review is to highlight eventual effects of folate supplementation on LDL-C levels, LDL-C oxidation and atherosclerosis-related complications. A comprehensive literature search was done in electronic database, including PubMed, Web of Science, Cochrane, and Scopus from inception up to January 2024. Based on the available evidence, epidemiological data, pathophysiological observations and meta-analyses of randomized clinical trials suggest that folic acid supplementation may modestly but significantly improve plasma lipid levels, lipid atherogenicity, and atherosclerosis-related early vascular damage, and that folic acid supplementation may significantly reduce the risk of cerebrovascular disease. Considering the low-cost and high safety profile of folic acid, its long-term supplementation could be considered for dyslypidaemic patients in secondary prevention for cardiovascular disease.

Lifestyle and Lipoprotein(a) Levels: Does a Specific Counseling Make Sense?

Lipoprotein(Lp)(a) is a variant of low-density lipoprotein (LDL), bound to apolipoprotein B100, whose levels are associated with a significant increase in the risk of atherosclerosis-related cardiovascular events, but also to aortic stenosis and atrial fibrillation. Since plasma levels of Lp(a) are commonly considered resistant to lifestyle changes, we critically reviewed the available evidence on the effect of weight loss, dietary supplements, and physical activity on this risk factor. In our review, we observed that relevant body weight loss, a relatively high intake of saturated fatty acids, the consumption of red wine, and intense physical exercise seems to be associated with significantly lower plasma Lp(a) levels. On the contrary, foods rich in trans-unsaturated fatty acids are associated with increased Lp(a) levels. With regard to dietary supplements, coenzyme Q10, L-Carnitine, and flaxseed exert a mild but significant lowering effect on plasma Lp(a).

Methotrexate & rheumatoid arthritis associated atherosclerosis: A narrative review of multidisciplinary approach for risk modification by the international board of experts.

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score.

Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts.

Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications are responsible for an incredible burden of mortality and morbidity in Western Countries. The study of the pathological mechanisms responsible for the cardiovascular complications in DM patients is key for the development of new therapeutic strategies. The metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia, results in a cascade of pathomorphological changes favoring the atherosclerotic process and leading to myocardial remodeling. Parallel to this, oxidative stress, calcium overload, mitochondrial dysfunction, activation of protein kinase C signaling pathways, myocardial lipomatosis, and low-grade inflammation of the myocardium - are the main pathways responsible for the diabetic cardiomyopathy development. This review aims to appraise and discuss the pathogenetic mechanisms behind the diabetic cardiomyopathy development.

Effect of dietary supplementation with a new nutraceutical formulation on cardiometabolic risk factors: a double-blind, placebo-controlled, randomized clinical study.

Introduction: The scientific community and consumers are increasingly interested in the potential cholesterol-lowering effect of various nutraceuticals and their combinations. The aim of our study was to test the short-term effect of a new lipid-lowering nutraceutical formulation in mildly hypercholesterolemic patients. Material and methods: We consecutively enrolled 80 mildly hypercholesterolemic patients with low-density lipoprotein-cholesterol (LDL-C) between 130 and 190 mg/dl with a low-estimated cardiovascular disease risk. After a 8 week-stabilization diet, the enrolled subjects were randomized to take 1 pill/evening of Zeta Colest (including: 400 mg of Berberis aristata dry extract with 340 mg of berberine, 98 mg of red yeast rice extract with 2.9 mg of total monacolins, 87.5 mg of milk thistle dry extract with 70 mg of silymarin, 50 mg of guggul dry extract with 1.3 mg of guggulsterones) or placebo for 8 weeks. Patients were followed up for metabolic and haemodynamic parameters. Results: After 8 week-supplementation with the tested combined nutraceuticals, we observed a significant reduction in total cholesterol (-15.2 ±1.4%), LDL-C (-18.1 ±1.9%), non-high-density lipoprotein cholesterol (-17.7 ±1.8%), apoB (-16.9 ±1.9%) and high-sensitivity C-reactive protein (-3.7 ±0.7%), versus both baseline (p < 0.05) and the control group (p < 0.05). No other metabolic or liver parameters significantly changed during the observation period. Endothelial reactivity also mildly but significantly improved by 2.96 ±0.23% with the tested product. Conclusions: In the short term, the tested combined nutraceutical improved lipid metabolism, systemic inflammation and vascular function in mildly hypercholesterolemic overweight subjects.

Sex X Time Interactions in Lp(a) and LDL-C Response to Evolocumab.

