Early-onset Myocardial Infarction Research Articles

Modifiable risk factors and risk of myocardial infarction in offspring with parental disease.

Children of patients with early-onset myocardial infarction (MI) are at increased risk, but the importance of concordant versus discordant parent-offspring risk factor profiles on MI risk is largely unknown. We quantified the long-term absolute risk of MI according to shared risk factors in adulthood. We sampled data on familial predisposed offspring and their parents from the Framingham Heart Study. Early MI was defined as a history of parental MI onset before age 55 in men or 65 in women. Individuals were matched 3:1 with non-predisposed offspring. Cardiovascular risk factors included obesity, smoking, hypertension, high cholesterol, and diabetes. We estimated the absolute 20-year incidence of MI using the Aalen-Johansen estimator. At age 40, the 20-year risk of MI varied by cholesterol level (high cholesterol 25.7% [95% confidence interval 11.2%; 40.2%] vs. non-high cholesterol 3.4% [0.5; 6.4]) among predisposed individuals and this difference was greater than in controls (high cholesterol 9.3% [1.5; 17.0] vs. non-high cholesterol 2.5% [1.1; 3.8]). Similar results were observed for prevalent hypertension (26.7% [10.8; 42.5] vs. 4.0% [0.9; 7.1] in predisposed vs. 10.8% [3.2; 18.3] and 2.1% [0.8; 3.4] in controls). Among offspring without risk factors, parental risk factors carried a residual impact on 20-year MI risk in offspring (0% [0; 11.6] for 0-1 parental risk factors versus 3.3% [0; 9.8] for ≥2 parent risk factors at age 40, versus 2.9% [0; 8.4] and 8.5% [0; 19.8] at age 50 years). Children of patients with early-onset MI have low absolute risks of MI in the absence of midlife cardiovascular risk factors, especially if the parent also had a low risk factor burden prior to MI.

LDL-C rebound after long-term evolocumab treatment and intravascular imaging evidence in a familial hypercholesterolemia patient with early-onset myocardial infarction.

LDL-C rebound after long-term evolocumab treatment and intravascular imaging evidence in a familial hypercholesterolemia patient with early-onset myocardial infarction.

Genetic Overlap of Spontaneous Dissection of Either the Thoracic Aorta or the Coronary Arteries

Ascending thoracic aortic dissection (ATAD) is a well-known vascular cause of sudden death. Spontaneous coronary artery dissections (SCAD) are emerging as an important cause of early-onset myocardial infarction and sudden death. Genetic variants in multiple connective tissue genes have been recognized to underlie ATAD; other genetic variants have similarly been recognized to underlie SCAD. Little data are available regarding any genetic commonality between ATAD and SCAD. Our objective is to determine and characterize any genetic overlap between genes coding for ATAD and SCAD. We identified and reviewed 17 retrospective and prospective genetic studies of thoracic aortic dissection and SCAD published between 2016 and 2022 identified through PubMed and Orbis. Articles highlighting the significant plausible triggers for ATAD or SCAD individually were analyzed. No previous study reviewed both ATAD and SCAD genetics together. Separate lists of causative genes were constructed for ATAD and SCAD-and then commonalities were sought. A Venn diagram was constructed to display the genetic overlap and common physiologic pathways involved. We identified a definite, meaningful overlap of 15 independent genes based on a genome-wide association study or other genetic methods. The associated genetic pathways involved various biologic processes including elastin degradation, smooth muscle cell function, and the TGFβ-pathway. The overlapping genes included the following: COL3A1, TGFB2, SMAD3, MYLK, TGFBR2, TGFBR1, LOX, FBN1, NOTCH1, ELN, COL5A1, COL5A2, COL1A2, MYH11, and TLN1. The corresponding molecular pathways were investigated and correlated for both diseases. We are not aware of other studies searching for genetic commonalities between ATAD and SCAD. We have successfully identified overlapping genes-and their corresponding molecular pathways-for ATAD and SCAD. We hope that these insights will lead to further clinical and scientific understanding of each disease through study of their fundamental commonalities.

