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Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship.
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Cicatriz , Fibrose , Infarto do Miocárdio , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/genética , Animais , Camundongos , Humanos , Cicatriz/metabolismo , Cicatriz/patologia , Cicatriz/genética , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Colágenos Fibrilares/metabolismo , Colágenos Fibrilares/genética , Feminino , Modelos Animais de Doenças , Colágeno/metabolismo , Pessoa de Meia-Idade , Camundongos Endogâmicos C57BLRESUMO
We aimed to assess the correlation of cardiovascular magnetic resonance (CMR)-derived epicardial adipose tissue (EAT) with infarct size (IS) and residual systolic function in ST-segment elevation myocardial infarction (STEMI). We enrolled patients discharged for a first anterior reperfused STEMI submitted to undergo CMR. EAT, left ventricular (LV) ejection fraction (LVEF), and IS were quantified at the 1-week (n = 221) and at 6-month CMR (n = 167). At 1-week CMR, mean EAT was 31 ± 13 mL/m2. Patients with high EAT volume (n = 72) showed larger 1-week IS. After adjustment, EAT extent was independently related to 1-week IS. In patients with large IS at 1 week (>30% of LV mass, n = 88), those with high EAT showed more preserved 6-month LVEF. This association persisted after adjustment and in a 1:1 propensity score-matched patient subset. Overall, EAT decreased at 6 months. In patients with large IS, a greater reduction of EAT was associated with more preserved 6-month LVEF. In STEMI, a higher presence of EAT was associated with a larger IS. Nevertheless, in patients with large infarctions, high EAT and greater subsequent EAT reduction were linked to more preserved LVEF in the chronic phase. This dual and paradoxical effect of EAT fuels the need for further research in this field.
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INTRODUCTION AND OBJECTIVES: Clinical and experimental studies have shown that, in patients with reperfused ST-segment elevation myocardial infarction (STEMI), abnormalities in the endothelial monolayer are initiated during ischemia but rapidly intensify upon restoration of blood perfusion to the ischemic area. We aimed to evaluate the effect of serum isolated after revascularization from STEMI patients on the degree of endothelial permeability in vitro, by promoting endothelial cell apoptosis and necrosis in vitro. We also investigated the association between the percentage of serum-induced endothelial cell apoptosis or necrosis in vitro and the extent of cardiovascular magnetic resonance (CMR)-derived parameters of reperfusion injury (edema, hemorrhage, and microvascular obstruction). METHODS: Human coronary artery endothelial cells were incubated with serum isolated 24hours after revascularization from 43 STEMI patients who underwent CMR and 14 control participants. We assessed the effect of STEMI serum on activation of apoptosis and necrosis, as well as on the permeability and structure of the endothelial monolayer. RESULTS: Serum from STEMI patients increased apoptosis (P <.01) and necrosis (P <.05) in human coronary artery endothelial cells and caused increased permeability of the endothelial monolayer in vitro (P <.01), due to enlarged intercellular spaces (P <.05 vs control in all cases). Higher serum-induced necrosis was associated with greater endothelial permeability in vitro (P <.05) and with more extensive CMR-derived indices of reperfusion injury and infarct size. CONCLUSIONS: Postreperfusion serum activates necrosis and apoptosis in endothelial cells and increases the degree of endothelial permeability in vitro. The more potent the necrosis-triggering effect of serum, the more deleterious the consequences in terms of the resulting cardiac structure.