The aim of this study was to evaluate whether there were significant sex x time interactions in lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) response to treatment with the Proprotein Convertase Subtilisin/Kexin type 9 inhibitor (PCSK9i) Evolocumab, in a real-life clinical setting. For this purpose, we pooled data from 176 outpatients (Men: 93; Women: 83) clinically evaluated at baseline and every six months after starting Evolocumab. Individuals who had been on PCSK9i for less than 30 months and nonadherent patients were excluded from the analysis. Over time, absolute values of Lp(a) plasma concentrations significantly decreased in the entire cohort (p-value < 0.001) and by sex (p-value < 0.001 in men and p-value = 0.002 in and women). However, there were no sex-related significant differences. Absolute plasma concentrations of LDL-C significantly decreased over time in the entire cohort and by sex (p-value < 0.001 always), with greater improvements in men compared to women. The sex x time interaction was statistically significant in LDL-C (all p-values < 0.05), while absolute changes in Lp(a) were not influenced by either sex or time (all p-value > 0.05). Our data partially reinforce the presence of differences in response to treatment to PCSK9i between men and women and are essential to gain a better understanding of the relationship between LDL-C and Lp(a) lowering in response to PCSK9i. Further research will clarify whether these sex-related significant differences translate into a meaningful difference in the long-term risk of ASCVD.

Estimating the Prevalence and Characteristics of Patients Potentially Eligible for Lipoprotein(a)-Lowering Therapies in a Real-World Setting.

High lipoprotein(a) (Lp(a)) plasma levels are significantly associated with an increased risk of developing atherosclerotic cardiovascular diseases (ASCVD). The aim of this analysis was to estimate the prevalence and characteristics of patients potentially eligible for Lp(a)-lowering therapies in a real-world setting (i.e., patients with ASCVD and Lp(a) levels > 70 mg/dL). For this reason, we pooled data from a large cohort of Italian outpatients (N = 5961; men: 2879, women: 3982) with dyslipidemia. A binary logistic regression analysis was used to determine the significant predictors of ASCVD in the cohort, which were age (Odds Ratio (OR): 1.158, 95% Confidence Interval (CI): 1.114 to 1.203, p < 0.001), low-density lipoprotein cholesterol at entry (OR: 1.989, 95% CI: 1.080 to 1.198, p = 0.020) and Lp(a) (OR: 1.090, 95% CI: 1.074 to 1.107, p < 0.001). In our cohort, almost half of patients with ASCVD (44.7%) may be eligible to be treated with Lp(a)-lowering agents. Interestingly, patients who do not meet the treatment criteria despite high Lp(a) (50-70 mg/dL), respectively, account for 4.7% and 7.3% of those in primary and secondary ASCVD prevention. In conclusion, in our large cohort of outpatients with dyslipidemia, the prevalence of individuals with ASCVD and very high Lp(a) plasma levels is quite high, even with a conservative estimation.

The Effect of Dietary Supplementation with Plant Sterols on Total and LDL-Cholesterol in Plasma Is Affected by Adherence to Mediterranean Diet: Insights from the DESCO Randomized Clinical Study.

Plant sterols are well-known natural lipid-lowering agents. The DESCO (Diet and plant sterols in the control of cholesterolemia) study was a single-center, randomized, double-blind, placebo-controlled, two-way crossover clinical trial designed to investigate the effect of a once-a-day ready-to-drink dietary supplement containing 2.5 g of phytosterols on the lipid profile, also in relation to the quality of the diet, in a cohort of 50 Italian individuals with polygenic hypercholesterolemia and low global cardiovascular risk. Eligible individuals were enrolled in a run-in period of 2 weeks. Then, participants who qualified for continuation in the study were randomly allocated (1:1) to a 3-week treatment with either phytosterols or placebo. After a 2-week washout period, enrolled individuals were crossed over to receive the alternative treatment. Dietary supplementation with phytosterols was associated with significant improvement in plasma levels of total cholesterol (TC; -11.8 ± 4.0 mg/dL, p = 0.016), low-density lipoprotein cholesterol (LDL-C; -7.8 ± 7.7 mg/dL, p = 0.021), and apolipoprotein B-100 (Apo B-100, -3.7 ± 4.1 mg/dL, p = 0.048) compared to baseline. The changes in TC and LDL-C were also significant compared to placebo, and greater adherence to the Mediterranean diet was significantly associated with greater reductions in LDL-C. Dietary supplementation with phytosterols was well tolerated and adherence to treatment was high. According to the findings of DESCO, the once-a-day ready-to-drink dietary supplement we tested is able to quickly and significantly decrease plasma levels of TC, LDL-C, and Apo B-100, with a greater effect in individuals more adhering to the Mediterranean dietary pattern.

