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BACKGROUND: Aortic valve sclerosis (AVSc) presents similar pathogenetic mechanisms to coronary artery disease and is associated with short- and long-term mortality in patients with coronary artery disease. Evidence of AVSc-specific pathophysiological traits in acute myocardial infarction (AMI) is currently lacking. Thus, we aimed to identify a blood-based transcriptional signature that could differentiate AVSc from no-AVSc patients during AMI. METHODS: Whole-blood transcriptome of AVSc (n=44) and no-AVSc (n=66) patients with AMI was assessed by RNA sequencing on hospital admission. Feature selection, differential expression, and enrichment analyses were performed to identify gene expression patterns discriminating AVSc from no-AVSc and infer functional associations. Multivariable Cox regression analysis was used to estimate the hazard ratios of cardiovascular events in AVSc versus no-AVSc patients. RESULTS: This cross-sectional study identified a panel of 100 informative genes capable of distinguishing AVSc from no-AVSc patients with 94% accuracy. Further analysis revealed significant mean differences in 143 genes, of which 30 genes withstood correction for age and previous AMI or coronary interventions. Functional inference unveiled a significant association between AVSc and key biological processes, including acute inflammatory responses, type I IFN (interferon) response, platelet activation, and hemostasis. Notably, patients with AMI with AVSc exhibited a significantly higher incidence of adverse cardiovascular events during a 10-year follow-up period, with a full adjusted hazard ratio of 2.4 (95% CI, 1.3-4.5). CONCLUSIONS: Our findings shed light on the molecular mechanisms underlying AVSc and provide potential prognostic insights for patients with AMI with AVSc. During AMI, patients with AVSc showed increased type I IFN (interferon) response and earlier adverse cardiovascular outcomes. Novel pharmacological therapies aiming at limiting type I IFN response during or immediately after AMI might improve poor cardiovascular outcomes of patients with AMI with AVSc.
Assuntos
Doença da Artéria Coronariana , Infarto do Miocárdio , Humanos , Doença da Artéria Coronariana/patologia , Valva Aórtica/patologia , Transcriptoma , Esclerose/patologia , Estudos Transversais , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Infarto do Miocárdio/epidemiologia , Imunidade , InterferonsRESUMO
BACKGROUND: ADP-induced platelet activation leads to cell surface expression of several proteins, including TF (tissue factor). The role of ADP receptors in platelet TF modulation is still unknown. We aimed to assess the (1) involvement of P2Y1 and P2Y12 receptors in ADP-induced TF exposure; (2) modulation of TFpos-platelets in anti-P2Y12-treated patients with coronary artery disease. Based on the obtained results, we revisited the intracellular localization of TF in platelets. METHODS: The effects of P2Y1 or P2Y12 antagonists on ADP-induced TF expression and activity were analyzed in vitro by flow cytometry and thrombin generation assay in blood from healthy subjects, P2Y12-/-, and patients with gray platelet syndrome. Ex vivo, P2Y12 inhibition of TF expression by clopidogrel/prasugrel/ticagrelor, assessed by VASP (vasodilator-stimulated phosphoprotein) platelet reactivity index, was investigated in coronary artery disease (n=238). Inhibition of open canalicular system externalization and electron microscopy (TEM) were used for TF localization. RESULTS: In blood from healthy subjects, stimulated in vitro by ADP, the percentage of TFpos-platelets (17.3±5.5%) was significantly reduced in a concentration-dependent manner by P2Y12 inhibition only (-81.7±9.5% with 100 nM AR-C69931MX). In coronary artery disease, inhibition of P2Y12 is paralleled by reduction of ADP-induced platelet TF expression (VASP platelet reactivity index: 17.9±11%, 20.9±11.3%, 40.3±13%; TFpos-platelets: 10.5±4.8%, 9.8±5.9%, 13.6±6.3%, in prasugrel/ticagrelor/clopidogrel-treated patients, respectively). Despite this, 15% of clopidogrel good responders had a level of TFpos-platelets similar to the poor-responder group. Indeed, a stronger P2Y12 inhibition (130-fold) is required to inhibit TF than VASP. Thus, a VASP platelet reactivity index <20% (as in prasugrel/ticagrelor-treated patients) identifies patients with TFpos-platelets <20% (92% sensitivity). Finally, colchicine impaired in vitro ADP-induced TF expression but not α-granule release, suggesting that TF is open canalicular system stored as confirmed by TEM and platelet analysis of patients with gray platelet syndrome. CONCLUSIONS: Data show that TF expression is regulated by P2Y12 and not P2Y1; P2Y12 antagonists downregulate the percentage of TFpos-platelets. In clopidogrel good-responder patients, assessment of TFpos-platelets highlights those with residual platelet reactivity. TF is stored in open canalicular system, and its membrane exposure upon activation is prevented by colchicine.
