Therapeutic effects of resveratrol on epigenetic mechanisms in age-related diseases: A comprehensive review.

Recently, various studies have shown that epigenetic changes are associated with aging and age-related diseases. Both animal and human models have revealed that epigenetic processes are involved in aging mechanisms. These processes happen at multiple levels and include histone modification, DNA methylation, and changes in noncoding RNA expression. Consequently, changes in the organization of chromatin and DNA accessibility lead to the regulation of gene expression. With increasing awareness of the pivotal function of epigenetics in the aging process, researchers' attention has been drawn to how these epigenetic changes can be modified to prevent, stop, or reverse aging, senescence, and age-related diseases. Among various agents that can affect epigenetic, polyphenols are well-known phytochemicals found in fruits, vegetables, and plants. Polyphenols are found to modify epigenetic-related mechanisms in various diseases and conditions, such as metabolic disorders, obesity, neurodegenerative diseases, cancer, and cardiovascular diseases. Resveratrol (RSV) is a member of the stilbene subgroup of polyphenols which is derived from various plants, such as grapes, apples, and blueberries. Therefore, herein, we aim to summarize how RSV affects different epigenetic processes to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer's, Parkinson's, osteoporosis, and cardiovascular diseases.

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies.

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions. CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Prediction of atherosclerotic cardiovascular risk in early childhood.

Atherosclerotic lesions are present even in very young individuals and therefore, risk stratification for cardiovascular (CV) disease should be implemented in childhood to promote early prevention strategies. In this review we critically appraise clinical, biochemical and genetic biomarkers available for pediatric clinical practice, which might be integrated to build effective algorithms to identify children at risk of future CV events. The first critical issue is to characterize in children aged 2-5 years, those CV risk factors/clinical conditions associated with dramatically accelerated atherosclerosis. Presence of clinical conditions such as obesity, diabetes mellitus, Kawasaki disease, etc., or positive family history for premature CV disease should be evaluated. Subsequently, a complete lipid profile and Lipoprotein(a) determination are recommended for children with increased baseline CV risk. Individuals with altered lipid profile could then undergo genetic testing for monogenic dyslipidemias to identify children with high CV genetic risk, who will be directed to appropriate therapeutic options. In perspective, calculation of a polygenic risk score, based on the analysis of several common single-nucleotide polymorphisms, could be integrated for better risk assessment. We here emphasize the importance of a "holistic" strategy integrating biochemical, anamnestic and genetic data to stratify CV risk in early childhood.

Investigation of the Relationship Between Serum Low-Density Lipoprotein Cholesterol Levels with Genetic Polymorphisms, Gut Microbiota, and Nutrition.

Background: To prevent cardiovascular disease (CVD), it is important to determine the factors that are associated with its development. High serum low-density lipoprotein (LDL) cholesterol (LDL-C) levels are a modifiable prevention and treatment target known to contribute to the development of CVD, but the factors affecting blood cholesterol levels, including LDL-C, remain controversial. Objective: In this study, the factors (genetic, nutritional, and gut microbiota) thought to be effective on serum LDL-C levels were discussed from a holistic perspective, and the effects of the relationship between these factors on LDL-C levels were examined. Methods: The study was carried out with 609 adults (48% male) who applied to a private health institution between 2016 and 2022. Results: It was observed that serum LDL-C levels were positively correlated with body mass index (BMI) (P = 0.000) and different ApoE alleles had significant effects on LDL-C levels. It was observed that the highest LDL-C levels were in the ɛ4+ group, followed by ɛ3+ and ɛ2+ groups, respectively (P = 0.000). Results showed that dietary cholesterol and fiber consumption did not significantly affect serum LDL-C levels (P = 0.705 and P = 0.722, respectively). It was also observed that enterotypes and the butyrate synthesis potential of intestinal microbiota did not cause significant changes in serum LDL-C levels (P = 0.369 and P = 975, respectively). Conclusion: Serum LDL-C levels are affected by modifiable factors such as BMI and nonmodifiable factors such as APOE genotype. By identifying these factors and conducting further studies on them, new ways to improve serum LDL-C levels, which is an important factor in the development of CVD, can be identified. In addition, no significant effect of gene-nutrient or microbiota-nutrient interactions on serum LDL-C levels was detected. Further research is needed, especially on the relationship between intestinal microbiota and serum LDL levels.

