Heavy Metal Exposure and Cardiovascular Disease.

Heavy metals are harmful environmental pollutants that have attracted widespread attention due to their health hazards to human cardiovascular disease. Heavy metals, including lead, cadmium, mercury, arsenic, and chromium, are found in various sources such as air, water, soil, food, and industrial products. Recent research strongly suggests a connection between cardiovascular disease and exposure to toxic heavy metals. Epidemiological, basic, and clinical studies have revealed that heavy metals can promote the production of reactive oxygen species, which can then exacerbate reactive oxygen species generation and induce inflammation, resulting in endothelial dysfunction, lipid metabolism distribution, disruption of ion homeostasis, and epigenetic changes. Over time, heavy metal exposure eventually results in an increased risk of hypertension, arrhythmia, and atherosclerosis. Strengthening public health prevention and the application of chelation or antioxidants, such as vitamins and beta-carotene, along with minerals, such as selenium and zinc, can diminish the burden of cardiovascular disease attributable to metal exposure.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

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.

Does Native Vitamin D Supplementation Have Pleiotropic Effects in Patients with End-Stage Kidney Disease? A Systematic Review of Randomized Trials.

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker C-reactive protein. Included trials were heterogeneous with regards to outcomes, and the majority studied small participant populations with a relatively short follow-up. We conclude that vitamin D supplementation corrects vitamin D deficiency and is safe and well-tolerated in humans with ESKD. However, it is not clear from clinical trials conducted to date that a causal pathway exists between 25(OH)D and pleiotropic effects that is responsive to vitamin D treatment.

Advances in the study of the vascular protective effects and molecular mechanisms of hawthorn (Crataegus anamesa Sarg.) extracts in cardiovascular diseases.

Hawthorn belongs to the rose family and is a type of functional food. It contains various chemicals, including flavonoids, terpenoids, and organic acid compounds. This study aimed to review the vascular protective effects and molecular mechanisms of hawthorn and its extracts on cardiovascular diseases (CVDs). Hawthorn has a wide range of biological functions. Evidence suggests that the active components of HE reduce oxidative stress and inflammation, regulate lipid levels to prevent lipid accumulation, and inhibit free cholesterol accumulation in macrophages and foam cell formation. Additionally, hawthorn extract (HE) can protect vascular endothelial function, regulate endothelial dysfunction, and promote vascular endothelial relaxation. It has also been reported that the effective components of hawthorn can prevent age-related endothelial dysfunction, increase cellular calcium levels, cause antiplatelet aggregation, and promote antithrombosis. In clinical trials, HE has been proved to reduce the adverse effects of CVDs on blood lipids, blood pressure, left ventricular ejection fraction, heart rate, and exercise tolerance. Previous studies have pointed to the benefits of hawthorn and its extracts in treating atherosclerosis and other vascular diseases. Therefore, as both medicine and food, hawthorn can be used as a new drug source for treating cardiovascular diseases.

Impact of biologic therapies and small molecules on the risk of major adverse cardiovascular events in patients with inflammatory bowel diseases: systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: The aim of this study is to estimate the risk of major adverse cardiovascular events (MACEs) in adult patients with inflammatory bowel disease (IBD) treated with biologic therapies and small molecules. METHODS: Databases were searched up to July 2022 to identify eligible studies that assessed the risk of MACEs in patients (age≥18 years) with IBD treated with biologic therapies and small molecules. Primary outcome was the rate of MACEs observed in patients receiving biologic or small molecules therapies during induction and maintenance phases of RCTs. RESULTS: In total 64 studies were included in the analysis. 22 RCTs involving 12,196 patients with Crohn's disease (CD) were included and 32 RCTs involving 22,007 patients with ulcerative colitis (UC). In patients with CD, risk of MACE was not higher than placebo during induction or maintenance phases, infliximab (OR 0.63, 95% CI 0.07-6.14) and ustekinumab (OR 0.50, 95% CI 0.03-8.04). In patients with UC, risk of MACE was not higher than placebo, tofacitinib (OR 1.30, 95% CI 0.15-11.21) and upadcitinib (OR 0.50, 95% CI 0.03-7.97) during induction or maintenance. CONCLUSION: The use of biologic therapies and small molecules among adult patients with IBD had no significant impact on the risk of MACEs during induction and maintenance period of RCTs. Real world data is warranted to assess long-term risks.