Role of Cardiovascular Imaging in Risk Assessment: Recent Advances, Gaps in Evidence, and Future Directions.

Optimal risk assessment for primary prevention remains highly challenging. Recent registries have highlighted major discrepancies between guidelines and daily practice. Although guidelines have improved over time and provide updated risk scores, they still fail to identify a significant proportion of at-risk individuals, who then miss out on effective prevention measures until their initial ischemic events. Cardiovascular imaging is progressively assuming an increasingly pivotal role, playing a crucial part in enhancing the meticulous categorization of individuals according to their risk profiles, thus enabling the customization of precise therapeutic strategies for patients with increased cardiovascular risks. For the most part, the current approach to patients with atherosclerotic cardiovascular disease (ASCVD) is homogeneous. However, data from registries (e.g., REACH, CORONOR) and randomized clinical trials (e.g., COMPASS, FOURIER, and ODYSSEY outcomes) highlight heterogeneity in the risks of recurrent ischemic events, which are especially higher in patients with poly-vascular disease and/or multivessel coronary disease. This indicates the need for a more individualized strategy and further research to improve definitions of individual residual risk, with a view of intensifying treatments in the subgroups with very high residual risk. In this narrative review, we discuss advances in cardiovascular imaging, its current place in the guidelines, the gaps in evidence, and perspectives for primary and secondary prevention to improve risk assessment and therapeutic strategies using cardiovascular imaging.

Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods.

Apolipoprotein(a) (apo(a)) is the protein component that defines lipoprotein(a) (Lp(a)) particles and is encoded by the LPA gene. The apo(a) is extremely heterogeneous in size due to the copy number variations in the kringle-IV type 2 (KIV2) domains. In this review, we aim to discuss the role of genetics in establishing Lp(a) as a risk factor for coronary heart disease (CHD) by examining a series of molecular biology techniques aimed at identifying the best strategy for a possible application in clinical research and practice, according to the current gold standard.

Comparative effect of a nutraceutical compound based on a flavonoid complex from bergamot on plasma lipids, glucose metabolism, and liver enzymes: a 3-arm, double-blind, placebo-controlled, randomized clinical trial.

Introduction: Bergamot and opuntia (prickly pear cladodes) standardized extracts have been demonstrated to have positive metabolic effects in preclinical and clinical models. Material and methods: The aim of this study was to evaluate the metabolic effect of a combined nutraceutical containing 150 mg of Opuntia ficus Indica extract, 400 mg of plant sterols, 12.5 mg of thiamine, and 200 mg of Brumex® a phytocomplex from bergamot fruit (Citrus bergamia Risso et Poiteau, fructus) standardized 40% in total flavonoids and min 5% in 3-hydroxy-3-methylglutaryl-flavanones. Thus, we carried out a randomized, double-blind, placebo-controlled clinical trial on 75 hypercholesterolaemic subjects randomized to take the active compound (2 tablets per day), placebo (2 tablets per day), or both (1 per product per day). Results: After 12 weeks of treatment with 1 tablet per day, we observed a significant reduction of a number of metabolic parameters: total cholesterol (TC) (-14.6%), low-density lipoprotein cholesterol (LDL-C) (-19.9%), non-high-density lipoprotein cholesterol (non-HDLC) (-22.1%), triglycerides (TG) (-13.1%), Apolipoprotein B (-16%) (all p < 0.05 both versus baseline and versus placebo), fasting plasma glucose (-5.1%), glutamate oxaloacetate transaminase (-7.8%), glutamate pyruvate transaminase (-7.3%), and γ-glutamyl transferase (-34.4%) (all p < 0.05 versus baseline). High-density lipoprotein cholesterol (HDL-C) was increased 6.9% by the use of 1 tablet per day (p < 0.05 versus baseline). All parameters were reduced to the same extent when taking the full dose (2 tablets), beyond TG. Conclusions: the tested nutraceutical compound based on a flavonoid complex from bergamot and opuntia showed a short-term positive impact on plasma lipids, fasting plasma glucose, and liver enzyme in overall healthy subjects affected by hypercholesterolaemia with low cardiovascular risk.