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Intervenção Coronária Percutânea , Traumatismo por Reperfusão , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Células Endoteliais , Imageamento por Ressonância Magnética/métodos , Necrose/etiologia , Traumatismo por Reperfusão/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Resultado do TratamentoRESUMO
Endothelial cells (ECs) are a key target for cardioprotection due to their role in preserving cardiac microvasculature and homeostasis after myocardial infarction (MI). Our goal is to identify the genes involved in post-MI EC proliferation, EC apoptosis, and angiogenesis regulation via RNA-sequencing transcriptomic datasets. Using eight studies from the Gene Expression Omnibus, RNA-sequencing data from 92 mice submitted to different times of coronary ischemia or sham were chosen. Functional enrichment analysis was performed based on gene ontology biological processes (BPs). Apoptosis-related BPs are activated up to day 3 after ischemia onset, whereas endothelial proliferation occurs from day 3 onwards, including an overrepresentation of up to 37 genes. Endothelial apoptosis post-MI is triggered via both the extrinsic and intrinsic signaling pathways, as reflected by the overrepresentation of 13 and 2 specific genes, respectively. BPs implicated in new vessel formation are upregulated soon after ischemia onset, whilst the mechanisms aiming at angiogenesis repression can be detected at day 3. Overall, 51 pro-angiogenic and 29 anti-angiogenic factors displayed altered transcriptomic expression post-MI. This is the first study using RNA sequencing datasets to evaluate the genes participating in post-MI endothelium physiology and angiogenesis regulation. These novel data could lay the groundwork to advance understanding of the implication of ECs after MI.
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Células Endoteliais , Infarto do Miocárdio , Camundongos , Animais , Células Endoteliais/metabolismo , Neovascularização Fisiológica/genética , Infarto do Miocárdio/metabolismo , RNA/metabolismo , Análise de Sequência de RNARESUMO
BACKGROUND: Extracellular matrix (ECM) suffers substantial alterations after myocardial infarction (MI), including the invasion of leukocyte subtypes. Despite a complete reopening at epicardial level, hypoperfusion within the infarcted myocardium, known as microvascular obstruction (MVO), occurs and exerts a negative impact on ventricular remodeling. In this study, ECM composition at MVO regions was described using a morphometric analysis. METHODS: MI was induced in female swine (n = 10) by transitory 90-minute coronary occlusion followed by seven days of reperfusion. Prior to euthanasia, intracoronary thioflavin-S was infused. Within the infarcted myocardium, regions displaying MVO (thioflavin-S-) or no MVO (thioflavin-S+) were isolated and stained to morphometrically compare ECM composition. RESULTS: As reflected by cell invasion through ECM, areas with MVO displayed an enlarged presence of neutrophils and lymphocytes, whilst no differences in the amount of macrophages and myofibroblasts were detected compared to infarcted myocardium without MVO. Indeed, those regions with macroscopic MVO showed lower capillary density than areas without MVO. Lastly, a significant reduction in the extension of total collagen, type I, but not type III, collagen, laminin, and fibronectin together with an augmentation of polysaccharides were noted in areas showing MVO compared to those without microvascular injury. CONCLUSIONS: ECM composition in infarcted regions with MVO isolated from female swine displays a higher presence of inflammatory infiltrate and polysaccharides as well as reduced number of microvessels and collagen content compared to those areas without microvascular hypoperfusion. These characteristics might underlie the development of adverse ventricular remodeling in MI patients with extensive MVO.
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Infarto do Miocárdio , Remodelação Ventricular , Humanos , Feminino , Suínos , Animais , Matriz Extracelular , Colágeno , PolissacarídeosRESUMO
BACKGROUND: Little is known about the occurrence and implications of persistent microvascular obstruction (MVO) after reperfused ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: The authors used cardiac magnetic resonance (CMR) to characterize the impact of persistent MVO on adverse left ventricular remodeling (ALVR). METHODS: A prospective registry of 471 STEMI patients underwent CMR 7 (IQR: 5-10) days and 198 (IQR: 167-231) days after infarction. MVO (≥1 segment) and ALVR (relative increase >15% at follow-up CMR) of left ventricular end-diastolic index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were determined. RESULTS: One-week MVO occurred in 209 patients (44%) and persisted in 30 (6%). The extent of MVO (P = 0.026) and intramyocardial hemorrhage (P = 0.001) at 1 week were independently associated with the magnitude of MVO at follow-up CMR. Compared with patients without MVO (n = 262, 56%) or with MVO only at 1 week (n = 179, 38%), those with persistent MVO at follow-up (n = 30, 6%) showed higher rates of ALVR-LVEDVI (22%, 27%, and 50%; P = 0.003) and ALVR-LVESVI (20%, 21%, and 53%; P < 0.001). After adjustment, persistent MVO at follow-up (≥1 segment) was independently associated with ΔLVEDVI (relative increase, %) (P < 0.001) and ΔLVESVI (P < 0.001). Compared with a 1:1 propensity score-matched population on CMR variables made up of 30 patients with MVO only at 1 week, patients with persistent MVO more frequently displayed ALVR-LVEDVI (12% vs 50%; P = 0.003) and ALVR-LVESVI (12% vs 53%; P = 0.001). CONCLUSIONS: MVO persists in a small percentage of patients in chronic phase after STEMI and exerts deleterious effects in terms of LV remodeling. These findings fuel the need for further research on microvascular injury repair.
