Reduced Risk Of Coronary Artery Disease Research Articles

Haptoglobin phenotype and intensive glycemic control for coronary artery disease risk reduction in people with type two diabetes: The Veterans Affairs Diabetes Trial

BackgroundIntensive glycemic control reduced the risk of coronary artery disease (CAD) events among White ACCORD study participants with the haptoglobin (Hp)2-2 phenotype, and not among participants without the Hp2-2 phenotype. It is unknown whether these results persist in a population with more severe diabetes. MethodsHaptoglobin phenotype was measured in 1746 (97 %) samples from the Veterans Affairs Diabetes Trial (VADT) randomized controlled trial. Multivariable-adjusted Cox regression models assessed the effect of intensive therapy on CAD risk among participants with and without the Hp2-2 phenotype separately and when stratified within pre-specified race/ethnicity-based subgroups. Time-varying (achieved) HbA1c data (<7.0 % or ≥8.0 % compared to 7.0–7.9, updated every 3 months) were also analyzed in relation to CAD risk within each phenotype. Results567 (32.5 %) participants had the Hp2-2 phenotype. Compared to standard therapy, intensive glycemic control was not associated with risk of CAD among participants with the non-Hp2-2 or the Hp2-2 phenotype or for any race/ethnicity-based group. Compared to HbA1c of 7.0–7.9 %, having HbA1c <7.0 % was not associated with CAD risk for either phenotype or among any race/ethnicity-based group. Having HbA1c ≥8.0 % was associated with an increased risk of CAD among Hispanic participants without the Hp2-2 phenotype (HR= 3.61, 95 % CI: 1.54–8.41, p-interaction=0.53). ConclusionThe effect of intensive glycemic therapy on CAD events was not dependent on Hp phenotype in the VADT study of veterans with severe diabetes who may represent a population where Hp phenotype information would not be useful for personalizing diabetes management. However, further research is needed to determine if these results are conclusive.

Haptoglobin Phenotype and Intensive Glycemic Control for Coronary Artery Disease Risk Reduction in People With Type 2 Diabetes: The ADVANCE Study.

Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82-1.32) or with (0.84, 0.63-1.14, Pinteraction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29-0.76, Pinteraction = 0.01). Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype.

Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region.

Phenotypic heterogeneity at genomic loci encoding drug targets can be exploited by multivariable Mendelian randomization to provide insight into the pathways by which pharmacological interventions may affect disease risk. However, statistical inference in such investigations may be poor if overdispersion heterogeneity in measured genetic associations is unaccounted for. In this work, we first develop conditional F statistics for dimension-reduced genetic associations that enable more accurate measurement of phenotypic heterogeneity. We then develop a novel extension for two-sample multivariable Mendelian randomization that accounts for overdispersion heterogeneity in dimension-reduced genetic associations. Our empirical focus is to use genetic variants in the GLP1R gene region to understand the mechanism by which GLP1R agonism affects coronary artery disease (CAD) risk. Colocalization analyses indicate that distinct variants in the GLP1R gene region are associated with body mass index and type 2 diabetes (T2D). Multivariable Mendelian randomization analyses that were corrected for overdispersion heterogeneity suggest that bodyweight lowering rather than T2D liability lowering effects of GLP1R agonism are more likely contributing to reduced CAD risk. Tissue-specific analyses prioritized brain tissue as the most likely to be relevant for CAD risk, of the tissues considered. We hope the multivariable Mendelian randomization approach illustrated here is widely applicable to better understand mechanisms linking drug targets to diseases outcomes, and hence to guide drug development efforts.

