DOXORUBICIN-RELATED CARDIOTOXICITY: REVIEW OF FUNDAMENTAL PATHWAYS OF CARDIOVASCULAR SYSTEM INJURY.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after six decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Efficacy and Safety of Low-Dose Bisoprolol/Hydrochlorothiazide Combination for the Treatment of Hypertension: A Systematic Review and Meta-Analysis.

Objectives: This systematic review and meta-analysis aimed to assess the blood pressure (BP)-lowering effect and the safety profile of low-dose bisoprolol/hydrochlorothiazide combination treatment in patients with hypertension. Methods: Multiple electronic databases were systematically searched, and five clinical studies were included in the meta-analysis. Results: Treatment with bisoprolol/hydrochlorothiazide significantly reduced systolic BP (SBP) [mean difference (MD): -8.35 mmHg, 95% confidence interval (CI): -11.44, -5.25 mmHg versus control; MD: -9.88 mmHg, 95%CI: -12.62, -7.14 mmHg versus placebo] and diastolic BP (DBP) [MD: -7.62 mmHg, 95%CI: -11.20, -4.04 mmHg, versus control; MD: -8.79 mmHg, 95%CI: -11.92, -5.67 mmHg versus placebo]. Moreover, BP response rate and BP control rate after low-dose bisoprolol/hydrochlorothiazide combination treatment were significantly greater compared to control [odd ratio (OR) for response rate: 4.86, 95%CI: 2.52, 9.37; OR for control rate: 1.67, 95%CI: 1.11, 2.51]. Finally, treatment with low-dose bisoprolol/hydrochlorothiazide was associated with a reduced risk of any adverse event (AE) and peripheral edema compared to control. Conclusions: Overall, our results reaffirm the safety and efficiency of prescribing bisoprolol/hydrochlorothiazide combination treatment in stage I and II hypertension.

Effect of Supplementation of a Butyrate-Based Formula in Individuals with Liver Steatosis and Metabolic Syndrome: A Randomized Double-Blind Placebo-Controlled Clinical Trial.

Postbiotics could exert different metabolic activities in animal models of non-alcoholic fatty liver disease (NAFLD) and in humans affected by metabolic syndrome. This is a randomized, double-blind, placebo-controlled, parallel-group clinical trial that enrolled a sample of 50 Caucasian healthy individuals with NAFLD, defined as liver steatosis, and metabolic syndrome. After a 4-week run-in, the enrolled individuals were randomized to take a food for special medical purposes with functional release, one tablet a day, containing calcium butyrate (500 mg/tablet), zinc gluconate (zinc 5 mg/tablet), and vitamin D3 (500 IU/tablet), or an identical placebo for 3 months. Liver and metabolic parameters were measured at baseline and at the end of the study. No subject experienced any adverse events during the trial. In both groups, a significant decrease in total cholesterol (TC) and triglycerides (TG) plasma levels was observed at the randomization visit vs. pre-run-in visit (p < 0.05). Regarding liver parameters, after treatment, the fatty liver index (FLI) improved significantly vs. baseline values (p < 0.05) and vs. placebo group (p < 0.05) in the active treatment group, and the hepatic steatosis index (HSI) improved significantly vs. baseline values (p < 0.05). Moreover, after active treatment, TC, TG, and gamma-glutamyl transferase (gGT) improved significantly vs. baseline values (p < 0.05), and TC and TG improved vs. placebo group (p < 0.05), as well. In the placebo group, liver parameters remained unchanged after treatment; only TG improved significantly vs. baseline values (p < 0.05). In our study, we observed that the butyrate-based formula improved FLI and plasma lipid patterns in individuals affected by liver steatosis and metabolic syndrome.

Effect of Coenzyme Q10 on Physical Performance in Older Adults with Statin-Associated Asthenia: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

