Lower Risk Of Coronary Heart Disease Research Articles

Differential effects of PCSK9 variants on risk of coronary disease and ischaemic stroke.

Aims PCSK9 genetic variants that have large effects on low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) have prompted the development of therapeutic PCSK9-inhibition. However, there is limited evidence that PCSK9 variants are associated with ischaemic stroke (IS).Methods and resultsAssociations of the loss-of-function PCSK9 genetic variant (rs11591147; R46L), and five additional PCSK9 variants, with IS and IS subtypes (cardioembolic, large vessel, and small vessel) were estimated in a meta-analysis involving 10 307 IS cases and 19 326 controls of European ancestry. They were then compared with the associations of these variants with LDL-C levels (in up to 172 970 individuals) and CHD (in up to 60 801 CHD cases and 123 504 controls). The rs11591147 T allele was associated with 0.5 mmol/L lower LDL-C level (P = 9 × 10−143) and 23% lower CHD risk [odds ratio (OR): 0.77, 95% confidence interval (CI): 0.69–0.87, P = 7 × 10−6]. However, it was not associated with risk of IS (OR: 1.04, 95% CI: 0.84–1.28, P = 0.74) or IS subtypes. Information from additional PCSK9 variants also indicated consistently weaker effects on IS than on CHD.Conclusion PCSK9 genetic variants that confer life-long lower PCSK9 and LDL-C levels appear to have significantly weaker, if any, associations with risk of IS than with risk of CHD. By contrast, similar proportional reductions in risks of IS and CHD have been observed in randomized trials of therapeutic PCSK9-inhibition. These findings have implications for our understanding of when Mendelian randomization can be relied upon to predict the effects of therapeutic interventions.

Healthful and Unhealthful Plant-Based Diets and the Risk of Coronary Heart Disease in U.S. Adults

BackgroundPlant-based diets are recommended for coronary heart disease (CHD) prevention. However, not all plant foods are necessarily beneficial for health. ObjectivesThis study sought to examine associations between plant-based diet indices and CHD incidence. MethodsWe included 73,710 women in NHS (Nurses’ Health Study) (1984 to 2012), 92,329 women in NHS2 (1991 to 2013), and 43,259 men in Health Professionals Follow-up Study (1986 to 2012), free of chronic diseases at baseline. We created an overall plant-based diet index (PDI) from repeated semiquantitative food-frequency questionnaire data, by assigning positive scores to plant foods and reverse scores to animal foods. We also created a healthful plant-based diet index (hPDI) where healthy plant foods (whole grains, fruits/vegetables, nuts/legumes, oils, tea/coffee) received positive scores, whereas less-healthy plant foods (juices/sweetened beverages, refined grains, potatoes/fries, sweets) and animal foods received reverse scores. To create an unhealthful PDI (uPDI), we gave positive scores to less-healthy plant foods and reverse scores to animal and healthy plant foods. ResultsOver 4,833,042 person-years of follow-up, we documented 8,631 incident CHD cases. In pooled multivariable analysis, higher adherence to PDI was independently inversely associated with CHD (hazard ratio [HR] comparing extreme deciles: 0.92; 95% confidence interval [CI]: 0.83 to 1.01; p trend = 0.003). This inverse association was stronger for hDPI (HR: 0.75; 95% CI: 0.68 to 0.83; p trend <0.001). Conversely, uPDI was positively associated with CHD (HR: 1.32; 95% CI: 1.20 to 1.46; p trend <0.001). ConclusionsHigher intake of a plant-based diet index rich in healthier plant foods is associated with substantially lower CHD risk, whereas a plant-based diet index that emphasizes less-healthy plant foods is associated with higher CHD risk.

Social Integration and Reduced Risk of Coronary Heart Disease in Women: The Role of Lifestyle Behaviors.

Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. This study sought to examine the associations between social integration and risk of incident CHD in a large female prospective cohort. Seventy-six thousand three hundred and sixty-two women in the Nurses' Health Study, free of CHD and stroke at baseline (1992), were followed until 2014. Social integration was assessed by a simplified Berkman-Syme Social Network Index every 4 years. End points included nonfatal myocardial infarction and fatal CHD. Two thousand three hundred and seventy-two incident CHD events occurred throughout follow-up. Adjusting for demographic, health/medical risk factors, and depressive symptoms, being socially integrated was significantly associated with lower CHD risk, particularly fatal CHD. The most socially integrated women had a hazard ratio of 0.55 (95% confidence interval, 0.41-0.73) of developing fatal CHD compared with those least socially integrated (P for trend <0.0001). When additionally adjusting for lifestyle behaviors, findings for fatal CHD were maintained but attenuated (P for trend =0.02), whereas the significant associations no longer remained for nonfatal myocardial infarction. The inverse associations between social integration and nonfatal myocardial infarction risk were largely explained by health-promoting behaviors, particularly through differences in cigarette smoking; however, the association with fatal CHD risk remained after accounting for these behaviors and, thus, may involve more direct biological mechanisms. Social integration is inversely associated with CHD incidence in women, but is largely explained by lifestyle/behavioral pathways.

Association of drinking pattern with risk of coronary heart disease incidence in the middle-aged and older Chinese men: Results from the Dongfeng-Tongji cohort.

BackgroundEpidemiologic studies have found that moderate alcohol consumption was associated with a decreased risk of coronary heart disease (CHD) incidence. Nevertheless, whether the drinking pattern is associated with CHD incidence still remains inconclusive.MethodsWe included 8,469 Chinese men aged 45–81 years, who were free of CHD, stroke, or cancer at baseline from Dongfeng-Tongji cohort. A semi-structured questionnaire was used to collect information on alcohol consumption and other covariates. Cox proportional hazard regression model was applied to estimate the multivariable-adjusted hazard rations (HRs) and 95% confidence intervals (95% CIs).ResultsDuring an average of 4.36 years of follow-up, we identified 959 incident CHD events. Compared with non-drinkers, the multivariable-adjusted HR (95% CI) of CHD incidence was 0.84 (0.71–0.98) in current drinkers. With respect to drinking pattern, men who consumed 20.01–40 grams ethanol once a time had a 24% lower risk of incident CHD (HR = 0.76, 95% CI = 0.62, 0.94) compared with non-drinkers. The adjusted HRs (95% CI) of CHD incidence were 0.80 (0.65, 0.99), 1.02 (0.84, 1.22), and 0.75 (0.59–0.96) in subjects who consumed 0.01–10, 10.01–30, and > 30 grams ethanol per day, respectively. Participants who consumed 20.01–40 grams ethanol per time with less than 5 times per week had the lowest risk of CHD incidence (HR = 0.73, 95% CI = 0.52, 0.96). No significant associations were observed between type or frequency of alcohol consumption and CHD incidence.ConclusionsDrinking was associated with a lower risk of CHD incidence in middle-aged and older Chinese men and moderate quantity of ethanol amounts once a time with lower frequency could been considered as a healthy drinking pattern, which might modify the relationship between alcohol consumption and incident CHD.

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.

Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Silent coronary heart disease in patients with type 2 diabetes: application of a screening approach in a follow-up study

AimsThe cost-effectiveness of screening for silent coronary heart disease (CHD) in type 2 diabetes (DM2) is still debated. MethodsWe applied a diagnostic algorithm for silent CHD detection, in a cohort of 102 asymptomatic DM2 subjects (57±7years), attending 5 Italian outpatient clinics, to verify its predictive value. The risk of silent CHD was calculated considering classical risk factors, and presence of microangiopathy/macroangiopathy. Patients were divided in 3 groups, i.e. group 1: normal ECG and low silent CHD risk; group 2: abnormal ECG, irrespective of silent CHD risk; group 3: high silent CHD risk, irrespective of ECG. To group 2 and 3, a functional test was recommended and performed in 78% of patients. ResultsSilent CHD prevalence was similar in group 2 and 3 (25 vs. 17% respectively; p=0.495). However, evaluating the entire cohort, a significant higher prevalence of silent CHD was observed in subjects with abnormal vs. normal ECG (23 vs. 4%; P=0.004), but not in subjects with high vs. low pre-test silent CHD risk (14 vs. 9%; p=0.472). ConclusionsAn abnormal ECG was a strong, independent predictor of silent CHD (OR 8.9; CI 1.27–62.5; p=0.028) in DM2. Therefore, a functional stress testing should be considered in DM2 patients with ECG abnormalities.

