RESUMEN
BACKGROUND: The Cardioband system enables percutaneous surgical-like direct mitral valve annuloplasty and, thereby, repair of severe functional mitral valve regurgitation (MR) in patients with advanced systolic heart failure (HF) and dilation of the left ventricular (LV) annulus. Since the device is anchored by screws in the LV annulus, limited myocardial injury is likely to occur. METHODS AND RESULTS: Five patients (Society of Thoracic Surgeons score: 2.7⯱ 0.7%) with severe HF (LV ejection fraction [LVEF]: 17⯱ 1%; LV end-diastolic diameter [LVEDD]: 71⯱ 3â¯mm) were treated with the Cardioband (sizes C-F) receiving 14-17 screws in the LV annulus region. Myocardial injury was monitored by measuring high-sensitive cardiac troponin T (hsTnT) levels and by echocardiography. All patients showed significant periprocedural increase in hsTnT levels. Peak hsTnT concentration was reached between day 1 and day 6 (593⯱ 141â¯pg/ml). None of the patients showed clinical signs of myocardial infarction, ST-segment elevation, new onset of deteriorated myocardial wall motion, or new ventricular tachycardia. hsTnT levels normalized in all patients after 14 days (hsTnT on day 0: 34⯱ 6â¯pg/ml vs. hsTnT on day 14: 36⯱ 6â¯pg/ml; pâ¯= 0.604). This nonischemic hsTnT kinetics was compared to a sixth patient who experienced proximal damage of the left circumflex artery (LCX) and ST-segment elevation during the Cardioband procedure, followed by immediate repair of the LCX, avoiding structural damage of the LV. CONCLUSION: Cardioband implantation is accompanied by significant elevation of hsTnT without causing structural myocardial damage or clinical symptoms such as worsening of LV function, new-onset LV regions exhibiting reduced wall motion, or ventricular tachycardia.
Asunto(s)
Biomarcadores , Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Troponina T , Biomarcadores/sangre , Ecocardiografía , Humanos , Troponina T/sangre , Función Ventricular IzquierdaRESUMEN
BACKGROUND AND PURPOSE: To determine the rate of peri-interventional silent brain infarcts after left atrial appendage occlusion (LAAO). METHODS: In this prospective, uncontrolled single-center pilot study, consecutive patients with atrial fibrillation undergoing LAAO between July 2013 and January 2016 were included. The Amplatzer Cardiac Plug, WATCHMAN or Amulet device was used. A neurological examination and cranial magnetic resonance imaging (MRI) were performed within 48 h before and after the procedure. MRI was evaluated for new diffusion-weighted imaging (DWI) hyperintensities, cerebral microbleeds (CMBs) and white-matter lesions (WMLs). RESULTS: Left atrial appendage occlusion was performed in 21 patients (mean age, 73.2 ± 9.5 years). Main reasons for LAAO were previous intracerebral hemorrhage (n = 11) and major systemic bleeding (n = 6). No clinically overt stroke occurred peri-interventionally. After the intervention, one patient had a small cerebellar hyperintensity on DWI (4.8%; 95% confidence interval, 0.0-14.3) that was not present on the MRI 1 day before the procedure. Among 11 patients with available MRI just before LAAO, there were no significant changes in the number of CMBs and the severity of WMLs after LAAO. CONCLUSIONS: This study of peri-interventional MRI in LAAO suggests a low rate of silent peri-procedural infarcts in this elderly population. Confirmation in larger studies is needed.
Asunto(s)
Apéndice Atrial , Infarto Cerebral/epidemiología , Infarto Cerebral/etiología , Oclusión Terapéutica/efectos adversos , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/complicaciones , Fibrilación Atrial/terapia , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etiología , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Proyectos Piloto , Estudios Prospectivos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Oclusión Terapéutica/estadística & datos numéricos , Resultado del Tratamiento , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.
Asunto(s)
Arritmias Cardíacas/terapia , Terapia Genética/efectos adversos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/efectos adversos , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/terapia , Infarto del Miocardio/complicaciones , Isquemia Miocárdica/complicaciones , Miocardio/metabolismo , Proteínas S100/uso terapéutico , Animales , Dependovirus/genética , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Humanos , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/terapia , Miocardio/patología , Proteínas S100/genética , Proteínas S100/metabolismo , Volumen Sistólico/fisiología , PorcinosAsunto(s)
Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/cirugía , Terapia de Resincronización Cardíaca , Fármacos Cardiovasculares/uso terapéutico , Terapia Combinada , Ecocardiografía Transesofágica , Insuficiencia Cardíaca/mortalidad , Implantación de Prótesis de Válvulas Cardíacas/mortalidad , Humanos , Válvula Mitral/fisiopatología , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/mortalidad , Intervención Coronaria Percutánea , Complicaciones Posoperatorias/mortalidad , Guías de Práctica Clínica como Asunto , Pronóstico , Factores de Riesgo , Instrumentos Quirúrgicos , Tasa de Supervivencia , Disfunción Ventricular Izquierda/mortalidad , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/cirugíaRESUMEN
Aortic valve stenosis is the most prevalent, clinically significant valvular disorder in adult patients. Surgical valve replacement is the standard therapy for patients with symptomatic and severe aortic stenosis; however, many patients are suboptimal candidates for surgery due to age and co-morbidities. The development of transcatheter aortic valve implantation (TAVI) has broadened the therapeutic options, especially in high-risk patients. The first randomized study comparing surgical valve replacement with TAVI in operable high-risk patients show similar mortality and reduction in symptoms after a 2-year follow-up. These data support the use of this technique in high-risk patients with severe aortic stenosis.
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Estenosis de la Válvula Aórtica/cirugía , Cateterismo Cardíaco/métodos , Cateterismo Cardíaco/tendencias , Predicción , Implantación de Prótesis de Válvulas Cardíacas/métodos , Implantación de Prótesis de Válvulas Cardíacas/tendencias , Prótesis Valvulares Cardíacas/tendencias , Anciano , Anciano de 80 o más Años , Cateterismo Cardíaco/instrumentación , Procedimientos Endovasculares , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Humanos , Medición de RiesgoRESUMEN
Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of ß-adrenergic receptor antagonism.
Asunto(s)
Quinasa 2 del Receptor Acoplado a Proteína-G/genética , Marcación de Gen/métodos , Terapia Genética/métodos , Insuficiencia Cardíaca/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Terapia Combinada , Quinasa 2 del Receptor Acoplado a Proteína-G/fisiología , Insuficiencia Cardíaca/fisiopatología , HumanosRESUMEN
S100A1, a Ca superset2+-binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been shown to enhance cardiac contractile performance by regulating both sarcoplasmic reticulum (SR) Ca superset2+-handling and myofibrillar Ca superset2+-responsiveness. In cardiac disease, the expression of S100A1 is dynamically altered as it is significantly down-regulated in end stage human heart failure (HF), and it is up-regulated in compensated hypertrophy. Therefore, the delivery of a transgene encoding for S100A1 to the myocardium might be an attractive strategy for improving cardiac function in HF by replacing lost endogenous S100A1. In this study we sought to test whether exogenous S100A1 gene delivery to alter global cardiac function is feasible in the normal rabbit heart. An adenoviral S100A1 transgene (AdvS100A1) also containing the green fluorescent protein (GFP) was delivered using an intracoronary injection method with a dose of 5 x 10 superset11 total virus particles (tvp) (n = 8). Rabbits treated with either a GFP-only adenovirus (AdvGFP) or saline were used as control groups (n = 11 each). Seven days after global myocardial in vivo gene delivery hemodynamic parameters were assessed. S100A1 overexpression as a result of the intracoronary delivery of AdvS100A1 significantly increased left ventricular (LV) +dP/dt subsetmax, -dP/dt subsetmin and systolic ejection pressure (SEP) compared to both control groups after administration of isoproterenol (0.1, 0.5 and 1.0 microg/kgBW/min), while contractile parameters remained unchanged under basal conditions. These results demonstrate that global myocardial in vivo gene delivery is possible and that myocardial S100A1 overexpression can increase cardiac performance. Therefore, substitution of down-regulated S100A1 protein expression levels may represent a potential therapeutic strategy for improving the cardiac performance of the failing heart.
Asunto(s)
Técnicas de Transferencia de Gen , Contracción Miocárdica/genética , Miocardio/metabolismo , Proteínas S100/genética , Adenoviridae , Animales , Vectores Genéticos , Proteínas Fluorescentes Verdes , Inyecciones , Masculino , Conejos , Proteínas S100/metabolismo , Función Ventricular IzquierdaRESUMEN
S100A1, a Ca(2+) binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been found to colocalize with the sarcoplasmic reticulum (SR) and the contractile filaments in cardiac tissue. Because S100A1 is known to modulate SR Ca(2+) handling in skeletal muscle, we sought to investigate the specific role of S100A1 in the regulation of myocardial contractility. To address this issue, we investigated contractile properties of adult cardiomyocytes as well as of engineered heart tissue after S100A1 adenoviral gene transfer. S100A1 gene transfer resulted in a significant increase of unloaded shortening and isometric contraction in isolated cardiomyocytes and engineered heart tissues, respectively. Analysis of intracellular Ca(2+) cycling in S100A1-overexpressing cardiomyocytes revealed a significant increase in cytosolic Ca(2+) transients, whereas in functional studies on saponin-permeabilized adult cardiomyocytes, the addition of S100A1 protein significantly enhanced SR Ca(2+) uptake. Moreover, in Triton-skinned ventricular trabeculae, S100A1 protein significantly decreased myofibrillar Ca(2+) sensitivity ([EC(50%)]) and Ca(2+) cooperativity, whereas maximal isometric force remained unchanged. Our data suggest that S100A1 effects are cAMP independent because cellular cAMP levels and protein kinase A-dependent phosphorylation of phospholamban were not altered, and carbachol failed to suppress S100A1 actions. These results show that S100A1 overexpression enhances cardiac contractile performance and establish the concept of S100A1 as a regulator of myocardial contractility. S100A1 thus improves cardiac contractile performance both by regulating SR Ca(2+) handling and myofibrillar Ca(2+) responsiveness.