RESUMEN

The role of uPA in tissue remodeling and cell migration is already well established. In addition, uPA was reported to stabilize p53, a key cell cycle control, DNA repair and apoptosis initiation protein. We aimed to determine the role of uPA-uPAR signaling towards cell survival or apoptosis in human adult cardiac myocytes (HACM). HACM were stimulated with uPA and DNA damage was inflicted by incubating cells with 200 µM H2O2. To analyze for apoptotic cells we applied TUNEL staining. Oxidative damage foci were analyzed by staining for 8-oxoguanine base pairs. In vivo qPCR analysis from RNA extracted from failing human hearts demonstrated a close relation of uPA with apoptosis and the p53 pathway. Furthermore, we observed a close correlation of uPA and p53 protein in homogenized tissue lysates. In vitro studies revealed that uPA preincubation protected HACM from oxidative damage induced cell death and reduced oxidative damage foci. uPA protection is independent of its catalytic activity, as the amino terminal fragment of uPA showed similar protection. A key enzyme for repairing oxidative DNA damage is the p53 target hOGG1. We found a significant increase of hOGG1 after pretreatment of HACM with uPA. Knockdown of hOGG1 completely abrogated the protective effect of uPA. We conclude that uPA might have a tissue protective role in human hearts besides its role in tissue remodeling. Tissue protection is mediated by the DNA repair protein hOGG1. This might be beneficial during tissue remodeling and thus could be a target for therapeutic approaches in the diseased heart.

Asunto(s)

ADN Glicosilasas/genética , Estrés Oxidativo/genética , Proteína p53 Supresora de Tumor/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Movimiento Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/toxicidad , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Estrés Oxidativo/efectos de los fármacos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Transducción de Señal/efectos de los fármacos

RESUMEN

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that occurs in males leading to immobility and death in early adulthood. Female carriers of DMD are generally asymptomatic, yet frequently develop dilated cardiomyopathy. This study aims to detect early cardiac manifestation in DMD using cardiovascular magnetic resonance (CMR) and to evaluate its association with clinical symptoms. METHODS: Clinical assessment of DMD carriers included six minutes walk tests (6MWT), blood analysis, electrocardiography, echocardiography, and CMR using FLASH sequences to detect late gadolinium enhancement (LGE). T1-mapping using the Modified Look-Locker Inversion recovery (MOLLI) sequence was performed quantify extracellular volume (ECV). RESULTS: Of 20 carriers (age 39.47 ± 12.96 years) 17 (89.5 %) were clinically asymptomatic. ECV was mildly elevated (29.79 ± 2.92 %) and LGE was detected in nine cases (45 %). LGE positive carriers had lower left ventricular ejection fraction in CMR (64.36 ± 5.78 vs. 56.67 ± 6.89 %, p = 0.014), higher bothCK (629.89 ± 317.48 vs. 256.18 ± 109.10 U/l, p = 0.002) and CK-MB (22.13 ± 5.25 vs. 12.11 ± 2.21 U/l, p = 0.001), as well as shorter walking distances during the 6MWT (432.44 ± 96.72 vs. 514.91 ± 66.80 m, p = 0.037). 90.9 % of subjects without LGE had normal pro-BNP, whereas in 66.7 % of those presenting LGE pro-BNP was elevated (p = 0.027). All individuals without LGE were in the NYHA class I, whereas all those in NYHA classes II and III showed positive for LGE (p = 0.066). CONCLUSIONS: Myocardial involvement shown as LGE in CMR occurs in a substantial number of DMD carriers; it is associated with clinical and morphometric signs of incipient heart failure. LGE is thus a sensitive parameter for the early diagnosis of cardiomyopathy in DMD carriers. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01712152 Trial registration: October 19, 2012. First patient enrolled: September 27, 2012 (retrospectively registered).

