Single-Cell RNA Sequencing Reveals an Immune Landscape of CD4+ T Cells in Coronary Culprit Plaques With Acute Coronary Syndrome in Humans-Brief Report.

BACKGROUND: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS. METHODS: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45+ immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis. RESULTS: CD4+ T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7+ (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3)+ regulatory CD4+ T cells. The proportion of central memory CD4+ T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4+ T cells into effector CD4+ T cells and that from naive CD4+ T cells into central memory CD4+ T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4+ T cells. CONCLUSIONS: For the first time, we revealed single cell-level characteristics of CD4+ T cells in patients with ACS. CD4+ T cells could be therapeutic targets of ACS. REGISTRATION: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN000040747.

Telomerase activity and hTERT gene expression in patients with acute coronary syndrome and stable coronary artery disease.

BACKGROUND: In this study, we aimed to examine the telomerase activity and hTERT gene expression in patients with acute coronary syndrome (ACS) and those with stable coronary artery disease (SCAD) and compare the results to controls. Additionally, we compared overall mortality rates relative to the telomerase activity. METHODS: A total of 211 patients (78 ACS and 71 SCAD patients) were included in the study. The telomerase concentration was measured by ELISA and used to determine telomerase activity. The hTERT gene expression was determined by real-time PCR. RESULTS: The serum telomerase enzyme concentration was lower in ACS (36.61 ± 1.54) and SCAD (36.79 ± 1.57) when compared to the control group (37.03 ± 2.25). However, this difference did not reach statistical significance (p = 0.890). The hTERT gene expression acting in telomerase enzyme synthesis was 2.7-fold lower in ACS group (p = 0.070) and 2.2-fold lower in the SCAD group (p = 0.101) compared to the control group. Patients were followed for a median of 32 months (minimum: 0.1, maximum: 46.8). The serum telomerase concentrations in patients who died and those survived in the SCAD group (35.98 ± 2.02 vs 36.86 ± 1.52 ng/ml, respectively; p = 0.529) were similar to those in the ACS group (36.39 ± 1.08 vs 36.63 ± 1.60 ng/ml, respectively p = 0.993). CONCLUSIONS: In the current study, telomerase activity or hTERT expression was similar in patients with ACS, SCAD, and controls. Moreover, telomerase activity was not associated with all- cause mortality during the 32-month follow-up (Tab. 3, Fig. 1, Ref. 29).

Association of Tenascin-C Gene Polymorphisms with Risk of Acute Coronary Syndrome in South Indian Population: A Case-Control Genetic Association Study.

Background: The extracellular matrix (ECM) glycoprotein changes are associated with the pathogenesis and complications of atherosclerosis, leading to acute coronary syndrome (ACS). Tenascin-C (TNC), an ECM protein, has been implemented in the pathogenesis, diagnosis, and prognosis of patients with cardiovascular disease. Aim: The study aimed to compare the genetic variants of the TNC gene (rs13321, rs2104772, and rs12347433) between South Indians with ACS and healthy participants. Materials and Methods: This case-control study recruited 150 ACS patients as cases and 150 healthy participants as controls. TNC genotyping was performed using TaqMan 5'-exonuclease allele discrimination assay. Serum TNC levels were measured by enzyme-linked immunosorbent assay. Results: Serum TNC levels were significantly higher in cases compared with controls. No significant difference was observed in allele and genotype frequencies of rs13321, rs2104772, and rs12347433 between cases and controls, which was confirmed by dominant, recessive, codominant, and homozygotic genetic models. The patients with heterozygous genotypes of rs13321, rs2104772, and rs12347433 had significantly lower serum TNC levels than patients with respective homozygous genotypes. Haplotype analyses revealed that the C-T-A haplotype in the block of rs13321-rs12347433-rs2104772 was associated with lower ACS risk (OR = 0.33, 95% CI: 0.15 - 0.75; p = 0.005). Also, the C-T-T and G-T-A haplotypes of the TNC gene were associated with higher and lower serum TNC levels, respectively. Conclusion: Our study demonstrated no genetic association between single nucleotide polymorphisms of the TNC gene and ACS risk; however, the C-T-A haplotype of the TNC gene might be associated with reduced ACS risk in South Indians.

