RESUMEN
The transcription factor BTB and CNC homology 1(BACH1) has been linked to coronary artery disease risk by human genome-wide association studies, but little is known about the role of BACH1 in vascular smooth muscle cell (VSMC) phenotype switching and neointima formation following vascular injury. Therefore, this study aims to explore the role of BACH1 in vascular remodeling and its underlying mechanisms. BACH1 was highly expressed in human atherosclerotic plaques and has high transcriptional factor activity in VSMCs of human atherosclerotic arteries. VSMC-specific loss of Bach1 in mice inhibited the transformation of VSMC from contractile to synthetic phenotype and VSMC proliferation and attenuated the neointimal hyperplasia induced by wire injury. Mechanistically, BACH1 suppressed chromatin accessibility at the promoters of VSMC marker genes via recruiting histone methyltransferase G9a and cofactor YAP and maintaining the H3K9me2 state, thereby repressing VSMC marker genes expression in human aortic smooth muscle cells (HASMCs). BACH1-induced repression of VSMC marker genes was abolished by the silencing of G9a or YAP. Thus, these findings demonstrate a crucial regulatory role of BACH1 in VSMC phenotypic transition and vascular homeostasis and shed light on potential future protective vascular disease intervention via manipulation of BACH1.
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Cromatina , Músculo Liso Vascular , Neointima , Fenotipo , Animales , Humanos , Ratones , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Cromatina/genética , Cromatina/metabolismo , Homeostasis , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Neointima/genética , Neointima/metabolismo , Neointima/patología , Neointima/prevención & control , Placa AteroscleróticaRESUMEN
BACKGROUND: The transcription factor BACH1 (BTB and CNC homology 1) suppressed endothelial cells (ECs) proliferation and migration and impaired angiogenesis in the ischemic hindlimbs of adult mice. However, the role and underlying mechanisms of BACH1 in atherosclerosis remain unclear. METHODS: Mouse models of atherosclerosis in endothelial cell (EC)-specific-Bach1 knockout mice were used to study the role of BACH1 in the regulation of atherogenesis and the underlying mechanisms. RESULTS: Genetic analyses revealed that coronary artery disease-associated risk variant rs2832227 was associated with BACH1 gene expression in carotid plaques from patients. BACH1 was upregulated in ECs of human and mouse atherosclerotic plaques. Endothelial Bach1 deficiency decreased turbulent blood flow- or western diet-induced atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules (ICAM1 [intercellular cell adhesion molecule-1] and VCAM1 [vascular cell adhesion molecule-1]), and reduced plasma TNF-α (tumor necrosis factor-α) and IL-1ß levels in atherosclerotic mice. BACH1 deletion or knockdown inhibited monocyte-endothelial adhesion and reduced oscillatory shear stress or TNF-α-mediated induction of endothelial adhesion molecules and/or proinflammatory cytokines in mouse ECs, human umbilical vein ECs, and human aortic ECs. Mechanistic studies showed that upon oscillatory shear stress or TNF-α stimulation, BACH1 and YAP (yes-associated protein) were induced and translocated into the nucleus in ECs. BACH1 upregulated YAP expression by binding to the YAP promoter. BACH1 formed a complex with YAP inducing the transcription of adhesion molecules. YAP overexpression in ECs counteracted the antiatherosclerotic effect mediated by Bach1-deletion in mice. Rosuvastatin inhibited BACH1 expression by upregulating microRNA let-7a in ECs, and decreased Bach1 expression in the vascular endothelium of hyperlipidemic mice. BACH1 was colocalized with YAP, and the expression of BACH1 was positively correlated with YAP and proinflammatory genes, as well as adhesion molecules in human atherosclerotic plaques. CONCLUSIONS: These data identify BACH1 as a mechanosensor of hemodynamic stress and reveal that the BACH1-YAP transcriptional network is essential to vascular inflammation and atherogenesis. BACH1 shows potential as a novel therapeutic target in atherosclerosis.