The role of registries and genetic databases in familial hypercholesterolemia.

To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine. Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility. In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.

Abstract P130: Ideal Cardiovascular Health and Incident Cardiovascular Disease: Heterogeneity Across Event Phenotype and Contribution of Multiple Biomarkers. The Prime Study

Background: To which extent the association between ideal cardiovascular health (CVH) and incident vascular events differ by main coronary heart disease (CHD) and main stroke phenotype is currently unknown. Furthermore, data on potential mediating factors underlying the association of ideal CVH with outcomes are lacking. Aims: We aimed to 1) quantify the association between ideal CVH and incident CHD and stroke, 2) to assess for potential heterogeneity across main CHD and main stroke phenotypes and between CHD and stroke; and 3) to assess the mediating effect of a selected panel of key circulatory biomarkers from different relevant disease pathways. Methods and Results: A total of 9312 men middle-aged men (50-59 years) free of CHD and stroke were recruited in the framework of WHO MONICA centres in Lille, Strasbourg, Toulouse (France) and Belfast (Northern Ireland) between 1991 and 1993 and enrolled in the PRIME study. According to the American Heart Association, men with 0-2, 3-4 and 5-7 metrics at the ideal level were categorized as having poor, intermediate and ideal CVH respectively. Hazards ratios (HRs) were estimated using Cox proportional hazards regression and were adjusted for age, centre, education, living alone, marital status, family history of CHD and blood fibrinogen. The contribution of baseline circulating, endothelial inflammatory and haemostatic biomarkers was explored in a case control study nested within the PRIME cohort and settled after 10 years of follow-up. An ideal CVH was observed in 7% of the participants. After a median follow-up of 10 years, 614 first CHD events (myocardial infarction, angina, coronary death) and 117 first stroke events (ischaemic and non ischaemic) were adjudicated. Compared to those with poor CVH, those with an ideal CVH at baseline had a 72% lower risk of CHD (HR=0.28; 95% CI: 0.17; 0.46) and a 76% lower risk of stroke (HR=0.24; 95% CI: 0.06; 0.98) in multivariate analysis. No heterogeneity was detected across main CHD and main stroke phenotypes. While significantly lower mean concentrations of hs-CRP, IL-6, ICAM-1, fibrinogen and von Willbrandt factor were noted in subjects with ideal or intermediate as compared to poor CVH status in the controls, none of these biomarkers contribute to the association of CVH with future CHD. Conclusion: In this study ideal CVH was associated with a substantially lower risk of CHD and stroke, without any difference across phenotypes. Neither inflammatory, endothelial nor haemostatic biomarkers explained the lower risk of CHD in men with ideal CVH.

Abstract MP049: Fermented vs. Non-fermented Dairy and Risk of Coronary Heart Disease in Men: the Kuopio Ischaemic Heart Disease Risk Factor Study