Biologic and new small molecule therapies have been shown to be effective in treating patients with moderate to severe inflammatory bowel disease (IBD), both Crohn's disease and ulcerative colitis. The risk of major adverse cardiovascular events (MACE), such as heart attack or heart failure, due to taking these medications in patients with IBD is not well established. The aim of this systematic review and meta-analysis is to estimate the risk of MACE in patients with IBD on biologic or small molecule therapies during induction and maintenance phases of randomized controlled trials. [Figure: see text].

Relationship between Coffee, Tea, and Carbonated Beverages and Cardiovascular Risk Factors.

We aimed to analyze the relationship between coffee, tea, and carbonated beverages and cardiovascular risk factors. We used data from the fourth to eighth Korea National Health and Nutrition Examination Surveys (2007-2016, 2019-2020). We categorized the frequency of intake into three groups (<1 time/week, 1 time/week to <1 time/day, and ≥1 time/day). Subsequently, logistic regression analyses by sex were performed to assess cardiovascular risk factors (hypertension (HTN), diabetes mellitus (DM), dyslipidemia (DL), or metabolic syndrome (MetS)) according to the frequency of coffee, tea, and carbonated beverage intake. For HTN, coffee intake showed an inverse relationship and tea intake showed a direct relationship. For DM, coffee intake showed an inverse relationship, and tea and carbonated beverage intake showed a direct relationship. For DL, coffee intake showed an inverse relationship, whereas tea intake demonstrated a direct relationship. In addition, carbonated beverage intake showed a direct relationship with MetS. Coffee intake showed an inverse relationship with HTN, DM, and DL. However, tea intake showed a direct relationship with HTN, DM, and DL, whereas carbonated beverage intake showed a direct relationship with DM and MetS.

Effect of omega-3 fatty acids on cardiovascular events in high-risk patients with hypertriglyceridemia in Japan: a 3-year post-marketing surveillance study (OCEAN3 survey).

BACKGROUND: Studies on the efficacy of prescription omega-3 polyunsaturated fatty acids to reduce cardiovascular events have produced conflicting results. RESEARCH DESIGN AND METHODS: This 3-year prospective post-marketing surveillance study evaluated the effect of omega-3-acid ethyl esters (O3AEE; usual dosage 2 g/day) on cardiovascular events in high-risk statin-treated Japanese patients with hypertriglyceridemia. Statin-treated patients not receiving O3AEE were included as a reference cohort. The composite primary endpoint was cardiovascular death, myocardial infarction, stroke, angina requiring coronary revascularization, or peripheral arterial disease requiring surgery or peripheral arterial intervention. RESULTS: At 3 years, Kaplan-Meier estimated cumulative incidence of the primary endpoint was 2.5% (95% confidence interval, 2.1%-2.9%) in O3AEE-treated patients (N = 6,580) and 2.7% (2.4%-3.1%) in non-O3AEE-treated patients (N = 7,784; hazard ratio, 0.99; 95% confidence interval, 0.79-1.23). Incidence of heart failure requiring hospitalization was 0.4% with O3AEE versus 0.8% in non-O3AEE-treated patients (hazard ratio, 0.47; 95% confidence interval, 0.28-0.78; P < 0.05). CONCLUSIONS: Among patients receiving statins, cardiovascular event incidence did not differ significantly between O3AEE-treated patients and non-O3AEE-treated patients. Further studies are required before definitive conclusions can be drawn on the effect of O3AEE on cardiovascular event incidence in high-risk patients with hypertriglyceridemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02285166.

Effects of Endocrine Therapy on Cardiovascular Diseases and Type 2 Diabetes Among Breast Cancer Survivors: The National Health Insurance Service Database of Korea.

Background Although endocrine therapy is an effective treatment for breast cancer, its antiestrogen effects are associated with increased risks of cardiovascular diseases and type 2 diabetes. This study aimed to investigate the association between endocrine therapy and the risk of cardiovascular diseases and type 2 diabetes among breast cancer survivors in Korea, in consideration of various age groups. Methods and Results In the National Health Insurance Service database of Korea, a total of 133 171 patients with breast cancer aged ≥20 years were included in the current study. Endocrine therapy was treated as time-varying exposure, and patients were categorized as nonusers, selective estrogen receptor modulator users, aromatase inhibitor users, and both users. Time-dependent Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. Age at diagnosis, socioeconomic status, histological type, other treatments, and comorbidities were adjusted in the model. Compared with nonusers, selective estrogen receptor modulator users were associated with higher risks of stroke (HR, 1.20 [95% CI, 1.04-1.40]) and venous thromboembolism (HR, 1.47 [95% CI, 1.13-1.90]), whereas aromatase inhibitor users were associated with a higher risk of coronary heart disease (HR, 1.22 [95% CI, 1.06-1.41]). The risk of type 2 diabetes was associated with selective estrogen receptor modulator users (HR, 1.13 [95% CI, 1.05-1.21]), aromatase inhibitor users (HR, 1.14 [95% CI, 1.05-1.23]), and both users (HR, 1.24 [95% CI, 1.10-1.39]). In particular, the risk of a composite of cardiovascular diseases was higher in younger or premenopausal patients. Conclusions In breast cancer survivors in Korea, endocrine therapy is associated with a higher risk of cardiovascular diseases and type 2 diabetes. Monitoring of cancer comorbidities after endocrine therapy is needed in younger and older patients.

Cardio-Oncology: Mechanisms, Drug Combinations, and Reverse Cardio-Oncology.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy have brought hope to cancer patients. With the prolongation of survival of cancer patients and increased clinical experience, cancer-therapy-induced cardiovascular toxicity has attracted attention. The adverse effects of cancer therapy that can lead to life-threatening or induce long-term morbidity require rational approaches to prevention and treatment, which requires deeper understanding of the molecular biology underpinning the disease. In addition to the drugs used widely for cardio-protection, traditional Chinese medicine (TCM) formulations are also efficacious and can be expected to achieve "personalized treatment" from multiple perspectives. Moreover, the increased prevalence of cancer in patients with cardiovascular disease has spurred the development of "reverse cardio-oncology", which underscores the urgency of collaboration between cardiologists and oncologists. This review summarizes the mechanisms by which cancer therapy induces cardiovascular toxicity, the combination of antineoplastic and cardioprotective drugs, and recent advances in reverse cardio-oncology.

Combined exposure to multiple metals on cardiovascular disease in NHANES under five statistical models.

BACKGROUND: It is well-documented that heavy metals are associated with cardiovascular disease (CVD). However, there is few studies exploring effect of metal mixture on CVD. Therefore, the primary objective of present study was to investigate the joint effect of heavy metals on CVD and to identify the most influential metals in the mixture. METHODS: Original data for study subjects were obtained from the National Health and Nutrition Examination Survey. In this study, adults with complete data on 12 kinds of urinary metals (antimony, arsenic, barium, cadmium, cobalt, cesium, molybdenum, mercury, lead, thallium, tungsten, and uranium), cardiovascular disease, and core covariates were enrolled. We applied five different statistical strategies to examine the CVD risk with metal exposure, including multivariate logistic regression, adaptive elastic net combined with Environmental Risk Score, Quantile g-computation, Weighted Quantile Sum regression, and Bayesian kernel machine regression. RESULTS: Higher levels of cadmium, tungsten, cobalt, and antimony were significantly associated with Increased risk of CVD when covariates were adjusted for multivariate logistic regression. The results from multi-pollutant strategies all indicated that metal mixture was positively associated with the risk of CVD. Based on the results of multiple statistical strategies, it was determined that cadmium, tungsten, cobalt, and antimony exhibited the strongest positive correlations, whereas barium, lead, molybdenum, and thallium were most associated with negative correlations. CONCLUSION: Overall, our study demonstrates that exposure to heavy metal mixture is linked to a higher risk of CVD. Meanwhile, this association may be driven primarily by cadmium, tungsten, cobalt, and antimony. Further prospective studies are warranted to validate or refute our primary findings as well as to identify other important heavy metals linked with CVD.

Cardiovascular Risks of Diclofenac Versus Other Older COX-2 Inhibitors (Meloxicam and Etodolac) and Newer COX-2 Inhibitors (Celecoxib and Etoricoxib): A Series of Nationwide Emulated Trials.

