Early-onset Coronary Artery Disease Patients Research Articles

An Evaluation of Plasma TNF, VEGF-A, and IL-6 Determination as a Risk Marker of Atherosclerotic Vascular Damage in Early-Onset CAD Patients.

Background: The pathogenesis of atherosclerosis is multifactorial and diverse. Pro-inflammatory cytokines are involved in these processes. It is suggested that inflammation may represent a novel and modifiable risk factor for cardiovascular disease. Therefore, this study aimed to gain insight into the relationship between plasma concentrations of TNF, VEGF, IL-6, and radiological parameters of atherosclerosis progression in patients with early-onset coronary artery disease (CAD). Methods: Seventy clinically stable patients were included in the study group. The age range for men was no more than 50 years, while for women, it was no more than 55 years. Fasting blood samples were obtained for plasma TNF, VEGF, and IL-6 protein measurements. Plasma cytokine concentrations were measured via ELISA. Doppler ultrasound of the carotid and peripheral arteries was performed in all patients. Results: After Bonferroni correction, there were no significant correlations between any cytokine and radiological parameters of atherosclerosis progression in our patients. Conclusions: The determination of plasma TNF, IL-6, and VEGF levels may not be a reliable marker for the vascular condition, and the measurement of these cytokines in plasma cannot replace the classical radiological examination of the vessels.

Genetic Testing Enables the Diagnosis of Familial Hypercholesterolemia Underdiagnosed by Clinical Criteria: Analysis of Japanese Early-Onset Coronary Artery Disease Patients.

Definitive diagnosis of familial hypercholesterolemia (FH) is paramount for the risk management of patients and their relatives. The present study aimed to investigate the frequency of gene variants contributing to low-density lipoprotein cholesterol (LDL-C) metabolism and their clinical relevance in patients with early-onset coronary artery disease (EOCAD). Among 63 consecutive patients with EOCAD (men <55 years or women <65 years) who underwent percutaneous coronary intervention (PCI) from 2013 to 2019 at Keio University Hospital, 52 consented to participate in this retrospective study. Targeted sequencing of LDLR, PCSK9, APOB, and LDLRAP1 was performed. Of the 52 patients enrolled (42 men; mean age: 50 ± 6 years), one (LDLR, c.1221_1222delCGinsT) harbored a pathogenic mutation, and one (APOB, c.10591A>G) harbored variants of uncertain significance. Both the patients harboring the variants were male, showing no history of diabetes mellitus or chronic kidney disease, no family history of EOCAD, and no physical findings of FH (i.e., tendon xanthomas or Achilles tendon thickening). Patients harboring the LDLR variant had three-vessel disease, were on a statin prescription at baseline, and had stable LDL-C levels; however, the case showed a poor response to the intensification of medication after PCI. Approximately 3.8% of patients with EOCAD harbored variants of gene related to LDL-C metabolism; there were no notable indicators in the patients' background or clinical course to diagnose FH. Given the difficulty in diagnosing FH based on clinical manifestations and family history, genetic testing could enable the identification of hidden risk factors and provide early warnings to their relatives.

Quantitative Assessment of Serum Amino Acids and Association with Early-Onset Coronary Artery Disease.

