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This study examined the association and predictive ability of several markers of internal workload on risk of injury in high-performance junior tennis players. Fifteen young, high-level tennis players (9 males, 6 females; age: 17.2 ± 1.1 years; height: 178.5 ± 8.7â cm; mass: 68.1 ± 4.8â kg) participated in this investigation. Data on injury epidemiology and internal workload during training were obtained for one competitive season. The session-rating of perceived exertion (s-RPE) was used to calculate internal workload markers in absolute (acute workload and chronic workload for 2-weeks, 3-weeks and 4-weeks) and relative terms (acute:chronic workload ratios [ACWR] for 2-weeks, 3-weeks and 4-weeks). Associations and diagnostic power for predicting tennis injuries were examined through generalised estimating equations and receiver operating characteristics analyses. During the season, a total of 40 injuries were recorded, corresponding to 3.5 injuries per 1000â h of tennis practice. The acute workload was highly associated with injury incidence (P=0.04), as injury risk increased by 1.62 times (95% CI: 1.01-2.62) for every increase of 1858.7 arbitrary units (AU) of the workload during the most recent training week. However, acute workload was a poor predictor of injury, and associations between injury and internal workload markers were weak (all P>0.05). These findings demonstrate an association between high values of acute workload and the risk of injury in high-level tennis players. However, a high acute workload is only one of the many factors associated with injury, and by itself, has low predictive ability for injury.
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Traumatismos en Atletas/epidemiología , Acondicionamiento Físico Humano/efectos adversos , Tenis/lesiones , Adolescente , Conducta Competitiva , Femenino , Humanos , Incidencia , Masculino , Percepción/fisiología , Esfuerzo Físico/fisiología , Estudios Prospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Scalp-recorded evoked potentials elicited by applying afferent electrical stimulation at the tragus region of the human external ear have shown inconsistent results. We aim to disentangle discrepant findings and interpretations, and put forward novel physiological explanations on the origin of the vagus nerve somatosensory evoked potentials (VSEP). METHODS: We systematically search and critically appraise in PubMed, Web of Science, and Scielo databases the scientific reports publishing VSEP findings elicited by afferent electrical stimulation at the tragus region from individuals without brain disorders. Eligible studies published from January 2000 to April 2020 were extracted. The following information was identified from each article: number of participants; age; gender; stimulating/recording and grounding electrodes as well as stimulus side, intensity, duration, frequency, and polarity. Information about physiological parameters and neurobiological variables was also extracted. Representative vignettes with novel scalp responses induced by stimulating the tragus were also included to add support to our conclusions. RESULTS: 140 healthy participants were identified from six selected reports. Mean age ranged from 24.3 to 61.5 years. Stimulating and recording aspects were miscellaneous among studies. Scalp responses marked as the VSEP were recorded in 76% of participants, and showed high variability, low validity and poor reproducibility. Age correlated with response latencies. There were not gender differences in scalp response parameters. Cardiovascular function was unaltered by tragus stimulation. Vignettes showed that the VSEP was scalp muscle responses. CONCLUSION: VSEP did not fulfil evoked potential guidelines. VSEP corresponded to volume conduction propagating from muscles surrounding scalp recording sites.
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Potenciales Evocados Somatosensoriales , Nervio Vago , Adulto , Encéfalo , Estimulación Eléctrica , Humanos , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
The trigeminocardiac reflex (TCR) is a complex and, sometimes, fatal event triggered by overstimulation of the trigeminal nerve (TN) and its territorial and spinal cord branches. We reviewed and compiled for the neurosurgeon key aspects of the TCR that include a novel and straightforward classification, as well as morphophysiology, pathophysiology, neuromonitoring and neuromodulation features. Further, we present intraoperative data from a patient who developed extraterritorial, or type IV, TCR while undergoing a cervical surgery. TCR complexity, severity and unwanted outcomes indicate that this event should not be underestimated or overlooked in the surgical room. Timely TCR recognition in surgical settings is valuable for applying effective intraoperative management to prevent catastrophic outcomes.
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AIMS: Clinical guidelines recommend early intravenous ß-blockers during ongoing myocardial infarction; however, it is unknown whether all ß-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous ß-blockers. METHODS AND RESULTS: Mice undergoing 45 min/24 h ischaemia-reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of ß-blockers on the conformation of the ß1 adrenergic receptor was studied in silico. Of the tested ß-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular ß1 adrenergic receptor conformational changes when bound to metoprolol than to the other two ß-blockers. CONCLUSIONS: Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of ß-blockers may be related to distinct conformational changes in the ß1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous ß-blocker of choice for patients with ongoing infarction.
