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INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by ventricular arrhythmias and heart failure. The variable phenotype suggesting that determined environmental factors may have an influence. The aim of our study was to discover the impact of the dynamic physical activity on patients with high-risk definite ARVC/D. METHODS AND RESULTS: Collection of data on physical activity at the time of diagnosis was conducted at an in-person clinical interview. The intensity of the activity was classified in accordance with the mean frequency of weekly physical exercise sessions in the 10 years before diagnosis and into the following three groups of dynamic activity: high/competitive (>3 h/wk), moderate (1 to 3 h) and minimal/inactive (<1 h). Seventeen patients practiced high dynamic physical activities. The intensity of dynamic activity was classified into three groups: 8 of high intensity, 9 moderate, and 19 inactive. The first major arrhythmic event and occurrence of severe right ventricular dysfunction were earlier in the high-intensity exercise group, followed by the moderate intensity group and at a later age in the low-intensity/inactive group. CONCLUSIONS: Dynamic exercise could be directly associated with the severity of the phenotype in relation to the precocity of major ventricular arrhythmic events and right ventricular systolic dysfunction in patients with high-risk definite ARVC/D.
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Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Ejercicio Físico/fisiología , Esfuerzo Físico/fisiología , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
INTRODUCTION AND OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium. This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. METHODS: This was an observational, retrospective cohort study, which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing. RESULTS: Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 ± 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. CONCLUSIONS: The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis.
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Displasia Ventricular Derecha Arritmogénica/genética , Análisis Mutacional de ADN/métodos , ADN/genética , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/mortalidad , Muerte Súbita Cardíaca/epidemiología , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , España/epidemiología , Tasa de Supervivencia/tendenciasRESUMEN
Aims: We aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD). Methods and results: The sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22-0.67; P < 0.001]. The Kaplan-Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0-4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups. Conclusion: Treatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided. The trial is registered with ClinicalTrials.gov, number NCT00862043.
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Enfermedades de las Válvulas Cardíacas/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Citrato de Sildenafil/uso terapéutico , Anciano , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/epidemiología , Enfermedades de las Válvulas Cardíacas/epidemiología , Enfermedades de las Válvulas Cardíacas/mortalidad , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Placebos/administración & dosificación , Presión Esfenoidal Pulmonar/efectos de los fármacos , Citrato de Sildenafil/administración & dosificación , Resultado del Tratamiento , Vasodilatadores/uso terapéuticoRESUMEN
This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF.
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Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/metabolismo , Colágeno/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , MicroARNs/genética , Miocardio/metabolismo , Anciano , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Biomarcadores , Comorbilidad , Ecocardiografía , Femenino , Fibrosis , Regulación de la Expresión Génica , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Pruebas de Función Cardíaca , Humanos , Masculino , MicroARNs/sangre , Interferencia de ARN , TranscriptomaRESUMEN
OBJECTIVES: Bicuspid aortic valve (BAV) is the most prevalent congenital cardiac malformation, frequently associated with aortic dilatation (AD). The molecular mechanisms involved in AD and its aetiological link with BAV formation are poorly understood. Altered fibrillin-1 (FBN1) and metalloprotease-2, -9 (MMP2,9) protein activities have been suggested to be involved in BAV aortopathy. In addition, FBN2 participates in embryonic valve formation, but its possible involvement in BAV-associated AD has never been explored. In this report, we evaluate the expression levels of MMP2,9 and FBN1,2 in the ascending aorta of patients with normal or dilated aortas and with tricuspid aortic valve (TAV) or BAV, using appropriate tissue-specific reference genes. METHODS: Gene expression was quantified by real-time quantitative polymerase chain reaction in 52 patients, using one or three reference genes previously validated in the same patient population. RESULTS: FBN2 expression was significantly increased in the aortas of patients with BAV compared with individuals with TAV (0.178 ± 0.042 vs 0.096 ± 0.021, P = 0.015), whereas differences in FBN1 did not reach statistical significance (1.946 ± 0.228 vs 1.430 ± 0.114, P = 0.090). When four groups of samples were considered, FBN2 expression was significantly higher in patients with BAV and AD compared with patients with TAV and AD (0.164 ± 0.035 vs 0.074 ± 0.027, P = 0.040). No significant differences were found when FBN1/FBN2 ratio, and MMP2 and MMP9 expression levels were analysed. No linear relationship between aortic diameter and gene expression levels were found. CONCLUSIONS: BAV patients have an increased FBN (especially FBN2) gene expression level in the ascending aorta, irrespective of dilatation, whereas MMP expression does not change significantly. These results add a new piece of information to the pathophysiology of BAV disease and point to FBN2 as a new molecular player.