Introduction: Most of the recent dairy studies, including multiple meta-analyses, show either no relationship or an inverse association between total dairy intake and risk of cardiovascular diseases. Some of these studies have suggested that especially fermented rather than non-fermented dairy might provide benefits on cardiovascular health, but the data is inconclusive. Also, the average dairy intake has been modest in many study populations, which reduces the generalizability of the findings to populations with high dairy intake. Hypothesis: We assessed the hypothesis that fermented and non-fermented dairy products have distinct associations with the risk of coronary heart disease (CHD) in men from eastern Finland, a population with high intake of dairy products. Methods: A total of 1981 men from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study from eastern Finland, aged 42-60 years, with no CHD at baseline, were included. The consumption of foods was assessed with instructed 4-day food recording by household measures. Dairy products with fat content &lt;3.5% were considered low-fat. Multivariable Cox regression analyses included age, examination year, smoking, leisure-time physical activity, education, family history of CHD, and intakes of alcohol, energy, fiber, polyunsaturated fatty acids, and fruits, berries and vegetables. Fatal and non-fatal CHD events were ascertained from national registries, with no loss to follow-up. Results: The mean±SD intakes were 733±375 g/d for total, 187±218 g/d for fermented and 546±345 g/d for non-fermented dairy. Low-fat products comprised 87% (162±218 g/d) of the fermented and 43% (317±291 g/d) of the non-fermented dairy intake. During the mean follow-up of 20.1 years, 472 CHD events occurred. The multivariable-adjusted hazard ratio (95% CI) in the highest (&gt;280 g) vs. the lowest (&lt;26 g) quartile of total fermented dairy was 0.73 (0.56-0.95, P-trend=0.02) and in the highest (&gt;727 g) vs. the lowest (&lt;258 g) quartile of total non-fermented dairy 1.44 (1.06-1.94, P-trend=0.009). When low-fat and high-fat dairy were evaluated separately, only low-fat products were associated with the risk. The extreme-quartile hazard ratios (95% CIs) were 0.74 (0.57-0.96, P-trend=0.02) for low-fat fermented dairy and 1.47 (1.08-1.99, P-trend=0.02) for low-fat non-fermented dairy. Intakes of total dairy (extreme-quartile HR 1.03, 95% CI 0.74-1.42, P-trend=0.727), high-fat fermented dairy (HR 0.92, 95% CI 0.69-1.22, P-trend=0.32) or high-fat non-fermented dairy (HR 1.09, 95% CI 0.77-1.56, P-trend=0.44) were not associated with the risk of CHD. Conclusions: Our results suggest that low-fat fermented dairy products are associated with a lower risk of CHD, whereas low-fat non-fermented dairy products are associated with a higher risk in a population with high intake of dairy products.

Association of platelet-activating factor receptor gene rs5938 (G/T) and rs313152 (T/C) polymorphisms with coronary heart disease and blood stasis syndrome in a Chinese Han population.

To explore the association of the platelet-activating factor receptor (PAFR) gene rs5938, rs313152 and rs76744145 polymorphisms with coronary heart disease (CHD) and blood stasis syndrome (BSS) of CHD in Chinese Han population. A total of 570 CHD patients (299 with BSS and 271 with non-BSS) and 317 controls were enrolled. The PAFR gene rs5938, rs313152 and rs76744145 polymorphisms were genotyped using the multiplex SNaPshot technology. The statistical analysis was conducted using a multiple variable logistic regression model. Significant differences were detected in the genotypes frequency distributions of the rs5938 (P<0.01), but not the rs313152 (P>0.05), between the controls and CHD patients. Individuals with an rs5938 or rs313152 mutated allele had a low risk for CHD [adjusted odds ratio (aOR)=0.35, 95% confidence interval (CI): 0.23 to 0.56, P<0.01; aOR=0.65, 95% CI: 0.46 to 0.91, P<0.05, respectively]. After the CHD patients were stratified as BSS or non-BSS according to their Chinese medicine patterns, the rs5938 polymorphism mutated alleles had a significant association with a low risk for BSS of CHD (aOR=0.32, 95% CI: 0.18 to 0.57, P<0.01) and non-BSS of CHD (aOR=0.31, 95% CI: 0.17 to 0.55, P<0.01). The rs313152 polymorphism was associated with a low risk for BSS (aOR=0.51, 95% CI: 0.33 to 0.79, P<0.01), but not for non-BSS (aOR=1.22, 95% CI: 0.81 to 1.85, P<0.05). Furthermore, the interaction effect of the rs5938 and rs313152 polymorphisms for BSS of CHD was significantly based on an aOR value associated with the combination of the rs5938 GT genotype with the rs313152 TC genotype of 0.27 (95% CI: 0.1 to 0.7, P<0.01). The PAFR gene rs5938 or rs313152 polymorphisms might be a potential biomarker for susceptibility to CHD, especially to BSS of CHD in Chinese Han population.

Coffee consumption and coronary heart disease risk using the Framingham risk score.