Discriminatory power of a circulating multi-noncoding RNA panel in acute coronary syndrome subtypes: Towards precision detection.

BACKGROUND: Acute Coronary Syndrome (ACS) stands as a significant contributor to cardiovascular mortality, necessitating improved diagnostic tools for early detection and tailored therapeutic interventions. Current diagnostic modalities, exhibit limitations in sensitivity and specificity, urging the quest for novel biomarkers to enhance discrimination of the different stages of ACS including unstable angina, Non-ST-segment Elevation Myocardial Infarction (NSTEMI), and ST-segment Elevation Myocardial Infarction (STEMI). METHODS: This study investigated the potential of a plasma-circulating multi-noncoding RNA (ncRNA) panel, comprising four miRNAs (miR-182-5p, miR-23a-3p, miR-146a-5p, and miR-183-5p) and three lncRNAs (SNHG15, SNHG5, and RMRP), selected based on their intricate involvement in ACS pathogenesis and signaling pathways regulating post-myocardial infarction (MI) processes. The differential expression of these ncRNAs was validated in sera of ACS patients and healthy controls via real-time polymerase chain reaction (RT-PCR). RESULTS: Analysis revealed a marked upregulation of the multi-ncRNAs panel in ACS patients. Notably, miRNA-182-5p and lncRNA-RMRP exhibited exceptional discriminatory power, indicated by the high area under the curve (AUC) values (0.990 and 0.980, respectively). Importantly, this panel displayed superior efficacy in discriminating between STEMI and NSTEMI, outperforming conventional biomarkers like creatine kinase-MB and cardiac troponins. Additionally, the four miRNAs and lncRNA RMRP showcased remarkable proficiency in distinguishing between STEMI and unstable angina. CONCLUSION: The findings underscore the promising potential of the multi-ncRNA panel as a robust tool for early ACS detection, and precise differentiation among ACS subtypes, and as a potential therapeutic target.

The Effect of Platelet Activity, ABCB1 Genetic Polymorphism, and Renal Function on the Development of Ticagrelor-Related Dyspnea in Patients with Acute Coronary Syndrome.

Purpose: The aim of this study was to determine the effect of ABCB1 genetic polymorphism and renal function on the occurrence of ticagrelor-related dyspnea. Patients and Methods: A total of 299 patients with acute with type 1, 2, or 3 myocardial infarction (with and without ST-segment elevation), who underwent coronary angiography and PTCA with stent implantation and were treated with antiplatelet drugs (ticagrelor and aspirin), were enrolled in this prospective study. For all enrolled patient's platelet aggregation (induction with high-sensitivity adenosine diphosphate, ADP HS) testing was performed using a MULTIPLATE® analyzer. Venous blood was also collected for genotyping. Results: Patients experiencing ticagrelor-related dyspnea had lower ADP HS value (ADP HS ≤ 19.5 U; OR = 2.254; P = 0.009), higher creatinine concentration (>90 µmol/l; OR = 3.414; P = 0.019), and lower GFR value (<60 mL/min/1.73 m2; OR = 2.211; P = 0.035). ABCB1 T allele was associated with ticagrelor-related dyspnea (OR = 2.550; P = 0.04). Conclusion: Ticagrelor-related dyspnea was found to be related to low platelet aggregation, increased plasma creatinine concentration, decreased GFR, and ABCB1 T allele. Carriers of the ABCB1 T allele had a higher plasma creatinine concentration that could be associated with an inhibitory effect of ticagrelor on P-glycoprotein function.

Cholesterol associated genetic risk score and acute coronary syndrome in Czech males.

