RESUMO
During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart. We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation. These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.
Assuntos
Glicogênio Sintase/metabolismo , Proteína Quinase 12 Ativada por Mitógeno/metabolismo , Proteína Quinase 13 Ativada por Mitógeno/metabolismo , Miocárdio/enzimologia , Animais , Animais Recém-Nascidos , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Dieta Hiperlipídica , Ativação Enzimática , Comportamento Alimentar , Feminino , Deleção de Genes , Intolerância à Glucose/enzimologia , Glicogênio/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/enzimologia , Especificidade de Órgãos , FosforilaçãoRESUMO
BACKGROUND: The effect of ß-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion). METHODS AND RESULTS: Patients with Killip class II or less anterior ST-segment-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were randomized to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The predefined primary end point was infarct size on magnetic resonance imaging performed 5 to 7 days after STEMI. Magnetic resonance imaging was performed in 220 patients (81%). Mean ± SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6 ± 15.3 versus 32.0 ± 22.2 g; adjusted difference, -6.52; 95% confidence interval, -11.39 to -1.78; P=0.012). In patients with pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction grade 0 to 1 flow, the adjusted treatment difference in infarct size was -8.13 (95% confidence interval, -13.10 to -3.16; P=0.0024). Infarct size estimated by peak and area under the curve creatine kinase release was measured in all study populations and was significantly reduced by intravenous metoprolol. Left ventricular ejection fraction was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09-5.21; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21). CONCLUSIONS: In patients with anterior Killip class II or less ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01311700. EUDRACT number: 2010-019939-35.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Cardiotônicos/uso terapêutico , Metoprolol/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea , Pré-Medicação , Antagonistas Adrenérgicos beta/administração & dosagem , Biomarcadores , Cardiotônicos/administração & dosagem , Terapia Combinada , Creatina Quinase Forma MB/sangue , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Humanos , Imageamento por Ressonância Magnética , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Necrose , Método Simples-Cego , Volume Sistólico/efeitos dos fármacos , Terapia TrombolíticaRESUMO
Selective stimulation of ß3 adrenergic-receptor (ß3AR) has been shown to reduce infarct size in a mouse model of myocardial ischemia/reperfusion. However, its functional long-term effect and the cardioprotective mechanisms at the level of cardiomyocytes have not been elucidated, and the impact of ß3AR stimulation has not been evaluated in a more translational large animal model. This study aimed at evaluating pre-perfusion administration of BRL37344 both in small and large animal models of myocardial ischemia/reperfusion. Pre-reperfusion administration of the ß3AR agonist BRL37344 (5 µg/kg) reduced infarct size at 2-and 24-h reperfusion in wild-type mice. Long-term (12-weeks) left ventricular (LV) function assessed by echocardiography and cardiac magnetic resonance (CMR) was significantly improved in ß3AR agonist-treated mice. Incubation with ß3AR agonist (BRL37344, 7 µmol/L) significantly reduced cell death in isolated adult mouse cardiomyocytes during hypoxia/reoxygenation and decreased susceptibility to deleterious opening of the mitochondrial permeability transition pore (mPTP), via a mechanism dependent on the Akt-NO signaling pathway. Pre-reperfusion BRL37344 administration had no effect on infarct size in cyclophilin-D KO mice, further implicating mPTP in the mechanism of protection. Large-white pigs underwent percutaneous coronary ischemia/reperfusion and 3-T CMR at 7 and 45 days post-infarction. Pre-perfusion administration of BRL37344 (5 µg/kg) decreased infarct size and improved long-term LV contractile function. A single-dose administration of ß3AR agonist before reperfusion decreased infarct size and resulted in a consistent and long-term improvement in cardiac function, both in small and large animal models of myocardial ischemia/reperfusion. This protection appears to be executed through inhibition of mPTP opening in cardiomyocytes.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Cardiotônicos/farmacologia , Etanolaminas/farmacologia , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Peptidil-Prolil Isomerase F , Ciclofilinas/deficiência , Ciclofilinas/genética , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Masculino , Camundongos Knockout , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Fatores de TempoRESUMO