G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction.

Beyond the influence of lifestyle-related risk factors for myocardial infarction (MI), the mechanisms of genetic predispositions for MI remain unclear. We sought to identify and characterize differentially expressed genes in early-onset MI in a translational approach. In an observational case−control study, transcriptomes from 112 early-onset MI individuals showed upregulated G protein-coupled receptor 15 (GPR15) expression in peripheral blood mononuclear cells compared to controls (fold change = 1.4, p = 1.87 × 10−7). GPR15 expression correlated with intima-media thickness (β = 0.8498, p = 0.111), C-reactive protein (β = 0.2238, p = 0.0052), ejection fraction (β = −0.9991, p = 0.0281) and smoking (β = 0.7259, p = 2.79 × 10−10). The relation between smoking and MI was diminished after the inclusion of GPR15 expression as mediator in mediation analysis (from 1.27 (p = 1.9 × 10−5) to 0.46 (p = 0.21)). The DNA methylation of two GPR15 sites was 1%/5% lower in early-onset MI individuals versus controls (p = 2.37 × 10−6/p = 0.0123), with site CpG3.98251219 significantly predicting risk for incident MI (hazard ratio = 0.992, p = 0.0177). The nucleotide polymorphism rs2230344 (C/T) within GPR15 was associated with early-onset MI (odds ratio = 3.61, p = 0.044). Experimental validation showed 6.3-fold increased Gpr15 expression in an ischemic mouse model (p < 0.05) and 4-fold increased Gpr15 expression in cardiomyocytes under ischemic stress (p < 0.001). After the induction of MI, Gpr15gfp/gfp mice showed lower survival (p = 0.042) and deregulated gene expression for response to hypoxia and signaling pathways. Using a translational approach, our data provide evidence that GPR15 is linked to cardiovascular diseases, mediating the adverse effects of smoking.

Abstract 11587: Intriguing Genetic Overlap Between SCAD and TAD

Importance: Thoracic aortic dissections (TAD) are a well-known vascular cause of sudden death. Spontaneous coronary artery dissections (SCAD) are emerging as an important cause of early-onset myocardial infarction and sudden death. Genetic variants in multiple connective tissue genes have been recognized to underlie TAD; other genetic variants have similarly been recognized to underlie SCAD. Little data is available regarding any genetic commonality between TAD and SCAD. Objective: To determine any genetic overlap between genes coding for TAD and SCAD. Methods: Extensive review of 17 various retrospective and prospective clinical studies published between 2016 and 2022 exploring genetic studies of TAD and SCAD was performed using PubMed and Orbis. Articles highlighting the significant plausible triggers for TAD or SCAD were analyzed. Separate lists of causative genes were constructed for TAD and SCAD—and then commonalities sought. A Venn diagram was constructed to display the genetic overlap and common physiological pathways involved. Results: We identified a definite, meaningful overlap of fourteen independent genes based on GWAS or other genetic methods. Associated genetic pathways involved various biological processes including: Elastin degradation, smooth muscle cell function and the TGF-pathway. Overlapping genes included the following: COL3A1, TGFB2, SMAD3, MYLK, TGFBR2, TGFBR1, LOX, FBN1, NOTCH1, ELN, COL5A1, COL5A2, COL1A2, MYH11. Corresponding molecular pathways were investigated and correlated for both diseases. Conclusions and relevance: We are not aware of other studies searching for genetic commonalities between TAD and SCAD. We have successfully identified overlapping genes—and their corresponding molecular pathways—for TAD and SCAD. We hope these insights will lead to further clinical and scientific understanding of each disease via study of their fundamental commonalities.