BACKGROUND: Despite a general decline in mean levels across populations, LDL-cholesterol levels remain a major risk factor for acute coronary syndrome (ACS). The APOB, LDL-R, CILP, and SORT-1 genes have been shown to contain variants that have significant effects on plasma cholesterol levels. METHODS AND RESULTS: We examined polymorphisms within these genes in 1191 controls and 929 patients with ACS. Only rs646776 within SORT-1 was significantly associated with a risk of ACS (P < 0.05, AA vs. + G comparison; OR 1.21; 95% CI 1.01-1.45). With regard to genetic risk score (GRS), the presence of at least 7 alleles associated with elevated cholesterol levels was connected with increased risk (P < 0.01) of ACS (OR 1.26; 95% CI 1.06-1.52). Neither total mortality nor CVD mortality in ACS subjects (follow up-9.84 ± 3.82 years) was associated with the SNPs analysed or cholesterol-associated GRS. CONCLUSIONS: We conclude that, based on only a few potent SNPs known to affect plasma cholesterol, GRS has the potential to predict ACS risk, but not ACS associated mortality.

Pharmacogenomic evaluation of CYP2C19 alleles linking low clopidogrel response and the risk of acute coronary syndrome in Indians.

BACKGROUND: Clopidogrel is an antiplatelet drug widely prescribed to prevent atherothrombotic events in coronary artery disease patients. However, there is evidence to suggest that the effectiveness of clopidogrel varies owing to genetic diversity in CYP2C19. This heterogeneity in South Asians, who are also known to have high risk of cardiac events than other population groups, highlights the importance of investigating CYP2C19 variants to estimate the risk proportion in the groups. METHODS: Given the high prevalence and genetic heterogeneity, the population-based case control was conducted in a cohort of 1191 subjects comprising 645 acute coronary syndrome (ACS) cases (unstable angina, ST-elevation myocardial infarction, and non-ST-elevation myocardial infarction) and 546 healthy controls of South Asian Indian origin. The metabolization status of CYP2C19 was assessed using *2, *3 and *17 variants in the stated cohorts to determine the prevalence of metabolization and its association with phenotypes. RESULTS: The results suggest a possible genetic association between studied CYP2C19 polymorphisms and ACS, since there was a higher proportion of intermediate and poor metabolizers present in the studied cohorts. The association analyses revealed that the *2 allele of CYP2C19 confers a significant risk for ACS, while the *17 allele provides protection. CONCLUSIONS: These findings contribute to the understanding of CYP2C19 genetic variants and their impact on clopidogrel response in South Asian Indians. Additionally, they underline the significance of assessing CYP2C19 variations in patients receiving clopidogrel therapy in order to improve therapeutic outcomes.

Net clinical benefit of clopidogrel versus ticagrelor in elderly patients carrying CYP2C19 loss-of-function variants with acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND AND AIMS: Elderly patients with acute coronary syndrome (ACS) tend to choose clopidogrel over potent P2Y12 receptor inhibitor such as ticagrelor after percutaneous coronary intervention (PCI) in China considering higher risks of bleeding. CYP2C19 genotype is regarded as a major factor influencing the efficacy of clopidogrel. The present study aims to investigate the efficacy and safety of ticagrelor relative to clopidogrel in elderly ACS patients after PCI in China with reduced CYP2C19 metabolism. METHODS: Between January 2016 and March 2019, 2751 ACS patients over 65 years old with CYP2C19 loss-of-function (LOF) variants after PCI were enrolled. All patients were treated with aspirin and P2Y12 receptor inhibitor, among whom 2056 received clopidogrel and 695 received ticagrelor. Net adverse clinical events (NACE), a composite of cardiac death, myocardial infarction (MI), ischemic stroke, target vessel revascularization and clinically relevant bleeding including Bleeding Academic Research Consortium (BARC) types 2, 3, 5 bleeding, were compared between the two groups at 12 months after PCI. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the two groups. RESULTS: Before and after PSM, NACE was significantly increased in ticagrelor group compared with clopidogrel group at 12 months post PCI (Before PSM, 15.18% vs. 25.61% p<0.001; After PSM, 11.66% vs. 26.01% p<0.001). MACE was comparable between the two groups (Before PSM, 5.45% vs. 5.32% p>0.999; After PSM, 3.59% vs. 5.38% p=0.146). BARC types 2, 3, 5 bleeding events were significantly increased in patients treated with ticagrelor relative to clopidogrel (Before PSM, 10.31% vs. 21.01% p<0.001; After PSM, 8.22% vs. 21.38% p<0.001), which was mainly attributed to a higher incidence of BARC type 2 bleeding events in ticagrelor group (Before PSM, 8.12% vs. 18.56% p<0.001; After PSM, 6.43% vs. 18.83% p<0.001). CONCLUSIONS: In the present real-world study, selection of ticagrelor over clopidogrel showed a significant increase in NACE with a higher incidence of bleeding and similar ischemic events in elderly ACS patients carrying CYP2C19 LOF variants after PCI.

Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

A systematic study to evaluate the safety of ticagrelor combined with aspirin in the treatment of PCI patients in Chinese population: A single nucleotide polymorphisms study.

The aim of this study was to identify genes and their associated loci related to ticagrelor pharmacokinetics and pharmacodynamics in Chinese patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). The study included 1115 patients with ACS who received a drug-eluting stent implantation between October 2019 and January 2021. Among them, 98 cases of adverse reactions were observed; thus, 97 cases without adverse reactions were selected as the comparison group. The steady-state serum drug concentration was determined via high-performance liquid chromatography-mass spectrometry, and 15 single nucleotide polymorphism (SNP) loci were genotyped using the SNaPshot SNP Multiplex System. Our results showed that age and sex may affect ticagrelor serum concentration in patients with ACS. In particular, the SNPs CYP3A4∗1 (rs2242480 C > T), IGT2B (rs5911 A > C), P2Y12 (rs6787801) and CYP3A5 (rs776746 C > T) may affect the steady-state blood concentration of ticagrelor after PCI in ACS patients, and CYP3A4∗1 may also be related to adverse events. In addition, we found that the SNPs PEAR1 (rs4661012 T > G) and P2Y12 (rs6787801 A > G) may be associated with dyspnea. These findings can provide a useful reference to establish guidelines for future clinical individualized dosage regimens of ticagrelor after PCI.

The Clinical Implementation of CYP2C19 Genotyping in Patients with an Acute Coronary Syndrome: Insights From the FORCE-ACS Registry.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor for acute coronary syndrome (ACS) patients. However, these P2Y12 inhibitors increase bleeding risk compared to clopidogrel. Although genotype-guided P2Y12-inhibitor selection has been shown to reduce bleeding risk, data on its clinical implementation is lacking. METHODS: The study included ACS patients receiving genotype-guided antiplatelet therapy, utilising either a point-of-care (POC) device or laboratory-based testing. We aimed to collect qualitative and quantitative data on genotyping, eligibility for de-escalation, physician adherence to genotype results, time to de-escalation and cost reduction. RESULTS: Of the 1,530 patients included in the ACS registry from 2021 to 2023, 738 ACS patients treated with ticagrelor received a CYP2C19 genotype test. The median turnover time of genotyping was 6.3 hours (interquartile range [IQR], 3.2-16.7), with 82.3% of the genotyping results known within 24 hours after admission. POC genotyping exhibited significantly shorter turnaround times compared to laboratory-based testing (with respective medians of 5.7 vs 47.8 hours; P < .001). Of the genotyped patients, 81.7% were eligible for de-escalation which was carried out within 24 hours in 70.9% and within 48 h in 93.0%. The time to de-escalation was significantly shorter using POC (25.4 hours) compared to laboratory-based testing (58.9 hours; P < .001). Implementing this strategy led to a reduction of €211,150.50 in medication costs. CONCLUSIONS: CYP2C19 genotype-guided-de-escalation in an all-comers ACS population is feasible. POC genotyping leads to shorter turnaround times and quicker de-escalation. Time to de-escalation from ticagrelor to clopidogrel in noncarriers was short, with high physician adherence to genotype results.