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Aorta Torácica/metabolismo , Válvula Aórtica/anomalías , Fibrilina-2/genética , Regulación de la Expresión Génica , Enfermedades de las Válvulas Cardíacas/genética , ARN/genética , Anciano , Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica Bicúspide , Femenino , Fibrilina-2/biosíntesis , Enfermedades de las Válvulas Cardíacas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Regulación hacia ArribaRESUMEN
MicroRNAs have been associated with cardiomyocyte apoptosis, a process involved in myocardial remodelling in aortic valve (Av) stenosis (AS). Our aim was to analyse whether the dysregulation of myocardial microRNAs was related to cardiomyocyte apoptosis in AS patients. Endomyocardial biopsies were obtained from 28 patients with severe AS (based on pressure gradients and Av area) referred for Av replacement and from necropsies of 10 cardiovascular disease-free control subjects. AS patients showed an increased (P<0.001) cardiomyocyte apoptotic index (CMAI) compared with controls. Two clusters of patients were identified according to the CMAI: group 1 (CMAI ≤ 0.08%; n=16) and group 2 (CMAI > 0.08%; n=12). Group 2 patients presented lower cardiomyocyte density (P<0.001) and ejection fraction (P<0.05), and higher troponin T levels (P<0.05), prevalence of heart failure (HF; P<0.05) and NT-proBNP levels (P<0.05) than those from group 1. miRNA expression profile analysed in 5 patients randomly selected from each group showed 64 microRNAs down-regulated and 6 up-regulated (P<0.05) in group 2 compared with group 1. Those microRNAs with the highest fold-change were validated in the full two groups corroborating that miR-10b, miR-125b-2* and miR-338-3p were down-regulated (P<0.05) in group 2 compared with group 1 and control subjects. These three microRNAs were inversely correlated (P<0.05) with the CMAI. Inhibition of miR-10b induced an increase (P<0.05) of apoptosis and increased expression (P<0.05) of apoptosis protease-activating factor-1 (Apaf-1) in HL-1 cardiomyocytes. In conclusion, myocardial down-regulation of miR-10b may be involved in increased cardiomyocyte apoptosis in AS patients, probably through Apaf-1 up-regulation, contributing to cardiomyocyte damage and to the development of HF.
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Estenosis de la Válvula Aórtica/genética , Estenosis de la Válvula Aórtica/fisiopatología , MicroARNs/genética , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Anciano , Estenosis de la Válvula Aórtica/metabolismo , Apoptosis , Regulación hacia Abajo , Femenino , Humanos , Masculino , MicroARNs/metabolismo , Troponina T/genética , Troponina T/metabolismoAsunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos Férricos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Maltosa/análogos & derivados , Disfunción Ventricular Izquierda/tratamiento farmacológico , Anciano , Anemia Ferropénica/sangre , Anemia Ferropénica/diagnóstico , Femenino , Compuestos Férricos/efectos adversos , Estudios de Seguimiento , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/diagnóstico , Humanos , Infusiones Intravenosas , Masculino , Maltosa/administración & dosificación , Maltosa/efectos adversos , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnósticoRESUMEN
AIMS: Hypertrophic cardiomyopathy is one of the main causes of sudden death in young people. Recent clinical practice guidelines include a risk prediction model for sudden death (HCM Risk-SCD), which facilitates the decision of whether to implant a defibrillator. The aim of our study was to ascertain the percentage of events in our series of primary prevention implantable cardioverter-defibrillator recipients with hypertrophic cardiomyopathy and whether HCM Risk-SCD predicts the onset of arrhythmic events. METHODS AND RESULTS: This was an observational, retrospective cohort study, which included 48 primary prevention defibrillator recipient patients with HCM. We compiled their demographic and clinical characteristics, estimated 5-year risk using HCM Risk-SCD, and collected the documentation on arrhythmias during follow-up. The majority was male (66.7%) and mean age at implantation was 44.44 ± 14.46 years. Non-sustained ventricular tachycardia was the most prevalent risk factor (66.67%), followed by a family history of sudden death (47.92%). Mean HCM Risk-SCD was 6.15 ± 5.01%. HCM Risk-SCD was the only factor independently associated with the onset of ventricular tachyarrhythmia, above any other classic risk factor or association [odds ratio = 1.46 (95% confidence interval 1.051-2.013); P = 0.02]. None of the 11 patients estimated as low risk using HCM Risk-SCD suffered any appropriate events (P < 0.05). CONCLUSIONS: During an average follow-up of 4 years, 16.67% presented appropriate events (4.16%/year). HCM Risk-SCD predicted the onset of events more suitably than classic risk factors.