BackgroundAmino acids play essential roles in protein construction and metabolism. Our study aims to provide a profile of amino acid changes in the serum of patients with early-onset coronary artery disease (EOCAD) and identify potential disease biomarkers.MethodsUltra-performance liquid chromatography-multiple reaction monitoring-multistage/mass spectrometry (UPLC-MRM-MS/MS) was used to determine the amino acid profile of patients with EOCAD in sample pools. In the validation stage, the serum levels of candidate amino acids of interest are determined for each sample.ResultsA total of 128 EOCAD patients and 64 healthy controls were included in the study. Eight serum amino acids associated with disease state were identified. Compared with the control group, serum levels of seven amino acids (L-Arginine, L-Methionine, L-Tyrosine, L-Serine, L-Aspartic acid, L-Phenylalanine, and L-Glutamic acid) increased and one (4-Hydroxyproline) decreased in the patient group. Results from the validation stage demonstrate that serum levels of 4-Hydroxyproline were significantly lower in myocardial infarction (MI) patients (9.889 ± 3.635 μg/mL) than those in the controls (16.433 ± 4.562 μmol/L, p < 0.001). Elevated serum 4-Hydroxyproline levels were shown to be an independent protective factor for MI (OR = 0.863, 95% CI: 0.822–0.901). The significant negative correlation was seen between serum 4-Hydroxyproline levels and cardiac troponin I (r = −0.667) in MI patients.ConclusionWe have provided a serum amino acid profile for EOCAD patients and screened eight disease state-related amino acids, and we have also shown that 4-Hydroxyproline is a promising target for further biomarker studies in early-onset MI.

Serum fatty acids profile and association with early-onset coronary artery disease.

Background:Fatty acids (FAs) play crucial roles in modulating and preventing diseases in humans, including early-onset coronary artery disease (EOCAD). In this study, we aimed to provide a profile of FAs in the serum of EOCAD patients and identify potential EOCAD-associated FAs.Methods:In the first stage, we analyzed the FAs profiles in pooled samples of patients with EOCAD using gas chromatography-mass spectrometry. In the second stage, the serum levels of the candidate FAs were validated in EOCAD patients.Results:A total of 128 EOCAD patients and 64 controls were included in the study. Forty-nine serum FAs were quantified in pooled samples; three ω-3 FAs were identified to be associated with EOCAD. Moreover, results from the validation stage indicated that serum levels of docosahexaenoic acid (DHA) were significantly lower in EOCAD patients (55.43 ± 33.86 µg/ml) and myocardial infarction (MI) patients (47.49 ± 28.44 μg/ml) than those in the controls (70.65 ± 43.56 µg/ml). Multivariate regression analysis revealed that elevated serum DHA level was an independent protective factor for EOCAD [odds ratio (OR) = 0.8917, 95% confidence interval (CI): 0.879–0.957] and MI (OR = 0.835, 95% CI: 0.799–0.862). Decreased serum levels of docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA) were observed in the early-onset MI group.Conclusion:The study provided the serum FAs profile of EOCAD and confirmed that the decrease in serum levels of DHA, DPA, and EPA was associated with EOCAD. These findings might contribute to understanding the cardiovascular effects of FAs, particularly the protective effects of ω-3 polyunsaturated FAs.

Genomic Risk Prediction of Recurrent Cardiovascular Diseases in the UK Biobank

Polygenic risk score (PRS) shows promise in predicting the risk of cardiovascular diseases (CVD) based on the genotypes of an individual, but most analyses have traditionally focused on the diseases’ onset. The usefulness of PRS to predict recurrence remains unclear. In this study, we built a meta-PRSCVD upon the candidate PRSs developed from state-of-the-art PRS methods for three CVD subtypes of significant importance: coronary artery disease (CAD), ischemic stroke, and heart failure. To evaluate the prediction performance of the meta-PRSCVD, we restricted our analysis to 24,704 white British CAD patients in the UK Biobank, among which 6,999 had CVD recurrent events. Results showed that the meta-PRSCVDwas significantly associated with CVD recurrence with a hazard ratio per standard deviation increase of 1.24 (95% CI: 1.20-1.27). After adjustment for age, sex, and the first ten principal components of genotypes, the meta-PRSCVD predicted the recurrence with an AUC of 0.64 (95% CI: 0.62-0.66). When restricted to the early-onset patients (onset age <= 55), the AUC was further increased to 0.75 (95% CI 0.72-0.78). Our results highlight the potential role of genomic screening for secondary preventions of CVD, especially among early-onset CAD patients.

IL17RA in early-onset coronary artery disease: Total leukocyte transcript analysis and promoter polymorphism (rs4819554) association

Background and aimsThe interleukin-17 (IL-17) pathway would play an important role in the pathogenesis of atherosclerosis and coronary-artery disease (CAD). The IL-17 inflammatory mediators are expressed by Th17 cells, a group of CD4 + leukocytes that infiltrate the vascular milieu and are pivotal in the origin, progression, stability and rupture of the atherosclerotic lesion. Cigarette smoke compounds stimulated the expression of IL-17 and IL-17-receptors. In atherogenic mice models the deficiency of IL-17RA resulted in a reduction of the atherosclerotic lesion size and leukocyte infiltrate. We hypothesised that common the IL-17RA transcript might be differential expressed in the leukocytes from CAD patients and healthy individuals. MethodsThe relative amount of the IL-17RA to ACTB transcript was determined in total leukocytes of 55 patients and 50 controls, all smokers. We genotyped the IL-17RA rs48195554 promoter polymorphisms in 390 healthy controls and 450 early-onset CAD patients. ResultsPatients showed significantly higher mean IL-17RA normalised transcript value than controls (p < 0.001). For the IL-17RA rs48195554 promoter polymorphisms, IL-17RA G-carriers showed higher transcript values. However, allele and genotype frequencies did not differ between patients and controls and we thus excluded a significant association with CAD. ConclusionsThe higher levels of the IL-17RA transcript among CAD-patients was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.

Association between ALMS 1 variants and early-onset coronary artery disease: a case-control study in Chinese population.

Background: Genome-wide linkage analysis revealed the polymorphism of rs6748040 and glutamic acid repeat are potential pathogenic factors of early-onset myocardial infarction (MI). The present study was designed to investigate the associations of Alström syndrome 1 (ALMS 1) gene in Chinese populations with early-onset coronary artery disease (CAD).Methods: The two variants of the ALMS 1 gene were genotyped in 1252 early-onset CAD patients and 1378 controls using PCR, followed by Sml I restriction enzyme digestion or direct sequencing of the PCR product. The associations were estimated using the odds ratio (OR) and the 95% confidence interval (CI).Results: A significant association between the ALMS 1 G/A variant and the risk of early-onset MI was detected in G vs.A (OR = 1.371, 95% CI: 1.183–1.589), GG vs. AA (OR = 2.037, 95% CI: 1.408–2.948), dominant genetic model (OR = 1.794, 95% CI: 1.254–2.567), and recessive genetic model (OR = 1.421, 95% CI: 1.177–1.716). 14 glutamic acid repeat (A14) is risk factor for early-onset MI (OR = 1.605, 95% CI: 1.313–1.962) and 17 glutamic acid repeat (A17) is protective factor for the disease (OR = 0.684, 95% CI: 0.601–0.827). These associations were not detected in early-onset CAD patients.Conclusions: Our findings indicated that G/A variant (rs6748040) and glutamic acid repeat polymorphism of the ALMS 1 gene associated with the risk of early-onset MI in the Chinese population.

Association of +138I/D and Lys198Asn Polymorphisms in the Endothelin-1 Gene with Early Onset of Coronary Artery Disease among the Chinese Han Population.

BackgroundHuman endothelin-1 (ET-1) gene polymorphism is closely associated with coronary artery disease (CAD). This study aimed to investigate the association of 2 single-nucleotide polymorphisms (SNPs), +138 I/D and Lys198Asn) of the ET-1 gene,with early onset of CAD in Han Chinese patients. We investigated the effects of Lys198Asn polymorphism on ET-1 protein expression upon stimulation with pro-inflammatory factors.Material/MethodsGenotyping of the 2 SNPs +138 I/D and Lys198Asn was performed in 88 early-onset CAD patients (≤55 years for males; ≤60 years for females) and 52 healthy control participants using a polymerase chain reaction direct sequencing method. The association of the 2 SNPs was analyzed with SPSS 17.0 software. Western blotting was performed to assess the effects of ET-1 polymorphisms on ET-1 protein expression upon tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and lipopolysaccharide (LPS) stimulation in HEK-293T cells.ResultsFisher’s exact test showed that the T allele (odds ratio [OR]=3.38, P=0.02) and GT/TT genotype (OR=3.76, P=0.02) of the ET-1 gene Lys198Asn were associated with increased early-onset CAD risk. Multivariate logistic regression analysis showed smoking was the single independent variable related to early-onset CAD (P<0.05). An increase of ET-1 protein levels in cells transfected with Asn198 plasmid was seen upon TNF-α or IL-6 stimulation.ConclusionsT allele frequency in Lys198Asn loci might be associated with the pathogenesis of early-onset CAD. T-variant might contribute to early-onset CAD by upregulating ET-1 expression upon inflammatory cytokines stimulation, and smokers who have the T allele might be vulnerable to CAD in the Chinese population.

