Familial Coronary Artery Disease Research Articles

Adapting transformer-based language models for heart disease detection and risk factors extraction

Efficiently treating cardiac patients before the onset of a heart attack relies on the precise prediction of heart disease. Identifying and detecting the risk factors for heart disease such as diabetes mellitus, Coronary Artery Disease (CAD), hyperlipidemia, hypertension, smoking, familial CAD history, obesity, and medications is critical for developing effective preventative and management measures. Although Electronic Health Records (EHRs) have emerged as valuable resources for identifying these risk factors, their unstructured format poses challenges for cardiologists in retrieving relevant information. This research proposed employing transfer learning techniques to automatically extract heart disease risk factors from EHRs. Leveraging transfer learning, a deep learning technique has demonstrated a significant performance in various clinical natural language processing (NLP) applications, particularly in heart disease risk prediction. This study explored the application of transformer-based language models, specifically utilizing pre-trained architectures like BERT (Bidirectional Encoder Representations from Transformers), RoBERTa, BioClinicalBERT, XLNet, and BioBERT for heart disease detection and extraction of related risk factors from clinical notes, using the i2b2 dataset. These transformer models are pre-trained on an extensive corpus of medical literature and clinical records to gain a deep understanding of contextualized language representations. Adapted models are then fine-tuned using annotated datasets specific to heart disease, such as the i2b2 dataset, enabling them to learn patterns and relationships within the domain. These models have demonstrated superior performance in extracting semantic information from EHRs, automating high-performance heart disease risk factor identification, and performing downstream NLP tasks within the clinical domain. This study proposed fine-tuned five widely used transformer-based models, namely BERT, RoBERTa, BioClinicalBERT, XLNet, and BioBERT, using the 2014 i2b2 clinical NLP challenge dataset. The fine-tuned models surpass conventional approaches in predicting the presence of heart disease risk factors with impressive accuracy. The RoBERTa model has achieved the highest performance, with micro F1-scores of 94.27%, while the BERT, BioClinicalBERT, XLNet, and BioBERT models have provided competitive performances with micro F1-scores of 93.73%, 94.03%, 93.97%, and 93.99%, respectively. Finally, a simple ensemble of the five transformer-based models has been proposed, which outperformed the most existing methods in heart disease risk fan, achieving a micro F1-Score of 94.26%. This study demonstrated the efficacy of transfer learning using transformer-based models in enhancing risk prediction and facilitating early intervention for heart disease prevention.

Prognostic value of a novel artificial intelligence-based coronary computed tomography angiography-derived ischemia algorithm for patients with suspected coronary artery disease