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Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Valor Preditivo dos Testes , Imageamento por Ressonância Magnética , Coração , Intervenção Coronária Percutânea/efeitos adversos , Microcirculação , Remodelação VentricularRESUMO
Extracellular matrix (ECM) changes after myocardial infarction (MI) need precise regulation, and next-generation sequencing technologies provide omics data that can be used in this context. We performed a meta-analysis using RNA-sequencing transcriptomic datasets to identify genes involved in post-MI ECM turnover. Eight studies available in Gene Expression Omnibus were selected following the inclusion criteria. We compare RNA-sequencing data from 92 mice submitted to permanent coronary ligation or sham, identifying differentially expressed genes (p-value < 0.05 and Log2FoldChange ≥ 2). Functional enrichment analysis was performed based on Gene Ontology biological processes (BPs). BPs implicated in response to extracellular stimulus, regulation of ECM organization, and ECM disassembly were detected soon after ischemia onset. ECM disassembly occurred between days one to seven post-MI, compared with ECM assembly from day seven onwards. We identified altered mRNA expression of 19 matrix metalloproteinases and four tissue inhibitors of metalloproteinases at post-infarcted ECM remodeling and altered transcriptomic expression of 42 genes encoding 26 collagen subunits at the fibrotic stage. To our knowledge, this is the first meta-analysis using RNA-sequencing datasets to evaluate post-infarcted cardiac interstitium healing, revealing previously unknown mechanisms and molecules actively implicated in ECM remodeling post-MI, which warrant further validation.
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Infarto do Miocárdio , Transcriptoma , Camundongos , Animais , Infarto do Miocárdio/metabolismo , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Perfilação da Expressão Gênica , RNA/metabolismo , Remodelação Ventricular/genética , Miocárdio/metabolismoRESUMO
BACKGROUND: Stress cardiac MRI permits comprehensive evaluation of patients with known or suspected chronic coronary syndromes (CCS). The impact of sex on the use of invasive cardiac angiography (ICA) after vasodilator stress cardiac MRI is unclear. PURPOSE: To evaluate the impact of sex on ICA use after vasodilator stress cardiac MRI. STUDY TYPE: Retrospective. POPULATION: A total of 6229 consecutive patients (age [mean ± standard deviation] 65.2 ± 11.5 years, 38.1% women). FIELD STRENGTH/SEQUENCE: A 5-T; a steady-state free-precession cine sequence; stress first-pass perfusion imaging; late enhancement imaging. ASSESSMENT: Patients underwent vasodilator stress cardiac MRI for known or suspected CCS. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model). STATISTICAL TESTS: Multivariate logistic regression was used to evaluate the potential differential association between ischemic burden and use of cardiac MRI-related ICA across sex. RESULTS: A total of 1109 (17.8%) patients were referred to ICA, among which there were significantly more men (762, 19.7%) than women (347, 14.6%). Overall, after multivariate adjustment, female sex was not associated with lower use of ICA (odds ratio [OR] = 0.99; confidence interval [CI] 95%: 0.84-1.18, P = 0.934). However, significant sex differences were detected across ischemic burden. Whereas women with nonischemic vasodilator stress cardiac MRI (0 ischemic segments) were less commonly submitted to ICA (OR = 0.49; CI 95%: 0.35-0.69) in patients with ischemia (>1 ischemic segment), adjusted use of ICA was more frequent in women than men (OR = 1.27; CI 95%: 1.1-1.5). DATA CONCLUSIONS: In patients with known or suspected CCS submitted to undergo vasodilator stress cardiac MRI, cardiac MRI-related ICA may be overused in men without ischemia. Furthermore, ICA referral in patients with negative ischemia resulted in greater odds of revascularization in men. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.
