Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

Detección de barreras e implementación de procedimientos para reducir la demora en el tratamiento del síndrome coronario agudo con elevación del segmento ST mediante angioplastia primaria / Barriers and Procedures to Reduce Treatment Delay in ST-Segment Elevation Acute Coronary Syndrome with Primary Percutaneous Coronary Intervention

RESUMEN Introducción: La demora a la reperfusión del síndrome coronario agudo con elevación del segmento ST es un factor determinante en el pronóstico. Su reducción podría disminuir la morbimortalidad. Objetivo: Identificar y modificar las barreras detectadas en 20 años de tratamiento del síndrome coronario agudo con elevación del segmento ST en un centro de tercer nivel de una ciudad de alta densidad demográfica para evaluar su efecto en el resultado del procedimiento. Material y métodos: Incluimos prospectiva y consecutivamente del 01/01/2000 al 31/12/2019, 3007 pacientes con síndrome coronario agudo con elevación del segmento ST dentro de las 12 h de iniciados los síntomas para realizar angioplastia primaria. Se dividió el tiempo desde el comienzo de los síntomas hasta la insuflación del balón en intervalos. Luego de identificar las barreras (2000-2009) se incorporaron cambios al procedimiento. Se organizó a la población en 2 grupos (G) G1: preimplementación de cambios (2000-2009) y G2: posimplementación (2010- 2019). Resultados: Se incluyeron en G1 1409 pacientes y en G2 1598. Sin diferencias demográficas, excepto por el tipo de angioplastia. Se identificaron demoras al realizar el diagnóstico, de comunicación entre médicos, del traslado y del ingreso del paciente a hemodinamia. Con los cambios, disminuimos el intervalo consulta-contacto con el hemodinamista [G1: 90 min (36-168) vs. G2: 77 min (36-144) p -0,01] y el intervalo contacto hemodinamista-ingreso a Hemodinamia [G1: 75 min (55-100) vs. G2: 51 min (34-70) p -0,01]. Se redujo la mortalidad intrahospitalaria (G1: 9,2% vs. G2:6,7% p -0,01) y al 6to mes (G1: 13,1% vs. G2: 7,5% p -0,01). Conclusiones: El retraso al diagnóstico, la dificultad en la comunicación y la forma de traslado fueron las principales causas de demora. La implementación de un protocolo de procedimientos permitió reducir las demoras. La evaluación continua de resultados y la educación permanente, constituyen los pilares fundamentales para la optimización de programas de atención en red.

ABSTRACT Background: The delay to reperfusion of ST-segment elevation acute coronary syndrome (STEACS) is a key factor in its prognosis, and its reduction could reduce morbidity and mortality. Objective: The aim of this study was to identify and modify the barriers detected in 20 years of STEACS treatment in a tertiary care center of a densely populated city to evaluate their effect on the outcome of the procedure. Methods: A total of 3007 patients with STEACS within 12 hours of symptoms onset were prospectively and consecutively included to undergo primary percutaneous coronary intervention (PCI) from January 1, 2000 to December 31, 2019. Time from symptoms onset to balloon inflation was divided into intervals. After barriers were identified (2000-2009), the procedure was changed. The population was divided into two groups (G) G1: pre-implementation (2000-2009) and G2: post-implementation (2010-2019) of changes. Results: G1 included 1409 and G2 1598 patients with no demographic differences except for the type of PCI. Delays were identified in diagnosis, communication between physicians, transfer and admission of the patient to the hemodynamics lab. Procedural changes decreased first medical contact-hemodynamic team contact interval [G1: 90 min (36-168) vs. G2: 77 min (36-144) p -0.01] and hemodynamic team contact-hemodynamics lab admission interval [G1: 75 min (55-100) vs. G2: 51 min (34-70) p -0.01] and reduced in-hospital (G1: 9,2% vs. G2: 6,7% p -0,01) and 6-month (G1: 13.1% vs. G2: 7.5% p -0. 01) mortality. Conclusions: Delay in diagnosis, difficulty in communication and type of transfer were the most important causes of delay. Implementing a procedural protocol reduced delays. Continuous evaluation of results and permanent education constitute the fundamental cornerstones for optimizing network care programs.

NFKB2 polymorphisms associate with the risk of developing rheumatoid arthritis and response to TNF inhibitors: Results from the REPAIR consortium.

This study sought to evaluate the association of 28 single nucleotide polymorphisms (SNPs) within NFKB and inflammasome pathway genes with the risk of rheumatoid arthritis (RA) and response to TNF inhibitors (TNFi). We conducted a case-control study in a European population of 1194 RA patients and 1328 healthy controls. The association of potentially interesting markers was validated with data from the DANBIO (695 RA patients and 978 healthy controls) and DREAM (882 RA patients) registries. The meta-analysis of our data with those from the DANBIO registry confirmed that anti-citrullinated protein antibodies (ACPA)-positive subjects carrying the NFKB2rs11574851T allele had a significantly increased risk of developing RA (PMeta_ACPA + = 0.0006) whereas no significant effect was found in ACPA-negative individuals (PMeta_ACPA- = 0.35). An ACPA-stratified haplotype analysis including both cohorts (n = 4210) confirmed that ACPA-positive subjects carrying the NFKB2TT haplotype had an increased risk of RA (OR = 1.39, P = 0.0042) whereas no effect was found in ACPA-negative subjects (OR = 1.04, P = 0.82). The meta-analysis of our data with those from the DANBIO and DREAM registries also revealed a suggestive association of the NFKB2rs1056890 SNP with larger changes in DAS28 (OR = 1.18, P = 0.007). Functional experiments showed that peripheral blood mononuclear cells from carriers of the NFKB2rs1005044C allele (in LD with the rs1056890, r2 = 1.00) showed increased production of IL10 after stimulation with LPS (P = 0.0026). These results provide first evidence of a role of the NFKB2 locus in modulating the risk of RA in an ACPA-dependent manner and suggest its implication in determining the response to TNFi. Additional studies are now warranted to further validate these findings.

Impacto de un sistema de evaluación de tiempos a la reperfusión en infarto agudo de miocardio con elevación del ST / Impact of an Evaluation System of Times to Reperfusion in ST-segment Elevation Acute Myocardial Infarction

RESUMEN • Introducción: El tratamiento del infarto con supradesnivel del ST (IAMCEST) es tiempo-dependiente, por lo que los centros con angioplastia primaria (ATCp) deben estar organizados para asegurar una rápida reperfusión. Objetivos: Evaluar el impacto de un sistema de evaluación sistemática de los tiempos de reperfusión y feedback de resultados en la reducción de las demoras. Material y métodos: Estudio observacional, prospectivo, realizado en 46 centros con ATCp 24/7 de la Iniciativa Stent-Save a Life! Argentina. Se incluyeron pacientes con IAMCEST sometidos a ATCp antes de las 12 h desde el inicio de los síntomas, asistidos entre marzo de 2016 y febrero de 2019. La población se dividió en tres etapas consecutivas de 1 año cada una desde la inclusión de cada centro. Resultados: Se incluyeron 3492 pacientes consecutivos (primer año: 1482; segundo año: 1166; tercer año: 844). Se observó una reducción significativa del tiempo puerta-balón (TPB) (68, 60 y 50 min; p < 0,0001) a lo largo de los años considerados, independientemente de dónde haya sido el primer contacto médico (PCM) y del tiempo desde el primer contacto médico (PCM) al balón (115, 112 y 98 min; p < 0,0001), sin diferencias en el tiempo desde el inicio de los síntomas al PCM ni en el tiempo total de isquemia (TTI). Asimismo, en aquellos pacientes que tuvieron su PCM en centros sin hemodinamia y fueron derivados para la realización de ATCp, se observó una disminución del TTI (274, 260 y 235 min; p < 0,001). Conclusiones: La implementación de un programa puerta-balón (PPB) en centros con ATCp permitió reducir los tiempos al tratamiento.

ABSTRACT • Background: Treatment of patients with ST-elevation myocardial infarction (STEMI) is time-dependent; therefore centers with primary percutaneous coronary intervention (pPCI) capability should be organized to achieve rapid reperfusion. Objectives: The aim of this study was to assess the impact of a systematic evaluation of reperfusion times with periodic feed-back of results in reducing delays to treatment. Methods: This was an observational, prospective study conducted in 46 centers with 24/7 pPCI capability participating in the Stent-Save a Life! Argentina Initiative. Patients with STEMI who underwent pPCI within 12 hours from the onset of symptoms were included from March 2016 to February 2019. The population was divided into three consecutive stages lasting one year each since the inclusion of each center in the Stent-Save a Life! Initiative. Results: A total of 3,492 patients were included (1st year: 1,482, 2nd year: 1,166, 3rd year: 844). There was a significant reduction in door-to-balloon (DTB) time (68, 60 and 50 min; p <0.0001), regardless of the type of first medical contact (FMC), and of the time from FMC to reperfusion (115, 112 and 98 min; p<0.0001), without differences in time from the onset of symptoms to FMC or total ischemic time (TIT). In addition, patients with FMC in centers without PCI capability who were referred for pPCI also evidenced a significant reduction of TIT (274, 260 and 235 min; p<0.001). Conclusion: The implementation of a DTB program in centers with pPCI capability resulted in a significant reduction of treatment times.

Is Dual-Axis Rotational Coronary Angiography Radiation Dose Reduction Achievable in a Population with 100% Suspected Coronary Artery Disease? A Randomized Trial.

BACKGROUND: Previous studies have shown a reduction in radiation dose and contrast volume using dual-axis rotational coronary angiography (DARCA), but this has not been replicated in a population with 100% coronary artery disease (CAD). OBJECTIVE: To find if DARCA dose reduction is achievable in this population, we sought to compare the radiation dose, contrast volume, and procedure time between DARCA and conventional coronary angiography (CCA) techniques in a setting characterized by a prevalence of 100% suspected coronary artery disease. METHODS: An all-comer, prospective, randomized, open-label trial was conducted. Cine acquisition dose-area product (DAP), cumulative air kerma (AK), effective dose (E), fluoroscopic time, contrast volume, AK, cine acquisition DAP (CADAP), fluoroscopic DAP (F-DAP), and total DAP were compared between DARCA and CCA groups. RESULTS: We included 503 consecutive patients with suspected CAD. 252 were assigned to DARCA and 251 to CCA. Stable coronary artery disease was reported in 465 cases and non-ST elevation acute coronary syndrome in 38. Mean age: 61.88 ± 11.2 years, male gender 70.2%. DARCA arm patients showed lower total E dose (6.85 [4.55-10.83] vs. 7.91 [5.58-11.94] Sv; P = .0023), and cine E (3.00 [2.00-4.00] vs. 4.00 [3.00-5.00] Sv; P < .0001). Total DAP was also lower (40.3 [26.8-63.7] vs. 46.5 [32.8-70.2] Gycm2; P = .0023), as a consequence of a lower CADAP (16.3 [10.5-22.9] vs. 23.4 [17.4-32.0] Gycm2; P < .0001), with lower AK (367 [248-1497] vs. 497 [381-1827] mGy; P < .0001), with less contrast medium used (90 [60.0-106.0] vs. 100 [75.0-120.0] mL; P = .014). CONCLUSION: In a population with 100% suspected coronary artery disease, DARCA provides accurate information required in CAD, is safe, and results in a significant decrease in contrast material volume and radiation dose compared with CCA. The required extra projections did not neutralize the DARCA radiation dose and contrast volume reduction achievements.

Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium.

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1, CYP2C9, ESR2, FcγR3A, and SHBG SNPs to modulate the risk of bone erosions (P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry (P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9rs1799853T/T genotype with serum vitamin D3 levels (P = 0.00085) and a modest effect on IL1ß levels after stimulation of PBMCs or blood with LPS and PHA (P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis (P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2, ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10-7). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF+ = 2.46•10-8) whereas no prediction was detected in seronegative patients (PRF- = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.

Iniciativa Stent-Save a Life! Argentina / Stent-Save a Life! Argentina Initiative

RESUMEN 31. Introducción: La iniciativa Stent-Save a Life! (SSL) es un programa europeo que busca mejorar el acceso de pacientes con infarto agudo de miocardio con elevación del ST (IAMCEST) a un tratamiento de reperfusión basado en las recomendaciones de las guías clínicas, reduciendo así su morbimortalidad. Objetivo: Describir los resultados de los primeros tres años de la iniciativa SSL Argentina Material y métodos: Se realizó inicialmente un mapeo para analizar la situación local y luego se desarrolló el Programa Puerta-Balón (PPB) como un proceso de mejora continua para centros con capacidad de realizar angioplastia primaria (ATCp). Resultados: Desde marzo de 2016 hasta marzo de 2018 se trataron 3041 pacientes con IAMCEST en 38 centros participantes del citado programa. El 20% (n = 610) de esos pacientes tuvo su primer contacto médico (PCM) con el servicio de emergencias médicas. Excluyendo los 184 pacientes sin lesiones coronarias (6% del total), el 93% fue reperfundido, principalmente con ATCp (95%). El tiempo global de isquemia fue de 117 minutos, variando según el momento del PCM. La mortalidad global intrahospitalaria fue del 7%. Conclusiones: La falta de una "cultura de reperfusión" fue la barrera en común de centros públicos y privados que motivó el desarrollo del PPB. La identificación de los puntos críticos que impiden un tratamiento a tiempo, junto con la organización de los centros puertas adentro, representan el primer paso para mejorar la atención de estos pacientes. Es necesario el trabajo integrado de todos los actores involucrados a partir de la organización de redes de atención, adaptadas a la realidad local de cada centro y región.

ABSTRACT 39. Introduction: The Stent-Save a Life! (SSL) initiative is a European program that seeks to improve the access of patients with ST-segment elevation acute myocardial infarction (STEMI) to reperfusion therapies based on clinical guideline recommendations, thus reducing morbidity and mortality. Objective: The aim of this study was to describe the results of the first three years of the SSL Argentina initiative. Methods: Initially, a mapping was carried out to analyze the local situation and then the Door-to- Balloon Program (DBP) was developed as a continuous improvement process for centers with primary percutaneous coronary intervention (pPCI) capability. Results: From March 2016 to March 2018, 3,041 patients with STEMI were treated in 38 centers participating in this program. In 20% of cases (n=610) patients had their first medical contact with the emergency medical services. After excluding 184 patients (6%) without coronary lesions, reperfusion therapy was performed in 93% of cases, mainly by pPCI (95%). Total ischemic time was 117 minutes, with differences according to the time of first medical contact. Overall in-hospital mortality was 7%. Conclusions: The lack of a "reperfusion culture" was the common barrier of public and private centers that motivated the development of the DBP. The identification of critical points that prevent treatment on time, together with enhancement of in-hospital organization, represent the first step to improve the care of these patients. The integrated work of all the involved parties is necessary to develop care networks adapted to the local reality of each center and region.

Polymorphisms at phase I-metabolizing enzyme and hormone receptor loci influence the response to anti-TNF therapy in rheumatoid arthritis patients.

The aim of this case-control study was to evaluate whether 47 single-nucleotide polymorphisms (SNPs) in steroid hormone-related genes are associated with the risk of RA and anti-TNF drug response. We conducted a case-control study in 3 European populations including 2936 RA patients and 2197 healthy controls. Of those, a total of 1985 RA patients were treated with anti-TNF blockers. The association of potentially interesting markers in the discovery population was validated through meta-analysis with data from DREAM and DANBIO registries. Although none of the selected variants had a relevant role in modulating RA risk, the meta-analysis of the linear regression data with those from the DREAM and DANBIO registries showed a significant correlation of the CYP3A4rs11773597 and CYP2C9rs1799853 variants with changes in DAS28 after the administration of anti-TNF drugs (P = 0.00074 and P = 0.006, respectively). An overall haplotype analysis also showed that the ESR2GGG haplotype significantly associated with a reduced chance of having poor response to anti-TNF drugs (P = 0.0009). Finally, a ROC curve analysis confirmed that a model built with eight steroid hormone-related variants significantly improved the ability to predict drug response compared with the reference model including demographic and clinical variables (AUC = 0.633 vs. AUC = 0.556; PLR_test = 1.52 × 10-6). These data together with those reporting that the CYP3A4 and ESR2 SNPs correlate with the expression of TRIM4 and ESR2 mRNAs in PBMCs (ranging from P = 1.98 × 10-6 to P = 2.0 × 10-35), and that the CYP2C9rs1799853 SNP modulates the efficiency of multiple drugs, suggest that steroid hormone-related genes may have a role in determining the response to anti-TNF drugs.KEY POINTS• Polymorphisms within the CYP3A4 and CYP2C9 loci correlate with changes in DAS28 after treatment with anti-TNF drugs.• A haplotype including eQTL SNPs within the ESR2 gene associates with better response to anti-TNF drugs.• A genetic model built with eight steroid hormone-related variants significantly improved the ability to predict drug response.

Vitamin D is Related to Markers of Vulnerable Plaque in Acute Myocardial Infarction.

BACKGROUND: Vitamin D is a fat soluble vitamin involved in calcium and bone metabolism; recently its deficiency has been related to cardiovascular disease. In cardiac tissue, vitamin D suppresses metalloproteinases (MMPs) expression, enzymes directly associated with vulnerable plaque. OBJECTIVE: To investigate whether the association between vitamin D and leptin is related to markers of vulnerable plaque, such as MMPs in patients with acute myocardial infarction. METHODS: We studied 66 male patients with acute myocardial infarction, undergoing primary angioplasty. Blood samples were obtained at admission and 24hs after the surgery. Leptin and vitamin D concentrations in serum and MMP-2 and -9 activities in plasma were determined. RESULTS: MMP-2 activity was increased in Vitamin D deficient/insufficient patients at admission (p=0.04) and 24 hs later (p=0.05). In a linear regression model, vitamin D explained 24% of the variance of MMP-2 activity (F=2.839 p=0.04). At admission, vitamin D correlated with serum leptin (r=-0.302 p=0.033), and explained 39.5% of its variation (F=4.432 p=0.003). CONCLUSION: In the studied population, vitamin D was inversely related to MMP-2 and leptin which are involved in coronary artery disease and acute myocardial infarction. The decrease in this hormone levels would be associated with a worse metabolic profile in acute coronary syndrome patients.

Reperfusión mecánica simple en el infarto agudo de miocardio: Determinantes, implicaciones en el pronóstico y relación con la histología del trombo / Simple mechanical reperfusion in acute myocardial infarction: determinants, prognostic implications and relation with thrombus histology

La reperfusión mecánica simple (RMS) es la lograda en la angioplastia primaria al atravesar la oclusión en la arteria responsable de infarto con la guía intracoronaria. Para evaluar los determinantes de la RMS, su implicación en el pronóstico y su relación con la histopatología del trombo rescatado, fueron analizados los casos de 601 pacientes con infarto agudo de miocardio con elevación del segmento ST y oclusión total de la arteria responsable de infarto (flujo TIMI 0). Se consideraron dos grupos según la presencia de RMS, definida por la visualización de contraste distal a la lesión luego de atravesarla con la guía intracoronaria. Se realizó el análisis histopatológico de los trombos en un subgrupo de 160 pacientes tratados con tromboaspiración. En 303 (50.4%) pacientes se obtuvo RMS. La RMS se asoció a menor ventana al tratamiento (248 vs. 286 minutos, p = 0.001), menor deterioro de la función sistólica ventricular izquierda inicial y shock al ingreso (9.2 vs.16.4%, p = 0.008), mayor tasa de éxito (94.7 vs. 78.5%, p < 0.0001) y de rescate de trombos (70/81 vs. 27/79 pacientes, p < 0.0001). La arteria responsable de infarto más frecuente fue la coronaria derecha. La RMS se asoció con menor tamaño del trombo, menor concentración de leucocitos y eritrocitos y mayor contenido de células inflamatorias, cristales de colesterol y colágeno provenientes de la placa. La RMS es un predictor independiente de éxito y su relación con la anatomía del trombo podría redefinir la indicación de la tromboaspiración.

Simple mechanical reperfusion (SMR) is defined as reperfusion achieved after wire insertion at the occluded infarct-related artery in primary angioplasty. The determinants and prognostic implications of SMR and its relationship with the histopathology of the rescued thrombus were evaluated in 601 patients with acute myocardial infarction showing ST elevation and pre-procedural total occlusion of the infarct-related artery (TIMI flow 0). Two groups were considered according to the presence of SMR, defined as the visualization of contrast material after crossing the occlusion with the guide wire. SMR was achieved in 303 patients (50.4%) and was found to be associated with less time to treatment (248 vs. 286 minutes; p = 0.001), less deteriorated initial left ventricular function and shock at admission (9.2 vs. 16.4%; p = 0.008), higher successful rate (94.7% vs. 78.5%; p < 0,0001) and of higher rate of thrombus rescue: 70/81 vs. 27/79 patients (p < 0.0001). The right coronary artery was the most frequent infarct-related artery. Histopathology of the retrieved thrombi was available for 160 patients treated with thrombus aspiration. SMR was associated with smaller thrombus, lower contents of leukocytes and erythrocytes, and higher thrombus content of inflammatory cells, cholesterol and collagen crystals from the atheromatous plaque. SMR is an independent predictor of procedure success and its relationship with the anatomy of the thrombus could redefine the indication of thrombus aspiration.

Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. MATERIALS AND METHODS: To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. RESULTS: Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). CONCLUSIONS: Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.

INTRODUCTION: The advent of anti-tumor necrosis factor alpha (anti-TNFα) drugs has considerably improved medical management in rheumatoid arthritis (RA) patients, although it has been reported to be ineffective in a fraction of them. MicroRNAs (miRNAs) are small, non-coding RNAs that act as fine-tuning regulators of gene expression. Targeting miRNAs by gain or loss of function approaches have brought therapeutic effects in various disease models. The aim of this study was to investigate serum miRNA levels as predictive biomarkers of response to anti-TNFα therapy in RA patients. METHODS: In total, 95 RA patients undergoing anti-TNFα/disease-modifying antirheumatic drugs (anti-TNFα/DMARDs) combined treatments were enrolled. Serum samples were obtained at 0 and 6 months and therapeutic efficacy was assessed. miRNAs were isolated from the serum of 10 patients before and after anti-TNFα/DMARDs combination therapy, cDNA transcribed and pooled, and human serum miRNA polymerase chain reaction (PCR) arrays were performed. Subsequently, selected miRNAs were analyzed in a validation cohort consisting of 85 RA patients. Correlation studies with clinical and serological variables were also performed. RESULTS: Ninety percent of RA patients responded to anti-TNFα/DMARDs combination therapy according to European League Against Rheumatism (EULAR) criteria. Array analysis showed that 91% of miRNAS were overexpressed and 9% downregulated after therapy. Functional classification revealed a preponderance of target mRNAs involved in reduction of cells maturation--especially on chondrocytes--as well as in immune and inflammatory response, cardiovascular disease, connective tissue and musculoskeletal system. Six out of ten miRNAs selected for validation were found significantly upregulated by anti-TNFα/DMARDs combination therapy (miR-16-5p, miR-23-3p, miR125b-5p, miR-126-3p, miRN-146a-5p, miR-223-3p). Only responder patients showed an increase in those miRNAs after therapy, and paralleled the reduction of TNFα, interleukin (IL)-6, IL-17, rheumatoid factor (RF), and C-reactive protein (CRP). Correlation studies demonstrated associations between validated miRNAs and clinical and inflammatory parameters. Further, we identified a specific plasma miRNA signature (miR-23 and miR-223) that may serve both as predictor and biomarker of response to anti-TNFα/DMARDs combination therapy. CONCLUSIONS: miRNA levels in the serum of RA patients before and after anti-TNFα/DMARDs combination therapy are potential novel biomarkers for predicting and monitoring therapy outcome.

Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs: a multicenter study.

BACKGROUND: Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs. METHODS: The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria. RESULTS: We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12). CONCLUSION: Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

Candidate's single-nucleotide polymorphism predictors of treatment nonresponse to the first anti-TNF inhibitor in ankylosing spondylitis.

The objective of this study is to identify single-nucleotide polymorphisms (SNPs) predictors of treatment nonresponse to the first anti-TNF-alpha agent in ankylosing spondylitis (AS). Patients were classified as "nonresponders" if they failed to achieve improvement ≥50 % of the initial BASDAI. We selected candidate SNPs previously reported, associated with susceptibility or pathogenesis of AS and with other spondylarthropaties (SpAs). The predictors of nonresponse were modeled with multiple logistic regression. The predictive power of the genetic model of nonresponse to treatment was tested with AUC-ROC. One hundred and twenty-one (121) AS patients fulfilled the inclusion criteria. Of the candidate SNPs tested for association with treatment effectiveness, five independent predictors were identified: rs917997, rs755622, rs1800896, rs3740691, and rs1061622. The genetic model of nonresponse to treatment had a predictive power of 0.77 (95 % CI 0.68-0.86). Our study identified several polymorphisms which could be the useful genetic biomarkers in predicting nonresponse to anti-TNF-alpha therapy.

Predictores clínicos de no-reflujo en la angioplastia coronaria por infarto agudo de miocardio / Clinical Predictors of No-Reflow in Percutaneous Coronary Intervention for Acute Myocardial Infarction

Introducción El fenómeno de no-reflujo en el contexto de la angioplastia por infarto agudo de miocardio (IAM) es un hecho relativamente frecuente y asociado con peor pronóstico. La detección de variables clínicas vinculadas a este fenómeno antes del inicio del procedimiento podría ayudar a la adopción de medidas preventivas y por consiguiente a mejorar los resultados. Objetivo Determinar predictores clínicos de no-reflujo en el contexto de la angioplastia por IAM con elevación del segmento ST antes del inicio del procedimiento. Material y métodos Se analizaron 742 pacientes con IAM de < 12 horas de evolución tratados con angioplastia primaria. Se excluyeron los pacientes con flujo epicárdico TIMI 0 posintervención y se consideró no-reflujo a la presencia de flujo TIMI 1-2 posangioplastia inmediato en ausencia de lesión residual. Se analizaron variables demográficas, factores de riesgo coronario, antecedentes y demora al tratamiento. Se realizó un análisis multivariado por regresión logística múltiple para determinar el valor pronóstico independiente de las variables relacionadas con el no-reflujo. Resultados Se incluyeron 675 pacientes. Presentaron fenómeno de no-reflujo 119 pacientes (17,6%). Los pacientes con no-reflujo tenían mayor edad (60,8 ± 12 vs. 57,0 ± 11 años; p = 0,0001) y menor frecuencia de tabaquismo activo (58,8% vs. 67,8%; p = 0,03) y de antecedentes familiares (22,7% vs. 37,8%; p = 0,0007), sin diferencias significativas en el resto de los factores de riesgo coronario y antecedentes cardiovasculares. Se observó también con mayor frecuencia localización anterior del IAM (58,8% vs. 43,7%; p = 0,002), signos clínicos de insuficiencia cardíaca al ingreso (17,6% vs. 10,1%; p = 0,01), así como mayor demora al tratamiento [240 (151-360) vs. 195 (120-302) minutos; p = 0,02]. El análisis multivariado determinó que los predictores independientes de no-reflujo fueron: edad > 60 años, localización anterior y demora al tratamiento > 3 horas. Conclusión La edad avanzada, la localización anterior y la demora al tratamiento resultaron predictores clínicos independientes de no-reflujo. La confirmación de estos hallazgos en estudios prospectivos permitiría implementar estrategias para prevenir su aparición y, eventualmente, mejorar los resultados clínicos a largo plazo.

Introduction The no-reflow phenomenon in the setting of primary coronary intervention for acute myocardial infarction (AMI) is relatively common and is associated with adverse outcomes. The detection of clinical variables associated with this phenomenon before the procedure might help to adopt preventive measures and thus improve the results. Objective The aim of this study was to identify clinical predictors of the no-reflow phenomenon in the setting of percutaneous coronary intervention for ST-segment elevation acute myocardial infarction, prior to the procedure. Methods A total of 742 patients with AMI < 12 hours since onset of symptoms treated with primary percutaneous coronary intervention were analyzed. Patients with epicardial TIMI grade 0 flow after the procedure were excluded. No-reflow was considered as the presence of TIMI grade 1-2 flow immediately after the procedure in the absence of residual stenosis. Demographic variables, coronary risk factors, family history and delay to reperfusion were analyzed. Multivariate logistic regression was used to determine the independent prognostic value of the variables associated with no-reflow. Results A total of 675 patients were included. The no-reflow phenomenon was present in 119 patients (17.6%). Patients with no-reflow were older (60.8 ± 12 vs. 57.0 ± 11 years; p = 0.0001) and had less prevalence of current smoking (58.8% vs. 67.8%, p = 0.03) and of previous history (22.7% vs. 37.8%, p = 0.0007), with no significant differences in the rest of coronary risk factors and history of cardiovascular disease. Anterior AMI (58.8% vs. 43.7%, p = 0.002), heart failure at admission (17.6% vs. 10.1%, p = 0.01) and delay to reperfusion (240 [151-360] vs. 195 [120-302] minutes, p=0.02) were more frequent in the no-reflow group. Multivariate analysis identified age > 60 years, anterior infarction and delay to reperfusion > 3 hours as independent predictors of no-reflow. Conclusion Advanced age, anterior infarction and delay to reperfusion were independent clinical predictors of no-reflow. The confirmation of these findings in prospective studies might allow the implementation of strategies to prevent this phenomenon and eventually improve the long-term clinical outcomes.

Resultados inmediatos y seguimiento a largo plazo de la valvuloplastia mitral percutánea / Immediate Outcomes and Long-Term Follow-Up of Percutaneous Mitral Valvuloplasty

Introducción El tratamiento de la estenosis mitral ha cambiado en las últimas décadas. Se ha demostrado que, frente al tratamiento quirúrgico, la valvuloplastia mitral percutánea (VMP) presenta resultados hemodinámicos comparables y una evolución similar. Objetivo Evaluar la eficacia y la evolución clínica y ecocardiográfica inmediata y a largo plazo de la VMP. Material y métodos Se incluyeron 132 pacientes que habían sido sometidos a VMP, con una mediana de seguimiento de 48 meses. Se consideró éxito primario cuando se obtuvo un área pos-VMP ≥ 1,5 cm². En el seguimiento se evaluaron: muerte, necesidad de reemplazo valvular mitral o de nueva VMP y reestenosis valvular. Resultados La media de edad fue de 44,6 años; el 88,5% de los pacientes (n = 115) eran de sexo femenino. La mediana del área valvular mitral pre-VMP era de 0,90 cm² (IIC 25-75: 0,81-1,00), la presión sistólica de la arteria pulmonar era de 44 mm Hg (IIC 25-75: 35-52) y el puntaje ecocardiográfico, de 7 (IIC 25-75: 6-9). Se obtuvo éxito primario en 104 pacientes (78,8%). En el seguimiento a 4 años, el 86,5% de los pacientes (n = 109) se encontraban asintomáticos. Se registraron tres muertes intrahospitalarias (2,2%) y tres en el seguimiento (2,2%). Se realizó una nueva VMP en 10 pacientes y reemplazo valvular mitral en cuatro. Las variables asociadas con reestenosis en el seguimiento fueron el puntaje ecocardiográfico > 8 (p = 0,04) y el área valvular mitral pos-VMP < 1,8 cm² (p = 0,02). Luego del análisis multivariado, el área valvular mitral pos-VMP < 1,8 cm² fue el único predictor de reestenosis (OR: 2,6; IC 95%: 1,08-6,25). Conclusiones La VMP es segura y eficaz, eficacia que se mantiene a largo plazo. Los mejores resultados inmediatos se obtienen en pacientes con puntaje ecocardiográfico bajo y en ritmo sinusal, mientras que aquellos con un área valvular mitral mayor pos-VMP son los que presentan menor reestenosis en el seguimiento.

Background The treatment of mitral valve stenosis has changed over the last decades. The hemodynamic results and the outcome of percutaneous mitral valvuloplasty (PMV) have proved to be comparable to those of surgical treatment. Objective To evaluate the efficacy and the immediate and long-term clinical and echocardiographic outcome of PMV. Methods A total of 132 patients undergoing PMV were included, with a median follow-up of 48 months. The primary success was defined as a mitral valve area of ≥ 1.5 cm² following PMV. Mortality, need for mitral valve replacement or new PMV and mitral valve restenosis were evaluated during follow-up. Results Mean age was 44.6 years; 88.5% of patients (n=115) were women. Median mitral valve area before PMV was 0.90 cm² (IQR 25-75: 0.81-1.00), systolic pulmonary artery pressure was 44 mm Hg (IQR 25-75: 35-52) and the echocardiographic score was 7 (IQR 25-75: 6-9). Primary success was achieved in 104 patients (78.8%). After four years of follow-up, 86.5% of patients (n=109) were free of symptoms. Three patients (2.2%) died during hospitalization and three (2.2%) during follow-up. A new PMV was performed in 10 patients and four patients underwent mitral valve replacement. During follow-up, an echocardiographic score of >8 (p=0.04) and a mitral valve area following PMV of 2 (p=0.02) were the variables associated with restenosis. After performing multivariate analysis, the only predictor associated with restenosis following PMV was a mitral valve area 2 (OR: 2.6; 95% CI: 1.08-6.25). Conclusions Percutaneous mitral valvuloplasty is a safe and efficient method with long-term efficacy. The best outcomes are achieved in patients with low echocardiographic score and who are in sinus rhythm, and those with greater mitral valve area following PMV have lower restenosis during follow-up.

Predictores de reperfusión miocárdica tisular luego de la angioplastia en el infarto agudo de miocardio / Predictors of Myocardial Tissue Reperfusion after Angioplasty in Acute Myocardial Infarction

Introducción La angioplastia primaria tiene una eficacia limitada ya que deja a un grupo considerable de pacientes sin lograr una reperfusión miocárdica tisular adecuada. Los factores clínicos, angiográficos y terapéuticos que influyen en el grado de reperfusión no han sido claramente establecidos. Objetivos Identificar los factores independientes asociados con la ausencia de reperfusión tisular luego de la angioplastia primaria. Material y métodos Se analizaron 140 pacientes incluidos prospectivamente en el estudio aleatorizado Protection of Distal Embolization in High-Risk Patients with Acute ST-Segment Elevation Myocardial Infarction Trial (PREMIAR). Este estudio evaluó la utilización de un filtro de protección distal durante la angioplastia en el infarto agudo de miocardio con supradesnivel del segmento ST en pacientes de alto riesgo trombótico (solamente incluyendo flujo coronario basal TIMI 0-2). El punto final primario fue la resolución completa del segmento ST a los 60 minutos, definida como disminución del ST ≥ 70% con el empleo de monitorización continua del segmento ST. Se desarrolló un modelo de regresión logística para identificar los predictores independientes. Resultados Se observó resolución completa del segmento ST a los 60 minutos luego de la angioplastia en 82 pacientes (63%), mientras que 53 pacientes (37%) presentaron resolución incompleta que se asoció con una tasa de mortalidad, reinfarto y/o insuficiencia cardíaca a los 30 días del 8,5% y 18,9%, respectivamente (p = 0,07). Los pacientes que no lograron una reperfusión tisular adecuada tuvieron con más frecuencia compromiso de localización anterior (79% versus 33%; p = 0,001), mayor frecuencia cardíaca (81 ± 20 versus 70 ± 15; p < 0,001) y menor proporción de fumadores actuales (25% versus 51%; p = 0,002) respecto de aquellos con reperfusión tisular óptima. Se observó además una tendencia a mayor presencia de diabetes (26% versus 16%; p = 0,13), mayor tiempo desde el inicio de los síntomas a la angioplastia (minutos) (217 ± 167 versus 182 ± 134; p = 0,19) y clase Killip > 1 (30% versus 17%; p = 0,07), respectivamente. El análisis multivariado demostró que el infarto de localización anterior (OR 8,22, IC 95% 3,67-18,4; p < 0,001) se asoció con ausencia de reperfusión completa, mientras que el uso de inhibidores de la glicoproteína IIb/IIIa (OR 4,21, IC 95% 1,34-13,22; p = 0,014) y el tabaquismo actual (OR 3,84, IC 95% 1,58-9,50; p = 0,003) se correlacionaron con una reperfusión completa. Conclusiones Una proporción considerable de pacientes sometidos a angioplastia primaria no logran una reperfusión tisular adecuada. Este fenómeno se asocia con peor pronóstico. La presencia de infarto de localización anterior se correlaciona con una extensión menor del grado de reperfusión tisular. Contrariamente, el tabaquismo actual y el uso de inhibidores de la glicoproteína IIb/IIIa se asocian con una reperfusión tisular más profunda luego de la angioplastia primaria.

Background The efficacy of primary angioplasty is limited due to the fact that a considerable number of patients do not achieve adequate levels of myocardial tissue perfusion. The degree of reperfusion depends on multiple clinical, angiographic and therapeutic factors. Objectives To identify the independent factors associated with the absence of myocardial tissue reperfusion after primary angioplasty. Material and Methods A total of 140 patients included in the Protection of Distal Embolization in High-Risk Patients with Acute ST-Segment Elevation Myocardial Infarction Trial (PREMIAR) were analyzed. This study evaluated the use of filter distal protection device during angioplasty in patients with acute STsegment elevation myocardial infarction at high risk of thrombosis (only including baseline TIMI grade 0-2 flow). The primary end point of the study was the rate of complete ST-segment resolution at 60 minutes, defined as ≥ 70% recovery compared with baseline during continuous ST-segment monitoring. A model of logistic regression was developed to identify independent predictors. Results Complete resolution of ST-segment deviation 60 minutes after angioplasty was observed in 82 patients (63%), while 53 patients (37%) presented partial ST-segment resolution which was associated with rates of mortality, reinfarction and/or heart failure at 30 days of 8.5% and 18.9%, respectively (p=0.07). The variables associated with absence of adequate myocardial tissue reperfusion were anterior infarction (79% versus 33%; p=0.001), higher heart rate (81±20 versus 70±15; p=0.001) and history of current smoking (25% versus 51%; p=0.002), compared to optimal tissue reperfusion. In addition, there was a trend towards greater prevalence of diabetes (26% versus 16%; p=0.13), longer time interval from the onset of symptoms to angioplasty (minutes) (217±167 versus 182±134; p=0.19) and Killip class >1 (30% versus 17%; p=0.07), respectively. Multivariate analysis demonstrated that anterior myocardial infarction was associated with absence of complete reperfusion (OR 8.22, 95% CI 3.67-18.4; p<0.001), while the use of glycoprotein IIb/IIIa inhibitors (OR 4.21, 95% CI 1.34-13.22; p=0.014) and current smoking (OR 3.84, 95% CI 1.58-9.50; p=0.003) correlated with complete reperfusion. Conclusions A considerable proportion of patients undergoing primary angioplasty do not achieve adequate myocardial tissue reperfusion. This phenomenon is associated with adverse outcomes. Anterior myocardial infarction correlates with less degree of tissue reperfusion. Conversely, current smoking and the use of glycoprotein IIb/IIIa inhibitors are associated with better tissue reperfusion after primary angioplasty.

Actividad inflamatoria en múltiples placas ateroscleróticas en pacientes fallecidos por infarto agudo de miocardio / Inflammatory Activity in Multiple Atherosclerotic Plaques of Patients Dying of Acute Myocardial Infarction

Introducción Estudios clínicos y anatomopatológicos sugieren que los procesos inflamatorios tienen un papel importante en la inestabilidad de la placa aterosclerótica, dado que en pacientes con síndromes coronarios agudos se observan infiltrados inflamatorios difusos en las arterias coronarias. Objetivos Evaluar y localizar la distribución de placas vulnerables e infiltrados inflamatorios en pacientes fallecidos por infarto agudo de miocardio. Material y métodos Mediante microscopia óptica se estudiaron las arterias coronarias de 58 pacientes fallecidos por infarto de miocardio. En las arterias coronarias relacionadas con el infarto y en las no relacionadas se registraron las siguientes variables: presencia de trombo, rotura de placa, hemorragia intraplaca y presencia de infiltrado inflamatorio. Resultados Al analizar las diferencias existentes entre las arterias responsables del infarto y en las no responsables se encontraron diferencias significativas con respecto a la presencia de trombo (69% versus 38%; p < 0,008) y de hemorragia intraplaca (69% versus 50%; p < 0,03). No se encontró una diferencia significativa entre la arteria responsable y la no responsable al evaluar la presencia de infiltrado inflamatorio en las placas ateroscleróticas (77% versus 71%; p = ns). Conclusión En el infarto agudo de miocardio se comprobó la presencia de actividad inflamatoria que afectaba a más de un vaso, con compromiso de otras arterias además de la responsable del infarto. Se detectó también accidente agudo de placa en más de una arteria coronaria.

Background Data from clinical and histopathologic studies suggest that inflammation plays a key role in instability of atherosclerotic plaque as patients with acute coronary syndromes present diffuse inflammatory infiltrates in the coronary arteries. Objectives To assess and locate the distribution of vulnerable plaques and inflammatory infiltrates in patients who died of acute myocardial infarction. Material and Methods We examined the coronary arteries from 58 patients who died of myocardial infarction using light microscopy. The following variables were evaluated in culprit and non-culprit coronary arteries: presence of thrombus, plaque rupture, intraplaque hemorrhage and inflammatory infiltrate. Results The presence of thrombus and intraplaque hemorrhage was significantly greater in culprit coronary arteries compared to non-culprit vessels (69% versus 38%; p<0.008, and 69% versus 50%; p<0.03, respectively). There were no significant differences in the presence of inflammatory infiltrates in atherosclerotic plaques from culprit and non-culprit coronary arteries (77% versus 71%; p=ns). Conclusion Inflammatory activity was demonstrated in acute myocardial infarction affecting not only the infarct-related artery but also other coronary vessels. Plaque accident was also present in more than one coronary artery.