Background: Available evidence from randomized clinical trials is contrasting and definitely inconclusive in determining whether or not CoQ10 dietary supplementation is advisable in patients with statin intolerance or poor statin tolerability. Methods: This randomized, double-blind, placebo-controlled clinical study aimed at investigating the effect of chronic dietary supplementation with coenzyme Q10 (CoQ10) phytosome on physical performance in older adults with a ≥3-month history of statin-associated asthenia. The study's participants were randomized to either a placebo or 300 mg daily CoQ10 phytosome (equivalent to 60 mg CoQ10; Ubiqsome®, Indena SpA, Milan, Italy). Asthenia, handgrip strength (HGs), 2-min step test (2MST), and 1-min sit-to-stand (STS) repetitions were assessed at baseline and at 8-week follow-up. Results: After the first 4 weeks of dietary supplementation, individuals taking CoQ10 phytosome showed a greater improvement in asthenia compared to the placebo group (p < 0.05). Even more significantly, at 8-week follow-up, participants receiving CoQ10 showed substantial improvements in asthenia (-30.0 ± 20.0%), HGS (+29.8 ± 3.6%), 2MST (+11.1 ± 1.8%), and 1-min STS repetitions (+36.4 ± 3.9%) compared to both baseline and placebo (p < 0.05). Conclusions: According to our findings, chronic dietary supplementation with CoQ10 phytosome significantly enhances physical performance in older adults with statin-associated asthenia. This could have relevant implications for improving the compliance of older adults with statin treatment.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial on the Effect of a Dietary Supplement Containing Dry Artichoke and Bergamot Extracts on Metabolic and Vascular Risk Factors in Individuals with Suboptimal Cholesterol Levels.

The aim of this study was to assess whether dietary supplementation with a nutraceutical blend comprising extracts of bergamot and artichoke-both standardized in their characteristic polyphenolic fractions-could positively affect serum lipid concentration and insulin sensitivity, high-sensitivity C-reactive protein (hs-CRP), and indexes of non-alcoholic fatty liver disease (NAFLD) in 90 healthy individuals with suboptimal cholesterol levels. Participants were randomly allocated to treatment with a pill of either active treatment or placebo. After 6 weeks, the active-treated group experienced significant improvements in levels of triglycerides (TG), apolipoprotein B-100 (Apo B-100), and apolipoprotein AI (Apo AI) versus baseline. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (Non-HDL-C), and hs-CRP also significantly decreased in the active-treated group compared to both baseline and placebo. At the 12-week follow-up, individuals allocated to the combined nutraceutical experienced a significant improvement in TC, LDL-C, Non-HDL-C, TG, Apo B-100, Apo AI, glucose, alanine transaminase (ALT), gamma-glutamyl transferase (gGT), hs-CRP, several indexes of NAFLD, and brachial pulse volume (PV) in comparison with baseline. Improvements in TC, LDL-C, Non-HDL-C, TG, fatty liver index (FLI), hs-CRP, and endothelial reactivity were also detected compared to placebo (p < 0.05 for all). Overall, these findings support the use of the tested dietary supplement containing dry extracts of bergamot and artichoke as a safe and effective approach for the prevention and management of a broad spectrum of cardiometabolic disorders.

Gut Microbiota Dysbiosis and Sleep Disorders: Culprit in Cardiovascular Diseases.

Background: Over the past decade, the gut microbiome (GM) has progressively demonstrated to have a central role in human metabolism, immunity, and cardiometabolic risk. Likewise, sleep disorders showed an impact on individual health and cardiometabolic risk. Recent studies seem to suggest multi-directional relations among GM, diet, sleep, and cardiometabolic risk, though specific interactions are not fully elucidated. We conducted a systematic review to synthesize the currently available evidence on the potential interactions between sleep and GM and their possible implications on cardiometabolic risk. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses, including articles from January 2016 until November 2022. Narrative syntheses were employed to describe the results. Results: A total of 8 studies were selected according to these criteria. Our findings indicated that the sleep disorder and/or the acute circadian rhythm disturbance caused by sleep-wake shifts affected the human GM, mainly throughout microbial functionality. Conclusions: Sleep disorders should be viewed as cardiovascular risk factors and targeted for preventive intervention. More research and well-designed studies are needed to completely assess the role of sleep deprivation in the multi-directional relationship between GM and cardiometabolic risk.

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.

Cholesterol-Lowering Bioactive Foods and Nutraceuticals in Pediatrics: Clinical Evidence of Efficacy and Safety.