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Doença da Artéria Coronariana , Síndrome da Plaqueta Cinza , Humanos , Plaquetas/metabolismo , Clopidogrel/farmacologia , Doença da Artéria Coronariana/metabolismo , Síndrome da Plaqueta Cinza/metabolismo , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/metabolismo , Testes de Função Plaquetária/métodos , Cloridrato de Prasugrel/metabolismo , Cloridrato de Prasugrel/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12 , Tromboplastina/metabolismo , TicagrelorRESUMO
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter-2 inhibitors (SGLT-2i) demonstrated cardiovascular and renal protection. Whether their benefits occur also during hospitalization for acute myocardial infarction (AMI) in patients with diabetes mellitus (DM) is not known. We evaluated in-hospital outcomes of patients hospitalized with AMI according to their chronic use of GLP-1 RA and/or SGLT-2i. METHODS: Using the health administrative databases of Lombardy, patients hospitalized with AMI from 2010 to 2019 were included. They were stratified according to DM status, then grouped into three cohorts using a propensity score matching: non-DM patients; DM patients treated with GLP-1 RA and/or SGLT-2i; DM patients not treated with GLP-1 RA/SGLT-2i. The primary endpoint of the study was the composite of in-hospital mortality, acute heart failure, and acute kidney injury requiring renal replacement therapy. RESULTS: We identified 146,798 patients hospitalized with AMI (mean age 71 ± 13 years, 34% females, 47% STEMI; 26% with DM). After matching, 3,090 AMI patients (1030 in each group) were included in the analysis. Overall, the primary endpoint rate was 16% (n = 502) and progressively increased from non-DM patients to DM patients treated with and without GLP-1 RA/SGLT-2i (13%, 16%, and 20%, respectively; P < 0.0001). Compared with non-DM patients, DM patients with GLP-1 RA/SGLT-2i had a 30% higher risk of the primary endpoint, while those not treated with GLP-1 RA/SGLT-2i had a 60% higher risk (P < 0.0001). CONCLUSION: Chronic therapy with GLP-1 RA and/or SGLT-2i has a favorable impact on the clinical outcome of DM patients hospitalized with AMI.
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Diabetes Mellitus Tipo 2 , Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hospitais , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistasRESUMO
Background: Patients on chronic dialysis are less likely to be treated with percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). This is due to the lack of evidence from randomized trials, concerns about possible PCI-related side effects, and multimorbidity. Therefore, routine use of PCI for treatment of dialysis patients with AMI remains an unresolved issue. Methods: We analyzed data of patients on chronic dialysis hospitalized with AMI from 2003 to 2018, by using the administrative Lombardy Health Database (Italy). Patients were grouped according to whether they underwent or not PCI during index hospitalization. The primary outcome was in-hospital mortality, 1-year mortality was the secondary endpoint. Results: During the study period, 265,048 patients were hospitalized with AMI. Of them, 3206 (1.2%) were on chronic dialysis (age 71 ± 11; 72% males). Among dialysis patients, 44% underwent PCI, while 54% underwent PCI among non-dialysis patients (p < 0.0001). Dialysis was an independent predictor of treatment with medical therapy only (OR 0.75 [95% CI 0.70-0.81]). In-hospital mortality in the dialysis cohort was 15%, significantly lower in patients treated with PCI than in those not treated with PCI (11% vs. 19%; p < 0.0001). One-year mortality was 47% and it was lower in PCI-treated patients (33% vs. 52%; p < 0.0001). The adjusted risk of the study endpoints was significantly lower in dialysis patients undergoing PCI: OR 0.62 (95% CI 0.50-0.76) for in-hospital mortality; HR 0.63 (95% CI 0.56-0.71) for 1-year mortality. Conclusions: This study showed that in AMI patients on chronic dialysis, PCI is associated with a significant in-hospital and 1-year survival benefit. Yet, they underwent PCI less frequently than patients with preserved renal function.
