Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice: Translational Implications for Human Coronary Artery Disease.

[Figure: see text].

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system.

AIMS: Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischaemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. METHODS AND RESULTS: Sirt5 transgenic (Sirt5Tg/0) and knock-out (Sirt5-/-) mice underwent photochemically induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) were treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to wild-type controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/- mice, arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expressions are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. CONCLUSION: SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events.

Factors which Influence the Levels of ST-2, Galectin-3 and MMP-9 in Acute Coronary Syndrome.

BACKGROUND: Several cardiac biomarkers are being studied to explore their potential in the prognostication of Acute Coronary Syndrome (ACS). However, there are limited studies exploring the relationship between these biomarkers and clinical, laboratory and demographic characteristics. OBJECTIVE: We sought to determine the factors which influence the concentration of novel cardiac biomarkers such as Galectin-3, suppression of tumorigenicity-2 (ST-2) and Matrix Metallopeptidase-9 (MMP-9) in patients with ACS. METHODS: A total of 122 patients with ACS were enrolled in the study. The study patients were categorized into two groups namely: STEMI (n=58) and NSTEMI/UA (n=64). Plasma samples were used to determine the level of biomarkers, Galectin-3 and ST-2, and serum samples were used to determine the levels of MMP-9 using the Enzyme-linked immunosorbent assay (ELISA). The association between the plasma and serum levels of biomarkers and, demographic, clinical and laboratory variables were determined. Statistical analyses for the study were performed using SPSS 16.0 software (SPSS Inc., Chicago, IL, USA). RESULTS: Elderly aged [0.107 (0.012-0.969); p=0.047] patients had higher ST-2. Galectin-3 was higher among female patients [3.693(1.253-10.887); p=0.018] and patients with low left ventricular ejection fraction [2.882 (1.041-7.978); p=0.042]. Patients with lower body mass index [3.385 (1.241-9.231); p=0.017], diabetes [3.650 (1.302-10.237); p=0.014] and high total leukocyte count [2.900 (1.114-7.551; p=0.029] had higher MMP-9 levels. CONCLUSION: The concentration of galectin-3, ST-2 and MMP-9 are independently influenced by demographic, clinical and laboratory characteristics. It is estimated that these factors should be accounted for when interpreting the results of the biomarker assays.

Control of cardiovascular risk factors and health behaviors in patients post acute coronary syndromes eligible for protein convertase subtilisin/kexin-9 inhibitors.

BACKGROUND: We aimed to examine cardiovascular risk factors and health behaviors in patients with acute coronary syndromes (ACS) according to potential extension of eligibility criteria for protein convertase subtilisin/kexin-9 inhibitors (PCSK9i) to all patients with low-density lipoprotein cholesterol (LDL-c) equal or above 1.8 mmol/l. METHODS: In this prospective cross-sectional study, patients with ACS between 2009 and 2016 and with available LDL-c at one year were considered. We defined three mutually exclusive groups of patients according to eligibility for PCSK9i: "not eligible", "currently eligible", and "newly eligible". We explored the control of cardiovascular risk factors and health behaviors. RESULTS: Out of 3025 patients who had an ACS one year ago, 1071 (35.4%) were not eligible for PCSK9i, 415 (13.7%) were currently eligible, and 1539 (50.9%) were newly eligible. The proportion of patients with uncontrolled hypertension in the not eligible group was lower than in the group currently eligible (27.6% vs 33.6%, p = 0.02), but similar to the group newly eligible (27.6% vs 28.2%, p = 0.73). The proportion of smokers in the not eligible group was lower than in the group currently eligible (21.2% vs 28.0%, p = 0.02), but similar to the group newly eligible (21.2% vs 22.5%, p = 0.51). CONCLUSIONS: More than half of patients with ACS would be additionally eligible for PCSK9i if prescription is extended from current guidelines to all patients with LDL-c equal or above 1.8 mmol/l. Patients currently eligible for PCSK9i one year after an ACS had a worst control of cardiovascular risk factors than patients potentially newly eligible.

Racial and insurance disparities among patients presenting with chest pain in the US: 2009-2015.