Polygenic Risk Score for Cardiovascular Diseases in Artificial Intelligence Paradigm: A Review.

Cardiovascular disease (CVD) related mortality and morbidity heavily strain society. The relationship between external risk factors and our genetics have not been well established. It is widely acknowledged that environmental influence and individual behaviours play a significant role in CVD vulnerability, leading to the development of polygenic risk scores (PRS). We employed the PRISMA search method to locate pertinent research and literature to extensively review artificial intelligence (AI)-based PRS models for CVD risk prediction. Furthermore, we analyzed and compared conventional vs. AI-based solutions for PRS. We summarized the recent advances in our understanding of the use of AI-based PRS for risk prediction of CVD. Our study proposes three hypotheses: i) Multiple genetic variations and risk factors can be incorporated into AI-based PRS to improve the accuracy of CVD risk predicting. ii) AI-based PRS for CVD circumvents the drawbacks of conventional PRS calculators by incorporating a larger variety of genetic and non-genetic components, allowing for more precise and individualised risk estimations. iii) Using AI approaches, it is possible to significantly reduce the dimensionality of huge genomic datasets, resulting in more accurate and effective disease risk prediction models. Our study highlighted that the AI-PRS model outperformed traditional PRS calculators in predicting CVD risk. Furthermore, using AI-based methods to calculate PRS may increase the precision of risk predictions for CVD and have significant ramifications for individualized prevention and treatment plans.

SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Circadian system microRNAs - Role in the development of cardiovascular diseases.

Circadian rhythm regulates numerous physiological processes, and disruption of the circadian clock can lead to cardiovascular disease. Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Small non-coding RNAs, microRNAs (miRNAs), are involved in regulating gene expression, both those important for the cardiovascular system and key circadian clock genes. Epigenetic mechanisms based on miRNAs are essential for fine-tuning circadian physiology. Indeed, some miRNAs depend on circadian periodicity, others are under the influence of light, and still others are under the influence of core clock genes. Dysregulation of miRNAs involved in circadian rhythm modulation has been associated with inflammatory conditions of the endothelium and atherosclerosis, which can lead to coronary heart disease and myocardial infarction. Epigenetic processes are reversible through their association with environmental factors, enabling innovative preventive and therapeutic strategies for cardiovascular disease. Here, is a review of recent findings on how miRNAs modulate circadian rhythm desynchronization in cardiovascular disease. In the era of personalized medicine, the possibility of treatment with miRNA antagomirs should be time-dependent to correspond to chronotherapy and achieve the most significant efficacy.

Phenome-wide association study and precision medicine of cardiovascular diseases in the post-COVID-19 era.

SARS-CoV-2 infection causes injuries of not only the lungs but also the heart and endothelial cells in vasculature of multiple organs, and induces systemic inflammation and immune over-reactions, which makes COVID-19 a disease phenome that simultaneously affects multiple systems. Cardiovascular diseases (CVD) are intrinsic risk and causative factors for severe COVID-19 comorbidities and death. The wide-spread infection and reinfection of SARS-CoV-2 variants and the long-COVID may become a new common threat to human health and propose unprecedented impact on the risk factors, pathophysiology, and pharmacology of many diseases including CVD for a long time. COVID-19 has highlighted the urgent demand for precision medicine which needs new knowledge network to innovate disease taxonomy for more precise diagnosis, therapy, and prevention of disease. A deeper understanding of CVD in the setting of COVID-19 phenome requires a paradigm shift from the current phenotypic study that focuses on the virus or individual symptoms to phenomics of COVID-19 that addresses the inter-connectedness of clinical phenotypes, i.e., clinical phenome. Here, we summarize the CVD manifestations in the full clinical spectrum of COVID-19, and the phenome-wide association study of CVD interrelated to COVID-19. We discuss the underlying biology for CVD in the COVID-19 phenome and the concept of precision medicine with new phenomic taxonomy that addresses the overall pathophysiological responses of the body to the SARS-CoV-2 infection. We also briefly discuss the unique taxonomy of disease as Zheng-hou patterns in traditional Chinese medicine, and their potential implications in precision medicine of CVD in the post-COVID-19 era.

Insight on Cardiac Chronobiology and Latest Developments of Chronotherapeutic Antihypertensive Interventions for Better Clinical Outcomes.

Cardiac circadian rhythms are an important regulator of body functions, including cardiac activities and blood pressure. Disturbance of circadian rhythm is known to trigger and aggravate various cardiovascular diseases. Thus, modulating the circadian rhythm can be used as a therapeutic approach to cardiovascular diseases. Through this work, we intend to discuss the current understanding of cardiac circadian rhythms, in terms of quantifiable parameters like BP and HR. We also elaborate on the molecular regulators and the molecular cascades along with their specific genetic aspects involved in modulating circadian rhythms, with specific reference to cardiovascular health and cardiovascular diseases. Along with this, we also presented the latest pharmacogenomic and metabolomics markers involved in chronobiological control of the cardiovascular system along with their possible utility in cardiovascular disease diagnosis and therapeutics. Finally, we reviewed the current expert opinions on chronotherapeutic approaches for utilizing the conventional as well as the new pharmacological molecules for antihypertensive chronotherapy.

Olive Oil in the Mediterranean Diet and Its Biochemical and Molecular Effects on Cardiovascular Health through an Analysis of Genetics and Epigenetics.

Human nutrition is a relatively new science based on biochemistry and the effects of food constituents. Ancient medicine considered many foods as remedies for physical performance or the treatment of diseases and, since ancient times, especially Greek, Asian and pre-Christian cultures similarly thought that they had beneficial effects on health, while others believed some foods were capable of causing illness. Hippocrates described the food as a form of medicine and stated that a balanced diet could help individuals stay healthy. Understanding molecular nutrition, the interaction between nutrients and DNA, and obtaining specific biomarkers could help formulate a diet in which food is not only a food but also a drug. Therefore, this study aims to analyze the role of the Mediterranean diet and olive oil on cardiovascular risk and to identify their influence from the genetic and epigenetic point of view to understand their possible protective effects.

Supplementation with the Prebiotic High-Esterified Pectin Improves Blood Pressure and Cardiovascular Risk Biomarker Profile, Counteracting Metabolic Malprogramming.

Supplementation with the prebiotic pectin is associated with beneficial health effects. We aimed to characterize the cardioprotective actions of chronic high-esterified pectin (HEP) supplementation (10%) in a model of metabolic malprogramming in rats, prone to obesity and associated disorders: the progeny of mild calorie-restricted dams during the first half of pregnancy. Results show that pectin supplementation reverses metabolic malprogramming associated with gestational undernutrition. In this sense, HEP supplementation improved blood pressure, reduced heart lipid content, and regulated cardiac gene expression of atrial natriuretic peptide and lipid metabolism-related genes. Moreover, it caused an elevation in circulating levels of fibroblast growth factor 21 and a higher expression of its co-receptor ß-klotho in the heart. Most effects are correlated with the gut levels of beneficial bacteria promoted by HEP. Therefore, chronic HEP supplementation shows cardioprotective actions, and hence, it is worth considering as a strategy to prevent programmed cardiometabolic alterations.

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia.

High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

The effects of astaxanthin supplementation on expression of microRNAs involved in cardiovascular diseases: a systematic review of current evidence.

MicroRNAs (miRNAs) have biological roles in controlling oxidative stress. Astaxanthin (AST) may regulate circulating miRNAs in cardiovascular diseases (CVDs); therefore, our study aimed to evaluate the effect of AST on miRNA involved in CVDs. A systematic literature search from inception to August 2022 resulted in 80 preliminary studies; 15 articles were included. In vitro studies indicated that AST up-regulated miRNAs compromised miR-138, miR-7, miR-29a-3p, and miR-200a, while down-regulated miR-382-5p, miR-31-5p, and miR-21. In vivo articles revealed that AST increased the expression of miR-124, miR-7, miR-29a-3p, and miR-200a but decreased miR-21 and miR-31-5p and the only clinical study showed a drop in miR-146a. The findings indicate that AST regulated different pathways of miRNAs implicated in various conditions. Therefore AST as a new therapeutic strategy could be essential in preventing and controlling CVDs. However, more studies, including clinical trials, are needed to determine the influence of AST on miRNAs associated with CVDs.

The complex genetic basis of fibromuscular dysplasia, a systemic arteriopathy associated with multiple forms of cardiovascular disease.

Artery stenosis is a common cause of hypertension and stroke and can be due to atherosclerosis accumulation in the majority of cases and in a small fraction of patients to arterial fibromuscular dysplasia (FMD). Artery stenosis due to atherosclerosis is widely studied with known risk factors (e.g. increasing age, male gender, and dyslipidemia) to influence its etiology, including genetic factors. However, the causes of noninflammatory and nonatherosclerotic stenosis in FMD are less understood. FMD occurs predominantly in early middle-age women, a fraction of the population where cardiovascular risk is different and understudied. FMD arteriopathies are often diagnosed in the context of hypertension and stroke and co-occur mainly with spontaneous coronary artery dissection, an atypical cause of acute myocardial infarction. In this review, we provide a comprehensive overview of the recent advances in the understanding of molecular origins of FMD. Data were obtained from genetic studies using complementary methodological approaches applied to familial, syndromic, and sporadic forms of this intriguing arteriopathy. Rare variation analyses point toward mechanisms related to impaired prostacyclin signaling and defaults in fibrillar collagens. The study of common variation, mainly through a recent genome-wide association study, describes a shared genetic link with blood pressure, in addition to point at potential risk genes involved in actin cytoskeleton and intracellular calcium homeostasis supporting impaired vascular contraction as a key mechanism. We conclude this review with future strategies and approaches needed to fully understand the genetic and molecular mechanisms related to FMD.

Causal Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Peripheral Artery Disease: A Mendelian Randomization Approach.

Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2-sample inverse-variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European-ancestry genomic summary data (P<5×10-8) for type 2 diabetes, lipid-fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million-Veteran-Program genome-wide association studies (cases=31 307, controls=211 753, 72% European-ancestry) and the GoLEAD-SUMMIT genome-wide association studies (11 independent genome-wide association studies, European-ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni-significant (P<0.00294), consistent over PAD-cohorts/sensitivity analyses), suggestive (P value: 0.00294-0.05, associations in 1 PAD-cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low-density lipoprotein cholesterol, triglyceride-levels, alcohol consumption, and inverse associations for high-density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low-density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid-fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low-density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.

Role of circulating polyunsaturated fatty acids on cardiovascular diseases risk: analysis using Mendelian randomization and fatty acid genetic association data from over 114,000 UK Biobank participants.

BACKGROUND: Despite early interest in the health effects of polyunsaturated fatty acids (PUFA), there is still substantial controversy and uncertainty on the evidence linking PUFA to cardiovascular diseases (CVDs). We investigated the effect of plasma concentration of omega-3 PUFA (i.e. docosahexaenoic acid (DHA) and total omega-3 PUFA) and omega-6 PUFA (i.e. linoleic acid and total omega-6 PUFA) on the risk of CVDs using Mendelian randomization. METHODS: We conducted the largest genome-wide association study (GWAS) of circulating PUFA to date including a sample of 114,999 individuals and incorporated these data in a two-sample Mendelian randomization framework to investigate the involvement of circulating PUFA on a wide range of CVDs in up to 1,153,768 individuals of European ancestry (i.e. coronary artery disease, ischemic stroke, haemorrhagic stroke, heart failure, atrial fibrillation, peripheral arterial disease, aortic aneurysm, venous thromboembolism and aortic valve stenosis). RESULTS: GWAS identified between 46 and 64 SNPs for the four PUFA traits, explaining 4.8-7.9% of circulating PUFA variance and with mean F statistics >100. Higher genetically predicted DHA (and total omega-3 fatty acids) concentration was related to higher risk of some cardiovascular endpoints; however, these findings did not pass our criteria for multiple testing correction and were attenuated when accounting for LDL-cholesterol through multivariable Mendelian randomization or excluding SNPs in the vicinity of the FADS locus. Estimates for the relation between higher genetically predicted linoleic acid (and total omega-6) concentration were inconsistent across different cardiovascular endpoints and Mendelian randomization methods. There was weak evidence of higher genetically predicted linoleic acid being related to lower risk of ischemic stroke and peripheral artery disease when accounting by LDL-cholesterol. CONCLUSIONS: We have conducted the largest GWAS of circulating PUFA to date and the most comprehensive Mendelian randomization analyses. Overall, our Mendelian randomization findings do not support a protective role of circulating PUFA concentration on the risk of CVDs. However, horizontal pleiotropy via lipoprotein-related traits could be a key source of bias in our analyses.

Serum levels of vitamin A, selenium, and better dietary total antioxidant capacity are related to lower oxidative DNA damage: A cross-sectional study of individuals at cardiovascular risk.

The risk for cardiovascular diseases (CVR) has been associated with oxidative DNA damage, but the genetic and environmental factors involved in the antioxidant and DNA repair system contributing to this damage are unknown. The aim was to evaluate the levels of oxidative DNA damage in CVR subjects and how it is related with some genetic and nutritional factors. The cross-sectional study evaluated 136 individuals of both sexes, aged 20-59 years, with at least one cardiovascular risk factor. The global risk score was used to classify individuals at low, intermediate, and high cardiovascular risk. The dietary total antioxidant capacity (DTAC) was calculated using table with FRAP values. The oxidative DNA damage was verified by the comet assay. The variants null of Glutathione-S-transferases Mu1 and Theta 1(GSTM1 and GSTT1) and rs25487 of X-Ray Repair Cross Complementing Protein 1 (XRCC1) were analyzed by real-time PCR and PCR-RFLP, respectively. The oxidative DNA damage was higher in patients with intermediate/high CVR than in patients with low CVR (P=.01). Individuals with GSTT1/GSTM1 null genotypes or arg/gln+gln/gln genotypes of the XRCC1 (rs25487) gene showed similar levels of oxidative DNA damage compared wild genotype. Multivariate regression analysis demonstrated that oxidative DNA damage in individuals with CVR depends on serum levels of vitamin A, selenium, and DTAC independently of the other factors [F(6.110)=8.213; P<.001; R2=0.330]. These findings suggest that nutritional factors such as DTAC, vitamin A and selenium may have a protective effect against oxidative DNA damage in these individuals.

Vitamin D status, genetic factors, and risks of cardiovascular disease among individuals with type 2 diabetes: a prospective study.

BACKGROUND: The presence of a threshold effect has been proposed, suggesting that beneficial effects from vitamin D supplementation may only be present when the vitamin D concentration is below a particular threshold. OBJECTIVES: We investigated the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations and genetic factors with risks of total and subtypes of cardiovascular disease (CVD) in individuals with type 2 diabetes (T2D), among whom vitamin D deficiency or insufficiency is particularly common. METHODS: This prospective study included 15,103 individuals with T2D who were initially free of CVD and had serum 25(OH)D measurements in the UK Biobank. Incidences of total and subtypes of CVD, including ischemic heart disease (IHD) and stroke, were ascertained via electronic health records. Weighted genetic risk scores (GRSs) were constructed for IHD and stroke. RESULTS: The mean serum 25(OH)D concentration was 43.4 nmol/L (SD: 20.4 nmol/L), and 65.7% of participants had a vitamin D concentration below 50 nmol/L. During a median of 11.2 years of follow-up, 3534 incident CVD events were documented. Compared with individuals with 25(OH)D concentrations <25 nmol/L, participants with 25(OH)D concentrations ≥75 nmol/L had HRs (95% CIs) of 0.75 (0.64, 0.88) for CVD, 0.69 (0.56, 0.84) for IHD, and 0.74 (0.52, 1.06) for stroke. Participants with 25(OH)D concentrations ≥50 nmol/L and low GRSs, as compared with individuals with 25(OH)D concentrations <25 nmol/L and high GRSs, had a 50% (39%, 65%) lower risk of IHD. No significant interactions were demonstrated between serum 25(OH)D concentrations and the GRSs and genetic variants in vitamin D receptors (VDR). CONCLUSIONS: Higher serum 25(OH)D concentrations were significantly associated with lower risks of total CVD and IHD among patients with T2D, regardless of their genetic susceptibility and the genetic variants in VDR. Risk reductions tended to plateau at serum 25(OH)D levels around 50 nmol/L. These findings suggest that maintaining an adequate vitamin D status and avoiding deficiency may help to prevent CVD complications among patients with T2D.

ncRNAs and polyphenols: new therapeutic strategies for hypertension.