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Metoprolol , Infarto del Miocardio , Antagonistas Adrenérgicos beta/farmacología , Animales , Atenolol/farmacología , Humanos , Inflamación , Metoprolol/farmacología , RatonesRESUMEN
Chromatin remodeling factors contribute to establish aberrant gene expression programs in cancer cells and therefore represent valuable targets for therapeutic intervention. BPTF (Bromodomain PhD Transcription Factor), a core subunit of the nucleosome remodeling factor (NURF), modulates c-MYC oncogenic activity in pancreatic cancer. Here, we analyze the role of BPTF in c-MYC-driven B-cell lymphomagenesis using the Eµ-Myc transgenic mouse model of aggressive B-cell lymphoma. We find that BPTF is required for normal B-cell differentiation without evidence of haploinsufficiency. In contrast, deletion of one Bptf allele is sufficient to delay lymphomagenesis in Eµ-Myc mice. Tumors arising in a Bptf heterozygous background display decreased c-MYC levels and pathway activity, together with increased activation of the NF-κB pathway, a molecular signature characteristic of human diffuse large B-cell lymphoma (DLBCL). In human B-cell lymphoma samples, we find a strong correlation between BPTF and c-MYC mRNA and protein levels, together with an anti-correlation between BPTF and NF-κB pathway activity. Our results indicate that BPTF is a relevant therapeutic target in B-cell lymphomas and that, upon its inhibition, cells acquire distinct oncogenic dependencies.
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Antígenos Nucleares/genética , Linfoma de Células B/genética , Proteínas del Tejido Nervioso/genética , Dependencia del Oncogén/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción/genética , Animales , Antígenos Nucleares/metabolismo , Linfocitos B/metabolismo , Carcinogénesis/genética , Ensamble y Desensamble de Cromatina/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células B/metabolismo , Ratones Noqueados , Ratones Transgénicos , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/genética , Factores de Transcripción/metabolismoRESUMEN
Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.
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Vasos Sanguíneos/inmunología , Ritmo Circadiano/inmunología , Neutrófilos/inmunología , Fagocitosis/inmunología , Animales , Vasos Sanguíneos/metabolismo , Candida albicans/inmunología , Candida albicans/fisiología , Células Cultivadas , Senescencia Celular/inmunología , Quimiocina CXCL2/inmunología , Quimiocina CXCL2/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Receptores CXCR4/inmunología , Receptores CXCR4/metabolismo , Factores de TiempoRESUMEN
OBJECTIVE: Functional movement disorders (FMDs) mimic a range of movements, neuropsychiatric and neurodegenerative disorders known to have smell dysfunction, which has been neglected in terms of its application to FMD. We aim to determine the smell status in FMD patients tested by a non-invasive, reliable and validated olfactory test. PATIENTS AND METHODS: We quantitatively assessed in thirty-five FMD patients their smell status and compared it to that of healthy age- and sex-matched controls, and of patients with Parkinson's disease (PD). All participants were administered the Brief Smell Identification Test (B-SIT), a standardized short version of the University of Pennsylvania Smell Identification Test (UPSIT). The Picture Identification Test (PIT), a visual test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds, was also administered. RESULTS: The B-SIT scores of the FMD patients were higher than those from PD patients [respective means (standard deviations: SDs) = FMD, 9.54 (1.57); PD, 4.64 (1.05), p < 0.01)] but similar to the smell scores from healthy controls [9.97 (1.77), p = 0.35]. Gender, age, time of disease onset, smoking status, and phenotypic expression did not influence the test scores. Fourteen FMD patients who mentioned having olfactory dysfunction before smell testing have their test results within normal range. PIT scores from patients and healthy controls were within normal range. CONCLUSIONS: These findings indicate that FMD patients have normal olfactory function. Olfactory testing may be helpful in identifying and differentiating FMD from other movement, neurodegenerative and neuropsychiatric diseases for which smell function is altered.
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Trastornos del Movimiento/fisiopatología , Trastornos del Olfato/fisiopatología , Enfermedad de Parkinson/fisiopatología , Olfato/fisiología , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Discinesias/diagnóstico , Discinesias/fisiopatología , Femenino , Humanos , Lactante , Masculino , Trastornos del Movimiento/diagnóstico , Pruebas Neuropsicológicas , Trastornos del Olfato/diagnóstico , Enfermedad de Parkinson/diagnóstico , Adulto JovenRESUMEN
The administration of the selective ß3 adrenergic receptor (ß3AR) agonist BRL-37344 protects from myocardial ischemia/reperfusion injury (IRI), although the lack of clinical approval limits its translatability. We tested the cardioprotective effect of mirabegron, the first-in-class ß3AR agonist approved for human use. A dose-response study was conducted in 6 pigs to select the highest intravenous dose of mirabegron without significant detrimental hemodynamic effect. Subsequently, closed chest anterior myocardial infarction (45 min ischemia followed by reperfusion) was performed in 26 pigs which randomly received either mirabegron (10 µg/kg) or placebo 5 min before reperfusion. Day-7 cardiac magnetic resonance (CMR) showed no differences in infarct size (35.0 ± 2.0% of left ventricle (LV) vs. 35.9 ± 2.4% in mirabegron and placebo respectively, p = 0.782) or LV ejection fraction (36.3 ± 1.1 vs. 34.6 ± 1.9%, p = 0.430). Consistent results were obtained on day-45 CMR. In conclusion, the intravenous administration of the clinically available selective ß3AR agonist mirabegron does not reduce infarct size in a swine model of IRI.
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Acetanilidas , Infarto del Miocardio , Miocardio , Tiazoles , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Masculino , Acetanilidas/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Modelos Animales de Enfermedad , Imagen por Resonancia Cinemagnética , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/complicaciones , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Distribución Aleatoria , Porcinos , Tiazoles/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Clinical protocols aimed to characterize the post-myocardial infarction (MI) heart by cardiac magnetic resonance (CMR) need to be standardized to take account of dynamic biological phenomena evolving early after the index ischemic event. Here, we evaluated the time course of edema reaction in patients with ST-segment-elevation MI by CMR and assessed its implications for myocardium-at-risk (MaR) quantification both in patients and in a large-animal model. METHODS: A total of 16 patients with anterior ST-segment-elevation MI successfully treated by primary angioplasty and 16 matched controls were prospectively recruited. In total, 94 clinical CMR examinations were performed: patients with ST-segment-elevation MI were serially scanned (within the first 3 hours after reperfusion and at 1, 4, 7, and 40 days), and controls were scanned only once. T2 relaxation time in the myocardium (T2 mapping) and the extent of edema on T2-weighted short-tau triple inversion-recovery (ie, CMR-MaR) were evaluated at all time points. In the experimental study, 20 pigs underwent 40-minute ischemia/reperfusion followed by serial CMR examinations at 120 minutes and 1, 4, and 7 days after reperfusion. Reference MaR was assessed by contrast-multidetector computed tomography during the index coronary occlusion. Generalized linear mixed models were used to take account of repeated measurements. RESULTS: In humans, T2 relaxation time in the ischemic myocardium declines significantly from early after reperfusion to 24 hours, and then increases up to day 4, reaching a plateau from which it decreases from day 7. Consequently, edema extent measured by T2-weighted short-tau triple inversion-recovery (CMR-MaR) varied with the timing of the CMR examination. These findings were confirmed in the experimental model by showing that only CMR-MaR values for day 4 and day 7 postreperfusion, coinciding with the deferred edema wave, were similar to values measured by reference contrast-multidetector computed tomography. CONCLUSIONS: Post-MI edema in patients follows a bimodal pattern that affects CMR estimates of MaR. Dynamic changes in post-ST-segment-elevation MI edema highlight the need for standardization of CMR timing to retrospectively delineate MaR and quantify myocardial salvage. According to the present clinical and experimental data, a time window between days 4 and 7 post-MI seems a good compromise solution for standardization. Further studies are needed to study the effect of other factors on these variables.
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Edema/etiología , Corazón/fisiopatología , Infarto del Miocardio/diagnóstico , Animales , Edema/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Factores de Riesgo , PorcinosRESUMEN
RATIONALE: The impact of cardioprotective strategies and ischemia duration on postischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction) is not well understood. OBJECTIVE: To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of-the-art imaging technology. METHODS AND RESULTS: Four 5-pig groups underwent different I/R protocols: 40-minute I/R (prolonged ischemia, controls), 20-minute I/R (short-duration ischemia), prolonged ischemia preceded by preconditioning, or prolonged ischemia followed by postconditioning. Serial cardiac magnetic resonance (CMR)-based tissue characterization was done in all pigs at baseline and at 120 minutes, day 1, day 4, and day 7 after I/R. Reference myocardium at risk was assessed by multidetector computed tomography during the index coronary occlusion. After the final CMR, hearts were excised and processed for water content quantification and histology. Five additional healthy pigs were euthanized after baseline CMR as reference. Edema formation followed a bimodal pattern in all 40-minute I/R pigs, regardless of cardioprotective strategy and the degree of intramyocardial hemorrhage or microvascular obstruction. The hyperacute edematous wave was ameliorated only in pigs showing cardioprotection (ie, those undergoing short-duration ischemia or preconditioning). In all groups, CMR-measured edema was barely detectable at 24 hours postreperfusion. The deferred healing-related edematous wave was blunted or absent in pigs undergoing preconditioning or short-duration ischemia, respectively. CMR-measured infarct size declined progressively after reperfusion in all groups. CMR-measured myocardial salvage, and the extent of intramyocardial hemorrhage and microvascular obstruction varied dramatically according to CMR timing, ischemia duration, and cardioprotective strategy. CONCLUSIONS: Cardioprotective therapies, duration of index ischemia, and the interplay between these greatly influence temporal dynamics and extent of tissue composition changes after I/R. Consequently, imaging techniques and protocols for assessing edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction should be standardized accordingly.
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Precondicionamiento Isquémico Miocárdico/métodos , Infarto del Miocardio/prevención & control , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/prevención & control , Isquemia Miocárdica/fisiopatología , Reperfusión Miocárdica/métodos , Animales , Masculino , Tomografía Computarizada Multidetector/métodos , Infarto del Miocardio/diagnóstico por imagen , Isquemia Miocárdica/diagnóstico por imagen , Porcinos , Factores de TiempoRESUMEN
AIMS: Heart failure (HF) has become an epidemic and constitutes a major medical, social, and economic problem worldwide. Despite advances in medical treatment, HF prognosis remains poor. The development of efficient therapies is hampered by the lack of appropriate animal models in which HF can be reliably determined, particularly in mice. The development of HF in mice is often assumed based on the presence of cardiac dysfunction, but HF itself is seldom proved. Lung ultrasound (LUS) has become a helpful tool for lung congestion assessment in patients at all stages of HF. We aimed to apply this non-invasive imaging tool to evaluate HF in mouse models of both systolic and diastolic dysfunction. METHODS AND RESULTS: We used LUS to study HF in a mouse model of systolic dysfunction, dilated cardiomyopathy, and in a mouse model of diastolic dysfunction, diabetic cardiomyopathy. LUS proved to be a reliable and reproducible tool to detect pulmonary congestion in mice. The combination of LUS and echocardiography allowed discriminating those mice that develop HF from those that do not, even in the presence of evident cardiac dysfunction. The study showed that LUS can be used to identify the onset of HF decompensation and to evaluate the efficacy of therapies for this syndrome. CONCLUSIONS: This novel approach in mouse models of cardiac disease enables for the first time to adequately diagnose HF non-invasively in mice with preserved or reduced ejection fraction, and will pave the way to a better understanding of HF and to the development of new therapeutic approaches.
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Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatías Diabéticas/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Derrame Pleural/diagnóstico por imagen , Edema Pulmonar/diagnóstico por imagen , Investigación Biomédica Traslacional/métodos , Ultrasonografía/métodos , Función Ventricular Izquierda , Animales , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/fisiopatología , Cardiomiopatías Diabéticas/complicaciones , Cardiomiopatías Diabéticas/fisiopatología , Diástole , Modelos Animales de Enfermedad , Ecocardiografía Doppler de Pulso , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Derrame Pleural/etiología , Derrame Pleural/fisiopatología , Valor Predictivo de las Pruebas , Edema Pulmonar/etiología , Edema Pulmonar/fisiopatología , Reproducibilidad de los Resultados , Volumen Sistólico , Sístole , Función Ventricular DerechaRESUMEN
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
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
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: Post-ischemia/reperfusion (I/R) myocardial edema was recently shown to follow a consistent bimodal pattern: an initial wave of edema appears on reperfusion and dissipates at 24 h, followed by a deferred wave that initiates days after infarction, peaking at 1 week. OBJECTIVES: This study examined the pathophysiology underlying this post-I/R bimodal edematous reaction. METHODS: Forty instrumented pigs were assigned to different myocardial infarction protocols. Edematous reaction was evaluated by water content quantification, serial cardiac magnetic resonance T2-mapping, and histology/immunohistochemistry. The association of reperfusion with the initial wave of edema was evaluated in pigs undergoing 40-min/80-min I/R and compared with pigs undergoing 120-min ischemia with no reperfusion. The role of tissue healing in the deferred wave of edema was evaluated by comparing pigs undergoing standard 40-min/7-day I/R with animals subjected to infarction without reperfusion (chronic 7-day coronary occlusion) or receiving post-I/R high-dose steroid therapy. RESULTS: Characterization of post-I/R tissue changes revealed maximal interstitial edema early on reperfusion in the ischemic myocardium, with maximal content of neutrophils, macrophages, and collagen at 24 h, day 4, and day 7 post-I/R, respectively. Reperfused pigs had significantly higher myocardial water content at 120 min and T2 relaxation times on 120 min cardiac magnetic resonance than nonreperfused animals. Permanent coronary occlusion or high-dose steroid therapy significantly reduced myocardial water content on day 7 post-infarction. The dynamics of T2 relaxation times during the first post-infarction week were altered significantly in nonreperfused pigs compared with pigs undergoing regular I/R. CONCLUSIONS: The 2 waves of the post-I/R edematous reaction are related to different pathophysiological phenomena. Although the first wave is secondary to reperfusion, the second wave occurs mainly because of tissue healing processes.
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Edema/fisiopatología , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/fisiopatología , Reperfusión Miocárdica/métodos , Animales , Edema/etiología , Masculino , Isquemia Miocárdica/complicaciones , Reperfusión Miocárdica/efectos adversos , Daño por Reperfusión Miocárdica/etiología , PorcinosRESUMEN
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.
Asunto(s)
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
BACKGROUND: Biomarkers are frequently used to estimate infarct size (IS) as an endpoint in experimental and clinical studies. Here, we prospectively studied the impact of left ventricular (LV) hypertrophy (LVH) on biomarker release in clinical and experimental myocardial infarction (MI). METHODS AND RESULTS: ST-segment elevation myocardial infarction (STEMI) patients (n=140) were monitored for total creatine kinase (CK) and cardiac troponin I (cTnI) over 72 hours postinfarction and were examined by cardiac magnetic resonance (CMR) at 1 week and 6 months postinfarction. MI was generated in pigs with induced LVH (n=10) and in sham-operated pigs (n=8), and serial total CK and cTnI measurements were performed and CMR scans conducted at 7 days postinfarction. Regression analysis was used to study the influence of LVH on total CK and cTnI release and IS estimated by CMR (gold standard). Receiver operating characteristic (ROC) curve analysis was performed to study the discriminatory capacity of the area under the curve (AUC) of cTnI and total CK in predicting LV dysfunction. Cardiomyocyte cTnI expression was quantified in myocardial sections from LVH and sham-operated pigs. In both the clinical and experimental studies, LVH was associated with significantly higher peak and AUC of cTnI, but not with differences in total CK. ROC curves showed that the discriminatory capacity of AUC of cTnI to predict LV dysfunction was significantly worse for patients with LVH. LVH did not affect the capacity of total CK to estimate IS or LV dysfunction. Immunofluorescence analysis revealed significantly higher cTnI content in hypertrophic cardiomyocytes. CONCLUSIONS: Peak and AUC of cTnI both significantly overestimate IS in the presence of LVH, owing to the higher troponin content per cardiomyocyte. In the setting of LVH, cTnI release during STEMI poorly predicts postinfarction LV dysfunction. LV mass should be taken into consideration when IS or LV function are estimated by troponin release.
Asunto(s)
Forma MB de la Creatina-Quinasa/metabolismo , Hipertrofia Ventricular Izquierda/sangre , Infarto del Miocardio/sangre , Investigación Biomédica Traslacional/métodos , Troponina I/metabolismo , Anciano , Animales , Área Bajo la Curva , Biomarcadores/sangre , Forma MB de la Creatina-Quinasa/sangre , Modelos Animales de Enfermedad , Electrocardiografía/métodos , Femenino , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Imagen por Resonancia Cinemagnética/métodos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Infarto del Miocardio/diagnóstico , Pronóstico , Estudios Prospectivos , Curva ROC , Análisis de Regresión , Índice de Severidad de la Enfermedad , Sus scrofa , Porcinos , Troponina I/sangre , Función Ventricular IzquierdaRESUMEN
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.