RESUMEN
BACKGROUND: The metabolic injury caused by protein glycation, monitored as the level of glycated hemoglobin (HbA1c), is not represented in most risk scores (i.e., Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease risk scale). OBJECTIVES: The purpose of this study was to assess the association between HbA1c and the extent of subclinical atherosclerosis (SA) and to better identify individuals at higher risk of extensive SA using HbA1c on top of key cardiovascular risk factors (CVRFs). METHODS: A cohort of 3,973 middle-aged individuals from the PESA (Progression of Early Subclinical Atherosclerosis) study, with no history of cardiovascular disease and with HbA1c in the nondiabetic range, were assessed for the presence and extent of SA by 2-dimensional vascular ultrasound and noncontrast cardiac computed tomography. RESULTS: After adjusting for established CVRFs, HbA1c showed an association with the multiterritorial extent of SA (odds ratio: 1.05, 1.27, 1.27, 1.36, 1.80, 1.87, and 2.47 for HbA1c 4.9% to 5.0%, 5.1% to 5.2%, 5.3% to 5.4%, 5.5% to 5.6%, 5.7% to 5.8%, 5.9% to 6.0%, and 6.1% to 6.4%, respectively; reference HbA1c ≤4.8%; p < 0.001). The association was significant in all pre-diabetes groups and even below the pre-diabetes cut-off (HbA1c 5.5% to 5.6% odds ratio: 1.36 [95% confidence interval: 1.03 to 1.80]; p = 0.033). High HbA1c was associated with an increased risk of SA in low-risk individuals (p < 0.001), but not in moderate-risk individuals (p = 0.335). Relative risk estimations using Systematic Coronary Risk Estimation or atherosclerotic cardiovascular disease predictors confirmed that inclusion of HbA1c modified the risk of multiterritorial SA in most risk categories. CONCLUSIONS: Routine use of HbA1c can identify asymptomatic individuals at higher risk of SA on top of traditional CVRFs. Lifestyle interventions and novel antidiabetic medications might be considered to reduce both HbA1c levels and SA in individuals without diabetes.
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Enfermedades Asintomáticas , Aterosclerosis/sangre , Factores de Riesgo Cardiometabólico , Hemoglobina Glucada/metabolismo , Placa Aterosclerótica/sangre , Adulto , Arterias/diagnóstico por imagen , Aterosclerosis/diagnóstico por imagen , Glucemia , Técnicas de Imagen Cardíaca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagen , Estudios Prospectivos , Medición de Riesgo , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
BACKGROUND: Atherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored. OBJECTIVES: This study sought to determine the association between brain metabolism, subclinical atherosclerosis, and CVRFs in middle-aged asymptomatic individuals. METHODS: This study included 547 asymptomatic middle-aged participants (50 ± 4 years, 82% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study with evidence of subclinical atherosclerosis. Participants underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography. Global brain FDG uptake and voxel-wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3-dimensional vascular ultrasound. RESULTS: Global FDG uptake showed an inverse correlation with 30-year Framingham Risk Score (FRS) (ß = -0.15, p < 0.001). This association was mainly driven by the presence of hypertension (d = 0.36, p < 0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (ß = -0.16, p < 0.001), even after adjusting for 30-year FRS. Voxel-wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30-year FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus. CONCLUSIONS: In asymptomatic middle-aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include those known to be affected in dementia. These data reinforce the need to control CVRFs early in life in order to potentially reduce the brain's midlife vulnerability to future cognitive dysfunction.