BACKGROUND: Infarct size predicts post-infarction mortality. Oral ß-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early intravenous (IV) ß-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)-based experimental studies, the ß(1)-blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion ß-blocker initiation in STEMI. OBJECTIVE: The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. DESIGN: The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with ß-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. CONCLUSIONS: The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Infarto Miocárdico de Parede Anterior/tratamento farmacológico , Metoprolol/administração & dosagem , Reperfusão Miocárdica , Administração Oral , Infarto Miocárdico de Parede Anterior/patologia , Esquema de Medicação , Humanos , Infusões Intravenosas/métodos , Imageamento por Ressonância Magnética , Método Simples-Cego , Volume SistólicoRESUMO
OBJECTIVE: Early prediction of atrial fibrillation (AF) development would improve patient outcomes. We propose a simple and cheap ECG based score to predict AF development. METHODS: A cohort of 16 316 patients was analysed. ECG measures provided by the computer-assisted ECG software were used to identify patients. A first group included patients in sinus rhythm who showed an ECG with AF at any time later (n=505). A second group included patients with all their ECGs in sinus rhythm (n=15 811). By using a training set (75% of the cohort) the initial sinus rhythm ECGs of both groups were analysed and a predictive risk score based on a multivariate logistic model was constructed. RESULTS: A multivariate regression model was constructed with 32 variables showing a predictive value characterised by an area under the curve (AUC) of 0.776 (95% CI: 0.738 to 0.814). The subsequent risk score included the following variables: age, duration of P-wave in aVF, V4 and V5; duration of T-wave in V3, mean QT interval adjusted for heart rate, transverse P-wave clockwise rotation, transverse P-wave terminal angle and transverse QRS complex terminal vector magnitude. Risk score values ranged from 0 (no risk) to 5 (high risk). The predictive validity of the score reached an AUC of 0.764 (95% CI: 0.722 to 0.806) with a global specificity of 61% and a sensitivity of 55%. CONCLUSIONS: The automatic assessment of ECG biomarkers from ECGs in sinus rhythm is able to predict the risk for AF providing a low-cost screening strategy for early detection of this pathology.
Assuntos
Fibrilação Atrial/diagnóstico , Eletrocardiografia/métodos , Frequência Cardíaca/fisiologia , Processamento de Sinais Assistido por Computador , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Evolut Pro (EVP) is a novel self-expandable aortic valve. This prosthesis consists of an external porcine pericardial wrap designed to reduce paravalvular leak (PVL), maintaining the benefits of its predecessor, the Evolut R (EVR). The aim was to compare the functional and clinical results in the short and medium term of the new EVP with the EVR system. METHODS: Consecutive patients receiving either the EVR (n=50) or the EVP (n=33) from June 2015 to October 2018 were compared. Baseline characteristics, cardiovascular imaging, procedural outcomes, short and mid-term follow-up outcomes were prospectively collected and assessed. RESULTS: Residual mild PVL was common and comparable in the two groups (EVR 79% vs. EVP 70%; P=0.4). In the EVR group, the presence of PVL was directly related to prosthesis size, but this correlation was not observed in the EVP group. Conduction abnormalities were more prevalent with the EVP, but these did not translate into a higher need of permanent pacemaker implantation. Vascular and bleeding complications were infrequent in both groups. At mid-term clinical follow-up (median survival time: EVR 11±0.3 months, EVP 12±0.2 months), the 1-year rate of adverse events was similar (EVR: 24%, EVP: 33%; P=0.3). CONCLUSIONS: Both protheses are effective for the treatment of severe aortic stenosis with excellent results at mid-term clinical follow up. The EVP remains associated with a significant rate of residual mild PVL that appears to be similar to that observed with EVR.
RESUMO
Plaque development has been extensively studied using magnetic resonance imaging (MRI) in animal models of rapidly progressing atherosclerosis, such as apolipoprotein E-knockout (apoE-KO) mice. Preclinical MRI plays a significant role in the study of experimental atherosclerosis. Currently, MRI is capable of detecting luminal narrowing, plaque size, and morphology with high accuracy and reproducibility, providing reliable measurements of plaque burden. Therefore, MRI offers a noninvasive approach to serially monitor the progression of the disease. Compared with other imaging modalities, MRI appears to have the greatest potential for plaque characterization, through the use of multiple contrast weightings (e.g., T1, T2, and proton density). Here, we illustrate a standard procedure to image the aorta of atherosclerotic mice using noninvasive MRI.
