Asociación de polimorfismos del gen factor de necrosis tumoral (TNF) con el desarrollo de reestenosis de stent post angioplastía coronaria / Polymorphisms of tumor necrosis factor gen: are they associated to stent restenosis after coronary angioplasty?

Introducción: La intervención coronaria percutánea (PCI en inglés) con implante de stent coronario es uno de los procedimientos más utilizados para la revascularización miocárdica en condiciones agudas o crónicas. Múltiples factores se han relacionado con la restenosis de stent, incluyendo aspectos clínicos, angiográficos, genéticos y epigenéticos. La respuesta inflamatoria en gran parte está determinada genéticamente y probablemente sea el rol más importante en la restenosis. El factor de necrosis tumoral a (TNF-α;) es un mediador clave en la respuesta inflamatoria actuando en sitios de injuria tisular inducida por el daño de las paredes del vaso. Objetivo: Determinar la asociación entre polimorfismos genéticos del TNF y restenosis en pacientes coronarios sometidos a angioplastía. Métodos: Se diseñó un estudio de casos y controles incidentes no pareados, aprobado por el comité de ética institucional. Se incluyeron pacientes con cardiopatía coronaria sometidos a PCI con implante de stent BMS o DES, con un tiempo de control angiográfico mayor de 6 meses. Los casos fueron definidos como aquellos pacientes con estenosis de stent >50% y como controles aquellos con estenosis <50%, con respecto del lumen del vaso de referencia. Se efectuó la genotipificación de los polimorfismos rs361525 (-238G/A) y rs1799964 (-1031 T/C) del gen TNF mediante PCR en tiempo real mediante sondas alelo-específicas. Además, se registraron variables clínicas y demográficas. Resultados: Se incluyó en este estudio de análisis de genotipificación del polimorfismo del gen TNF 82 pacientes como casos, y 102 controles. No hubo diferencias significativas en las siguientes variables clínicas y demográficas: edad (63.7 ± 10.5 vs. 65.4 ± 9.6 años; p=0.24), género masculino (75 vs. 69%, p=0.5), IMC (28.5 ± 3.6 vs. 28 ± 3.8 Kg/m2; p=0.78) y tabaquismo (79 vs. 77%; p=0.7). En contraste, se observó una diferencia significativa en la frecuencia de DM-2 casos y controles (43.2 vs. 26.5%; p=0.03) y %HbA1c entre ambos grupos (6.78 ± 1.5 vs. 6.1 ± 0.8%; p=0.01). Respecto a las variantes genéticas estudiadas, no hubo diferencias significativas en la frecuencia relativa del alelo mutado tanto para el polimorfismo rs361525 (Alelo A, casos: 0.06 vs. controles: 0.08; p=0.37), como para la variante rs1799964 (Alelo C, casos: 0.2 vs. controles: 0.2; p=0.96). Las OR asociadas a dichos alelos fueron 0.68 (I.C. 95%= 0.29 - 1.59) y 0.99 (I.C. 95%= 0.58 - 1.67), respectivamente; confirmando la ausencia de asociación. Conclusión: Nuestros datos sugieren que las variantes genéticas estudiadas no están relacionadas al desarrollo de restenosis en los sujetos estudiados, y probablemente en nuestra población los factores clínicos sean más determinantes para el desarrollo de reestenosis coronaria post angioplastía que los factores genéticos.

Multiple factors have been associated to the development of stent restenosis after coronary angioplasty (PCA). including clinical, angiographic, genetic and epigenetic factors. The inflammatory response is genetically determined and it may be the most important factor. Tumor necrosis factor a (TNFα) is a potent mediator of this response at the endothelial wall. Aim: To determine the association between TNFα; genetic polymorphisms and stent restenosis. Methods: A case-control study was performed in patients submitted to PTCA with stent implantation(-bare metal or drug eluting stent) at least 6 months prior to the study. Cases were defined by the presence of >50% intra stent stenosis. PCR was used for type classification of polymorphisms rs361525 (-238G/A) y rs1799964 (-1031 T/C) of the TNFα; gene. Results: 82 cases and 102 controls were included. No differences were observed in clinical and demographic variables: age (63.7 ± 10.5 vs. 65.4 ± 9.6 years, p=0.24, for cases and controls, respectively), male gender (75 vs. 69%, p=0.5), BMI (28.5 ± 3.6 vs. 28 ± 3.8 Kg/m2, p=0.78) and active smoking (79 vs. 77%, p=0.7). In contrast, Diabetes was more frequent in cases than in controls (43.2 vs. 26.5%, p=0.03). There was no difference in the relative frequency of mutations of the rs361525 polymorphism (Allele A, 0.06 vs 0.08, p=0.37 for cases and controls, respectively) nor for variant rs1799964 (0.2 in both cases and controls). Non significant associations were confirmed by Odd ratios with 0 included in the 95% confidence interval. Conclusion: No association of genetic polymorphisms of TNFa and stent restenosis was found, which suggests that clinical factors my be more important for the development of post PTCA stent restenosis.

Estudo clínico, angiográfico, de procedimento e polimorfismos: eventos maiores e reestenose após intervenção coronariana percutânea / Clinical and angiographic study of procedures and polymorphisms: major events and restenosis after percutaneous coronary intervention

Fundamentos: Diferenças genéticas são encontradas entre os indivíduos com coronárias normais e os coronariopatas. Há fatores de risco para eventos e reestenose após intervenção coronariana percutânea(ICP).Objetivos: Comparar a frequência genotípica de pacientes com coronárias normais com coronariopatas. Avaliar as características clínicas, angiográficas, de procedimento e genéticas, resultados e evolução com eventos ou reestenose e possíveis fatores de risco. Métodos: Estudo prospectivo, não randomizado, envolvendo 182 pacientes submetidos à ICP de outubro2001 a dezembro 2007 e 36 pacientes com coronárias normais, para avaliação dos resultados, da evolução clínica e dos polimorfismos da ECA I/D e do AT1R A/C.Resultados: Estudados 182 pacientes: 26,9% femininos e 73,1% masculinos, submetidos a 221 procedimentos de ICP. A frequência do genótipo AT1R dos pacientes foi AA=74,2%, AC=23,1% e CC=2,7%, sendo diferente esignificativa em relação ao grupo-controle (p=0,0026). O tempo de evolução foi 22±11 (2 a 60) meses. Nos grupos com e sem reestenose encontrou-se diâmetro de referência de 2,81±0,60mm e 2,80±0,52mm, respectivamente (p=0,8556) e extensão da lesão 17,1±6,6mm e 15,8±8,8mm(p=0,4494). Houve reestenose em 29 (13,48%) dos procedimentos. Não houve associação dos genótipos da ECA e AT1R com óbito, revascularização, infarto do miocárdio e reestenose após ICP. Conclusões: Entre o grupo-controle e o de coronariopatas houve diferença significativa quanto à frequência do polimorfismo AT1R. Não houve diferença entre reestenose clínica comprovada angiograficamente, dados da angiografia quantitativa e polimorfismos AT1R e ECA. Não houve diferença entre os polimorfismos AT1R e ECA e sobrevida e sobrevida livre de eventos maiores e reestenose.

Background: There are genetic differences between patients with coronary artery disease (CAD) and normal coronary arteries. There are risk factors for events and restenosis after percutaneous coronary intervention(PCI).Objectives: To compare the genotype frequency of patients with normal coronary arteries with CAD patients, evaluating clinical, angiographic, procedural and genetic characteristics, outcomes, and progress with events or restenosis, and possible risk factors. Methods: Prospective non-randomized study of 182 patients undergoing PCI from October 2001 to December 2007 and 36 patients with normal coronary arteries, inorder to evaluate outcomes, clinical progress and ACEI/D and AT1R A/C polymorphisms. Results: A total of 182 patients were evaluated, 26.9% female and 73.1% male, undergoing 221 PCI procedures.The frequency of AT1R genotype in patients was:AA=74.2%, AC=23.1% e CC=2.7%, which was significantly different from the control group (p=0.0026). The progression period was 22±11 (2-60) months. Reference diameters were 2.81±0.60 and 2.80±0.52mm with lesion lengths of 17.1±6.6mm and 15.8±8.8mm in the groups with and without restenosis respectively. Restenosis tookplace in 29 (13.48 %) of the procedures. There was no association between death and ACE I/D and AT1R A/C, nor revascularization, myocardial infarction and restenosis after PCI. Conclusions: There was a significant difference between the control group and the CAD patients for the genoty pefrequency of AT1R polymorphism, with no difference noted between angiographically documented clinical restenosis, quantitative angiographic data and AT1R and ACE polymorphisms. No difference was noted between AT1R and ACE polymorphisms and survival, major event-free survival and restenosis.