Abstract Introduction Coronary computed tomography angiography (CCTA) has emerged as the first-line, non-invasive imaging tool to detect coronary artery disease (CAD) in patients with low to intermediate pre-test probability of CAD. However, CCTA cannot directly assess the presence of ischemia, which may lead to further downstream testing. A novel artificial-intelligence (AI)-based algorithm, comprising a machine-learned method that leverages atherosclerosis and vascular morphology features to determine vessel-level coronary ischemia from CCTA images, may be useful in this regard. Purpose We aimed to investigate the prognostic value of the AI-based ischemia algorithm for clinical events among symptomatic patients with suspected CAD referred for CCTA. Methods The AI-based ischemia algorithm was calculated by analysts blinded for patient characteristics and clinical outcomes using CCTA data from patients with suspected CAD who underwent clinically indicated CCTA at a large tertiary care center from February 2007 to December 2016. The primary endpoint was the composite of death, myocardial infarction (MI), and unstable angina pectoris (uAP) throughout a median follow-up of 8.1 years (IQR 6.0-9.6). Secondary endpoints were the association between the AI-based ischemia algorithm and the primary endpoint among patients with no/non-obstructive (i.e. ≤50%) CAD vs. obstructive (i.e. >50% stenosis) CAD in CCTA. Results 1574 patients were evaluated by the AI-based ischemia algorithm and 1540 were analyzable. Patients with positive AI-based ischemia findings (30.4%, n=468) had a significantly higher crude rate of the primary endpoint as compared to patients with negative AI-based ischemia findings (69.6%, n=1072) (HR 2.37, 95% CI 1.80-3.11, p<0.001), driven by higher rates of all endpoint composites (death: HR 1.48, 95% CI 1.13-2.22, p=0.007; MI: HR 5.42, 95% CI 3.10-9.49, p<0.001; uAP: HR 6.76, 95% CI 3.01-15.20, p<0.001). Results were consistent after adjusting for clinical confounders (age, sex, diabetes mellitus, smoking, hypertension, dyslipidemia, BMI>25 kg/m2, CAD family history) (primary endpoint: HR 1.66, 95% CI 1.24-2.22, p=0.001). Positive AI-based ischemia findings were associated with a significantly higher rate of the primary endpoint among patients with no/non-obstructive CAD in CCTA (n=1001/1487) (HR 2.56, 95% CI 1.53-4.27, p<0.001), but not among those with anatomically obstructive CAD in CCTA (n=486/1487) (HR 1.08, 95% CI 0.70-1.66, p=0.715). Conclusions A novel AI-based CCTA-derived ischemia algorithm was associated with a 1.7-fold increased adjusted rate of long-term death, MI, or uAP. This AI-based ischemia algorithm may be helpful to improve risk stratification, especially among patients with normal/non-obstructive CCTA.Kaplan Meier CCTA ≤50% and >50% stenosis

Abstract 12124: GlycA is Associated With Both Coronary Artery Calcium Incidence and Progression: ELSA-Brasil Cohort Analysis

Introduction: GlycA is an emerging systemic inflammatory marker and quantifies N-acetyl glucosamine within the glycan region of acute phase proteins. Elevated levels of GlycA, are associated with a higher risk for coronary artery disease (CAD). There is conflicting evidence on whether GlycA levels can predict subclinical CAD progression in healthy adults. Hypothesis: High GlycA levels can predict subclinical CAD progression in healthy patients. Methods: We included 2,690 participants from the ELSA-Brasil cohort without cardiovascular/chronic inflammatory disease not receiving statin therapy who had GlycA level measured and two interval coronary artery calcium score (CAC) assessments between 2010 through 2018. Multivariable regression models adjusted for demographics, lifestyle, comorbidities, and laboratory parameters were used to assess the consistency of GlycA levels and CAC incidence and progression (Berry definition). CAC incidence required that the first CAC = 0. CAC progression required that the first CAC > 0. Therefore, the presence of CAC incidence and progression were mutually exclusive. Results: The mean age of participants was 48.6 ± 7.7 years, 56.7% were female, 54.6% and 16.1% (429/2690) were White and Black, respectively. The mean CAC interscan period was 5.1 ± 0.9 years, the mean GlycA level was 414.7 ± 65 μmol/L, and the incidence of CAC was 13.1%. GlycA level odds ratio (OR) for CAC incidence was 1.002 (95% CI 1.0005-1.005, p = .016) adjusted for demographics, lifestyle, early (≤60 years) CAD family history, lipid panel, and comorbidities. The GlycA (≤p25 vs >p75) OR for CAC progression (Berry definition) was 1.77 (95% CI 1.07-2.96, p = .03) in a similar multivariable adjustment model. Conclusions: Higher GlycA levels were associated with CAC incidence and progression even after adjusting for multivariable risk factors in a healthy Brazilian cohort. GlycA may have potential to further stratify CAD risk in healthy patients.