Asunto(s)
Aterosclerosis , Placa Aterosclerótica , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/farmacología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/prevención & control , Ratones , Ratones Endogámicos C57BL , Placa Aterosclerótica/patología , Factores de Transcripción/metabolismoRESUMEN
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
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Insuficiencia Cardíaca , Trasplante de Corazón , Calidad de Vida , Humanos , Consenso , Europa (Continente) , Ejercicio Físico , Insuficiencia Cardíaca/rehabilitación , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/efectos adversos , Sociedades MédicasRESUMEN
BACKGROUND: One anastomosis gastric bypass (OAGB) has been proposed as an effective alternative to the current standard procedure in Switzerland, Roux-en-Y gastric bypass (RYGB). Prospective data comparing both procedures are scarce. Therefore, we performed a non-inferiority randomized controlled trial assessing the effectiveness and safety of these 2 operative techniques. METHOD: Eighty patients were randomized 1:1. OAGB consisted of a very long gastric pouch with a 200 cm biliopancreatic limb, RYGB of a 150 cm ante-colic alimentary and a 60 cm biliopancreatic limb, respectively. Primary endpoint was the percent excess weight loss (%EWL) at 12 months after surgery. RESULTS: Mean %EWL at 12 months was 87.9% (SD24.4) in the RYGB group and 104.1% (SD24.6) in the OAGB group (p = 0.006). There was no mortality. The rate of marginal ulcers was higher in patients with OAGB compared to those with RYGB (p = 0.011), while the total number of late complications did not statistically differ between the two groups. Except for the remission of GERD, which was higher in the RYGB group compared to OAGB, there was no difference between the groups regarding the remission of comorbidities. OAGB showed improved glucose control compared to the RYGB after 1 year (p = 0.001). Furthermore, glucagon-like peptide-1 increase was significantly higher in OAGB at 6 weeks (p = 0.041) and 1 year after surgery (p = 0.029). Quality of life improved after both surgeries, without differences between the groups. CONCLUSIONS: %EWL 1 year after surgery was higher in OAGB than in RYGB. A better glycemic control with a higher increase in GLP-1 was observed after OAGB compared to RYGB. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov under the identifier NCT02601092.
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Derivación Gástrica , Laparoscopía , Humanos , Derivación Gástrica/métodos , Femenino , Masculino , Laparoscopía/métodos , Estudios Prospectivos , Adulto , Persona de Mediana Edad , Pérdida de Peso , Obesidad Mórbida/cirugía , Resultado del Tratamiento , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
Cardiac compartmental size depends on sex, with smaller values found in (healthy) women compared to a matched group of men. Various types of heart disease may cause dilation of the affected chamber. For example, atrial fibrillation (AF) is associated with enlarged left atrial (LA) size, often also implying increased left ventricular (LV) size. Sex-specific differences appear to persist during disease states. Thus, chamber volumes depend on both sex and the severity of the underlying disorder, and require quantification to evaluate the effect of interventions. Often, we rely on the popular performance metric ejection fraction (EF) which refers to the ratio of the minimum and maximum LV or LA volumetric values observed during the cardiac cycle. Here we discuss a sex stratified analysis of LVEF and LAEF in AF patients as treated by LA appendage closure, while comparing those with or without device-related thrombosis. Also, an alternative analysis based on primary data is presented while emphasizing its attractiveness. In any event, age- and sex-specific reference values as broadly documented for various imaging modalities should be applied to LA and LV.
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Fibrilación Atrial , Volumen Sistólico , Trombosis , Humanos , Volumen Sistólico/fisiología , Femenino , Masculino , Trombosis/fisiopatología , Trombosis/etiología , Fibrilación Atrial/fisiopatología , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/fisiopatologíaRESUMEN
The advent of single-cell biology opens a new chapter for understanding human biological processes and for diagnosing, monitoring, and treating disease. This revolution now reaches the field of cardiovascular disease (CVD). New technologies to interrogate CVD samples at single-cell resolution are allowing the identification of novel cell communities that are important in shaping disease development and direct towards new therapeutic strategies. These approaches have begun to revolutionize atherosclerosis pathology and redraw our understanding of disease development. This review discusses the state-of-the-art of single-cell analysis of atherosclerotic plaques, with a particular focus on human lesions, and presents the current resolution of cellular subpopulations and their heterogeneity and plasticity in relation to clinically relevant features. Opportunities and pitfalls of current technologies as well as the clinical impact of single-cell technologies in CVD patient care are highlighted, advocating for multidisciplinary and international collaborative efforts to join the cellular dots of CVD.