The MHC2TA gene polymorphisms are not associated with restenosis after coronary stenting in Mexican patients / Los polimorfismos del gen MHC2TA no se asocian con la reestenosis después del implante de stent coronario en pacientes mexicanos

Objective: The aim of this study was to test for association between MHC2TA gene polymorphisms and risk for restenosis after coronary stent placement in a group of Mexican patients. Methods: The MHC2TA-168A>G (rs3087456), 1614C>G (rs4774), and 2536G>A (rs2229320) single nucleotide polymorphisms were genotyped using 5' exonuclease TaqMan genotyping assays in a group of 202 patients, who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed, looking for angiographic predictors of restenosis and follow-up angiography was performed to screen for binary restenosis. Results: The results obtained in this study showed that the frequency of the three polymorphisms studied was similar in patients with and without restenosis. Univariate analysis showed that the use of drug-eluting stent (DES) reduces the risk of developing restenosis (p < 0.001, OR = 0.26). In contrast, the diameter< 2.5 mm of the stent and bifurcations increased the risk of developing restenosis (p = 0.049, OR = 1.74 and p = 0.041, OR = 1.8). Conclusion: The present study suggests that the MHC2TA polymorphisms are not involved in the risk of developing restenosis after coronary stent placement.

Objetivo: El propósito de este estudio fue evaluar la asociación de los polimorfismos del gen MHC2TA y el riesgo de desarrollar reestenosis, después del implante de stent coronario en un grupo de pacientes mexicanos. Métodos: Los polimorfismos de un solo nucleótido MHC2TA-168A>G (rs3087456), 1614C>G (rs4774) y 2536G>A (rs2229320), se determinaron en un grupo de 202 pacientes tratados con stent coronario. Los polimorfismos fueron evaluados utilizando ensayos de genotipificacion Taq-Man 5' exonucleasa. El procedimiento basal y la búsqueda de predictores de reestenosis fueron analizados por medio de angiografía coronaria, y seguimiento angiográfico con el fin de detectar reestenosis binaria. Resultados: Los resultados obtenidos en este estudio mostraron que la distribución génica de los tres polimorfismos estudiados fue muy similar, en pacientes con o sin reestenosis. Sin embargo, el análisis univariado mostró que el uso de los stent medicados reducen el riesgo de desarrollar reestenosis (p < 0.001, OR = 0.26). En contraste, con las bifurcaciones y el diámetro < 2.5 mm del stent que se incrementa el riesgo de desarrollar reestenosis (p = 0.049, OR = 1.74 y p = 0.041, OR = 1.8). Conclusión: El presente estudio sugiere que los polimorfismos del gen MHC2TA no están asociados con el riesgo de desarrollar reestenosis, después del implante de stent coronario.

Expressão gênica de adiponectina no tecido adiposo epicárdico após intervenção coronária percutânea com implante de stent metálico / Adiponectin expression in epicardial adipose tissue after percutaneous coronary intervention with bare-metal stent

INTRODUÇÃO: A visão clássica de tecido adiposo como um reservatório passivo para o armazenamento de energia não é mais válido. Na última década, o tecido adiposo tem demonstrado funções endócrinas, sendo o peptídeo mais abundante secretado pelos adipócitos a adiponectina. O tecido adiposo epicárdico (TAE) é distribuído em torno das artérias coronárias e, a lesão endovascular causada pela presença de stent metálico intracoronário, poderia promover alterações inflamatórias na gordura periadventicial, contribuindo para reestenose. OBJETIVO: Determinar a expressão gênica de mediadores inflamatórios no tecido adiposo epicárdico após implante de stent metálico com reestenose que haviam sido encaminhados para tratamento cirúrgico. MÉTODOS: Amostras pareadas de TAE foram colhidas no momento da cirurgia de revascularização miocárdica (CRM) em 11 pacientes (n = 22), uma amostra foi obtida do tecido em torno da area com stent e outra amostra em torno da artéria coronária sem stent. Expressão local de adiponectina foi determinada por reação em cadeia de polymerase em tempo real utilizando Taq DNA polimerase. RESULTADOS: Em duas amostras, não houve expressão do gene da adiponectina. Fomos capazes de identificar adiponectina em 20 amostras, no entanto, o padrão de expressão gênica foi heterogêneo. Não percebemos especificidade quando comparamos TAE obtido próximo à área de stent ou distante da área de stent. CONCLUSÃO: Não houve correlação entre a expressão do gene de adiponectina e a presença de stent intracoronário.

BACKGROUND: The classical view of adipose tissue as a passive reservoir for energy storage is no longer valid. In the past decade, adipose tissue has been shown to have endocrine functions and the most abundant peptide secreted by adipocytes is adiponectin. Pericardial adipose tissue (PAT) is distributed around coronary arteries and endovascular injury, caused by the presence of intracoronary bare-metal stent (BMS), could promote inflammatory changes in the periadvential fat, contributing to vascular restenosis. OBJECTIVE: We sought to determine gene expression of inflammatory mediator in pericardial adipose tissue after bare-metal stent implantation and vascular restenosis that had been referred to operative treatment. METHODS: Paired samples of PAT were harvested at the time of elective coronary artery bypass surgery (CABG) in 11 patients (n=22), one sample was obtained of the tissue around BMS area and another sample around coronary artery without stent. Local expression of adiponectin was determined by real-time polymerase chain reaction (RT-PCR) using Taq DNA polymerase. RESULTS: In two samples, there was no gene expression of adiponectin. We are able to identify adiponectin in 20 samples, however, the pattern of gene expression were heterogeneous.We did not notice specificity when we compared PAT obtained near BMS area or far from BMS area. CONCLUSION: There were no correlation between adiponectin gene expression and presence of BMS.

Relation of angiotensin converting enzyme activity and gene polymorphism to restenosis after percutaneous transluminal coronary angioplasty

Early restenosis in up to 30% of cases limits the benefits of percutaneous transluminal coronary angioplasty [PTCA]. The mechanisms that underlie restenosis are uncertain, although experimental evidence suggests that the renin-angiotensin system is involved in the vascular response to angioplasty. The ACE gene is one of the major genes of the renin-angiotensin and kallikrein-kinin systems and is a candidate gene for several cardiovascular diseases for which a genetic predisposition has been established. The ACE gene contains a common insertion deletion polymorphism termed I and D, respectively. The three possible genotypes are DD, ID and II, and the plasma level of ACE is highest with the DD genotype. This work aimed to investigate whether ACE gene polymorphism influences the risk of restenosis after PTCA to explore a relation between the total ACE level and restenosis and to compare the ACE genotypes of the patients of the study with those of a control group of healthy subjects. This study included 53 patients with CAD, 48 males and 5 females, their age ranged from 36 to 63 years. All patients were compared to 46 control subjects with age and sex matched. The patients were divided into two groups: group [A][40 patients with no restenosis] and group [B][13 patients with restenosis]. All patients were subjected to: full history and clinical examination, laboratory investigations which include estimation of serum angiotensin converting enzyme levels and detection of genotypes of the ACE gene I/D polymorphism, 12-lead electrocardiogram, treadmill exercise stress testing, coronary angiography and PTCA. The distribution of ACE genotype [DD] was not significantly different in-group B patients with restenosis compared with group A patients with no restenosis [8 out of 13, versus 15 out of 40 respectively, P> 0.05]. Plasma ACE levels did not differ between patients and control subjects [P value > 0.05]. Although plasma ACE levels were significantly higher in relation to ACE genotypes [P value < 0.05], plasma ACE levels were insignificant in relation to restenosis [P value > 0.05]. Since there was no evidence that variation at the ACE gene defined by the I/D polymorphism influences the extent of restenosis, it could be concluded that determination of ACE I/D genotypes is unlikely to be useful in identifying patients at higher risk of restenosis after PTCA and continued studies with clinically different subsets of patients is warranted