RESUMEN

AIMS: Recent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) is unknown. METHODS AND RESULTS: We prospectively enrolled 171 HFpEF patients who underwent CMR in addition to invasive and non-invasive testing. RVSD, defined as right ventricular (RV) EF <45% by CMR, was present in 33 (19.3 %) patients. Patients were followed for 573 ± 387 days, during which 41 had a cardiac event. Patients with RVSD presented with more frequent history of AF (P = 0.038), significantly higher resting heart rate (P = 0.009), shorter 6-min walk distance (P = 0.036), and higher NT-pro BNP serum levels (P < 0.001), and were more symptomatic (P < 0.001). With respect to haemodynamic parameters, RVSD was associated with respect to haemodynamic parameters, RVSD was associated with higher diastolic pulmonary artery pressure (P = 0.045), with higher pulmonary vascular resistance (P = 0.048), higher transpulmonary gradient (P = 0.042), and higher diastolic pulmonary vascular pressure gradient (P = 0.007). In the multivariable Cox analysis, RVSD (P < 0.001) remained significantly associated with cardiac events, in addition to diabetes (P = 0.011), 6-min walk distance (P = 0.018), and systolic pulmonary artery pressure (P = 0.003). CONCLUSIONS: Although HFpEF is considered a disease of the left ventricle, respective imaging parameters are not related to outcome. In contrast, RVSD by CMR is independently associated with mortality and clinical status in these patients, and provides a useful tool for risk stratification.

Asunto(s)

Cateterismo Cardíaco/métodos , Diabetes Mellitus/epidemiología , Insuficiencia Cardíaca , Hipertensión Pulmonar/epidemiología , Imagen por Resonancia Cinemagnética/métodos , Disfunción Ventricular Derecha , Anciano , Austria/epidemiología , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/análisis , Fragmentos de Péptidos/análisis , Pronóstico , Medición de Riesgo/métodos , Factores de Riesgo , Volumen Sistólico , Disfunción Ventricular Derecha/diagnóstico , Disfunción Ventricular Derecha/epidemiología , Disfunción Ventricular Derecha/fisiopatología , Función Ventricular Izquierda

RESUMEN

OBJECTIVES: The purpose of this study was to prospectively investigate the diagnostic and prognostic impact of cardiac magnetic resonance (CMR) T1 mapping and validate it against left ventricular biopsies. BACKGROUND: Extracellular volume (ECV) expansion is a key feature of heart failure. CMR T1 mapping has been developed as a noninvasive technique to estimate ECV; however, the diagnostic and prognostic impacts of this technique have not been well established. METHODS: A total of 473 consecutive patients referred for CMR (49.5% female, age 57.8 ± 17.1 years) without hypertrophic cardiomyopathy, cardiac amyloidosis, or Anderson-Fabry disease were studied. T1 mapping with the modified Look-Locker inversion recovery (MOLLI) sequence was used for ECV calculation (CMR-ECV). For methodological validation, 36 patients also underwent left ventricular biopsy, and ECV was quantified by TissueFAXS analysis (TissueFAXS-ECV). To assess the prognostic value of CMR-ECV, its association with hospitalization for cardiovascular reasons or cardiac death was tested in a multivariable Cox regression model. RESULTS: TissueFAXS-ECV was 26.3 ± 7.2% and was significantly correlated with CMR-ECV (r = 0.493, p = 0.002). Patients were followed up for 13.3 ± 9.0 months and divided into CMR-ECV tertiles for Kaplan-Meier analysis (tertiles were ≤ 25.7%, 25.8% to 28.5%, and ≥ 28.6%). Significantly higher event rates were observed in patients with higher CMR-ECV (log-rank p = 0.013). By multivariable Cox regression analysis, CMR-ECV was independently associated with outcome among imaging variables (p = 0.004) but not after adjustment for clinical parameters. CONCLUSIONS: CMR T1 mapping allows accurate noninvasive quantification of ECV and is independently associated with event-free survival among imaging parameters. Its prognostic value on top of established clinical risk factors warrants further investigation in long-term studies.

Asunto(s)

Insuficiencia Cardíaca/patología , Ventrículos Cardíacos/patología , Imagen por Resonancia Magnética , Miocardio/patología , Adulto , Anciano , Biopsia , Distribución de Chi-Cuadrado , Medios de Contraste , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos/fisiopatología , Hospitalización , Humanos , Interpretación de Imagen Asistida por Computador , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Compuestos Organometálicos , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reproducibilidad de los Resultados , Factores de Riesgo , Volumen Sistólico , Factores de Tiempo , Función Ventricular Izquierda , Función Ventricular Derecha