Assuntos
Aorta/patologia , Doenças da Aorta/patologia , Aterosclerose/patologia , Imageamento por Ressonância Magnética , Placa Aterosclerótica , Animais , Aorta/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Biópsia , Modelos Animais de Doenças , Interpretação de Imagem Assistida por Computador , Camundongos Knockout , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
Cardiovascular imaging has become an indispensable tool for patient diagnosis and follow up. Probably the wide clinical applications of imaging are due to the possibility of a detailed and high quality description and quantification of cardiovascular system structure and function. Also phenomena that involve complex physiological mechanisms and biochemical pathways, such as inflammation and ischemia, can be visualized in a non-destructive way. The widespread use and evolution of imaging would not have been possible without animal studies. Animal models have allowed for instance, (i) the technical development of different imaging tools, (ii) to test hypothesis generated from human studies and finally, (iii) to evaluate the translational relevance assessment of in vitro and ex-vivo results. In this review, we will critically describe the contribution of animal models to the use of biomedical imaging in cardiovascular medicine. We will discuss the characteristics of the most frequent models used in/for imaging studies. We will cover the major findings of animal studies focused in the cardiovascular use of the repeatedly used imaging techniques in clinical practice and experimental studies. We will also describe the physiological findings and/or learning processes for imaging applications coming from models of the most common cardiovascular diseases. In these diseases, imaging research using animals has allowed the study of aspects such as: ventricular size, shape, global function, and wall thickening, local myocardial function, myocardial perfusion, metabolism and energetic assessment, infarct quantification, vascular lesion characterization, myocardial fiber structure, and myocardial calcium uptake. Finally we will discuss the limitations and future of imaging research with animal models.
RESUMO
Despite being the most effective means of limiting infarct size, coronary reperfusion comes at a price and induces additional damage to the myocardium. Lethal reperfusion injury (death of myocytes that were viable at the time of reperfusion) is an increasingly acknowledged phenomenon. There are many interconnected mechanisms involved in this type of cell death. Calcium overload (generating myocyte hypercontracture), rapid recovery of physiological pH, neutrophil infiltration of the ischemic area, opening of the mitochondrial permeability-transition-pore (PTP), and apoptotic cell death are among the more important mechanisms involved in reperfusion injury. The activation of a group of proteins called reperfusion injury salvage kinases (RISK) pathway confers protection against reperfusion injury, mainly by inhibiting the opening of the mitochondrial PTP. Many interventions have been tested in human trials triggered by encouraging animal studies. In the present review we will explain in detail the main mechanism involved in reperfusion injury, as well as the various approaches (pre-clinical and human trials) performed targeting these mechanisms. Currently, no intervention has been consistently shown to reduce reperfusion injury in large randomized multicenter trials, but the research in this field is intense and the future is highly promising.
Assuntos
Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Reperfusão Miocárdica/efeitos adversos , Reperfusão Miocárdica/tendências , Animais , Humanos , Traumatismo por Reperfusão Miocárdica/terapiaRESUMO
Acute myocardial infarction is caused by sudden coronary artery occlusion. Persistent ischemia results in necrosis of the myocardial tissue supplied by the occluded vessel. It has recently been shown that the final size of the infarct is a major predictor of future clinical events, and is, therefore, used as a surrogate outcome in clinical trials. Moreover, it has become clear that the duration of ischemia in the main determinant of the success of myocardial salvage (i.e. of non-necrotic at-risk myocardium). In addition to minimizing the time between symptom onset and reperfusion, there is considerable interest in finding therapies that can further limit the size of the infarction (i.e. cardioprotective therapies) and they are the focus of numerous clinical studies. Oral ß-blockade within the first few hours of an AMI is a class-IA indication in clinical practice guidelines. However, early intravenous ß-blockade, even before coronary artery reperfusion, is not routinely recommended. Preclinical research has demonstrated that the selectiveß1-blocker metoprolol is able to reduce the infarct size only when administered before coronary artery reperfusion, which indicates that its cardioprotective properties are secondary to its ability to reduce reperfusion injury. In addition, retrospective studies of AMI suggest that starting intravenous ß-blockade early has clinical benefits (i.e. lower mortality and better recovery of left ventricular contractility) in patients without contraindications. Our general hypothesis is that early administration of metoprolol (i.e. intravenously before reperfusion) results in smaller infarcts than administering the drug orally after reperfusion. The Effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion (METOCARD-CNIC) trial will test this hypothesis in patients with ST-segment elevation AMI.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Doença Aguda , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Imageamento por Ressonância Magnética , Metoprolol/uso terapêutico , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Projetos de Pesquisa , Resultado do TratamentoRESUMO
The aim of this study was to determine the prevalence of left ventricular hypertrophy (LVH), left ventricular diastolic dysfunction (LVDD) and left ventricular systolic dysfunction (LVSD) in a group of elderly Spanish individuals. Data were obtained on a subgroup of 371 individuals from the Lista district of Madrid, Spain who were taking part in the EPICARDIAN study. In hypertensive subjects, the prevalence of LVH was 51.8%-61.8%, that of LVDD was 86%, and that of LVSD was 6.2%. In normotensive subjects, the prevalences were 14%-30% for LVH, 86% for LVDD, and 6% for LVSD. The isovolumic relaxation time was 115+/-33 ms in the hypertensive group and 105+/-24 ms in the normotensive group. In this study, the only factor that differentiated between the diagnoses of LVDD due to age and LVDD due to hypertension was a longer isovolumic relaxation time.