Identification of Molecular Markers Predicting the Outcome of Anti-thrombotic Therapy After Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome and Atrial fibrillation: Evidence from a Meta-analysis and Experimental Study.

Acute coronary syndrome (ACS) and atrial fibrillation (AF) often coexist in clinical practice, and patients with these conditions often have a critical illness with high risk of both ischemia and bleeding. This study aims to report potential molecular markers for predicting the efficacy based on a meta-analysis of microarray data from the GEO database. In 40 patients with acute coronary syndrome (ACS) and atrial fibrillation (AF) treated with PCI, P2RX1's effects on platelet aggregation, medication resistance, and predictive value were examined. Twenty up-regulated genes in peripheral blood samples of ACS and AF patients were down-regulated after PCI, while 7 down-regulated genes were up-regulated. ACS affected eight potential genes. P2RX1, one of the four LASSO analysis-retrieved disease characteristic genes, accurately predicted AF patients' thrombosis risk and PCI's anti-thrombotic impact. Therefore, P2RX1 may be a molecular marker to predict the effect of anti-thrombotic therapy in patients with ACS and AF after PCI.

The genetic polymorphisms and activity of glyoxalase 1 as a risk factor for acute coronary syndrome in South Indians with type 2 diabetes mellitus.

OBJECTIVE: The individuals' genetic traits predispose them to a higher or lower risk of Type 2 diabetes mellitus (T2DM) and its complications, for example, acute coronary syndrome (ACS). As carbonyl stress is responsible for the pathogenesis and complications of T2DM, and glyoxalase 1 (GLO1) is the most crucial determinant of carbonyl stress, the study aimed to explore the association between GLO1 gene polymorphism, GLO1 activity in red blood cell (RBC), plasma methylglyoxal (MG) levels, and ACS risk in South Indian T2DM patients. METHODS: A total of 150 T2DM patients with ACS as cases and 150 T2DM patients without ACS as controls were recruited in a case-control study. The rs4746, rs1049346 and rs1130534 of the GLO1 gene were analysed using TaqMan allele discrimination assay. The RBC GLO1 activity and plasma MG levels were measured. RESULTS: Significantly lower RBC GLO1 activity and higher plasma MG levels were found in cases compared to controls (p < 0.001 and p = 0.008, respectively). The genotype and allele frequencies of rs1049346 significantly differed between cases and controls (p < 0.001). For rs1130534 and rs1049346, no significant difference was found. For rs1049346, the TT and CC genotypes were associated with higher (p = 0.002) and lower (p = 0.001) ACS risk, respectively, in various genetic models. The TT genotype of rs1049346 was associated with lower RBC GLO1 activity (p = 0.004) and higher MG level (p = 0.010). In haplotype analysis, higher ACS susceptibility with the TAT haplotype (p < 0.001) and lower ACS susceptibility with the TAC haplotype (p < 0.001) were observed. Also, lower RBC GLO1 activity was associated with the TAT haplotype (p = 0.002). CONCLUSIONS: The rs1049346 of the GLO1 gene may be associated with ACS risk in South Indian T2DM patients, and the T and C allele might be essential precipitating and protective factors, respectively.

Elevated Levels of Circulating lncRNAs LIPCAR and MALAT1 Predict an Unfavorable Outcome in Acute Coronary Syndrome Patients.