Association of metabolic comorbidity with myocardial infarction in individuals with a family history of cardiovascular disease: a prospective cohort study

BackgroundThe association between metabolic comorbidity and myocardial infarction (MI) among individuals with a family history of cardiovascular disease (CVD) is yet to be elucidated. We aimed to examine the combined effects of metabolic comorbidities, including diabetes mellitus, hypertension, and dyslipidemia, with a family history of CVD in first-degree on the risk of incident MI.MethodsThis cohort study consisted of 81,803 participants aged 40–89 years without a previous history of MI at baseline from the Korean Genome and Epidemiology Study. We performed Cox proportional hazard regression analysis to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for MI and early-onset MI risk associated with metabolic comorbidity in individuals with a family history of CVD.ResultsDuring a median follow-up of 5 years, 1,075 and 479 cases of total and early-onset MI were reported, respectively. According to the disease score, among individuals who had a positive family history of CVD, the HRs for MI were 1.92 (95% CI: 1.47–2.51) in individuals with one disease, 2.75 (95% CI: 2.09–3.61) in those with two diseases, and 3.74 (95% CI: 2.45–5.71) in those with three diseases at baseline compared to individuals without a family history of CVD and metabolic diseases. Similarly, an increase of the disease score among individuals with a positive family history of CVD was associated with an increase in early-onset MI risk.ConclusionMetabolic comorbidity was significantly associated with an increased risk of MI among individuals with a family history of CVD.

Discovering Patterns of Cardiovascular Disease and Diabetes in Myocardial Infarction Patients Using Association Rule Mining

Highlights: Association Rule Mining tools predict the association of early-onset Myocardial Infarction with Hypertension and Diabetes Mellitus. Association Rule Mining tools using clinical and biochemical attributes can predict the development of Hypertension and Diabetes Mellitus in Myocardial Infarction patients. Abstract: Cardiovascular diseases (CVDs) are a major cause of mortality in diabetic patients. Hypertensive patients are more likely to develop diabetes and hypertension contributes to the high prevalence of CVDs, in addition to dyslipidemia and smoking. This study was to find the different patterns and overall rules among CVD patients, including rules broken down by age, sex, cholesterol and triglyceride levels, smoking habits, myocardial infarction (MI) type on ECG, diabetes, and hypertension. The cross-sectional study was performed on 240 subjects (135 patients of ST-elevation MI below 45 years and 105 age matched controls). Association rule mining was used to detect new patterns for early-onset myocardial infarction. A hotspot algorithm was used to extract frequent patterns and various promising rules within real medical data. The experiment was carried out using "Weka'', a tool for extracting rules to find out the association between different stored real parameters. In this study, we found out various rules of hypertension like “Rule 6” says that if levels of BP Systolic &gt; 131 mmHg, LpA2 &gt; 43.2 ng/ml, hsCRP &gt; 3.71 mg/L, initial creatinine &gt; 0.5 mg/dl, and initial Hb ≤15 g/dl (antecedent), then the patient will have 88% chance of developing hypertension (consequent). Similarly for diabetes mellitus with finding their lift and confidence for different support like “Rule 6”, if MI type on ECG = ’Inferior Wall MI’ with STATIN=No, and levels of Triglycerides ≤325 (antecedent), then the patient had a 67% chance of developing diabetes mellitus. We concluded that early-onset myocardial infarction is significantly associated with hypertension and diabetes mellitus.Using association rule mining, we can predict the development of hypertension and diabetes mellitus in MI patients.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction

ImportanceThere is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure.MethodsA nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1–22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG).ResultsST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52–0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up.ConclusionsThere are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes.Trial Registration4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Lifestyle and metabolic risk factors in patients with early-onset myocardial infarction: a case-control study.

