RESUMO
Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Soluções Cardioplégicas/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Glicólise/efeitos dos fármacos , Miocárdio/metabolismo , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Idoso , Biomarcadores/sangue , Fosfatases de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Genótipo , Glucose/administração & dosagem , Humanos , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Potássio/administração & dosagem , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4.75 × 10(-7)) and infarct size with GIK (P2df < 0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P2df ⩽ 4.26 × 10(-7)), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Variação Genética/genética , Glucose/administração & dosagem , Insulina/administração & dosagem , Potássio/administração & dosagem , Alelos , Glicemia/genética , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas/métodos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).
