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Background and Aims: Etiologic associations between some modifiable factors (metabolic risk factors and lifestyle behaviors) and cardiovascular disease (CVD) remain unclear. To identify targets for CVD prevention, we evaluated the causal associations of these factors with coronary artery disease (CAD) and ischemic stroke using a two-sample Mendelian randomization (MR) method., Methods and Results: Previously published genome-wide association studies (GWASs) for blood pressure (BP), glucose, lipids, overweight, smoking, alcohol intake, sedentariness, and education were used to identify instruments for 15 modifiable factors. We extracted effects of the genetic variants used as instruments for the exposures on coronary artery disease (CAD) and ischemic stroke from large GWASs (N = 60 801 cases/123 504 controls for CAD and N = 40 585 cases/406 111 controls for ischemic stroke). Genetically predicted hypertension (CAD: OR, 5.19 [95% CI, 4.21-6.41]; ischemic stroke: OR, 4.92 [4.12-5.86]), systolic BP (CAD: OR, 1.03 [1.03-1.04]; ischemic stroke: OR, 1.03 [1.03-1.03]), diastolic BP (CAD: OR, 1.05 [1.05-1.06]; ischemic stroke: OR, 1.05 [1.04-1.05]), type 2 diabetes (CAD: OR, 1.11 [1.08-1.15]; ischemic stroke: OR, 1.07 [1.04-1.10]), smoking initiation (CAD: OR, 1.26 [1.18-1.35]; ischemic stroke: OR, 1.24 [1.16-1.33]), educational attainment (CAD: OR, 0.62 [0.58-0.66]; ischemic stroke: OR, 0.68 [0.63-0.72]), low-density lipoprotein cholesterol (CAD: OR, 1.55 [1.41-1.71]), high-density lipoprotein cholesterol (CAD: OR, 0.82 [0.74-0.91]), triglycerides (CAD: OR, 1.29 [1.14-1.45]), body mass index (CAD: OR, 1.25 [1.19-1.32]), and alcohol dependence (OR, 1.04 [1.03-1.06]) were causally related to CVD., Conclusion: This systematic MR study identified 11 modifiable factors as causal risk factors for CVD, indicating that these factors are important targets for preventing CVD., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease is a public health problem. The purpose of this study was to compare the effects of sevelamer and calciumbased binders on mortality of hemodialysis patients. PubMed, EMBASE and Web of Science were searched for related articles published before May 14, 2020. We included six studies with 43330 participants, of which 21147 and 22183 received calciumbased phosphate binders and sevelamer, respectively. In the analysis of unadjusted data, sevelamer could lower cardiovascular mortality. When adjusted HRs was pooled, the cardiovascular mortality did not differ significantly in the sevelamer and calcium-based phosphate binders groups. Additionally, the all-cause mortality rate in sevelamer group was different from that in calcium-based phosphate binders group. However, sevelamer could not lower all-cause mortality in terms of the adjusted data. No significant difference was found in calcium and phosphorus between calcium-based phosphate binders and sevalmer. Sensitivity analysis showed that partial results of the study were inconsistent. There was no difference in the effect of sevelamer and calciumbased phosphate binders on the risk of all-cause mortality in patients with hemodialysis, after adjusting confounders. However, given the instability of the results, the results need to be further confirmed by a large sample and high quality RCTs.  DOI: 10.52547/ijkd.6814.

Purpose: A meta-analysis was conducted to assess the benefits and risks of aspirin for the primary prevention of cardiovascular disease and all-cause mortality events in adults with diabetes., Methods: An extensive and systematic search was conducted in MEDLINE (via PubMed), Cinahl (via Ebsco), Scopus, and Web of Sciences from 1988 to December 2020. A detailed literature search was conducted using aspirin, cardiovascular disease (CVD), diabetes, and efficacy to identify trials of patients with diabetes who received aspirin for primary prevention of CVD. Demographic details with the primary outcome of events and bleeding outcomes were analyzed. The Cochrane Collaboration's risk of bias tool was used to assess the methodological quality of the included studies. Random-effects meta-analysis was used to calculate the pooled odds ratio for outcomes of cardiovascular events, death, and adverse events., Findings: A total of 8 studies were included with 32,024 patients with diabetes; 16,001 allocated to aspirin, and 16,023 allocated to the control group. There was no difference between aspirin and control groups with respect to all-cause mortality, cardiovascular mortality, or bleeding events. However, MACE was significantly lower in the aspirin group., Implications: Although aspirin has no significant risk on primary endpoints of cardiovascular events and bleeding outcomes in patients with diabetes compared to control, major adverse cardiovascular events (MACE) were significantly lower in the aspirin group. Further research on the use of aspirin alone or in combination with other antiplatelet drugs is required in patients with diabetes to supplement currently available research., Systematic Review Registration: identifier [XU#/IRB/2020/1005]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Gu, Niu, Li and Wang.)