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Doença da Artéria Coronariana , Imagem de Perfusão do Miocárdio , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Angiografia Coronária/métodos , Vasodilatadores , Imagem de Perfusão do Miocárdio/métodos , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Valor Preditivo dos TestesRESUMO
INTRODUCTION AND OBJECTIVES: Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI. METHODS: We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated. RESULTS: The mean age of the sample was 59±13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P=.021) and larger infarct size (P=.019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P=.011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P=.010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P=.009) and higher left ventricular end-systolic volume (P=.043). CONCLUSIONS: EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI.
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Molécula de Adesão da Célula Epitelial/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Imagem Cinética por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Volume Sistólico , Função Ventricular EsquerdaRESUMO
INTRODUCTION AND OBJECTIVES: The management of elderly patients with chronic coronary syndrome (CCS) is challenging. We explored the prognostic value and usefulness for decision-making of ischemic burden determined by vasodilator stress cardiac magnetic resonance (CMR) imaging in elderly patients with known or suspected CCS. METHODS: The study group comprised 2496 patients older than 70 years who underwent vasodilator stress CMR for known or suspected CCS. The ischemic burden (number of segments with stress-induced perfusion deficit) was calculated following the 17-segment model. Subsequently, we retrospectively analyzed its association with all-cause mortality and the effect of CMR-guided revascularization. RESULTS: During a median follow-up of 4.58 years, there were 430 deaths (17.2%). A higher ischemic burden was an independent predictor of mortality (HR, 1.04; 95%CI, 1.01-1.07 for each additional ischemic segment; P=.006). This association was also found in patients older than 80 years and in women (P <.001). An interaction between revascularization and mortality was detected toward deleterious consequences at low ischemic burden and a protective effect in patients with extensive ischemia. CONCLUSIONS: Vasodilator stress CMR is a valuable tool to stratify risk in elderly patients with CCS and might be helpful to guide decision-making in this scenario.
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Doença da Artéria Coronariana , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Imagem Cinética por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , VasodilatadoresRESUMO
AIMS: Lymphopenia after ST-segment elevation myocardial infarction (STEMI) correlates with deleterious cardiac consequences and worse prognosis. An in-depth examination of genes implicated in lymphocyte proliferation, activation and regulation and their association with short- and long-term cardiac structure and function is therefore of great interest. METHODS: Peripheral blood mononuclear cells were isolated from 10 control subjects and 64 patients with a first STEMI treated with primary percutaneous coronary intervention and submitted to cardiac magnetic resonance after 1 week and 6 months. mRNA expression of genes implicated in lymphocyte activation (CD25 and CD69) and regulation [programmed death (PD)-1 and cytotoxic T-lymphocyte antigen (CTLA)-4] were determined by qRT-PCR. RESULTS: In comparison to controls, STEMI patients showed heightened mRNA expression of CD25 and lower PD-1 and CTLA-4 96 h after coronary reperfusion. Patients with extensive infarctions (>30% of left ventricular mass) at 1 week displayed a notable reduction in CD25, CD69, PD-1, and CTLA-4 expression (p < 0.05). However, CD25 was the only predictor of 1-week extensive infarct size in multivariate logistic regression analysis (odds ratio 0.019; 95% confidence interval [0.001-0.505]; p = 0.018). Regarding long-term ventricular function, mRNA expression of CD25 under the mean value was associated with worse ventricular function and more adverse remodelling. CONCLUSIONS: Following STEMI, heightened expression of genes expressed in regulatory T cells (CD25 and CD69) and immune checkpoints (PD-1 and CTLA-4) correlates with a better short- and long-term cardiac structure and function. Advancing understanding of the pathophysiology of lymphopenia and evaluating novel immunomodulatory therapies will help translate these results into future clinical trials.
