A clinically relevant bi-cellular murine mammary tumor model as a useful tool for evaluating the effect of retinoic acid signaling on tumor progression.

BACKGROUND: The effect of retinoic acid (RA) on breast cancer progression is controversial. Our objective was to obtain information about breast cancer progression, taking advantage of the ER-negative murine mammary adenocarcinoma model LM38 (LM38-LP constituted by luminal (LEP) and myoepithelial-like cells (MEP), LM38-HP mainly composed of spindle-shaped epithelial cells, and LM38-D2 containing only large myoepithelial cells), and to validate the role of the retinoic acid receptors (RARs) in each cell-type compartment. MATERIALS AND METHODS: We studied the expression and functionality of the RARs in LM38 cell lines. We analyzed cell growth and cell cycle distribution, apoptosis, the activity of proteases, motility properties, and expression of the molecules involved in these pathways. We also evaluated tumor growth and dissemination in vivo under retinoid treatment. RESULTS: LM38 cell lines expressed most retinoic receptor isotypes that were functional. However, only the bi-cellular LM38-LP cells responded to retinoids by increasing RARß2 and CRBP1 expression. The growth of LM38 cell sublines was inhibited by retinoids, first by inducing arrest in MEP cells, then apoptosis in LEP cells. Retinoids induced inhibitory effects on motility, invasiveness, and activity of proteolytic enzymes, mainly in the LM38-LP cell line. In in-vivo assays with the LM38-LP cell line, RA treatment impaired both primary tumor growth and lung metastases dissemination. CONCLUSION: These in-vivo and in-vitro results show that to achieve maximum effects of RA on tumor progression both the LEP and MEP cell compartments have to be present, suggesting that the interaction between the LEP and MEP cells is crucial to full activation of the RARs.

[Clinical characteristics and long-term outcome in patients with heart failure complicating acute myocardial infarction]. / Características clínicas y evolución a largo plazo de pacientes con insuficiencia cardíaca como complicación del infarto agudo de miocardio.

INTRODUCTION AND OBJECTIVES: To evaluate the clinical characteristics and prognosis of heart failure (HF) development in patients hospitalized for acute myocardial infarction (AMI). PATIENTS AND METHOD: Between May 1990 and March 2000, 836 consecutive patients were admitted with a diagnosis of AMI within 24 h of symptom onset. HF was defined as the presence of rales and a third heart sound with gallop, and evidence of pulmonary congestion on chest x-ray. It was diagnosed in 263 subjects (31.5%). RESULTS: The mean age of patients with HF (group 1) was 63.4 (11.4) years compared with 59.9 (11.6) years in those without HF (group 2) (P<.01). There were differences between groups 1 and 2 in history of diabetes (36% vs 20%; P<.001) or previous HF (9.2% vs 1.1%; P<.001). The reperfusion strategy used in patients with Q-wave infarction, with or without HF, was primary angioplasty in 15% and 14%, respectively (P=.81), and thrombolytic agents in 28% and 37%, respectively (P=.013). Patients with HF were more likely to develop recurrent angina (26.8% vs 19.6%; P=.02), pericarditis (17.5% vs 6.3%; P<.001), and atrial fibrillation (12.3% vs 5.1%; P<.01). In-hospital mortality in groups 1 and 2 was 15.6% and 2.3% (P<.001), respectively, and 10-year survival was 10% and 30%, respectively (P<.001). The variables associated with mortality were: age (HR=1.022; P<.001), hyperglycemia (HR=1.748 per 1.0-g/L increase; P<.001), leukocytosis (HR=1.035 per 1000-cell/.L increase; P<.001), and HF (HR=1.308; P=.028). CONCLUSIONS: AMI is still frequently complicated by HF, which increases short- and long-term morbidity and mortality. Heart failure, age, hyperglycemia, and leukocytosis at admission were independent predictors of mortality during follow-up.