Three arms, double-blind, non-inferiority, randomized clinical study testing the lipid-lowering effect of a novel dietary supplement containing red yeast rice and artichoke extracts compared to Armolipid Plus® and placebo.

Introduction: There is growing interest in head-to-head comparison between different lipid-lowering nutraceuticals. The aim of our study was to test the lipid-lowering effect of dietary supplementation with low-dose monacolins from red yeast rice (2.8 mg per daily dose) combined with berberine (Armolipid Plus®) or highly standardized artichoke extract versus placebo. Material and methods: 60 overall healthy adult volunteers with polygenic hypercholesterolemia (baseline low-density lipoprotein cholesterol (LDL-C) = 160.2 ±9.2 mg/dl) were enrolled in a 3-arm, double-blind, non-inferiority, randomized, parallel-group clinical trial. After 4-week diet standardization, enrolled individuals were randomized to be treated for 8 weeks with red yeast rice and highly standardized artichoke extracts (ATC group), Armolipid Plus®, or placebo. Results: At the enrolment visit, LDL-C values were similar in the compared groups. After 8 weeks, all actively treated subjects experienced significant improvements in baseline total cholesterol (TC), LDL-C and apolipoprotein B (Apo-B) (all p < 0.01) (ATC group: TC = -18.9%, LDL-C = -26.7% (placebo-corrected: -12.4%), Apo-B = -19.6%; Armolipid Plus®: TC = -18.4%, LDL-C = -25.8% (placebo-corrected: -12.1%), Apo-B = -23.2%; placebo: TC = -6.2%, LDL-C = -8%, Apo-B = -8.4%). Participants in the ATC group attained significantly lower body mass index (BMI) values (-2.1%), while individuals treated with Armolipid Plus® showed improvements in baseline high-density lipoprotein cholesterol (HDL-C) (+8.7%) and triglyceride (TG) (+17.5%) levels. Finally, baseline hepatic steatosis index (HSI) values significantly decreased in both actively treated groups (by -2.4% and -2.4% in ATC and in Armolipid Plus®, respectively). Conclusions: Patients with polygenic hypercholesterolemia experienced a significant improvement in several cardiovascular risk factors in both ATC and Armolipid Plus® groups.

Metabolic and vascular effect of a new standardized bergamot phytocomplex: a three-arm, placebocontrolled, double-blind clinical trial.

Introduction: In addition to healthy lifestyle and balanced diet, nutraceutical supplementation may be useful to maintain overall metabolic wellness. The aim of the present study was to assess the metabolic and vascular effects of a new, highly standardized bergamot phytocomplex supplement in healthy volunteers with the features of metabolic syndrome. Material and methods: We carried out a double-blind, randomized, placebo-controlled, three-arm, parallel-group clinical trial in 90 adult subjects (30 per group) treated for 12 weeks with two different dosages of a highly standardized bergamot phytocomplex (Endoberg by AKHYNEX and Kalita by Giellepi) or placebo. Lipid plasma levels, glycemia, plasma hs-CRP, HOMA-IR, body fat, endothelial reactivity and fatty liver index were assessed at baseline, after 6 weeks and at the end of treatment in all subjects. Results: At the end of treatment, both tested bergamot extract doses were able to significantly improve atherogenic dyslipidemia and insulin sensitivity (p < 0.05) compared to placebo. In the high-dose treated group, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) improved versus placebo (p < 0.05) just after 6 weeks of treatment. After 12 weeks of treatment, TC decreased by 13.2 ±2.1%, LDL-C by 17.7 ±3.2%, non-HDL-C by 17.5 ±3.1%, TG by 16.6 ±3.3%, TG/HDL-C by 22.5 ±4.4%, homeostasis insulin resistance index (HOMA-IR) by 12.2 ±2.1%, γ-glutamyl transferase (GGT) by 22.2 ±4.6%, and high-sensitivity C-reactive protein (hs-CRP) by 17.9 ±3.4% versus baseline (p < 0.05) and vs. placebo (p < 0.05). Percentage body fat and endothelial reactivity improved versus baseline, but not versus placebo, in the high-dose treatment only (p < 0.05). Conclusions: The tested bergamot phytocomplex was able to significantly improve glucose and lipid metabolism, as well as inflammation, and might represent a novel multi-target approach to control metabolic syndrome.

Possibilities of dapagliflozin-induced cardioprotection on doxorubicin + cyclophosphamide mode of chemotherapy-induced cardiomyopathy.