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Aterosclerosis/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Adulto , Enfermedades Asintomáticas , Arterias Carótidas/diagnóstico por imagen , Estudios de Cohortes , Femenino , Arteria Femoral/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , UltrasonografíaRESUMEN
BACKGROUND: Left ventricular (LV) hypertrabeculation fulfilling noncompaction cardiomyopathy criteria has been detected in athletes. However, the association between LV noncompaction (LVNC) phenotype and vigorous physical activity (VPA) in the general population is disputed. OBJECTIVES: The aim of this study was to assess the relationship between LVNC phenotype on cardiac magnetic resonance (CMR) imaging and accelerometer-measured physical activity (PA) in a cohort of middle-aged nonathlete participants in the PESA (Progression of Early Subclinical Atherosclerosis) study. METHODS: In PESA participants (n = 4,184 subjects free of cardiovascular disease), PA was measured by waist-secured accelerometers. CMR was performed in 705 subjects (mean age 48 ± 4 years, 16% women). VPA was recorded as total minutes per week. The study population was divided into 6 groups: no VPA and 5 sex-specific quintiles of VPA rate (Q1 to Q5). The Petersen criterion for LVNC was evaluated in all subjects undergoing CMR. For participants meeting this criterion (noncompacted-to-compacted ratio ≥2.3), 3 more restrictive LVNC criteria were also evaluated (Jacquier, Grothoff, and Stacey). RESULTS: LVNC phenotype prevalence according to the Petersen criterion was significantly higher among participants in the highest VPA quintile (Q5 = 30.5%) than in participants with no VPA (14.2%). The Jacquier and Grothoff criteria were also more frequently fulfilled in participants in the highest VPA quintile (Jacquier Q5 = 27.4% vs. no VPA = 12.8% and Grothoff Q5 = 15.8% vs. no VPA = 7.1%). The prevalence of the systolic Stacey LVNC criterion was low (3.6%) and did not differ significantly between no VPA and Q5. CONCLUSIONS: In a community-based study, VPA was associated with a higher prevalence of CMR-detected LVNC phenotype according to diverse established criteria. The association between VPA and LVNC phenotype was independent of LV volumes. According to these data, vigorous recreational PA should be considered as a possible but not uncommon determinant of LV hypertrabeculation in asymptomatic subjects.
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Ejercicio Físico/fisiología , Ventrículos Cardíacos/fisiopatología , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Función Ventricular Izquierda/fisiología , Adulto , Ecocardiografía , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , No Compactación Aislada del Miocardio Ventricular/diagnóstico , Imagen por Resonancia Cinemagnética/métodos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , SístoleRESUMEN
Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.
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Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Metoprolol/administración & dosificación , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/patología , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Administración Intravenosa , Animales , Técnicas de Imagen Cardíaca , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Imagen por Resonancia Magnética , Masculino , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Daño por Reperfusión Miocárdica/patología , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/patología , Porcinos , Factores de TiempoRESUMEN
BACKGROUND: Conflicting evidence is available on the efficacy and safety of early intravenous beta-blockers before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. We performed a patient-pooled meta-analysis of trials comparing early intravenous beta-blockers with placebo or routine care in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. AIM: The aim of this study was to evaluate the clinical and safety outcomes of intravenous beta-blockers in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. METHODS: Four randomized trials with a total of 1150 patients were included. The main outcome was one-year death or myocardial infarction. Secondary outcomes included biomarker-based infarct size, left ventricular ejection fraction during follow-up, ventricular tachycardia, and a composite safety outcome (cardiogenic shock, symptomatic bradycardia, or hypotension) during hospitalization. RESULTS: One-year death or myocardial infarction was similar among beta-blocker (4.2%) and control patients (4.4%) (hazard ratio: 0.96 (95% confidence interval: 0.53-1.75, p=0.90, I2=0%). No difference was observed in biomarker-based infarct size. One-month left ventricular ejection fraction was similar, but left ventricular ejection fraction at six months was significantly higher in patients treated with early intravenous beta-blockade (52.8% versus 50.0% in the control group, p=0.03). No difference was observed in the composite safety outcome or ventricular tachycardia during hospitalization. CONCLUSION: In ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention, the administration of early intravenous beta-blockers was safe. However, there was no difference in the main outcome of one-year death or myocardial infarction with early intravenous beta-blockers. A larger clinical trial is warranted to confirm the definitive efficacy of early intravenous beta-blockers.
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Antagonistas Adrenérgicos beta/administración & dosificación , Intervención Coronaria Percutánea , Ensayos Clínicos Controlados Aleatorios como Asunto , Infarto del Miocardio con Elevación del ST/terapia , Administración Intravenosa , HumanosRESUMEN
BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).
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Arterias , Aterosclerosis/diagnóstico , Imagen por Resonancia Magnética/métodos , Placa Aterosclerótica , Tomografía de Emisión de Positrones/métodos , Adulto , Arterias/diagnóstico por imagen , Arterias/inmunología , Enfermedades Asintomáticas , Calcinosis/diagnóstico , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Fluorodesoxiglucosa F18/farmacología , Humanos , Inflamación/diagnóstico , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/inmunología , Radiofármacos/farmacología , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).
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Aterosclerosis/sangre , LDL-Colesterol/sangre , Diagnóstico Precoz , Adulto , Enfermedades Asintomáticas , Aterosclerosis/diagnóstico , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The ß1-adrenergic-receptor (ADRB1) antagonist metoprolol reduces infarct size in acute myocardial infarction (AMI) patients. The prevailing view has been that metoprolol acts mainly on cardiomyocytes. Here, we demonstrate that metoprolol reduces reperfusion injury by targeting the haematopoietic compartment. Metoprolol inhibits neutrophil migration in an ADRB1-dependent manner. Metoprolol acts during early phases of neutrophil recruitment by impairing structural and functional rearrangements needed for productive engagement of circulating platelets, resulting in erratic intravascular dynamics and blunted inflammation. Depletion of neutrophils, ablation of Adrb1 in haematopoietic cells, or blockade of PSGL-1, the receptor involved in neutrophil-platelet interactions, fully abrogated metoprolol's infarct-limiting effects. The association between neutrophil count and microvascular obstruction is abolished in metoprolol-treated AMI patients. Metoprolol inhibits neutrophil-platelet interactions in AMI patients by targeting neutrophils. Identification of the relevant role of ADRB1 in haematopoietic cells during acute injury and the protective role upon its modulation offers potential for developing new therapeutic strategies.
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Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Metoprolol/farmacología , Metoprolol/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Metoprolol/administración & dosificación , Ratones , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Neutrófilos/citología , Agregación Plaquetaria/efectos de los fármacos , ARN Mensajero/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismoRESUMEN
Reperfusion, despite being required for myocardial salvage, is associated with additional injury. We hypothesize that infarct size (IS) will be reduced by a period of bloodless reperfusion with hemoglobin-based oxygen carriers (HBOC) before blood-flow restoration. In the pig model, we first characterized the impact of intracoronary perfusion with a fixed volume (600 ml) of a pre-oxygenated acellular HBOC, HBOC-201, on the healthy myocardium. HBOC-201 was administered through the lumen of the angioplasty balloon (i.e., distal to the occlusion site) immediately after onset of coronary occlusion at 1, 0.7, 0.4, or 0.2 ml/kg/min for 12, 17, 30, and 60 min, respectively, followed by blood-flow restoration. Outcome measures were systemic hemodynamics and LV performance assessed by the state-of-the-art cardiac magnetic resonance (CMR) imaging. The best performing HBOC-201 perfusion strategies were then tested for their impact on LV performance during myocardial infarction, in pigs subjected to 45 min mid-left anterior descending (LAD) coronary occlusion. At the end of the ischemia duration, pigs were randomized to regular reperfusion (blood-only reperfusion) vs. bloodless reperfusion (perfusion with pre-oxygenated HBOC-201 distal to the occlusion site), followed by blood-flow restoration. Hemodynamics and CMR-measured LV performance were assessed at 7- and 45-day follow-up. In modifications of the HBOC-201 procedure, glucose and insulin were included to support cardiac metabolism. A total of 66 pigs were included in this study. Twenty healthy pigs (5 per infusion protocol) were used in the study of healthy myocardium. Intracoronary administration of HBOC-201 (600 ml) at varying rates, including a flow of 0.4 ml/kg/min (corresponding to a maximum perfusion time of 30 min), did not damage the healthy myocardium. Slower perfusion (longer infusion time) was associated with permanent LV dysfunction and myocardial necrosis. A total of 46 pigs underwent MI induction. Compared with regular reperfusion, bloodless reperfusion with pre-oxygenated HBOC-201 alone increased IS. This effect was reversed by enrichment of pre-oxygenated HBOC-201 solution with glucose and insulin, resulting in no increase in IS or worsening of long-term ventricular function despite further delaying restoration of blood flow in the LAD. Bloodless reperfusion with a pre-oxygenated HBOC-201 solution supplemented with glucose and insulin is feasible and safe, but did not reduce infarct size. This strategy could be, however, used to deliver agents to the myocardium to treat or prevent ischemia/reperfusion injury before blood-flow restoration.
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Hemodinámica/efectos de los fármacos , Hemoglobinas/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Reperfusión Miocárdica/métodos , Animales , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Infarto del Miocardio/complicaciones , Distribución Aleatoria , PorcinosRESUMEN
BACKGROUND: Marine omega-3 eicosapentaenoic acid (EPA) is readily incorporated into cardiomyocyte membranes, partially displacing the omega-6 arachidonic acid (AA). Whereas AA is a substrate for pro-inflammatory eicosanoids, the release of EPA from cell membranes generates anti-inflammatory lipid mediators, contributing to the infarct-limiting effect observed experimental models. Clinical data are lacking. METHODS: In this observational study conducted in 100 patients with a reperfused anterior ST-elevation myocardial infarction (STEMI), at hospital admission we quantified by gas-chromatography the red blood cell proportions of AA, EPA, and the AA:EPA ratio, a valid surrogate for cardiomyocyte membrane content. Patients underwent cardiac magnetic resonance imaging in the acute phase (one week post-STEMI), and at long-term (6 months) follow-up. Infarct size (delayed gadolinium enhancement) and cardiac function (left ventricular ejection fraction [LVEF]) were correlated with exposures of interest by multivariate regression analysis. RESULTS: AA:EPA ratio directly related to acute infarct size (coefficient [95% CI]: 6.19 [1.68 to 10.69], P = 0.008) and inversely to long-term LVEF (coefficient [95% CI]: − 4.02 [− 7.15 to − 0.89], P = 0.012). EPA inversely related to acute infarct size (coefficient [95% CI]: − 6.58; [− 11.46 to − 1.70]; P = 0.009), while a direct association with LVEF at follow-up (coefficient [95% CI]: 3.67 [0.25 to 7.08]; P = 0.036) was observed. CONCLUSIONS: A low AA:EPA ratio in red blood cells at the time of STEMI is associated with smaller acute infarct size and preserved long-term ventricular function. Our results are consistent with prior work in experimental models and add to the notion of omega-3 fatty acids as a healthy fat. TRIAL REGISTRATION: http://www.clinicaltrials.gov/NCT01311700
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Ácido Araquidónico/sangre , Ácido Eicosapentaenoico/sangre , Infarto del Miocardio con Elevación del ST/sangre , Antiarrítmicos/uso terapéutico , Dieta , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Metoprolol/uso terapéutico , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/fisiopatología , Alimentos Marinos , Volumen Sistólico/fisiología , Resultado del TratamientoRESUMEN
Beta-3 adrenergic receptor (ß3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of ß3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of ß3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of ß3AR mRNA and the vasodilator response of ß3AR agonists in pulmonary arteries. Single intravenous administration of the ß3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different ß3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. +1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. +1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in ß3AR agonists-treated pigs. ß3AR was expressed in human pulmonary arteries and ß3AR agonists produced vasodilatation. ß3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.
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Agonistas de Receptores Adrenérgicos beta 3/farmacología , Hipertensión Pulmonar/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Resistencia Vascular/efectos de los fármacos , Acetanilidas/farmacología , Animales , Western Blotting , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Nebivolol/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo , Distribución Aleatoria , Reacción en Cadena en Tiempo Real de la Polimerasa , Porcinos , Tiazoles/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
INTRODUCTION: Direct quantification of atherosclerotic plaque volume by three-dimensional vascular ultrasound (3DVUS) is more reproducible than 2DUS-based three-dimensional (2D/3D) techniques that generate pseudo-3D volumes from summed 2D plaque areas; however, its accuracy has not been reported. We aimed to determine 3DVUS accuracy for plaque volume measurement with special emphasis on small plaques (a hallmark of early atherosclerosis). METHODS: The in vitro study consisted of nine phantoms of different volumes (small and medium-large) embedded at variable distances from the surface (superficial vs. >5 cm-depth) and comparison of 3DVUS data generated using a novel volumetric-linear array method with the real phantom volumes. The in vivo study was undertaken in a rabbit model of atherosclerosis in which 3DVUS and 2D/3D volume measurements were correlated against gold-standard histological measurements. RESULTS: In the in vitro setting, there was a strong correlation between 3DVUS measures and real phantom volume both for small (3.0-64.5 mm(3) size) and medium-large (91.1-965.5 mm(3) size) phantoms embedded superficially, with intraclass correlation coefficients (ICC) of 0.99 and 0.98, respectively; conversely, when phantoms were placed at >5 cm, the correlation was only moderate (ICC = 0.67). In the in vivo setting there was strong correlation between 3DVUS-measured plaque volumes and the histological gold-standard (ICC = 0.99 [4.02-92.5 mm(3) size]). Conversely, the correlation between 2D/3D values and the histological gold standard (sum of plaque areas) was weaker (ICC = 0.87 [49-520 mm(2) size]), with large dispersion of the differences between measurements in Bland-Altman plots (mean error, 79.2 mm(2)). CONCLUSIONS: 3DVUS using the volumetric-linear array method accurately measures plaque volumes, including those of small plaques. Measurements are more accurate for superficial arterial territories than for deep territories.
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Procesamiento de Imagen Asistido por Computador/métodos , Placa Aterosclerótica/diagnóstico por imagen , Ultrasonografía , Animales , Estudios de Cohortes , Humanos , Imagenología Tridimensional , Modelos Lineales , Fantasmas de Imagen , Conejos , Reproducibilidad de los Resultados , Programas InformáticosRESUMEN
BACKGROUND: Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: This study sought to determine how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval. METHODS: We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short- and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (-25 min) or short (-5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings. RESULTS: For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3% vs. 43.9%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR). CONCLUSIONS: In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study.
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Antagonistas de Receptores Adrenérgicos beta 1/administración & dosificación , Metoprolol/administración & dosificación , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/tratamiento farmacológico , Volumen Sistólico/efectos de los fármacos , Tiempo de Tratamiento , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Servicios Médicos de Urgencia , Femenino , Humanos , Inyecciones Intravenosas , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Reperfusión Miocárdica , Intervención Coronaria Percutánea , Porcinos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Exercise has been proposed as a trigger for arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotype manifestation; however, research is hampered by the limited availability of animal models in which disease-associated mutations can be tested. OBJECTIVES: This study evaluated the impact of exercise on ARVC cardiac manifestations in mice after adeno-associated virus (AAV)-mediated gene delivery of mutant human PKP2, which encodes the desmosomal protein plakophilin-2. METHODS: We developed a new model of cardiac tissue-specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype. RESULTS: Stable cardiac expression of mutant PKP2 (c.2203C>T), encoding the R735X mutant protein, was achieved 4 weeks after a single AAV9-R735X intravenous injection. High-field cardiac magnetic resonance over a 10-month postinfection follow-up did not detect an overt right ventricular (RV) phenotype in nonexercised (sedentary) mice. In contrast, endurance exercise training (initiated 2 weeks after AAV9-R735X injection) resulted in clear RV dysfunction that resembled the ARVC phenotype (impaired global RV systolic function and RV regional wall motion abnormalities on cardiac magnetic resonance). At the histological level, RV samples from endurance-trained R735X-infected mice displayed connexin 43 delocalization at intercardiomyocyte gap junctions, a change not observed in sedentary mice. CONCLUSIONS: The introduction of the PKP2 R735X mutation into mice resulted in an exercise-dependent ARVC phenotype. The R735X mutation appears to function as a dominant-negative variant. This novel system for AAV-mediated introduction of a mutation into wild-type mice has broad potential for study of the implication of diverse mutations in complex cardiomyopathies.
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Displasia Ventricular Derecha Arritmogénica/genética , Mutación/genética , Fenotipo , Condicionamiento Físico Animal/fisiología , Placofilinas/genética , Animales , Displasia Ventricular Derecha Arritmogénica/metabolismo , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Condicionamiento Físico Animal/métodos , Placofilinas/biosíntesisRESUMEN
Early detection of right ventricular (RV) involvement in chronic pulmonary hypertension (PH) is essential due to prognostic implications. T1 mapping by cardiac magnetic resonance (CMR) has emerged as a noninvasive technique for extracellular volume fraction (ECV) quantification. We assessed the association of myocardial native T1 time and equilibrium contrast ECV (Eq-ECV) at the RV insertion points with pulmonary hemodynamics and RV performance in an experimental model of chronic PH. Right heart catheterization followed by immediate CMR was performed on 38 pigs with chronic PH (generated by surgical pulmonary vein banding) and 6 sham-operated controls. Native T1 and Eq-ECV values at the RV insertion points were both significantly higher in banded animals than in controls and showed significant correlation with pulmonary hemodynamics, RV arterial coupling, and RV performance. Eq-ECV values also increased before overt RV systolic dysfunction, offering potential for the early detection of myocardial involvement in chronic PH.
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Ventrículos Cardíacos/fisiopatología , Hipertensión Pulmonar/fisiopatología , Imagen por Resonancia Magnética , Animales , Cateterismo Cardíaco , Enfermedad Crónica , Hemodinámica , Hipertensión Pulmonar/patología , Masculino , Miocardio/patología , PorcinosRESUMEN
BACKGROUND: It is widely accepted that edema occurs early in the ischemic zone and persists in stable form for at least 1 week after myocardial ischemia/reperfusion. However, there are no longitudinal studies covering from very early (minutes) to late (1 week) reperfusion stages confirming this phenomenon. OBJECTIVES: This study sought to perform a comprehensive longitudinal imaging and histological characterization of the edematous reaction after experimental myocardial ischemia/reperfusion. METHODS: The study population consisted of 25 instrumented Large-White pigs (30 kg to 40 kg). Closed-chest 40-min ischemia/reperfusion was performed in 20 pigs, which were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5), and 7 days (n = 5) after reperfusion and processed for histological quantification of myocardial water content. Cardiac magnetic resonance (CMR) scans with T2-weighted short-tau inversion recovery and T2-mapping sequences were performed at every follow-up stage until sacrifice. Five additional pigs sacrificed after baseline CMR served as controls. RESULTS: In all pigs, reperfusion was associated with a significant increase in T2 relaxation times in the ischemic region. On 24-h CMR, ischemic myocardium T2 times returned to normal values (similar to those seen pre-infarction). Thereafter, ischemic myocardium-T2 times in CMR performed on days 4 and 7 after reperfusion progressively and systematically increased. On day 7 CMR, T2 relaxation times were as high as those observed at reperfusion. Myocardial water content analysis in the ischemic region showed a parallel bimodal pattern: 2 high water content peaks at reperfusion and at day 7, and a significant decrease at 24 h. CONCLUSIONS: Contrary to the accepted view, myocardial edema during the first week after ischemia/reperfusion follows a bimodal pattern. The initial wave appears abruptly upon reperfusion and dissipates at 24 h. Conversely, the deferred wave of edema appears progressively days after ischemia/reperfusion and is maximal around day 7 after reperfusion.
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Edema/etiología , Daño por Reperfusión Miocárdica/complicaciones , Animales , Modelos Animales de Enfermedad , Edema/patología , Imagen por Resonancia Magnética , Masculino , Daño por Reperfusión Miocárdica/patología , Miocardio/química , Miocardio/patología , Porcinos , Agua/análisisRESUMEN
STUDY OBJECTIVE: We seek to examine the efficacy and safety of prereperfusion emergency medical services (EMS)-administered intravenous metoprolol in anterior ST-segment elevation myocardial infarction patients undergoing eventual primary angioplasty. METHODS: This is a prespecified subgroup analysis of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction trial population, who all eventually received oral metoprolol within 12 to 24 hours. We studied patients receiving intravenous metoprolol by EMS and compared them with others treated by EMS but not receiving intravenous metoprolol. Outcomes included infarct size and left ventricular ejection fraction on cardiac magnetic resonance imaging at 1 week, and safety by measuring the incidence of the predefined combined endpoint (composite of death, malignant ventricular arrhythmias, advanced atrioventricular block, cardiogenic shock, or reinfarction) within the first 24 hours. RESULTS: From the total population of the trial (N=270), 147 patients (54%) were recruited during out-of-hospital assistance and transferred to the primary angioplasty center (74 intravenous metoprolol and 73 controls). Infarct size was smaller in patients receiving intravenous metoprolol compared with controls (23.4 [SD 15.0] versus 34.0 [SD 23.7] g; adjusted difference -11.4; 95% confidence interval [CI] -18.6 to -4.3). Left ventricular ejection fraction was higher in the intravenous metoprolol group (48.1% [SD 8.4%] versus 43.1% [SD 10.2%]; adjusted difference 5.0; 95% CI 1.6 to 8.4). Metoprolol administration did not increase the incidence of the prespecified safety combined endpoint: 6.8% versus 17.8% in controls (risk difference -11.1; 95% CI -21.5 to -0.6). CONCLUSION: Out-of-hospital administration of intravenous metoprolol by EMS within 4.5 hours of symptom onset in our subjects reduced infarct size and improved left ventricular ejection fraction with no excess of adverse events during the first 24 hours.