Abstract P457: Age Dependence of Genetic Risk Scores in Relation to Coronary Artery Disease

Background: Coronary artery disease (CAD) is an age-related multi-factorial disease with a high public health burden. Genetic loci for CAD have been discovered and collectively predict CAD risk independent of traditional risk factors. It remains unclear whether age modifies the genetic predisposition to CAD. Methods: A total of 173,315 Caucasian subjects from the UK Biobank were included in this study, including 26,472 CAD patients with age of onset ranging from 32 to 78 years old, and 146,843 control subjects &gt; 60 years old without CAD. CAD diagnosis was extracted from in-patient Hospital Episode Statistics (HES) and National Death Registry based on ICD-10 and OPCS-4 codes. CAD genetic risk score (GRS) was calculated based on the 161 known CAD loci. Sub-GRSs for body mass index (BMI, 16 loci), blood pressure (BP, 26 loci) and lipids (17 loci) were constructed to examine the genetic risk for CAD from certain intermediate trait. The CAD GRSs among onset age groups were compared to the controls using linear regression models, controlling for sex, BMI, creatinine, c-reactive protein, high density lipoprotein, low density lipoprotein, triglyceride, diabetes, heart failure history, hypertension and smoking status. The sub-GRSs were compared using the same models, excluding sub-GRS specific intermediate traits. Interactions of age groups and GRSs were tested using logistic regression models for CAD status, controlling for the same variables described above. Association analyses of each GRS were performed within each category of CAD age at onset comparing to controls. Results: Compared to the controls, the mean CAD GRS in CAD patients with age of onset ≤ 50 years was 0.58 standard deviations (SD) higher (95% CI 0.53-0.63), followed by CAD age of onset between 50 and 60 years (0.50 SD higher, 95% CI 0.48-0.52), between 60 and 70 years (0.35 SD higher, 95% CI 0.33-0.37), and &gt; 70 years (0.25 SD higher, 95% CI 0.21-0.29). The sub-GRSs showed the similar trend. Age of onset stratified analysis revealed a significant CAD GRS-age interaction (p&lt;0.001) on CAD risk where genetic effect is stronger among those early onset CAD patients - the odds ratios (OR) per CAD GRS SD among subjects with CAD onset age ≤ 50, 50 to 60, 60 to 70, &gt; 70 years were 1.80 (95% CI 1.71-1.89), 1.66 (95% CI 1.62-1.70), 1.44 (1.41-1.47), 1.29 (95%CI 1.24-1.35), respectively. Among the three sub-GRSs, significant GRS-age interactions were observed for BP sub-GRS and lipids sub-GRS but not BMI sub-GRS. Conclusion: The observed gene-age interaction indicates that the genetic susceptibility for CAD decreases for older subjects. The contribution of the CAD GRS to CAD risk is almost 64% lower in those developing CAD at age &gt; 70 years compared to those ≤ 50 years. Future considerations and applications of CAD genetic risk in precision medicine needs to include age of onset to accurately evaluate the genetic contribution.

Associations between IL-6 and Echo-Parameters in Patients with Early Onset Coronary Artery Disease.

Background: Over the last two decades, many studies have investigated the association between interleukin 6 (IL-6) and pathogenesis and progression of coronary artery disease (CAD). Patients with CAD manifested at a young age are a particularly interesting group. They differ from older patients, not only in terms of the severity of coronary artery atherosclerosis, but also risk factor profiles, short- and long-term prognosis after myocardial infarction (MI). The role of IL-6 in younger patients with CAD is less well-known. Therefore, our study aimed to analyze the relationship between IL-6 level and other inflammations, atherosclerosis, and cardiac function parameters in early onset CAD patients. Methods: The study covered 100 patients with early onset CAD and a group of 50 healthy participants. Plasma levels of IL-6 and basic biochemical parameters, anthropometric, echocardiographic, and arteries Doppler ultrasound measurements were performed. Results: We did not observe a significant difference in IL-6 concentration in plasma between patients with early onset CAD and a control group, but IL-6 level was negatively correlated with echocardiographic measurements of ascending aorta diameter, left ventricular shortening fraction, and right ventricular end-diastolic diameter in our patients. Conclusions: In patients with early onset CAD, plasma IL-6 level is associated with other inflammation parameters and with cardiac function, potentially contributing to right ventricular remodeling and left ventricular systolic dysfunction. This suggests possible prognostic benefits of long-time observation of IL-6 level after the acute coronary syndrome.

Association Between MTHFR Gene Common Variants, Serum Homocysteine, and Risk of Early-Onset Coronary Artery Disease: A Case-Control Study.

The common variants of the methylenetetrahydrofolate reductase (MTHFR) gene are related to the activity of the MTHFR enzyme and the concentrations of blood homocysteine (Hcy). This study was designed to investigate the associations of MTHFR in Chinese populations with early-onset coronary artery disease (EOCAD). The two common variants of the MTHFR gene were genotyped in 875 EOCAD patients and 956 controls using PCR, followed by direct sequencing of the PCR product. Serum levels of Hcy were measured using an automatic biochemistry analyzer. A significant association between the MTHFR-677C/T variant and the risk of EOCAD was detected in CC versus TT (odds ratio (OR) 1.456, 95% confidence interval (CI) 1.120-1.892), dominant genetic model (OR 1.266, 95% CI 1.027-1.546), and recessive genetic model (OR 1.306, 95% CI 1.040-1.639). Hcy was most abundant in TT genotype (18.31 ± 7.22μmol/L), least abundant in CC genotype (11.37 ± 5.23μmol/L), and detectable at intermediate levels in heterozygotes (15.25 ± 6.58μmol/L). Elevated serum Hcy levels were an independent risk factor for EOCAD (ORadjust 1.431, 95% CI 1.135-1.763). Our findings indicated that the T allele of -677C/T MTHFR variant predisposes to high levels of Hcy, and that the T allele is an important risk factor for EOCAD in the Chinese population.

Serum Uric Acid as an Independent Risk Factor for the Presence and Severity of Early-Onset Coronary Artery Disease: A Case-Control Study.

Serum uric acid (UA) is the final product of purine metabolism in humans. The present study is aimed at identifying the potential association between serum UA and early-onset coronary artery disease (EOCAD). The study population consisted of 1093 EOCAD patients aged ≤50 years, and 1117 age- and sex-matched apparently healthy people served as controls. The concentrations of UA were measured by uricase method. The severity of CAD was evaluated by Gensini score. The mean serum level of UA was 5.843 ± 1.479 mg/dl in EOCAD patients and 5.433 ± 1.529 mg/dl in controls. Serum UA levels were significantly higher in the EOCAD group than those in the control group (P < 0.001) and was an independent risk factor for EOCAD (OR = 1.100, 95% CI: 1.022–1.185). The early-onset myocardial infarction patients with 3-vessel disease had higher serum UA levels than those with 1- or 2-vessel disease. The serum UA levels of EOCAD patients with acute coronary syndrome were significantly higher than those with chronic coronary artery disease. EOCAD patients with hyperuricemia had higher Gensini scores than those without hyperuricemia. In addition, the serum UA levels were affected by drinking (P < 0.01) and were positively correlated with serum creatinine (r = 0.323) and weight (r = 0.327). Our results show that serum UA was an independent risk factor for EOCAD. The serum UA levels were associated with the presence and severity of EOCAD and suggested that UA may be involved in the progression of EOCAD.

A 45-SNP genetic risk score is increased in early-onset coronary artery disease but independent of familial disease clustering

Background and aimsCommon genetic risk variants may contribute to the heritability of early-onset coronary artery disease (CAD). We aimed to investigate the association of a genetic risk score (GRS) with age upon CAD-onset and to test the association between the GRS, familial clustering, and CAD severity in early-onset CAD. Methods134 early-onset CAD patients (<40 years), 446 late-onset CAD patients (male >55 years/female >65 years), and 89 healthy controls were genotyped for 45 CAD-associated SNPs and a GRS was created. In early-onset CAD patients, family pedigrees with information on 1585 1st and 2nd degree relatives were used to calculate a stratified log-rank family score (SLFS) as a measure of familial clustering. ResultsEarly-onset patients had a higher mean GRS than late-onset CAD patients (p = 0.02) and healthy controls (p < 0.0001). In the adjusted model, a GRS increase of one SD was associated with 1.2 years (95% CI 0.1–2.2) earlier onset. The GRS was not associated with the SLFS in the regression model (p = 0.41) and did not differ between SLFS tertiles (p = 0.98). The SLFS predicted the number of affected coronary vessels (OR [95% CI] per SD increase in SLFS: 2.0 [1.4–3.0]), whereas the association between the GRS and CAD severity was not statistically significant (OR [95% CI] per SD increase in GRS: 1.3 [0.9–1.9]). ConclusionsThe GRS was increased in early-onset CAD patients, but not associated with the SLFS, suggesting that these common genetic variants are of minor importance in familial clustering of early-onset CAD. Furthermore, family pedigree analysis may predict CAD severity more precisely than common variants.

Increased serum concentrations of asymmetric dimethylarginine (ADMA) in patients with early-onset coronary artery disease

BackgroundAsymmetric dimethylarginine (ADMA) has been associated with an increased risk of cardiovascular disease. We investigated the role of serum ADMA concentrations in early-onset coronary artery disease (EOCAD). MethodsCandidates for coronary artery angiography (age<50y for men and <55y for women) who met the inclusion criteria were enrolled in this study. Serum concentrations of ADMA were determined using ELISA. Severity of coronary atherosclerosis was estimated by number of diseased vessels. ResultsA total of 601 subjects (286 with EOCAD patients and 315 controls) were included in the study. ADMA concentrations were found to be significantly higher in the EOCAD group (0.480±0.110μmol/l) than in the control group (0.457±0.091, P=0.007). ADMA concentrations significantly increased with the number of diseased vessels (P<0.001). In addition, serum ADMA concentrations were affected by diabetes mellitus and smoking status, and were positively correlated with serum creatinine and body mass index (BMI). ConclusionsOur results show that serum ADMA concentrations were associated with the presence and severity of EOCAD, suggesting that ADMA may be involved in the progression of EOCAD.

Is plasma-soluble CD36 associated with density of atheromatous plaque and ankle–brachial index in early-onset coronary artery disease patients?

CD36 is a major macrophage scavenger receptor for oxidised low-density lipoprotein particles. Soluble CD36 (sCD36) is circulating as a ligand-bound complex and may be present in microparticles shed from cells such as platelets, monocytes/macrophages, or adipocytes. Positive association of plasma sCD36 with insulin resistance has been reported, and it has been proposed that sCD36 might represent a marker of macrophage activation and inflammation leading to atherosclerosis. Recently we have identified an association between CD36 polymorphism and low thickness of atheromatous plaque, suggesting its protective effect against atherosclerosis development. To obtain insight into the relationship between plasma concentration of sCD36 and radiological parameters of atherosclerosis in patients with early-onset coronary artery disease (CAD). The study group comprised 70 clinically stable patients (18 women and 52 men) with early CAD (aged no more than 50 years for men and 55 years for women). Fasting blood sample was taken for serum glucose, lipid profile, ApoA1, ApoB, Lp(a), and plasma sCD36 protein measurements. Each subject's weight, height, waist and hip circumference, and systolic and diastolic blood pressure were measured, and the body mass index, waist-to-hip ratio, and mean arterial pressure were calculated. Doppler ultrasound examinations of carotid and peripheral arteries were performed in all patients. Thickness of intima-media complex (IMC) of common carotid (CCA) and brachial arteries, as well as density and thickness of atheromatous plaque at CCA bifurcation, were measured with M'Ath programme. Plasma concentrations of CD36 antigen were measured by ELISA. Correlations between quantitative variables and sCD36 plasma concentration were assessed with the Spearman rank correlation coefficient (Rs). Associations between qualitative variables and sCD36 plasma concentration were tested with the Mann-Whitney U test. We observed no significant correlations between sCD36 concentration and radiological parameters of atherosclerosis. We found only borderline significant negative correlation of sCD36 concentration with thickness of IMC of left brachial artery. We also observed a significantly negative correlation with CCA plaque density, but only in the female subgroup and on the right side. Borderline higher sCD36 plasma concentrations were observed in patients with lower ankle-brachial index value (< 0.9). The results of the study show no strong associations and do not prove either detrimental or beneficial influence of sCD36 on radiological parameters of atherosclerosis. Further research is necessary to assess the association of high plasma sCD36 concentrations with the risk of plaque instability in patients with early-onset CAD.

Serum uric acid and its relationship with cardiovascular risk profile in Chinese patients with early-onset coronary artery disease.

The prevalence of coronary artery disease (CAD) is growing in the young population. We aimed to investigate the association between serum uric acid (SUA) levels and cardiovascular involvement in individuals under 45 years old diagnosed with early-onset CAD (EOCAD). Seven hundred eighty-six EOCAD patients were recruited and stratified into four groups by SUA levels. General information, serum indicators, and results of coronary angiography and echocardiography were recorded. The associations between SUA levels were explored by univariate and multivariate logistic regressions. With the increasing of SUA levels, the prevalence of hypertension and hyperlipidemia, triple branches involved, heart failure, and cardiac enlargement of left ventricle (LV), left atrium (LA), and right ventricle (RV) were significantly higher (all P < 0.05). The fourth group (SUA >8 mg/dl) had the highest proportions than other groups (all P < 0.05). After controlling potential confounders, multiple logistic regression analysis showed that odds ratios of SUA >8 mg/dl were 2.345 for triple branches involved (95 % confidence interval (CI) 1.335-4.119), 4.168 for heart failure (95 % CI 1.599-10.862), and 4.122 for LV enlargement (95 % CI 1.874-9.065) (P < 0.05). SUA >8 mg/dl was independently associated with triple branches involvement, heart failure and LV enlargement in Chinese EOCAD patients. Higher SUA level might play an important role in cardiac dysfunction and severity of EOCAD.

Age differences in periventricular and deep white matter lesions

Deep white matter hyperintensity (DWMH) and periventricular (PV) white matter lesion volumes are associated with age and subsequent stroke. We studied age differences in these volumes accounting for collinearity and risk factors. Subjects were 563 healthy family members of early-onset coronary artery disease patients. Using 3T magnetic resonance imaging, lesions were classified as DWMH or PV. Age association with lesion classification was analyzed using random effects Tobit regression, adjusting for intracranial volume (ICV) and risk factors. Subjects were 60% women, 36% African-American, mean age 51 ± 11 years. In multivariable analysis adjusted for PV and ICV, DWMH was associated with age (p < 0.001) and female sex (p = 0.003). PV, adjusted for DWMH and ICV, was age associated (p < 0.001). For each age decade, DWMH showed 0.07 log units/decade greater volume (95% CI = 0.04–0.11); PV was 0.18 log units/decade greater (95% CI = 0.14–0.23); slope differences (p < 0.001). In people with a family history of coronary artery disease, PV and DWMH are independently and differentially associated with age controlling for traditional risk factors.

Association between HMW adiponectin, HMW-total adiponectin ratio and early-onset coronary artery disease in Chinese population

ObjectiveAdiponectin is an adipose-secreting protein that shows atheroprotective property and has inverse relation with coronary artery disease (CAD). High-molecular weight (HMW) adiponectin is reported as the active form of adiponectin. In the present study, we aimed to investigate the association between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis, and to compare their evaluative power for the risk of CAD. MethodsSerum levels of total and HMW adiponectin were measured in 382 early-onset CAD (EOCAD) patients and 305 matched controls undergoing coronary angiography by enzyme-linked immunosorbent assay (ELISA). Gensini score was used to evaluate the severity of coronary atherosclerosis. ResultsCAD onset age was positively correlated with HMW adiponectin (r = 0.383, P < 0.001) and HMW-total adiponectin ratio (r = 0.429, P < 0.001) in EOCAD patients. Total and HMW adiponectin and HMW-total adiponectin ratio were all inversely correlated with Gensini score (r = −0.417, r = −0.637, r = −0.578, respectively; all P < 0.001). Multivariate binary logistic regression analysis demonstrated that HMW adiponectin and HMW-total adiponectin ratio were both inversely correlated with the risk of CAD (P < 0.05). ROC analysis indicated that areas under the ROC curves of HMW adiponectin and HMW-total adiponectin ratio were larger than that of total adiponectin (P < 0.05). ConclusionsAdiponectin is cardioprotective against coronary atherosclerosis onset in EOCAD patients. HMW adiponectin and HMW-total adiponectin ratio show stronger negative associations with the severity of coronary atherosclerosis than total adiponectin does. HMW adiponectin and HMW-total adiponectin ratio are effective biomarkers for the risk of CAD in Chinese population.

Functional Analysis LRP6 Novel Mutations in Patients with Coronary Artery Disease

BackgroundGenetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients.MethodsWe systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese.ResultsIn total, we identified 5 patient-specific mutations including K82N (two patients), S488Y (one patient), P1066T (two patients), P1206H (two patients) and I1264V (one patient) All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs) when compared with wild type (WT) LRP6.ConclusionOur results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD.

Lack of association between a common polymorphism of the endothelial lipase gene and early-onset coronary artery disease in a Chinese Han population

A growing body of evidence suggests that the 584C/T polymorphism in the endothelial lipase (EL) gene contributes to the process of coronary artery disease (CAD). The present study aimed to reveal the potential relationship between the EL 584C/T gene polymorphism and early-onset CAD, CAD severity, and lipid levels in a Chinese Han population. Participants comprised 135 early-onset CAD patients and 166 controls. EL 584C/T genotypic and allelic frequencies were detected by PCR. The frequencies of the CC, CT, and TT genotypes were 58.4, 38.6, and 3.0%, respectively, within the control group, and 62.2, 33.3, and 4.5%, respectively, in the early-onset CAD group. There was no significant difference in the frequency of CC genotype and T allele carriers between early-onset CAD patients and controls. The frequency of the T allele was 22.3% in the control group and 21.1% in the early-onset CAD group. The T allele frequency of the variant was not significantly different between the two groups (P = 0.766), even after adjustments for age, gender, smoking status, hypertension, DM, and lipids were made. There was also no significant association between the genotype and the severity of CAD (P = 0.596). Furthermore, there was no correlation between the genotype and lipid levels or their ratios in both groups. The EL 584C/T gene polymorphism, therefore, was not associated with early-onset CAD or the severity of CAD in this Chinese Han population, suggesting that this variant is not always involved in the pathogenesis of early-onset CAD.