Although concerns regarding the influence of coffee consumption on human health have accompanied the massive increase in coffee consumption, the effects of coffee intake on the risk for coronary heart disease (CHD) remain controversial. Therefore, we evaluated the association between coffee consumption and CHD risk as estimated using the Framingham risk model in Korean adults. This cross-sectional study involved 3,987 participants aged 30-74 years who participated in the fifth Korea National Health and Nutrition Examination Survey conducted in 2010. The frequency of coffee consumption was self-reported and classified into 4 categories (non-drinker, 1, 2, and >=3 cups/day). The 10-year risk for CHD was determined from the Framingham risk score. Across the levels of coffee consumption, there were significant differences in the frequency of smoking among men and advanced age, low high-density lipoprotein cholesterol level, diabetes, and smoking among women. In the multiple logistic regression analyses, the adjusted odds ratios (95% CI) for >=20% 10-year CHD risk was 0.211 (0.060-0.745) for women who consumed >=3 cups of coffee per day compared with women who consumed <1 cup per day. For women, a significant dose-response inverse association between the level of coffee consumption and 10-year CHD risk persisted even after adjusting for multiple confounding factors. For the men, however, there was no significant association between coffee consumption and 10-year CHD risk. Coffee consumption is associated with a lower risk for CHD in Korean women.

Neural Network-Based Coronary Heart Disease Risk Prediction Using Feature Correlation Analysis.

Background Of the machine learning techniques used in predicting coronary heart disease (CHD), neural network (NN) is popularly used to improve performance accuracy. Objective Even though NN-based systems provide meaningful results based on clinical experiments, medical experts are not satisfied with their predictive performances because NN is trained in a “black-box” style. Method We sought to devise an NN-based prediction of CHD risk using feature correlation analysis (NN-FCA) using two stages. First, the feature selection stage, which makes features acceding to the importance in predicting CHD risk, is ranked, and second, the feature correlation analysis stage, during which one learns about the existence of correlations between feature relations and the data of each NN predictor output, is determined. Result Of the 4146 individuals in the Korean dataset evaluated, 3031 had low CHD risk and 1115 had CHD high risk. The area under the receiver operating characteristic (ROC) curve of the proposed model (0.749 ± 0.010) was larger than the Framingham risk score (FRS) (0.393 ± 0.010). Conclusions The proposed NN-FCA, which utilizes feature correlation analysis, was found to be better than FRS in terms of CHD risk prediction. Furthermore, the proposed model resulted in a larger ROC curve and more accurate predictions of CHD risk in the Korean population than the FRS.

Identification of the Functional Variant(s) that Explain the Low-Density Lipoprotein Receptor (LDLR) GWAS SNP rs6511720 Association with Lower LDL-C and Risk of CHD.

BackgroundThe Low-Density Lipoprotein Receptor (LDLR) SNP rs6511720 (G>T), located in intron-1 of the gene, has been identified in genome-wide association studies (GWAS) as being associated with lower plasma levels of LDL-C and a lower risk of coronary heart disease (CHD). Whether or not rs6511720 is itself functional or a marker for a functional variant elsewhere in the gene is not known.MethodsThe association of LDLR SNP rs6511720 with incidence of CHD and levels of LDL-C was determined by reference to CARDIoGRAM, C4D and Global lipids genetics consortium (GLGC) data. SNP annotation databases were used to identify possible SNP function and prioritization. Luciferase reporter assays in the liver cell line Huh7 were used to measure the effect of variant genotype on gene expression. Electrophoretic Mobility Shift Assays (EMSAs) were used to identify the Transcription Factors (TFs) involved in gene expression regulation.ResultsThe phenotype-genotype analysis showed that the rs6511720 minor allele is associated with lower level of LDL-C [beta = -0.2209, p = 3.85 x10-262], and lower risk of CHD [log (OR) = 0.1155, p = 1.04 x10-7]. Rs6511720 is in complete linkage. Rs6511720 is in complete linkage disequilibrium (LD) with three intron-1 SNPs (rs141787760, rs60173709, rs57217136). Luciferase reporter assays in Huh7 cells showed that the rare alleles of both rs6511720 and rs57217136 caused a significant increase in LDLR expression compared to the common alleles (+29% and +24%, respectively). Multiplex Competitor-EMSAs (MC-EMSA) identified that the transcription factor serum response element (SRE) binds to rs6511720, while retinoic acid receptor (RAR) and signal transducer and activator of transcription 1 (STAT1) bind to rs57217136.ConclusionBoth LDLR rs6511720 and rs57217136 are functional variants. Both these minor alleles create enhancer-binding protein sites for TFs and may contribute to increased LDLR expression, which is consequently associated with reduced LDL-C levels and 12% lower CHD risk.

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

BackgroundGenomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation. ObjectivesThe goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD. MethodsWe leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. ResultsOne SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. ConclusionsBeyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.

Distinguishing between those dying suddenly or not suddenly from coronary heart disease: long-term prospective results from the Northwick Park Heart Study

AimTo establish whether ECG findings are associated with subsequent risk of sudden death from coronary heart disease (CHD).Methods and resultsPotential risk factors for CHD were measured at entry to the...

Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol

To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40mg/dl, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100mg (n= 153), anacetrapib 25mg (n= 152), or placebo (n= 154) for 24weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the anacetrapib 25mg, 100mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

Abuse, nocturnal stress hormones, and coronary heart disease risk among women with HIV

ABSTRACTThis study investigated the relationships among abuse, nocturnal levels of cortisol and norepinephrine (NE), and coronary heart disease (CHD) risk as measured by the Framingham risk score among women with human immunodeficiency virus (HIV). Participants (n = 53) from the Chicago Women’s Interagency HIV Study (WIHS), a longitudinal prospective cohort study initiated in 1994, were enrolled in this study during 2012. At WIHS baseline and annual follow-up visits, women were asked about recent experiences of abuse. Summary variables captured the proportion of visits for which women reported recent (past 12 months) physical, sexual, and domestic abuse. Cortisol and NE were assayed in overnight urine samples and adjusted for creatinine levels. Recent abuse was not significantly associated with levels of cortisol, NE, or NE/cortisol ratio. However, higher NE/cortisol ratio was significantly related to higher CHD risk score, higher cortisol was significantly related to lower CHD risk score, and NE was not associated with CHD risk score. In addition, higher proportions of visits with recent sexual abuse, physical abuse, and domestic abuse were significantly related to higher CHD risk score. The association between abuse exposure and CHD risk in the context of HIV infection is likely complex and may involve dysregulation of multiple neurobiological systems. Future research is needed to better understand these relationships and prevention and intervention efforts are needed to address abuse among women with HIV.

ASGR1 - a new target for lowering non-HDL cholesterol.

Non-HDL cholesterol (non-HDL-C) has been introduced as an alternative cardiovascular (CV) risk marker and a secondary therapeutic target in patients with combined hyperlipidemia, diabetes mellitus, metabolic syndrome, or chronic kidney disease. An important genetic study on the Icelandic population has recently identified a strong link between a new gene – ASGR1 (for asialoglycoprotein receptor) – mutation, plasma non-HDL-C levels, and coronary heart disease (CHD). Heterozygous carriers of a rare noncoding 12-base-pair (bp) deletion (del12 deletion) in intron 4 of ASGR1 had a 13.6 mg/dl lower level of non-HDL-C and a 34% lower risk of CHD than non carriers. The cardioprotective effect of ASGR1 loss-of-function is surprisingly larger than predicted by its effect on the levels of non-HDL-C, which suggests that the atheroprotective effects of del12 mutation go beyond the lowering of serum cholesterol levels. This has shed some light on a new path – the sialylation pathway – possibly leading to a novel therapy that neutralize ASGR1 for heart disease prevention and treatment.

Progressing Insights into the Role of Dietary Fats in the Prevention of Cardiovascular Disease.

Dietary fats have important effects on the risk of cardiovascular disease (CVD). Abundant evidence shows that partial replacement of saturated fatty acids (SAFA) with unsaturated fatty acids improves the blood lipid and lipoprotein profile and reduces the risk of coronary heart disease (CHD). Low-fat diets high in refined carbohydrates and sugar are not effective. Very long-chain polyunsaturated n-3 or omega-3 fatty acids (n-3 VLCPUFA) present in fish have multiple beneficial metabolic effects, and regular intake of fatty fish is associated with lower risks of fatal CHD and stroke. Food-based guidelines on dietary fats recommend limiting the consumption of animal fats high in SAFA, using vegetable oils high in monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA), and eating fatty fish. These recommendations are part of a healthy eating pattern that also includes ample intake of plant-based foods rich in fiber and limited sugar and salt.