BACKGROUND: Nationally representative studies have shown significant racial and socioeconomic disparities in the triage and diagnostic evaluation of patients presenting to the emergency department (ED) with chest pain. However, these studies were conducted over a decade ago and have not been updated amidst growing awareness of healthcare disparities. OBJECTIVE: We aimed to reevaluate the effect of race and insurance type on triage acuity and diagnostic testing to assess if these disparities persist. METHODS: We identified ED visits for adults presenting with chest pain in the 2009-2015 National Hospital Ambulatory Health Care Surveys. Using weighted logistic regression, we examined associations between race and payment type with triage acuity and likelihood of ordering electrocardiography (ECG) or cardiac enzymes. RESULTS: A total of 10,441 patients met inclusion criteria, corresponding to an estimated 51.4 million patients nationwide. When compared with white patients, black patients presenting with chest pain were less likely to have an ECG ordered (adjusted odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.69-0.99). Patients with Medicare, Medicaid, and no insurance were also less likely to have an ECG ordered compared to patients with private insurance (Medicare: OR = 0.79, CI = 0.63-0.99; Medicaid: OR = 0.67, CI = 0.53-0.84; no insurance: OR = 0.68, CI = 0.55-0.84). Those with Medicare and Medicaid were less likely to be triaged emergently (Medicare: OR = 0.84, CI = 0.71-0.99; Medicaid: OR = 0.76, CI = 0.64-0.91) and those with Medicare were less likely to have cardiac enzymes ordered (OR = 0.84, CI = 0.72-0.98). CONCLUSIONS: Persistent racial and insurance disparities exist in the evaluation of chest pain in the ED. Compared to earlier studies, disparities in triage acuity and cardiac enzymes appear to have diminished, but disparities in ECG ordering have not. Given current Class I recommendations for ECGs on all patients presenting with chest pain emergently, our findings highlight the need for improvement in this area.

Prognostic Role of Elevated Myeloperoxidase in Patients with Acute Coronary Syndrome: A Systemic Review and Meta-Analysis.

BACKGROUND: Myocardial inflammation following acute ischemic injury has been linked to poor cardiac remodeling and heart failure. Many studies have linked myeloperoxidase (MPO), a neutrophil and inflammatory marker, to cardiac inflammation in the setting of acute coronary syndrome (ACS). However, the prognostic role of MPO for adverse clinical outcomes in ACS patients has not been well established. METHODS: MEDLINE and Cochrane databases were searched for studies from 1975 to March 2018 that investigated the prognostic value of serum MPO in ACS patients. Studies which have dichotomized patients into a high MPO group and a low MPO group reported clinical outcomes accordingly and followed up patients for at least 30 days to be eligible for enrollment. Data were analyzed using random-effects model. Sensitivity analyses were conducted for quality control. RESULTS: Our meta-analysis included 13 studies with 9090 subjects and a median follow-up of 11.4 months. High MPO level significantly predicted mortality (odds ratio (OR) 2.03; 95% confidence interval (CI): 1.40-2.94; P < 0.001), whereas it was not significantly predictive of major adverse cardiac events and recurrent myocardial infarction (MI) (OR 1.28; CI: 0.92-1.77, P = 0.14 and OR 1.23; CI: 0.96-1.58, P = 0.101, respectively). Hypertension, diabetes mellitus, and age did not affect the prognostic value of MPO for clinical outcomes, whereas female gender and smoking status have a strong influence on the prognostic value of MPO in terms of mortality and recurrent MI (metaregression coefficient -8.616: 95% CI -14.59 to -2.633, P = 0.0048 and 4.88: 95% CI 0.756 to 9.0133, P = 0.0204, respectively). CONCLUSIONS: Our meta-analysis suggests that high MPO levels are associated with the risk of mortality and that MPO can be incorporated in risk stratification models that guide therapy of high-risk ACS patients.

Association between serum lipoprotein-associated phospholipase A2, ischemic modified albumin and acute coronary syndrome: a cross-sectional study.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a newly emerging biomarker with strong pro-inflammatory effects, and is an independent risk predictor of atherosclerotic plaque rupture and thrombosis. In addition, ischemic modified albumin (IMA) is another important marker for the evaluation of myocardial ischemia, and has been approved by the U.S. Food and Drug Administration. The objective of this study was to investigate serum Lp-PLA2 and IMA in the early diagnosis, progression and prognosis of acute coronary syndrome (ACS). Serum Lp-PLA2 and IMA were detected using an AU5800 automatic biochemical analyzer in samples from 180 patients with ACS [n = 60 with unstable angina pectoris (UA), n = 56 with non-ST segment elevation myocardial infarction (NSTEMI), and n = 64 with ST segment elevation myocardial infarction (STEMI)] and 60 healthy control subjects. The relationship between Lp-PLA2 and IMA with Gensini score and the number of coronary artery lesions was explored, and logistic regression was conducted to identify risk factors for major adverse cardiovascular events (MACE). Serum Lp-PLA2 and IMA were significantly higher in all ACS subgroups compared to the control group (P < 0.05), were positively associated with the severity of ACS based on the Gensini score (P < 0.05), and were significantly higher in patients with double- and triple-vessel lesions compared to those with single-vessel lesions and healthy controls (P < 0.05). Logistic regression identified Lp-PLA2, IMA, and troponin I levels as independent risk factors for MACE. Lp-PLA2 and IMA were predictive of the degree of myocardial ischemia in patients with ACS, and may provide important clinical significance for the early diagnosis of ACS and the choice of treatment strategy.

Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction.

BACKGROUND: Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling. METHODS AND RESULTS: Patients with acute MI had higher plasma CatK levels (20.49 ±â€¯7.07 pmol/L, n = 26) than those in subjects with stable angina pectoris (8.34 ±â€¯1.66 pmol/L, n = 28, P = .01) or those without coronary heart disease (6.63 ±â€¯0.84 pmol/L, n = 93, P = .01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4+ T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk-/-) and their wild-type (Ctsk+/+) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk+/+ littermates (fractional shortening percentage: 5.01 ±â€¯0.68 vs. 8.62 ±â€¯1.04, P < .01, 7 days post-MI; 4.32 ±â€¯0.52 vs. 7.60 ±â€¯0.82, P < .01, 28 days post-MI). At 7 days post-MI, hearts from Ctsk-/- mice contained less CatK-specific type-I collagen fragments (10.37 ±â€¯1.91 vs. 4.60 ±â€¯0.49 ng/mg tissue extract, P = .003) and more fibrosis (1.67 ±â€¯0.93 vs. 0.69 ±â€¯0.20 type-III collagen positive area percentage, P = .01; 14.25 ±â€¯4.12 vs. 6.59 ±â€¯0.79 α-smooth muscle actin-positive area percentage, P = .016; and 0.82 ±â€¯0.06 vs. 0.31 ±â€¯0.08 CD90-positive area percentage, P = .008) than those of Ctsk+/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival. CONCLUSION: Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death.

Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia).

BACKGROUND: The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. METHODS: The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. RESULTS: In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. CONCLUSIONS: The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.

Serum MMP-9 Diagnostics, Prognostics, and Activation in Acute Coronary Syndrome and Its Recurrence.

Matrix metalloproteinase (MMP)-9 is crucial in atherosclerotic plaque rupture and tissue remodeling after a cardiac event. The balance between MMP-9 and endogenous inhibitor, tissue inhibitors of matrix metalloproteinase 1 (TIMP-1), is important in acute coronary syndrome (ACS). This is an age- and gender-matched case-control study of ACS (N = 669). Patients (45.7%) were resampled after recovery, and all were followed up for 6 years. The molecular forms of MMP-9 were investigated by gelatin zymography. Diagnostically, MMP-9 and the MMP-9/TIMP-1 molar ratio were associated with ACS (OR 5.81, 95% CI 2.65-12.76, and 4.96, 2.37-10.38). The MMP-9 concentrations decreased 49% during recovery (p < 0.001). The largest decrease of these biomarkers between acute and recovery phase (ΔMMP-9) protected the patients from major adverse cardiac events, especially the non-fatal events. The fatal events were associated with in vitro activatable MMP-9 levels (p = 0.028). Serum MMP-9 and the MMP-9/TIMP-1 molar ratio may be valuable in ACS diagnosis and prognosis. High serum MMP-9 activation potential is associated with poor cardiovascular outcome.

Mitochondria-targeted esculetin inhibits PAI-1 levels by modulating STAT3 activation and miR-19b via SIRT3: Role in acute coronary artery syndrome.