The impact of sociodemographic status on the association of classical cardiovascular risk factors with coronary artery disease: a stratified Mendelian randomization study

ObjectivesLow socioeconomic status (SES) is associated with cardiovascular risk factors and increased coronary artery disease (CAD) risk. We tested whether SES is an effect modifier of the association between classical cardiovascular risk factors and CAD using SES-stratified Mendelian Randomization in European-ancestry participants from UK Biobank. Study Design and SettingWe calculated weighted genetic risk scores (GRS) for the risk factors body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, and triglycerides. Participants were stratified by Townsend deprivation index score. Logistic regression models were used to investigate associations between GRSs and CAD occurrence. Additionally, stratification based on GRS-adjusted Townsend deprivation index residuals was conducted to correct for possible collider-stratification bias. ResultsIn a total sample size of N = 446,485, with 52,946 cases, the risk for CAD per standard deviation increase in genetically influenced BMI was highest in the group with the lowest 25% SES (odds ratio: 1.126, 95% confidence interval: 1.106–1.145; odds ratio: 1.081, 95% confidence interval: 1.059–1.103 in high SES), remaining similar after controlling for possible collider-stratification bias. The effects of genetically influenced systolic blood pressure, low-density lipoprotein cholesterol, and triglyceride on CAD were similar between SES groups. ConclusionCAD risk attributable to increased BMI is not homogenous and could be modified by SES. This emphasizes the need of tailor-made approaches for BMI-associated CAD risk reduction.

Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.

Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia, may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (eg, inflammatory) and protective (eg, increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. We selected a cross-sectional sample of 471 877 participants from the UK Biobank, with 4974 ascertained to have OSA, 25 988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with intermittent hypoxia and CAD, we tested pathway-specific polygenic risk scores for the HIF1 (hypoxia-inducible factor 1), VEGF (vascular endothelial growth factor), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and TNF (tumor necrosis factor) signaling pathways. In a multivariable-adjusted logistic generalized additive model, elevated pathway-specific polygenic risk scores for the Kyoto Encyclopedia of Genes and Genomes VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, P=6×10-4). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.

The Benefits of High-Resistant Starch and Beta-Carotene Snack in Ameliorating Atherogenic Index and Inflammation in Obesity

BACKGROUND: In obesity, lipid abnormalities may be related to the higher risk of cardiovascular diseases associated with increased oxidation of lipids and inflammation. Resistant starch and beta-carotene reduce atherosclerosis risk related to low-grade inflammation and oxidative stress in obesity. AIM: This study aimed to evaluate the benefits of a snack containing high-resistant starch and beta-carotene in improving the atherogenic index of plasma (AIP) and inflammation in obesity. METHODS: This study used a single-blinded and randomized controlled design. Fifty subjects received 42 g of snacks per day for 6 weeks, either tested snacks or standard snacks. Anthropometry, body composition, lipid profile, tumor necrosis factor-alpha (TNF-α), and oxidized low-density lipoprotein (ox-LDL) were measured before and after intervention. RESULTS: The snack containing high-resistant starch and beta-carotene significantly decreased LDL, AIP, and TNF-α (p &lt; 0.05). Positive correlations were found between AIP and triglycerides in both snacks (p &lt; 0.05), LDL or TNF-α in the standard snack (p &lt; 0.05), and TNF-α and ox-LDL in both snacks (p &lt; 0.05). A negative correlation was found between AIP and HDL in both snacks (p &lt; 0.05). CONCLUSIONS: A snack containing high-resistant starch and beta-carotene reduced AIP and inflammation by preventing LDL oxidation.

Genome-wide pleiotropy analysis of coronary artery disease and pneumonia identifies shared immune pathways.

Coronary artery disease (CAD) remains the leading cause of death despite scientific advances. Elucidating shared CAD/pneumonia pathways may reveal novel insights regarding CAD pathways. We performed genome-wide pleiotropy analyses of CAD and pneumonia, examined the causal effects of the expression of genes near independently replicated SNPs and interacting genes with CAD and pneumonia, and tested interactions between disruptive coding mutations of each pleiotropic gene and smoking status on CAD and pneumonia risks. Identified pleiotropic SNPs were annotated to ADAMTS7 and IL6R. Increased ADAMTS7 expression across tissues consistently showed decreased risk for CAD and increased risk for pneumonia; increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. We similarly observed opposing CAD/pneumonia effects for NLRP3. Reduced ADAMTS7 expression conferred a reduced CAD risk without increased pneumonia risk only among never-smokers. Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R, and related genes.

Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73–0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.

Potential of Phenolic Compounds and Their Gut Microbiota-Derived Metabolites to Reduce TMA Formation: Application of an In Vitro Fermentation High-Throughput Screening Model.

Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic product of dietary choline metabolism generated by a microbiome-host axis. The first step in this pathway is the enzymatic metabolism of choline to trimethylamine (TMA) by the gut microbiota. This reaction could be targeted to reduce atherosclerosis risk. We aimed to evaluate potential inhibitory effects of select dietary phenolics and their relevant gut microbial metabolites on TMA production via a human ex vivo-in vitro fermentation model. Various phenolics inhibited choline use and TMA production. The most bioactive compounds tested (caffeic acid, catechin, and epicatechin) reduced TMA-d9 formation (compared to control) by 57.5 ± 1.3 to 72.5 ± 0.4% at 8 h and preserved remaining choline-d9 concentrations by 194.1 ± 6.4 to 256.1 ± 6.3% at 8 h. These inhibitory effects were achieved without altering cell respiration or cell growth. However, inhibitory effects decreased at late fermentation times, which suggested that these compounds delay choline metabolism rather than completely inhibiting TMA formation. Overall, caffeic acid, catechin, and epicatechin were the most effective noncytotoxic inhibitors of choline use and TMA production. Thus, these compounds are proposed as lead bioactives to test in vivo.

Association of m.5178C>A variant with serum lipid levels: a systematic review and meta-analysis.

Background: Emerging evidence shows that m.5178C>A variant is associated with a lower risk of coronary artery disease (CAD). However, the specific mechanisms remain elusive. Since dyslipidemia is one of the most critical risk factors for CAD and accounts for at least 50% of the population-attributable risk, it is tempting to speculate that the reduced CAD risk caused by the m.5178C>A variant may stem from an improved lipid profile. In order to verify this hypothesis, we conducted the present study to clarify the association of m.5178C>A variant with lipid levels.Methods: By searching ten databases for studies published before 30 June 2021. Thirteen East Asian populations (7587 individuals) were included for the analysis.Results: The present study showed that m.5178C>A variant was associated with higher high-density lipoprotein cholesterol (HDL-C) [standardized mean difference (SMD) = 0.12, 95% confidence interval (CI) = 0.06–0.17, P<0.001] and total cholesterol (TC) (SMD = 0.08, 95% CI = 0.02–0.14, P=0.01) levels. In subgroup analysis, the association of m.5178C>A variant with higher HDL-C levels were observed in Japanese (SMD = 0.09, 95% CI = 0.01–0.17, P=0.03) and Chinese populations (SMD = 0.13, 95% CI = 0.07–0.20, P<0.001). However, the association of m.5178C>A variant with lower low-density lipoprotein cholesterol (LDL-C) levels were only observed in Japanese populations (SMD = −0.11, 95% CI = −0.22 to 0.00, P=0.04).Conclusions: The m.5178C>A variant was associated with higher HDL-C and lower LDL-C levels in Japanese populations, which may contribute to decreased CAD risk and longevity of Japanese.

Abstract 12121: Coronary Disease Association With ADAMTS7 is Due to Protease Activity: Implications for Therapeutic Development

Background: Despite contemporary therapy, coronary artery disease (CAD) remains a leading cause of mortality. Genetic variants at ADAMTS7 have been associated with CAD and the loss of ADAMTS7 is protective for atherosclerosis. ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) is a secreted metalloproteinase and complex proteoglycan, yet the mechanism linking ADAMTS7 to CAD risk remains unresolved. Methods and Results: We established a new purification strategy for full-length mouse ADAMTS7 and demonstrated the loss of activity in the catalytic mutant form of ADAMTS7. To test if the enzymatic activity of ADAMTS7 mediates atherosclerosis, we generated a catalytically inactive mutant mouse allele and compared it to the Adamts7 knockout. Using two models of atherosclerosis, we found that reducing either ADAMTS7 dosage or catalytic function decreased the burden of atherosclerosis. We demonstrate impaired vascular smooth muscle migration in both Adamts7 catalytic mutant and null cells using a lateral migration wound healing assay. Expression of the WT allele rescued the migration phenotype in Adamts7 null cells while expression of the catalytic mutant protein did not. We then characterized a human ADAMTS7 coding variant rs3825807 (Ser214Pro) associated with reduced CAD risk. This variant had a hypomorphic effect on ADAMTS7 secretion and migration of vascular smooth muscle cells, findings consistent with our mouse studies. Conclusions: We demonstrated that loss of ADAMTS7 catalytic function protects against atherosclerosis via phenotype switch of VSMCs and that the atherosclerosis protective effects could be mediated by a loss-of-function coding variant associated with CAD risk. In aggregate, we provide compelling evidence that dosage of ADAMTS7 and catalytic function are responsible for the atherosclerotic phenotype, suggesting that the catalytic domain would be an attractive therapeutic target for CAD.

Robust estimates of heritable coronary disease risk in individuals with type 2 diabetes.

Type 2 diabetes (T2D) is an important heritable risk factor for coronary artery disease (CAD), the risk of both diseases being increased by metabolic syndrome (MS). With the availability of large‐scale genome‐wide association data, we aimed to elucidate the genetic burden of CAD risk in T2D predisposed individuals within the context of MS and their shared genetic architecture. Mendelian randomization (MR) analyses supported a causal relationship between T2D and CAD [odds ratio (OR) = 1.13 per log‐odds unit 95% confidence interval (CI): 1.10–1.16; p = 1.59 × 10−17]. Simultaneously adjusting MR analyses for the effects of the T2D instrument including blood pressure, dyslipidaemia, and obesity attenuated the association between T2D and CAD (OR = 1.07, 95% CI: 1.04–1.11). Bayesian locus‐overlap analysis identified 44 regions with the same causal variant underlying T2D and CAD genetic signals (FDR < 1%) at a posterior probability >0.7; five (MHC, LPL, ABO, RAI1 and MC4R) of these regions contain genome‐wide significant (p < 5 × 10−8) associations for both traits. Given the small effect sizes observed in genome‐wide association studies for complex diseases, even with 44 potential target regions, this has implications for the likely magnitude of CAD risk reduction that might be achievable by pure T2D therapies.

A Missense Variant in the IL-6 Receptor and Protection From Peripheral Artery Disease

A Missense Variant in the IL-6 Receptor and Protection From Peripheral Artery Disease

Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease

BackgroundLipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants. ObjectivesThis study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD. MethodsWe genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project. ResultsThe 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably. ConclusionsFunctional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction.

Coronary Disease Association With ADAMTS7 Is Due to Protease Activity.

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Mitochondrial DNA copy number and trimethylamine levels in the blood: New insights on cardiovascular disease biomarkers.

Among cardiovascular disease (CVD) biomarkers, the mitochondrial DNA copy number (mtDNAcn) is a promising candidate. A growing attention has been also dedicated to trimethylamine-N-oxide (TMAO), an oxidative derivative of the gut metabolite trimethylamine (TMA). With the aim to identify biomarkers predictive of CVD, we investigated TMA, TMAO, and mtDNAcn in a population of 389 coronary artery disease (CAD) patients and 151 healthy controls, in association with established risk factors for CVD (sex, age, hypertension, smoking, diabetes, glomerular filtration rate [GFR]) and troponin, an established marker of CAD. MtDNAcn was significantly lower in CAD patients; it correlates with GFR and TMA, but not with TMAO. A biomarker including mtDNAcn, sex, and hypertension (but neither TMA nor TMAO) emerged as a good predictor of CAD. Our findings support the mtDNAcn as a promising plastic biomarker, useful to monitor the exposure to risk factors and the efficacy of preventive interventions for a personalized CAD risk reduction.

Development of a High Throughput In Vitro Fecal Fermentation Method to Screen for TMA Production Inhibitors

ObjectivesCholine is metabolized by gut bacteria to trimethylamine (TMA), which is further metabolized by the host into trimethylamine N-oxide (TMAO). There is significant interest in reducing TMAO formation to reduce atherosclerosis risk. Our objective was to develop an in vitro fermentation methodology to screen for bioactives able to reduce TMA formation. MethodsCholine (5–100 μM) fermentation was optimized under anaerobic conditions at 37°C with the presence of human fecal slurry (OpenBiome) diluted 1:10 in PBS 1X (5–45%) over 36 h. Common dietary phenolics (gallic acid and chlorogenic acid, 0.1–10 mM) were evaluated as TMA production inhibitors under optimal fermentation conditions. 3,3-dimethyl-1-butanol (DMB, 10 mM) was used as a positive control. TMA and choline levels were monitored and analyzed by UPLC-ESI-MS/MS. Cell density (O.D. at 600 nm) was evaluated to account potential cytotoxicity. ResultsTMA kinetic production curves from choline at >25 μM were statistically different from background (no choline added), suggesting its potential to be used to assay inhibition of TMA production. Fecal slurry concentration of 5% did not reach a TMA plateau within 36 h of fermentation, while the kinetics reported by 45% were fast, reaching a plateau at 12 h, suggesting the need for intermediate fecal concentrations. Optimal fermentation conditions were 100 μM choline and 20%. fecal slurry Under those conditions, exogenous choline was consumed within the first 12 h of fermentation, during which TMA formation plateaued. Under optimal conditions plus gallic acid or chlorogenic acid, TMA formation was significantly reduced, reaching 50% of inhibitor-free control at concentrations >5 mM at 8 h. Also, >2 mM reported higher inhibition potential than DMB 10 mM. Of note, no reductions in cell density were reported due to treatment administration, suggesting a lack of cytotoxicity. ConclusionsOur results suggest that gallic acid and chlorogenic acid are promising compounds for in vivo studies. Moreover, our fermentation method can be used to screen for TMA production inhibitors in a high-throughput fashion. Funding SourcesSupported by through startup funding from North Carolina State University and the Hatch Program of the National Institute of Food and Agriculture, U.S. Department of Agriculture.

Genetic associations of TP53 codon Pro72Arg polymorphism (rs1042522) in coronary artery disease: A meta-analysis of candidate genetic mutants

BackgroundThe tumour suppressor p53 gene involved in cell cycle regulation and exhibit important role in atherosclerosis. Both genetic and environmental risk factors play an important role and confer susceptibility to coronary artery disease (CAD). A functional polymorphism Pro72Arg located on codon 72 (rs1042522) at exon 4 may influence CAD pathophysiology. MethodsCorrelate the association of TP53 gene with CAD by increasing various statistical parameters, a meta-analysis of 7 studies were performed. ResultsA significant correlation between Pro72Arg polymorphisms and reduced CAD risk observed in Caucasian subgroup. In recessive comparison model a significant reduced CAD risk was found in pooled out data (PP vs PP + RP: odd ratio (OR) = 0.338, 95% confidence interval (CI) = 0.238 to 0.47, P = 0.00*) and also in Caucasian subgroup (PP vs PP + RP: OR = 0.296, 95% CI = 0.185 to 0.473, P = 0.00*), (PP vs PP + RP: OR = 0.326, 95% CI = 0.193 to 0.552, P = 0.00*), (PP vs PP + RP: OR = 0.140, 95% CI = 0.076 to 0.258, P = 0.00*), (PP vs PP + RP: OR = 0.269, 95% CI = 0.138 to 0.525, P = 0.00*), Black subgroup (PP vs PP + RP: OR = 0.386, 95% CI = 0.226 to 0.657, P = 0.00*) and Asian subgroup (PP vs PP + RP: OR = 0.467, 95% CI = 0.284 to 0.767, P = 0.00*). ConclusionsPresent meta-analysis suggest that PP genotype of the p53 Pro72Arg polymorphism reduces the risk of CAD significantly in Caucasian population. However, the future studies considering the gene-environment interaction are needed to confirm the observed association.

Reproductive risk factors for angiographic obstructive coronary artery disease among postmenopausal women.

Reproductive factors are female-specific coronary artery disease (CAD) risk factors. However, the importance of reproductive factors in angiographic obstructive CAD in postmenopausal women remains uncertain. This study aimed to compare reproductive factors between postmenopausal women with no apparent CAD, nonobstructive CAD, and obstructive CAD and identify reproductive risk factors for obstructive CAD. In this hospital-based cross-sectional study, 1,474 postmenopausal women, admitted with chest pain and referred for invasive coronary angiography were enrolled between April 2013 and October 2018. Adjusted odds ratio (95% CI) for obstructive CAD were 1.81 (1.03-3.17) for multigravidity (three or more pregnancies), 1.77 (1.14-2.76) for early menopause (≤40 y old), and 1.72 (1.26-2.35) for short reproductive life span (≤30 y). Each additional year in age at menopause or reproductive life span was associated with a 4% reduction in obstructive CAD risk in postmenopausal women (odds ratio, 0.96; 95% CI, 0.94-0.99; P = 0.011). The other reproductive factors, including parity, age at first birth, spontaneous abortion, induced abortion, stillbirth, hypertensive disorders of pregnancy, gestational diabetes mellitus, and age at menarche, were not correlated with obstructive CAD risk in postmenopausal women. Multigravidity (three or more pregnancies), early menopause, and a shorter reproductive life span were independent risk factors of angiographic obstructive CAD among postmenopausal women, which suggested that pregnancy and ovarian function may be important for the early identification and prevention of increased risk of female angiographic obstructive CAD.

Imaging and Targeting Coronary Artery Inflammation.

Significance: Coronary artery disease (CAD) continues to be a leading cause of morbidity and mortality across the world despite significant progress in the prevention, diagnosis, and treatment of atherosclerotic disease. Recent Advances: The focus of the cardiovascular community has shifted toward seeking a better understanding of the inflammatory mechanisms driving residual CAD risk that is not modulated by current therapies. Significant progress has been achieved in revealing both proinflammatory and anti-inflammatory mechanisms, and how shift of the balance in favor of the former can drive the development of disease. Critical Issues: Advances in the noninvasive detection of coronary artery inflammation have been forthcoming. These advances include multiple imaging modalities, with novel applications of computed tomography both with and without positron emission tomography, and experimental ultrasound techniques. These advances will enable better selection of patients for anti-inflammatory treatments and assessment of treatment response. The rapid advancement in pharmaceutical design has enabled the production of specific antibodies against inflammatory pathways of atherosclerosis, with modest success to date. The pursuit of demonstrating the efficacy and safety of novel anti-inflammatory and/or proinflammatory resolution therapies for atherosclerotic CAD has become a major focus. Future Directions: This review seeks to provide an update of the latest evidence of all three of these highly related but disparate areas of inquiry: Our current understanding of the key mechanisms by which inflammation contributes to coronary artery atherosclerosis, the evidence for noninvasive assessment of coronary artery inflammation, and finally, the evidence for targeted therapies to treat coronary inflammation for the reduction of CAD risk. Antioxid. Redox Signal. 34, 1217-1243.