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Ativação Linfocitária/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Idoso , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Antígeno CTLA-4/genética , Feminino , Expressão Gênica , Coração/diagnóstico por imagem , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Lectinas Tipo C/genética , Leucócitos Mononucleares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Remodelação VentricularRESUMO
INTRODUCTION AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Atrial fibrillation (AF) is common in acute situations, where it is associated with more complications and higher mortality. METHODS: Analysis of the international HOPE registry (NCT04334291). The objective was to assess the prognostic information of AF in COVID-19 patients. A multivariate analysis and propensity score matching were performed to assess the relationship between AF and mortality. We also evaluated the impact on mortality and embolic events of the CHA2DS2-VASc score in these patients. RESULTS: Among 6217 patients enrolled in the HOPE registry, 250 had AF (4.5%). AF patients had a higher prevalence of cardiovascular risk factors and comorbidities. After propensity score matching, these differences were attenuated. Despite this, patients with AF had a higher incidence of in-hospital complications such as heart failure (19.3% vs 11.6%, P = .021) and respiratory insufficiency (75.9% vs 62.3%, P = .002), as well as a higher 60-day mortality rate (43.4% vs 30.9%, P = .005). On multivariate analysis, AF was independently associated with higher 60-day mortality (hazard ratio, 1.234; 95%CI, 1.003-1.519). CHA2DS2-VASc score acceptably predicts 60-day mortality in COVID-19 patients (area ROC, 0.748; 95%CI, 0.733-0.764), but not its embolic risk (area ROC, 0.411; 95%CI, 0.147-0.675). CONCLUSIONS: AF in COVID-19 patients is associated with a higher number of complications and 60-day mortality. The CHA2DS2-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.
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INTRODUCTION AND OBJECTIVES: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Atrial fibrillation (AF) is common in acute situations, where it is associated with more complications and higher mortality. METHODS: Analysis of the international HOPE registry (NCT04334291). The objective was to assess the prognostic information of AF in COVID-19 patients. A multivariate analysis and propensity score matching were performed to assess the relationship between AF and mortality. We also evaluated the impact on mortality and embolic events of the CHA2DS2-VASc score in these patients. RESULTS: Among 6217 patients enrolled in the HOPE registry, 250 had AF (4.5%). AF patients had a higher prevalence of cardiovascular risk factors and comorbidities. After propensity score matching, these differences were attenuated. Despite this, patients with AF had a higher incidence of in-hospital complications such as heart failure (19.3% vs 11.6%, P=.021) and respiratory insufficiency (75.9% vs 62.3%, P=.002), as well as a higher 60-day mortality rate (43.4% vs 30.9%, P=.005). On multivariate analysis, AF was independently associated with higher 60-day mortality (hazard ratio, 1.234; 95%CI, 1.003-1.519). CHA2DS2-VASc score acceptably predicts 60-day mortality in COVID-19 patients (area ROC, 0.748; 95%CI, 0.733-0.764), but not its embolic risk (area ROC, 0.411; 95%CI, 0.147-0.675). CONCLUSIONS: AF in COVID-19 patients is associated with a higher number of complications and 60-day mortality. The CHA2DS2-VASc score may be a good risk marker in COVID patients but does not predict their embolic risk.
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Fibrilação Atrial , COVID-19 , Acidente Vascular Cerebral , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , COVID-19/complicações , Humanos , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Fatores de RiscoRESUMO
This study aimed to assess the time course of circulating neutrophil and lymphocyte counts and their ratio (NLR) in ST-segment elevation myocardial infarction (STEMI) and coronavirus disease (COVID)-19 and explore their associations with clinical events and structural damage. Circulating neutrophil, lymphocyte and NLR were sequentially measured in 659 patients admitted for STEMI and in 103 COVID-19 patients. The dynamics detected in STEMI (within a few hours) were replicated in COVID-19 (within a few days). In both entities patients with events and with severe structural damage displayed higher neutrophil and lower lymphocyte counts. In both scenarios, higher maximum neutrophil and lower minimum lymphocyte counts were associated with more events and more severe organ damage. NLR was higher in STEMI and COVID-19 patients with the worst clinical and structural outcomes. A canonical deregulation of the immune response occurs in STEMI and COVID-19 patients. Boosted circulating innate (neutrophilia) and depressed circulating adaptive immunity (lymphopenia) is associated with more events and severe organ damage. A greater understanding of these critical illnesses is pivotal to explore novel alternative therapies.
