RESUMEN
Myostatin (MSTN) is a transforming growth factor (TGF)-ß superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups (n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFß receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFß receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF.NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.
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Receptores de Activinas Tipo II/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/fisiopatología , Remodelación Ventricular/efectos de los fármacos , Animales , Ecocardiografía , Fibrosis , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/patología , Miostatina/antagonistas & inhibidores , Miostatina/metabolismo , Péptido Natriurético Encefálico/metabolismo , Fosforilación , Resistencia Física , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to 1) characterize the changes in Ca2+/calmodulin-dependent protein kinase type-IIδ (CaMKIIδ), growth signaling, structural proteins, fibrosis, apoptosis, and gene expression before and after LVAD support and 2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. Left ventricular apex tissue and serum pairs were collected in patients with dilated cardiomyopathy ( n = 25, 23 men and 2 women) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts ( n = 4) and normal serum from age-matched control hearts ( n = 4). The duration of LVAD support ranged from 48 to 1,170 days (median duration: 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor 2, sustained histone deacetylase-4 phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all P < 0.05). Increased CaMKIIδ phosphorylation, nuclear myocyte enhancer factor 2, and cardiac MSTN significantly correlated with the duration of support. Phosphorylation of SMAD2 and apoptosis decreased with a shorter duration of LVAD support but increased with a longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy. NEW & NOTEWORTHY A long duration of left ventricular assist device support may be detrimental for myocardial recovery, based on myocardial tissue experiments in patients with prolonged support showing significantly worsened activation of Ca2+/calmodulin-dependent protein kinase-IIδ, increased nuclear myocyte enhancer factor 2, increased myostatin and its signaling by SMAD2, and apoptosis as well as sustained histone deacetylase-4 phosphorylation, structural protein dysregulation, and fibrosis.
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Cardiomiopatía Dilatada/terapia , Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos/metabolismo , Corazón Auxiliar , Miocardio/metabolismo , Función Ventricular Izquierda , Apoptosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Estudios de Casos y Controles , Femenino , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Histona Desacetilasas/metabolismo , Humanos , Factores de Transcripción MEF2/metabolismo , Masculino , Persona de Mediana Edad , Miostatina/metabolismo , Fosforilación , Diseño de Prótesis , Recuperación de la Función , Proteínas Represoras/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Remodelación VentricularRESUMEN
Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.
RESUMEN
BACKGROUND: Left ventricular assist devices are increasingly being used in patients with advanced heart failure as both destination therapy and bridge to transplant. We aimed to identify histomorphometric, structural and inflammatory changes after pulsatile- and continuous-flow left ventricular assist device placement. METHODS: Clinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by Western blot. RESULTS: Decellularization of the aortic tunica media was observed in patients receiving continuous-flow support. Both device types showed an increased inflammatory response after left ventricular assist device placement with variable T-cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall. CONCLUSIONS: Left ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous-flow left ventricular assist and associated with aortic media decellularization. The present findings help to explain the progressive aortic root dilation and vascular dysfunction in patients after continuous-flow device placement.
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Corazón Auxiliar , Aorta , Insuficiencia Cardíaca , Humanos , Inflamación , Resultado del TratamientoRESUMEN
BACKGROUND: Del Nido (DN) cardioplegia, a calcium-free, hyperkalemic solution containing lidocaine and magnesium has been developed to help reduce intracellular calcium influx and the resulting myocyte damage in the immediate postischemic period following cardiac arrest. DN cardioplegia has been used for pediatric cardiac surgery but its use in complex reoperative surgery has not been studied. We specifically report the outcomes of patients undergoing reoperative cardiac surgery after previous coronary artery bypass grafting with a patent internal mammary artery (IMA). METHODS: Patients undergoing reoperative cardiac surgery with prior coronary bypass grafting surgery were studied between 2010 and 2013. Fourteen patients were identified who required continued retrograde cardioplegia administration. In all cases, an initial antegrade dose was given, followed by continuous retrograde administration. Demographics, co-morbidities, intra-operative variables including cardioplegia volumes, post-operative complications, and patient outcomes were collected. RESULTS: The mean age of all patients was 73.3+/-6.7 years, and 93 % were male. Aortic cross clamp time and cardiopulmonary bypass times were 81+/-35 and 151+/-79 mins, respectively. Antegrade, retrograde and total cardioplegia doses were 1101+/-398, 3096+/-3185 and 4367+/-3751 ml, respectively. An average of 0.93+/-0.92 inotropes and 1.50+/-0.76 pressors were used on ICU admission after surgery. ICU and total hospital lengths of stay were 5.5+/-7.4 and 9.6+/-8.0 days, respectively. Complications occurred in two patients (14 %) (pneumonia and prolonged mechanical ventilation) and new arrhythmias occurred in five patients (36 %) (four new-onset atrial fibrillation and one pulseless electrical activity requiring 2 min of chest compression). No perioperative myocardial infarctions were noted based on electrocardiograms and cardiac serum markers. Postoperatively, left ventricular function was preserved in all patients whereas two patients (14 %) had mild decrease in right ventricular function as assessed by echocardiography. No mortality was observed. CONCLUSION: Del Nido cardioplegia solution provides acceptable myocardial protection for cardiac surgery that requires continuous retrograde cardioplegia administration. DN cardioplegia's administration in a continuous retrograde fashion with a patent IMA is believed to provide adequate myocardial protection while avoiding injuring the IMA through dissection and clamping.