RATIONALE: The global burden of cardiovascular (CV) and oncological diseases continues to increase. In this regard, the prevention of CV diseases (CVD) before and after cancer treatment is an urgent and unsolved problem in medicine. For this reason, our research group aimed to investigate the possibility of dapagliflozin-related cardioprotection, using an experimental model of chronic Doxorubicin (Adriamycin) + Cyclophosphamide (AC)-mode of chemotherapy-induced cardiomyopathy. OBJECTIVE: The redox balance, lipid metabolism, endothelial dysfunction, and myocardial damage parameters were measured to evaluate the pathways of dapagliflozin-induced stabilization of CV homeostasis. METHODS: For this study, 80 inbred Wistar rats were randomly assigned to four equally sized groups. A model of chronic cardiotoxicity was attained by using doxorubicin and cyclophosphamide co-administration. In the case, the markers of redox-balance, cholesterol metabolism, endothelial dysfunction, myocardial alteration, and morphological examination were assessed. RESULTS: For all parameters, statistically significant deviations were obtained, emphasizing the sequel of AC-mode chemotherapy-related detergent effect on CV system (group 2). Moreover, the data obtained from dapagliflozin-treated groups (group 3) showed that this strategy provide limitation of lipid peroxidation, cholesterol metabolism and endothelial function normalization, with subsequent morphological preservation of myocardium. CONCLUSION: Dapagliflozin has a broad spectrum of pleiotropic influences, namely cholesterol-lowering, anti-inflammatory, and endothelium-stabilizing properties. These properties provide a favorable environment for the prevention of chemotherapy-related cardiomyopathy.

An Evolving Definition of a "Healthy Diet".

Throughout life, most of us eat at least three meals a day for 365 days a year [...].

Effect of dietary supplementation with Diuripres® on blood pressure, vascular health, and metabolic parameters in individuals with high-normal blood pressure or stage I hypertension: The CONDOR randomized clinical study.

Our aim was to evaluate if a nutritional intervention with a dietary supplement (Diuripres®) containing magnesium, standardized extract of orthosiphon, hawthorn, and hibiscus could positively affect blood pressure (BP), vascular health, and metabolic parameters in 60 individuals with high-normal BP or stage I hypertension. Participants followed a low-fat low-sodium Mediterranean diet for 4 weeks before being randomly allocated to 8-week treatment with two pills each day of either Diuripres® or placebo. Diuripres® significantly decreased systolic BP compared to placebo after 4 weeks (3.1 ± 0.8 mmHg; p < 0.05) and more consistently after 8 weeks (3.4 ± 0.9 mmHg; p < 0.05). At 8-week follow-up, after correction for multiple testing, dietary supplementation with Diuripres® was associated with significant improvements in diastolic BP (-3.1 ± 0.6 mmHg; p < 0.05), aortic BP (-4.3 ± 0.4 mmHg; p < 0.05), and high-sensitivity C-reactive protein (hs-CRP; 0.04 ± 0.01 mg/dL; p < 0.05) in comparison with baseline. The reductions in diastolic BP (--3.8 ± 0.7 mmHg; p < 0.05), aortic BP (-5.2 ± 1.0 mmHg; p < 0.05), and hs-CRP (-0.03 ± 0.01 mg/dL; p < 0.05) were also significant compared to placebo. Therefore, our study shows that dietary supplementation with Diuripres® may be useful in individuals with high-normal BP or stage I hypertension.

Nutraceuticals as Modulators of Immune Function: A Review of Potential Therapeutic Effects.

Dietary supplementation with nutraceuticals can promote optimal immune system activation, modulating different pathways that enhance immune defenses. Therefore, the immunity-boosting effects of nutraceuticals encompass not only immunomodulatory but also antioxidant, antitumor, antiviral, antibacterial, and antifungal properties, with therapeutic effects against diverse pathological conditions. However, the complexity of the pathways that regulate the immune system, numerous mechanisms of action, and heterogeneity of the immunodeficiencies, and subjects treated make their application in the clinical field difficult. Some nutraceuticals appear to safely improve immune system function, particularly by preventing viral and bacterial infections in specific groups, such as children, the elderly, and athletes, as well as in frail patients, such as those affected by autoimmune diseases, chronic diseases, or cancer. Several nutraceuticals, such as vitamins, mineral salts, polyunsaturated omega-3 fatty acids, many types of phytocompounds, and probiotic strains, have the most consolidated evidence in humans. In most cases, further large and long-term randomized clinical trials are needed to confirm the available preliminary positive data.