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BACKGROUND: Following myocardial infarction (MI), we aimed to characterize morphometric and genetic changes in extracellular matrix (ECM) components from ischemia onset until late phases after coronary reperfusion in necrotic and salvaged myocardium. RESULTS: Swine were divided into one control (n = 5) and three MI groups: 90-min of ischemia without reperfusion, or followed by 1-week or 1-month reperfusion (n = 5 per group). In samples from the necrotic and salvaged areas, ECM components were morphometrically quantified and mRNA levels of factors involved in ECM remodeling were evaluated. After 90-min of ischemia, fibronectin, laminin, and elastic fibers content as well as upregulated mRNA expression of tissue inhibitors of metalloproteinases (TIMP)1, TIMP2, TIMP3 and connective tissue growth factor increased in the necrotic and salvaged myocardium. In both reperfused MI groups, collagen-I, collagen-III, elastic fibers, glycosaminoglycans, laminin, and fibronectin levels heightened in the necrotic but not the salvaged myocardium. Moreover, mRNA expression of TIMP1, TIMP2 and TIMP3, as well as metalloproteinase-2 and metalloproteinase-9 heightened in the necrotic but not in the salvaged myocardium. CONCLUSIONS: Matrix remodeling starts after ischemia onset in both necrotic and salvaged myocardium. Even if ECM composition from the salvaged myocardium was altered after severe ischemia, ECM makes a full recovery to normal composition after reperfusion. Therefore, rapid coronary reperfusion is essential not only to save cardiomyocytes but also to preserve matrix, thus avoiding impaired left ventricular remodeling.
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Matriz Extracelular/patologia , Infarto do Miocárdio/fisiopatologia , Reperfusão Miocárdica , Animais , Colágeno/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Modelos Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sus scrofa , Inibidores Teciduais de Metaloproteinases/metabolismo , Remodelação Ventricular/fisiologiaRESUMO
Delayed enhancement cardiovascular magnetic resonance (MR) is the gold-standard for non-invasive assessment after myocardial infarction (MI). MR microscopy (MRM) provides a level of detail comparable to the macro objective of light microscopy. We used MRM and correlative histopathology to identify infarct and remote tissue in contrast agent-free multi-sequence MRM in swine MI hearts. One control group (n = 3 swine) and two experimental MI groups were formed: 90 min of ischemia followed by 1 week (acute MI = 6 swine) or 1 month (chronic MI = 5 swine) reperfusion. Representative samples of each heart were analysed by contrast agent-free multi-sequence (T1-weighting, T2-weighting, T2*-weighting, T2-mapping, and T2*-mapping). MRM was performed in a 14-Tesla vertical axis imager (Bruker-AVANCE 600 system). Images from MRM and the corresponding histopathological stained samples revealed differences in signal intensities between infarct and remote areas in both MI groups (p-value < 0.001). The multivariable models allowed us to precisely classify regions of interest (acute MI: specificity 92% and sensitivity 80%; chronic MI: specificity 100% and sensitivity 98%). Probabilistic maps based on MRM images clearly delineated the infarcted regions. As a proof of concept, these results illustrate the potential of MRM with correlative histopathology as a platform for exploring novel contrast agent-free MR biomarkers after MI.
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Imageamento por Ressonância Magnética/métodos , Microscopia/métodos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Animais , Modelos Animais de Doenças , Humanos , SuínosRESUMO
OBJECTIVES: The aim of this study was to evaluate the prognostic value of strain as assessed by tissue tracking (TT) cardiac magnetic resonance (CMR) soon after ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The prognostic value of myocardial strain as assessed post-STEMI by TT-CMR is unknown. METHODS: The authors studied the prognostic value of TT-CMR in 323 patients who underwent CMR 1 week post-STEMI. Global (average of peak segmental values [%]) and segmental (number of altered segments) longitudinal (LS), circumferential, and radial strain were assessed using TT-CMR. Global and segmental strain cutoff values were derived from 32 control patients. CMR-derived left ventricular ejection fraction, microvascular obstruction, and infarct size were determined. Results were validated in an external cohort of 190 STEMI patients. RESULTS: During a median follow-up of 1,085 days, 54 first major adverse cardiac events (MACE), which included 10 cardiac deaths, 25 readmissions for heart failure, and 19 readmissions for reinfarction were documented. MACE was associated with more severe abnormalities in all strain indexes (p < 0.001), although only global LS was an independent predictor (p < 0.001). The MACE rate was higher in patients with a global LS of ≥-11% (22% vs. 9%; p = 0.001). After adjustment for baseline and CMR variables, global LS (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.11 to 1.32; p < 0.001) was associated with MACE. In the external validation cohort, a global LS ≥-11% was seen in a higher proportion of patients with MACE (34% vs. 9%; p < 0.001). Global LS predicted MACE after adjustment for baseline and CMR variables (HR: 1.18; 95% CI: 1.04 to 1.33; p = 0.008). The addition of global LS to the multivariate models, including baseline and CMR variables, did not significantly improve the categorical net reclassification improvement index in either the study group (-0.015; p = 0.7) or in the external validation cohort (-0.019; p = 0.9). CONCLUSIONS: TT-CMR provided prognostic information soon after STEMI. However, it did not substantially improve risk reclassification beyond traditional CMR indexes.