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Arritmias Cardíacas/epidemiología , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/terapia , Muerte Súbita Cardíaca/epidemiología , Prevención Primaria/métodos , Adulto , Arritmias Cardíacas/prevención & control , Muerte Súbita Cardíaca/prevención & control , Desfibriladores Implantables , Femenino , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Estudios Retrospectivos , Factores de Riesgo , EspañaAsunto(s)
Insuficiencia de la Válvula Aórtica/etiología , Prolapso de la Válvula Aórtica/patología , Válvula Aórtica/patología , Traumatismos Torácicos/complicaciones , Heridas no Penetrantes/complicaciones , Anciano , Válvula Aórtica/lesiones , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/sangre , Insuficiencia de la Válvula Aórtica/diagnóstico , Insuficiencia de la Válvula Aórtica/cirugía , Prolapso de la Válvula Aórtica/sangre , Prolapso de la Válvula Aórtica/etiología , Prolapso de la Válvula Aórtica/cirugía , Ecocardiografía Transesofágica/métodos , Electrocardiografía/métodos , Humanos , Masculino , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Traumatismos Torácicos/sangre , Resultado del Tratamiento , Heridas no Penetrantes/sangreRESUMEN
BACKGROUND AIMS: Endothelial progenitor cells (EPCs) are known to play a beneficial role by promoting postnatal vasculogenesis in pathological events, such as ischemic heart disease and peripheral artery disease. However, little is known about the potential of EPCs to restore heart damage tissue. We compared the cardiac differentiation capacity of EPCs isolated from peripheral blood of patients with acute myocardial infarction (AMI) with EPCs obtained from umbilical cord blood (UCB). METHODS: EPCs from both origins were isolated by density gradient centrifugation and characterized through the use of endothelial markers (UEA-1lectin, CD133 and KDR) and endothelial cell colony-forming unit assay. Cardiac differentiation capacity of EPCs was assessed by immunofluorescence and reverse transcriptase-polymerase chain reaction after 5-azacytidine (5-aza) induction. RESULTS: No significant differences were observed between the number of endothelial cell colony-forming units in peripheral blood of patients with AMI and samples from UCB. Moreover, 5-aza induced the appearance of myotube-like structures and the positive expression of sarcomeric α-actinin, cardiac troponin I and T and desmin in a similar pattern for both cell sources, which indicates a comparable acquisition of a cardiac-like phenotype. CONCLUSIONS: For the first time, we have compared, in vitro, the cardiomyogenic potential of EPCs derived from patients with AMI with UCB-derived EPCs. Our data indicate that EPCs obtained from both origins have similar plasticity and functions and suggest a potential therapeutic efficacy in cardiac cell therapy.