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BACKGROUND: Diabetes mellitus (DM) is associated with an increased mortality risk in patients hospitalized with acute myocardial infarction (AMI); however, no studies have investigated the impact of the duration of DM on in-hospital mortality. In this study, we evaluated in-hospital mortality in AMI patients according to DM status and its duration. METHODS: Using health administrative databases of Lombardy, DM patients≥50 years hospitalized with AMI from 2010 to 2019 were included in the analysis and were stratified according to the duration of DM: <5, 5-10, and > 10 years. The primary endpoint was mortality during AMI hospitalization and the secondary endpoint was 1-year mortality in comparison with No-DM patients. Logistic and Cox regressions analyses were used to estimate odds ratios (ORs, CI 95%) and hazard ratios (HRs, CI 95%) for the outcomes, according to DM status and duration and AMI type (STEMI and NSTEMI). RESULTS: Our study cohort comprised 29,566 and 109,247 DM and No-DM patients, respectively. Adjusted ORs and HRs showed a significantly higher risk of in-hospital mortality (OR 1.50, 95% CI 1.43-1.58) and 1-year mortality (HR 1.51, 95% CI 1.46-1.55) in DM patients in comparison with those without. These risks increased progressively with the duration of DM, with the highest risk observed in patients with DM duration ≥ 10 years (OR 1.59, 95% CI 1.50-1.69 for in-hospital mortality and HR 1.59, 95% CI 1.53-1.64 for 1-year mortality). These findings were similar in STEMI and in NSTEMI patients. CONCLUSIONS: Our study demonstrates that the duration of DM parallels mortality risk in patients hospitalized with AMI, highlighting that DM duration should be considered as an important early prognostic risk factor in patients with AMI.
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Diabetes Mellitus , Infarto do Miocárdio , Infarto do Miocárdio sem Supradesnível do Segmento ST , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Diabetes Mellitus/diagnóstico , Mortalidade Hospitalar , Hospitalização , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/terapia , Infarto do Miocárdio/complicações , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/terapia , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicaçõesRESUMO
The coronavirus disease (COVID)-19 pandemic continues to have an impact on health care. A potential new wave can be foreseen concerning the impact of the pandemic on medical research and literature. We focused our attention on journals belonging to "Medicine, General and Internal" Clarivate™ category and "Q1" journal impact factor quartile. We found that since January 2020, 9621 papers regarding COVID-19 have been published in these journals. This occurred at the expense of non-COVID-19-related scientific papers as most journals did not increase the total number of their published articles. Thus, our analysis may outlook a new potential scientific wave related to COVID-19, in addition to the clinical ones, possibly delaying the improvement in the quality of care for other diseases in the next years.
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Pesquisa Biomédica , COVID-19 , Humanos , Fator de Impacto de Revistas , PandemiasRESUMO
Monocyte recruitment after vascular injury and their migration through the vessel wall represent crucial events in the initiation, progression, and destabilization of atherosclerotic plaque. Circulating monocytes are exposed to stimuli that alter their physiological state, and among them, lipids play a key role. Several studies investigated the mechanisms by which lipids affect monocyte functions promoting coronary atherosclerotic plaque initiation, but information on the relationship between lipid composition and function of monocyte is scant. We aimed at studying the migration of circulating monocytes isolated from patients with acute myocardial infarction (AMI) at hospital presentation and investigating its correlation with cellular lipid profile. The migration of monocytes was tested using both fetal bovine serum (FBS) and autologous serum as chemoattractant stimuli. Monocyte lipid profile was evaluated through an untargeted lipidomics approach, using a liquid chromatography/time-of-flight mass spectrometry platform. We observed that AMI patients' monocytes showed a significant increase in FBS and autologous serum-mediated migration compared to controls. Moreover, a different monocyte lipidomic profile between the two study groups was detected. In particular, AMI patients' monocytes showed an altered composition in ceramides, with an increase in lactosylceramide and in phospholipids (ie, phosphatidylethanolamine and lisophosphatidylethanolamine). Of note, a positive correlation between lactosylceramide levels and monocyte migration was observed. Furthermore, the lactosylceramide synthase inhibition significantly reduced FBS-induced monocyte migration. Our results highlight the influence of lactosylceramide on the monocyte migration capacity, pointing out a new possible mechanism of lipids in the onset of atherothrombosis and, hence, in AMI.