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Procedimientos Quirúrgicos Cardíacos/métodos , Soluciones Cardiopléjicas/administración & dosificación , Paro Cardíaco Inducido/métodos , Cardiopatías/cirugía , Anciano , Estudios de Factibilidad , Femenino , Humanos , Masculino , ReoperaciónRESUMEN
BACKGROUND: Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of ω-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. METHODS AND RESULTS: In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either l-alanyl-l-glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak VO2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1α, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. CONCLUSIONS: The combined supplementation of l-alanyl-l-glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01534663.
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Composición Corporal , Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Glutamina/uso terapéutico , Insuficiencia Cardíaca/terapia , Calidad de Vida , Enfermedad Crónica , Método Doble Ciego , Tolerancia al Ejercicio/fisiología , Femenino , Fuerza de la Mano/fisiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/psicología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Resultado del TratamientoRESUMEN
Abnormal intracellular calcium (Ca(2+)) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2α), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2α, and XBP1s levels. Apoptosis as reflected by C/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2α/eIF2α and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca(2+) storing protein calsequestrin, Na(+)-Ca(2+) exchanger, sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca(2+) content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca(2+) handling in patients with advanced HF. These changes may impact the potential for myocardial recovery.
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Cardiomiopatía Dilatada/metabolismo , Estrés del Retículo Endoplásmico , Corazón Auxiliar , Respuesta de Proteína Desplegada , Apoptosis , Calreticulina/genética , Calreticulina/metabolismo , Cardiomiopatía Dilatada/fisiopatología , Cardiomiopatía Dilatada/cirugía , Estudios de Casos y Controles , Línea Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Factores de Transcripción del Factor Regulador X , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.
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Metabolismo Energético/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Infarto del Miocardio/complicaciones , PPAR gamma/agonistas , Resistencia Física/efectos de los fármacos , Tiazoles/farmacología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Tolerancia al Ejercicio/efectos de los fármacos , Ácidos Grasos/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Ratones Endogámicos C57BL , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Oxidación-Reducción , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
UNLABELLED: Myostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors. METHODS: Coronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total). RESULTS: Cardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN-dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac-derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1. CONCLUSION: Our study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1.