Coronary artery disease (CAD) is a leading cause of mortality worldwide. In this study, we aimed to assess the potential of plasma long non-coding RNAs (lncRNAs) LIPCAR and MALAT1 and microRNAs (miRNAs) miR-142-3p and miR-155-5p to discriminate unstable CAD patients from stable ones. 23 stable angina (SA), 21 unstable angina (UA), and 50 ST-segment elevation myocardial infarction (STEMI) patients were enrolled; their plasma was collected. ncRNA plasma levels were evaluated using RT-qPCR. All measured ncRNA levels were significantly increased in UA patients' plasma compared to SA patients' plasma and in STEMI-with major adverse cardiovascular event (MACE) patients' plasma vs. STEMI-without MACE patients' plasma. ROC analysis showed that increased levels of LIPCAR and MALAT1 were associated with UA, and the prognostic model improved with the addition of miR-155-5p levels. The assessed lncRNAs discriminated between hyperglycemic (HG) and normoglycemic (NG) UA patients, and they were associated with MACE incidence in STEMI patients; this prediction was improved by the addition of miR-142-3p levels to the ROC multivariate model. We propose LIPCAR and MALAT1 as effective diagnostic markers for vulnerable CAD, their association with HG in UA patients, and as robust predictors for unfavorable evolution of STEMI patients.

The contribution of genotype-guided selection of P2Y12 inhibitor on prognosis in ACS /CCS patients undergoing percutaneous coronary intervention: a retrospective cohort study.

PURPOSE: We aimed to explore the contribution of genotype-guided selection of P2Y12 inhibitors on prognosis in Chinese patients with acute coronary syndromes (ACS) or chronic coronary syndromes (CCS) undergoing percutaneous coronary intervention (PCI). METHODS: Totally, 2063 patients were included. They were divided into empiric treatment group (n = 1025) and individualized treatment group (n = 1038) depending on whether taken CYP2C19 genetic testing. The incidences of clinical endpoint events were compared in two groups at 1-year follow-up. The effective endpoint events were major adverse cardiovascular events (MACEs), including all-cause mortality, in-stent restenosis, nonfatal myocardial infarction, nonfatal stroke and severe recurrent ischemia. Meanwhile, the safe endpoint was bleeding events defined by the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: Finally, 66.83% patients were diagnosed with ACS and 33.17% patients were diagnosed with CCS in empiric group. 68.11% patients were diagnosed with ACS and 31.89% patients were diagnosed with CCS in individualized group. At 1-year follow-up, individualized group showed lower MACEs rate than empiric group (19.61% vs. 10.69%, HR: 1.915; 95% CI: 1.534 to 2.392; P < 0.0001, log-rank test; adjusted HR: 1.983; 95% CI: 1.573 to 2.501; P = 0.000, cox proportional hazards regression models), while bleeding events were significantly less common in empiric group than in individualized group (7.32% vs. 10.40%, HR: 0.693; 95% CI: 0.519 to 0.926; P = 0.0132, log-rank test; adjusted HR: 0.695; 95% CI: 0.518 to 0.933; P = 0.016, cox proportional hazards regression models). It was mainly manifested in BARC class 1 bleeding, which did not warrant the interruption of antiplatelet therapy (ITA). Further, subgroup analyses illustrated that no significant difference existed in cumulative MACEs-free survival rate between all treatment arms of individualized group (P = 0.6579 by log-rank test), and CYP2C19 intermediate metabolizer (IM) genetype appeared to be significantly associated with bleeding events for patients treated with ticagrelor (clopidogrel vs. ticagrelor: 6.80% vs. 14.88%; adjusted HR:0.440; 95% CI: 0.246 to 0.787; adjusted P = 0.006). CONCLUSIONS: Genotype-guided selection of P2Y12 inhibitor made a very positive contribution on the prognosis in Chinese ACS/CCS patients undergoing PCI. Instead of intensifying antiplatelet strategies, conventional-dose clopidogrel could be recommended as P2Y12 inhibitor after weighing MACEs and bleeding events in CYP2C19 IM patients.

