Increased Risk Of Atherosclerosis Research Articles

Atherogenic index of plasma and coronary artery disease: a systematic review and meta-analysis of observational studies

BackgroundAtherogenic index of plasma (AIP), a novel logarithmic index that combines fasting triglyceride and high-density lipoprotein cholesterol concentrations, is associated with the burden of atherosclerosis. This study aimed to evaluate the relationship between AIP and coronary artery disease (CAD) risk, severity, and prognosis in populations with and without established CAD.MethodsPubMed, Embase, and Web of Science were systematically searched from the inception of each database to August 13, 2024. Cross-sectional studies, case-control studies, and prospective or retrospective cohort studies using multivariate analysis were included. Given that the true effect size may differ across studies, a random-effects model for all analyses was applied.ResultsFifty-one observational studies were included in this study. Patients with higher AIP were more likely to have CAD (odds ratio (OR): 2.79, 95% CI 1.75–4.45, P < 0.00001). Furthermore, these patients were more likely to have coronary artery calcification (OR: 2.28, 95% CI 1.74–3.00, P < 0.00001), multivessel CAD (OR: 2.04, 95% CI 1.50–2.77, P < 0.00001), and an increased risk of plaque progression (OR: 1.49, 95% CI 1.17–1.91, P = 0.001). In populations without established CAD, higher AIP levels were associated with an increased risk of Major adverse cardiovascular events (MACE) (hazard ratio (HR): 1.28, 95% CI 1.22–1.35, P < 0.00001). Interestingly, this finding was consistent in patients presenting with acute coronary syndrome (HR: 1.59, 95% CI 1.33–1.89, P < 0.00001) and patients with chronic coronary syndrome or stable CAD (HR: 1.65, 95% CI 1.15–2.37, P = 0.007).ConclusionsThis meta-analysis demonstrates that elevated AIP is strongly associated with increased CAD risk, greater severity, and poorer prognosis in populations with and without established CAD. However, more studies are needed to evaluate the predictive performance and determine the optimal cut-off for AIP in different populations.Graphical abstract

Dantrolene is an HDL-associated paraoxonase-1 activator with immunosuppressive and atheroprotective properties.

Human paraoxonase 1 (PON1) an enzyme bound to high-density lipoprotein (HDL) hydrolyzes oxidized lipids and contributes to HDL atheroprotective functions. Decreased serum paraoxonase and arylesterase activities of PON1 have been reported in patients at increased atherosclerosis risk, such as rheumatoid arthritis patients, and associated with arthritis severity and cardiovascular risk. Agents that can modulate PON1 activity and HDL-mediated effects have not been discovered. Aiming to discover chemical tools that enhance PON1 activity, we screened a library of marketed drugs (956 compounds) to identify small molecules that can increase HDL-associated PON1 activity. Screening was performed by a kinetic absorbance assay using human HDL as a source of PON1, and paraoxon and phenyl acetate as substrates to measure paraoxonase and arylesterase activities, respectively. Screening identified the drug dantrolene as a potential PON1 activator, which was confirmed by enzymatic kinetic assays using recombinant wild-type PON1, as well as the PON1[L55M] variant displaying decreased enzyme activity in humans. Furthermore, we used the collagen-induced arthritis (CIA) mouse model to examine the effect of dantrolene on HDL properties and arthritis in vivo. Administration of dantrolene in CIA mice increased paraoxonase and arylesterase activities of PON1, as well as the antioxidant capacity of HDL, and reduced arthritis severity by inhibition of naïve CD4+ T cell differentiation to effector memory cells and generation of Th1 cells. Collectively, our in vitro and in vivo findings indicate using small molecules to enhance HDL-associated PON1 activity is a tractable approach that could lead to novel therapeutics targeting immune responses and atherosclerosis.

Investigating the Relationship Between Cigarettes and Hookah Smoking with Coronary Artery Disease

Background: Cardiovascular disease (CVD) is recognized as a leading global cause of mortality, with tobacco use being one of the established risk factors responsible for 29% of related deaths. Although tobacco smoking, particularly through hookah, is increasing globally, limited data are available to evaluate its impact on CVD. This study aimed to investigate the relationship between cigarette and hookah smoking and coronary artery disease (CAD). Objectives: This study evaluated the relationship between cigarette and hookah smoking and coronary artery involvement based on coronary angiography findings. Methods: In this hospital-based cross-sectional study, 256 patients were included, with 128 patients in the CAD group (showing at least 50% stenosis in the left main artery or over 70% stenosis in other coronary arteries) and 128 patients in the normal angiography group. We assessed their smoking status, categorizing participants as current smokers, ex-smokers, or never-smokers. To ensure the collection of accurate and reliable data, we conducted face-to-face interviews, observations, and administered a questionnaire and medical checklist. Results: Based on multivariable logistic regression models, after adjusting for additional risk factors, individuals who smoked exhibited an approximately eight-fold higher likelihood of developing CAD compared to non-smokers. Additionally, hookah users showed a five-fold increase in CAD risk compared to non-hookah users (P = 0.001). Conclusions: Cigarette and hookah smoking are significantly associated with CAD, with cigarette smoking showing a comparatively stronger association with CAD than hookah use when considering other risk factors.

The Relationship Between Periodontitis, Gingivitis, Smoking, Missing Teeth, Endodontic Infections, Aortic Aneurysm, and Coronary Artery Disease: The 10-Year Results of 25 Patients.

Background Emerging research suggests a correlation between poor oral health and cardiovascular diseases (CVDs), with inflammation being a central mechanism. Periodontitis and gingivitis are chronic inflammatory diseases that can lead to systemic health issues if untreated. It has beenindicated previously that endodontic infections and missing teeth may contribute to elevated cardiovascular risk, and smoking exacerbates both periodontal and cardiovascular conditions. This study expands upon existing research by examining both periodontal and endodontic health factors together and investigating smoking as a potentially amplifying factor. Poor periodontal health may contribute to systemic inflammation, whichis a recognized risk factor for atherosclerosis and cardiovascular events. This study aims to evaluate these relationships over a decade, providing insights into the potential preventive impact of periodontal care on cardiovascular health. Materials and methods This 10-year retrospective study examines the complex relationships among periodontal health factors (including periodontitis, gingivitis, and missing teeth), endodontic infections, smoking, and cardiovascular conditions, specifically coronary artery disease (CAD) and aortic aneurysm. By analyzing data from 25 patients aged 45-75, the study aims to assess whether these oral health indicators correlate with increased cardiovascular risks. The study's methodology included comprehensive dental and cardiovascular evaluations for each patient, with baseline data collected at the study's inception and follow-ups over the next decade. Oral health assessments documented the severity of periodontal diseases and recorded the presence of endodontic infections.Cardiovascular evaluations were conducted to establish the incidence and progression of CAD and aortic aneurysm, while lifestyle factors, particularly smoking, were noted as significant contributors. This approach allowed for an in-depth exploration of the possible causal pathways linking oral health to cardiovascular outcomes. Results Results demonstrated that severe periodontitis, high numbers of missing teeth, and the presence of endodontic infections were significantly associated with higher incidences of CAD and aortic aneurysm. Smoking, as expected, acted as a compounding factor, intensifying the risk of cardiovascular outcomes in patients with poor oral health. Interaction terms further highlighted how smoking combined with advanced periodontitis notably increased CAD risk. The findings align with the hypothesis that severe periodontal disease and endodontic infections contribute to cardiovascular risk, especially among smokers. These results indicate that periodontal disease may serve as a marker for systemic inflammation, which has far-reaching effects beyond oral health alone. Conclusion The 10-year study showed a strong association between periodontal disease, smoking, hypertension,periodontitis and CVDs. This study underscores the importance of maintaining good oral health and cessation of smoking to mitigate cardiovascular risk. The results advocate for a multidisciplinary approach to patient care, integrating dental health with broader cardiovascular risk management. Future research is recommended to confirm these findings in larger, more diverse cohorts and to explore further the underlying mechanisms connecting oral infections and systemic inflammation with cardiovascular health.

Abstract 4137682: Genome wide association study for residualized apolipoprotein B elucidates its role in coronary artery disease risk