Características clínicas y evolución a largo plazo de pacientes con insuficiencia cardíaca como complicación del infarto agudo de miocardio / Clinical characteristics and long-term outcome in patients with heart failure complicating acute myocardial infarction

Introducción y objetivos. Evaluar las características clínico-evolutivas y el pronóstico a largo plazo del desarrollo de insuficiencia cardíaca (IC) en pacientes hospitalizados por un infarto agudo de miocardio (IAM). Pacientes y método. Entre mayo de 1990 y marzo de 2000 se ingresó a 836 pacientes consecutivos con IAM dentro de las 24 h de evolución. La IC definida por presencia de estertores, tercer ruido y signos de congestión pulmonar en la radiografía de tórax se diagnosticó en 263 sujetos (31,5%). Resultados. La edad media de los pacientes con IC (grupo 1) y sin IC (grupo 2) fue de 63,4 ± 11,4 frente a 59,9 ± 11,6 años (p < 0,01). Hubo diferencias en ambos grupos en los antecedentes de diabetes (36 y 20%; p < 0,001) e IC previa (9,2 y 1,1%; p < 0,001). La reperfusión utilizada en los pacientes con infarto con ondas Q, con y sin IC, fue la angioplastia primaria (el 15 frente al 14%; p = 0,81) y la administración de trombolíticos (el 28 frente al 37%; p = 0,013). Una mayor proporción de sujetos con IC evolucionaron con angina postinfarto (el 26,8 y el 19,6%; p = 0,02), pericarditis (el 17 y el 6,3%; p < 0,001) y fibrilación auricular (el 12,3 y el 5,1%; p < 0,01). La mortalidad hospitalaria en los grupos 1 y 2 fue del 15,6 y del 2,3% (p < 0,001), y la supervivencia a 10 años fue del 10 y del 30%, respectivamente (p < 0,001). Las variables asociadas a la mortalidad en el seguimiento fueron la edad (harzard ratio [HR] = 1,022; p < 0,001), la glucemia (incremento de 1,0 g/l: HR = 1,748; p < 0,001), la leucocitosis (aumento de 1.000 células/μl; HR = 1,035; p < 0,001) y la IC (HR = 1,308; p = 0,028) Conclusiones. El fallo cardíaco continúa siendo una complicación frecuente en el IAM y se asoció a una elevada morbimortalidad hospitalaria y tardía. La IC, la edad avanzada, la glucemia y la leucocitosis en el momento del ingreso fueron marcadores independientes de mortalidad tardía

Introduction and objectives. To evaluate the clinical characteristics and prognosis of heart failure (HF) development in patients hospitalized for acute myocardial infarction (AMI). Patients and method. Between May 1990 and March 2000, 836 consecutive patients were admitted with a diagnosis of AMI within 24 h of symptom onset. HF was defined as the presence of rales and a third heart sound with gallop, and evidence of pulmonary congestion on chest x-ray. It was diagnosed in 263 subjects (31.5%). Results. The mean age of patients with HF (group 1) was 63.4 (11.4) years compared with 59.9 (11.6) years in those without HF (group 2) (P<.01). There were differences between groups 1 and 2 in history of diabetes (36% vs 20%; P<.001) or previous HF (9.2% vs 1.1%; P<.001). The reperfusion strategy used in patients with Q-wave infarction, with or without HF, was primary angioplasty in 15% and 14%, respectively (P=.81), and thrombolytic agents in 28% and 37%, respectively (P=.013). Patients with HF were more likely to develop recurrent angina (26.8% vs 19.6%; P=.02), pericarditis (17.5% vs 6.3%; P<.001), and atrial fibrillation (12.3% vs 5.1%; P<.01). In-hospital mortality in groups 1 and 2 was 15.6% and 2.3% (P<.001), respectively, and 10-year survival was 10% and 30%, respectively (P<.001). The variables associated with mortality were: age (HR=1.022; P<.001), hyperglycemia (HR=1.748 per 1.0-g/L increase; P<.001), leukocytosis (HR=1.035 per 1000-cell/μL increase; P<.001), and HF (HR=1.308; P=.028).Conclusions. AMI is still frequently complicated by HF, which increases short- and long-term morbidity and mortality. Heart failure, age, hyperglycemia, and leukocytosis at admission were independent predictors of mortality during follow-up

High levels of troponin T are associated with ventricular remodeling and adverse in-hospital outcome in heart failure.

BACKGROUND: Heart failure progression is associated with ventricular remodeling and ongoing myofibrillar degradation. We hypothesized that myocardial damage, detected by high levels of troponin T, would correlate with echocardiographic measurements of left ventricular remodeling and worse in-hospital course in decompensated heart failure. MATERIAL/METHODS: 159 patients with decompensated heart failure without acute coronary event were included. A troponin T value >0.2 ng/ml in samples taken 6, 12 or 24 hours after admission was considered abnormal. RESULTS: High troponin T levels were identified in 24 patients (15%) (Group 1). Mean age for group 1 was 65.9 vs. 63.7 years in patients with troponin T<0.2 (Group 2) (p=ns). Ischemic etiology in groups 1 and 2 was found in 58.3 and 38.5% (p=0.07). Two-dimensional echocardiograms in groups 1 and 2 revealed higher left ventricular diameters, diastolic (61.7+/-10 vs. 56.9+/-10.3 mm, p=0.041) as well as systolic (49.4+/-13.5 vs. 42.0+/-12.0 mm, p=0.012), and lower ejection fraction (30.1+/-14 vs. 39.0+/-17.7%, p=0.03). Incidence of combined end point of death or refractory heart failure was 20.8 and 3.7% in groups 1 and 2 (p=0.007; OR=6.8; CI95%=1.5-31.2). In a multiple regression model, a history of infarction and chronic obstructive pulmonary disease, tissue hypoperfusion, radiographic pulmonary edema, and high troponin T levels emerged as the independent predictors. CONCLUSIONS: High troponin T levels were found in 15% of patients with acute exacerbation of heart failure; this finding was independently associated with worse prognosis. Echocardiograms suggested that more severe ventricular remodeling is one subjacent mechanism related with biochemically detected myocardial injury in this setting.

Cardiac troponin T levels are associated with poor short- and long-term prognosis in patients with acute cardiogenic pulmonary edema.

BACKGROUND: The clinical determinants of increased cardiac troponin T (cTnT) in patients with acute cardiogenic pulmonary edema are not well defined, and the ability of this marker to predict long-term mortality has not yet been documented. METHODS: Eighty-four patients with acute cardiogenic pulmonary edema without acute myocardial infarction were prospectively enrolled. cTnT was measured in samples obtained 6 and 12 hours after admission. RESULTS: cTnT levels of 0.1 ng/mL or greater were found in 46 patients (55%). Thirty-two patients (38%) died during follow-up. The area under the receiver operating characteristic curve for cTnT was 0.70 and 0.69 at 6 and 12 hours (P =.47), and the cTnT cutoff value of 0.1 ng/mL was 66% and 69% sensitive and 63% and 71% specific, respectively, in predicting subsequent mortality. Patients were assigned to group 1 if they had cTnT lower than 0.1 ng/mL and to group 2 if they had cTnT levels of 0.1 ng/mL or greater. A history of coronary artery disease was present in 72% of group 2 versus 50% of group 1 patients (P =.04). Patients in group 2 were also older than those in group 1 (mean age, 68 years vs 61 years; P =.021). The 3-year survival in group 1 was 76% compared with 29% in group 2 (log-rank test, P <.001). In a Cox proportional hazards model, elevated cTnT emerged as the only prognostic marker of long-term mortality (risk ratio [RR] = 2.31; 95% CI, 1.011-5.280; P =.047). CONCLUSIONS: A cTnT level of 0.1 ng/mL or greater was associated with poor long-term survival and emerged as a powerful independent predictor of mortality in patients with acute cardiogenic pulmonary edema.