Polyphenols have gained significant attention in protecting several chronic diseases, such as cardiovascular diseases (CVDs). Accumulating evidence indicates that polyphenols have potential protective roles for various CVDs. Hypertension (HTN) is among the hazardous CVDs accounting for nearly 8.5 million deaths worldwide. HTN is a complex and multifactorial disease and a combination of genetic susceptibility and environmental factors play major roles in its development. However, the underlying regulatory mechanisms are still elusive. Polyphenols have shown to cause favourable and beneficial effects in the management of HTN. Noncoding RNAs (ncRNAs) as influential mediators in modulating the biological properties of polyphenols, have shown significant footprints in CVDs. ncRNAs control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct link with blood pressure (BP) regulation is highly probable. Recent evidence suggests that a number of ncRNAs, including main small ncRNAs, microRNAs (miRNAs) and long ncRNAs (lncRNAs), play crucial roles with respect to the antihypertensive effects of polyphenols. Indeed, targeting lncRNAs by polyphenols will be a novel and promising strategy in the management of HTN. Herein, we reviewed the effects of polyphenols in HTN. Additionally, we emphasized on the potential effects of polyphenols on regulations of main ncRNAs, which imply the role of polyphenols in regulating ncRNAs in order to exert protective effects and thus proposing them as new targets for HTN treatment.Abbreviations : CVD: cardiovascular disease; BP: blood pressure; HTN: hypertension, lncRNAs: long noncoding RNAs; p38-MAPK: p38-mitogenactivated protein kinase; OPCs: oligomeric procyanidins; GTP: guanosine triphosphate; ROS: reactive oxygen species; cGMP: cyclic guanosine monophosphate; SGC: soluble guanylate cyclase; PI3K: phosphatidylinositol 3-kinase; cGMP: Cyclic GMP; eNOS: endothelial NO synthase; ERK ½: extracellular signal-regulated kinase ½; L-Arg: L-Arginine; MAPK: mitogen-activated protein kinases; NO: Nitric oxide; P: Phosphorus; PDK1: Phosphoinositide-dependent kinase 1; PI3-K: Phosphatidylinositol 3-kinase; PIP2: Phosphatidylinositol diphosphate; ncRNAs: non-protein-coding RNA; miRNAs: microRNAs; OPCs: oligomeric procyanidins; RES: resveratrol; GE: grape extract; T2DM: type 2 diabetes mellitus; IL: interleukin; TNF-α: tumour necrosis factor-alpha; NF-κB: nuclear factor NF-kappa-B; ALP: alkaline phosphatase; PARP1: poly [ADP-ribose] polymerase 1; HIF1a: Hypoxia-inducible-factor 1A; NFATc2: nuclear factor of activated T cells 2; PAD: peripheral artery disease; SHR: spontaneously hypertensive rat; RAAS: renin-angiotensin-aldosterone system; AT1R: angiotensin type-1 receptor; Nox: NADPH oxidase; HO-1: haem oxygenase-1; JAK/STAT: Janus kinase/signal transducers/activators of the transcription; PNS: panax notoginseng saponin; snoRNA: small nucleolar RNA; hnRNA: heterogeneous nuclear RNA; VSMCs: vascular smooth muscle cells; irf7: interferon regulatory factor 7; limo2: LIM only domain 2; GWAS: genome-wide association study; GAS5: Growth arrest-specific 5; Asb3, Ankyrin repeat and SPCS box containing 3; Chac2: cation transport regulator homolog 2; Pex11b: peroxisomal membrane 11B; Sp5: Sp5 transcription factor; EGCG: epigallocatechin gallate; ApoE: Apo lipoprotein E; ERK-MAP kinase: extracellular signal-regulated kinases-mitogen-activated protein kinase; PAH: pulmonary artery hypertension; PAP: pulmonary arterial pressure; HIF1a: hypoxia-inducible-factor 1A; NFATc2: nuclear factor of activated T cells 2; HMEC-1: Human microvascular endothelial cells; stat2: signal transducers and activators of transcription 2; JNK: c-Jun N-terminal kinase; iNOS: inducible NO synthase. SNP: single nucleotide polymorphism; CAD: coronary artery disease.