Background: Recent studies have shown apolipoprotein B (ApoB), the principle atherogenic lipoproteins, to have greater predictive ability for coronary artery disease (CAD) risk over standard lipid parameters. Moreover, discordantly high ApoB relative to Low-density lipoprotein cholesterol (LDLC) has repeatedly been associated with increased CAD risk. Aim: Given the strong genetic effects of ApoB and LDLC, we sought to characterize the discordance between ApoB and LDLC by genetics to obtain mechanistic insights into this emerging risk factor. Method: We derived residualized-ApoB regressing ApoB on LDLC in European-like populations (N = 383,500) in the UK Biobank. Using residualized-ApoB as an outcome, we explored clinical associations and conducted genome wide association study (GWAS). Result: Residualized-ApoB only modestly correlated with ApoB and LDLC (Spearman’s rho = 0.248 and -0.0079 respectively). We observed increased residualized-ApoB in males and individuals with lipid lowering therapy. Increased residualized-ApoB was associated with increased risk for CAD [Odds Ratio; 1.25 (95% Confidence interval 1.23-1.27)] independent from LDLC, ApoB, and Triglycerides. By GWAS, we observed significant heritability for residualized-ApoB [h 2 = 12.3 (SE 0.012)] and 195 significantly associated genetic loci ( P &lt; 5 × 10 -8 ). Only 59 of these lead variants were associated with ApoB or LDLC. We also found different effects in ApoB-related loci. For example, ApoB-increasing alleles at APOB (rs533617) and APOE (rs7412) loci increased residualized-ApoB but ApoB-increasing alleles at ABCG8 (rs4245791) and HAPLN4-TM6SF2 (rs150641967) loci decreased residualized-ApoB. Conclusions: Exploiting genetics, we determined significant heritability of residualized-ApoB which was partially correlated with ApoB/LDLC. We identified distinct effects of genetic variants on residualized-ApoB. Our results provide the clues for further precise understanding of regulatory mechanisms between ApoB and LDLC.

Abstract 4128377: Association between Mean Platelet Volume (MPV) and coronary artery disease: An analysis of NHANEs 2017-2020

Background: Recent data showed that mean platelet volume (MPV) is linked to mortality after myocardial infarction and restenosis following coronary angioplasty. However, its association with coronary artery disease (CAD) remains unclear. Therefore, we aim to investigate the association between MPV and CAD using a nationwide database. Methods: We analyzed retrospective cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020, including participants aged 18 years and older. The data on MPV were classified into three groups: below the 10th percentile (P10), between the 10th and 90th percentiles (P10 to P90), and above the 90th percentile (P90). Univariable and multivariable logistic regression models were utilized to identify the association between MPV and CAD. Results: A total of 12,156 patients with MPV results were identified. Their mean age was 37 ± 24 years, with females constituting 51.0% of the population. The racial distribution was primarily White at 33.8%, Black at 25.7%, Mexican American at 13.2%, Asian at 10.7%, and other races at 16.6%. The participants were categorized into three MPV groups: below P10 (11.2%), P10 to P90 (77.3%), and above P90 (11.5%), with median MPV values of 6.8, 8, and 9.7 fL, respectively. In a univariable analysis using participants with MPV in the P10 to P90 as a reference, those with MPV above the 90th percentile had a significantly higher risk of CAD, with an OR of 1.39 (P90-MPV: 95% CI 1.05, 1.83; P=0.021). No significant association was found between participants with MPV below the 10th percentile and risk of CAD (P10-MPV: OR 0.91, 95% CI 0.59, 1.41; P=0.684). After adjusting for age, gender, smoking status, blood pressure (SBP &gt;130 vs &lt;130 mmHg), type 2 diabetes, urine albumin creatinine levels, serum creatinine, heart failure, and stroke history, the association between those with MPV above P90 and increased CAD risk remained significant (P90-MPV aOR 1.65; 95% CI 1.16, 2.34; P=0.005). Gender and race did not modify this effect. Conclusion: Our findings indicate that high MPV (above the 90th percentile) is positively associated with the risk of CAD in the general population. Further longitudinal cohort studies are necessary to explore this relationship and its clinical implications thoroughly.

ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.

apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk. An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow-derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)-treated macrophages was determined by Western blot analysis. Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet-fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow-derived cells instead of non-bone marrow-derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK-dependent manner. The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK-dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.

Causal Links Between Renal Function and Cardiac Structure, Function, and Disease Risk.