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Movimento Celular , Lactosilceramidas/metabolismo , Lipidômica/métodos , Lipídeos/análise , Monócitos/metabolismo , Infarto do Miocárdio/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismoRESUMO
Clinical data indicate that low circulating l-homoarginine (HArg) concentrations are associated with cardiovascular (CV) disease, CV mortality, and all-cause mortality. A high number of LC-based analytical methods for the quantification of HArg, in combination with the l-arginine (Arg)-related pathway metabolites, have been reported. However, these methods usually consider a limited panel of analytes. Thus, in order to achieve a comprehensive picture of the Arg metabolism, we described an improved targeted metabolomic approach based on a multiple reaction monitoring (MRM) mass spectrometry method for the simultaneous quantification of the Arg/nitric oxide (NO) pathway metabolites. This methodology was then employed to quantify the plasma concentrations of these analytes in a cohort of individuals with different grades/types of coronary artery disease (CAD) in order to increase knowledge about the role of HArg and its associated metabolites in the CV field. Our results showed that the MRM method here implemented is suitable for the simultaneous assessment of a wide panel of amino acids involved in the Arg/NO metabolic pathway in plasma samples from patients with CV disease. Further, our findings highlighted an impairment of the Arg/NO metabolic pathway, and suggest a sex-dependent regulation of this metabolic route.
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Doença da Artéria Coronariana/diagnóstico por imagem , Homoarginina/sangue , Metabolômica/métodos , Óxido Nítrico/sangue , Idoso , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Caracteres SexuaisRESUMO
BACKGROUND: Reliable preprocedural risk scores for the prediction of Contrast-Induced Acute Kidney Injury (CI-AKI) following Percutaneous Coronary Intervention (pPCI) in patients with ST-elevation myocardial infarction (STEMI) are lacking. Aim of this study was to derive and validate a preprocedural Risk Score in this setting. METHODS: Two prospectively enrolled patient cohorts were used for derivation and validation (n = 3,736). CI-AKI was defined as creatinine increase ≥0.5 mg/dl <72 h postpPCI. Odds ratios from multivariable logistic regression model were converted to an integer, whose sum represented the Risk Score. RESULTS: Independent CI-AKI predictors were: diabetes, Killip class II-III (2 points each), age > 75 years, anterior MI (3 points), Killip class IV (4 points), estimated GFR < 60 ml/min/1.73m2 (5 points). The Risk Score c-statistic was 0.84 in both cohorts. Compared with patients with Risk Score ≤ 4, the relative risks of CI-AKI among patients scoring 5-9 were 6.2 (derivation cohort) and 7.1 (validation cohort); among patients scoring ≥10, 19.8, and 21.4, respectively. CONCLUSIONS: Among STEMI patients, a simple preprocedural Risk Score accurately and reproducibly predicted the risk of CI-AKI, identifying » of patients with a seven-fold risk and 1/10 of patients with a 20-fold risk. This knowledge may help tailored strategies, including delaying revascularization of nonculprit vessels in patients at high risk of CI-AKI.
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Injúria Renal Aguda , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Idoso , Meios de Contraste , Creatinina , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Diabetes mellitus (DM) is a frequent comorbidity in ST-elevation-myocardial infarction (STEMI) patients and carries a higher risk of in-hospital mortality. We recently demonstrated that the higher in-hospital mortality of STEMI patients with DM, when compared to that of patients without DM, is mainly associated with their more frequent cardiac and renal dysfunction. These exploratory results prompted us to hypothesize that this higher risk in DM patients is mediated by their lower cardio-renal functional reserve. METHODS AND RESULTS: We included 5152 STEMI patients treated with primary angioplasty. By using an advanced statistical methodology (path analysis), able to clarify the putative causal paths between variables of interest, we reported that the higher in-hospital mortality of STEMI patients with DM is possibly caused by its adverse impact on cardio-renal function. CONCLUSION: This statistical approach allows to reinforce the well-known notion that DM is associated with an increased in-hospital mortality risk in STEMI and sheds lights on the causal relationship among DM, cardio-renal dysfunction, and higher in-hospital mortality. Whether the mortality gap between DM and non-DM patients with STEMI can be reduced by pharmacological strategies combining cardio-renal protective effects is an intriguing question that deserves an answer in the future.