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Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Isquemia Miocárdica/patología , Miocardio/metabolismo , Miostatina/metabolismo , Regulación hacia Arriba , Animales , Biomarcadores/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteínas Musculares/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/patología , Isquemia Miocárdica/sangre , Miocardio/patología , Miostatina/sangre , Proteínas Ligasas SKP Cullina F-box/metabolismo , Transducción de Señal , Proteínas Smad/metabolismo , Factores de Tiempo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: A percentage of patients with a left ventricular assist device (LVAD) require device exchange. Although this is an important clinical entity, there are only a handful of relevant studies on this topic in the literature. METHODS: From 2004 to 2012, 30 device exchanges (HeartMate II to HeartMate II) were performed. Since June 2011, we have employed the subcostal approach for device exchange if indicated. Sixteen patients underwent device exchange through a subcostal approach (S group), whereas 14 patients had devices exchanged through a full sternotomy (F group). Pre- and post-operative data were retrospectively reviewed. RESULTS: There was no difference in baseline patient characteristics between the two groups. Overall, mean duration between primary surgery and device exchange was 425 ± 407 days. Surgical indications included device thrombus/hemolysis (N = 19), device malfunction (N = 9) and infection (N = 2). Cardiopulmonary bypass time was significantly shorter in the S group (S: 40 ± 23 minutes, F: 105 ± 84 minutes; p < 0.05), and post-operative bleeding within 24 hours after surgery was less in the S group (S: 362 ± 367 ml, F: 1,286 ± 971 ml; p < 0.05). Length of ICU stay was significantly shorter in the S group (S: 4.6 ± 1.8 days, F: 8.2 ± 4.9 days; p < 0.05). There was no difference in post-operative complications, except for prolonged intubation (F: N = 6 [43%], S: N = 1 [6.3%]; p < 0.05). There were 3 deaths in the F group and 0 in the S group, with no statistical difference (p = 0.09). Also, there was no significant difference in other outcomes, including transplantation, device explantation and ongoing LVAD support. CONCLUSIONS: A subcostal approach may be preferred for HeartMate II device exchange if indicated.
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Insuficiencia Cardíaca/terapia , Corazón Auxiliar/efectos adversos , Procedimientos Quirúrgicos Torácicos/mortalidad , Procedimientos Quirúrgicos Torácicos/métodos , Disfunción Ventricular Izquierda/terapia , Adulto , Anciano , Falla de Equipo , Femenino , Hemólisis , Humanos , Infecciones/complicaciones , Masculino , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Tasa de Supervivencia , Trombosis/complicacionesRESUMEN
Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α-myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.
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Aldehído Reductasa/fisiología , Insuficiencia Cardíaca/enzimología , Isquemia Miocárdica/enzimología , Miocitos Cardíacos/enzimología , Aldehído Reductasa/biosíntesis , Aldehído Reductasa/genética , Animales , Apoptosis , Ceramidas/metabolismo , Ácidos Grasos/metabolismo , Fibrosis/enzimología , Fructosa/metabolismo , Glucosa/metabolismo , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/fisiopatología , Miocardio/enzimología , Miocardio/metabolismo , Miocardio/patología , Cadenas Pesadas de Miosina/genética , Oxidación-Reducción , PPAR alfa/genética , Regiones Promotoras Genéticas , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función , Daño por Reperfusión/enzimología , Daño por Reperfusión/fisiopatología , UltrasonografíaRESUMEN
BACKGROUND: Controversy exists whether heart transplantation (HTx) is an appropriate treatment option for patients with cardiac sarcoidosis due to its potential recurrence and multi-organ involvement. Recent data from the United Network for Organ Sharing dataset suggest that the clinical outcome of cardiac sarcoidosis patients is equivalent or even better than that of the general HTx population. METHODS: We retrospectively reviewed the clinical course of 14 patients with cardiac sarcoidosis among a total of 825 patients who underwent HTx at Columbia University Medical Center between 1997 and 2010. Post-transplant survival of patients with sarcoidosis was compared with that of non-sarcoidosis patients. RESULTS: More than half of cardiac sarcoidosis patients were initially diagnosed after HTx by tissue analysis of the explanted heart. While only 2/14 cases showed recurrence of cardiac sarcoidosis, the clinical outcome of sarcoid patients showed a trend toward higher mortality than that of non-sarcoidosis patients following HTx (1- and 5-year survival, 78.5 versus 87.2%, 52.4 versus 76.2%, respectively, p=0.09). CONCLUSIONS: Although this is a single-center, retrospective analysis of a small number of cardiac sarcoidosis patients who underwent HTx, a concerning trend toward a higher mortality of patients with cardiac sarcoidosis was noted. A careful candidate selection in patients with known cardiac sarcoidosis should be discussed.
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Cardiomiopatías/terapia , Trasplante de Corazón , Sarcoidosis/terapia , Adulto , Cardiomiopatías/mortalidad , Femenino , Trasplante de Corazón/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoidosis/mortalidad , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Bilirrubina/sangre , Insuficiencia Cardíaca , Corazón Auxiliar , Albúmina Sérica/metabolismo , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Chronic heart failure is associated with higher risk for developing diabetes mellitus. Secretory products from adipocytes may contribute to the deterioration in glycemic control and increased insulin resistance (IR). Retinol binding protein 4 (RBP4) is an adipose tissue-derived protein with pro-diabetogenic effects. The aim of the present study was to investigate the relationship of RBP4 in patients with heart failure. METHODS AND RESULTS: Serum levels of RBP4, insulin, and fasting glucose were assessed in 58 patients with severe heart failure at the time of left ventricular assist device (LVAD) implantation and in 44 patients at the time of explantation, as well as in 10 normal control subjects. Serum RBP4 levels were measured by specific enzyme-linked immunosorbent assay, and IR was assessed using the homeostatic model of IR (HOMA-IR). Fasting glucose, insulin and HOMA-IR were significantly higher in patients at the time of LVAD implantation compared to controls (all P<0.01). RBP-4 and HOMA-IR significantly decreased after LVAD implantation (21.7 ± 8.8 mg/dl to 16.0 ± 3.8 mg/dl, P<0.05; 4.2 ± 2.7 to 2.5 ± 2.0, P<0.01). CONCLUSIONS: Patients with advanced heart failure have increased levels of RBP4, and LVAD implantation reduces RBP4. These findings implicate RBP4 in the cascade of reversible metabolic derangements in advanced heart failure.
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Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Hemodinámica , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adulto , Anciano , Glucemia/metabolismo , Ensayo de Inmunoadsorción Enzimática , Ayuno/sangre , Femenino , Humanos , Insulina/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cardiac extracellular matrix (ECM) is a dynamic and metabolically active collagenous network that responds to mechanical strain. The association between ECM turnover and right ventricular failure (RVF) development after left ventricular assist device (LVAD) implantation in patients with advanced heart failure (HF) was investigated. METHODS: Circulating levels of osteopontin, metalloproteinases (MMP)-2 and MPP-9, and tissue inhibitor of MMP (TIMP)-1 and TIMP-4 were measured in 61 patients at LVAD implantation and explantation and in 10 control subjects. RVF was defined as the need for RVAD, nitric oxide inhalation > 48 hours and/or inotropic support > 14 days. RESULTS: All ECM markers were elevated in patients with HF compared with controls (all p < 0.05). RVF developed in 23 patients (37.7%) on LVAD support. All ECM markers decreased on LVAD support in patients without RVF (all p < 0.05), but serum MMP-2, TIMP-1, TIMP-4, and osteopontin remained elevated in RVF patients. Multivariate analysis identified that right ventricular stroke work index (RVSWI), circulating B-type natriuretic peptide, and osteopontin were associated with RVF (all p < 0.05). Osteopontin correlated inversely with RVSWI (r = -0.44, p < 0.001). Osteopontin levels > 260 ng/ml discriminate patients who develop RVF from those without RVF (sensitivity, 83%; specificity, 82%). CONCLUSIONS: Marked elevation of osteopontin levels before LVAD placement is associated with RVF development. Persistent elevation of circulating ECM markers after LVAD implantation characterizes patients who develop RVF. These novel biomarkers would have a potential role in the prediction of RVF development in patients undergoing LVAD implantation.
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Biomarcadores/sangre , Matriz Extracelular/metabolismo , Insuficiencia Cardíaca/terapia , Corazón Auxiliar/efectos adversos , Disfunción Ventricular Derecha/sangre , Remodelación Ventricular/fisiología , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Metaloproteinasa 1 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/sangre , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidores Tisulares de Metaloproteinasas/sangre , Disfunción Ventricular Derecha/etiología , Disfunción Ventricular Derecha/fisiopatología , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
BACKGROUND: Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous-flow versus pulsatile-flow LVADs on myocardial structure and function in this population. METHODS AND RESULTS: Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: group P, n=31; continuous-flow LVAD: group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP), and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative LV ejection fraction was greater (33.2±12.6% versus 17.6±8.8%, P<0.0001) and the mitral E/E' was lower (9.9±2.6 versus 13.2±3.8, P=0.0002) in group P versus group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9, and tissue inhibitor of MMP (TIMP)-4 were significantly lower in group P compared with group C (BNP: 552.6±340.6 versus 965.4±805.7 pg/mL, P<0.01; MMP9: 309.0±220.2 versus 475.2±336.9 ng/dL, P<0.05; TIMP4: 1490.9±622.4 versus 2014.3±452.4 ng/dL, P<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in group P (P=0.024). CONCLUSIONS: Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/cirugía , Corazón Auxiliar/clasificación , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/cirugía , Remodelación Ventricular/fisiología , Adulto , Anciano , Biomarcadores/metabolismo , Diástole/fisiología , Matriz Extracelular/metabolismo , Femenino , Insuficiencia Cardíaca/metabolismo , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Miocardio/metabolismo , Miocardio/patología , Péptido Natriurético Encefálico/metabolismo , Estudios Retrospectivos , Sístole/fisiología , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/metabolismo , Inhibidor Tisular de Metaloproteinasa-4RESUMEN
OBJECTIVE: Infections, especially those involving drivelines, are among the most serious complications that follow ventricular assist device implantation. Staphylococci are the most common causes of these infections. Once driveline infections are established, they can remain localized or progress as an ascending infection to cause metastatic seeding of other tissue sites. Although elaboration of biofilm appears to be critical in prosthetic device infections, its role as a facilitator of staphylococcal infection and migration along the driveline and other prosthetic devices is unclear. METHODS: A murine model of driveline infection was used to investigate staphylococcal migration along the driveline. A biofilm-producing strain of Staphylococcus epidermidis and a Staphylococcus aureus strain and its intercellular adhesion gene cluster (ica)-negative (biofilm-deficient) isogenic mutant were used in these studies. Bacterial density on the driveline and the underlying tissue was measured over time. Scanning electron microscopy was used to examine the morphology of S epidermidis biofilm formation as the infection progressed. RESULTS: The biofilm-deficient S aureus mutant was less effective at infecting and migrating along the driveline than the wild-type strain over time. However, the ica mutation had no effect on the ability of the strain to infect underlying tissue. S aureus exhibited more rapid migration than S epidermidis. Scanning electron microscopy revealed the deposition of host matrix on the Dacron material after implantation. This was followed by elaboration of a bacterial biofilm that correlated with more rapid migration along the driveline. CONCLUSIONS: Biofilm formation is a critical virulence determinant that facilitates the progression of drivelines infections.
Asunto(s)
Biopelículas , Corazón Auxiliar/microbiología , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/crecimiento & desarrollo , Staphylococcus epidermidis/crecimiento & desarrollo , Animales , Adhesión Bacteriana/genética , Proteínas Bacterianas/genética , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Rastreo , Mutación , Tereftalatos Polietilenos , Diseño de Prótesis , Staphylococcus aureus/genética , Staphylococcus aureus/patogenicidad , Staphylococcus aureus/ultraestructura , Staphylococcus epidermidis/patogenicidad , Staphylococcus epidermidis/ultraestructura , Factores de TiempoRESUMEN
Staphylococcus epidermidis remains the predominant pathogen in prosthetic-device infections. Ventricular assist devices, a recently developed form of therapy for end-stage congestive heart failure, have had considerable success. However, infections, most often caused by Staphylococcus epidermidis, have limited their long-term use. The transcutaneous driveline entry site acts as a potential portal of entry for bacteria, allowing development of either localized or systemic infections. A novel in vitro binding assay using explanted drivelines obtained from patients undergoing transplantation and a heterologous lactococcal system of surface protein expression were used to identify S. epidermidis surface components involved in the pathogenesis of driveline infections. Of the four components tested, SdrF, SdrG, PIA, and GehD, SdrF was identified as the primary ligand. SdrF adherence was mediated via its B domain attaching to host collagen deposited on the surface of the driveline. Antibodies directed against SdrF reduced adherence of S. epidermidis to the drivelines. SdrF was also found to adhere with high affinity to Dacron, the hydrophobic polymeric outer surface of drivelines. Solid phase binding assays showed that SdrF was also able to adhere to other hydrophobic artificial materials such as polystyrene. A murine model of infection was developed and used to test the role of SdrF during in vivo driveline infection. SdrF alone was able to mediate bacterial adherence to implanted drivelines. Anti-SdrF antibodies reduced S. epidermidis colonization of implanted drivelines. SdrF appears to play a key role in the initiation of ventricular assist device driveline infections caused by S. epidermidis. This pluripotential adherence capacity provides a potential pathway to infection with SdrF-positive commensal staphylococci first adhering to the external Dacron-coated driveline at the transcutaneous entry site, then spreading along the collagen-coated internal portion of the driveline to establish a localized infection. This capacity may also have relevance for other prosthetic device-related infections.