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Células Sanguíneas/patología , Células Progenitoras Endoteliales/fisiología , Endotelio Vascular/fisiología , Infarto del Miocardio/terapia , Miocitos Cardíacos/fisiología , Enfermedad Aguda , Adulto , Anciano , Azacitidina/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular , Células Cultivadas , Femenino , Regeneración Tisular Dirigida/métodos , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Cordón Umbilical/citologíaRESUMEN
AIMS: Previous studies showed unfavourable effects of right ventricular (RV) pacing. Ventricular pacing (VP), however, is required in many patients with atrioventricular (AV) block. The PREVENT-HF study explored left ventricular (LV) remodelling during RV vs. biventricular (BIV) pacing in AV block without advanced heart failure. The pre-specified PREVENT-HF German Substudy examined exercise capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: Patients with expected VP ≥80% were randomized to RV or BIV pacing. Endpoints were peak oxygen uptake (pVO2), oxygen uptake at the anaerobic threshold (VO2AT), ventilatory efficiency (VE/VCO2), and logNT-proBNP. Considering crossover, intention to treat (ITT), and on-treatment (OT) analyses of covariance (ANCOVA) were performed. For exercise testing 44 (RV: 25, BIV: 19), and for NT-proBNP 53 patients (RV: 29, BIV: 24) were included. The ITT analysis revealed significant differences in pVO2 [ANCOVA effect 2.83 mL/kg/min, confidence interval (CI) 0.83-4.91, P = 0.007], VO2AT (ANCOVA effect 2.14 mL/min/k, CI 0.14-4.15, P = 0.03), and VE/VCO2 (ANCOVA effect -5.46, CI -10.79 to -0.13, P = 0.04) favouring BIV randomization. The significant advantage in pVO2 persisted in OT analysis, while VO2AT and VE/VCO2 showed trends favouring BIV pacing. LogNT-proBNP did not differ between groups. (ITT: ANCOVA effect 0.008, CI -0.40 to +0.41, P = 0.97; OT: ANCOVA effect -0.03, CI -0.44 to 0.30, P = 0.90). CONCLUSION: Our study suggests that BIV pacing produces better exercise capacity over 1 year compared with RV pacing in patients without advanced heart failure and AV block. In contrast, we observed no significant changes of NT-proBNP. Larger trials will allow appraising the clinical usefulness of BIV pacing in AV block. ClinicalTrials.gov Identifier: NCT00170326.
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Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/prevención & control , Dispositivos de Terapia de Resincronización Cardíaca/clasificación , Dispositivos de Terapia de Resincronización Cardíaca/estadística & datos numéricos , Prueba de Esfuerzo/estadística & datos numéricos , Tolerancia al Ejercicio , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Bloqueo Atrioventricular/sangre , Biomarcadores/sangre , Femenino , Humanos , Masculino , Recuperación de la Función , Resultado del TratamientoRESUMEN
miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-ß1 (transforming growth factor-ß type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF-ß1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF >15%; n=15) and non-SF (CVF ≤15%; n=13). TGF-ß1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 miRNAs were down-regulated and 19 up-regulated in the SF patients compared with the non-SF patients. Those miRNAs potentially targeting TGF-ß1 were validated by real-time RT (reverse transcription)-PCR in the whole test population, corroborating that miR-122 and miR-18b were down-regulated in patients with SF compared with those with non-SF and the control subjects. Additionally, miR-122 was inversely correlated with the CVF, TGF-ß1 and the TGF-ß1-regulated PCPE-1 (procollagen C-terminal proteinase enhancer-1) in all patients. Experiments in human fibroblasts demonstrated that miR-122 targets and inhibits TGF-ß1. In conclusion, for the first time we show that myocardial down-regulation of miR-122 might be involved in myocardial fibrosis in AS patients, probably through TGF-ß1 up-regulation.
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Estenosis de la Válvula Aórtica/fisiopatología , Regulación hacia Abajo , Fibrosis/fisiopatología , MicroARNs/fisiología , Factor de Crecimiento Transformador beta1/fisiología , Regulación hacia Arriba , Anciano , Femenino , Humanos , Hibridación in Situ , MasculinoRESUMEN
The NADPH oxidases are a key family of ROS (reactive oxygen species)-producing enzymes which may differentially contribute to cardiac pathophysiology. Animal studies show uncertain results regarding the regulation of cardiac Nox4 by pressure overload and no data are available on human myocardial Nox4. In the present study, we evaluated Nox4 expression and its relationship with myocardial remodelling and LV (left ventricular) function in patients with severe AS (aortic valve stenosis). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. LV morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-CVDs (cardiovascular diseases) were analysed as controls. Nox4 localization was evaluated by immunohistochemistry and quantified by Western blot. Myocardial capillary density, fibrosis and cardiomyocyte dimensions and apoptosis were assessed histologically to evaluate myocardial remodelling. Nox4 was present in samples from all subjects and expressed in cardiomyocytes, VSMCs (vascular smooth muscle cells), endothelium and fibroblasts. Nox4 levels were reduced 5-fold in AS patients compared with controls (P<0.01). Nox4 levels directly correlated with cardiomyocyte cross-sectional area (r=0.299, P<0.05) and diameter (r=0.406, P<0.05) and capillary density (r=0.389, P<0.05), and inversely with cardiomyocyte apoptosis (r=-0.316, P<0.05) in AS patients. In addition, Nox4 levels correlated with echocardiographic parameters (LV ejection fraction: r=0.353, P<0.05; midwall fractional shortening: r=0.355, P<0.05; deceleration time: r=-0.345, P<0.05) in AS patients. Nox4 is expressed in human myocardium and reduced in AS patients. The observed associations of Nox4 with cardiomyocyte parameters and capillary density in AS patients suggest a potential role of Nox4 deficiency in the myocardial remodelling present in the human pressure-overloaded heart.
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Estenosis de la Válvula Aórtica/enzimología , Miocardio/enzimología , NADPH Oxidasas/análisis , Adulto , Anciano , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/fisiopatología , Apoptosis , Biopsia , Western Blotting , Capilares/patología , Regulación hacia Abajo , Ecocardiografía Doppler de Pulso , Femenino , Fibrosis , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Miocardio/patología , NADPH Oxidasa 4 , Proteínas Nucleares/análisis , Índice de Severidad de la Enfermedad , Volumen Sistólico , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
INTRODUCTION AND OBJECTIVES: There is little data available for Spain on the outcomes of surgical treatment for severe tricuspid regurgitation. The aim of this study was to analyze clinical and echocardiographic outcomes in a series of patients who received surgical treatment for severe tricuspid regurgitation and to compare outcomes according to the operative approach to valve repair or replacement. METHODS: Retrospective study in 119 consecutive patients with severe tricuspid regurgitation undergoing valve surgery between April 1996 and February 2010. RESULTS: A total of 61 ringless and 23 ring annuloplasties were performed and 11 bioprostheses and 24 mechanical prostheses were implanted. Perioperative mortality was 18.5% and was associated with age and cardiopulmonary bypass time. During clinical follow-up (median, 41 [interquartile range, 24-89] months), 2 reoperations were required in the ring annuloplasty and mechanical prosthesis groups; prosthetic thrombosis was diagnosed in 4 patients in the latter group. Total mortality after follow-up was 29.9% and was associated with age>70 years and extracorporeal circulation time. The emergence of new severe tricuspid regurgitation was associated with age and ringless annuloplasty (P=.04). CONCLUSIONS: Ringless repair was significantly associated with recurrence of severe tricuspid regurgitation. The use of mechanical prostheses was associated with a high rate of thrombosis. No significant differences in perioperative or total mortality were found between the different methods used for repair or valve replacement.
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Implantación de Prótesis de Válvulas Cardíacas/métodos , Insuficiencia de la Válvula Tricúspide/cirugía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reoperación , Resultado del TratamientoRESUMEN
The aim of this study was to determine the effects of atorvastatin in patients of South Asian versus European origin who participated in the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. ACTFAST was a 12-week prospective, open-label study in patients at high risk for atherosclerosis (European origin, n = 1978; South Asian origin, n = 64). Compared with patients of European origin, patients of South Asian origin were younger, were less likely to smoke, and had lower body mass index, systolic blood pressure, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Because significant differences were observed in baseline characteristics between patient groups, case control propensity scores were used. In the unmatched analysis, South Asians had greater LDL-C response to atorvastatin than patients of European origin. However, after propensity matching, atorvastatin lowered LDL-C and high-sensitivity C-reactive protein (hs-CRP) to a similar degree in both groups, with no differences in safety profile. The authors observed no correlation between change in hs-CRP and LDL-C concentrations in either population. In conclusion, atorvastatin lowered both LDL-C and hs-CRP to a similar degree in patients of South Asian or European origin, suggesting usual starting doses of atorvastatin (with appropriate monitoring), rather than lower starting doses as has been advocated by some, may be used in patients of South Asian origin.
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Proteína C-Reactiva/análisis , LDL-Colesterol/sangre , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Pirroles/uso terapéutico , Anciano , Pueblo Asiatico , Aterosclerosis/epidemiología , Aterosclerosis/etnología , Atorvastatina , Índice de Masa Corporal , Estudios de Casos y Controles , Terapia Combinada , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hiperlipidemias/sangre , Hiperlipidemias/etnología , Hiperlipidemias/terapia , Estilo de Vida , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Pirroles/efectos adversos , Riesgo , Población BlancaRESUMEN
Endothelial progenitor cells (EPC) represent a relatively rare cell population, and expansion of sufficient cell numbers remains a challenge. Nevertheless, human adipose-derived stem cells (hASC) can be easily isolated and possess the ability to differentiate into endothelial cells. Here, we propose the isolation and characterization of multipotent endothelial-like cells (ME-LC) with the capacity to maintain their vascular progenitor properties for long periods. hASC were isolated from lipoaspirates and cultured through distinct consecutive culture stages for 2 months to enrich ME-LC: first in Dulbecco's modified Eagle's medium-fetal bovine serum (stage I), followed by a stage of culture in absent of fetal bovine serum (stage II), a culture in SFO3 medium (stage III), and, finally, the culture of ME-LC into collagen IV-coated flasks in endothelial growth medium (EGM-2) (stage IV). ME-LC display increased expression levels of endothelial and hematopoietic lineage markers (CD45, KDR, and CXCR4) and EPC markers (CD34 and CD133), whereas the expression of CD31 was barely detectable. Reverse transcription (RT)-polymerase chain reaction assays showed expression of genes involved in early stages of EPC differentiation and decreased expression of genes associated to differentiated EPC (TIE-2, DLL4, and FLT-1). ME-LC formed capillary-like structures when grown on Matrigel, secreted increased levels of stromal cell-derived factor-1 (SDF-1), and showed the ability to migrate attracted by SDF-1, vascular endothelial growth factor, and hematopoietic growth factor cytokines. Importantly, ME-LC retained the capacity to differentiate into cardiomyocyte-like cells. We present a simplified and efficient method to generate large numbers of autologous ME-LC from lipoaspirates-derived hASC, opening up potential cell-based therapies for cardiovascular regenerative medicine.
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Tejido Adiposo/citología , Enfermedades Cardiovasculares/terapia , Células Endoteliales/citología , Células Madre Multipotentes/citología , Medicina Regenerativa/métodos , Tejido Adiposo/metabolismo , Animales , Antígenos de Diferenciación/metabolismo , Bovinos , Separación Celular , Células Cultivadas , Células Endoteliales/metabolismo , Femenino , Regulación de la Expresión Génica/fisiología , Humanos , Masculino , Células Madre Multipotentes/metabolismo , Células Madre Multipotentes/trasplanteRESUMEN
INTRODUCTION AND OBJECTIVES: Most studies have shown that prognosis of heart failure with preserved systolic function is as poor as that of heart failure with depressed systolic function, although these results may be biased by the fact that these types of heart failure have different characteristics (age, comorbidity, treatment), which can influence prognosis. Our aim was to determine whether short-term morbidity and mortality differed in these 2 subgroups of heart failure patients when they were comparable in terms of age, associated comorbidity, and therapy. METHODS: We analyzed 2 groups of patients aged >70 years who were candidates to receive beta blockers (preserved systolic function, 245; depressed systolic function, 374), consecutively discharged from 53 participating Spanish hospitals with a diagnosis of heart failure, and compared cardiovascular morbidity and mortality 3 months after discharge. RESULTS: Mean age was similar (77.5±4.8 vs 78.2±5.5 years). Left ventricular ejection fraction was 56.2%±8.1% vs 33%±6.9% (P<.001). The combined event rate (death, hospitalization for heart failure, acute coronary syndrome, or stroke) at 3 months after discharge was lower in patients with heart failure and preserved systolic function (13.4% vs 20.6%; P=.026). Depressed systolic function was an independent predictor of greater incidence of events (odds ratio=1.732; P=.048). CONCLUSIONS: In patients of similar age and receiving similar treatment, short-term prognosis is better in patients with heart failure and preserved systolic function than in those with depressed systolic function.
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Antagonistas Adrenérgicos beta/uso terapéutico , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Sístole/fisiología , Anciano , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/terapia , Comorbilidad , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca Sistólica/complicaciones , Insuficiencia Cardíaca Sistólica/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Pronóstico , España/epidemiología , Volumen Sistólico/fisiología , Resultado del TratamientoRESUMEN
AIMS: Previous experimental and clinical studies have consistently suggested that right ventricular (RV) apical pacing has important adverse effects. Ventricular pacing (VP), however, is required, and cannot be reduced in many patients with atrioventricular (AV) block. The PREVENT-HF study was an international randomized trial that explored differences in left ventricular (LV) remodelling during RV apical vs. biventricular (BIV) pacing in patients with AV block. METHODS AND RESULTS: Patients with an expected VP prevalence ≥80% were assigned to RV apical or BIV pacing. The primary endpoint was the change in LV end-diastolic volume (EDV) >12 months. Secondary endpoints were LV end-systolic volume (ESV), LV ejection fraction (EF), mitral regurgitation (MR), and a combination of heart failure (HF) events and cardiovascular hospitalizations. Overall, 108 patients were randomized (RV: 58; BIV: 50). Intention to treat and on-treatment analyses revealed no significant differences in any of the outcomes. Analysis of covariance (ANCOVA) difference for treatment according to randomization (in mL): LVEDV -3.92 (-18.71 to 10.85), P= 0.6; LVESV -1.38 (-12.07 to 9.31), P= 0.80; LVEF 2.47 (-3.00 to 7.94), P= 0.37. Analysis of covariance difference for the on-treatment analysis: LVEDV -4.90 (-20.02 to 10.22, PP= 0.52; LVESV -6.45 (-17.28 to 4.38), P= 0.24, LVEF 2.18 (-3.37 to 7.73), P= 0.44. Furthermore, secondary endpoints did not differ significantly. CONCLUSION: This study did not demonstrate significant LV volume differences >12 months between RV apical and BIV pacing for AV block. Thus, BIV pacing cannot be recommended as a routine treatment for AV block in these patients. However, the results encourage and inform the design of subsequent larger trials with higher power for detecting small volume changes. ClinicalTrials.gov Identifier: NCT00170326.
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Bloqueo Atrioventricular/terapia , Estimulación Cardíaca Artificial/métodos , Terapia de Resincronización Cardíaca/métodos , Insuficiencia Cardíaca/fisiopatología , Disfunción Ventricular/prevención & control , Remodelación Ventricular/fisiología , Anciano , Anciano de 80 o más Años , Bloqueo Atrioventricular/fisiopatología , Estimulación Cardíaca Artificial/efectos adversos , Terapia de Resincronización Cardíaca/efectos adversos , Estudios de Cohortes , Ecocardiografía , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos , Humanos , Masculino , Persona de Mediana Edad , Volumen SistólicoRESUMEN
OBJECTIVE: To analyze whether genetic variants of PPARA are associated with the development of stage C heart failure. METHODS: We analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms in genomic DNA extracted from peripheral blood cells of 534 patients in different heart failure stages and 63 healthy individuals. The mRNA expression of the peroxisome proliferator-activated receptor (PPAR)α target genes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was measured in myocardial biopsies of a subgroup of stage B and C patients. Functional studies were performed in HL-1 cardiomyocytes. RESULTS: The V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stage A and B patients and healthy individuals. Patients with the V162 allele exhibited decreased myocardial LCHAD and MCAD mRNA expression as compared to L162 homozygote patients. In addition, stage C patients exhibited lower myocardial LCHAD and MCAD mRNA expression than stage B patients. Cardiomyocytes transfected with the V162 allele presented decreased PPARα transcriptional activity, LCHAD mRNA expression and ATP production compared to cardiomyocytes transfected with the L162 variant. CONCLUSIONS: These findings suggest that the V162 allele of the human PPARA gene can be a new risk factor in the development of stage C heart failure, likely via depressed cardiac PPARα activity.