INTRODUCTION: Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown. AIMS: The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs). METHODS: Using Danish nationwide health registries (1999-2020), we conducted a series of emulated trials (n = 264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n = 1,600,202), meloxicam (n = 10,903), etodolac (n = 238,538), celecoxib (n = 77,591), and etoricoxib (n = 12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events). RESULTS: MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10-1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21-2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15-1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05-1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13-1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94-2.26) and etodolac (aIRR 1.18, 95% CI 1.09-1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85-1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88-1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66-1.10). CONCLUSIONS: The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib).

Colchicine Ameliorates 5-Fluorouracil-Induced Cardiotoxicity in Rats.

Background and Objective. 5-Fluorouracil is one of the most common chemotherapeutic agents used in the treatment of solid tumors. 5-Fluorouracil-associated cardiotoxicity is the second cause of cardiotoxicity induced by chemotherapeutic drugs after anthracyclines. Colchicine is a strong anti-inflammatory drug used to prevent and treat acute gout and treat familial Mediterranean fever. And also, its protective effects on cardiovascular disease have been reported in various studies. The current study is aimed at appraising the effect of colchicine on 5-fluorouracil-induced cardiotoxicity in rats. Methods. Twenty male Wistar rats were divided into four groups as follows: control, 5-fluorouracil, colchicine (5 mg/kg), and 5-fluorouracil+5 mg/kg colchicine. Cardiotoxicity was induced with an intraperitoneal injection of a single dose of 5-fluorouracil (100 mg/kg). The control group received normal saline, and the treatment groups received colchicine with an intraperitoneal injection for 14 days. Findings. 5-Fluorouracil resulted in significant cardiotoxicity represented by an increase in cardiac enzymes, malondialdehyde levels, cyclooxygenase-2 and tumor necrosis factor-alpha expression, cardiac enzymes, and histopathological degenerations. 5-Fluorouracil treatment also decreased body weight, total antioxidant capacity and catalase values, blood cells, and hemoglobin levels. In addition, 5-fluorouracil disrupted electrocardiographic parameters, including increased elevation in the ST segment and increased QRS duration. Treatment with colchicine reduced oxidative stress, cardiac enzymes, histopathological degenerations, and cyclooxygenase-2 expression in cardiac tissue, improved electrocardiographic disorders, and enhanced the number of blood cells and total antioxidant capacity levels. Moreover, body weight loss was hampered after treatment with colchicine. Our results demonstrated that treatment with colchicine significantly improved cardiotoxicity induced by 5-fluorouracil in rats.

Polystyrene bead ingestion promotes adiposity and cardiometabolic disease in mice.

Vast amounts of plastic materials are produced in the modern world and despite recycling efforts, large amounts are disposed in water systems and landfills. Under these storage conditions, physical weathering and photochemical processes break down these materials into smaller particles of the micro- and nano-scale. In addition, ecosystems can be contaminated with plastic particles which are manufactured in these size ranges for commercial purposes. Independent of source, microplastics are abundant in the environment and have found their way into water supplies and the food cycle where human exposure is inevitable. Nevertheless, the health consequences of microplastic ingestion, inhalation, or absorption are largely unknown. In this study we sought to determine if ingestion of microplastics promoted pre-clinical cardiovascular disease (CVD). To do this, we supplied mice with normal drinking water or that supplemented with polystyrene beads of two different sizes (0.5 µm and 5 µm) and two different doses (0.1 µg/ml and 1 µg/ml) each for 12 weeks and measured several indices of metabolism and glucose homeostasis. As early as 3 weeks of consumption, we observed an accelerated weight gain with a corresponding increase in body fat for some exposure groups versus the control mice. Some exposure groups demonstrated increased levels of fasting plasma glucose. Those mice consuming the smaller sized beads (0.5 µm) at the higher dose (1 µg/ml), had increased levels of fasting plasma insulin and higher homeostatic model assessment of insulin resistance (HOMA-IR) scores as well. This was accompanied by changes in the gut microbiome consistent with an obese phenotype. Using samples of perivascular adipose tissue collected from the same group, we observed changes in gene expression consistent with increased adipogenesis. These results suggest that ingestion of polystyrene beads promotes a cardiometabolic disease phenotype and thus may be an unrecognized risk factor for CVD.

[Pathophysiological mechanisms of major mental disorders related to cardiovascular disease].

Although the relationship of mental health with cardiovascular dysfunction is not a recent finding, scientific data has appeared approximately at the middle of the last century. Firstly, depression was studied as a risk factor for premature death in cases of cardiovascular disease (CVD). Much later, the mechanism of psychosis and schizophrenia in the development of CVD were studied, as it was observed that most premature deaths in schizophrenia were related to cardiovascular disease. This interaction is supported both by epidemiological data and by the associated mechanisms. Inflammation, oxidative and biologic stress, and hormonal and neurotransmitter disorders in coagulation, tissue perfusion, vascular dysfunction and genetic factors get involved in these mental disorders. The combination of these pathophysiological mechanisms and the general risk factors for CVD (sex, age, smoking, systolic blood pressure, body weight, glucose levels) leads, to some extent, to increased rates of comorbidity and mortality. Patients with severe mental disorders are often not monitored and do not receive appropriate treatment for cardiovascular risk factors. In studies of patients with comorbid coronary heart disease and depression, there were signs of cardiovascular dysfunction, including increased heart rate, mainly in stress, QT prolongation and ventricular arrhythmia. At the same time, there is a dose-response relationship between the severity of depression and cardiovascular risk, with the presence of even mild symptoms of untreated depression involving some cardiovascular risk. In addition, improving the symptoms of depression through medication has been associated with increased survival. Moreover, the causes of increased mortality in patients with schizophrenia are similar to those of the general population with metabolic syndrome and diabetes mellitus, while failure to receive antipsychotic medication could lead to obesity, insulin resistance, dyslipidemia and hypertension. These data could be used as a source for future anti-inflammatory therapeutic approaches, but also for the appropriate selection of therapeutic agents, by taking a more holistic view of the patient's comorbidity. The interdisciplinary collaboration and liaison - consultation psychiatry are important factors for the timely prevention, recognition and treatment of potent complications of the cardiovascular system in mentally ill patients. The aim of this review was to present the pathophysiological mechanisms of serious mental disorders, such as depression, bipolar disorder, and schizophrenia that may be related to the development of CVD.

Preventive effects of Pycnogenol® on cardiovascular risk factors (including endothelial function) and microcirculation in subjects recovering from coronavirus disease 2019 (COVID-19).

BACKGROUND: The aim of this open supplement study was to evaluate the effects of Pycnogenol® in comparison with controls on symptoms of post-COVID-19 syndrome and in improving endothelial function, microcirculation, inflammatory markers and oxidative stress over 3 months in symptomatic subjects recovering from COVID-19. METHODS: Sixty subjects recovering from symptomatic COVID-19 were included. One group of 30 followed a standard recovery management while 30 comparable subjects received a supplement of 150 mg Pycnogenol® daily (in 3 doses of 50 mg) in addition to standard management. RESULTS: Two groups of selected subjects were comparable at baseline. The groups progressively improved both with the SM (standard management) and with the SM in combination with the supplement. Patients, supplemented with Pycnogenol® showed significantly better improvement compared to the control group patients. No side effects from the supplementation were observed; tolerability was optimal. The progressive evolution over time was visible in all target measurements. Physiological tests: endothelial function, low in all subjects at inclusion was assessed by flow mediated dilation (FMD) and finger reactive hyperemia in the microcirculation (laser Doppler measurements) after the release of an occluding suprasystolic cuff. It was significantly improved in the Pycnogenol® group after one month and after 3 months (P<0.05 vs. controls). The rate of ankle swelling (RAS) by strain gauge decreased significantly in the supplemented group (P<0.05) in comparison with controls showing an improvement of the capillary filtration rate. At inclusion, the kidney cortical flow velocity indicated a decrease in perfusion (lower systolic and diastolic flow velocity) in all patients. Kidney cortical flow velocity increased significantly with the supplement (P<0.05) in comparison with controls with improvement in systolic velocity and in diastolic component. High sensitivity CRP (hs-CRP) and Il-6 plasma levels decreased progressively over 3 months with a significant more pronounced decrease in the supplement group (P<0.05). The number of patients with normal plasma IL-6 levels at the end of the study was higher (P<0.05) with the supplement. ESR followed the same pattern with a progressive and a more significant decrease in the supplemented subjects (P<0.02). Oxidative stress decreased significantly in the supplemented group (P<0.05) compared with the control group. Systolic blood pressure was significantly lower in the supplemented group (P<0.05) at the end of the study. Finally, the scores of Quality-of-life, mood and fatigue questionnaire and the Karnofsky Scale Performance Index significantly improved in the supplement group (P<0.05) compared to controls after 1 and 3 months. All other blood parameters (including platelets and clotting factors) were within normal values at the end of the study. CONCLUSIONS: In conclusion, Pycnogenol® may offer a significant option for managing some of the signs and symptoms associated with post-COVID-19 syndrome. This pilot evaluation offers some potential rationale for the use of Pycnogenol® in this condition that will have significant importance in the coming years.

The Dietary Nutrient Trimethylamine N-Oxide Affects the Phospholipid Vesicle Membrane: Probable Route to Adverse Intake.

Trimethylamine N-oxide (TMAO), a choline-containing dietary supplement obtained from red meat, egg, and other animal resources, on excess accumulation is known to cause cardiovascular diseases (CVDs) like atherosclerosis. To understand the molecular mechanism of the pathogenesis of TMAO-induced CVDs, we have set up 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membrane in water that mimicked the endothelial cell membrane-blood interface of the artery wall and investigated the effect of an elevated concentration of TMAO on the membrane. We found that TMAO exerts an "action at a distance" mechanism through electrostatic force of attraction that significantly alters various properties of the membrane, like hydrophobicity, lateral organization, and interfacial water dynamics, which elevates the rigidity of the membrane. Such an effect was found to be further amplified in the presence of known causes of CVDs, i.e., high content of cholesterol (Chol). Therefore, TMAO-induced membrane rigidity may restrict the intrinsic elasticity of an artery membrane, expected to be introducing "hardening of the arteries", which makes the membrane atherosclerotic.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney disease: Advantages and disadvantages.

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Association of Cardiovascular Outcomes and Mortality With Sustained Long-Acting Insulin Only vs Long-Acting Plus Short-Acting Insulin Treatment.

Importance: Cardiovascular events and mortality are the principal causes of excess mortality and health care costs for people with type 2 diabetes. No large studies have specifically compared long-acting insulin alone with long-acting plus short-acting insulin with regard to cardiovascular outcomes. Objective: To compare cardiovascular events and mortality in adults with type 2 diabetes receiving long-acting insulin who do or do not add short-acting insulin. Design, Setting, and Participants: This retrospective cohort study emulated a randomized experiment in which adults with type 2 diabetes who experienced a qualifying glycated hemoglobin A1c (HbA1c) level of 6.8% to 8.5% with long-acting insulin were randomized to continuing treatment with long-acting insulin (LA group) or adding short-acting insulin within 1 year of the qualifying HbA1c level (LA plus SA group). Retrospective data in 4 integrated health care delivery systems from the Health Care Systems Research Network from January 1, 2005, to December 31, 2013, were used. Analysis used inverse probability weighting estimation with Super Learner for propensity score estimation. Analyses took place from April 1, 2018, to June 30, 2019. Exposures: Long-acting insulin alone or with added short-acting insulin within 1 year from the qualifying HbA1c level. Main Outcomes and Measures: Mortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for heart failure. Results: Among 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up (median follow-up of 11 [interquartile range, 5-20] calendar quarters), the LA plus SA group was associated with increased all-cause mortality compared with the LA group (hazard ratio, 1.27; 95% CI, 1.05-1.49) and a decreased risk of acute myocardial infarction (hazard ratio, 0.89; 95% CI, 0.81-0.97). Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality. Conclusions and Relevance: Findings of this retrospective cohort study suggested an increased risk of all-cause mortality and a decreased risk of acute myocardial infarction for the LA plus SA group compared with the LA group. Given the lack of an increase in major cardiovascular events or cardiovascular mortality, the increased all-cause mortality with long-acting plus short-acting insulin may be explained by noncardiovascular events or unmeasured confounding.

Neuro-nutraceuticals: Natural products nourish the brain but be aware of contrary effects.

In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address the holistic benefit of herbal medicines and their multi-targeted actions, which improve brain function in diverse cellular and animal models of brain injury. Not only are new targets for nutraceuticals reported, but their benefits on neurobehavioural problems are elucidated in conditions as diverse as obesity and menopause. Inflammation in neuropathologies, including Alzheimer's disease (AD), remains a huge focus and diverse nutraceuticals demonstrate therapeutic applicability via glial-mediated actions. While contrary actions should be borne in mind in the search for novel neurotherapeutics, the great promise offered by herbal medicines and their newly identified active principles offers unique options for the management of diverse neurological and psychiatric conditions.