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BACKGROUND: An accurate evaluation of the degree of sedation is mandatory to adjust the dosage of sedative drugs. OBJECTIVES: To determine the correlation between head height above the ground and ataxia degree in horses sedated with detomidine and the correlation existing between accelerometric variables and both parameters. STUDY DESIGN: Retrospective study. METHODS: Twelve horses were given 0.01 mg/kg of detomidine hydrochloride iv. Measured accelerometric parameters, with one accelerometer positioned between both sacral tuberosities, included speed, stride frequency and length, regularity, dorsoventral, longitudinal, mediolateral and total accelerometric activities, relative force index and dorsoventral, longitudinal and mediolateral parts of the accelerometric activities. Head height above the ground (cm) and subjective ataxia degree were also measured. Baseline values (-15 min) and values measured 5 and 15 min after the injection and then every 15 min for a period of 2 h were obtained. RESULTS: There was a negative and strong correlation between head height above the ground and ataxia degree (Pearson r = -0.78, p < 0.001), particularly during the first 45 min. A significant correlation was found between head height above the ground and almost all accelerometric parameters. This correlation was very strong with stride frequency, regularity and dorsoventral and total accelerometric activities in both cases, but for ataxia, also with total accelerometric activity. MAIN LIMITATIONS: Experimental conditions may not represent real clinical situations. CONCLUSIONS: Stride frequency and regularity are the most reliable parameters to determine degree of sedation and are related to the sedation produced. Ataxia should not be considered a separate property of sedation and does not need to be assessed separately to the depth of sedation.
HISTORIAL: Una evaluación precisa del grado de sedación es importante para ajustar la dosis de drogas sedantes. OBJETIVOS: Determinar la correlación entre la altura de cabeza con respecto al suelo y el grado de ataxia en caballos sedados con detomidina y la correlación que existe entre las variables acelerométricas y ambos parámetros. DISEÑO DEL ESTUDIO: Estudio retrospectivo. MÉTODOS: A doce caballos se les administró 0.01 mg/kg de hidrocloruro de detomidina por vía endovenosa. Parámetros acelerométricos fueron medidos, con un acelerómetro posicionado entre ambas tuberosidades sacrales, que incluyeron velocidad, frecuencia y largo del paso, regularidad, actividades acelerométricas dorso ventral, longitudinal, medio lateral y total, índice de fuerza relativo y partes dorso ventral, longitudinal, medio lateral de actividades acelerométricas. También se midieron la altura de la cabeza sobre el nivel del suelo (cm) y grado de ataxia subjetiva. Se obtuvieron valores de base (15 min) y valores medidos 5 y 15 min después de la inyección y subsecuentemente cada 15 min por un periódo de 2h. RESULTADOS: Hubo una correlación fuerte, negativa, estadísticamente significativa entre la altura de la cabeza sobre el nivel del suelo y el grado de ataxia (Pearson r = 0.78, p<0.001), con una correlación mayor durante los primeros 45 minutos. En cuanto a la ataxia, se encontró una correlación significativa entre cabeza sobre el suelo y casi todos los parámetros acelerométricos. Esta correlación fue muy fuerte con la frecuencia y regularidad del paso, actividades acelerométricas dorso ventral y total en ambos casos pero para ataxia también con actividad acelerométrica total. LIMITACIONES PRINCIPALES: Condiciones experimentales no imitan completamente las situaciones clínicas reales. CONCLUSIONES: La frecuencia y regularidad del paso parecen ser los parámetros más confiables para determinar el grado de sedación y están estrictamente relacionados con la sedación producida. Además, la ataxia no debería considerarse como una propiedad separada de la sedación y no necesita ser evaluada en forma separada a la profundidad de la sedación.
