Early-onset Coronary Artery Disease Research Articles

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.

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
 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
 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
 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
 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.
 References
 
 Samad Z, Hanif B. Cardiovascular Diseases in Pakistan: Imagining a Postpandemic, Postconflict Future. Circulation. 2023;147(17):1261-3.
 Liaquat A, Javed Q. Current trends of cardiovascular risk determinants in Pakistan. Cureus. 2018;10(10):e3409.
 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.
 Shah SU, Waseem T, Afridi T, Shah MI. Nutritional Needs for Cardiovascular Health in Pakistani Population. Pak Heart J. 2022;55(2):101-13.
 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
 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
 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
 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

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.

Peripheral artery disease: an underdiagnosed condition in familial hypercholesterolemia? A systematic review.

Familial hypercholesterolemia (FH) is one of the most common inherited diseases characterized by elevated LDL-cholesterol levels, leading to early-onset atherosclerosis. While the association between FH and coronary and carotid artery disease is well-established, its association with peripheral artery disease (PAD) is less robust. This systematic review aims at exploring existing evidence on PAD prevalence and incidence in FH individuals. A comprehensive search was conducted on MEDLINE and Embase databases, for studies published between January 2013 and December 2023, evaluating prevalence and incidence of PAD in FH patients. Literature reviews, case reports, responses to editors and non-English language articles were excluded. The initial research provided 53 results. After article screening, 28 articles were fully reviewed and 24 were finally included in the analysis. Among these, 19 reported PAD prevalence, while 5 PAD incidence over a mean follow-up time of 8.7 years. PAD prevalence and incidence ranged from 0.3 to 60% and from 0.5 to 4.2% respectively, probably reflecting the heterogeneity in PAD definition criteria. This systematic review sheds light on the limited number of studies on PAD in FH patients. Particularly, considering the potential positive effects of newly available lipid-lowering strategies on PAD outcomes, addressing this research gap is pivotal for a more comprehensive understanding of peripheral vascular manifestations in FH patients and for optimal management of this population.

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.

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.

Triglyceride-glucose index is associated with severe obstructive coronary artery disease and atherosclerotic target lesion failure among young adults

BackgroundEarly diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF).MethodsWe recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC).ResultsAmong the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23–1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03–0.17, p = 0.005). During a medium of 33 month (IQR: 31–34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07–5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01–1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722–0.734, p = 0.04) to predict TLF.ConclusionsTyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.

PB0027 Assessing Genetic Risk Factors for Early-Onset Coronary Artery Disease in Iranians

PB0027 Assessing Genetic Risk Factors for Early-Onset Coronary Artery Disease in Iranians

Assessment of Inflammatory Hematological Ratios (NLR, PLR, MLR, LMR and Monocyte/HDL-Cholesterol Ratio) in Acute Myocardial Infarction and Particularities in Young Patients.

Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such as neutrophils, lymphocytes, monocytes, and macrophages. These cells orchestrate the inflammatory process, a core component in the initiation and progression of atherosclerosis. The activation of these pathways and the subsequent lipid, fibrous element, and calcification accumulation can result in vessel narrowing. Hematological parameters derived from routine blood tests offer insights into the underlying inflammatory state. Recent studies have highlighted the potential of inflammatory hematological ratios, such as the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and lymphocyte/monocyte ratio. These parameters are not only accessible and cost-effective but also mirror the degree of systemic inflammation. Several studies have indicated a correlation between these markers and the severity, prognosis, and presence of CAD. Despite the burgeoning interest in the relationship between inflammatory markers and CAD, there remains a paucity of data exploring these parameters in young patients with acute myocardial infarction. Such data could offer valuable insights into the unique pathophysiology of early-onset CAD and improve risk assessment and predictive strategies.

A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants.