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Diabetes Mellitus/mortalidade , Coração/fisiopatologia , Mortalidade Hospitalar , Rim/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Comorbidade , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Taxa de Filtração Glomerular , Coração/efeitos dos fármacos , Humanos , Hipoglicemiantes/uso terapêutico , Pacientes Internados , Rim/efeitos dos fármacos , Intervenção Coronária Percutânea/mortalidade , Prognóstico , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Diabetes mellitus (DM) is an important risk factor for acute myocardial infarction (AMI) and a frequent co-morbidity in patients hospitalized with AMI, being present in about 30% of cases. Although current treatment of AMI has considerably improved survival in both patients with and without DM, the presence of DM still doubles the case fatality rate during both the acute phase of AMI and at long-term follow-up. This higher mortality risk of DM patients strongly indicates a particular need for better treatment options in these patients and suggests that intensive medical treatment, prolonged surveillance, and stringent control of other risk factors should be carefully pursued and maintained for as long as possible in them.In this review, we will focus on the close association between DM and in-hospital and long-term mortality in AMI patients. We will also aim at providing current evidence on the mechanisms underlying this association and on emerging therapeutic strategies, which may reduce the traditional mortality gap that still differentiates AMI patients with DM from those without.
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Diabetes Mellitus/mortalidade , Infarto do Miocárdio/mortalidade , Mortalidade Hospitalar , Humanos , Fatores de RiscoRESUMO
Diabetes mellitus (DM) is one of the most common and costly disorders that affect humans around the world. Recently, clinicians and scientists have focused their studies on the effects of glycemic variability (GV), which is especially associated with cardiovascular diseases. In healthy subjects, glycemia is a very stable parameter, while in poorly controlled DM patients, it oscillates greatly throughout the day and between days. Clinically, GV could be measured by different parameters, but there are no guidelines on standardized assessment. Nonetheless, DM patients with high GV experience worse cardiovascular disease outcomes. In vitro and in vivo studies showed that high GV causes several detrimental effects, such as increased oxidative stress, inflammation, and apoptosis linked to endothelial dysfunction. However, the evidence that treating GV is beneficial is still scanty. Clinical trials aiming to improve the diagnostic and prognostic accuracy of GV measurements correlated with cardiovascular outcomes are needed. The present review aims to evaluate the clinical link between high GV and cardiovascular diseases, taking into account the underlined biological mechanisms. A clear view of this challenge may be useful to standardize the clinical evaluation and to better identify treatments and strategies to counteract this DM aspect.
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Doenças Cardiovasculares/etiologia , Complicações do Diabetes/complicações , Hiperglicemia/complicações , Animais , Glicemia/metabolismo , Doenças Cardiovasculares/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Hiperglicemia/metabolismo , Estresse OxidativoRESUMO
The identification of new biomarkers allowing an early and more accurate characterization of patients with ST-segment elevation myocardial infarction (STEMI) is still needed, and exosomes represent an attractive diagnostic tool in this context. However, the characterization of their protein cargo in relation to cardiovascular clinical manifestation is still lacking. To this end, 35 STEMI patients (17 experiencing resuscitated out-of-hospital cardiac arrest (OHCA-STEMI) and 18 uncomplicated) and 32 patients with chronic coronary syndrome (CCS) were enrolled. Plasma exosomes were characterized by the nanoparticle tracking analysis and Western blotting. Exosomes from STEMI patients displayed a higher concentration and size and a greater expression of platelet (GPIIb) and vascular endothelial (VE-cadherin) markers, but a similar amount of cardiac troponin compared to CCS. In addition, a difference in exosome expression of acute-phase proteins (ceruloplasmin, transthyretin and fibronectin) between STEMI and CCS patients was found. GPIIb and brain-associated marker PLP1 accurately discriminated between OHCA and uncomplicated STEMI. In conclusion, the exosome profile of STEMI patients has peculiar features that differentiate it from that of CCS patients, reflecting the pathophysiological mechanisms involved in STEMI. Additionally, the exosome expression of brain- and platelet-specific markers might allow the identification of patients experiencing ischemic brain injury in STEMI.
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Exossomos/metabolismo , Parada Cardíaca Extra-Hospitalar/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Idoso , Biomarcadores/sangue , Ceruloplasmina/análise , Exossomos/química , Fibronectinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Albumina/análise , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Troponina/sangueRESUMO
BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) elevation frequently occurs in acute myocardial infarction (AMI) and is associated with adverse outcomes. Since diabetes mellitus (DM) is characterized by an underlying chronic inflammation, hs-CRP may have a different prognostic power in AMI patients with and without DM. METHODS: We prospectively included 2064 AMI patients; hs-CRP was measured at hospital admission. Patients were grouped according to hs-CRP quartiles and DM status. The primary endpoint was a composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema. Two-year all-cause mortality was the secondary endpoint. RESULTS: Twenty-six percent (n = 548) of patients had DM and they had higher hs-CRP levels than non-DM patients (5.32 vs. 3.24 mg/L; P < 0.0001). The primary endpoint incidence in the overall population (7%, 9%, 13%, 22%; P for trend < 0.0001), in DM (14%, 9%, 21%, 27%; P = 0.0001), and non-DM (5%, 8%, 10%, 19%; P < 0.0001) patients increased in parallel with hs-CRP quartiles. The adjusted risk of the primary endpoint increased in parallel with hs-CRP quartiles in DM and non-DM patients but this relationship was less evident in DM patients. In the overall population, the adjusted OR of the primary endpoint associated with an hs-CRP value ≥ 2 mg/L was 2.10 (95% CI 1.46-3.00). For the same risk, hs-CRP was 7 and 2 mg/L in patients with and without DM. A similar behavior was observed for the secondary endpoint when the HR associated with an hs-CRP value ≥ 2 mg/L found in the overall population was 2.25 (95% CI 1.57-3.22). For the same risk, hs-CRP was 8 and 1.5 mg/L in DM and non-DM patients. CONCLUSIONS: This study shows that hs-CRP predicts in-hospital outcome and two-year mortality in AMI patients with and without DM. However, in DM patients, the same risk of developing events as in non-DM patients is associated to higher hs-CRP levels.
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Proteína C-Reativa/análise , Diabetes Mellitus/sangue , Mediadores da Inflamação/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Admissão do Paciente , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Edema Pulmonar/sangue , Edema Pulmonar/mortalidade , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Choque Cardiogênico/sangue , Choque Cardiogênico/mortalidade , Regulação para CimaRESUMO
The involvement of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a 12-lipooxygenase product of arachidonic acid, has been suggested in atherosclerosis. However, its effect on macrophage functions is not completely understood, so far. The uptake of apoptotic cells (efferocytosis) by macrophages is an anti-inflammatory process, impaired in advanced atherosclerotic lesions. This process induces the release of the anti-inflammatory cytokine interleukin-10 (IL-10), and it is regulated by Rho-GTPases, whose activation involves the isoprenylation, a modification inhibited by statins. We assessed 12-HETE levels in serum of coronary artery disease (CAD) patients, and explored 12(S)-HETE in vitro effect on monocyte-derived macrophage (MDM) efferocytosis. Sixty-four CAD patients and 24 healthy subjects (HS) were enrolled. Serum 12-HETE levels were measured using a tandem mass spectrometry method. MDMs, obtained from a spontaneous differentiation of adherent monocytes, were treated with 12(S)-HETE (10-50 ng/mL). Efferocytosis and RhoA activation were evaluated by flow cytometry. IL-10 was measured by ELISA. CAD patients showed increased 12-HETE serum levels compared to HS (665.2 [438.1-896.2] ng/mL and 525.1 [380.1-750.1] ng/mL, respectively, p < 0.05) and reduced levels of IL-10. MDMs expressed the 12(S)-HETE cognate receptor GPR31. CAD-derived MDMs displayed defective efferocytosis vs HS-MDMs (9.4 [7.7-11.3]% and 11.1 [9.6-14.1]% of MDMs that have engulfed apoptotic cells, respectively, p < 0.01). This reduction is marked in MDMs obtained from patients not treated with statin (9.3 [7.4-10.6]% statin-free CAD vs HS, p = 0.01; and 9.9 [8.6-11.6]% statin-treated CAD vs HS, p = 0.07). The in vitro treatment of MDMs with 12(S)-HETE (20 ng/mL) induced 20% decrease of efferocytosis (p < 0.01) and 71% increase of RhoA activated form (p < 0.05). Atorvastatin (0.1 µM) counteracted these 12(S)-HETE-mediated effects.These results show a 12(S)-HETE pro-inflammatory effect and suggest a new potential contribution of this mediator in the development of atherosclerosis.
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Aterosclerose/imunologia , Doença da Artéria Coronariana/imunologia , Ácidos Hidroxieicosatetraenoicos/imunologia , Macrófagos/imunologia , Apoptose , Aterosclerose/sangue , Células Cultivadas , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Inflamação/sangue , Inflamação/imunologia , Células Jurkat , MasculinoRESUMO
Patients with acute myocardial infarction (AMI) are at increased risk of recurrent ischemic events after hospital discharge, despite optimal medical therapy. Current practice guidelines strongly encourage the early assessment of the residual ischemic risk in post-AMI patients, in order to identify those who may benefit from a prolonged dual antiplatelet therapy. To this end, some scoring systems have been proposed. However, most scores were developed for patients with stable coronary artery disease undergoing percutaneous coronary intervention. Moreover, nearly all failed to be implemented in everyday clinical practice, probably because of the perceived complexity due to the large number of incorporated variables. Therefore, the identification of the ideal AMI patient who can benefit from a prolonged (beyond 1 year after the index event) dual antiplatelet therapy remains to be clarified, especially when the bleeding risk associated with such therapy is considered. In this review, we summarize the current evidence on the prolonged use of dual antiplatelet therapy after AMI, with a special focus on recent advances regarding the identification of high-risk patients who may derive a favorable net clinical benefit from such a therapeutic strategy.
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Terapia Antiplaquetária Dupla/métodos , Infarto do Miocárdio/terapia , Inibidores da Agregação Plaquetária/administração & dosagem , Doença da Artéria Coronariana/terapia , Terapia Antiplaquetária Dupla/efeitos adversos , Humanos , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/efeitos adversos , Guias de Prática Clínica como Assunto , Fatores de TempoRESUMO
RATIONALE: In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin, functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients. OBJECTIVE: To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome c. METHODS AND RESULTS: We prospectively assessed cytochrome c serum levels at hospital presentation in 2 cohorts: a diagnostic cohort of patients presenting with suspected AMI and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic end point, and prognostic prediction of in-hospital mortality was the primary prognostic end point. Serum cytochrome c had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals 0.44-0.58; P=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome c was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with nondetectable cytochrome c (6% versus 1%; P<0.001). This result was mainly driven by the high mortality rate observed in ST-segment-elevation AMI patients with detectable cytochrome c, as compared with those with nondetectable cytochrome c (11% versus 1%; P<0.001). At multivariable analysis, cytochrome c remained a significant independent predictor of in-hospital mortality (odds ratio 3.0; 95% confidence interval 1.9-5.7; P<0.001), even after adjustment for major clinical confounders (odds ratio 4.01; 95% confidence interval 1.20-13.38; P=0.02). CONCLUSIONS: Cytochrome c serum concentrations do not have diagnostic but substantial prognostic utility in AMI.
Assuntos
Citocromos c/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Admissão do Paciente/tendências , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: In acute coronary syndromes (ACS), serum creatinine (sCr) levels have short- and long-term prognostic value. However, it is possible that repeated evaluations of sCr during hospitalization, rather than measuring sCr value at admission only, might improve risk assessment. We investigated the relationship between sCr baseline value, its changes, and in-hospital mortality in patients hospitalized with ACS. METHODS: In 2,756 ACS patients, sCr was measured at hospital admission and then daily, until discharge from coronary care unit. Patients were grouped according to the maximum sCr change observed: <0.3 mg/dL change from baseline (stable renal function [SRF] group), ≥0.3 mg/dL decrease (improved renal function [IRF] group), and ≥0.3 mg/dL increase (worsening renal function [WRF] group). RESULTS: Of the 2,756 patients, 2,163 (78%) had SRF, 292 (11%) had IRF, and 301 (11%) had WRF. In-hospital mortality in the 3 groups was 0.5%, 2%, and 14% (P < .001), respectively. Peak sCr value was a more powerful predictor of mortality (area under the curve 0.86, 95% CI 0.81-0.92) than the initial sCr value (area under the curve 0.69, 95% CI 0.63-0.77; P < .001). When sCr and its change patterns during coronary care unit stay were evaluated together, improved mortality risk stratification was found. CONCLUSIONS: In ACS patients, daily sCr value and its change pattern are stronger predictors of in-hospital mortality than the initial sCr value only; thus, their combined evaluation provides a more accurate and dynamic stratification of patients' risk. Finally, the intermediate mortality risk of IRF patients possibly reflects acute kidney injury started before hospitalization.