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Stress leukogram includes eosinopenia as one of its main markers (neutrophilia, eosinopenia, lymphopenia, and mild monocytosis). Cortisol is the main stress biomarker, which is also strongly correlated with the severity of gastrointestinal diseases. This study aimed to determine the relationship between salivary cortisol and the eosinophil cell count (EC) in equids with abdominal pain. To do this, 39 horses with abdominal pain referred to an emergency service were included. All samples were taken on admission, and several parameters and clinical data were included. Equids were classified according to the outcome as survivors and non-survivors. Non-surviving equids presented higher salivary cortisol concentrations (Non-Survivors: 1.580 ± 0.816 µg/dL; Survivors 0.988 ± 0.653 µg/dL; p < 0.05) and lower EC (Non-Survivors: 0.0000 × 103/µL (0.000/0.0075); Survivors: 0.0450 × 103/µL (0.010/0.1825); p < 0.01). In addition, the relationship between salivary cortisol concentration, EC, and the WBC was determined. Only a strong correlation (negative) was observed between cortisol and EC (r = -0.523, p < 0.01). Since cortisol is not an analyte that can be measured routinely in clinical settings such as emergencies, the EC could be a good alternative. While the results are promising, further studies are needed before EC can be used confidently in routine practice to predict survival in cases of abdominal pain.
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Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.
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Hipertensión Pulmonar , Animales , Humanos , Ratones , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/tratamiento farmacológico , Hipoxia , Pulmón , Miocardio , Arteria Pulmonar , PorcinosRESUMEN
Introduction: Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. Methods: In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Results: Although both drugs reduced capillary pruning, a combination of experiments based on ex vivo imaging, proteomics, electron microscopy and in vivo functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Discussion: Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage.
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Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism.
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Ácidos Grasos , Glucosa , Corazón , Leche Humana , Ácido gammalinolénico , Femenino , Humanos , Recién Nacido , Embarazo , Cromatina/genética , Ácidos Grasos/metabolismo , Ácido gammalinolénico/metabolismo , Ácido gammalinolénico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Corazón/efectos de los fármacos , Corazón/embriología , Corazón/crecimiento & desarrollo , Homeostasis , Técnicas In Vitro , Leche Humana/química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Receptores X Retinoide/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Cardiac cine magnetic resonance imaging (MRI) can be considered the optimal criterion for measuring cardiac function. This imaging technique can provide us with detailed information about cardiac structure, tissue composition and even blood flow, which makes it highly used in medical science. But due to the image time acquisition and several other factors the MRI sequences can easily get corrupted, causing radiologists to misdiagnose 40 million people worldwide each and every single year. Hence, the urge to decrease these numbers, researchers from different fields have been introducing novel tools and methods in the medical field. Aiming to the same target, we consider in this work the application of the higher order dynamic mode decomposition (HODMD) technique. The HODMD algorithm is a linear method, which was originally introduced in the fluid dynamics domain, for the analysis of complex systems. Nevertheless, the proposed method has extended its applicability to numerous domains, including medicine. In this work, HODMD in used to analyze sets of MR images of a heart, with the ultimate goal of identifying the main patterns and frequencies driving the heart dynamics. Furthermore, a novel interpolation algorithm based on singular value decomposition combined with HODMD is introduced, providing a three-dimensional reconstruction of the heart. This algorithm is applied (i) to reconstruct corrupted or missing images, and (ii) to build a reduced order model of the heart dynamics.