RESUMEN

BACKGROUND: Previous work indicates that dilatation of the pulmonary artery (PA) itself or in relation to the ascending aorta (PA:Ao ratio) predicts pulmonary hypertension (PH). Whether these results also apply for heart failure with preserved ejection fraction (HFpEF) is unknown. In the present study we evaluated the diagnostic and prognostic power of PA diameter and PA:Ao ratio on top of right ventricular (RV) size, function, and septomarginal trabeculation (SMT) thickness by cardiovascular magnetic resonance (CMR) in HFpEF. METHODS AND RESULTS: 159 consecutive HFpEF patients were prospectively enrolled. Of these, 111 underwent CMR and invasive hemodynamic evaluation. By invasive assessment 64 % of patients suffered from moderate/severe PH (mean pulmonary artery pressure (mPAP) ≥30 mmHg). Significant differences between groups with and without moderate/severe PH were observed with respect to PA diameter (30.9 ± 5.1 mm versus 26 ± 5.1 mm, p < 0.001), PA:Ao ratio (0.93 ± 0.16 versus 0.78 ± 0.14, p < 0.001), and SMT diameter (4.6 ± 1.5 mm versus 3.8 ± 1.2 mm; p = 0.008). The strongest correlation with mPAP was found for PA:Ao ratio (r = 0.421, p < 0.001). By ROC analysis the best cut-off for the detection of moderate/severe PH was found for a PA:Ao ratio of 0.83. Patients were followed for 22.0 ± 14.9 months. By Kaplan Meier analysis event-free survival was significantly worse in patients with a PA:Ao ratio ≥0.83 (log rank, p = 0.004). By multivariable Cox-regression analysis PA:Ao ratio was independently associated with event-free survival (p = 0.003). CONCLUSION: PA:Ao ratio is an easily measureable noninvasive indicator for the presence and severity of PH in HFpEF, and it is related with outcome.

Asunto(s)

Aorta/patología , Presión Arterial , Insuficiencia Cardíaca/diagnóstico , Hipertensión Pulmonar/diagnóstico , Imagen por Resonancia Cinemagnética , Arteria Pulmonar/patología , Volumen Sistólico , Función Ventricular Izquierda , Anciano , Aorta/fisiopatología , Área Bajo la Curva , Austria , Cateterismo Cardíaco , Dilatación Patológica , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Arteria Pulmonar/fisiopatología , Curva ROC , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo

RESUMEN

BACKGROUND: Lipoprotein(a) (Lp(a)) is a proatherogenic plasma lipoprotein currently established as an independent risk factor for the development of atherosclerotic disease and as a predictor for acute thrombotic complications. In addition, Lp(a) is the major carrier of proinflammatory oxidized phospholipids (OxPL). Today, atherosclerosis is considered to be an inflammatory disease of the vessel wall in which monocytes and monocyte-derived macrophages are crucially involved. Circulating monocytes can be divided according to their surface expression pattern of CD14 and CD16 into at least 3 subsets with distinct inflammatory and atherogenic potential. OBJECTIVE: The aim of this study was to examine whether elevated levels of Lp(a) and OxPL on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) are associated with changes in monocyte subset distribution. METHODS: We included 90 patients with stable coronary artery disease. Lp(a) and OxPL/apoB were measured, and monocyte subsets were identified as classical monocytes (CMs; CD14++CD16-), intermediate monocytes (IMs; CD14++CD16+), and nonclassical monocytes (NCMs; CD14+CD16++) by flow cytometry. RESULTS: In patients with elevated levels of Lp(a) (>50 mg/dL), monocyte subset distribution was skewed toward an increase in the proportion of IM (7.0 ± 3.8% vs 5.2 ± 3.0%; P = .026), whereas CM (82.6 ± 6.5% vs 82.0 ± 6.8%; P = .73) and NCM (10.5 ± 5.3 vs 12.8 ± 6.0; P = .10) were not significantly different. This association was independent of clinical risk factors, choice of statin treatment regime, and inflammatory markers. In addition, OxPL/apoB was higher in patients with elevated Lp(a) and correlated with IM but not CM and NCM. CONCLUSIONS: In conclusion, we provide a potential link between elevated levels of Lp(a) and a proatherogenic distribution of monocyte subtypes in patients with stable atherosclerotic disease.