Familial hypercholesterolemia (FH), caused by PCSK9 p.E32K, is characterized by early-onset coronary artery disease. However, the relationship between PCSK9 p.E32K and cerebrovascular disease is unclear. One of our patients with the PCSK9 p.E32K had several intracranial artery stenoses (ICAS). The objective of this case series was to identify factors that may be associated with ICAS in the variant carriers. A 75-year-old Japanese woman with FH carrying PCSK9 p.E32K was found to have 5 asymptomatic ICAS when brain magnetic resonance angiography (MRA) was performed. We retrospectively investigated additional patients with FH who underwent brain MRA at our institution to explore the unknown factors accelerating ICAS. We investigated an additional 5 patients with FH who underwent brain MRA. Of them, only one had mild ICAS. The RNF213 p.R4810K that is an established genetic risk for ICAS, particularly in East Asians, was identified only in the patient with 5 ICAS. PCSK9 and RNF213 play an important role in lipid metabolism and endothelial integrity. Therefore, together, these variants could be involved in the development of multiple ICAS. Our case series indicated that PCSK9 p.E32K carriers should undergo early brain screening to obtain appropriate stroke prevention measures in the asymptomatic stage.

Evolutionary Action-Machine Learning Model Identifies Candidate Genes Associated With Early-Onset Coronary Artery Disease.

Background Coronary artery disease is a primary cause of death around the world, with both genetic and environmental risk factors. Although genome-wide association studies have linked >100 unique loci to its genetic basis, these only explain a fraction of disease heritability. Methods and Results To find additional gene drivers of coronary artery disease, we applied machine learning to quantitative evolutionary information on the impact of coding variants in whole exomes from the Myocardial Infarction Genetics Consortium. Using ensemble-based supervised learning, the Evolutionary Action-Machine Learning framework ranked each gene's ability to classify case and control samples and identified 79 significant associations. These were connected to known risk loci; enriched in cardiovascular processes like lipid metabolism, blood clotting, and inflammation; and enriched for cardiovascular phenotypes in knockout mouse models. Among them, INPP5F and MST1R are examples of potentially novel coronary artery disease risk genes that modulate immune signaling in response to cardiac stress. Conclusions We concluded that machine learning on the functional impact of coding variants, based on a massive amount of evolutionary information, has the power to suggest novel coronary artery disease risk genes for mechanistic and therapeutic discoveries in cardiovascular biology, and should also apply in other complex polygenic diseases.

Risk Factor Burden in Familial Hypercholesterolaemia With Early Onset Coronary Artery Disease

Risk Factor Burden in Familial Hypercholesterolaemia With Early Onset Coronary Artery Disease

Smooth muscle α-actin missense variant promotes atherosclerosis through modulation of intracellular cholesterol in smooth muscle cells.

The variant p.Arg149Cys in ACTA2, which encodes smooth muscle cell (SMC)-specific α-actin, predisposes to thoracic aortic disease and early onset coronary artery disease in individuals without cardiovascular risk factors. This study investigated how this variant drives increased atherosclerosis. Apoe-/- mice with and without the variant were fed a high-fat diet for 12 weeks, followed by evaluation of atherosclerotic plaque formation and single-cell transcriptomics analysis. SMCs explanted from Acta2R149C/+ and wildtype (WT) ascending aortas were used to investigate atherosclerosis-associated SMC phenotypic modulation. Hyperlipidemic Acta2R149C/+Apoe-/- mice have a 2.5-fold increase in atherosclerotic plaque burden compared to Apoe-/- mice with no differences in serum lipid levels. At the cellular level, misfolding of the R149C α-actin activates heat shock factor 1, which increases endogenous cholesterol biosynthesis and intracellular cholesterol levels through increased HMG-CoA reductase (HMG-CoAR) expression and activity. The increased cellular cholesterol in Acta2R149C/+ SMCs induces endoplasmic reticulum stress and activates PERK-ATF4-KLF4 signaling to drive atherosclerosis-associated phenotypic modulation in the absence of exogenous cholesterol, while WT cells require higher levels of exogenous cholesterol to drive phenotypic modulation. Treatment with the HMG-CoAR inhibitor pravastatin successfully reverses the increased atherosclerotic plaque burden in Acta2R149C/+Apoe-/- mice. These data establish a novel mechanism by which a pathogenic missense variant in a smooth muscle-specific contractile protein predisposes to atherosclerosis in individuals without hypercholesterolemia or other risk factors. The results emphasize the role of increased intracellular cholesterol levels in driving SMC phenotypic modulation and atherosclerotic plaque burden.