Glu298Asp variant of the endothelial nitric oxide synthase gene and acute coronary syndrome or premature coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Several published studies have reported an association between the Glu298Asp polymorphism (rs1799983), residing in the endothelial nitric oxide synthase (NOS3) gene, and lower levels of circulating nitric oxide, as well as an increased risk of coronary artery disease (CAD). However, association status of this genetic variant with acute coronary syndrome (ACS) or premature CAD (PCAD) is still unclear. Against this background, we conducted a systematic review and study level meta-analysis to assess the association of the NOS3 Glu298Asp polymorphism with ACS or PCAD. MATERIALS AND METHODS: A comprehensive online search to identify relevant studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science. The identified studies were stratified into two ancestral subgroups: 'European ancestry' and 'All other ancestries combined'. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random/fixed effects employing a Z test. RESULTS: Out of a total of 195 distinct records identified through online search, 37 articles with 39 different studies, with a total sample size of 27,441 (11,516 cases/15,925 controls) were included for quantitative synthesis. Pooled results suggested significant associations of the NOS3 Glu298Asp polymorphism with ACS or PCAD through dominant as well as allelic genetic models (p ≤ 0.002), primarily driven by the 'All other ancestries combined' subgroup. The 'All other ancestries combined' subgroup demonstrated an additional risk of 36% for ACS or PCAD, through both dominant and allelic genetic models (OR = 1.36, 95%CI = 1.13, 1.63, p = 0.001 and OR = 1.36, 95%CI = 1.14, 1.61, p = 0.0005 respectively). On the other hand, the 'European ancestry' subgroup did not show any significant associations. Sensitivity analysis and a sub-analysis for the myocardial infarction endpoint further supported these observed associations. CONCLUSIONS: This meta-analysis indicates towards an association between the NOS3 Glu298Asp polymorphism and ACS or PCAD, predominantly driven by 'All other ancestries combined' subgroup. In contrast, the 'European ancestry' subgroup did not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.

Circulating mir-483-5p as a novel diagnostic biomarker for acute coronary syndrome and its predictive value for the clinical outcome after PCI.

BACKGROUND: MicroRNA (miRNA) plays a critical function in the progression of acute coronary syndrome (ACS) and is associated with major adverse cardiovascular events (MACEs) after undergoing percutaneous coronary intervention (PCI). This research was designed to probe the diagnostic accuracy of miR-483-5p in patients with ACS and its predictive value of MACEs. METHODS: 118 patients with ACS (40 with unstable angina pectoris [UAP] and 78 with acute myocardial infarction [AMI]) and 75 healthy controls were enrolled. Serum miR-483-5p was detected in the subjects by reverse transcription-quantitative real-time PCR (RT-qPCR). ROC curve and logistic regression models were employed to estimate the diagnosis. Patients were monitored for 6 months after PCI to document the occurrence of MACEs. Kaplan-Meier survival was conducted to explore the predictive significance of miR-483-5p for the MACEs. RESULTS: Serum miR-483-5p levels were higher in ACS patients and associated with SYNTAX score and Gensini score. miR-483-5p was effective in identifying ACS patients from healthy individuals (AUC = 0.919) and AMI patients from ACS patients (AUC = 0.867), demonstrating a high diagnostic value, proven by logistic regression (OR = 9.664, 95%CI = 4.462-20.928, P < 0.001). The prevalence of MACEs during follow-up were 24.58%, and a higher prevalence of MACEs were observed in patients with elevated miR-483-5p (P = 0.01). miR-483-5p was also an effective predictor of MACE occurrence (HR = 5.955, 95%CI = 1.928-18.389, P = 0.002). CONCLUSION: Expression of serum miR-483-5p can be utilized as a non-invasive marker for diagnosing ACS and predicting the onset of MACE after PCI.

Rates of 30-Day and 90-Day Readmission Between Genotype-Optimal and Genotype-Suboptimal Antiplatelet Therapy Prescribing After Percutaneous Coronary Intervention.