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Aterosclerosis , Enfermedades Cardiovasculares , Placa Aterosclerótica , Humanos , Aterosclerosis/patología , Placa Aterosclerótica/patologíaRESUMEN
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective, well-tolerated, and safe glucose-lowering compounds for patients with type 2 diabetes mellitus (T2DM). SGLT2i benefit encompasses protection from heart and kidney failure, independently of the presence of diabetes. In addition, SGLT2i consistently reduce the risk of hospitalization for heart failure and, although with some heterogeneity between specific members of the class, favourably affect the risk of cardiovascular outcomes. The molecular mechanisms underlying the cardiovascular favourable effect are not fully clarified. Studies testing the efficacy of SGLT2i in human cohorts and experimental models of atherosclerotic cardiovascular disease (ASCVD) have reported significant differences in circulating levels and composition of lipoprotein classes. In randomized clinical trials, small but significant increases in low-density lipoprotein cholesterol (LDL-C) levels have been observed, with a still undefined clinical significance; on the other hand, favourable (although modest) effects on high-density lipoprotein cholesterol (HDL-C) and triglycerides have been reported. At the molecular level, glycosuria may promote a starving-like state that ultimately leads to a metabolic improvement through the mobilization of fatty acids from the adipose tissue and their oxidation for the production of ketone bodies. This, however, may also fuel hepatic cholesterol synthesis, thus inhibiting atherogenic lipoprotein uptake from the liver. Long-term studies collecting detailed information on lipid-lowering therapies at baseline and during the trials with SGLT2i, as well as regularly monitoring lipid profiles are warranted to disentangle the potential implications of SGLT2i in modulating lipoprotein-mediated atherosclerotic cardiovascular risk.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Aterosclerosis/tratamiento farmacológico , Triglicéridos , LDL-Colesterol , Lipoproteínas , Glucosa , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & controlRESUMEN
BACKGROUND: Coronary microvascular dysfunction (CMD) is usually evaluated measuring coronary flow velocity reserve (CFVR). A more comprehensive analysis of CFVR including additional consideration of the associated logical companion-CFVR, where hyperemic diastolic coronary flow velocity may act as surrogate, was applied in this study to elucidate the mechanism of CMD in psoriasis. METHODS AND RESULTS: Coronary flow velocity reserve was analysed using transthoracic echocardiographs of 127 psoriasis patients (age 36 ± 8 years; 104 males) and of 52 sex- and age-matched healthy controls. CFVR determination was repeated in the patient subgroup (n = 78) receiving anti-inflammatory therapy. Baseline and hyperemic microvascular resistance (MR) were calculated. CMD was defined as CFVR ≤ 2.5. Four endotypes of CMD were identified referring to concordant or discordant impairments of hyperemic flow or CFVR. We evaluated the companion-CFVR, as derived from the quadratic mean of hyperemic and diastolic flow velocity at rest. Coronary flow parameters, including CFVR (p = 0.01), were different among the two endotypes having CFVR > 2.5. Specifically, all 11 (14%) patients with CFVR deterioration despite therapy, belonged to endotype 1, and had higher baseline and hyperemic MR (p < 0.0001, both). Interestingly, while CFVR was comparable in patients with worsened versus those with improved CFVR, the companion-CFVR could discriminate by being lower in patients with worsened CFVR (p = 0.01). CONCLUSIONS: The reduced CFVR in psoriasis is driven by decreased companion-CFVR, combined with increased hyperemic MR. Adoption of the mandatory companion-CFVR enables a personalized characterization superior to that achieved by exclusive consideration of CFVR.
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Circulación Coronaria , Psoriasis/fisiopatología , Adulto , Estudios Transversales , Femenino , Humanos , MasculinoRESUMEN
Extensive evidence demonstrates that lowering blood pressure can substantially reduce the risk of atherosclerotic cardiovascular disease and death.In light of the latest 2018 European Society of Cardiology/European Society of Hypertension Joint Guidelines, we summarize the current recommendations about lifestyle intervention strategies, pharmacotherapy, and device-based treatments for the management of arterial hypertension. Special attention is given to direct effects exerted by some antihypertensive drugs targeting vascular wall cell components that are involved in the pathogenesis of atherosclerosis.
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Cardiología , Hipertensión , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea , Determinación de la Presión Sanguínea , Humanos , Hipertensión/tratamiento farmacológicoRESUMEN
AIMS: Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)-based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). METHODS AND RESULTS: A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > - 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220-6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218-3.686, p = 0.008; and HR 2.071, 95% CI: 1.111-3.861, p = 0.022). CONCLUSION: FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex.
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Enfermedad de la Arteria Coronaria , Imagen de Perfusión Miocárdica , Anciano , Calcio , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Humanos , Inflamación/diagnóstico por imagen , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Although health disparities in women presenting with acute coronary syndrome (ACS) have received growing attention in recent years, clinical outcomes from ACS are still worse for women than for men. Women continue to experience higher patient and system delays and receive less aggressive invasive treatment and pharmacotherapies. Gender- and sex-specific variables that contribute to ACS vulnerability remain largely unknown. Notwithstanding the sex differences in baseline coronary anatomy and function, women and men are treated the same based on guidelines that were established from experimental and clinical trial data over-representing the male population. Importantly, younger women have a particularly unfavourable prognosis and a plethora of unanswered questions remains in this younger population. The present review summarizes contemporary evidence for gender and sex differences in vascular biology, clinical presentation, and outcomes of ACS. We further discuss potential mechanisms and non-traditional risk conditions modulating the course of disease in women and men, such as unrecognized psychosocial factors, sex-specific vascular and neural stress responses, and the potential impact of epigenetic modifications.
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Síndrome Coronario Agudo , Fármacos Cardiovasculares , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/terapia , Fármacos Cardiovasculares/uso terapéutico , Femenino , Humanos , Masculino , Pronóstico , Factores de Riesgo , Caracteres Sexuales , Factores Sexuales , Resultado del TratamientoRESUMEN
AIMS: Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. METHODS AND RESULTS: We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerotic lesions characterized by larger necrotic cores and thinner fibrous caps. The immunometabolic effects of NCOR1 are mediated via suppression of peroxisome proliferator-activated receptor gamma (PPARγ) target genes in mouse and human macrophages, which lead to an enhanced expression of the CD36 scavenger receptor and subsequent increase in oxidized low-density lipoprotein uptake in the absence of NCOR1. Interestingly, in human atherosclerotic plaques, the expression of NCOR1 is reduced whereas the PPARγ signature is increased, and this signature is more pronounced in ruptured compared with non-ruptured carotid plaques. CONCLUSIONS: Our findings show that macrophage NCOR1 blocks the pro-atherogenic functions of PPARγ in atherosclerosis and suggest that stabilizing the NCOR1-PPARγ binding could be a promising strategy to block the pro-atherogenic functions of plaque macrophages and lesion progression in atherosclerotic patients.
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Aterosclerosis , Macrófagos , Co-Represor 1 de Receptor Nuclear , PPAR gamma , Animales , Aterosclerosis/genética , Aterosclerosis/prevención & control , Células Espumosas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Co-Represor 1 de Receptor Nuclear/genética , PPAR gamma/genética , Receptores de LDLAsunto(s)
Sueño , Función Ventricular Izquierda , Humanos , Estimulación Acústica , Sueño/fisiología , ElectroencefalografíaRESUMEN
Nowadays, it is generally appreciated that studies in the medical field should not only include sex-related aspects but also consider age. In the past, taking the era of Hippocrates as a starting point for the Western medical sciences, such aspects were less urgent and barely relevant. However, considering such details during daily life became increasingly important as the traditional roles of men and women in society and household converged. In the Western world, this fundamental transition process started recently and is advancing at an accelerated pace. Research about the role of women has also evolved, starting from plain history about the lives of women to a description of the relation between men and women, resulting in the gender concept. The present survey highlights a historical selection of observations referring to the impact of men and women on the medical sciences, as patient, study object, and professional. Whenever relevant, focus will be on the field of cardiovascular investigations as documented in the Western world. Rather than being exhaustive, we focus on a few remarkable icons, including Trota of Salerno, Hildegard von Bingen, and Miguel Serveto.