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Imageamento por Ressonância Magnética , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Idoso , Circulação Coronária , Feminino , Humanos , Masculino , Microcirculação , Pessoa de Meia-Idade , Miocárdio/patologia , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Volume Sistólico , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
In extensive nonreperfused myocardial infarction (MI), remote fibrosis has been documented. Early reperfusion by primary angioplasty represents the gold standard method to minimize the extension of the infarction. We aimed to ascertain whether fibrosis also affects remote regions in reperfused MI in swine and patients. Swine were subjected to a transient occlusion of the left anterior descending artery followed by 1-week or 1-month reperfusion. Collagen content in the remote area macroscopically, microscopically, by magnetic resonance microimaging, and at the molecular level was similar to controls. In patients with previous MI, samples from autopsies displayed a significant increase in collagen content only in the infarct region. In patients with previous MI submitted to cardiac magnetic resonance-T1 mapping, the extracellular volume fraction in remote segments was similar to that for controls. In all scenarios, the remote region did not show a significant increase of collagen content in comparison with controls.
Assuntos
Infarto do Miocárdio/terapia , Miocárdio/patologia , Intervenção Coronária Percutânea , Idoso , Idoso de 80 Anos ou mais , Animais , Autopsia , Estudos de Casos e Controles , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Sus scrofa , Fatores de Tempo , Resultado do TratamentoRESUMO
We aimed to characterize the organization of collagen within a fibrotic scar in swine and human samples from patients with chronic infarctions. Swine were subjected to occlusion of the left anterior descending artery followed by reperfusion 1 week (acute myocardial infarction group) or 1 month (chronic myocardial infarction group) after infarction. The organization of the collagen fibers (Fast Fourier Transform of samples after picrosirius staining; higher values indicate more disorganization) was studied in 100 swine and 95 human samples. No differences in collagen organization were found between the acute and chronic groups in the core area of the scar in the experimental model. In the chronic group, the endocardium [0.90 (0.84-0.94); median (interquartile range)], epicardium [0.84 (0.79-0.91)] and peripheral area [0.73 (0.63-0.83)] displayed a much more disorganized pattern than the core area of the fibrotic scar [0.56 (0.45-0.64)]. Similarly, in human samples, the collagen fibers were more disorganized in all of the outer areas than in the core of the fibrotic scar (P < 0.0001). Both in a highly controlled experimental model and in patient samples, collagen fibers exhibited an organized pattern in the core of the infarction, whereas the outer areas displayed a high level of inhomogeneity. This finding contributes pathophysiological information regarding the healing process and may lead to a clearer understanding of the genesis and invasive treatment of arrhythmias after acute myocardial infarction.
Assuntos
Cicatriz/patologia , Colágeno/análise , Vasos Coronários/patologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Suínos , CicatrizaçãoRESUMO
INTRODUCTION AND OBJECTIVES: Microvascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model. METHODS: Myocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation). RESULTS: In comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14%±7%), peaked in the 1-week reperfusion group (21%±7%), and significantly decreased in the 1-month reperfusion group (4%±3%; P<.001). CONCLUSIONS: We present proof-of-concept evidence on the crucial role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction.