Effect of age, gender, and time of day on pain-to-call times in patients with acute ST-segment elevation myocardial infarction: the CLOC'AGE study. / Efecto de la edad, el sexo y el momento del día en el tiempo hasta el aviso a emergencias en pacientes con infarto agudo de miocardio con elevación del segmento ST. Estudio CLOC'AGE.

BACKGROUND: The time lapse between onset of symptoms and a call to an emergency dispatch center (pain-to-call time) is a critical prognostic factor in patients with chest pain. It is therefore important to identify factors related to delays in calling for help. OBJECTIVES: To analyze whether age, gender, or time of day influence the pain-to-call delay in patients with acute STsegment elevation myocardial infarction (STEMI). MATERIAL AND METHODS: Data were extracted from a prospective registry of STEMI cases managed by 39 mobile intensive care ambulance teams before hospital arrival within 24 hours of onset in our region, the greater metropolitan area of Paris, France. We analyzed the relation between pain-to-call time and the following factors: age, gender, and the time of day when symptoms appeared. We also assessed the influence of pain-to-call time on the rate of prehospital decisions to implement reperfusion therapy. RESULTS: A total of 24 662 consecutive patients were included; 19 291 (78%) were men and 4371 (22%) were women. The median age was 61 (interquartile range, 52-73) years (men, 59 [51-69] years; women, 73 [59-83] years; P .0001). The median pain-to-call time was 60 (24-164) minutes (men, 55 [23-150] minutes; women, 79 [31-220] minutes; P .0001). The delay varied by time of day from a median of 40 (17-101) minutes in men between 5 pm and 6 pm to 149 (43-377) minutes in women between 2 am and 3 am. The delay was longer in women regardless of time of day and increased significantly with age in both men and women (P .001). A longer pain-to-call time was significantly associated with a lower rate of implementation of myocardial reperfusion (P .001). CONCLUSION: Pain-to-call delays were longer in women and older patients, especially at night. These age and gender differences identify groups that would benefit most from health education interventions.

INTRODUCCION: En el dolor torácico, el tiempo desde el inicio de los síntomas hasta el aviso al sistema de emergencias (TAE) es un factor pronóstico decisivo. Es necesario conocer los factores que pueden influir en su duración. OBJETIVO: Analizar el efecto de la edad, el sexo y el momento del día en el TAE en pacientes con infarto agudo de miocardio con elevación del segmento ST (IAMEST). METODO: Se analizaron los datos de un registro regional prospectivo que incluye a todos los pacientes con IAMEST y 24 horas de evolución atendidos por 39 equipos de ambulancias de soporte vital avanzado en un entorno prehospitalario en el área metropolitana de París, Francia. Se analizó el TAE en relación con la edad, el sexo y el momento de aparición de los síntomas. Se valoró la influencia del TAE en la decisión prehospitalaria de tratamiento de reperfusión. RESULTADOS: Se incluyeron 24.662 pacientes consecutivos, de los cuales 19.291 (78%) eran hombres; la edad mediana fue de 61 años (RIC 52-73); 59 (51-69) en hombres y 73 (59-83) en mujeres (p 0,0001). El TAE fue de 60 minutos (24-164); 55 (23-150) minutos en hombres y 79 (31-220) minutos en mujeres (p 0,0001), y oscilaba entre 40 (17-101) minutos en hombres entre las 17:00 y las 18:00 y 149 (43-377) en mujeres entre las 02:00 y las 03:00. Independientemente de la hora de aparición del dolor, el TAE fue mayor en mujeres, y aumentó con la edad, tanto en hombres como en mujeres (p 0,001). El TAE prolongado se asoció con un descenso significativo en la decisión prehospitalaria de tratamiento de reperfusión (p 0,001). CONCLUSIONES: El intervalo de TAE fue más largo en mujeres y pacientes mayores, especialmente por la noche. Estos resultados permiten identificar los grupos de pacientes que más se beneficiarían de medidas de educación sanitaria.

Decision to deploy coronary reperfusion is not affected by the volume of ST-segment elevation myocardial infarction patients managed by prehospital emergency medical teams.

OBJECTIVE: Mortality in patients with ST-segment elevation myocardial infarction (STEMI) has been associated with the volume of activity of percutaneous coronary intervention (PCI) facilities. This observational study investigated whether the coronary reperfusion-decision rate is associated with the volume of activity in a prehospital emergency setting. METHODS: Prospectively collected data for the period 2003-2013 were extracted from a regional registry of all STEMI patients handled by eight dispatch centers (SAMUs) in and around Paris [41 mobile ICU (MICUs)]. A possible association between volume of activity (number of STEMIs) and coronary reperfusion-decision rate, and subsidiarily between volume of activity and choice of technique (fibrinolysis vs. primary PCI), were investigated. Explanatory factors (patient age, sex, delay between pain onset and first medical contact, and access to a PCI facility) were analyzed in a multivariate analysis. RESULTS: Overall, 18 162 patients; male/female 3.5/1; median age 62 (52-72) years were included in the analysis. The median number of STEMIs per MICU was 339 (IQ 220-508) and that of reperfusion-decisions was 94% (91-95). There was no association between the decision rate and the number of STEMIs (P = 0.1). However, the decision rate was associated with age, sex, delay, and access to a PCI facility (P < 0.0001) in a highly significant way. Fibrinolysis was a more frequent option for low-volume (remoter PCI facilities) than high-volume MICUs (30 vs. 16%). CONCLUSION: The decision of coronary reperfusion in a prehospital emergency setting depended on patient characteristics, delay between pain onset and first medical contact, and access to a PCI facility, but not on volume of activity. Promoting fibrinolysis use in underserved areas might help increase the reperfusion-decision rate.

Incidence, Mortality, and Outcome-Predictors of Sudden Cardiac Arrest Complicating Myocardial Infarction Prior to Hospital Admission.

BACKGROUND: Mortality of ST-segment-elevation myocardial infarction (STEMI) decreased drastically, mainly through reduction in inhospital mortality. Prehospital sudden cardiac arrest (SCA) became one of the most feared complications. We assessed the incidence, outcome, and prognosis' predictors of prehospital SCA occurring after emergency medical services (EMS) arrival. METHODS AND RESULTS: Data were taken between 2006 and 2014 from the e-MUST study (Evaluation en Médecine d'Urgence des Strategies Thérapeutiques des infarctus du myocarde) that enrolls all STEMI managed by EMS in the Greater Paris Area, including those dead before hospital admission. Among 13 253 STEMI patients analyzed, 749 (5.6%) presented EMS-witnessed prehospital SCA. Younger age, absence of cardiovascular risk factors, symptoms of heart failure, extensive STEMI, and short pain onset-to-call and call-to-EMS arrival delays were independently associated with increased SCA risk. Mortality rate at hospital discharge was 4.0% in the nonSCA group versus 37.7% in the SCA group ( P<0.001); 26.8% of deaths occurred before hospital admission. Factors associated with increased mortality after SCA were age, heart failure, and extensive STEMI, while male sex and cardiovascular risk factors were associated with decreased mortality. Among patients admitted alive, PCI was the most important mortality-reduction predictor (odds ratio, 0.40; 95% CI, 0.25-0.63; P<0.0001). CONCLUSIONS: More than 1 of 20 STEMI presents prehospital SCA after EMS arrival. SCA occurrence is associated with a 10-fold higher mortality at hospital discharge compared with STEMI without SCA. PCI is the strongest survival predictor, leading to a twice-lower mortality. This highlights the persistently dramatic impact of SCA on STEMI and the major importance of PCI in this setting.

Evolution of ST-Elevation Acute Myocardial Infarction Prevalence by Gender Assessed Age Pyramid Analysis-The Piramyd Study.

INTRODUCTION: Recent studies reported a decrease in the incidence of acute myocardial infarction. This favorable evolution does not extend to young women. The interaction between gender, risk factors and myocardial infarction incidence remains controversial. OBJECTIVE: To compare the evolution of the age pyramid of patients with ST-elevation myocardial infarction (STEMI) according to gender. METHODS: Data from patients with STEMI managed in pre-hospital settings prospectively collected in the greater Paris area. Evolution of patient demographics and risk factors was investigated. RESULTS: 28,249 patients with STEMI were included in the registry between 2002 and 2014, 21,883 (77%) males and 6,366 (23%) females. The sex ratio did not significantly vary over the study period (p = 0.4). Median patient age was 60.1 years (51.1⁻73.0) and was significantly different between males and females, respectively 57.9 (50.0⁻68.3) vs. 72.9 years (58.3⁻82.2) (p = 0.0004). The median age of males significantly (p = 0.0044) increased from 57.6 (50.1⁻70.0) in 2002 to 58.1 years (50.5⁻67.8) in 2014. The median age of females significantly (p = 0.0006) decreased from 73.7 (57.9⁻81.8) to 69.6 years (57.0⁻82.4). The median gap between the age of men and women significantly (p = 0.0002) decreased, from 16.1 to 11.5 years. Prevalence of risk factors was unchanged or decreased except for hypertension which significantly increased in males. The rate of STEMI without reported risk factors increased in both males and females. CONCLUSION: The age of STEMI onset significantly decreased in females, whereas it significantly increased in males. The prevalence of risk factors decreased in males, whereas no significant variation was found in females.

Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.

Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1ß (IL-1ß), which curtails anticancer immunity. Chemotherapy-triggered IL-1ß secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1ß induced secretion of IL-17 by CD4(+) T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3(-/-) or Casp1(-/-) mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.

Efecto de la edad, el sexo y el momento del díaen el tiempo hasta el aviso a emergenciasen pacientes con infarto agudo de miocardiocon elevación del segmento ST. Estudio CLOC’AGE / Effect of age, gender, and time of day on pain-to-call times in patients with acute ST-segment elevation myocardial infarction: the CLOC’AGE study

Objetivos: La indicación de intervencionismo coronario percutáneo primario (ICPP) en hospitales sin hemodinámica (HSH) se asocia con tiempos primera asistencia-apertura de la arteria (TPA) prolongados. Es pertinente identificar los factores implicados, especialmente aquellos relacionados con la organización de los servicios de urgencias. Método: Análisis de un registro de pacientes atendidos en HSH en una región sanitaria con una red asistencial para infarto agudo de miocardio con elevación del segmento ST (IAMEST) establecida y de sus tiempos de actuación. Resultados: En 2.542 pacientes, de edad 63 ± 13 años, se alcanzó un TPA# 120 minutos en un 42% de casos. En 9 de los 16 HSH analizados existía un box de dolor torácico en el área de urgencias, que se comportó como factor predictor independiente de un TPA# 120 minutos [OR 0,64 (IC 95% 0,54-0,77), p < 0,001], con una reducción de 11 minutos de este. Se asociaron de forma independiente con un TPA superior a 120 minutos la intubación y shock durante la primera asistencia, edad, sexo, atención en horario nocturno, bloqueo de rama izquierda y la clase Killip. La mortalidad al mes y al año aumentó en los HSH proporcionalmente al TPA (1,7% y 3,5% si TPA# 106 minutos y del 7,3% y 12,4% si TPA# 176 minutos, p <0,001). Conclusiones: El TPA alcanzado en activaciones procedentes de HSH supera las recomendaciones en el 58% de casos y se relaciona inversamente con la disponibilidad de un box de dolor torácico en urgencias. La mortalidad al mes y al año es proporcional al grado de retraso en la reperfusión. (AU)

Objetive: The need for primary percutaneous coronary intervention in hospitals without hemodynamic support capability is associated with delays between first medical contact (FMC) and reperfusion. It is important to identify factors involved in delays, particularly if they are relevant to the organization of emergency services. Methods: Analysis of a registry of patients treated in hospitals without advanced hemodynamic support systems in a catchment area with an established care network for acute ST-segment elevation myocardial infarction (STEMI). The registry included care times. Results: The network served 2542 patients with a mean (SD) age of 63 (13) years. FMC-to-reperfusion time was within 120 minutes in 42% of the cases. Nine of the hospitals had a chest-pain unit in the emergency department, and this factor was an independent predictor of FMC-to-reperfusion times of 120 minutes or less (odds ratio, 0.64; 95% CI, 0.54–0.77; P < .0001); the time was shortened by 11 minutes in such hospitals. FMC-to-reperfusion was delayed beyond 120 minutes in relation to the following factors: shock and need for intubation at start of care, age, gender, FMC at night, left bundle branch block, and Killip class. One-month and 1-year mortality rates increased in hospitals without hemodynamic support systems in proportion to reperfusion delay, by 1.7% and 3.5% if the delay was 106 minutes or less and by 7.3% and 12.4% if the delay was 176 minutes or longer (P < .0001). Conclusions: FMC-to-reperfusion time in STEMI exceeds recommendations in 58% of the hospitals without hemodynamic support systems and delay is inversely proportional to the availability of an emergency department chest pain unit. One-month and 1-year mortality is proportional to the degree of delay. (AU)

Neuropilin-2 expression promotes TGF-ß1-mediated epithelial to mesenchymal transition in colorectal cancer cells.

Neuropilins, initially characterized as neuronal receptors, act as co-receptors for cancer related growth factors and were recently involved in several signaling pathways leading to cytoskeletal organization, angiogenesis and cancer progression. Then, we sought to investigate the ability of neuropilin-2 to orchestrate epithelial-mesenchymal transition in colorectal cancer cells. Using specific siRNA to target neuropilin-2 expression, or gene transfer, we first observed that neuropilin-2 expression endows HT29 and Colo320 for xenograft formation. Moreover, neuropilin-2 conferred a fibroblastic-like shape to cancer cells, suggesting an involvement of neuropilin-2 in epithelial-mesenchymal transition. Indeed, the presence of neuropilin-2 in colorectal carcinoma cell lines was correlated with loss of epithelial markers such as cytokeratin-20 and E-cadherin and with acquisition of mesenchymal molecules such as vimentin. Furthermore, we showed by surface plasmon resonance experiments that neuropilin-2 is a receptor for transforming-growth factor-ß1. The expression of neuropilin-2 on colon cancer cell lines was indeed shown to promote transforming-growth factor-ß1 signaling, leading to a constitutive phosphorylation of the Smad2/3 complex. Treatment with specific TGFß-type1 receptor kinase inhibitors restored E-cadherin levels and inhibited in part neuropilin-2-induced vimentin expression, suggesting that neuropilin-2 cooperates with TGFß-type1 receptor to promote epithelial-mesenchymal transition in colorectal cancer cells. Our results suggest a direct role of NRP2 in epithelial-mesenchymal transition and highlight a cross-talk between neuropilin-2 and TGF-ß1 signaling to promote cancer progression. These results suggest that neuropilin-2 fulfills all the criteria of a therapeutic target to disrupt multiple oncogenic functions in solid tumors.

Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.