Family history is a known risk factor for early-onset myocardial infarction (EOMI). However, the role of modifiable lifestyle and metabolic factors in EOMI risk is unclear and may differ from that of older adults. This case-control study included myocardial infarction (MI) patients aged ≤45 years from the Bremen ST-elevation MI Registry and matched controls randomly selected from the general population (German National Cohort) at the same geographical region. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the individual and combined associations of lifestyle and metabolic factors with EOMI risk, overall and according to family history for premature MI. A total of 522 cases and 1191 controls were included. Hypertension, current smoking, elevated waist-to-hip ratio, and diabetes mellitus were strongly associated with the occurrence of EOMI. By contrast, higher frequency of alcohol consumption was associated with decreased EOMI risk. In a combined analysis of the risk factors hypertension, current smoking, body mass index ≥25.0 kg/sqm, and diabetes mellitus, participants having one (OR = 5.4, 95%CI = 2.9-10.1) and two or more risk factors (OR = 42.3, 95%CI = 22.3-80.4) had substantially higher odds of EOMI compared to those with none of these risk factors, regardless of their family history. This study demonstrates a strong association of smoking and metabolic risk factors with the occurrence of EOMI. The data suggest that the risk of EOMI goes beyond family history and underlines the importance of primary prevention efforts to reduce smoking and metabolic syndrome in young persons.

Fibrillar Collagen Variants in Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology. To assess which genes contribute to the development of SCAD. To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46 468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021. The frequency and identity of rare genetic variants in individuals with SCAD. Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter. Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA)

BackgroundAcute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. MethodsThe Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. ResultsMINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57–1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08–0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52–1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87–3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43–1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15–0.47;p < 0.001). ConclusionsMINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

CHEST PAIN IN WOMEN. IS IT ALWAYS ATHEROSCLEROTIC?

Patients both male and female with diagnosis of Acute Coronary Syndrome (ACS) present with chest pain as presenting complaint. Lichtman JH et al. in his study with ACS showed that 93% of women presented with chest pain or discomfort.1 As compared to men women experience more associated symptoms as primary complaint. The associated symptoms are fatigue, dyspnea, backache, flue like symptoms, indigestion, palpitations and most common is anxiety &amp; feeling scarry.2 Keeping these scenarios in mind one should inquire this associated presentation along with chest pain or discomfort in evaluating ACS in women. In continuation with symptoms there is quite a debate on pathophysiology of Acute Myocardial infraction in men and women regarding coronary pathologic features.3 Type 1 plaque rupture most common in both genders with plaque erosion most common in women in non-obstructive coronary artery disease.4 Spontaneous coronary artery dissection (SCAD) having high mortality exists in the absence of risk factor of ACS.5 It was found in women up to 35% of patients with mean age of 42 to 53 years with a MACE (Major acute coronary event) of 47.4% and 10 years mortality rate of 7.7%2 SCAD seen in peripartum cases, oral contraception use, lack of exercise, connective tissue disorders and vasculidites. It is important for the physician to have in mind these disorders to avoid complications of coronary interventions. In a scientific statement from AHA, Mehte LS et al. showed a lower prevalence of atheroscrotic CAD in women.3 These are certain scoring system,6 that under present women because of vague symptoms and presentation. These scoring systems lead to decrease hospital admission and less noninvasive cardiac testing. For risk satisfaction of chest pain female gender should not be taken as sole criteria for presence or absence of coronary events in presence of other multiple factors. The last but not the least is the psychosocial stress more in women than in men. It has been found that young women who present with early onset myocardial infarction have more psychosocial risk factors in comparison to men of similar age,3 probably having high rates of poverty and trauma exposure during childhood because of various reasons.7 Different studies are endorsing relationship between depression and ischemic heart disease as prognostic factor after ACS.7 In our population where there is lack of education, poverty, awareness of disease especially in women the physician should ponder on different factors mentioned above i.e. presentation perceptions, prevalence, pathophysiology and psychosocial stress for evaluation and management of chest pain.

189 Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease

Abstract Aims Data regarding long-term prognosis of MINOCA are very limited and conflicting. Methods and results The Italian Genetic Study on early-onset MI enrolled 2000 patients who had a first MI before they were 45. The median follow-up was 19.9 years, the equivalent of 39 535 person-years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalization for coronary revascularization. MINOCA was experienced by 317 patients (15.9%). The risk of MACE was not significantly different between MINOCA patients and those with obstructive coronary artery disease (MICAD, 27.8% vs. 37.5%; adj. HR: 0.79, 95% CI: 0.57–1.09; P = 0.15, Figure 1). There was no between-group difference in the rate of non-fatal MI (17.3% vs. 25.4%; adj. HR: 0.76, 95% CI: 0.52–1.13; P = 0.18), non-fatal ischaemic stroke (9.5% vs. 3.7%; adj. HR: 1.79, 95% CI: 0.87–3.70; P = 0.12), or all-cause mortality (14.1% vs. 20.7%; adj. HR: 0.73, 95% CI: 0.43–1.25; P = 0.26), but the rates of CV death (6.2% vs. 8.4%; adj. HR: 0.26, 95% CI: 0.08–0.86; P = 0.03) and coronary revascularization (6.7% vs. 27.7%; HR: 0.27, 95% CI: 0.15–0.47; P &amp;lt; 0.001) were lower in the MINOCA group. Conclusions MINOCA is frequent in early-onset MI patients and is not benign with a long-term risk of MACE and overall mortality not significantly different from that of the MICAD patients. 189 Figure 1 Composite primary endpoint of CV death, non-fatal MI, and non-fatal stroke

Genetic Analysis for Coronary Artery Disease Toward Diverse Populations.

Coronary artery disease is one of the leading causes of death in the world, and as such, it is one of the diseases for which genetic analyses have been actively conducted. In the early days, analyses of families with the aggregation of early-onset myocardial infarction, such as those with familial hypercholesterolemia, was the main focus, but since the practical application of genome-wide association study, the analysis of coronary artery disease as a common disease has progressed, and many disease-susceptibility loci have been identified. In addition, with the advancement of technologies, it has become possible to identify relatively rare genetic variants in a population-based analysis. These advances have not only revealed the detailed disease mechanisms but have also enabled the quantification of individual genetic risk and the development of new therapeutic agents. In this paper, some of those items, which are important to know in the current genetic analyses for coronary artery disease, are discussed.

Polygenic Risk Score for Coronary Artery Disease Improves the Prediction of Early-Onset Myocardial Infarction and Mortality in Men.

Several risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established. A PRSCAD including the weighted effects of >1.14 million single nucleotide polymorphisms associated with CAD was calculated in UK Biobank (n=408 422), using LDpred. Cox regressions were performed, stratified by age quartiles and sex, for incident myocardial infarction (MI) and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRSCAD to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI0.02) and continuous NRI (NRI>0). From 7746 incident MI cases and 393 725 controls, hazard ratio for MI reached 1.53 (95% CI, 1.49-1.56; P=2.69×10-296) per SD increase of PRSCAD. PRSCAD was significantly associated with MI in both sexes, with a stronger association in men (interaction P=0.002), particularly in those aged between 40 and 51 years (hazard ratio, 2.00 [95% CI, 1.86-2.16], P=1.93×10-72). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI0.02, 0.199 [95% CI, 0.157-0.248] and NRI>0, 0.602 [95% CI, 0.525-0.683]). From 23 982 deaths, hazard ratio for mortality was 1.08 (95% CI, 1.06-1.09; P=5.46×10-30) per SD increase of PRSCAD, with a stronger association in men (interaction P=1.60×10-6). Our PRSCAD predicts MI incidence and all-cause mortality, especially in men aged between 40 and 51 years. PRS could optimize the identification and management of individuals at risk for CAD.

A polygenic risk score for coronary artery disease predicts early-onset myocardial infarction and mortality in men

Many risk factors for coronary artery disease (CAD) have been described, some of which are genetic. Since the genetic profile can be generated at an early age, its use as a polygenic risk score (PRS) could improve the prediction of CAD risk. To develop a PRS from genetic variants (SNPs) associated with CAD and to assess its association with the incidence of myocardial infarction and mortality, by age and sex. A PRS including the weighted effects of > 1.14 millions of SNPs associated with CAD (CARDIoGRAMplusC4D data) was calculated in the UK Biobank cohort ( n = 408,422), using the LDpred software. Cox regressions were performed, stratified by age quartiles and sex, for MI and mortality, with a median follow-up of 11.1 years. Improvement in risk prediction of MI was assessed over a 10-year period by comparing the PRS to a clinical score, the pooled cohort equation, with categorical net reclassification index for a 2% threshold (NRI 0.02 ) and continuous NRI (NRI > 0 ). From 7744 incident MI cases and 393,751 controls, hazard ratio (HR) for MI reaches 1.53 (95% CI [1.49–1.56], P = 1.3e-296) by SD of PRS. PRS is significantly associated with MI incidence in both sexes, with a stronger association for men (interaction P = 0.002), particularly those aged between 40-51 years (1st quartile) (HR = 2.01, 95% CI [1.86–2.17], P = 4.3e-73). This group presents the highest reclassification improvement (NRI 0.02 = 0.26, 95% CI [0.20–0.29] and NRI > 0 = 0.61, 95% CI [0.52–0.69]), mainly driven by the reclassification of cases to a higher risk. From 23,982 deaths, HR for mortality is 1.08 (95% CI [1.06–1.09], P = 5.5e-30) per SD of PRS, with a stronger association in men (interaction P = 1.6e-06). Our PRS is associated with MI incidence and all-cause mortality, especially in men aged between 40–51 years. The use of PRS could optimize the identification and management of patients at risk for CAD.

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

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

Association of PHACTR1 intronic variants with the first myocardial infarction and their effect on PHACTR1 mRNA expression in PBMCs.

Myocardial infarction (MI) and underlining atherosclerosis are the main causes of death worldwide. Phosphatase and actin regulator 1 (PHACTR1) variants have been associated with early onset MI, coronary artery disease and carotid dissection. PHACTR1 mRNA expression has been detected in tissues and cells related to atherosclerosis. Nonetheless, the true effect of PHACTR1 on vascular diseases is still unknown. Our aim was to examine the association of PHACTR1 intronic variants, rs9349379, rs2026458 and rs2876300, with MI and multi-vessel disease (MVD) and to assess their effect on PHACTR1 and EDN1 mRNA expression in PBMCs of patients six months after MI. The study enrolled 537 patients with the first MI and 310 controls. Gene expression was assessed in 74 patients six months after MI and 37 healthy controls. Rs9349379, rs2026458, rs2876300 and relative mRNA expressions were detected by TaqMan® technology. The significant association between PHACTR1 variants and MI was not found, either individually or in haplotype. A higher frequency of rs2876300G-allele in MVD was rendered not significant after Bonferroni correction. PHACTR1 mRNA was significantly increased in PBMCs of patients six months after MI compared to controls (p=0.02). Patients that carry ACG haplotype have increased PHACTR1 mRNA expression in PBMCs (p=0.04). There was no effect of PHACTR1 variants on EDN1 mRNA expression. Our findings suggest that PHACTR1 intronic variants may have a role in severity and progression of coronary atherosclerosis. Future research is needed to clarify the mechanism underlying the role of PHACTR1 in coronary atherosclerosis and MI.

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

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

A substitution mutation in LRP8 gene is significantly associated with susceptibility to familial myocardial infarction.

BACKGROUNDMyocardial infarction (MI) is a multifactorial disease caused by the suspension of blood circulation in a part of the myocardium. Understanding the genetic basis of MI can provide insight regarding the pathogenesis of the disease. The aim of this study was to investigate the association between pathogenic mutations and early-onset MI in five families with familial MI and without common MI risk factor.METHODSPatients with MI younger than 50 years with family history of MI and without common diagnostic criteria (obesity, diabetes, familial hypercholesterolemia, opium/alcohol use) were evaluated for pathogenic mutations by whole exome sequencing (WES) and mutation was confirmed by polymerase chain reaction (PCR)-Sanger sequencing.RESULTSThe c.2855G > A missense mutation with homozygous autosomal recessive inheritance was identified in low-density lipoprotein receptor-related protein 8 (LRP8) gene in all patients of a family.CONCLUSIONThe c.2855G > A (R952Q) mutation in LRP8 gene in homozygous state could be considered as a possible etiology of early-onset familial MI.