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Corazón , Imagen por Resonancia Cinemagnética , Humanos , Imagen por Resonancia Cinemagnética/métodos , Corazón/diagnóstico por imagen , Algoritmos , Imagen por Resonancia Magnética/métodos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) prevalence is increasing, and large clinical trials have failed to reduce mortality. A major reason for this outcome is the failure to translate results from basic research to the clinics. Evaluation of HFpEF in mouse models requires assessing three major key features defining this complex syndrome: the presence of a preserved left ventricular ejection fraction (LVEF), diastolic dysfunction, and the development of HF. In addition, HFpEF is associated with multiple comorbidities such as systemic arterial hypertension, chronic obstructive pulmonary disease, sleep apnea, diabetes, and obesity; thus, non-cardiac disorders assessment is crucial for a complete phenotype characterization. Non-invasive procedures present unquestionable advantages to maintain animal welfare and enable longitudinal analyses. However, unequivocally determining the presence of HFpEF using these methods remains challenging. MAIN TEXT: Transthoracic echocardiography (TTE) represents an invaluable tool in HFpEF diagnosis, allowing evaluation of LVEF, diastolic dysfunction, and lung congestion in mice. Since conventional parameters used to evaluate an abnormal diastole like E/A ratio, isovolumic relaxation time, and E/e' may pose limitations in mice, including advanced TTE techniques to characterize cardiac motion, including an assessment under stress, will improve diagnosis. Patients with HFpEF also show electrical cardiac remodelling and therefore electrocardiography may add valuable information in mouse models to assess chronotropic incompetence and sinoatrial node dysfunction, which are major contributors to exercise intolerance. To complete the non-invasive diagnosis of HF, low aerobic exercise capacity and fatigue using exercise tests, impaired oxygen exchange using metabolic cages, and determination of blood biomarkers can be determined. Finally, since HFpEF patients commonly present non-cardiac pathological conditions, acquisition of systemic and pulmonary arterial pressures, blood glucose levels, and performing glucose tolerance and insulin resistance tests are required for a complete phenotyping. CONCLUSION: Identification of reliable models of HFpEF in mice by using proper diagnosis tools is necessary to translate basic research results to the clinics. Determining the presence of several HFpEF indicators and a higher number of abnormal parameters will lead to more reliable evidence of HFpEF.
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Insuficiencia Cardíaca , Función Ventricular Izquierda , Animales , Biomarcadores , Glucemia , Insuficiencia Cardíaca/diagnóstico , Ratones , Oxígeno , Volumen SistólicoRESUMEN
Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69-/- mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69-/- mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.
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Insuficiencia Cardíaca , Infarto del Miocardio , Animales , Ratones , Traslado Adoptivo/métodos , Apoptosis , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Interleucina-17/metabolismo , Infarto del Miocardio/patología , Linfocitos T ReguladoresRESUMEN
Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein-protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.
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Empalme Alternativo , Cardiopatías , Animales , Ratones , Proteína de Unión al Tracto de Polipirimidina/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Corazón , Cardiopatías/genéticaRESUMEN
In this work, we study in detail the performance of Higher Order Dynamic Mode Decomposition (HODMD) technique when applied to echocardiography images. HODMD is a data-driven method generally used in fluid dynamics and in the analysis of complex non-linear dynamical systems modeling several complex industrial applications. In this paper we apply HODMD, for the first time to the authors knowledge, for patterns recognition in echocardiography, specifically, echocardiography data taken from several mice, either in healthy conditions or afflicted by different cardiac diseases. We exploit the HODMD advantageous properties in dynamics identification and noise cleaning to identify the relevant frequencies and coherent patterns for each one of the diseases. The echocardiography datasets consist of video loops taken with respect to a long axis view (LAX) and a short axis view (SAX), where each video loop covers at least three cardiac cycles, formed by (at most) 300 frames each (called snapshots). The proposed algorithm, using only a maximum quantity of 200 snapshots, was able to capture two branches of frequencies, representing the heart rate and respiratory rate. Additionally, the algorithm provided a number of modes, which represent the dominant features and patterns in the different echocardiography images, also related to the heart and the lung. Six datasets were analyzed: one echocardiography taken from a healthy subject and five different sets of echocardiography taken from subjects with either Diabetic Cardiomyopathy, Obesity, SFSR4 Hypertrophy, TAC Hypertrophy or Myocardial Infarction. The results show that HODMD is robust and a suitable tool to identify characteristic patterns able to classify the different pathologies studied.
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Hidrodinámica , Infarto del Miocardio , Animales , Ecocardiografía/métodos , Corazón/fisiología , Humanos , Hipertrofia , RatonesRESUMEN
Cardiac function and morphology by mouse fetal echocardiography can be assessed by scanning the uterus extracted from the abdominal cavity (trans-uterine ultrasound) or the womb (trans-abdominal ultrasound). Advantages of trans-abdominal ultrasound include (1) non-invasive longitudinal analysis at different stages, reducing animal use; and (2) maintenance of natural environment, diminishing perturbations on functional parameters, which are more frequent in trans-uterine conditions. Here we describe both approaches, explaining how to identify congenital cardiac defects and defining the correlation between echocardiography findings and histological analysis. For complete details on the use and execution of this protocol, please refer to (Menendez-Montes et al., 2016) and (Menendez-Montes et al., 2021).
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Ecocardiografía/métodos , Embrión de Mamíferos/diagnóstico por imagen , Corazón Fetal/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Interpretación de Imagen Asistida por Computador/métodos , Animales , Femenino , Masculino , Ratones , Embarazo , Ultrasonografía Prenatal/métodosRESUMEN
Heart diseases are associated with changes in the biomechanical properties of the myocardial wall. However, there is no modality available to assess myocardial stiffness directly. Brillouin microspectroscopy (mBS) is a consolidated mechanical characterization technique, applied to the study of the viscoelastic and elastic behavior of biological samples and may be a valuable tool for assessing the viscoelastic properties of the cardiac tissue. In this work, viscosity and elasticity were assessed using mBS in heart samples obtained from healthy and unhealthy mice (n = 6 per group). Speckle-tracking echocardiography (STE) was performed to evaluate heart deformation. We found that mBS was able to detect changes in stiffness in the ventricles in healthy myocardium. The right ventricle showed reduced stiffness, in agreement with its increased compliance. mBS measurements correlated strongly with STE data, highlighting the association between displacement and stiffness in myocardial regions. This correlation was lost in pathological conditions studied. The scar region in the infarcted heart presented changes in stiffness when compared to the rest of the heart, and the hypertrophied left ventricle showed increased stiffness following aortic stenosis, compared to the right ventricle. We demonstrate that mBS can be applied to determine myocardial stiffness, that measurements correlate with functional parameters and that they change with disease.
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Estenosis de la Válvula Aórtica/patología , Infarto del Miocardio/patología , Miocardio/patología , Animales , Estenosis de la Válvula Aórtica/diagnóstico , Modelos Animales de Enfermedad , Ecocardiografía , Elasticidad , Diagnóstico por Imagen de Elasticidad , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/diagnóstico , Análisis EspectralRESUMEN
OBJECTIVE: To determine demographic, preoperative and anaesthesia-related variables that may be associated with unsatisfactory recovery quality in horses undergoing emergency abdominal surgery (colic) in an equine teaching hospital. STUDY DESIGN: Retrospective case series. ANIMALS: A total of 313 horses. METHODS: The anaesthetic records of horses admitted for surgical treatment of colic between 2005 and 2018 were examined. Overall quality of recovery was assessed as dangerous, poor, fair, good or excellent. The following categories were constructed as a dichotomic variable: unsatisfactory recovery (poor and dangerous recoveries) and satisfactory recovery (excellent, good and fair recoveries). Univariable and multivariable analyses were performed to evaluate the association between all studied variables and recovery. RESULTS: All recoveries were unassisted. Unsatisfactory recovery quality totalled 17.2% (3.5% and 13.7% were dangerous and poor recoveries, respectively), whereas satisfactory recoveries totalled 82.8% (26.2%, 40.9% and 15.7% were fair, good and excellent recoveries, respectively). Univariable analysis showed that unsatisfactory recoveries were associated with high preoperative packed cell volume, pain behaviour, poor premedication and induction quality, high intraoperative mean heart rate, low mean arterial blood pressure, dobutamine dose ≥1.5 µg kg-1 minute-1, non-administration of romifidine, long anaesthesia time and prolonged time to stand. The multivariable model showed that factors strongly associated with unsatisfactory recovery quality were dobutamine dose ≥1.5 µg kg-1 minute-1 [adjusted odds ratio (AOR) = 6.60; 95% confidence interval (CI), 2.91-14.96], poor premedication quality (AOR=4.60; 95% CI, 1.73-12.23) and a time to stand > 70 minutes (AOR=2.59; 95% CI, 1.13-5.91). CONCLUSIONS AND CLINICAL RELEVANCE: Our study shows that high dobutamine requirements, poor premedication quality and a prolonged time to stand are risk factors for unsatisfactory recovery quality in horses undergoing anaesthesia for colic surgery. Addressing these factors may enable clinicians to improve the quality of recovery phase.
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Anestesia , Cólico , Enfermedades de los Caballos , Anestesia/veterinaria , Animales , Cólico/veterinaria , Demografía , Caballos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Standing surgery under sedation reduces anesthetic-related mortality in horses. Medetomidine, alone and combined with morphine in a constant rate infusion (CRI), has been described for standing surgery but their cardiorespiratory, sedative and antinociceptive effects have never been compared. The addition of ketamine could improve analgesia in these procedures with minimal cardiorespiratory consequences. The objectives were to compare the cardiorespiratory effects, quality of sedation, antinociception and ataxia produced by administration of a medetomidine-based CRI with morphine, ketamine or both, in standing horses. A prospective, blind, randomized crossover, experimental design with six healthy adult horses was performed, in which four treatments were administered to all horses with at least two weeks of washout period: medetomidine (M); medetomidine and ketamine (MK); medetomidine and morphine (MMo); and medetomidine, morphine and ketamine (MMoK). Dosages were the same in all treatment groups: medetomidine at 5 µg/kg bwt followed by 5 µg/kg bwt/h, ketamine at 0.4 mg/kg/h and morphine at 50 µg/kg bwt, followed by morphine 30 µg/kg bwt/h. Drug infusions were maintained for 120 min. Cardiorespiratory variables, sedation degree and antinociceptive effects were evaluated during the procedure. All combinations produced similar sedation and antinociceptive effects and no clinically relevant alterations in cardiorespiratory variables occurred. Medetomidine CRI combined with morphine, ketamine or both are suitable and safe protocols for standing sedation in horses and the addition of morphine and/or ketamine did not cause any negative effect but no improving effect on sedation and antinociception was detected.
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[Figure: see text].
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Hipertrofia Ventricular Izquierda/metabolismo , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/metabolismo , Receptores de Glucocorticoides/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Animales , Células Cultivadas , Hipertrofia Ventricular Izquierda/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/genética , Receptores de Glucocorticoides/genética , Factores de Empalme Serina-Arginina/genética , TranscriptomaRESUMEN
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (ß-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice. METHODS: TMEM43mut male/female mice were treated with metoprolol (ß-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + ß-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed. RESULTS: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice. CONCLUSIONS: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Displasia Ventricular Derecha Arritmogénica/tratamiento farmacológico , Displasia Ventricular Derecha Arritmogénica/mortalidad , Enalapril/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Corazón/efectos de los fármacos , Insuficiencia Cardíaca/mortalidad , Ventrículos Cardíacos/efectos de los fármacos , Ratones , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFß1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.
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Endotelio Vascular/metabolismo , Transición Epitelial-Mesenquimal , Macrófagos/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Infarto del Miocardio/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Colágeno/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis , Citometría de Flujo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microcirculación , Fenotipo , Daño por Reperfusión , Disfunción Ventricular IzquierdaRESUMEN
BACKGROUND: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. METHODS: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. RESULTS: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and ß-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and ß-actin, and activation of glycogen synthase kinase-3ß (GSK3ß). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aß1 results in GSK3ß inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3ß inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3ß inhibition. CONCLUSIONS: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aß1 in TMEM43 mutant mice or chemical GSK3ß inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.