The Cardiovascular and Cognitive Health Study (CCHS-Beijing) is a population-based study of cardiovascular disease (CVD) and cognitive impairment in adults aged 55 and older in Beijing. The main aims of the study are to investigate the prevalence rates of CVD, asymptomatic atherosclerosis, and cognitive impairment, as well as validate the risk factors related to the onset and development of CVD, Alzheimer's disease (AD) and mild cognitive impairment (MCI). The study was designed to detect the traditional and new risk factors in this age group. Participants were recruited randomly from residential regions in the greater Beijing municipality area based on the average levels of development in Beijing, China in 2012 (based on socioeconomic, demographic, and geographical characteristics). Thorough physical and laboratory examination were performed at baseline (also the cross-sectional survey) to identify the risk factors such as hypertension, dyslipidemia, diabetes, as well as newly defined risk factors like elevated homocysteine, high sensitivity C-reactive protein, and urine micro-albumin. Subclinical disease of the cerebral vasculature included atherosclerosis of carotid arteries, intracranial arteries, and retinal vessels. Subclinical cardiac diseases included left ventricular enlargement, arrhythmias, chamber hypertrophy and myocardial ischemia. Blood pressure was documented using the ankle-arm method. In addition, neuropsychological assessments were performed for all subjects aged 65 and above. Baseline evaluation began during the period August 2013 to December 2014. Follow-up examination will occur in 5 years. The initial and recurrent CVD, AD and MCI events will be verified and validated during the follow-up period., (© 2016 S. Karger AG, Basel.)

The aim of this study was to investigate the association between peroxisome proliferator-activator receptor-γ (PPAR-γ) genotype and additional gene-smoking interaction on cardiovascular disease (CVD) based on a Chinese population. A total of 1248 subjects (613 men, 635 women), with a mean age of 55.5±11.8 years old, were selected, including 620 CVD patients and 628 normal controls. Logistic regression was performed to investigate association between single nucleotide polymorphism (SNP) and CVD. Generalized MDR (GMDR) was used to analysis the gene-environment interaction, cross-validation consistency, the testing balanced accuracy, and the sign test, to assess each selected interaction were calculated. The carriers of homozygous mutant of two SNP revealed increased CVD risk than those with wild-type homozygotes, OR (95% CI) were 1.31 (1.16-1.95) and 1.68 (1.29-2.06), respectively. GMDR analysis for one- to three-locus models indicated that there was a significant two-locus model (p=0.0107) involving rs1805192 and smoking, indicating a potential gene-gene interaction between rs1805192 and smoking. Overall, the two- locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 62.17%. We found that smokers with Pro/Ala or Ala/Ala genotype have highest CVD risk, compared to non-smokers with Pro/Pro genotype, OR (95% CI) was 3.46 (1.31-3.42), after covariates adjustment. We found a significant association between genotypes of variants in rs10865710 and rs1805192 with increased CVD risk and a potential gene-gene interaction between rs1805192 and smoking., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, posing a significant threat to public health. Research on the relationship between CVD and temperature has primarily focused on developed urban settings, with limited studies conducted in rural regions with lower levels of development. Additionally, compared to relative risks, attributable risks can provide more information when assessing the risk of CVD hospitalizations associated with exposure to apparent temperature (AT). Apparent temperature is a composite temperature index that takes into account both meteorological factors and temperature, providing an objective reflection of human thermal sensation. Therefore, this study investigates the impact of AT on CVD hospitalization and quantifies the burden of CVD admission in the rural areas of China. We employed the distributed lag non-linear model (DLNM) to estimate the relationship between AT and the relative risk (RR) of CVD hospitalization. Finally, we used attributable risk methods to quantify this relationship further. [ABSTRACT FROM AUTHOR]

Exposure to airborne fine particulate matter (PM 2.5 ) is associated with cardiovascular diseases. However, a comprehensive understanding of the underlying mechanisms by which PM 2.5 induces or aggravates these diseases is still insufficiently clear. The present study investigated whether PM 2.5 alters the expression of the endothelin subtype B (ET B ) and endothelin subtype A (ET A ) receptors in the coronary artery and examined the underlying mechanisms. Rat coronary artery segments were cultured with PM 2.5 in the presence or absence of MEK/ERK1/2, JNK, and p38 pathway inhibitors. Contractile reactivity was measured by myography. ET B and ET A receptor expression was evaluated using RT-PCR, western blot and immunohistochemistry. Compared with fresh arteries, the cultured coronary arteries showed a significantly enhanced contraction mediated by the ET B receptor and an unaltered contraction mediated by the ET A receptor. Culture with PM 2.5 significantly enhanced the contraction and the mRNA and protein expression levels of the ET B and ET A receptors in the coronary arteries, suggesting that PM 2.5 induces an upregulation of ET A and ET B receptors. In addition, the PM 2.5 -induced increases in ET B - and ET A -mediated vasoconstriction and receptor expressions could be notably decreased by MEK1/2 inhibitor, U0126 and Raf inhibitor, SB386023, suggesting that the upregulation of ET B and ET A receptors is related with MEK/ERK1/2 pathway. In conclusion, PM 2.5 induces the ET B and ET A receptor upregulation in rat coronary arteries, and the MEK/ERK1/2 pathway may be involved in this process. [ABSTRACT FROM AUTHOR]

Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O2) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR- 128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR- 141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR- 135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart. [ABSTRACT FROM AUTHOR]

The pathophysiology of coronary atherosclerotic plaques is a complex process. Early detection of coronary atherosclerotic plaques is critical in the prevention, prognostic and therapeutic intervention of cardiovascular disease. MicroRNAs (miRNAs), endogenous short non-coding RNAs, have been reported to play an important role in cardiovascular diseases and are also used as disease markers. However, the miRNA expression profile in early coronary atherosclerotic plaques has yet been reported. We hypothesize that miRNAs can be used as effective disease markers for detection of early coronary atherosclerotic plaques. In this analysis, coronary artery samples from three patients with early coronary atherosclerosis were harvested and miRNA expression profile determined using microarray analysis. Compared with healthy controls, a total of 44 miRNAs were upregulated and 57 miRNAs were downregulated. Among the dysregulated miRNAs, eight were significantly upregulated while five miRNAs were significantly downregulated, as determined by t- test ( P < 0.05). Four of the significantly dysregulated miRNAs, including miR-221, miR-155, miR-100 and hsa-miR-1273, were selected and verified by real-time PCR. The real-time PCR results were consistent with the microarray data that miR-221, miR-155 and miR-100 were significantly downregulated in plaques, whereas miR-1273 was significantly upregulated. These results indicate that miRNAs expression level can be used as potential markers for early coronary atherosclerotic plaque formation. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a typical complex multi-factorial disease and many molecules at different levels and pathways were involved in its development. Some studies have investigated the dysregulation in atherosclerosis at mRNA, miRNA or DNA methylation level, respectively. However, to our knowledge, the studies that integrated these data and revealed the abnormal networks of atherosclerosis have not been reported. Using microarray technology, we analyzed the omics data in atherosclerosis at mRNA, miRNA and DNA methylation levels. Our results demonstrated that the global DNA methylation and expression of miRNA/mRNA were significantly decreased in atherosclerotic plaque than in normal vascular tissue. The interaction network constructed using the integrative data revealed many genes, cellular processes and signaling pathways which were widely considered to play crucial roles in atherosclerosis and also revealed some genes, miRNAs or signaling pathways which have not been investigated in atherosclerosis until now (e.g. miR-519d and SNTB2). Moreover, the overall protein ubiquitination in atherosclerotic plaque was significantly increased. The proteasome activity was increased early but decreased in advanced atherosclerosis. Our study revealed many classic and novel genes and miRNAs involved in atherosclerosis and indicated the effects of ubiquitin-proteasome system on atherosclerosis might be closely related to the course of atherosclerosis. However, the efficacy of proteasome inhibitors in the treatment of atherosclerosis still needs more research. [ABSTRACT FROM AUTHOR]

Abstract: Although it is well known that 3,4-methylenedioxymethamphetamine (MDMA) can cause various cardiovascular abnormalities and even sudden death from cardiac arrhythmia, whether it has any effect on myocardial gap junctions, which might be one of the targets mediating MDMA-induced cardiotoxicity, remains unclear. Objective: To test the hypothesis that MDMA may affect the myocardial gap junction protein connexin43 (Cx43) and induce cardiac dysrhythmia. Method: (1) In vivo study: adult rats were treated with a single dose MDMA administration (20mg/kg, i.p.). Electrocardiogram detection and immunohistochemical analysis were performed to evaluate cardiac function and expression of Cx43, respectively; (2) in vitro study: cultured ventricular myocytes of neonatal rats were treated with MDMA (10, 100, 1000μmol/L) for 1h. Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were performed to investigate the total Cx43 mRNA expression. Immunofluorescent analysis was used to evaluate the amount of junctional Cx43. The phosphorylation status of Cx43 at site Ser368 and intracellular Ca2+ oscillation were also studied. Results: Obvious changes in electrocardiographic patterns were found in rats following MDMA administration. They were characterized by prolonged QRS duration associated with increased amplitude of QRS complex. The heart rates in treated rats were significantly decreased compared to the rats in the control group. The immunohistochemical findings revealed a significant decrease in Cx43 expression. The in vitro study also showed a marked decline in total Cx43 protein associated with reduction of Cx43 mRNA, whereas the phosphorylated Cx43 at Ser368 was increased. Decrease of junctional Cx43 was found correlated with reduction in N-cadherin induced by high concentration of MDMA. Additionally, confocal microscopy findings revealed alteration of intracellular calcium oscillation patterns characterized by high frequency and increasing influx Ca2+. Conclusions: MDMA reduces expression of cardiac gap junction protein Cx43. The increase of phosphorylation status of Cx43 at Ser368 induced by MDMA is attributed, at least in part, to the Ca2+-dependent regulation of protein kinase C (PKC) activity. Our findings provide first evidence of MDMA-mediated changes in those cardiac gap junctions that may underlie MDMA-induced cardiac arrhythmia. [Copyright &y& Elsevier]

There are multiple pathways for communication of gut microbes with human organs. Trimethylamine N-oxide (TMAO) is generated via a metaorganismal pathway, which begins with the conversion of dietary phosphatidyl choline into trimethylamine in the gut of microbes, followed by liver oxidation of TMAO by flavin monooxygenases in the host. The gut-liver axis that links the liver metabolism and the gut microbiota plays an important role in the mechanisms of liver diseases. Translocated lipopolysaccharide (LPS) enters the liver through hepatic portal vein and causes damage to the liver function. Changes in the gut microbiota can affect the function of central nervous system through multiple signaling pathways, including the hypothalamus-pituitary-adrenal axis, immune regulation, serotonin metabolism, and production of neuroactive compounds. Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; GABA, gamma-aminobutyric acid; HPA, hypothalamic–pituitary–adrenal; LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; 5-HT, serotonin; TMA, trimethylamine; TMAO, trimethylamine oxide. • Dysbiosis of intestinal microbiota is related to various diseases. • A. muciniphila is a new target for treating diabetes, obesity, intestinal diseases, liver diseases and neuropsychiatric diseases. • Herbal medicine are widely accepted for treating diseases by regulating intestinal microbiota and microbial metabolites. • Herbal medicine exert a prebiotic effect on A. muciniphila in the treatment of various ailments. There are trillions and trillions of microorganisms in the human gut, and these microorganisms and their metabolites are closely related to human health. Recent studies have found that the abundance of Akkermansia muciniphila is decreased in many diseases. Supplementation of A. muciniphila is used to treat many diseases, suggesting it as a probiotic. Herbal medicines are considered as valuable asset of traditional Chinese medicine. Recent studies have revealed traditional Chinese medicine as a potential prebiotic agent for the treatment of many diseases. Hence, in this review, we aimed to provide a plausible mechanistic basis for the interactions between herbal medicines and A. muciniphila , and therapeutic benefits on this interaction in various illnesses. [ABSTRACT FROM AUTHOR]