In this study we explored the microRNAs responsible for the regulation of PAI-1 during LPS-stimulated inflammation in human aortic endothelial cells and subsequently studied the effect of a newly synthesized mitochondria-targeted esculetin (Mito-Esc) that was shown for its anti-atherosclerotic potential, in modulating PAI-1 levels and its targeted miRs during angiotensin-II-induced atherosclerosis in ApoE-/- mice. LPS-stimulated PAI-1 was accompanied with an upregulation of miR-19b and down-regulation of miR-30c. These effects of LPS on PAI-1 were reversed in the presence of both parent esculetin and Mito-Esc. However, the effect of Mito-Esc was more pronounced in the regulation of PAI-1. In addition, LPS-stimulated PAI-1 expression was significantly decreased in cells treated with Anti-miR-19b, thereby suggesting that miR-19b co-expression plays a key role in PAI-1 regulation. The results also show that incubation of cells with Stattic, an inhibitor of STAT-3, inhibited LPS-stimulated PAI-1 expression. Interestingly, knockdown of SIRT3, a mitochondrial biogenetic marker, enhanced PAI-1 levels via modulation of miR-19b and -30c. Mito-Esc treatment significantly inhibited Ang-II-induced PAI-1, possibly via altering miR-19b and 30c in ApoE-/- mice. The association between PAI-1, miR-19b and -30c were further confirmed in plasma and microparticles isolated from patients suffering from acute coronary syndrome of various degrees. Taken together, LPS-induced PAI-1 involves co-expression of miR-19b and down regulation of miR-30c, and Mito-Esc treatment by modulating miR-19b and miR-30c through SIRT3 activation, inhibits PAI-1 levels that, in part, contribute to its anti-atherosclerotic effects. Moreover, there exists a strong positive correlation between miR-19b and PAI-1 in patients suffering from ST-elevated myocardial infarction.

Utility of myeloperoxidase in the differential diagnosis of acute coronary syndrome.

OBJECTIVES: To determine the usefulness of myeloperoxidase in discriminating between patients with acute coronary syndrome and patients with chest pain by other causes. METHODS: The study included all patients over 18 years of age who come consecutively to the emergency department from September 2015 to December 2015 with chest pain of non-traumatic origin. The initial patient evaluation was performed according to the study protocol for patients with suspected acute coronary syndrome (ACS) in our Emergency Department. This included the serial measurement of troponin, and in this case myeloperoxidase, with serialization on admission and at 6h. For the determination of myeloperoxidase (MPO), a single step sandwich enzyme immunoassay by Siemens, automated on a Dimension analyser, was used. RESULTS: Statistically significant differences were observed in the concentration of myeloperoxidase at time 0 among patients diagnosed with ACS: 505 (413)pmol/L, and non-ACS patients: 388 (195)pmol/L (p<.001), as well as at 6h (p<.001). An area under the curve ROC of 0.824 was obtained at 6h for ACS patients, with a confidence interval of 95% from 0.715 to 0.933 and a level of significance of p<.001. Statistically significant differences were also found in the concentration of myeloperoxidase at time 0 and at 6h among patients with ACS and patients with heart disease other than coronary artery disease. CONCLUSIONS: The concentration of MPO helps to differentiate between ACS and non-ACS patients, as well as between ACS patients and patients with heart diseases other than coronary artery disease.

Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells.

Aims: In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results: To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042). Conclusion: Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.

Utility of myeloperoxidase in the differential diagnosis of acute coronary syndrome / Utilidad de la determinación de mieloperoxidasa en el diagnóstico diferencial del síndrome coronario agudo

Abstract Objectives: To determine the usefulness of myeloperoxidase in discriminating between patients with acute coronary syndrome and patients with chest pain by other causes. Methods: The study included all patients over 18 years of age who come consecutively to the emergency department from September 2015 to December 2015 with chest pain of non- traumatic origin. The initial patient evaluation was performed according to the study protocol for patients with suspected acute coronary syndrome (ACS) in our Emergency Department. This included the serial measurement of troponin, and in this case myeloperoxidase, with serialization on admission and at 6 h. For the determination of myeloperoxidase (MPO), a single step sandwich enzyme immunoassay by Siemens, automated on a Dimension analyser, was used. Results: Statistically significant differences were observed in the concentration of myeloperoxidase at time 0 among patients diagnosed with ACS: 505 (413) pmol/L, and non-ACS patients: 388 (195) pmol/L (p < .001), as well as at 6 h (p < .001). An area under the curve ROC of 0.824 was obtained at 6 h for ACS patients, with a confidence interval of 95% from 0.715 to 0.933 and a level of significance of p <.001. Statistically significant differences were also found in the concentration of myeloperoxidase at time 0 and at 6 h among patients with ACS and patients with heart disease other than coronary artery disease. Conclusions: The concentration of MPO helps to differentiate between ACS and non-ACS patients, as well as between ACS patients and patients with heart diseases other than coronary artery disease.