Long-term exposure to even slightly elevated plasma cholesterol levels significantly increases the risk of developing cardiovascular disease. The latest evidence recommends an improvement in plasma lipid levels, even in children who are not affected by severe hypercholesterolemia. The risk-benefit profile of pharmacological treatments in pediatric patients with moderate dyslipidemia is uncertain, and several cholesterol-lowering nutraceuticals have been recently tested. In this context, the available randomized clinical trials are small, short-term and mainly tested different types of fibers, plant sterols/stanols, standardized extracts of red yeast rice, polyunsaturated fatty acids, soy derivatives, and some probiotics. In children with dyslipidemia, nutraceuticals can improve lipid profile in the context of an adequate, well-balanced diet combined with regular physical activity. Of course, they should not be considered an alternative to conventional lipid-lowering drugs when necessary.

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).

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.

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.

Evaluation of the effect of a dietary supplementation with a red yeast rice and fish oil-containing nutraceutical on lipid pattern, high sensitivity C-reactive protein, and endothelial function in moderately hypercholesterolaemic subjects: a double-blind, placebo-controlled, randomized clinical trial.

Introduction: Red yeast rice and omega-3 polyunsaturated fatty acids (PUFAs) are dietary supplements with well-known lipid-lowering, anti-inflammatory, and vascular health improving effects. However, they have rarely been tested in combination. The aim of our study was to test the short-term effect of a combined nutraceutical including red yeast rice and PUFAs on plasma lipids, jigh-sensitive C-reactive protein (hsCRP), and endothelial function in healthy subjects. Material and methods: We carried out a double-blind, randomized, placebo-controlled clinical trial with parallel groups testing the effect of 8 weeks of supplementation with softgels containing red yeast rice (2.8 mg monacolins) and PUFAs (588 mg of fish oil, standardized in PUFAs: 350 EPA, 45 mg DHA) versus placebo. A full lipid panel, hsCRP, and endothelial reactivity were measured at the baseline and after 8 weeks of treatment. Results: The tested combined nutraceutical was very well tolerated, and after 8 weeks of supplementation it was associated with a 17.3 ±3.4% reduction of lipid-density lipoprotein-cholesterol (LDL-C), a 12.1 ±2.2% reduction of total cholesterol (TC), a 22.3 ±4.3% reduction of apoB, and a -14.9 ±1.8% reduction of hsCRP, as well as a significant improvement of pulse volume change by 5.0 ±0.9%. Conclusions: The tested combined dietary supplement containing red yeast rice and PUFAs was very well tolerated and significantly improved LDL-C, TC, apoB, hsCRP and endothelial function in healthy subjects with suboptimal LDL-cholesterolaemia.

Efficacy and safety of inclisiran a newly approved FDA drug: a systematic review and pooled analysis of available clinical studies.

Study objective: This systematic review and meta-analysis aimed to assess the efficacy and safety profile of treatment with inclisiran, a drug that has been recently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Design: A systematic literature search was conducted in order to identify randomized controlled trials (RCTs) assessing the effect on lipoproteins and the safety profile of inclisiran. Results: Data were pooled from 5 RCTs, which included 4226 subjects. Meta-analyses of data suggested that the multiple-dose regimens of inclisiran yielded a significant reduction in serum levels of proprotein convertase subtilisin/kexin type 9 (MD = -78.23%, 95%CI: -86.74, -69.71) and low-density lipoprotein cholesterol (MD = -45.48%, 95%CI: -50.36%, -40.61%) throughout the studies. Furthermore, treatment with inclisiran significantly affected total cholesterol (MD = -13.67%, 95%CI: -20.78%, -6.57%), high-density lipoprotein cholesterol (MD = 8.29%, 95%CI: 4.66%,11.93%), non-HDL cholesterol (MD = -39.45%, 95%CI: -43.6%, -35.31%), apolipoprotein B (MD = -34.58%, 95%CI: -38.78%, -30.78%) and lipoprotein(a) (MD = -20.9%, 95%CI: -25.8%, -15.99%). Multiple-dose regimens of inclisiran were associated with increased risk of injection-site reactions (any reaction: OR = 5.86, 95%CI: 3.44, 9.98; mild reactions: OR = 5.19, 95%CI: 1.68, 16.07; moderate reactions: OR = 13.37, 95%CI: 3.17, 56.46), and bronchitis (OR = 1.58, 95%CI: 1.10, 2.26), while the incidence of the pre-specified exploratory CV endpoint significantly decreased at 18 months (OR = 0.74, 95%CI: 0.58, 0.94). Conclusion and relevance: Inclisiran has favourable effects on serum lipid levels and an acceptable safety profile. Further well-designed RCTs are needed to explore its longer-term safety.