Asunto(s)

Aterosclerosis/sangre , Enfermedad de la Arteria Coronaria/sangre , Monocitos/metabolismo , Oxidación-Reducción , Anciano , Apolipoproteína B-100/sangre , Aterosclerosis/patología , Linaje de la Célula , Enfermedad de la Arteria Coronaria/patología , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Receptores de Lipopolisacáridos/sangre , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Monocitos/patología , Fosfolípidos/sangre , Receptores de IgG/sangre , Factores de Riesgo

RESUMEN

OBJECTIVE: Atherosclerosis is considered to be an inflammatory disease in which monocytes and monocyte-derived macrophages play a key role. Circulating monocytes can be divided into three distinct subtypes, namely in classical monocytes (CM; CD14++CD16-), intermediate monocytes (IM; CD14++CD16+) and non-classical monocytes (NCM; CD14+CD16++). Low density lipoprotein particles are heterogeneous in size and density, with small, dense LDL (sdLDL) crucially implicated in atherogenesis. The aim of this study was to examine whether monocyte subsets are associated with sdLDL serum levels. METHODS: We included 90 patients with angiographically documented stable coronary artery disease and determined monocyte subtypes by flow cytometry. sdLDL was measured by an electrophoresis method on polyacrylamide gel. RESULTS: Patients with sdLDL levels in the highest tertile (sdLDL≥4mg/dL;T3) showed the highest levels of pro-inflammatory NCM (15.2±7% vs. 11.4±6% and 10.9±4%, respectively; p<0.01) when compared with patients in the middle (sdLDL=2-3mg/dL;T2) and lowest tertile (sdLDL=0-1mg/dL;T1). Furthermore, patients in the highest sdLDL tertile showed lower CM levels than patients in the middle and lowest tertile (79.2±8% vs. 83.9±7% and 82.7±5%; p<0.01 for T3 vs. T2+T1). Levels of IM were not related to sdLDL levels (5.6±4% vs. 4.6±3% vs. 6.4±3% for T3, T2 and T1, respectively). In contrast to monocyte subset distribution, levels of circulating pro- and anti-inflammatory markers were not associated with sdLDL levels. CONCLUSION: The atherogenic lipoprotein fraction sdLDL is associated with an increase of NCM and a decrease of CM. This could be a new link between lipid metabolism dysregulation, innate immunity and atherosclerosis.

Asunto(s)

Biomarcadores/análisis , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/patología , Lipoproteínas LDL/sangre , Monocitos/patología , Anciano , Angiografía Coronaria , Estudios Transversales , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

OBJECTIVE: High-density lipoprotein (HDL) particles are heterogeneous in structure and function and the role of HDL subfractions in atherogenesis is not well understood. It has been suggested that small HDL may be dysfunctional in patients with coronary artery disease (CAD). Monocytes are considered to play a key role in atherosclerotic diseases. Circulating monocytes can be divided into three subtypes according to their surface expression of CD14 and CD16. Our aim was to examine whether monocyte subsets are associated with HDL subfractions in patients with atherosclerosis. METHODS: We included 90 patients with angiographically stable CAD. Monocyte subsets were defined as classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). HDL subfractions were measured by electrophoresis on polyacrylamide gel. RESULTS: Serum levels of small HDL correlated with circulating pro-inflammatory NCM and showed an inverse relationship to circulating CM independently from other lipid parameters, risk factors, inflammatory parameters or statin treatment regime, respectively. IM were not associated with small HDL. In particular, patients with small HDL levels in the highest tertile showed dramatically increased levels of NCM (14.7 ± 7% vs. 10.7 ± 5% and 10.8 ± 5%; p = 0.006) and a decreased proportion of CM (79.3 ± 7% vs. 83.7 ± 6% and 83.9 ± 6%; p = 0.004) compared to patients in the two lower tertiles. In contrast, intermediate HDL, large HDL and total HDL were not associated with monocyte subset distribution. CONCLUSION: Small HDL levels are associated with pro-inflammatory NCM and inversely correlated with CM. This may suggest that small HDL could have dysfunctional anti-inflammatory properties in patients with established CAD.