Resumen Objetivos: Conocer la utilidad de mieloperoxidasa (MPO) para discriminar entre pacientes con síndrome coronario agudo y dolor torácico de otras causas. Métodos: De septiembre a diciembre de 2015 se incluyeron todos los pacientes mayores de 18 años que acudieron de forma consecutiva al servicio de urgencias con dolor torácico de origen no traumático. La evaluación inicial del paciente se realizó de acuerdo con el protocolo de estudio para pacientes con sospecha de síndrome coronario agudo (SCA) en nuestro servicio de urgencias, que incluye la medición de troponina y en este caso MPO, con serialización al ingreso y a las 6 h. Para la determinación de MPO se utilizó un inmunoensayo enzimático de tipo sándwich, de una sola etapa de Siemens, automatizado en un equipo Dimension . Resultados: Se obtuvieron diferencias estadísticamente significativas en la concentración de MPO a tiempo 0 entre los pacientes con diagnóstico de SCA: 505 (413) pmol/l y los pacientes no SCA: 388 (195 pmol/l (p < 0.001), así como a las 6 h (p < 0.001). Se obtuvo a las 6 h un área bajo la curva ROC para pacientes con SCA de 0.824 con un intervalo de confianza del 95% de 0.715 a 0.933 y un grado de significación p < 0.001. También se obtuvieron diferencias estadísticamente significativas en la concentración de MPO tanto a tiempo 0 como a las 6 h entre pacientes con SCA y pacientes con enfermedad cardiaca diferente de enfermedad coronaria. Conclusiones: La concentración de MPO sirve para diferenciar entre pacientes SCA y pacientes que no son SCA, así como entre pacientes SCA y pacientes con otras enfermedades cardiacas diferentes a la enfermedad coronaria.

Aspirin safety in glucose-6-phosphate dehydrogenase deficiency patients with acute coronary syndrome undergoing percutaneous coronary intervention.

The use of aspirin, as part of a dual antiplatelet therapy regimen, is an established standard following coronary stenting in patients suffering from acute coronary syndrome (ACS). However, in glucose-6-phosphate dehydrogenase (G6PD) deficient patients, precaution is always taken with aspirin use, due to the risk of haemolysis. We reviewed all previous cases of G6PD deficient patients with ACS, in addition to a review of the available literature, to better understand the safety of aspirin use in this population. To date, there are no reported cases of haemolysis following aspirin use in this patient group and no guideline is established to date.

CYP2C19 activity and cardiovascular risk factors in patients with an acute coronary syndrome. / Actividad de CYP2C19 y factores de riesgo cardiovascular en pacientes con síndrome coronario agudo.

INTRODUCTION: CYP2C19 is a major isoform of cytochrome P450 that metabolizes a number of drugs and is involved in the glucocorticoids synthesis. CYP2C19 polymorphisms have been associated with the genetic risk for type 2 diabetes. METHODS: Five hundred and three patients with an acute coronary event were studied to assess the association between the CYP2C19 activity (CYP2C19*2, CYP2C19*3 and CYP2C19*17 variants) and the type of acute coronary syndrome, cardiovascular risk factors (arterial systemic hypertension, diabetes mellitus, dyslipidemia and smoking), analytical parameters and the extent and severity of coronary atherosclerosis. RESULTS: Genotype distribution in our series was similar to that expected in the Caucasian population. Among the traditional cardiovascular risk factors, very poor metabolizer patients (*2/*2, *3/*3 or *2/*3) had a greater tendency to present diabetes mellitus needing insuline (P=.067). Conversely, when we compared very poor, poor and normal metabolizers vs. rapid and ultrarapid metabolizers we found significant differences in those diabetic patients under insulin treatment (64 patients [18%] vs. 17 patients [11%]; P=.032). On the contrary, analytical parameters, systemic arterial hypertension, dyslipidemia, smoking or the personal/family history of coronary artery disease did not reach statistical significance regardless of CYP2C19 activity. Similarly, the number and the type of coronary disease (thrombotic, fibrotic or both) did not differ between patients with different CYP2C19 enzyme activity. CONCLUSION: Patients with an acute coronary event and a very poor, poor and normal CYP2C19 metabolizer genotype have a higher prevalence of diabetes mellitus needing insuline than patients with the rapid and ultrarapid metabolizers CPY2C19 genotype.

Glutathione peroxidase activity and expression levels are significantly increased in acute coronary syndromes.

