Basis Of Coronary Artery Disease Research Articles

Mitochondrial Melatonin: Beneficial Effects in Protecting against Heart Failure.

Cardiovascular disease is the cause of physical infirmity and thousands of deaths annually. Typically, during heart failure, cardiomyocyte mitochondria falter in terms of energy production and metabolic processing. Additionally, inflammation and the accumulation of non-contractile fibrous tissue contribute to cardiac malfunction. Melatonin, an endogenously produced molecule, experimentally reduces the initiation and progression of atherosclerotic lesions, which are often the basis of coronary artery disease. The current review critically analyzes published data related to the experimental use of melatonin to forestall coronary artery pathologies. Collectively, these studies document melatonin's anti-atherosclerotic actions in reducing LDL oxidation and triglyceride levels, lowering endothelial malfunction, limiting adhesion molecule formation, preventing macrophage polarization to the M1 pro-inflammatory phenotype, changing cellular metabolism, scavenging destructive reactive oxygen species, preventing the proliferation and invasion of arterial smooth muscle cells into the lesioned area, restricting the ingrowth of blood vessels from the vasa vasorum, and solidifying the plaque cap to reduce the chance of its rupture. Diabetic hyperglycemia, which aggravates atherosclerotic plaque formation, is also inhibited by melatonin supplementation in experimental animals. The potential value of non-toxic melatonin as a possible inhibitor of cardiac pathology in humans should be seriously considered by performing clinical trials using this multifunctional molecule.

Abstract 13953: A Genome-Wide European Ancestry Study Identifies Coronary Artery Disease-Associated Loci Through Gene-Sex Hormone Interaction

Background: Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of coronary artery disease (CAD). While sex-differences in CAD have been observed, little is known about the role of sex hormones in CAD genetics. Accounting for sex hormone levels may help identify CAD-risk loci and extend our knowledge of its genetic architecture. Methods: We performed a GWAS to identify CAD risk loci by incorporating gene-sex hormone interactions in 365,662 individuals of European ancestry enrolled in the UK Biobank (UKB). Genetic interactions of total testosterone (TT), bioavailable testosterone (BAT) and sex-hormone binding globulin (SHBG) were evaluated. GEM software was used to conduct sex-stratified genome-wide interaction analysis with prevalent CAD. Enrollment age and principal components 1-10 were model covariates. The online post-GWAS tool FUMA was used to annotate the biological functions of marginal, interaction, and joint effects summary statistics. Results: We identified 64 loci in males and 8 loci in females that reached genome-wide significance (p < 5х10 -8 ) for CAD ( Table 1 ). Among males, 3 significant loci were identified for BAT, one for TT and one for SHBG using joint effect model that did not overlap with those identified with marginal effect. Among females, 5 significant loci were identified, all for TT using joint effect that that did not overlap with those identified with marginal effect. Of these 5 loci, two loci were independently identified with significant SNP-TT interaction. These loci were mapped close to the TRDN and THADA genes that have been implicated in congenital ventricular tachycardia and polycystic ovarian syndrome, respectively. Conclusion: This Genome-wide gene-sex hormone interaction study identified genomic-risk loci that may contribute to the differential CAD risk between men and women, which would otherwise not have been discovered in traditional GWAS only including marginal genetic effect.

Blockade of CXCR4 promotes macrophage autophagy through the PI3K/AKT/mTOR pathway to alleviate coronary heart disease

ObjectiveAutophagy is important in regulating inflammation and cholesterol efflux, suggesting that targeting autophagy may slow down atherosclerosis (AS). Since the pathological basis of coronary artery disease (CAD) is atherosclerosis, it is crucial to investigate the role of autophagy in atherosclerosis. This study aimed to investigate the role of the chemokine CXC chemokine receptor 4 (CXCR4) in promoting macrophage autophagy through the phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway to alleviate coronary artery disease. MethodsThe human left coronary artery and myocardium were collected to detect CXCR4, MAP1LC3(LC3) and SQSTM1(p62) expression. ApoE−/− mice were used to establish an atherosclerosis mice model, while human monocytes (THP-1) were used to establish a foam cell model and co-cultured with foam cells using siRNACXCR4. Western blotting was conducted to quantify CXCR4, PI3K/AKT/mTOR pathway protein, LC3, Beclin1 and p62 protein levels. The left coronary artery from humans and mouse aorta and myocardium were stained with Hematoxylin and Eosin (H&E), macrophages with Oil Red O staining and foam cells were assessed by Movat's staining. CXCR4 levels, PI3K/AKT/mTOR pathway protein, LC3 and p62 were detected by immunohistochemistry (IHC) and immunofluorescence assays. Detection of autophagosomes in macrophages using transmission electron microscopy. We further assessed whether the effect of CXCR4-mediated macrophage autophagy on the formation of atherosclerosis and structural changes in the myocardium was mediated via the PI3K/AKT/mTOR signaling pathway. ResultsCXCR4 and p62 proteins were upregulated in human coronary lesions, mouse aorta, myocardial tissue, and foam cells, while LC3II/LC3I was downregulated. p85 (P-PI3K), Ser473 (P-AKT), and Ser2448 (P-mTOR) phosphorylated proteins associated with the PI3K/AKT/mTOR pathway were detected in AS and foam cell models. Upregulated CXCR4 inhibited autophagy of macrophages and increased the severity of atherosclerotic lesions. After specific knockdown of CXCR4 by adeno-associated virus (AAV9-CXCR4-RNAi) and siRNACXCR4, the above indicators were reversed, macrophage autophagy was promoted, the severity of atherosclerotic lesions was reduced, and the disorganized arrangement of myocardial architecture was improved. ConclusionKnockdown of CXCR4 reduces the extent of coronary artery disease by promoting macrophage autophagy through the PI3K/AKT/mTOR pathway to attenuate atherosclerosis.

Paraoxonase gene polymorphisms: Understanding the biochemical and genetic basis of coronary artery disease

ObjectivesSerum paraoxonase (PON) is a glycoprotein with antioxidant and anti-atherosclerotic activities. The Q192R and L55M gene polymorphisms of PON have been implicated as risk factors for coronary artery disease (CAD) but have not been extensively explored in South Indians. We aimed to assess the Q192R and L55M genetic polymorphisms of the PON1 gene in participants with CAD, including genotypes and allele frequencies for PON1 gene polymorphism. MethodsThis prospective case-control study involved 20 participants in each group. Patients with angiographically demonstrated CAD were included in the case group. PON1 activity was measured, and PON gene polymorphism was determined. Serum PON was quantitatively analyzed with a RayBio® Human PON1 ELISA kit. Chi square tests were used to assess the association of the genotypes with sex and any comorbidities in cases and controls. A p value ≤ 0.05 was considered significant. ResultsMutant type L55M polymorphism was observed in 50% of patients, whereas wild type Q192R polymorphism was observed in 42.5% of the participants. The mean PON values between groups did not significantly differ, whereas PON U/L was significantly (p = 0.001) lower in the case group. The L55M polymorphism did not significantly differ between the case and the control groups (p = 0.213), whereas the Q192R polymorphism was statistically significant in cases compared with controls (p ≤ 0.001) ConclusionLow plasma PON1 and HDL levels, and higher LDL, total cholesterol and triglyceride levels were observed in patients with CAD. More patients with CAD than healthy individuals had Q192R polymorphism.

Electronic Cigarette and Atherosclerosis: A Comprehensive Literature Review of Latest Evidences.

Coronary artery diseases (CAD), also known as coronary heart disease (CHD), are the world's leading cause of death. The basis of coronary artery disease is the narrowing of the heart coronary artery lumen due to atherosclerosis. The use of electronic cigarettes has increased significantly over the years. However, harmful effects of electronic cigarettes are still not firm. The aim of this article is to review the impact of electronic cigarette and its role in the pathogenesis of atherosclerosis from recent studies. The results showed that several chemical compounds, such as nicotine, propylene glycol, particulate matters, heavy metals, and flavorings, in electronic cigarette induce atherosclerosis with each molecular mechanism that lead to atherosclerosis progression by formation of ROS, endothelial dysfunction, and inflammation. Further research is still needed to determine the exact mechanism and provide more clinical evidence.

Broad clinical manifestations of polygenic risk for coronary artery disease in the Women’s Health Initiative

BackgroundThe genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.MethodsWe measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women’s Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes.ResultsPolygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal.ConclusionPolygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

OA28 Exploring the potential of polygenic risk scores for predicting coronary artery disease in patients with rheumatoid arthritis

Abstract Background/Aims Patients with rheumatoid arthritis (RA) have a higher prevalence of coronary artery disease (CAD) than the general population which contributes to early mortality. Current screening tools for CAD, which are developed in the general population, are less effective for estimating CAD risk in patients with RA. This reduced performance is mainly due to the differing contribution from traditional risk factors and the contribution from disease-specific factors. Our understanding of the genetic basis of CAD has improved over recent years and shows promise for improving risk prediction in the form of polygenic risk scores (PRS). We hypothesise that PRS can help us improve CAD risk prediction in patients with RA by providing more accurate models of risk. Methods Patients were recruited from the Norfolk Arthritis Register (NOAR), a detailed community-based longitudinal observational study focused on the cause and outcome of inflammatory polyarthritis, between 1990 and 2017. Analysis was restricted to patients who satisfied the 2010 ACR criteria cumulatively over five years and had detailed clinical history at baseline and follow-up. We developed a prediction model based on traditional risk factors and explored the inclusion of a PRS (49K SNPs) in a subset of patients with available genetic data. Cox proportional hazards models were used to derive risk equations for evaluation of 10-year risk of CAD. We applied multiple imputations with chained equations using the Random Forest algorithm to replace missing values. Measures of calibration and discrimination were determined in the validation cohort of 423 individuals. Results A total of 2123 patients were included in the analysis with 136 incident cases of self-reported CAD. The model using only traditional risk factors achieved an AUC of 0.72 (95% CI 0.71, 0.73), with a calibration slope of 1.03, and explained approximately 50% (95% CI 47, 52%) of the variance of the outcome. We found that being male reduces the risk by a factor of 0.82 (95% CI 0.68, 1.00). The hazard ratio for age was found to be 1.00 (95% CI 0.99, 1.01) indicating risk remains the same across all age groups. Inclusion of a CAD PRS increased the performance with an AUC of 0.76 (95% CI 0.75, 0.77), explained variance of 53% (95% CI 49, 56%) but with a slightly worse calibration slope of 0.91. Conclusion An integrated risk score, that combines traditional risk factors with a PRS, improves CAD prediction in patients with RA. Further research is required to better understand the role of heritable components contributing to CAD risk in RA patients. By refining the underlying PRS, we hope to further improve CAD risk prediction in RA patients, through this integrated approach. Disclosure M. Soomro: None. M. Stadler: None. S. Viatte: None. A. MacGregor: None. S. Verstappen: None. A. Barton: None. J. Bowes: None.

Modern methods for studying atherosclerosis and coronary artery disease: flow cytometry

The problem of atherosclerosis, which forms the pathological basis of coronary artery disease (CAD), is one of the most discussed ones in development of cardiovascular diseases. This chronic inflammatory disease involves interactions between different cells, and an atherosclerotic plaque is a complex immunological environment. Modern quantitative methods increase the understanding of the pathophysiological processes responsible for progression of atherosclerotic plaques. Flow cytometry is a powerful modern method that allows for a complex and simultaneous cell analysis. This review is devoted to studies on atherosclerosis and CAD performed using flow cytometry.

Research advance of ANRIL on atherosclerosis by regulating cell proliferation and apoptosis

Atherosclerosis is an important pathological basis for coronary artery disease. ANRIL is an antisense non-coding RNA located in Chr9p21 locus, which was identified as the most significant risk locus associated with atherosclerosis. ANRIL can produce multiple transcripts including linear and circular transcripts after various transcript splicing. It has been illustrated that ANRIL plays important roles in the pathology of atherosclerosis by regulating the proliferation and apoptosis of vascular cells. Linear ANRIL can regulate the proliferation of vascular smooth muscle cells (VSMCs) in plaques by chromatin modification, as well as influence the proliferation and the apoptosis of macrophages in post transcription; circular ANRIL can affect the proliferation and apoptosis of VSMCs by chromatin modification as well as interfering with rRNA maturation. In this review, we describe the ANRIL evolution, different transcripts characteristics, and their roles in the proliferation and apoptosis of vascular cells to participate in the process of atherosclerosis, for further understanding the pathogenesis of atherosclerosis and finding potential targets for diagnosis and treatment of atherosclerosis.

Mediation analysis for the relationship between dyslipidemia and coronary artery disease via hypersensitive C-reactive protein in a case-control study.

The pathological basis of coronary artery disease (CAD) is atherosclerosis which is associated with inflammation and dyslipidemia. However, the involvement of hypersensitive C-reactive protein (hs-CRP) in lipid metabolism and how it affects the pathogenesis of CAD is uncertain. To explore whether the relationship between dyslipidemia and CAD is partly mediated by hs-CRP levels. Three hundred fifteen pairs of randomly sexand age-matched CAD and non-CAD subjects collected from Zhongda Hospital Affiliated to Southeast University were involved in the final analysis. We gathered information about each subjects clinical history as well as their results of detected hs-CRP and lipid levels. Linear regression analysis was used to determine the association between dyslipidemia and hs-CRP levels in which univariate and multivariate logistic regression analyzes were performed to determine the relationship between hs-CRP levels and CAD as well as dyslipidemia and CAD. Mediation analysis was used to evaluate whether hs-CRP levels act as a mediator of the relationship between dyslipidemia and CAD. Dyslipidemia and hs-CRP levels were significantly associated with an increased risk of CAD, with β = 0.594 (P = 0.001) and β = 0.016 (P = 0.024), respectively, and there was a correlation between dyslipidemia and hs-CRP levels (β = 3.273, P = 0.004). Mediation analysis results revealed that the correlation between dyslipidemia and CAD was 8.27% mediated by hs-CRP levels with a direct effect of 0.621 and an indirect effect of 0.056. Hs-CRP levels played a partial mediation role in the association between dyslipidemia and CAD.

Large-scale gene analysis of rabbit atherosclerosis to discover new biomarkers for coronary artery disease.

Atherosclerosis is the pathological basis of coronary artery disease (CAD) and causes high mortality. Thus, early detection is thought to be crucial in reducing the risk of CAD. Uncovering the mechanisms of the progression and regression of atherosclerosis will provide insights into discovering novel biomarkers to identify subjects at risk for CAD and improve prevention. We established atherosclerosis progression and regression in a rabbit model. Then, we extracted mRNA of the abdominal aorta from control, model and recovery groups to perform gene chip analysis. Candidate biomarkers were screened by large-scale gene analysis and validated in patients with CAD or with CAD recovery by ELISA. The differentially expressed genes in the progression and regression of atherosclerosis were mainly enriched in four clusters. Genes associated with inflammation and extracellular matrix were returned to normal or close-to-normal levels much earlier than genes associated with metabolism and sarcoplasmic proliferation, and they were maintained downregulated or upregulated after feeding a normal diet. We then selected four candidate biomarkers and found that lipoprotein lipase (LPL), bone morphogenetic protein 7 and somatostatin concentrations could indicate CAD diagnosis. In addition, LPL and macrophage cationic peptide 2 can be indicators of the prognosis of CAD. Molecular changes during the progression and regression of atherosclerosis in rabbits were revealed, and candidate regulators were identified. The identified factors could be used as novel biomarkers and targets for improving the diagnosis and prognosis of human CAD in the future.

Genome-Wide Association Studies of Coronary Artery Disease: Recent Progress and Challenges Ahead.

Genome-wide association studies (GWAS) have been the primary tool for unbiased assessment of the genetic basis of coronary artery disease (CAD) for more than a decade. We summarize successes as well as shortcomings of recent studies in this context. The number of CAD-associated loci has more than doubled in the past year to 161. This rapid progress has been in large part due to the release of genome-wide genotyping data for the largely European participants of the UK Biobank study which has been combined with existing GWAS from the CARDIoGRAMplusC4D consortium. Additional discoveries have been achieved through large-scale genotyping of participants using custom high-yield genotyping arrays including the Metabochip and the Exome chip. As a consequence, the ability of genetic risk scores in predicting incident CAD events has improved but that improvement has only been shown in European populations. GWAS have proven to be a fruitful approach for uncovering the genetic drivers of CAD. However, determining the mechanisms of association of GWAS findings remains a challenging endeavor requiring long-term investment. Genetic risk scores offer an opportunity for recent findings to have an immediate clinical impact. Going forward, CAD genetics will benefit greatly from the release of more genetic data produced by mega-biobanks. These new data will allow for the more comprehensive examination of underrepresented populations.

Aspirin in heart failure: don't throw the baby (aspirin) out with the bathwater.

Aspirin in heart failure: don't throw the baby (aspirin) out with the bathwater.

Quantification of Various Inflammatory Cells in Advanced Atherosclerotic Plaques.

Atherosclerosis, the pathological basis of coronary artery disease is being extensively studied as understanding of the complex processes involved in the formation and progression that can provide an insight into prevention and treatment of the same. This is an autopsy study to identify and quantify various inflammatory cells in advanced atherosclerotic plaques. This study aims at identifying and categorizing the various inflammatory cells present in advanced atherosclerotic plaques, noting their distribution in the plaque, quantifying them using histomorphometry and comparing them across plaques of different AHA types. Post-mortem angiogram was performed on 3 heart specimens obtained at autopsy of random Road Traffic Accident (RTA) cases which revealed evidence of coronary artery disease. End-arterectomy was done and the arteries with atherosclerotic plaques were cut into serial sections and made into tissue blocks. Sections from these blocks were stained with H & E stain and the plaques were classified based on AHA classification. 50 advanced atherosclerotic plaques of AHA Type IV and V were chosen for this study and were screened for inflammatory cells, first with H & E stain and then with different immunohistochemical stains for T-lymphocytes, B-lymphocytes and neutrophils. The T-lymphocytes thus identified was further sub-typed into CD4+ and CD8+ cells again using IHC markers and the percentage area of each was measured using histomorphometry. Then, these values were compared between AHA Type IV and AHA Type V lesions. It was found that the inflammatory cells found in advanced atherosclerotic plaques were predominantly T-lymphocytes as evidenced by their CD3 positivity and they were found to be distributed mainly around the shoulder region and fibrous cap of the plaque. When categorized further, it was found that CD8+ T-cells were always more than CD4+ T-cells in advanced lesions. Meloperoxidase stain for neutrophils was negative in all the plaques examined. The difference in the amount of inflammatory cells between AHA type IV and Type V was not statistically significant. The study of the amount of inflammatory cells in atherosclerotic plaques and understanding their role in the pathophysiology of advanced plaques may have therapeutic implications.

The Genetic Basis of Coronary Artery Disease and Atrial Fibrillation: A Search for Disease Mechanisms and Therapeutic Targets.

ORONARY ARTERY disease (CAD) and arrhythmias such as atrial fibrillation (AF) significantly contribute to perioperative mortality and morbidity. The 30-day postoperative mortality rate is increased significantly in patients with AF (6.4%) and (CAD) (2.9%). 1 The VISION trial found that 11.6% of patients undergoing noncardiac surgery had increased troponin levels postoperatively, and these patients had an increased 30-day mortality compared with the reference group. 2 Postoperative AF patients have longer hospital stays and increased mortality. 3–6 Postoperative AF is common not only after cardiac surgery, but is seen after major noncardiac surgery as well. As anesthesiologists continue to focus on perioperative care for surgical patients, they must examine all options for decreasing mortality and morbidity for patients with coronary artery disease and arrhythmias undergoing noncardiac surgery. The genetic predisposition for CAD and AF has garnered more attention in the past decade due to innovative technology and ready access to human genomic information that has improved the ability to identify single nucleotide polymorphisms in the genome. Although advances continue to be made in the management of CAD and AF, prevention likely will be the most effective way to decrease ischemic heart disease and atrial fibrillation in the patient population. Medical management has an important role for perioperative prevention of major adverse cardiac events; however, the 2014 ACC/AHA guidelines reflect important contributions from recent studies regarding the safety and efficacy of perioperative beta-blockade. The only class I recommendation for perioperative beta-blockade is the continuation of beta-blockers for patients who have been taking them chronically. 1 The initiation of beta-blockers for patients with high-risk myocardial ischemia or for patients with multiple risk factors is a class IIb recommendation. There is continued concern about the risk of perioperative stroke related to betablockers and the safest time to initiate beta-blockers before surgery. Perioperative myocardial revascularization has been examined as a method to decrease major perioperative adverse cardiac events. The CARP trial showed that at medial longterm follow-up, there was no difference in mortality between revascularized and nonrevascularized patients undergoing vascular surgery even in high-risk groups such as those with multivessel coronary artery disease 7 Therefore, medical and surgical interventions have limited ability to decrease perioperative risk when there is a clear unmet need for better risk assessment and management strategy. This review will focus on the recent progress made in establishing the genetic basis for coronary artery disease and atrial fibrillation. The clinical relevance of CAD and perioperative myocardial infarction are closely linked; however, they do not share many genetic variants. These genetic differences will be highlighted using specific genes as examples, including 9p21. A thorough understanding of the genes and their contribution to these disease processes may lead to improved risk stratification and prevention of these common perioperative complications.

Abstract MP57: Pathway and Network Analysis of GWAS reveals Novel Candidate Causal Links between Key Biological Processes and Coronary Artery Disease

Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, for most of these variants the causal biological mechanisms remain unclear. By integrating GWA data with prior biological knowledge about pathways and functional networks, we sought to obtain novel insights into the causal processes of CAD. Using the iGSEA4GWAS analysis tool and the Reactome pathway database, we carried out a two-stage gene set enrichment analysis strategy. From a discovery cohort of seven large GWAS data sets for CAD (n=9,889 cases, 11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of nine additional studies (n=15,502 cases, 55,730 controls) that were part of the CARDIoGRAM Consortium. A total of 32 of the 639 pathways tested representing 22 distinct biological processes showed convincing association with CAD (replication p< 0.05). After adjusting for redundancies by removing pathways with 50% or greater identity with other pathways, 19 pathways representing 9 biological processes remained including those relevant to Notch signaling, extracellular matrix integrity, innate immunity, and lipid metabolism. Network analysis of 751 unique genes within replicated pathways further revealed several interconnected functional modules representing novel associations (semaphorin regulated axonal guidance pathway) as well as confirmatory known processes (lipid metabolism). Our analyses point to potentially novel causal associations between CAD and several biological processes, many of which were not previously linked to CAD. These findings improve our understanding of the biological basis of CAD and highlight potential novel therapeutic targets.

Genetic Predisposition to Higher Blood Pressure Increases Coronary Artery Disease Risk

Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

Beneficial Effects of Grape Resveratrol on Serum Adiponectin and Inflammation: Clinical Trial in Patients with Stable Coronary Artery Disease

Coronary artery disease (CAD) is a leading cause of heart failure on a world-wide basis [1–3]. The epidemic proportion of CAD is increasing worldwide irrespective of gender [3, 4]. Coronary artery disease is associated with lower oxygen supply and demand ratio due to abnormalities of the coronary vasculature. The coronary arteries supply oxygenated blood to the heart muscle and due to the process of atherosclerosis leading to plaque rupture and acute coronary syndrome, myocardial blood supply is compromised leading to myocardial ischemia/infarction and heart failure [5, 6]. Many clinicians and cardiovascular researchers recognize the clinical as well as molecular pathophysiological basis of coronary artery disease. There are many research groups actively searching the intervention strategies to prevent CAD. Many of these studies confirmed that CAD can be favorably prevented by lifestyle modifications (dietary control, exercise and smoking cessation) and pharmacotherapy [7]. However current pharmacotherapies which include anti-platelet drugs (aspirin, clopidogrel and prasugrel), betablockers, statin therapy and ACE inhibitors, are suboptimal [8, 9]. Resveratrol is a polyphenolic flavonoid with phytoalexin properties and has several pleotropic effects on cardiovascular function such as anti-oxidant and antiinflammatory effects and metabolic modulation (Fig. 1) [10–14]. However, these studies were performed in animal models and clinical evidence of the therapeutic effectiveness of resveratrol in humans is limited. In this issue of Cardiovascular Drugs and Therapy, Tome-Carneiro et al. investigate and analyze the beneficial pleotropic effects of 1 year dietary intervention with resveratrol containing grape extract (U.V treated grapes) on inflammatory as well as fibrinolytic status in patients with stable coronary artery disease [15]. Naturally the content of resveratrol in dietary sources is very low and the consumption of these natural food items (wine and grapes) does not exert beneficial effects in the prevention of many cardiovascular complications. As such Tome-Carneiro et al. used a novel resveratrol rich grape extract (GE-RES) obtained from U.V treated grapes (GE-RSE) in dietary intervention of CAD patents. Resveratrol is a potent therapeutical phytochemical with cardioprotective effects [10]. It targets and modulates pathological death signals and can protect patients by preventing several cardiovascular risk factors from causing endothelial dysfunction, inflammation, atherosclerotic plaque formation and dyslipidemia [1]. Inflammation and atherogenesis are the initial manifestations in coronary artery disease, which is associated with focal S. K. Das :V. B. Patel :G. Y. Oudit Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada

Understanding coronary artery disease using twin studies

Twins have fascinated human communities since the beginning of recorded history. In cardiovascular research, twin studies played a pivotal role in the discovery of the genetic basis of coronary artery...

Peripheral blood gene expression profile of atherosclerotic coronary artery disease in patients of different ethnicity in Malaysia

The molecular basis of coronary artery disease (CAD) has been widely studied in the western world but there is no published work on the Malaysian population. This study looked at the global gene expression profiling of the peripheral blood of patients with CAD from the 3 main ethnic groups in Malaysia. Male subjects selected were based on angiographically confirmed CAD (≥50% stenosis) and normal control subjects (0% stenosis) with age range of 55.6±5.3 and 51.0±5.5years, respectively. The global gene expression of 12 angiographically documented CAD patients and 11 matched control subjects were performed. The combined group samples identified 6 up regulated differential expression (DE) genes (GHRL, LTA, CBS, HP, ITGA2B, and OLR1) and 12 down regulated DE genes (IL18R1, ITGA2B, IL18RAP, HP, OLR1, SOD2 ITGB3, IL1B, MMP9, PLA2G7, UTS2, and CBS) to be involved in CAD at the fold change of 1.3 with fault discovery rate (FDR) of 1%. Three genes, MMP9, IL1B, and SOD2 were down regulated in all the 3 ethnic groups making them potential biomarker candidates for CAD across all three ethnicities. Further verification in a cohort study is needed.