Induced myocardial ischemia in candidates to liver transplantation without evidence of heart disease

Background Coronary artery disease (CAD) is associated with perioperative liver transplantation (LT) mortality. In absence of a defined risk algorithm, we aimed to test whether stress echocardiography and coronary computed tomography angiography (CCTA) could detect CAD in end-stage liver disease (ESLD) patients without previous evidence of heart disease. Methods LT candidates ≥30 years underwent a cardiovascular (CV) assessment through stress echocardiography. CCTA was performed in patients ≥50 years with two or more CV risk factors (e.g. diabetes, CAD family history, dyslipidaemia). Coronary angiography (CAG) was scheduled when stress echocardiography and/or CCTA were positive. Sensibility, specificity, positive and negative predictive values of stress echocardiography and CCTA were assessed by numbers of coronary revascularization (true positives) and lack of acute coronary events over a mean follow-up of 3 years (true negatives). Results Stress echocardiography was performed in 273 patients, CCTA in 34 and CAG in 41. Eight patients had critical coronary lesions, and 19 not-critical lesions. Sensitivity, specificity, positive and negative predictive values were 50.0%, 90.2%, 13.3% and 98.4% for stress echocardiography and 100%, 76.7%, 36.4% and 100% for CCTA. Among 163 patients who underwent LT (57.6%), 16 died and 5 had major adverse CV events over a mean follow-up of 3 years. Conclusions A very low prevalence of CAD in a selected population of ESLD at intermediate to high CV risk was found. A screening based on stress echocardiography and CCTA resulted in low incidence of post-LT acute coronary events in ELSD patients. CAD has no impact on mid-term survival.

Association between inflammation, body mass index, and long-term outcomes in patients after percutaneous coronary intervention: A large cohort study.

Association between inflammation, body mass index, and long-term outcomes in patients after percutaneous coronary intervention: A large cohort study.

Ailesel Koroner Arter Hastalığına Yatkınlıkta Güçlü Adaylar PON1, ITGB3 ve CYP3A4 Genlerinin Hastalıkla İlişkisi ve Haplotip Analizi

Objective: Genetic predisposition is very common among the patients with coronary artery disease (CAD), a complex and multifactorial disease. Our objective was to determine the possible association between the most remarkable functional variants in the paraoxonase 1(PON1), cytochrome P450 3A4 (CYP3A4), integrin subunit beta 3 (ITGB3) genes and familial CAD. Materials and Methods: We included 117 patients diagnosed with familial CAD and 99 healthy subjects with no family history of CAD. PON1 Q192R, PON1 L55M, CYP3A4*1G and ITGB3 L33P single nucleotide polymorphisms were genotyped using the Sequenom MassARRAY system. Results: Comparison of genotype and allele frequencies in inheritance models of polymorphisms between the patient and control groups did not reveal any significant findings related to CAD. Stratified analysis by gender did also not display any association both in females and males. There was no significant difference in the frequencies of the haplotypes of the PON1 Q192R and L55M polymorphisms between the groups. Conclusions: Our findings confirmed previous studies that did not consider PON1, CYP3A4 and ITGB3 genes as risk loci. The fact that our study was conducted only in patients with familial CAD shows the originality and importance of our results.

Les résultats immédiats, à moyen et à long terme de l'angioplastie coronaire par stent actif très long : à propos d'une étude multicentrique observationnelle