Chronic kidney disease (CKD) increases the risk of adverse cardiovascular outcomes. However, the causal relationships between renal function and cardiovascular diseases (CVD) remain incompletely understood. This study aimed to determine the causal relationships between genetic susceptibility to impaired renal function and the risk of CVD endpoints, as well as cardiac structure and function detectable by cardiac magnetic resonance imaging (CMR). Bidirectional Mendelian randomization (MR) analyses were conducted using summary-level data from genome-wide association studies. The exposures were blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and CKD. The outcomes included atrial fibrillation, coronary artery disease (CAD), myocardial infarction, heart failure, stroke, and various CMR parameters. Sensitivity analyses, multivariable MR adjusting for cardiometabolic traits, and replication in the FinnGen cohort were performed. Elevated BUN levels (OR 1.505; 95% CI 1.077 to 2.103; P = 0.017) were causally associated with increased CAD risk, but this relationship was attenuated after adjusting for cardiometabolic traits. Increased UACR was causally linked to higher risks of CAD (OR 1.260; 95% CI 1.042 to 1.523; P = 0.017), myocardial infarction (OR 1.424; 95% CI 1.137 to 1.783; P = 0.002), and stroke (OR 1.182; 95% CI 1.012 to 1.379; P = 0.035), with the association for stroke remaining significant after multivariable adjustment. Reduced eGFR was causally related to decreases in ascending aorta diameter, proximal pulmonary artery diameter, right atrial size, left ventricular stroke volume, and right ventricular volumes, even after accounting for potential confounders. CKD was causally associated with a reduced pulmonary artery-to-aorta ratio and proximal pulmonary artery diameter. This comprehensive MR study establishes causal roles of genetic susceptibility to impaired renal function influencing cardiovascular outcomes and cardiac structure.

Methionine synthetase A2756G and Cystathionine-β-synthase 844ins68 polymorphisms and coronary artery disease: a meta-analysis

Objective: Methionine synthetase (MS) A2756G and Cystathionine-β-synthase (CBS) 844ins68 gene polymorphisms were indicated to be associated with increased coronary artery disease (CAD) risk. Nevertheless, because the results of each experiment are different, there is no consensus till now. This meta-analysis aimed to clarify the relationship between MS gene A2756G and CBS gene 844ins68 polymorphisms and CAD.Methods: 11,555 participants from 24 individual studies, 2162 participants from 6 individual studies were included in the MS gene A2756G and CBS 844ins68 gene polymorphisms meta-analysis respectively. To determine whether MS gene A2756G or CBS gene 844ins68 polymorphism was associated with CAD risk, a random or fixed-effect genetic model was adopted using pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).Results:MS gene A2756G polymorphism was significantly associated with CAD under recessive (OR: 1.400, 95% CI: 1.119-1.751, P=0.003) and homozygous genetic models (OR: 1.360, 95% CI: 1.084-1.706, P=0.008). In the African subgroup, the association was significant under the allelic, recessive, dominant, heterozygous, homozygous and additive (P<0.05) genetic models. In the Asian subgroup, the association was significant under the allelic, recessive and homozygous genetic models (P<0.05). No significant association was found between CBS 844ins68 gene polymorphism and CAD under all of the genetic models (P>0.05).Conclusions:MS gene A2756G polymorphism was significantly associated with increased CAD risk, especially in the African and Asian population. The G allele carriers of MS gene A2756G polymorphism were more susceptible to be suffered from CAD disease than others.

Relationship of EDNRA rs6842241 and MRAS rs9818870 polymorphic variants with predisposition to coronary artery disease and their effect on the lipid-lowering effect of rosuvastatin

Aim. To study the effect of EDNRA rs6842241 and MRAS rs9818870 polymorphic variants on the lipid-lowering effect of rosuvastatin in patients with coronary artery disease (CAD), and to determine the role of these loci in the development of CAD among Central Russia residents.Material and methods. The pharmacogenetic study involved 116 patients with class II-III stable angina. Patients received rosuvastatin with dose titration to achieve target low-density lipoprotein cholesterol (LDL-C) levels. The genetic and epidemiological study included DNA samples of 1960 Central Russia residents (1261 patients with CAD and 699 healthy individuals). Genotyping of polymorphic variants was performed on a MassARRAY-4 genomic mass spectrometer. Associations of polymorphisms with lipid changes for 1, 6 and 12 months of follow-up were calculated using linear regression analysis adjusted for sex, age, body mass index and rosuvastatin dose; associations with CAD risk — using logistic regression analysis adjusted for sex and age. The statistical significance of associations was calculated using the permutation test.Results. Carriage of the AA and CA genotypes of EDNRA rs6842241 variant was associated with a weakening of the rosuvastatin lipid-lowering effect in relation to total cholesterol (β=0,075, p=0,001) and LDL-C (β=0,145, p=0,017) at the end of the first month and 12 months of therapy (β=0,049, p=0,013 and β=0,072, p=0,040, respectively). Carriage of the AA genotype of EDNRA rs6842241 variant was associated with an increased CAD risk (odds ratio 5,36; 95% confidence interval 1,62-17,71, p=0,004). MRAS rs9818870 variant was not associated with rosuvastatin pharmacogenetics or with the CAD risk. Both polymorphic variants were not associated with lipid levels outside of lipid-lowering therapy, as well as with the triglyceride changes. High-density lipoprotein cholesterol levels during the entire follow-up period changed insignificantly.Conclusion. The EDNRA rs6842241 variant is associated with both a weakening of the lipid-lowering effect of rosuvastatin in CAD and an increased risk of its development in the population.

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

Investigating the Added Value of Beck's Depression Inventory in Atherosclerosis Prediction: Lessons from Paracelsus 10,000.

Background: Depression is the most common mental illness worldwide and generates an enormous health and economic burden. Furthermore, it is known to be associated with an elevated risk of arteriosclerotic cardiovascular diseases (ASCVD), particularly stroke. However, it is not a factor reflected in many ASCVD risk models, including SCORE2. Thus, we analysed the relationship between depression, ASCVD and SCORE2 in our cohort. Methods: We analysed 9350 subjects from the Paracelsus 10,000 cohort, who underwent both a carotid artery ultrasound and completed a Beck Depression Inventory (BDI) screening. Patients were categorised binomially based on the BDI score. Atherosclerotic carotid plaque or absence was dichotomised for logistic regression modelling. Odds ratios and adjusted relative risks were calculated using Stata. Results: Subjects with an elevated BDI (≥14) had higher odds for carotid plaques compared to subjects with normal BDI, especially after adjusting for classical risk factors included in SCORE2 (1.21; 95%CI 1.03-1.43, p = 0.023). The adjusted relative risk for plaques was also increased (1.09; 95%CI 1.01-1.18, p = 0.021). Subgroup analysis showed an increased odds of plaques with increases in depressive symptoms, particularly in women and patients ≤55 yrs. Conclusions: In our cohort, the BDI score is associated with subclinical atherosclerosis beyond classical risk factors. Thus, depression might be an independent risk factor which may improve risk stratification if considered in ASCVD risk prediction models, such as SCORE2. Furthermore, reminding clinicians to take mental health into consideration to identify individuals at increased atherosclerosis risk may provide added opportunities to address measures which can reduce the risk of ASCVD.

LDLR variant classification for improved cardiovascular risk prediction in familial hypercholesterolemia

Background and aimsFamilial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles. MethodsParticipants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model. ResultsOut of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97–5.0) to 12.0 (95%CI 5.5–24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively. ConclusionsThis study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods.

Evaluation of Polygenic Risk Scores for Prediction of Coronary Artery Disease in a Greek Case-Control Study.

Coronary artery disease (CAD) stands as the most predominant type of cardiovascular disease (CVD). Polygenic risk scores (PRSs) have become essential tools for quantifying genetic susceptibility, and researchers endeavor to improve their predictive precision. The aim of the present work is to assess the performance and the relative contribution of PRSs developed for CVD or CAD within a Greek population. The sample under study comprised 924 Greek individuals (390 cases with CAD and 534 controls) from the THISEAS study. Nine PRSs drawn from the PGS catalog were replicated and tested for CAD risk prediction. PRSs computations were performed in the R language, and snpStats was used to process genotypic data. Descriptive characteristics of the study were analyzed using the statistical software IBM SPSS Statistics v21.0. The effectiveness of each PRS was assessed using the PRS R2 metric provided by PRSice2. Among nine PRSs, PGS000747 greatly increased the predictive value of primary CAD risk factors by 21.6% (p-value = 2.63 × 10-25). PGS000012 was associated with a modest increase in CAD risk by 2.2% (p-value = 9.58 × 10-4). The remarkable risk discrimination capability of PGS000747 stands out as the most noteworthy outcome of our study.

Lifestyle factors, genetic susceptibility to obesity and their interactions on coronary artery disease risk: A cohort study in the UK Biobank

ObjectiveWe aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk. MethodsA total of 328,606 participants (54% women) were included using data from the UK Biobank. We evaluated the risk of developing CAD associated with obesity-related polygenic scores (PGSs) and healthy lifestyle scores (HLSs). HLSs were constructed using six lifestyle factors. Obesity PGSs were created using genetic variants identified by genome-wide association studies, including 941 variants for body mass index (BMI) and 457 for waist-to-hip ratio (WHR). Both HLSs and PGSs were categorized into three groups. ResultsDuring a 9-year median follow-up, 14,541 participants developed CAD. An unhealthy lifestyle was significantly associated with an increased CAD risk (hazard ratio [HR] = 2.24, 95% confidence interval [CI] = 2.09–2.40). High BMI and WHR PGSs were each significantly associated with an increased CAD risk (HRBMI = 1.23, 1.17–1.29; HRWHR = 1.15, 1.09–1.21). Lifestyle factors explained 41% (95% CI = 38%–45%) of CAD, while genetic variants for BMI explained only 10% (7%–14%). Risks of CAD were increased with poorer HLS independent of obesity-related PGSs. Individuals with the most unhealthy lifestyle and highest BMI PGS had the highest risk of CAD risk (HR = 2.59, 95% CI = 2.26–2.97), compared with participants with the healthiest lifestyle and lowest BMI PGS. ConclusionsWhile the observational nature of the study precludes the establishment of causality, our study provides supports for a causal association between obesity and CAD risk and the importance of lifestyle modification in the prevention of CAD.

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality

Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Genetically predicted apoB, LDL-C, and TG. The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. This study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

Association of flavonoid intake with coronary artery disease risk in the older population based on the National Health and Nutrition Examination Survey.

We investigated the association between flavonoid intake and coronary artery disease (CAD) risk in older adults. Data were extracted from the National Health and Nutrition Examination Survey (age ≥ 70 years; 2007-2010 and 2017-2018; n = 2 417). The total flavonoid and flavonoid subclass intake was calculated using validated food frequency questionnaires. The association between flavonoid intake and CAD risk was examined using generalized linear models with restricted cubic spline models. After multivariate adjustment, anthocyanin intake was positively associated with CAD risk; no significant associations were observed between other flavonoid subcategories and endpoint outcomes. Anthocyanins exhibited a non-linear association with CAD risk, and threshold effect analysis showed an inflection point of 15.8 mg/day for anthocyanins. Per unit increase in anthocyanins, the odds of CAD on the left of the inflection point decreased by 2%, while the odds on the right increased by 35.8%. Excessive flavonoid intake may increase CAD risk in the older population.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility

BackgroundBoth genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD.MethodsWe utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models.ResultsThe hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx).ConclusionExposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Factors associated with secondary coronary artery disease in rheumatoid arthritis patients: A systematic review and meta-analysis based on observational studies.

The main objective of this systematic review was to investigate the factors influencing the development of coronary artery disease (CAD) in patients with rheumatoid arthritis (RA). PubMed, Embase, Web of Science, Wan Fang Date, CBM, CNKI, and VIP databases were systematically searched to select the relevant literature. The quality of the incorporated studies was assessed with reference to the Newcastle-Ottawa Scale. Stata16 was adopted to summarise the odds ratios, risk ratios, hazard ratios, and 95% confidence intervals for meta-analysis. A total of 29 studies were included in this analysis, wherein the average age of RA patients was 50.5-81years and the proportion of women was 44.4%-92%. The present meta-analysis suggested that increased CAD risk in RA patients was associated with age, male gender, smoking, glucocorticoids, Health Assessment Questionnaire scores, hyperlipidaemia, hypertension, diabetes, and C-reactive protein concentration. The present systematic review revealed the influencing factors of secondary CAD in RA patients, some of which could reduce the risk of secondary CAD through effective interventions, such as smoking cessation, exercise, and medications. However, the effects of age, RA severity, and different medication subgroups on CAD risk stratification warrant further investigation.

Does gestational diabetes mellitus increase the risk of cardiovascular disease? A Mendelian randomization study.

In recent years, epidemiological studies have revealed the relationship between gestational diabetes mellitus (GDM) and cardiovascular disease (CVD). In this study, we utilized Mendelian randomization (MR) to investigate the potential causal impact of GDM on cardiovascular disease for the first time. We retrieved summary statistics from published genome-wide association studies. MR was first performed using significant SNPs extracted from the eighth data release of the FinnGen study. Next, a replication analysis for coronary artery disease (CAD) was conducted in another European ancestry population to validate our findings. Finally, mediation analysis was carried out to assess potential mediation effects. Our data analysis revealed that genetically predicted GDM was significantly associated with increased CAD risk (OR 1.10, 95% CI 1.02-1.18, p 0.006). Replication analysis confirmed a significant genetic association between GDM and CAD (OR 1.07, 95% CI 1.02-1.12, p 0.003) in another European ancestry population. Mediation analysis indicated no significant mediation effect by type 2 diabetes mellitus (T2DM)on the GDM-CAD relationship (mediation effect β [95% CI]: 0.005 [-0.003, -0.017]). Women with a prior history of GDM face an elevated risk of future CAD. This increased risk of CAD cannot be solely attributed to the subsequent onset of diabetes. Regular CAD risk assessment and primary prevention strategies are of paramount importance for women with a history of GDM.