Asunto(s)

Enfermedad de la Arteria Coronaria/sangre , Lipoproteínas HDL/sangre , Monocitos/citología , Anciano , Aterosclerosis , Atorvastatina , Presión Sanguínea , Angiografía Coronaria , Estudios Transversales , Femenino , Fluorobencenos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Ácidos Heptanoicos/uso terapéutico , Humanos , Inflamación , Interleucina-10/metabolismo , Lípidos/química , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Factores de Riesgo , Rosuvastatina Cálcica , Sulfonamidas/uso terapéutico

RESUMEN

BACKGROUND: Therapeutic decisions in cardiology are determined frequently by cardiac chamber size. To decide whether cardiac dimensions are still in the normal range, reliable reference values are needed. However, published reference values mostly refer to historical cohorts using motion-mode measurements and have not been adjusted for sex or age. The impact of body size was only vaguely addressed. The importance of such adjustments is illustrated by studies, which show that smaller individuals and women are at risk of delayed treatment and impaired outcome when currently used reference values are applied. The aim of the present study was to assess the impact of body size, sex, and age on the normal heart size. METHODS AND RESULTS: We prospectively studied 622 individuals (52.7% women; 17-91 years; 143-200 cm; 32-240 kg) without cardiac disease by standard transthoracic echocardiography. Multivariable linear regression analyses of the impact of sex, age, height, and weight on cardiac chamber size were performed. By multivariable regression analysis (n=500), all 4 variables independently influenced cardiac chamber size. The validity of cardiac dimensions predicted by the regression model was tested prospectively in a validation cohort (n=122). A calculator is proposed that estimates cardiac dimensions on the basis of the regression analysis. CONCLUSIONS: Sex, height, weight, and age significantly affect the normal heart size. These parameters need to be considered when cutoff values indicating the need for treatment or even surgery are established.

Asunto(s)

Estatura , Peso Corporal , Volumen Cardíaco/fisiología , Ecocardiografía/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Valores de Referencia , Factores Sexuales , Adulto Joven

RESUMEN

BACKGROUND: The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. METHODS AND RESULTS: Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; P=0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03-1.13; P<0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00-1.01; P=0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group (P<0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time (R=0.98; P<0.01). T1 time also correlated with right ventricular-pulmonary arterial coupling (pulmonary vascular resistance: R=-0.36; P<0.01; right ventricular ejection fraction: R=0.28; P=0.01). CONCLUSIONS: In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

Asunto(s)

Insuficiencia Cardíaca/fisiopatología , Imagen por Resonancia Cinemagnética/métodos , Volumen Sistólico , Función Ventricular Izquierda/fisiología , Anciano , Femenino , Estudios de Seguimiento , Insuficiencia Cardíaca/diagnóstico , Humanos , Masculino , Pronóstico , Estudios Prospectivos , Curva ROC

RESUMEN

BACKGROUND: Hereditary amyloidosis with predominant renal disease can be caused by mutations in the gene encoding the fibrinogen Aα-chain (AFib). Here, we describe the clinical course of AFib amyloidosis associated with the rare R554L mutation, and the significance of extrarenal amyloid deposits and their possible influence on cardiovascular morbidity. METHODS: We report on 101 members of a family after having conducted patient interviews, chart review, genetic testing, renal biopsies and assessment for extrarenal amyloid deposition. RESULTS: Ten family members had chronic kidney disease with late-onset gross proteinuria and a variable course of declining renal function, starting in the fourth decade of life. In two affected living members, we identified the AFib R554L mutation. Renal biopsies from two affected members revealed almost complete obliteration of the mesangial glomerular architecture, although kidney function was only moderately impaired. There was neither evidence of extrarenal amyloidosis nor accelerated atherosclerosis. CONCLUSIONS: Renal amyloidosis associated with the R554L AFib variant dominated the clinical picture in this family, which was similar to that associated with the much more prevalent E526V mutation. Although it has been hypothesized that vascular deposits of fibrinogen amyloid may be associated with accelerated atherosclerosis, there was no suggestion of this in this particular kindred.

Asunto(s)

Amiloide/genética , Amiloidosis Familiar/etiología , Fibrinógeno/genética , Enfermedades Renales/complicaciones , Trasplante de Riñón/efectos adversos , Mutación/genética , Anciano , Amiloidosis Familiar/diagnóstico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/patología , Femenino , Humanos , Enfermedades Renales/terapia , Masculino , Persona de Mediana Edad , Linaje , Pronóstico , Proteinuria/etiología , Proteinuria/patología , Literatura de Revisión como Asunto , España