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Cardiología , Identidad de Género , Sujetos de Investigación , Femenino , Humanos , Masculino , Factores SexualesRESUMEN
The heart can be viewed not just as muscle pump but also as an important checkpoint for a complex network of nervous, endocrine, and immune signals. The heart is able to process neurological signals independently from the brain and to crosstalk with the endocrine and immune systems. The heart communicates with the psyche through the neuro-endocrine-immune system in a highly integrated way, in order to maintain the homeostasis of the whole body with peculiarities specific to males and females.
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Encéfalo/metabolismo , Cardiopatías/metabolismo , Corazón/inervación , Sistema Inmunológico/metabolismo , Miocardio/metabolismo , Neuroinmunomodulación , Sistemas Neurosecretores/metabolismo , Estrés Psicológico/metabolismo , Animales , Encéfalo/inmunología , Femenino , Disparidades en el Estado de Salud , Cardiopatías/inmunología , Cardiopatías/fisiopatología , Cardiopatías/psicología , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiopatología , Masculino , Miocardio/inmunología , Sistemas Neurosecretores/inmunología , Sistemas Neurosecretores/fisiopatología , Factores Sexuales , Transducción de Señal , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
Orthotopic heart transplantation (OHT) is the "gold standard" treatment for patients with end-stage heart failure, with approximately 5000 transplants performed each year worldwide. Heart transplantation survival rates have progressively improved at all time points, despite an increase in donor and recipient age and comorbidity and greater recipient urgency; according to the registry of the International Society of Heart and Lung Transplantation (ISHLT), the median survival of patients posttransplantation is currently 12.2 years.Long-term survival is sub-optimal, and outcomes after OHT remain constrained by the development of acute rejection and cardiac allograft vasculopathy (CAV). Moreover, donor organs are in short supply, making optimal organ utilization an ongoing priority. For these reasons, substantial interest continues to exist in identifying factors portending increased survival and improved organ utilization.
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Disparidades en el Estado de Salud , Disparidades en Atención de Salud , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón , Femenino , Rechazo de Injerto/etiología , Supervivencia de Injerto , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Humanos , Masculino , Recuperación de la Función , Factores de Riesgo , Factores Sexuales , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: Myocardial fibrosis critically contributes to cardiac dysfunction in inflammatory dilated cardiomyopathy (iDCM). Activation of transforming growth factor-ß (TGF-ß) signalling is a key-step in promoting tissue remodelling and fibrosis in iDCM. Downstream mechanisms controlling these processes, remain elusive. METHODS AND RESULTS: Experimental autoimmune myocarditis (EAM) was induced in BALB/c mice with heart-specific antigen and adjuvant. Using heart-inflammatory precursors, as well as mouse and human cardiac fibroblasts, we demonstrated rapid secretion of Wnt proteins and activation of Wnt/ß-catenin pathway in response to TGF-ß signalling. Inactivation of extracellular Wnt with secreted Frizzled-related protein 2 (sFRP2) or inhibition of Wnt secretion with Wnt-C59 prevented TGF-ß-mediated transformation of inflammatory precursors and cardiac fibroblasts into pathogenic myofibroblasts. Inhibition of T-cell factor (TCF)/ß-catenin-mediated transcription with ICG-001 or genetic loss of ß-catenin also prevented TGF-ß-induced myofibroblasts formation. Furthermore, blocking of Smad-independent TGF-ß-activated kinase 1 (TAK1) pathway completely abrogated TGF-ß-induced Wnt secretion. Activation of Wnt pathway in the absence of TGF-ß, however, failed to transform precursors into myofibroblasts. The critical role of Wnt axis for cardiac fibrosis in iDCM is also supported by elevated Wnt-1/Wnt-5a levels in human samples from hearts with myocarditis. Accordingly, and as an in vivo proof of principle, inhibition of Wnt secretion or TCF/ß-catenin-mediated transcription abrogated the development of post-inflammatory fibrosis in EAM. CONCLUSION: We identified TAK1-mediated rapid Wnt protein secretion as a novel downstream key mechanism of TGF-ß-mediated myofibroblast differentiation and myocardial fibrosis progression in human and mouse myocarditis. Thus, pharmacological targeting of Wnts might represent a promising therapeutic approach against iDCM in the future.