ABSTRACT
CONTEXT AND OBJECTIVES: Glycoprotein inhibitors (abciximab, eptifibatide and tirofiban) are used in patients with unstable angina and non-ST-segment elevation myocardial infarction before percutaneous coronary intervention. Of these, tirofiban is the least effective. We hypothesized that the response to tirofiban might be associated with glycoprotein gene mutations. DESIGN AND SETTING: Prospective study at Emergency Unit, Heart Institute (InCor), University of São Paulo. METHOD: Intrahospital evolution and platelet aggregation in response to tirofiban were analyzed in relation to four glycoprotein mutations in 50 patients indicated for percutaneous coronary intervention: 17 (34%) with unstable angina and 33 (66%) with non-ST-segment elevation myocardial infarction. Platelet aggregation was analyzed using the Born method. Blood samples were obtained before and one hour after tirofiban infusion. Glycoproteins Ia (807C/T ), Ib (Thr/Met) , IIb (Ile/Ser ) and IIIa (PIA ) were the mutations selected. RESULTS: Hypertension, dyslipidemia, diabetes, smoking, previous coronary artery disease and stroke were similar between the groups. Mutant glycoprotein IIIa genotypes had lower platelet aggregation before tirofiban administration than that of the wild genotype (41.0% ± 22.1% versus 55.9% ± 20.8%; P = 0.035). Mutant glycoprotein IIIa genotypes correlated moderately with lower platelet inhibition (r = -0.31; P = 0.030). After tirofiban administration, platelet glycoprotein Ia, Ib, IIb and IIIa mutations did not influence the degree of inhibition of platelet aggregation or intrahospital mortality. CONCLUSIONS: Mutations of glycoproteins Ia, Ib, IIb and IIIa did not influence platelet aggregation in response to tirofiban in patients with unstable angina and non-ST-segment elevation myocardial infarction.
RESUMO CONTEXTO E OBJETIVOS: Inibidores da glicoproteína (abciximab, eptifibatide, tirofiban) são utilizados em pacientes com angina instável e infarto do miocárdio sem elevação do segmento ST (IAMSSST) antes da intervenção coronária percutânea. Dentre eles, o tirofiban é o menos eficaz. Nossa hipótese é que a resposta ao tirofiban possa estar associada a mutações no gene da glicoproteína. DESENHO E LOCAL: Estudo prospectivo na Unidade de Emergência do Instituto do Coração (InCor), Universidade de São Paulo (USP). MÉTODOS: Foram analisadas a evolução intra-hospitalar e agregabilidade plaquetária em resposta ao tirofiban de 4 mutações da glicoproteína em 50 pacientes com indicação para intervenção coronária percutânea, 17 (34%) com angina instável e 33 (66%) com IAMSSST. A agregação plaquetária foi analisada pelo método de Born. Amostras de sangue foram obtidas antes e uma hora após infusão do tirofiban. As glicoproteínas Ia (807C/T ), Ib (Thr/Met ), IIb (Ile/Ser ) e IIIa (PIA ) foram as mutações selecionadas. RESULTADOS: Hipertensão, dislipidemia, diabetes, tabagismo, doença coronariana e acidente vascular cerebral prévios foram semelhantes entre os grupos. Observou-se menor agregabilidade plaquetária dos genótipos mutantes da glicoproteína IIIa antes da administração de tirofiban do genótipo selvagem (41% ± 22% versus 56% ± 21%; P = 0,035). Genótipos mutantes da glicoproteína IIIa correlacionaram-se moderadamente com menor inibição plaquetária (r = -0,31; P = 0,030). Após a administração tirofiban, as mutações das glicoproteínas Ia, Ib, IIb, e IIIa não influenciaram o grau de inibição da agregação plaquetária e mortalidade intra-hospitalar. CONCLUSÕES: Mutações das glicoproteínas Ia, Ib, IIb e IIIa não influenciaram a agregação plaquetária em resposta ao tirofiban nos pacientes com angina instável e IAMSSST.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Tyrosine/analogs & derivatives , Platelet Aggregation Inhibitors/therapeutic use , Platelet Membrane Glycoproteins/genetics , Acute Coronary Syndrome/drug therapy , Mutation , Peptides/therapeutic use , Tyrosine/therapeutic use , Immunoglobulin Fab Fragments/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation/genetics , Polymerase Chain Reaction , Prospective Studies , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Platelet Glycoprotein GPIIb-IIIa Complex/genetics , Acute Coronary Syndrome/genetics , Abciximab , Tirofiban , Eptifibatide , Genotype , Angina, Unstable/genetics , Angina, Unstable/drug therapy , Antibodies, Monoclonal/therapeutic useABSTRACT
La enfermedad arterial coronaria (EAC) es la primera causa de muerte en todo el mundo y representa un problema de salud pública en México. El infarto agudo del miocardio (IAM) representa la principal complicación trombótica de la EAC. Aproximadamente 9 % de los nuevos casos está constituido por sujetos menores de 45 años. El IAM se produce por el desarrollo de un trombo en el sitio de la placa aterosclerosa, generando oclusión arterial súbita con isquemia y muerte celular. El IAM resulta de la interacción entre factores genéticos y ambientales. Existen diversos factores de riesgo modificables como la hipertensión arterial, la diabetes mellitus, el tabaquismo, la obesidad y la hipercolesterolemia asociados con el IAM. Sin embargo, numerosos pacientes con IAM no presentan factores de riesgo modificables. En la última década se han identificado variantes genéticas en las proteínas relacionadas con los sistemas de coagulación y fibrinólisis, receptores plaquetarios, disfunción endotelial, flujo sanguíneo anormal, metabolismo de la homocisteína, estrés oxidativo, los cuales se asocian a desarrollo del IAM. La identificación de los polimorfismos asociados a la enfermedad arterial coronaria permitirá desarrollar mejores estrategias de tratamiento e identificación de individuos con alto riesgo para EAC y medidas preventivas en etapas tempranas.
BACKGROUND: Coronary artery disease (CAD) is the first cause of death worldwide and represents a public health issue in our country. Acute myocardial infarction (AMI) represents the main thrombotic complication of CAD. Approximately 9% of the new events of MI occur in patients <45 years of age. DISCUSSION: AMI is produced by development of a thrombus at the site of an atherosclerotic plaque that initiates abrupt arterial occlusion, with ischemia and cell death. AMI results from the interaction of gene-environment factors. There are several modifiable factors such as hypertension, diabetes, smoking, obesity, and hypercholesterolemia associated with AMI. However, in a large number of patients with AMI, modifiable risk factors are not present. In the last decade, several genetic variants (polymorphisms) have been identified associated with AMI in genes related to coagulation proteins, fibrinolytic system, platelet receptors, homocysteine metabolism, endothelial dysfunction, abnormal blood flow and oxidative stress. CONCLUSIONS: Identifying the genes associated with CAD will allow us to develop more efficacious treatment strategies and will also help to identify at-risk subjects, thereby enabling the introduction of early preventive measures. Thus, many research efforts continue to address the identification of acquired and inherited risk factors of this complex disease.