RESUMEN

Interleukin-33 (IL-33) is a recently described member of the IL-1 family of cytokines, which was identified as a ligand for the ST2 receptor. Components of the IL-33/ST2 system were shown to be expressed in normal and pressure overloaded human myocardium, and soluble ST2 (sST2) has emerged as a prognostic biomarker in myocardial infarction and heart failure. However, expression and regulation of IL-33 in human adult cardiac myocytes and fibroblasts was not tested before. In this study we found that primary human adult cardiac fibroblasts (HACF) and human adult cardiac myocytes (HACM) constitutively express nuclear IL-33 that is released during cell necrosis. Tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-1ß significantly increased both IL-33 protein and IL-33 mRNA expression in HACF and HACM as well as in human coronary artery smooth muscle cells (HCASMC). The nuclear factor-κB (NF-κB) inhibitor dimethylfumarate inhibited TNF-α- and IL-1ß-induced IL-33 production as well as nuclear translocation of p50 and p65 NF-κB subunits in these cells. Mitogen-activated protein/extracellular signal-regulated kinase inhibitor U0126 abrogated TNF-α-, IFN-γ-, and IL-1ß-induced and Janus-activated kinase inhibitor I reduced IFN-γ-induced IL-33 production. We detected IL-33 mRNA in human myocardial tissue from patients undergoing heart transplantation (n=27) where IL-33 mRNA levels statistically significant correlated with IFN-γ (r=0.591, p=0.001) and TNF-α (r=0.408, p=0.035) mRNA expression. Endothelial cells in human heart expressed IL-33 as well as ST2 protein. We also reveal that human cardiac and vascular cells have different distribution patterns of ST2 isoforms (sST2 and transmembrane ST2L) mRNA expression and produce different amounts of sST2 protein. Both human macrovascular (aortic and coronary artery) and heart microvascular endothelial cells express specific mRNA for both ST2 isoforms (ST2L and sST2) and are a source for sST2 protein, whereas cardiac myocytes, cardiac fibroblasts and vascular SMC express only minor amounts of ST2 mRNA and do not secrete detectable amounts of sST2 antigen. In accordance with the cellular distribution of ST2 receptor, human cardiac fibroblasts and myocytes as well as HCASMC did not respond to treatment with IL-33, as recombinant human IL-33 did not induce NF-κB p50 and p65 subunits nuclear translocation or increase IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) level in HACF, HACM and HCASMC. In summary, we found that endothelial cells seem to be the source of sST2 and the target for IL-33 in the cardiovascular system. IL-33 is expressed in the nucleus of human adult cardiac fibroblasts and myocytes and released during necrosis. Proinflammatory cytokines TNF-α, IFN-γ and IL-1ß increase IL-33 in these cells in vitro, and IL-33 mRNA levels correlated with TNF-α and IFN-γ mRNA expression in human myocardial tissue.

Asunto(s)

Vasos Coronarios/metabolismo , Fibroblastos/metabolismo , Regulación de la Expresión Génica/fisiología , Interleucinas/biosíntesis , Músculo Liso Vascular/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos del Músculo Liso/metabolismo , Receptores de Superficie Celular/biosíntesis , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/fisiología , Adulto , Butadienos/farmacología , Núcleo Celular/metabolismo , Células Cultivadas , Vasos Coronarios/citología , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/citología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Musculares/metabolismo , Músculo Liso Vascular/citología , Miocardio/citología , Miocitos Cardíacos/citología , Miocitos del Músculo Liso/citología , Subunidad p50 de NF-kappa B/metabolismo , Nitrilos/farmacología , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/fisiología , ARN Mensajero/biosíntesis , Factor de Transcripción ReIA/metabolismo

Asunto(s)

Reanimación Cardiopulmonar , Hipotermia Inducida/efectos adversos , Rabdomiólisis/etiología , Fibrilación Ventricular/terapia , Amiodarona/uso terapéutico , Quimioterapia Combinada , Electrocardiografía , Epinefrina/uso terapéutico , Humanos , Hipotermia Inducida/métodos , Masculino , Resultado del Tratamiento , Vasodilatadores/uso terapéutico , Adulto Joven

