Early-onset Coronary Artery Disease Research Articles

Sex-differences in the clinical features, managements and outcomes of early-onset atherosclerotic coronary artery disease in China

Abstract Background/Introduction There is an alarming rise in the incidence of atherosclerotic coronary artery disease (CAD) among young adults, particularly in young women. Sex disparities of early-onset CAD in the context of contemporary cardiovascular practice are not well understood. Purpose We aimed to delineate the differences in clinical profiles and prognosis between young men and women with established early-onset CAD. Methods This is a nationwide, hospital-based, longitudinal prospective cohort study. Young patients (aged ≥18 years and ≤ 45 years) with angiographically confirmed severe atherosclerotic obstructive coronary arteries (luminal narrowing ≥ 70%) were included from 38 hospitals across China between May 2017 and May 2020. Coronary risk factors, clinical features and treatments were compared between men and women at baseline. Participants were followed for 3 years. The outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), unplanned revascularization, and ischemic stroke. The Cox regression analyses were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for outcome. Results There were 1524 patients (female: 4.4%) included in this study. The female patients were older than the male patients (41.1±4.0 years for females vs. 39.6±4.4 years for males, p=0.006). They showed a lower prevalence of hypertension, lipid disorders, and smoking or drinking (all p<0.01). The female patients were less likely to have at least 1 modifiable risk factors (female: n=45 (67.2%) vs. male: n=1382 [94.6 %], p<0.001); they showed more favorable laboratory results at baseline, including lipids, serum creatinine and uric acid (all p<0.05) as compared to male patients. Besides, young females presented more often with stable angina on admission, whereas young males tended to present with acute MI (p<0.001). There was no significant sex difference in Gensini Score (p=0.15). Female patients were less likely to undergo revascularization procedures than male patients (73.1% vs. 85.3%, p=0.01). During the 3 years of follow-up, female patients were at a significantly higher risk of MACE compared to their male counterparts (13.4% vs. 5.8%, adjusted HR: 3.07, 95% CI:1.36–6.94, p=0.007) after adjusting for age, smoking, drinking, body mass index, hypertension, diabetes, dyslipidemia, diagnosis and revascularization. Conclusions Distinct sex disparities, unfavorable to young females, were documented among patients with early-onset CAD, with the largest gaps noted in the treatment and prognosis. Despite more favorable baseline profiles, young female patients had insufficient care and 3-fold greater risk for MACE compared to young males. These results highlight the need for strengthening the treatment strategies for this vulnerable disease entity.Figure 1

Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia (APH-19): results from the efficacy phase of an open-label, multicentre, phase 3 study

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder characterised by extremely high concentrations of LDL cholesterol, leading to early-onset atherosclerosis. Lomitapide is an orally administered microsomal triglyceride transfer protein (MTP) inhibitor that effectively lowers LDL cholesterol and is approved for adults with HoFH. We aimed to investigate the efficacy and safety of lomitapide in paediatric patients with HoFH receiving standard-of-care lipid-lowering therapy. APH-19 is an open-label, single-arm, phase 3 trial performed at 12 study centres in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. A 6-week run-in period was followed by a 24-week efficacy phase and an 80-week safety phase. Patients aged 5-17 years, on stable lipid-lowering therapy, with HoFH diagnosed using the criteria from the 2014 European Atherosclerosis Society Consensus Panel on HoFH were titrated to maximum tolerated doses of oral lomitapide, starting at 2 mg (patients aged 5-15 years) or 5 mg (patients aged 16-17 years). The primary endpoint was the percentage change from baseline to week 24 in LDL cholesterol, which was assessed in patients who had received at least one dose of lomitapide, and who had a baseline and at least one post-baseline measurement. The secondary outcomes were the percentage change from baseline at week 24 in total cholesterol, non-HDL cholesterol, VLDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein(a). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04681170. Between Dec 20, 2020, and Oct 16, 2022, 43 patients were included and treated (24 [56%] were female and 19 [44%] were male, and median age was 10·7 years [7·0-14·0]). Mean change from baseline in LDL cholesterol at week 24 was -53·5% (95% CI -61·6 to -45·4, p<0·0001). Mean percentage reductions were observed at week 24 for non-HDL cholesterol (-53·9%, 95% CI -61·7 to -46·1, p<0·0001), total cholesterol (-50·0%, 95% CI -57·6 to -42·4, p<0·0001), VLDL cholesterol (-50·2%, -59·1 to -41·2, p<0·0001), apolipoprotein B (-52·4%, -60·3 to -44·5, p<0·0001), triglycerides was -49·9% (-58·8 to -41·0, p<0·0001), and lipoprotein(a) (-11·3%, -32·9 to 10·3 [in 21 patients with measurements in mg/dL]; -23·6%, -38·2 to -9·0 [in 22 patients with measurements in nmol/L]; p=0·0070 combined). Adverse events were mostly mild, and gastrointestinal and hepatic in nature. Adverse events of special interest were reported for five (12%) patients (gastrointestinal in two patients and hepatic in three). One serious treatment-emergent adverse event was reported (also classed as an adverse event of special interest): an increase in hepatic enzymes, resulting in two dose interruptions, two dose reductions, and a repeated dose escalation. Lomitapide provided a significant, clinically meaningful LDL cholesterol reduction and has the potential to be an efficient, LDL receptor-independent option for paediatric patients with HoFH. Amryt Pharmaceuticals.

Association of hsCRP and Serum Kalirin Levels with the Development and Severity of Premature Coronary Artery Disease in Iraqi Patients

Background: Coronary artery disease (CAD) is a major contributor to morbidity and mortality worldwide. Early-onset CAD, also known as PCAD, is a severe form of CAD associated with high mortality and a poor prognosis. Early diagnosis is crucial to reducing complications. While hsCRP is an established biomarker for CAD, kalirin is a potential novel biomarker due to its role in promoting smooth muscle proliferation and endothelial dysfunction. Objective: To evaluate the relationship between serum kalirin and hsCRP levels with the presence and severity of PCAD and to compare the diagnostic value of both biomarkers. Method: The study recruited 92 participants into two groups: the PCAD group (46) included patients with confirmed CAD by angiographic findings and the second group was the non-CAD group (46) with negative findings by coronary angiography. The levels of serum kalirin and hsCRP were measured for both groups using enzyme-linked immunosorbent assay (ELISA) kits. Results: Serum levels of kalirin and hsCRP were strongly associated with the presence of PCAD (p&lt;0.001), and both biomarkers were associated with disease severity (p=0.002, &lt;0.001, respectively). ROC analysis showed that hsCRP possesses a slight advantage (AUC=0.796) over kalirin (ROC=0.717) as a diagnostic marker for PCAD. Conclusions: Serum kalirin and hsCRP levels are associated with PCAD and with the severity of the disease, both markers possess moderate diagnostic capabilities for PCAD with a slight advantage for hsCRP.

Clinical and Coronary Angiographic Insights Into Acute ST-Elevation Myocardial Infarction in Young Patients: A Study From a Tertiary Care Cardiac ICU.

Background This investigation addresses the major effects of early-onset coronary artery disease (CAD) on community health, noting its association with elevated incidences of recurrent ischemic events and mortality. The study specifically explores the contributing factors, clinical symptoms, angiographic findings, and management strategies for individuals aged 45 or younger who experience their initial ST-elevation myocardial infarction (STEMI). Methodology This observational study took place over a six-month period within the cardiology unit, involving 100 sequential patients diagnosed with STEMI. Results With a mean age of 42.5 years, the research had 100 patients, of which nine (9%) were under 25, 24 (24%) were between 26 and 35, and 67 (67%) were over 36. Of these, 89 (89%) were male. The following risk variables were found: obstructive CAD, smoking, being overweight, diabetes, hypertension, chest discomfort, and syncope. In 99 patients (99%), the most prevalent symptom was chest discomfort. Most often impacted was the left anterior descending (LAD) artery in 24 patients (24%), then the right coronary artery in 14 patients (14%). A total of 50 patients (50%) had percutaneous coronary intervention (PCI), with 15 patients (15%) undergoing elective PCI, 10 patients (10%) with pharmaco-invasive PCI, and 20 patients (20%) receiving primary PCI. In eight cases (8%), coronary artery bypass grafting (CABG) was required. Furthermore, 40 patients (40%) were under medical care, and 32 patients (32%) had recanalized and normal coronaries. No mortality was recorded in this study. Conclusions Acute myocardial infarction is most frequently seen in very young adult males, and the most common risk factor is smoking. The most common clinical manifestation, anterior wall myocardial infarction, was caused by the main source of involvement, the LAD artery.

Influence of pseudoxanthoma elasticum on the lipid profile and prognostic implications.

Background: Pseudoxanthoma elasticum (PXE) is a rare, inherited disease characterised by specific skin lesions, progressive loss of vision and early onset atherosclerosis. Atherosclerosis in PXE leads to an increased rate of vascular occlusion and severe intermittent claudication. Although genetically determined, the individual course of PXE is highly variable. Up to now, there is no sufficient parameter to identify individuals at risk of rapid disease progression. This present study focused the lipid profile of patients with PXE and its possible influence on the clinical severity of peripheral artery disease (PAD). Patients and methods: 112 patients with PXE were retrospectively screened. Patients without a complete lipid profile consisting of total cholesterol (TC), triglycerides (TGC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and Lipoprotein(a) (Lp[a]) where excluded as well as patients with already initiated lipid-lowering therapy. 52 patients met the inclusion criteria. An age-adjusted ordinal regression model was applied to determine the association of each lipid fraction with the severity of PAD assessed as Fontaine classification. Results: The lipid profile of patients with PXE was unremarkable (TGC: 135.8±105.8 mg/dl; TC: 172.5±44.4 mg/dl; HDL: 63.0±18.2 mg/dl; Lp[a]: 64.7±93.5 nmol/l). Ordinal regression showed a significant association of Lp(a) with the severity of PAD with an odds ratio of 1.01 (1.00-1.02; p = 0.004), whereas the other fractions of the lipid profile had no significant influence. Conclusions: This study provides the largest evaluation of blood lipids up to now and the first characterization of Lp(a) levels in patients with PXE. We were able to provide first evidence of a correlation between elevated levels of Lp(a) and the severity of PAD. The present results suggest that determination of Lp(a) in early stages of PXE could help to identify patients at risk of rapid disease progression and with the need of intensified walking exercise training.

Joint impact of polygenic risk score and lifestyles on early- and late-onset cardiovascular diseases.

Understanding the interactions between genetic risk and lifestyles on different types and age onsets of cardiovascular disease (CVD) risk can help identify individuals for whom lifestyle changes would be beneficial. Here we developed three polygenic risk scores, called MetaPRSs, for coronary artery disease, ischaemic stroke and intracerebral haemorrhage by combining PRSs for CVD and CVD-related risk factors in 96,400 participants from the prospective China Kadoorie Biobank. Genetic and lifestyle risks were categorized by the disease-specific MetaPRSs and the number of unfavourable lifestyles. High genetic risk and unfavourable lifestyles were found to be more strongly associated with early than late onset of CVD outcomes in men and women. Change from unfavourable to favourable lifestyles resulted in 14.7-, 2.5- and 2.6-fold greater reductions in incidence rates of early-onset coronary artery disease and ischaemic stroke and late-onset coronary artery disease in high than low genetic risk group. Young adults at high genetic risk may have larger benefits in preventing CVD from lifestyle improvements.

Potentials of artificial intelligence in familial hypercholesterolemia: Advances in screening, diagnosis, and risk stratification for early intervention and treatment

Familial hypercholesterolemia (FH) poses a global health challenge due to high incidence rates and underdiagnosis, leading to increased risks of early-onset atherosclerosis and cardiovascular diseases. Early detection and treatment of FH is critical in reducing the risk of cardiovascular events and improving the long-term outcomes and quality of life for affected individuals and their families. Traditional therapeutic approaches revolve around lipid-lowering interventions, yet challenges persist, particularly in accurate and timely diagnosis. The current diagnostic landscape heavily relies on genetic testing of specific LDL-C metabolism genes, often limited to specialized centers. This constraint has led to the adoption of alternative clinical scores for FH diagnosis. However, the rapid advancements in artificial intelligence (AI) and machine learning (ML) present promising solutions to these diagnostic challenges. This review explores the intricacies of FH, highlighting the challenges that are encountered in the diagnosis and management of the disorder. The revolutionary potential of ML, particularly in large-scale population screening, is highlighted. Applications of ML in FH screening, diagnosis, and risk stratification are discussed, showcasing its ability to outperform traditional criteria. However, challenges and ethical considerations, including algorithmic stability, data quality, privacy, and consent issues, are crucial areas that require attention. The review concludes by emphasizing the significant promise of AI and ML in FH management while underscoring the need for ethical and practical vigilance to ensure responsible and effective integration into healthcare practices.

Early-Onset or Premature Coronary Artery Disease.

The aim of this review was to examine the literature regarding younger individuals without classical risk factors for atherosclerosis who develop coronary artery disease (CAD) prematurely at an early age. An extensive literature review was undertaken in Pubmed, Scopus, and Google Scholar regarding early-onset or premature atherosclerosis, CAD, its diagnosis, management, and prophylaxis. There are individuals of both genders, particularly in the younger age group of 20-40 years of age, who lack the traditional/ classical risk factors and still develop CAD and other manifestations of atherosclerosis. Even the 10-year age gap in manifesting CAD that is noted between women and men ascribable to a cardioprotective effect of sex hormones may not be noted under these circumstances. This indicates that the risk profile differs in young patients with non-- classical atherosclerotic risk factors, and factors such as genetics, inflammation, thrombosis, psychosocial, environmental, and other parameters play an important role in atherosclerosis and other mechanisms that lead to CAD in younger individuals. These patients are at risk of major adverse cardiac events, which determine their prognosis. Unfortunately, current major guidelines do not acknowledge that many patients who manifest premature CAD are at high risk, and as a consequence, many of these patients may not be receiving guideline-directed hypolipidemic and other therapies before they present with symptoms of CAD. Caretakers need to be more vigilant in offering efficacious screening and strategies of prevention for early-onset or premature CAD to younger individuals.

Glycoprotein Acetyls Is a Novel Biomarker Predicting Cardiovascular Complications in Rheumatoid Arthritis.

The relationship between rheumatoid arthritis (RA) and early onset atherosclerosis is well depicted, each with an important inflammatory component. Glycoprotein acetyls (GlycA), a novel biomarker of inflammation, may play a role in the manifestation of these two inflammatory conditions. The present study examined a potential mediating role of GlycA within the RA-atherosclerosis relationship to determine whether it accounts for the excess risk of cardiovascular disease over that posed by lipid risk factors. The UK Biobank dataset was acquired to establish associations among RA, atherosclerosis, GlycA, and major lipid factors: total cholesterol (TC), high- and low-density lipoprotein (HDL, LDL) cholesterol, and triglycerides (TGs). Genome-wide association study summary statistics were collected from various resources to perform genetic analyses. Causality among variables was tested using Mendelian Randomization (MR) analysis. Genes of interest were identified using colocalization analysis and gene enrichment analysis. MR results appeared to indicate that the genetic relationship between GlycA and RA and also between RA and atherosclerosis was explained by horizontal pleiotropy (p-value = 0.001 and <0.001, respectively), while GlycA may causally predict atherosclerosis (p-value = 0.017). Colocalization analysis revealed several functionally relevant genes shared between GlycA and all the variables assessed. Two loci were apparent in all relationships tested and included the HLA region as well as SLC22A1. GlycA appears to mediate the RA-atherosclerosis relationship through several possible pathways. GlycA, although pleiotropically related to RA, appears to causally predict atherosclerosis. Thus, GlycA is suggested as a significant factor in the etiology of atherosclerosis development in RA.

Food and Cardiovascular Disease: What to Eat and What Not to Eat

In 2019, the Global Burden of Disease study revealed alarming statistics regarding cardiovascular disease (CVD) in Pakistan. The estimated age-standardized incidence and death rates were 918.18 and 357.88 per 100,000 respectively, surpassing global averages.1 Notably, Pakistan faces unique challenges with a high prevalence of Rheumatic heart disease and early onset coronary artery disease.1&#x0D; The World Health Organization's 2021 factsheet underscores four pivotal modifiable behavioral risk factors for CVD and stroke: unhealthy diet, physical inactivity, tobacco use, and harmful alcohol consumption. These behaviors manifest in individuals as elevated blood pressure, glucose, lipids, and adverse body mass index, exacerbating cardiovascular risk.2 In Pakistan, the consumption of unhealthy foods and excessive calories significantly contributes to adverse cardiometabolic profiles, including obesity and dyslipidemia.2&#x0D; Recent research, such as that by Daruish Mozaffain et al. in "Food is Medicine," advocates for food-based interventions tailored to individual health conditions, ranging from medically tailored meals to nutritional and culinary education.3 However, Pakistani patients with CVD face challenges due to the lack of localized guidelines, educational resources, and accessible nutritionists. Shah et al.'s review underscores the importance of providing clear and culturally relevant dietary guidance for the local population.4&#x0D; Addressing these challenges requires the development of high-quality, culturally sensitive educational materials. These resources should be readily understandable, pictorial, and integrated into both inpatient and outpatient care. Local experts, including dietitians and researchers, can play a crucial role in creating tailored educational content. Figures 1 exemplify the efforts of these experts to provide practical guidance to the Pakistani population.4&#x0D; In conclusion, there is an urgent need for comprehensive, easy-to-understand patient education resources catering to the unique nutritional needs of Pakistani individuals with cardiovascular disease. By addressing these gaps, we can empower patients to make informed dietary choices and improve cardiovascular outcomes.&#x0D; References&#x0D; &#x0D; Samad Z, Hanif B. Cardiovascular Diseases in Pakistan: Imagining a Postpandemic, Postconflict Future. Circulation. 2023;147(17):1261-3.&#x0D; Liaquat A, Javed Q. Current trends of cardiovascular risk determinants in Pakistan. Cureus. 2018;10(10):e3409.&#x0D; Mozaffarian D, Aspry KE, Garfield K, Kris-Etherton P, Seligman H, Velarde GP, et al. “Food Is Medicine” Strategies for Nutrition Security and Cardiometabolic Health Equity: JACC State-of-the-Art Review. J Am Coll Cardiol. 2024;83(8):843-64.&#x0D; Shah SU, Waseem T, Afridi T, Shah MI. Nutritional Needs for Cardiovascular Health in Pakistani Population. Pak Heart J. 2022;55(2):101-13.&#x0D; American Heart Association. Lifestyle Changes for Heart Failure. Accessed on March 30, 2024. Available at: https://www.heart.org/en/health-topics/heart-failure/treatment-options-for-heart-failure/lifestyle-changes-for-heart-failure&#x0D; American Diabetes Association. What superstar foods are good for diabetes? Accessed on March 30, 2024. Available at: https://diabetes.org/food-nutrition/food-and-blood-sugar/diabetes-superstar-foods&#x0D; American Heart Association. The American Heart Association Diet and Lifestyle Recommendations. Accessed on March 30, 2024. Available at: https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/nutrition-basics/aha-diet-and-lifestyle-recommendations&#x0D; American Heart Association. Managing Blood Pressure with a Heart-Healthy Diet. Accessed on March 30, 2024. Available at: https://www.heart.org/en/health-topics/high-blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/managing-blood-pressure-with-a-heart-healthy-diet&#x0D;

Stem cell-derived vessels-on-chip for cardiovascular disease modeling

The metabolic syndrome is accompanied by vascular complications. Human invitro disease models are hence required to better understand vascular dysfunctions and guide clinical therapies. Here, we engineered an open microfluidic vessel-on-chip platform that integrates human pluripotent stem cell-derived endothelial cells (SC-ECs). The open microfluidic design enables seamless integration with state-of-the-art analytical technologies, including single-cell RNA sequencing, proteomics by mass spectrometry, and high-resolution imaging. Beyond previous systems, we report SC-EC maturation by means of barrier formation, arterial toning, and high nitric oxide synthesis levels under gravity-driven flow. Functionally, we corroborate the hallmarks of early-onset atherosclerosis with low sample volumes and cell numbers under flow conditions by determining proteome and secretome changes in SC-ECs stimulated with oxidized low-density lipoprotein and free fatty acids. More broadly, our organ-on-chip platform enables the modeling of patient-specific human endothelial tissue and has the potential to become a general tool for animal-free vascular research.

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.

Could Tumor Necrosis Factor Serve as a Marker for Cardiovascular Risk Factors and Left Ventricular Hypertrophy in Patients with Early-Onset Coronary Artery Disease?

Introduction: Tumor necrosis factor (TNF), a pro-inflammatory cytokine, can be produced by cardiomyocytes, leading to metabolic disorders in the myocardium. The objective of this study was to assess the relationship between plasma levels of the TNF cytokine and the presence of known biochemical and clinical risk factors for cardiovascular disease, along with the parameters of cardiac morphology in patients diagnosed with coronary artery disease (CAD) at a young age. Materials and Methods: The study group included 75 men aged up to 50 years and 25 women aged up to 55 years. The plasma TNF concentration was measured by use of the ELISA assay. Echocardiography and electrocardiographic examinations were performed in all patients. Results: We observed positive correlations for TNF with the BMI ratio, weight, waist and hip circumference. We also found negative correlations for TNF with HDL levels and ApoA concentrations, and positive correlations with the ApoB/ApoA1 ratio, Apo B, IL6, LDL and TG concentrations. These results suggest an association between higher plasma TNF concentrations and components of metabolic syndrome, including dyslipidemia. TNF may be a potential risk factor for impaired diastolic function. Conclusions: While TNF may be useful for diagnosing certain risks in CAD patients, the TNF measurement cannot be used as a surrogate test for echocardiography.

The relationship between early-onset coronary artery disease and familial hypercholesterolemia: a cohort study based on the Hakka population in Meizhou, China.

The low diagnosis and treatment rates of familial hypercholesterolemia (FH) have become a global issue. This study aims to explore the correlation between early-onset coronary artery disease (CAD) and FH in the Hakka population in Meizhou, Guangdong. Clinical data of Hakka patients with early-onset CAD, admitted to the Meizhou People's Hospital from January 2023 to January 2024 were retrospectively analyzed. The patients were categorized into an FH group and a non-FH group. Biochemical indicators, lipid levels, echocardiographic parameters, clinical phenotypes, and genetic typing of early-onset CAD patients in the Hakka population were analyzed for their correlation with FH. A total of 167 Hakka patients with early-onset CAD were included, among whom 22 patients had FH. The FH group showed lower triglyceride (TG) level [1.785 (1.40, 2.10) vs. 2.090 (1.80, 2.30), P = 0.002] and higher levels of total cholesterol (TC) [6.635 (5.60, 7.10) vs. 4.830 (4.00, 5.40), P<0.001], low-density lipoprotein cholesterol (LDL-C) [4.440 (3.90, 5.20) vs. 2.820 (2.40, 3.30), P<0.001], and apolipoprotein B (Apo B) [1.600 (1.30, 1.80) vs. 0.910 (0.70, 1.10), P<0.001]. FH was correlated with TG, TC, LDL-C and Apo B levels (r1 = -0.235; r2 = 0.441; r3 = 0.483; r4 = 0.538). TG is a risk factor while TC, LDL-C and Apo B are protective factors for FH. The incidence of FH is relatively high among early-onset CAD patients in the Hakka population in Meizhou. TG, TC, LDL-C, and Apo B levels are valuable in aiding clinical differential diagnosis of CAD patients with FH.

Association between serum gamma-glutamyltransferase and early-onset coronary artery disease: a retrospective case-control study

BackgroundSerum gamma-glutamyltransferase (GGT) activity has been proposed as a promising predictor of atherosclerosis-related complications and a prognostic marker for cardiovascular diseases. The objective of this study was to investigate the potential correlation between serum levels of GGT and early-onset coronary artery disease (EOCAD).MethodsA retrospective, hospital-based case-control study was conducted, which included 860 patients with EOCAD and gender- and age-matched controls. Serum levels of GGT were measured using the reference measurement procedure on an automatic biochemistry analyser.ResultsThe serum GGT levels of patients with EOCAD (34.90 ± 31.44 U/L) were significantly higher than those of the control group (21.57 ± 16.44 U/L, p < .001). Elevated serum levels of GGT were found to be an independent risk factor for EOCAD, with an odds ratio (OR) of 1.021 (95% confidence interval (CI): 1.014–1.029). Additionally, for every quartile increase in serum GGT levels, the risk of developing EOCAD increased by 1.6-fold. Moreover, serum GGT levels were significantly associated with disease severity, with lower GGT levels observed in patients without significant vascular disease (31.74 ± 24.06 U/L) compared to those with two-vessel disease (33.06 ± 25.00 U/L, p = .002) and three-vessel disease (37.75 ± 36.76 U/L, p = .001).ConclusionsThe results of this study suggest that elevated serum GGT levels are associated with the development of EOCAD, and GGT may be implicated in the pathogenesis of the disease. Further large-scale prospective studies are needed to explore the potential relationship between serum GGT levels and the dynamic development of EOCAD.

Risk factor burden in familial hypercholesterolaemia with early onset coronary artery disease

Abstract Background Familial hypercholesterolaemia (FH) is considered a causal risk factor for premature coronary artery disease (CAD) with a priority placed on identifying index cases and their relatives for preventative interventions. However recent population sequencing studies have identified that not all FH mutation carriers develop CAD. We hypothesised that a significant burden of traditional risk factors is required in addition to genetic risk to develop CAD. Methods We interrogated the clinical registry of patients attending the CVD risk and Lipids clinic at St Bartholomew’s Hospital in London which serves a large multi-ethnic population. Patients were prioritized for genetic testing based on Simon Broome and Dutch Lipid criteria. A second cohort of patients from the clinic consisted of premature CAD patients without phenotypic FH. CAD was defined as &amp;gt; 50% stenosis in an epicardial vessel by invasive or non-invasive imaging. Results We identified 40 patients with genetically confirmed FH and CAD (FH+/CAD+) and 116 people with FH and without CAD (FH+/CAD-). Of 10 traditional risk factors evaluated, prevalence of each was higher in FH +/CAD+ compared to FH+/CAD- patients. Collectively, FH+/ CAD+ patients had a median number of risk factors of 5(4,6) compared to 4(3,5) for FH+/CAD- patients, (P&amp;lt;0.001). In non-FH patients, risk factors burden was higher in those with CAD (FH-/CAD+), compared to those without CAD: 5(4,6) V. 4(3,5) risk factors, respectively(P&amp;lt;0.001). Importantly, in patients who developed CAD, the traditional risk factor burden was greater in FH- patients than that of FH+ patients whereas, the genetic risk burden was greater in FH+ patients (Figure-1). The mean age of onset of CAD in both FH+ and FH- patients was comparable: 43± 10 V. 43± 12years. Patients with FH+/CAD+ were older (53± 11 V 49± 13 years, P=0.276) but had an earlier onset of CAD, when risk burden was greater (43± 8 years if ≥ 5 risk factors v 49± 15 years if &amp;lt; 5 risk factors, P=0.192). Conclusion In a selected population from a large specialist lipid clinic, we demonstrate that traditional risk factor burden is additive to genetic risk for the development and age of onset of CAD, supporting a disease liability threshold model in FH.Figure-1.Risk Burden in FH with CAD

Meta-analysis: increased risk of subclinical atherosclerosis in young women after preeclampsia

Abstract Background Preeclampsia leads to a two-to-eight fold increased risk of developing future cardiovascular disease (CVD). It is vital to identify the subgroup of high-risk women who will ultimately develop CVD. Preeclampsia is characterized by systemic endothelial dysfunction with a hyper inflammatory state. In combination with the pregnancy specific hypercholesteraemic state, this may trigger early onset atherosclerosis which could underlie future development of CVD. Purpose This meta-analysis aims to determine the prevalence of subclinical atherosclerosis at different age intervals, in young women after preeclamptic pregnancies compared to non-preeclamptic pregnancies. Methods A systematic search identified studies reporting prevalence of atherosclerosis. Only studies including a preeclamptic and non-preeclamptic group using CT or ultrasound scan were included. There was no restriction on follow up duration. All subtypes of atherosclerotic plaque in any maternal vessel were included. Quality of articles was assessed by the Newcastle-Ottawa scale. Odds ratios (OR) were calculated with logistic regression as a measure of effect size for the prevalence of any atherosclerotic plaque. The Random effects model pooled odds ratios to produce an overall odds ratio and also stratified data using maternal age and imaged artery. Results Nine studies included 4148 women in total: 1444 (35%) with preeclampsia and 2704 (65%) without preeclampsia. Prevalence of atherosclerosis was higher in women with previous preeclampsia. The overall OR of having atherosclerosis after preeclampsia was 1.67 (95% CI 1.38-2.02) with an I2 of 62%. The odds of atherosclerosis after preeclampsia &amp;lt;40 years of age was 0.64 (0.10-4.32), 40-49 was 1.59 (1.30-1.93) and &amp;gt;50 was 2.67 (1.84-3.89). Conclusion Women with preeclampsia have a significantly increased risk of early-onset atherosclerosis compared to women with healthy pregnancies. This elevated risk starts from 40 years onwards suggestive of accelerated atherosclerosis. Early lifestyle or pharmacological preventive measures should be considered and investigated to reduce CVD burden after preeclamptic pregnancies.Overall resultsTable of odds ratios

Abstract 18666: SR-BI and Tyrosine Kinase Inhibitors: A Novel Pathway for Atherosclerotic Cardiovascular Disease Therapeutic Development

Introduction: Cardiovascular disease (CVD) is the leading cause of death in the U.S., where coronary artery disease (CAD) accounts for 42.1% of all CVD deaths. Current therapeutics focus on lowering LDL-C, as previous attempts to raise HDL-C were not successful in altering CVD outcomes. However, the therapeutic potential of HDL has not been fully explored. Variants in SCARB1, the gene that encodes HDL receptor Scavenger Receptor B1 (SR-BI), are associated with dyslipidemia and atherosclerotic CVD (ASCVD), and we first to identified Mendelian inheritance of SCARB1 variants that cause severe early-onset CAD and dyslipidemia. Limited clinical evidence suggests imatinib reduces total cholesterol in chronic myeloid leukemia (CML). Additionally, TKI treatment in atherosclerotic mice reduced total cholesterol (imatinib) and atherosclerotic lesions (dasatinib). Yet, no data is available on the effects of TKIs on HDL and RCT. Hypothesis: Our findings suggest that HDL function (vs. HDL-C concentration) in reverse cholesterol transport (RCT) may be a promising target for cholesterol-based therapy and studying TKIs in RCT may provide a novel mechanism for therapeutic development. Methods: We performed a high throughput drug screen with 788 FDA-approved compounds, using HepG2 cells to measure endogenous HDL binding. We identified four compounds that significantly increased HDL binding, of which, imatinib was the only one to increase SR-BI. Wildtype C57Bl/6 mice on a high fat, high cholesterol diet, underwent imatinib treatment for 4 weeks and measured biweekly serum lipids. Results: We have found that imatinib and dasatinib significantly enhance HDL binding, where imatinib increased SR-BI, ABCA1, and ABCG1 in vitro. Furthermore, in vivo imatinib treatment decreased plasma total cholesterol, HDL-C and triglyceride levels, and elevated hepatic SR-BI. Knockdown of SR-BI in HepG2 cells ameliorated the imatinib-induced HDL binding increase suggesting an SR-BI-specific mechanism. Mass spectrometry revealed a novel SR-BI methionine oxidation site with imatinib treatment. Conclusions: Our data supports the exploration of TKI-mediated SR-B1 regulation, HDL metabolism, and RCT mechanism to identify new therapeutic targets for dyslipidemia and ASCVD.

Role of the Autism Risk Gene Shank3 in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses.

Increased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. Shank3 plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD development in young adults with ASD. In this study, we investigated whether Shank3 facilitates the development of atherosclerosis. Using Gene Set Enrichment Analysis software (Version No.: GSEA-4.0.3), we analyzed the data obtained from Shank3 knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan's National Health Insurance Research Database), and a Shank3 knockdown cellular model. Shank3 knockout upregulated the expression of genes of cholesterol homeostasis and fatty acid metabolism but downregulated the expression of genes associated with inflammatory responses. Individuals with autism had higher risks of hyperlipidemia (adjusted hazard ratio (aHR): 1.39; p < 0.001), major adverse cardiac events (aHR: 2.67; p < 0.001), and stroke (aHR: 3.55; p < 0.001) than age- and sex-matched individuals without autism did. Shank3 downregulation suppressed tumor necrosis factor-α-induced fatty acid synthase expression; vascular cell adhesion molecule 1 expression; and downstream signaling pathways involving p38, Jun N-terminal kinase, and nuclear factor-κB. Thus, Shank3 may influence the development of early-onset atherosclerosis and CVD in ASD. Furthermore, regulating Shank3 expression may reduce inflammation-related disorders, such as atherosclerosis, by inhibiting tumor necrosis factor-alpha-mediated inflammatory cascades.

Exploration of Hub Genes and Pathogenetic Pathways in Systemic Lupus Erythematosus Complicated with Early Onset Atherosclerosis

Background. Notwithstanding the mounting evidence to suggest that systemic lupus erythematosus (SLE) accelerates the progression of atherosclerosis, the mechanisms underlying this phenomenon are yet to be completely understood. This research examined the molecular mechanism behind this vascular complication. Methods. The Gene Expression Omnibus database was retrieved to acquire the gene expression datasets for SLE (GSE109248) and atherosclerosis (GSE100927). The shared differentially expressed genes (DEGs) of SLE and atherosclerosis were screened with the help of the “limma” package in R software, followed by function enrichment analysis, protein–protein interaction (PPI) network construction, key module analysis, hub gene selection, and coexpression analysis. Results. In GSE109248 and GSE100927, 1195 and 418 DEGs in totals were identified, respectively. Subsequently, we acquired 78 common DEGs (70 upregulated genes and eight downregulated genes) with the same expression trends by using the Venn diagram. Finally, 12 hub genes, including PTPRC, TYROBP, FCGR3A, ITGAX, LCP2, IL1B, IRF8, LILRB2, CD68, C1QB, CCR7, and C1QA were identified by using seven different algorithms in Cytohubba. The functional analysis illustrates that these genes were predominantly enriched in immune and inflammation response, lipid and atherosclerosis, and osteoporosis. These results indicate an important role of SLE in inducing excessive inflammation, which may be medicate by these hub genes and can induce osteoporosis and imbalance of the normal mineral balance in the body as well as lipid abnormalities, which eventually leads to premature onset of atherosclerosis. In total, nine transcription factors (TFs) that may participate in regulating the function of these genes were identified. All hub genes and four TFs were validated successfully. Conclusion. The results of our research show that SLE and atherosclerosis have common DEGs, pathophysiology, and hub genes. These findings can provide fresh evidence and insights into a further investigation into the mechanisms at play.