IntroductionVery long coronary lesions account for 20% of coronary stenoses in the real world. There are few data on the effectiveness of angioplasty of these lesions with very long active stents (DES) in the literature. We conducted this study to assess the long-term outcomes of angioplasty with DES length ≥ 40 mm in a population with multiple cardiovascular risk factors. Patients and methodsThis is a retrospective, multicenter, descriptive, and prognostic study, conducted between January 2015 and January 2020, in four Tunisian centers, including all patients who underwent angioplasty with a DES of length ≥ 40 mm with a follow-up of at least one year. The primary outcome was a combined criteria (major cardiovascular and Cerebral events: MACCE) (stroke, acute coronary syndrome, revascularization of the target lesion: TLR, cardiovascular death: CVD). ResultsWe included 480 procedures. More than half of the patients had at least three risk factors. The prevalence of high blood pressure, diabetes and smoking were 61.1%, 56.6% and 60.4%, respectively. The treated lesions were complex: 23.54% calcified lesions, 8.75% chronic occlusions, 25% bifurcation lesions and 12.08% ostial lesions. The average length of the stents was 47.72 mm. We noted 17 cases of per-procedural complications (3.55%). The median follow-up was 35 months (extremes 1–60 months). The rate of stent thrombosis was 0.83%. The incidence of MACCE, TLR and CVD were respectively 16.25%, 8.12% and 5.2%. In multivariate analysis, diabetes (HR = 1.7, 95% CI [1.01–2.9]), dyslipidemia (HR = 2.08, 95% CI [1.3–3.3]), familial coronary artery disease (HR = 1.9, 95% CI [1.01–3.6]), left ventricle dysfunction (HR = 2.07, 95% CI [1.1–3.6]) and bifurcation lesions (HR = 1.9, 95% CI [1.2–3.14]) were the independent predictors of MACCE, while statin intake (HR = 0.38, 95% CI [0.19–0.78]) was a protective factor. ConclusionAngioplasty with very long DES is associated with low levels of MACCE, TLR, stent thrombosis and CVD in our population. Therefore, it could be an interesting alternative to cardiac surgery. Randomized comparative studies of the two treatment options are needed.

P343 VALIDATION OF ESC 2014 GUIDELINES PROTOCOL FOR CORONARY ARTERY DISEASE DETECTION IN PATIENTS CANDIDATES TO LIVER TRANSPLANTATION

Abstract Introduction Orthotopic liver transplantation (OLT) is the only effective treatment in patients with end–stage liver disease. Coronary artery disease (CAD) is associated with increased peri–operative OLT mortality. Thus, identification of CAD is crucial in pre–OLT evaluation. There is not a specific pre–OLT accepted diagnostic algorithm for CAD detection. 2014 ESC guidelines for non–cardiac surgery management consider OLT as a high–risk abdominal surgery and only patients with CAD history, suspected symptoms and low exercise capacity are invited to undergo to specific functional exams such as stress–echo. Purpose of the present study was to compare the ESC protocol with our cardiologic pre–OLT protocol, in which tests of ischemia and coronary CT are largely administered on based on presence of risk factors. Methods. From 2014 to 2021 all OLT candidates have been evaluated by visit, electrocardiography, rest and, when possible, stress echocardiography. In subject aged > 50 years with diabetes and/or two or more of the following risk factors: smoking, CAD family history, peripheral vascular disease, CT was performed. CGF was scheduled when CAD history and typical symptoms of angina. We theoretically re–analyse our database in order to consider the potential destiny of each patient in case of application of ECS 2014 protocol. We were able to calculate the differences in the number of potentially loss CAD diagnosis. Results. 367 patients (58.2%, age 57±5.7 years, males 74%) underwent OLT. Stress Echo was performed in 239 (65.1%) and positivity was found in 24 pz (6,5%). Coronary CT was performed in 95 (25,8%). CGF was performed in 75 patients (20.1%), 38 (9,2%) directly for known CAD and/or symptoms. Critical coronary lesions were found in 12 patients (3,2 %): 7 revascularized by PTCA, 1 by CABG and 4 medically managed, 25 patients had non critical lesions (7.8%), 31 patients (9.6%) referred to CGF were subsequently removed by transplant list, whereas OLT was successfully performed in PTCA patients (n = 8). During follow–up (35±20 months) 28 patients died (14.2%), 5 with symptoms of congestive heart failure, but no ischemic events were observed. Conclusions CAD detectionis remains a clinical challenge in candidates to OLT. The large number of normal stress echoes and normal CGF, even in presence of cardiovascular risk factors, demonstrates that CAD prevalence in ESLD is no higher than in general population, but a gold method to detect CAD is still unclear.

Relationship between Expression of Plasma lncRNA-HEIH and Prognosis in Patients with Coronary Artery Disease.

Objective We aimed to investigate the expression of long noncoding RNA- (lncRNA-) HEIH in patients with coronary artery disease (CAD) and its impact on patients' prognosis. Patients and Methods. From July 2015 to December 2018, 250 patients who underwent coronary angiography, including 50 in the control group and 150 in the CAD group, were collected for detection of the expression of lncRNA-HEIH by real-time quantitative polymerase chain reaction (qPCR). The severity of CAD was evaluated through SYNTAX scoring system. In addition, these patients with CAD were followed up for 3 years, and the major cardiac adverse events such as myocardial infarction and revascularization were recorded. Results The expression of lncRNA-HEIH in plasma of patients with CAD was remarkably higher than that in the control subjects and was verified to be relevant to the severity of CAD. Meanwhile, it was found that CAD patients with high expression of lncRNA-HEIH had higher rates of dyslipidemia as well as CAD family history and higher overall incidence of major cardiac adverse events than those with low expression of lncRNA-HEIH. Conclusions lncRNA-HEIH expression is upregulated in the plasma of CAD patients, which is capable of affecting the prognosis of patients.

Erectile Dysfunction in Men Burdened with the Familial Occurrence of Coronary Artery Disease.

Erectile dysfunction (ED) and coronary artery disease (CAD) share common risk factors, some of which have genetic backgrounds, while others may be stimulated by family lifestyle. We investigated the impact of the familial occurrence of CAD on the presence of ED and the presence of classic risk factors for ED in men with CAD. This cross-sectional observational study involved 751 men with CAD who were subjected to cardiac rehabilitation. Overall, 75.63% of the men had ED. CAD was diagnosed in 39.28% of the studied men’s relatives. ED was less frequent in the men with familial CAD than in those without (71.53% vs. 78.29%). Similar relations were observed for the presence of CAD in parents (70.43% vs. 78.34%) and the father (69.95% vs. 77.46%). The International Index of Erectile Function 5 score was significantly higher in patients with familial CAD (median (interquartile range); 17 (12–22) vs. 16 (10–21); p = 0.0118), in parents (18 (12–22) vs. 16 (10–20); p = 0.021), and in the father (18 (12–22) vs. 16 (10–21); p = 0.0499). Age and education minimized the effect of familial CAD. Familial CAD increased the incidence of hypertension, dyslipidemia, and smoking but not sedentary lifestyle. Despite the higher prevalence of selected risk factors for ED in men with familial CAD, a higher incidence of ED was not observed.

Myocardial infarction in young adults: are the risk profile and mortality outcomes different from older patients?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The incidence of acute myocardial infarction (AMI) among young patients is increasing. The YOUNG-MI Registry reported that those under 40 years had similar risk profiles and outcomes compared to those aged 41 to 50. We aimed to evaluate cardiovascular risk factors and mortality outcomes in two age cohorts from southern European. Methods We retrospectively evaluated 4758 patients admitted to our coronary intensive care unit between 2004 and 2017 with AMI. We only included patients <60 years in two subgroups: cohort A < 50 years and cohort B 50-60 years. Results From the 1233 patients included (mean age 50.5 ± 6.5 years, 82.2% male), 53% had STEMI. Cohort B had higher rates of hypertension (59.8 vs. 42.9%, p < 0.001), diabetes (41.8 vs. 28.9%, p < 0.001), and dyslipidemia (59.4 vs. 46.4%, p < 0.001), while cohort A had higher rates of familial premature coronary artery disease (20.9 vs. 13.2%, p < 0.001) and smoking habits (54.4 vs. 40.0%, p < 0.001). Regarding coronary angiography, cohort B had higher rates of obstructive disease in each epicardial artery, except for left main involvement and non-obstructive disease (Fig. 1). Cohort A had lower all-cause mortality rates at the index hospitalization (1.3 vs. 3.2%, p = 0.045), 6-months (2.9 vs.5.4, p = 0.038), 1-year (3.1 vs. 6.3%, p = 0.014), and 3-years (3.6 vs 8.4, p = 0.001). After multivariable adjustment, we found no relationship between age cohorts and all-cause mortality for any follow-up timing: HR 1.57 (95% CI 0.56-4.37), 1.37 (95% CI 0.50-3.74), and 0.92 (95% CI 0.35-2.39) at 6-months, 1-year, and 3-years, respectively. Conclusion Among patients who suffer AMI, those under 50 years old have a different risk profile, compared to the 50-60 years cohort. However, there is no significant difference in all-cause mortality. Abstract Figure.

Rationale, design, and baseline characteristics of Chinese registry in early detection and risk stratification of coronary plaques (C-STRAT) study.

Rationale, design, and baseline characteristics of Chinese registry in early detection and risk stratification of coronary plaques (C-STRAT) study.

Chest pain in Brugada syndrome: Prevalence, correlations, and prognosis role

Brugada syndrome (BrS) is sometimes diagnosed because of chest pain. Prevalence and characteristics of such BrS patients are unknown. A total of 200 BrS probands were retrospectively included. BrS diagnosis made because of chest pain (n=34, 17%) was compared to the other ones. BrS probands with diagnosis because of chest pain had significantly more often smoker habits, increased body mass index, and familial history of coronary artery disease but less frequently previous resuscitated sudden death/syncope or atrial fibrillation. Presence of coronary spasm and familial coronary artery disease were independently associated with BrS diagnosed because of chest pain. They presented more often with spontaneous type 1 ST elevation (59%vs 26%, P=.0004) and higher ST elevation during the episode of chest pain compared to other patients or compared to baseline electrocardiogram after chest pain resumption. ST elevation during chest pain was lower compared to ajmaline test. A total of 20% of them had significant coronary artery disease and four (11%) had coronary spasm, and they experienced more often recurrent chest pain episodes (24%vs 5%, P=.0002). Presence of chest pain at BrS diagnosis was not correlated to future arrhythmic events in univariate analysis. Only previous sudden cardiac death (SD)/syncope and familial SD were still significantly associated with outcome in multivariate analysis. Chest pain is a common cause for BrS diagnosis, although major part is not apparently explained by ischemic heart disease. Mechanisms leading to chest main remain unknown in the other ones. ST elevation is higher in this situation but does not seem to carry poor prognosis.

761 Waist Circumference as a Metabolic Risk Factor Improves Prediction of Subclinical Atherosclerosis in Non-Diabetics with Familial Coronary Artery Disease

Recent evidence that elevated Triglycerides (TG) and HDL cholesterol increase cardiovascular (CVD) risk in familial premature CAD (F-PCAD) is not evident in standard risk tools. We evaluated whether metabolic risk factors predict coronary artery calcium (CAC) in non-diabetic, primary prevention pts with history of F-PCAD. 1005 asymptomatic, low-intermediate risk, non-diabetic and statin-naïve individuals with F-PCAD underwent risk factor assessment and CAC. 5-year predicted Australian CVD risk (ACVDR), BMI, Triglycerides and waist circumference were analysed as continuous variables and HDL (mmol/L) was categorised as high (≥2.0), low (≤1.0) or normal (1-2). Multivariable logistic regression was performed for high CAC (>100) and linear regression was for log-transformed CAC scores. 456 and 148 participants had CAC >0 (median CAC 41, IQR 8-121) or ≥100 respectively. High TG (>2mmol/L) was present in 104 (10%), waist circumference >102 cm in 388 (39%) and high HDL in 131 (13%). Higher ACVDR and waist circumference were associated with greater CAC on linear and logistic regression. Neither low nor high HDL was associated with greater CAC. In a non-diabetic population only ACVDR and waist circumference predicted higher CAC scores. HDL and TG were not associated with subclinical CAC.Table 1Association of metabolic risk factors with CAC score.Metabolic Risk FactorLogistic Regression CCS≥100;Coef. (95% CI)Linear RegressionLog(CAC + 1)Betap-valueACVDR0.19 (0.15, 0.25)0.23<0.01Triglycerides-0.08 (-0.37, 0.19)-0.250.01Waist circum.<0.01 (-0.00, 0.01)0.01<0.01HDL-<1-0.16 (-0.94, 0.54)-0.400.88REF: 1-2 mmol/L--≥20.28 (-0.34, 0.84)0.230.21 Open table in a new tab

P650Lipopolysaccharide-nuclear factor-kappa B pathway and lipoprotein apheresis effects in patients with familial hypercholesterolemia and coronary artery disease

Abstract Abstract Background Inflammation may play an important role in atherosclerosis in familial hypercholesterolemia (FH). Lipopolysaccharide (LPS)-nuclear factor-kappa B (NF-κB) pathway is a routine signal process activated in inflammatory status. Purpose This study aimed to examine the LPS-NF-κB axis status and the impact of lipoprotein apheresis (LA) on this pathway in patients with FH and coronary artery disease (CAD). Methods In this matched case-control study a genetically diagnosed FH cohort who presented stable CAD (n=63) was compared with 63 non-FH CAD and 63 non-FH non-CAD controls matched by sex and age. Plasma LPS levels and NF-κB activity were compared among the three groups. In addition, we studied in vitro LPS-induced interleukin-6 (IL-6) production by mononuclear cells from 16 FH cases without previous statin use and compared them with their respective matched control groups. Subsequently, these 16 FH patients underwent LA. Blood samples were taken immediately before and regularly after LA for measuring LPS and NF-κB. Results FH plus CAD had higher LPS levels and NF-κB activity than CAD and non-CAD controls (all p values &lt;0.01). LPS-induced IL-6 production by mononuclear cells of FH plus CAD was also much higher compared with CAD and non-CAD controls (both p values &lt;0.01). Moreover, plasma LPS levels (p&lt;0.001) and NF-κB activity (p&lt;0.01) were dramatically reduced after apheresis in FH patients. Conclusion Genetically confirmed FH patients with CAD had a marked activation of LPS-NF-κB axis, while LA significantly attenuated this key inflammatory pathway, suggesting that inflammation may be an important therapeutic target for FH patients.

Evaluation of Genome in Early Familial Coronary Artery Disease: A Case Report

Evaluation of Genome in Early Familial Coronary Artery Disease: A Case Report

Association of genetic variants previously implicated in coronary artery disease with age at onset of coronary artery disease requiring revascularizations.

BackgroundThe relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography.Methods1599 individuals (mean age 64 years [min-max 29–96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010–2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies.ResultsSelf-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively.ConclusionsYoung individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a “missing heritability” in early-onset CAD warrants more research.

Arginase-1 Variants and the Risk of Familial Coronary Artery Disease in Subjects Originating from Pakistan.

Genetic polymorphisms in the human arginase-1 (ARG1) gene locus and their effects on cardiovascular disease have not been thoroughly elucidated. The aim of the present study was to investigate the association of the variant ARG1 alleles rs2781666 and rs2781667 with coronary artery disease (CAD). ARG1 rs2781666G/T and rs2781667C/T polymorphisms were characterized in a case-control study consisting of 200 complex Pakistani families with CAD history. Heritability of susceptibility/variant alleles was investigated from parent-offspring trios in these families. Determination of serum liped levels was performed spectrophotometrically, while serum arginase-1 activity and the concentrations of nitric oxide metabolites were detected by enzyme colorimetric assay. Genotyping of the two polymorphic sites in the ARG1 gene was performed using polymerase chain reaction and restriction analysis. A significant increase in arginase-1 activity was observed in CAD patients compared with controls (p < 0.0001). Arginase-1 was negatively correlated with serum nitrite and nitrate (r = -0.8137 and r = -0.8444, respectively). There was a significant difference in distribution of genotypes for rs2781666 and rs2781667 polymorphisms between patients and controls (p < 0.001 for each). Similarly, the variant T allele at both loci showed a significant association with the disease compared with subjects free of CAD (p < 0.0001 for each). The transmission-disequilibrium test revealed a significant association of rs2781666 and rs2781667 polymorphisms with CAD (p < 0.0001 for each). This report is the first to describe arginase-1 activity and an association between ARG1 gene polymorphisms and familial CAD from Pakistan.

Abstract 387: Apolipoprotein E Receptor-2 Restricts Cardiomyocyte Proliferation and Controls Heart Size

Introduction: Apolipoprotein E receptor 2 (ApoER2) is highly expressed in brain and testes, but also in macrophages, endothelial and vascular smooth muscle cells, as well as heart. Importantly, genome-wide association studies have linked polymorphisms in the LRP8 gene to familial and premature coronary artery disease (CAD) and myocardial infarction (MI). However, the mechanisms by which ApoER2, the protein encoded by the LRP8 gene, affect CAD and MI are incompletely understood. Hypothesis: The goal of the current study was to examine the function of ApoER2 in the heart. Methods and Results: Morphological analysis revealed an increase in heart size and cross-sectional area with elevated cardiomyocyte proliferation in mice deficient for ApoER2 compared to wild-type control mice. Echocardiography showed a significant increase in left ventricular diameter in ApoER2 KO mice, while no significant differences in fractional shortening and ejection fraction were observed. Loss of ApoER2 attenuated expression of Disabled-2 (Dab2) and Axin2, thereby preventing formation of the destruction complex, resulting in increased levels of β-catenin. Consistent with previous studies that demonstrated that stabilized β-catenin alters expression of the T-box protein Tbx20, ApoER2 deficiency was associated with increased Tbx20 expression, a transcription factor necessary and sufficient to promote cardiomyocyte proliferation. Conclusions: Together, these data indicate that ApoER2 promotes β-catenin degradation and modulates Tbx20 expression to restrain cardiomyocyte proliferation and heart size, providing a mechanism by which ApoER2 dysfunction may contribute to premature CAD and MI.

All-Cause Mortality for Life Insurance Applicants with a Family History of Coronary Artery Disease Before 60.

-To determine the all-cause mortality of life insurance applicants having a family history of coronary artery disease (CAD) before age 60. -Epidemiological studies have shown that a family history of premature CAD is an independent risk factor for CAD events. The strength of the association between family history and CAD is greatest with earlier age of presentation of CAD in the family member and when multiple family members are affected. Despite earlier insurance studies on this relationship, there is sparse current data on the association between family history of CAD and all-cause mortality in life insurance applicants. -Life insurance applicants with reported family history of Coronary Artery Disease (CAD) were extracted from data covering United States residents between October 2009 and October 2016. Information about these applicants was matched to the Social Security Death Master (SSDMF) file for deaths occurring from 2009 to 2012 and to another commercially available death source file (Other Death Source, ODS) for deaths occurring from 2009 to 2016 to determine vital status. Actual to Expected (A/E) mortality ratios were calculated using the Society of Actuaries 2015 Valuation Basic Table (2015VBT), select and ultimate table (age last birthday). All expected bases were not smoker distinct. Confidence bands around these mortality ratios were calculated. The variables of interest were applicant age, gender, number of family members with CAD before age 60, and the presence of cardiac or cardiovascular conditions. -Overall, the mortality of applicants with family members with a history of CAD before age 60 was slightly lower than expected mortality based on the 2015 VBT. Applicants with a cardiac or cardiovascular comorbid condition had a significantly higher mortality ratio. For applicants aged 25-54 and 65-75 with cardiac comorbid conditions, the mortality ratio was 2 times that of those without a cardiac comorbid condition. For those aged 55-64 with cardiovascular comorbid conditions, the mortality ratio was 2.9 times that of those without a cardiovascular comorbid condition. Females had a slightly higher mortality ratio for all age groups, number of family members with CAD before age 60, and cardiovascular conditions. -A family history of CAD before the age of 60 in an insurance applicant may be associated with increased all-cause mortality. Overall in this study, life insurance applicants had a mortality slightly lower than the expected mortality based on the 2015 VBT. However, applicants with a positive family history and a cardiac or cardiovascular comorbid condition had a significantly higher mortality ratio.