RESUMEN

OBJECTIVE: Interleukin (IL)-33 is the most recently described member of the IL-1 family of cytokines and it is a ligand of the ST2 receptor. While the effects of IL-33 on the immune system have been extensively studied, the properties of this cytokine in the cardiovascular system are much less investigated. Methods/Results- We show here that IL-33 promoted the adhesion of human leukocytes to monolayers of human endothelial cells and robustly increased vascular cell adhesion molecule-1, intercellular adhesion molecule-1, endothelial selectin, and monocyte chemoattractant protein-1 protein production and mRNA expression in human coronary artery and human umbilical vein endothelial cells in vitro as well as in human explanted atherosclerotic plaques ex vivo. ST2-fusion protein, but not IL-1 receptor antagonist, abolished these effects. IL-33 induced translocation of nuclear factor-κB p50 and p65 subunits to the nucleus in human coronary artery endothelial cells and human umbilical vein endothelial cells and overexpression of dominant negative form of IκB kinase 2 or IκBα in human umbilical vein endothelial cells abolished IL-33-induced adhesion molecules and monocyte chemoattractant protein-1 mRNA expression. We detected IL-33 and ST2 on both protein and mRNA level in human carotid atherosclerotic plaques. CONCLUSIONS: We hypothesize that IL-33 may contribute to early events in endothelial activation characteristic for the development of atherosclerotic lesions in the vessel wall, by promoting adhesion molecules and proinflammatory cytokine expression in the endothelium.

Asunto(s)

Moléculas de Adhesión Celular/biosíntesis , Células Endoteliales/fisiología , Inflamación/etiología , Interleucinas/fisiología , Placa Aterosclerótica/etiología , Adhesión Celular , Células Cultivadas , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Leucocitos/fisiología , FN-kappa B/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Receptores de Superficie Celular/fisiología

Asunto(s)

Válvula Aórtica/patología , Estenosis Coronaria/terapia , Embolia/etiología , Fibroma/complicaciones , Neoplasias Cardíacas/complicaciones , Anciano , Angioplastia Coronaria con Balón/métodos , Válvula Aórtica/cirugía , Procedimientos Quirúrgicos Cardíacos/métodos , Angiografía Coronaria/métodos , Reestenosis Coronaria/diagnóstico , Reestenosis Coronaria/etiología , Reestenosis Coronaria/cirugía , Estenosis Coronaria/diagnóstico por imagen , Ecocardiografía Transesofágica , Embolia/diagnóstico , Embolia/cirugía , Femenino , Fibroma/diagnóstico , Fibroma/cirugía , Estudios de Seguimiento , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/cirugía , Humanos , Imagen por Resonancia Magnética , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/terapia , Medición de Riesgo , Resultado del Tratamiento

RESUMEN

The pleiotropic cytokine oncostatin M (OSM), a member of the glycoprotein (gp)130 ligand family, plays a key role in inflammation and cardiovascular disease. As inflammation precedes and accompanies pathological angiogenesis, we investigated the effect of OSM and other gp130 ligands on vascular endothelial growth factor (VEGF) production in human vascular smooth muscle cells (SMC). Human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) were treated with different gp130 ligands. VEGF protein was determined by ELISA. Specific mRNA was detected by RT-PCR. Western blotting was performed for signal transducers and activators of transcription1 (STAT1), STAT3, Akt and p38 mitogen-activated protein kinase (p38 MAPK). OSM mRNA and VEGF mRNA expression was analyzed in human carotid endaterectomy specimens from 15 patients. OSM increased VEGF production in both HCASMC and HASMC derived from different donors. OSM upregulated VEGF and OSM receptor-specific mRNA in these cells. STAT3 inhibitor WP1066, p38 MAPK inhibitors SB-202190 and BIRB 0796, extracellular signal-regulated kinase1/2 (Erk1/2) inhibitor U0126, and phosphatidylinositol 3-kinase (PI3K) inhibitors LY-294002 and PI-103 reduced OSM-induced VEGF synthesis. We found OSM expression in human atherosclerotic lesions where OSM mRNA correlated with VEGF mRNA expression. Interferon-γ (IFN-γ), but not IL-4 or IL-10, reduced OSM-induced VEGF production in vascular SMC. Our findings that OSM, which is present in human atherosclerotic lesions and correlates with VEGF expression, stimulates production of VEGF by human coronary artery and aortic SMC indicate that OSM could contribute to plaque angiogenesis and destabilization. IFN-γ reduced OSM-induced VEGF production by vascular SMC.

Asunto(s)

Interferón gamma/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Oncostatina M/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Aterosclerosis/metabolismo , Células Cultivadas , Vasos Coronarios/metabolismo , Femenino , Humanos , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Mensajero/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti-angiogenic mediators in the heart are scarce. Here we study the expression of the anti-angiogenic factor pigment epithelium-derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2'dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor-alpha decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF-induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down-regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease.

Asunto(s)

Inhibidores de la Angiogénesis/metabolismo , Proteínas del Ojo/metabolismo , Fibroblastos/metabolismo , Hipoxia/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Serpinas/metabolismo , Adulto , Animales , Células Cultivadas , Proteínas del Ojo/genética , Fibroblastos/citología , Humanos , Miocitos Cardíacos/citología , Factores de Crecimiento Nervioso/genética , Serpinas/genética , Factores de Transcripción/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

Pulmonary veins (PV) display a variety of anomalies with a common trunk of the inferior pulmonary veins being the most infrequent. We report on a 65-year-old man who underwent an ablation procedure for atrial fibrillation (AF) exclusively based on electro-anatomical mapping. After recurrence of AF, a common trunk of the inferior PV was detected by computed tomography imaging resulting in a modified ablation approach. Due to a possible role of the common inferior trunk for the initiation of AF, a repeat procedure was performed by en bloc isolation of the common inferior trunk with the left superior PV. The right superior PV was ablated separately. Off antiarrhythmic medication, the patient has remained free of any arrhythmia during a 14 month follow-up.

Asunto(s)

Fibrilación Atrial/diagnóstico por imagen , Fibrilación Atrial/cirugía , Sistema de Conducción Cardíaco/anomalías , Sistema de Conducción Cardíaco/diagnóstico por imagen , Venas Pulmonares/anomalías , Venas Pulmonares/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Anciano , Sistema de Conducción Cardíaco/cirugía , Humanos , Masculino , Venas Pulmonares/cirugía

RESUMEN

Plasminogen activator inhibitor-1 (PAI-1) plays a pivotal role in the regulation of the fibrinolytic system and in the modulation of extracellular proteolysis. Increased PAI-1 was found in atherosclerotic lesions, and high PAI-1 plasma levels were associated with coronary heart disease. Smooth muscle cells (SMC) are a major source of PAI-1 within the vascular wall, and PAI-1 was implicated in SMC migration, proliferation, and apoptosis. We treated human coronary artery SMC (HCASMC) and human aortic SMC (HASMC) with the glycoprotein 130 (gp130) ligands cardiotrophin-1, interleukin-6 (IL-6), leukemia inhibitory factor (LIF), or oncostatin M (OSM). Only OSM increased PAI-1 antigen and activity production significantly in these cells up to 20-fold. OSM upregulated mRNA specific for PAI-1 up to 4.5-fold in these cells. HCASMC and HASMC express gp130, OSM receptor, IL-6 receptor, and LIF receptor. OSM induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylations in HASMC. A phosphatidylinositol 3-kinase inhibitor and a mitogen-activated protein/extracellular signal-regulated kinase inhibitor reduced Akt and ERK1/2 phosphorylation, respectively, and abolished OSM-induced PAI-1 upregulation. A janus kinase/signal transducer and activator of transcription inhibitor, a p38 mitogen-activated protein kinase inhibitor, or c-Jun NH(2)-terminal kinase inhibitor I did not inhibit the OSM-dependent PAI-1 induction. OSM enhanced proliferation of both HCASMC and HASMC by 77 and 90%, respectively. We hypothesize that, if the effect of OSM on PAI-1 expression in smooth muscle cells is operative in vivo, it could, via modulation of fibrinolysis and extracellular proteolysis, be involved in the development of vascular pathologies such as plaque progression, destabilization and subsequent thrombus formation, and restenosis and neointima formation.

Asunto(s)

Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Músculo Liso Vascular/metabolismo , Oncostatina M/farmacología , Oncostatina M/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Transducción de Señal/fisiología , Aorta/citología , Aorta/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Vasos Coronarios/citología , Vasos Coronarios/metabolismo , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Humanos , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Morfolinas/farmacología , Músculo Liso Vascular/citología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo

RESUMEN

The chemokine MCP-1 is thought to play a key role - among many other pathophysiological processes - in myocardial infarction. MCP-1 is not only a key attractant for monocytes and macrophages and as such responsible for inflammation but might also be directly involved in the modulation of repair processes in the heart. We show that cultured human cardiac cells express MCP-1 and that its expression is upregulated by inflammatory cytokines and downregulated by hypoxia. We hypothesize that inflammation but not hypoxia is the main trigger for monocyte recruitment in the human heart.

Asunto(s)

Hipoxia de la Célula/fisiología , Quimiocina CCL2/metabolismo , Mediadores de Inflamación/farmacología , Miocardio/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Inmunohistoquímica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa