Regional QT Interval Dispersion as an Early Predictor of Reperfusion in Patients with Acute Myocardial Infarction after Fibrinolytic Therapy / A Dispersão do Intervalo QT Regional como Preditor Precoce de Reperfusão em Pacientes com Infarto Agudo do Miocárdio Pós-terapia Fibrinolítica

Abstract Background: Patients with ST-elevation acute myocardial infarction attending primary care centers, treated with pharmaco-invasive strategy, are submitted to coronary angiography within 2-24 hours of fibrinolytic treatment. In this context, the knowledge about biomarkers of reperfusion, such as 50% ST-segment resolution is crucial. Objective: To evaluate the performance of QT interval dispersion in addition to other classical criteria, as an early marker of reperfusion after thrombolytic therapy. Methods: Observational study including 104 patients treated with tenecteplase (TNK), referred for a tertiary hospital. Electrocardiographic analysis consisted of measurements of the QT interval and QT dispersion in the 12 leads or in the ST-segment elevation area prior to and 60 minutes after TNK administration. All patients underwent angiography, with determination of TIMI flow and Blush grade in the culprit artery. P-values < 0.05 were considered statistically significant. Results: We found an increase in regional dispersion of the QT interval, corrected for heart rate (regional QTcD) 60 minutes after thrombolysis (p = 0.06) in anterior wall infarction in patients with TIMI flow 3 and Blush grade 3 [T3B3(+)]. When regional QTcD was added to the electrocardiographic criteria for reperfusion (i.e., > 50% ST-segment resolution), the area under the curve increased to 0.87 [(0.78-0.96). 95% IC. p < 0.001] in patients with coronary flow of T3B3(+). In patients with ST-segment resolution >50% and regional QTcD > 13 ms, we found a 93% sensitivity and 71% specificity for reperfusion in T3B3(+), and 6% of patients with successful reperfusion were reclassified. Conclusion: Our data suggest that regional QTcD is a promising non-invasive instrument for detection of reperfusion in the culprit artery 60 minutes after thrombolysis.

Resumo Fundamento: Pacientes com infarto do miocárdico com elevação do segmento-ST atendidos em centros de atendimento primário e tratados de acordo com a estratégia fármaco-invasiva são submetidos à fibrinólise seguida de coronariografia em período de 2-24h. Neste cenário, o conhecimento de marcadores de reperfusão como a redução em 50% do segmento-ST é fundamental. Objetivo: Analisar o desempenho da dispersão do intervalo QT em adição aos critérios clássicos, como marcador precoce de reperfusão pós-terapia trombolítica. Métodos: Estudo observacional com a inclusão de 104 pacientes tratados com tenecteplase (TNKase) e referenciados a hospital de atendimento terciário. A análise dos eletrocardiogramas (ECG) consistiu em mensuração do intervalo QT e sua dispersão nas 12 derivações, e também apenas na região com supradesnivelamento-ST antes e 60min pós-TNKase. A angiografia foi realizada em todos os pacientes com obtenção do fluxo TIMI e Blush da artéria culpada. Foram considerados significantes valores de p < 0,05. Resultados: Observamos aumento da dispersão do intervalo QT, corrigido pela frequência cardíaca, regional (dQTcR) 60min pós-lise (p = 0,006) em infartos de parede anterior nos casos com fluxo TIMI 3 e Blush 3 [T3B3(+)]. Adicionando a dQTcR ao critério ECG (redução do ST > 50%) de reperfusão, a área sob a curva aumentou para 0,87 [(0,78-0,96), IC95%, p < 0,001] em pacientes com fluxo coronário T3B3(+). Nos pacientes com critério de ECG para reperfusão e dQTcR > 13 ms a sensibilidade e especificidade foram 93% e 71%, respectivamente, para reperfusão em T3B3(+), possibilitando reclassificar 6% dos pacientes com sucesso de reperfusão. Conclusão: Os dados sugerem a dQTcR como instrumento promissor na identificação não invasiva de reperfusão na artéria coronária culpada, 60min pós-trombólise.

Regional QT Interval Dispersion as an Early Predictor of Reperfusion in Patients with Acute Myocardial Infarction after Fibrinolytic Therapy.

BACKGROUND: Patients with ST-elevation acute myocardial infarction attending primary care centers, treated with pharmaco-invasive strategy, are submitted to coronary angiography within 2-24 hours of fibrinolytic treatment. In this context, the knowledge about biomarkers of reperfusion, such as 50% ST-segment resolution is crucial. OBJECTIVE: To evaluate the performance of QT interval dispersion in addition to other classical criteria, as an early marker of reperfusion after thrombolytic therapy. METHODS: Observational study including 104 patients treated with tenecteplase (TNK), referred for a tertiary hospital. Electrocardiographic analysis consisted of measurements of the QT interval and QT dispersion in the 12 leads or in the ST-segment elevation area prior to and 60 minutes after TNK administration. All patients underwent angiography, with determination of TIMI flow and Blush grade in the culprit artery. P-values < 0.05 were considered statistically significant. RESULTS: We found an increase in regional dispersion of the QT interval, corrected for heart rate (regional QTcD) 60 minutes after thrombolysis (p = 0.06) in anterior wall infarction in patients with TIMI flow 3 and Blush grade 3 [T3B3(+)]. When regional QTcD was added to the electrocardiographic criteria for reperfusion (i.e., > 50% ST-segment resolution), the area under the curve increased to 0.87 [(0.78-0.96). 95% IC. p < 0.001] in patients with coronary flow of T3B3(+). In patients with ST-segment resolution >50% and regional QTcD > 13 ms, we found a 93% sensitivity and 71% specificity for reperfusion in T3B3(+), and 6% of patients with successful reperfusion were reclassified. CONCLUSION: Our data suggest that regional QTcD is a promising non-invasive instrument for detection of reperfusion in the culprit artery 60 minutes after thrombolysis.

Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease.

BACKGROUND: Metabolic syndrome (MS) is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. OBJECTIVES: To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS). METHODS: Patients (n = 116, 68% males) aged 56 (9) years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1), methylenotetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (ENOS), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), apolipoprotein C3 (APOC3), lipoprotein lipase (LPL) were analysed by polymerase chain reaction (PCR) technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. RESULTS: Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 ± 1.5 vs. 13.0 ± 1.6, p = 0.066), with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078). CONCLUSIONS: The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease.

Association of Multiple Genetic Variants with the Extension and Severity of Coronary Artery Disease / Associação de Múltiplas Variantes Genéticas com a Extensão e Gravidade da Doença Coronária

Abstract Background: Metabolic syndrome (MS) is a condition that, when associated with ischemic heart disease and cardiovascular events, can be influenced by genetic variants and determine more severe coronary atherosclerosis. Objectives: To examine the contribution of genetic polymorphisms to the extension and severity of coronary disease in subjects with MS and recent acute coronary syndrome (ACS). Methods: Patients (n = 116, 68% males) aged 56 (9) years, with criteria for MS, were prospectively enrolled to the study during the hospitalization period after an ACS. Clinical and laboratory parameters, high-sensitivity C-reactive protein, thiobarbituric acid reactive substances, adiponectin, endothelial function, and the Gensini score were assessed. Polymorphisms of paraoxonase-1 (PON-1), methylenotetrahydrofolate reductase (MTHFR), endothelial nitric oxide synthase (ENOS), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), apolipoprotein C3 (APOC3), lipoprotein lipase (LPL) were analysed by polymerase chain reaction (PCR) technique, followed by the identification of restriction fragment length polymorphisms (RFLP, and a genetic score was calculated. Parametric and non-parametric tests were used, as appropriate. Significance was set at p < 0.05. Results: Polymorphisms of PON-1, MTHFR and ENOS were not in the Hardy-Weinberg equilibrium. The DD genotype of LPL was associated with higher severity and greater extension of coronary lesions. Genetic score tended to be higher in patients with Gensini score < P50 (13.7 ± 1.5 vs. 13.0 ± 1.6, p = 0.066), with an inverse correlation between genetic and Gensini scores (R = -0.194, p = 0.078). Conclusions: The LPL polymorphism contributed to the severity of coronary disease in patients with MS and recent ACS. Combined polymorphisms were associated with the extension of coronary disease, and the lower the genetic score the more severe the disease.

Resumo Fundamento: A síndrome metabólica (SM) é condição que, associada à doença coronária e a eventos cardiovasculares, pode ser influenciada por variantes genéticas, determinando maior gravidade da aterosclerose coronária. Objetivos: Avaliar a contribuição de polimorfismos genéticos para a extensão da doença coronária em indivíduos com SM e recente síndrome coronária aguda (SCA). Métodos: Pacientes (n = 116, 68% homens) com 56 (9) anos e critérios para SM foram prospectivamente selecionados no período de hospitalização após uma SCA. Parâmetros clínicos e laboratoriais, proteína C-reativa ultrassensível, substâncias reativas ao ácido tiobarbitúrico, adiponectina, função endothelial e o escore de Gensini foram analisados. Os polimorfismos da paraoxonase-1 (PON-1), metilenotetrahidrofolato redutase (MTHFR), óxido nítrico sintase endotelial (ENOS), enzima conversora da angiotensina (ECA), receptor tipo 1 da angiotensina II (AT1R), apolipoproteína C3 (APOC3), lipoproteína lipase (LPL) foram analisados por reação em cadeia da polimerase (PCR) seguida da identificação dos polimorfismos no comprimento do fragmento de restrição (RFLP), criando-se um escore genético. Testes paramétricos e não-paramétricos foram utilizados, conforme apropriado, com p < 0,05 considerado como significativo. Resultados: Os polimorfismos da PON-1, MTHFR e ENOS não estavam em equilíbrio de Hardy-Weinberg. O genótipo DD da LPL associou-se com lesões coronarianas mais graves e extensas. O escore genético tendeu a ser maior nos pacientes com escore de Gensini < P50 (13,7 ± 1,5 vs. 13,0 ± 1,6, p = 0,066), com correlação inversa entre o escore genético e o de Gensini (R = -0,194, p = 0,078). Conclusões: O polimorfismo da LPL associou-se à maior gravidade da doença coronária em pacientes com SM e SCA. Combinação de polimorfismos genéticos associou-se à extensão da doença coronariana, sendo a doença mais grave quanto menor o escore genético.

Efeitos da terapia combinada atorvastatina e clopidogrel na biodisponibilidade da estatina e na função plaquetária em pacientes com doença coronária estável / Effects of the artovastatin and clopidogrel combination therapy on station bioavailability and platelet function of patients with stable coronary disease

Introdução: Atorvastatina 80 mg é recomendada a pacientes portadores de doença coronária para redução de eventos cardiovasculares, havendo controvérsia sobre as interações farmacocinéticas entre doses elevadas das estatinas e uso concomitante de clopidogrel, por compartilharem a mesma via de biotransformação. Este estudo avaliou os efeitos da terapia combinada atorvastatina/clopidogrel na farmacocinética da estatina e função plaquetária em pacientes com doença coronária estável, sob uso crônico e efetivo de estatina. Método: Os pacientes foram admitidos quatro vezes para internação (V1 a V4) em leito-dia. Sete dias (D) antes da primeira internação a estatina em uso foi suspensa. A seguir, receberam atorvastatina 80 mg (D1 a D22) e clopidogrel 75 mg/dia (D8 a D29). Em todas as V foram obtidas amostras de sangue em jejum para dosagens lipídicas, avaliação da função plaquetária (técnica da placa e cone) e quantificação dos níveis plasmáticos de atorvastatina (cromatografia líquida e espectrometria de massa). Resultados: A suspensão por uma semana da estatina modificou o perfil lipídico (P < 0,05 vs. basal), ocorrendo rápida melhora de todas as frações lipídicas após atorvastatina 80 mg (P < 0,005; V1 > V2, V3 e V4). A adesão plaquetária foi menor com clopidogrel isolado (P = 0,003; V4 < V1, V2 e V3), enquanto para a agregação houve menor valor com tratamento combinado atorvastatina/clopidogrel ou clopidogrel isolado comparado aos demais períodos (P < 0,0001; V3 e V4 < V1 e V2). O clopidogrel não modificou as concentrações de atorvastatina. Conclusão: Atorvastatina em alta dose não afetou as meias respostas plaquetárias ao clopidogrel; entretanto, curto período de suspensão da estatina piorou o perfil lipídico e a função plaquetária.

Background: Atorvastatin 80 mg is recommended in patientswith coronary artery disease to reduce cardiovascular events, however, there is controversy regarding the pharmacokinetic interactions between high doses of statins and the concomitant use of clopidogrel, since they share the same biotransformation pathway. This study evaluated theeffects of the atorvastatin/clopidogrel combination therapy on the pharmacokinetics of statins and on platelet function of patients with stable coronary artery disease receivingchronic statins. Method: Patients were admitted four times (V1 to V4) to a day-clinic. Statin was discontinued sevendays (D) before the first admission. Patients then received atorvastatin 80 mg (D1 to D22) and clopidogrel 75 mg/day (D8 to D29). Fasting blood samples were obtained at all time points for lipid measurements, platelet function tests (cone and plate technique), and quantification of atorvastatin plasma levels (liquid chromatography and mass spectrometry). Results: The discontinuation of statins for one weekchanged the lipid profile (P < 0.05 vs. baseline), with an early improvement of all lipid parameters after the administration of atorvastatin 80 mg (P < 0.005; V1 > V2, V3 and V4). Platelet adhesion was lower with clopidogrel alone (P = 0.003; V4 < V1, V2 and V3), whereas platelet aggregation values were lower following the atorvastatin/clopidogrel combination therapy or clopidogrel alone when compared to the other time points (P < 0.0001; V3 and V4 < V1 and V2). The use of clopidogrel did not affect atorvastatin serum levels. Conclusion: High-dose atorvastatin did not affectplatelet responses to clopidogrel, however the short-term statindiscontinuation worsened the lipid profile and platelet function.