Current evidence increasingly supports CYP2C19 genotype-guided P2Y12 inhibitor selection. Clopidogrel remains the most prescribed P2Y12 inhibitor despite higher readmission rates than those of more efficacious third-generation P2Y12 inhibitors. It remains unclear whether pharmacogenetically (PGx)-guided antiplatelet therapy directly reduces readmissions after percutaneous coronary intervention (PCI). A single-center retrospective observational cohort study at a tertiary academic medical center was conducted. Patients receiving CYP2C19 genotyping after PCI were included and stratified into 2 groups (PGx-optimal vs PGx-suboptimal P2Y12 inhibitor prescribed) on the basis of CPIC (Clinical Pharmacogenetics Implementation Consortium) recommendations. Primary outcomes included 30-day and 90-day readmissions after index PCI. Most patients (78%) were of non-European ancestry. Among patients receiving PGx-optimal therapy, 50% had acute coronary syndromes whereas 61% receiving PGx-suboptimal therapy had stable coronary artery disease. Comparable 30-day (12% vs 10%, p = 0.481) and 90-day readmission rates (24% vs 28%, p = 0.323) were observed between patients receiving PGx-optimal or PGx-suboptimal therapies. PGx-optimal therapy was associated with fewer emergency department visits (3.4% vs 4.0%, p = 0.021) within 30 days, and patients initially prescribed PGx-suboptimal therapy were switched more often to PGx-optimal therapy during a readmission than were patients prescribed PGx-suboptimal antiplatelet therapy (p <0.001). In conclusion, CYP2C19 genotype-guided P2Y12 inhibitor therapy did not improve 30- and 90-day all-cause readmission rates in a predominantly non-European population. However, P2Y12 inhibitor therapy became concordant with CYP2C19 genotype in approximately half of patients during the first readmission after PCI, which may present further opportunities to revisit and optimize dual antiplatelet therapy in patients who undergo PCI.

Economic evaluation of pharmacogenomic-guided antiplatelet treatment in Spanish patients suffering from acute coronary syndrome participating in the U-PGx PREPARE study.

BACKGROUND: Cardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS. METHODS: In this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. RESULTS: Based on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04-1.10) versus 1.06 (95% CI, 1.03-1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20-1.26) and 1.23 (95% CI, 1.19-1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [€883 (95% UI, €316-€1582), compared to €1,755 (95% UI, €765-€2949)]. CONCLUSION: These findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.

Implementation of CYP2C19 genotyping and clinical outcomes following percutaneous coronary intervention in East Asian patients treated with oral P2Y12 inhibitors.

BACKGROUND: The CYP2C19 loss-of-function variants have significant impact on response to clopidogrel. The efficacy and safety of tailored antiplatelet therapy under the guidance of CYP2C19 genetic polymorphisms remains elusive for patients undergoing percutaneous coronary intervention (PCI). OBJECTIVES: The aims of the present study were to investigate the impact of clinical implementation of CYP2C19 genotyping on the selection of oral P2Y12 inhibitor therapy following PCI, and to estimate the risk of adverse outcomes for patients with different genotype status treated with alternative or traditional P2Y12 inhibitor. METHODS: Data from a single-center registry enrolling 41,090 consecutive PCI patients treated with dual antiplatelet therapy after PCI were analyzed. Risk of major adverse cardiovascular events (MACEs) and bleeding events within 12 months after PCI were compared across CYP2C19 genotype and antiplatelet therapy groups using Cox proportional hazards models. RESULTS: CYP2C19 genotyping was successfully achieved for 9081 patients, of whom baseline characteristics significantly differed from non-genotyped patients. A higher proportion of genotyped patients were prescribed ticagrelor compared with non-genotyped patients (27.0 % vs. 15.5 %, P < 0.001). CYP2C19 metabolic status was an independent predictor for use of ticagrelor (P < 0.001). Ticagrelor was significantly associated with a lower risk of MACEs in poor metabolizers (adjusted hazard ratio 0.62, 95 % confidence interval 0.42 to 0.92, P = 0.017), but not in intermediate metabolizers or normal metabolizers. The interaction was not statistically significant (P for interaction = 0.252). CONCLUSIONS: Genotype information on CYP2C19 metabolic status was associated with an increase in the use of potent antiplatelet therapy in PCI patients. Patients prescribed with clopidogrel has a higher risk of MACEs among poor metabolizers, which suggested the potential application of genotype-guided P2Y12 inhibitor selection for improving clinical outcomes.