High levels of the antioxidant enzyme, glutathione peroxidase (GPx), have been associated with improved outcomes following acute coronary syndromes (ACS), suggesting a protective role. How GPx levels are altered with coronary disease is not clearly established. This study examined GPx activity, protein, and mRNA levels in healthy controls, patients with stable coronary artery disease (CAD), and patients with ACS. We studied 20 individuals from each of the healthy control, stable CAD, and ACS groups. GPx activity and protein levels, along with oxidized low-density lipoprotein (oxLDL) were assayed in plasma. GPx mRNA levels from whole blood were quantified using real-time PCR. Levels of GPx activity in the plasma were higher in ACS (109±7.7 U/mL) compared with patients with stable CAD (95.2±16.4 U/mL, p<0.01) and healthy controls (87.6±8.3 U/mL, p<0.001). Plasma GPx protein levels were also elevated in ACS (21.6±9.5 µg/mL) compared with patients with stable CAD (16.5±2.8 µg/mL, p<0.05) and healthy controls (16.3±5.3 µg/mL, p<0.05). Levels of GPX1, GPX3, and GPX4 mRNA were significantly higher in the patients with ACS. Levels of oxLDL were also significantly higher in patients with ACS (61.9±22.2 U/L) than in patients with stable CAD (47.8±10.4 U/L, p<0.05) and healthy controls (48.9±11.9 U/L, p<0.05). Levels of oxLDL, GPx activity, protein, and mRNA are all significantly higher in patients with ACS compared with patients with stable CAD and healthy controls. These findings suggest that GPx may be upregulated in response to a change in oxidative stress during an ACS.

Elevated plasma interleukin-37 playing an important role in acute coronary syndrome through suppression of ROCK activation.

OBJECTIVE: The plasma level of interleukin-37 is elevated in patients with acute coronary syndrome, however, its function during the onset and progress of the disease remains unclear. This study aimed to investigate the clinical significance of IL-37 in acute coronary syndrome and its underlying mechanism. METHODS: 124 patients with acute coronary syndrome and 40 healthy controls were recruited in this study. Plasma interleukin-37 levels were measured in 41 patients with ST elevation myocardial infarction (STEMI), 41 patients with non-STEMI, 42 patients with unstable angina, and 40 controls. Mortality was defined as an event. RESULTS: In this study, the mean follow-up period was 824±306 days (2-1077 days). 22% (n=27) of patients died. The mortality rate was significantly lower in patients with interleukin-37 serum levels below the median (6.4 pg/mL) than those with interleukin-37 serum levels above 6.4 pg/mL at 36-month follow-up (16% vs. 24%, p=0.02, log rank X2=5.39). Highly concentration of the anti-inflammatory interleukin-37 exerted a protective effect by suppressing the activated Rho Kinase (ROCK) activity in the peripheral blood mononuclear cells in vivo and in vitro after ischemia/reperfusion injury and stimulation of the Rho activator, calpeptin. CONCLUSIONS: The interleukin-37 level is significantly increased in acute coronary syndrome. Elevated baseline interleukin-37 levels in patients on admission are associated with poor outcomes. Thus, we propose that interleukin-37 could be a biomarker predictive of mortality in acute coronary syndrome. Moreover, this study reveals that the protective effect of interleukin-37 against atherosclerosis may involve the inhibition of ROCK activity.

CYP2C19 LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis.

PURPOSE: This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y12 inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y12 inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider. RESULTS: Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y12 inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y12 inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively. CONCLUSIONS: Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y12 inhibitor therapy for ACS patients with PCI.

Relationship between Glutathione Peroxidase, Platelet Reactivity, and Reactive Oxygen Species in an Acute Coronary Syndrome Population.

Low activity levels of the antioxidant enzyme, glutathione peroxidase (GPx), have been implicated in adverse clinical outcomes in coronary artery disease. A potential mechanistic link for this relationship is that low GPx activity predisposes patients to thrombotic complications due to impaired reactive oxygen species (ROS) metabolism. GPx potentially regulates the bioavailability of nitric oxide (NO) - a potent platelet inhibitor - therefore indirectly affecting platelet activation. This study examined the relationship between levels of GPx activity, ROS, and platelet activation in 51 acute coronary syndrome (ACS) patients. No relationship was observed between GPx activity and platelet reactivity nor between ROS levels and platelet reactivity. However patients with low GPx activity had significantly higher ROS levels (r2=0.1, p<0.05), suggesting a differential capacity to upregulate antioxidant defence in response to oxidative stress. Low levels of GPx activity may contribute to increased clinical risk by an inability to protect against oxidant-mediated damage.