RESUMEN

BACKGROUND: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort. METHODS AND RESULTS: The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype. CONCLUSIONS: This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.

Asunto(s)

Síndrome Coronario Agudo , Factor A de Crecimiento Endotelial Vascular , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple

RESUMEN

BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.

Asunto(s)

Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/genética , Polimorfismo de Nucleótido Simple , Pterinas/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/mortalidad , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Angiografía Coronaria , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Activación de Macrófagos , Macrófagos/metabolismo , Masculino , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo

RESUMEN

BACKGROUND AND AIMS: The methylene-tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene is involved in mitochondrial tetrahydrofolate metabolism. Polymorphisms in MTHFD1L, including rs6922269, have been implicated in risk for coronary artery disease (CAD). We investigated the association between rs6922269 and known metabolic risk factors and survival in two independent cohorts of coronary heart disease patients. METHODS AND RESULTS: DNA and plasma from 1940 patients with acute coronary syndromes were collected a median of 32 days after index hospital admission (Coronary Disease Cohort Study, CDCS). Samples from a validation cohort of 842 patients post-myocardial infarction (PMI) were taken 24-96 hours after hospitalization. DNA samples were genotyped for rs6922269, using a TaqMan assay. Homocysteine and active vitamin B12 were measured by immunoassay in baseline CDCS plasma samples, but not PMI plasma. All cause mortality was documented over follow-up of 4.1 (CDCS) and 8.8 (PMI) years, respectively. rs6922269 genotype frequencies were AA n = 135, 7.0%; GA n = 785, 40.5% and GG n = 1020, 52.5% in the CDCS and similar in the PMI cohort. CDCS patients with AA genotype for rs6922269 had lower levels of co-variate adjusted baseline plasma active vitamin B12 (p = 0.017) and poorer survival than patients with GG or GA genotype (mortality: AA 19.6%, GA 12.0%, GG 11.6%; p = 0.007). In multivariate analysis, rs6922269 genotype predicted survival, independent of established covariate predictors (p = 0.03). However the association between genotype and survival was not validated in the PMI cohort. CONCLUSION: MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart disease.

Asunto(s)

Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/mortalidad , Alelos , Aminohidrolasas/genética , Formiato-Tetrahidrofolato Ligasa/genética , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Complejos Multienzimáticos/genética , Polimorfismo Genético , Síndrome Coronario Agudo/sangre , Biomarcadores , Estudios de Cohortes , Estudios de Seguimiento , Estudios de Asociación Genética , Genotipo , Humanos , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Pronóstico , Análisis de Supervivencia , Factores de Tiempo , Vitamina B 12/sangre

RESUMEN

AIMS: The endothelin type A receptor, encoded by EDNRA, mediates the effects of endothelin-1 to promote vasoconstriction, vascular cell growth, adhesion, fibrosis and thrombosis. We investigated the association between EDNRA haplotype and cardiovascular outcomes in patients with coronary artery disease. METHODS: Coronary disease patients (n = 1007) were genotyped for the His323His (rs5333) variant and one tag SNP from each of the major EDNRA haplotype blocks (rs6537484, rs1568136, rs5335 and rs10003447). EDNRA haplotype associations with clinical history, natriuretic peptides cardiac function and cardiovascular outcomes were tested over a median 3.8 years. RESULTS: Univariate analysis identified a 'low-risk' EDNRA haplotype associated with later age of Type 2 diabetes onset (p = 0.004) smaller BMI (p = 0.021), and reduced mortality (log rank p = 0.001). Cox proportional hazards analysis including established cardiovascular risk factors revealed an independent association between haplotype and mortality (p < 0.0001). CONCLUSION: These data highlight the potential importance of the endothelin system, and in particular EDNRA in coronary disease.

RESUMEN

INTRODUCTION: The KCNE family is a group of small transmembrane channel proteins involved in potassium ion (K(+)) conductance. The X-linked KCNE5 gene encodes a regulator of the K(+) current mediated by the potassium channel KCNQ1. Polymorphisms in KCNE5 have been associated with altered cardiac electrophysiological properties in human studies. We investigated associations of the common rs697829 polymorphism from KCNE5 with baseline characteristics, baseline electrocardiographic (ECG) measurements, and patient survival in a cohort of post-acute coronary syndromes (ACS) patients (the Coronary Disease Cohort Study cohort). METHODS AND RESULTS: DNA samples (n = 1,740) were genotyped for rs697829 using a TaqMan assay. Baseline ECG data revealed corrected QT (QTc) interval was associated with rs697829 in male, but not female, patients, being extended in the G genotype group (A 416 ± 1.71; G 431 ± 4.25 ms, P = 0.002). Covariate-adjusted survival was poorest in G genotype patients in Cox proportional hazard modeling of mortality data of males (P(overall) = 0.020). Male patients with G genotype had a hazard ratio of 1.44 (1.11-2.33) for death when compared to the A genotype male patients (P = 0.048) after adjustment for age, baseline log-transformed N-terminal pro-B-type natriuretic peptide (NTproBNP), ß-blocker and insulin treatment, QTc interval, history of myocardial infarction, and physical activity score. CONCLUSION: This study suggests an association between rs697829, a common single nucleotide polymorphism (SNP) from KCNE5, and ECG measurements and survival in postacute ACS patients. Prolonged subclinical QT interval may be a marker of adverse outcome in this group of patients.

Asunto(s)

Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/fisiopatología , Electrocardiografía , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Canales de Potasio con Entrada de Voltaje/genética , Regiones no Traducidas 3'/genética , Síndrome Coronario Agudo/diagnóstico por imagen , Anciano , Análisis de Varianza , Estudios de Cohortes , Creatina Quinasa/genética , ADN/biosíntesis , ADN/genética , Ecocardiografía , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/genética , Neurotransmisores/metabolismo , Neurotransmisores/fisiología , Fragmentos de Péptidos/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple/genética , Polimorfismo de Nucleótido Simple/fisiología , Canales de Potasio con Entrada de Voltaje/fisiología , Modelos de Riesgos Proporcionales , Caracteres Sexuales , Sobrevida , Análisis de Supervivencia , Troponina T/genética

RESUMEN

BACKGROUND: Genome-wide association studies have identified gene variants associated with coronary artery disease risk; however, whether they affect disease progression is largely unknown. This study investigated associations between polymorphisms at 1p13.3 (rs599839), 1q41 (rs17465637), and 3q22.3 (rs9818870) and cardiovascular outcomes in healthy volunteers and in patients with established heart disease. METHODS AND RESULTS: Canterbury Healthy Volunteer study (HV) (n=1649), Coronary Disease Cohort Study (CDCS) (n=1797), and Post-Myocardial Infarction study (PMI) (n=906) participants (New Zealand), were genotyped for rs599839, rs9818870, and rs17465637. Associations between genotype and anthropometric characteristics, neurohormonal analysis, echocardiography, and clinical outcomes over medium-long-term follow-up (median HV, 5.9 years; CDCS, 3.7 years; PMI, 11.3 years) were tested. At 1p13.3, HV and CDCS participants carrying 1 or more rs599839 G allele had a lower prevalence of dyslipidemia (P ≤ 0.005) or lower levels of low-density lipoprotein (P=0.031) and total (P=0.004) cholesterol and/or less history of myocardial infarction (P ≤ 0.04) compared with AA participants. Moreover, CDCS and PMI AG/GG participants had better cardiac function as indicated by echocardiography (P ≤ 0.026), and fewer CDCS AG/GG participants were readmitted for a non-ST-segment elevation MI (P=0.012) during follow-up. The polymorphism at 1q41 (rs17465637) was associated with better cardiovascular outcomes in the HV (P=0.028) and PMI (P=0.008) cohorts, and 3q22.3 (rs9818870) was a predictor of death/admission in the HV cohort (P=0.045). CONCLUSIONS: These data suggest that coronary artery disease genomic risk variants at 1p13.3 and 1q41 are associated with subsequent clinical outcome in heart patients and confirm rs9818870 at 3q22.3 as a predictor of cardiovascular risk in individuals free of overt heart disease.

Asunto(s)

Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 3/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Polimorfismo Genético , Factores de Riesgo , Adulto Joven

RESUMEN

Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n=1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p=0.003 to p=0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p=0.001 to p=0.03), and reduced E/E(1) (p=0.011), or LVESVI (p=0.001) and LVEDVI (p=0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p=0.01 to p=0.03), and rs479651 was associated with lower LVESVI (p=0.008) and LVEDVI (p=0.018). NPR2 rs10758325 was associated with smaller LVMI (p<0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p<0.0001), NPPB rs632793 (p<0.0001), rs198388 (p<0.0001), rs198389 (p<0.0001), and NPR2 rs10758325 (p<0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events.

Asunto(s)

Factor Natriurético Atrial/genética , Enfermedad Coronaria/genética , Péptido Natriurético Encefálico/genética , Péptido Natriurético Tipo-C/genética , Anciano , Factor Natriurético Atrial/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Tipo-C/sangre , Polimorfismo Genético/genética , Receptores del Factor Natriurético Atrial/genética

RESUMEN

BACKGROUND: Chromosome 9p21.3 (chr9p21.3) recently was identified by several genome-wide association studies as the genomic region most strongly associated with the risk of coronary artery disease. Within the chr9p21.3 locus, the single-nucleotide polymorphism rs1333049 has been demonstrated to be most strongly associated with susceptibility to developing coronary artery disease. However, the effect of rs1333049 on clinical outcomes in patients with established coronary disease has yet to be determined. METHODS AND RESULTS: Coronary Disease Cohort Study (CDCS) (n=1054) and Post-Myocardial Infarction (PMI) (n=816) study participants were genotyped for rs1333049. Clinical history, circulating lipids, neurohormones, cardiac function, and discharge medications were documented. All-cause mortality and cardiovascular hospital readmissions were recorded over a median follow-up period of 4.0 years for the CDCS cohort and 9.1 years for the PMI cohort. The CDCS patients homozygous for the high-risk C allele had an age of onset 2 to 5 years earlier for coronary disease (P=.005), angina (P=.025), myocardial infarction (P=.022), and percutaneous transluminal coronary angioplasty (P=.009). Patients with the CC genotype also had higher levels of total cholesterol (P=.033) and triglycerides (P=.003). The PMI participants with the CC genotype were 3 years younger on admission (P=.009). Cox proportional hazards analysis adjusting for established predictors of increased risk showed no significant association between rs1333049 genotype and mortality in either the CDCS (P=.214) or the PMI (P=.696) cohorts. CONCLUSIONS: The chr9p21.3 polymorphism rs1333049 was associated with an earlier age of disease onset in 2 coronary disease cohorts but not with poorer clinical outcome in either cohort.

Asunto(s)

Cromosomas Humanos Par 9 , Enfermedad Coronaria/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Colesterol/sangre , Estudios de Cohortes , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/mortalidad , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Triglicéridos/sangre

RESUMEN

1. The CYP1A1 T6235C polymorphism (rs4646903) gene polymorphism has been linked to the development of coronary heart disease and cigarette smoking-related lung cancer. The present study investigated associations between survival in acute coronary syndromes (ACS), smoking and the CYP1A1 T6235C polymorphism. 2. Patients with ACS (n = 1251) were genotyped for the CYP1A1 T6235C polymorphism. Patients had a mean age of 67.0 years, 69.8% were male and follow up occurred over a median of 1.9 years. 3. Overall genotype frequencies were CC 2.2%, TC 21.7% and TT 76.1%. The CC genotype was associated with baseline characteristics of a higher incidence of Type 2 diabetes (P = 0.017), elevated body mass index (P = 0.001) and younger age (P = 0.045). Patients with the CC genotype had significantly worse survival than TT/TC patients (P = 0.014), independent of ethnicity and established clinical risk factors. When survival was stratified by smoking history, the T6235C genotype was particularly associated with mortality in past or current smokers (mortality 23.5 vs 9.4% in CC and TT/TC patients, respectively; P = 0.019) compared with those who had never smoked (mortality 11.1 vs 11.5% in CC and TT/TC patients, respectively; P = 0.853). 4. The results indicate that the homozygous CYP1A1 6235C genotype is associated with greater mortality following the onset of ACS, independent of ethnicity and clinical risk factors, but related to smoking history.

Asunto(s)

Síndrome Coronario Agudo/mortalidad , Citocromo P-450 CYP1A1/genética , Fumar/genética , Anciano , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Pronóstico

RESUMEN

BACKGROUND: A variant in the promoter of the human uncoupling protein 2 (UCP2) gene, the G-866A polymorphism, has been associated with future risk of coronary heart disease events, in those devoid of traditional risk factors and in those suffering from diabetes. We thus examined the impact of the G-866A polymorphism on 5-year survival in a cohort of 901 post-myocardial infarction patients, and the impact of type-2 diabetes on this relationship. The association of UCP2 with baseline biochemical and hormonal measurements, including levels of the inflammatory marker myeloperoxidase, was also examined. METHODS: UCP2 G-866A genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Myeloperoxidase levels were measured in plasma samples taken from 419 cohort patients 24-96 hours after admission. RESULTS: Genotypes were obtained for 901 patients with genotype frequencies AA 15.5%, GA 45.5%, and GG 39.0%. Genotype was not associated with survival in the overall cohort (mortality: AA 15.6%, GA 16.8%, GG 19.4%, p = 0.541). However, amongst diabetics, AA and GA genotype groups had significantly worse survival than GG diabetic patients (p < 0.05) with an attributable risk of 23.3% and 18.7% for those of AA and GA genotype respectively. Multivariate analysis using a Cox proportional hazards model confirmed that the interaction of diabetes with genotype was significantly predictive of survival (p = 0.031). In the cohort's diabetic subgroup AA/GA patients had higher myeloperoxidase levels than their GG counterparts (GA/AA, n = 51, 63.9 +/- 5.23; GG, n = 34, 49.1 +/- 3.72 ng/ml, p = 0.041). Further analysis showed that this phenomenon was confined to male patients (GA/AA, n = 36, 64.3 +/- 6.23; GG, n = 29, 44.9 +/- 3.72 ng/ml, p = 0.015). CONCLUSION: Diabetic patients in this post-myocardial infarction cohort with UCP2 -866 AA/GA genotype have poorer survival and higher myeloperoxidase levels than their GG counterparts.

Asunto(s)

Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/mortalidad , Canales Iónicos/genética , Proteínas Mitocondriales/genética , Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Polimorfismo Genético/genética , Estudios de Cohortes , Diabetes Mellitus Tipo 2/enzimología , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/metabolismo , Peroxidasa/biosíntesis , Regiones Promotoras Genéticas/genética , Tasa de Supervivencia/tendencias , Proteína Desacopladora 2

RESUMEN

BACKGROUND: Polymorphisms of the angiotensin-converting enzyme 2 (ACE2) gene, which is located on the X chromosome, have been associated with hypertension and left ventricular hypertrophy in previous studies. We tested the hypothesis that the rare allele of an ACE2 gene polymorphism was associated with risk factors for and adverse outcome after acute coronary syndrome (ACS) events. METHODS: Patients (n = 1,042) were recruited after admission for an ACS event and were genotyped for the A1075G polymorphism of the angiotensin-converting enzyme 2 gene. This genetic marker was tested for association with baseline measurements, echocardiographic measurements, and clinical outcome, over a median 2.19 years follow-up. As the ACE2 gene is X-linked, analyses were performed separately for males and females. Patients were predominantly of European ethnicity (90.1%). RESULTS: The A1075 allele was significantly associated with covariate-adjusted mortality in male patients (hazard ratio 1.95, 95% CI 1.10-3.46, P = .047) but not unadjusted (hazard ratio 1.14, 95% CI 0.736-1.76, P = .56). The G1075 (P < .035) allele was more frequent in patients of Maori compared to European ancestry. E/E', an echocardiographic index of left ventricular diastolic function and filling pressure, was higher in males in the A1075 group (G allele group 10.5 [95% CI 10.0-11.0], A allele group 11.4 [95% CI 10.8-12.1], P = .024). A1075 genotype was significantly associated with male survival in the absence of (mortality: A 12.8%, n = 39; G 29.2%, n = 48; P = .037) but not in the presence of beta-blocker treatment (mortality: A 13.5% n = 273; G 8.2% n = 304, P = nonsignificant). CONCLUSIONS: The A1075 allele was associated with covariate-adjusted mortality in male patients.

Asunto(s)

Síndrome Coronario Agudo/genética , Síndrome Coronario Agudo/mortalidad , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Síndrome Coronario Agudo/etnología , Anciano , Alelos , Enzima Convertidora de Angiotensina 2 , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda , Factores de Riesgo , Análisis de Supervivencia

RESUMEN

AIMS: Plasma aldosterone levels have been shown to be associated with adverse clinical outcomes after ST-elevation myocardial infarction (STEMI). We investigated whether aldosterone levels in patients presenting with STEMI or non-STEMI, are predictive of mortality during prolonged follow-up. METHODS AND RESULTS: Aldosterone levels were assayed in plasma taken from 583 patients within 24-96 h following acute myocardial infarction (MI). The median plasma aldosterone level was 108 pmol/L and all values were below the upper limit of the normal range (800 pmol/L) except for five patients (0.9%). Aldosterone tertile was significantly associated with increasing plasma levels of NTproBNP (N-terminal pro-B-type natriuretic peptide), BNP (B-type natriuretic peptide), epinephrine, and endothelin-1 (P or=25.3% mortality, P >or= 0.026). CONCLUSION: Plasma aldosterone levels post-MI are independent predictors of survival and hospitalization for heart failure over a 5-year-follow-up period.

Asunto(s)

Aldosterona/sangre , Infarto del Miocardio/sangre , Factor Natriurético Atrial/sangre , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/mortalidad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Valor Predictivo de las Pruebas , Análisis de Regresión , Análisis de Supervivencia

RESUMEN

Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (n=451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (n=86) were 3 years younger at admission (P=0.011), and, in those with hypertension, diagnosis was made approximately 10 years earlier than other patients. Patients carrying >or=1 174M allele (n=94) were more likely to have a previous history of heart failure (P=0.044) and increased mortality during follow-up (risk ratio: 1.69, 95% CI: 1.03 to 2.79; P=0.038) compared with 174TT homozygotes (n=355), despite having a higher left ventricular ejection fraction (P=0.009). "High-risk" genotype combinations (defined a priori as 235TT and/or >or=1 174M allele; n=144; 32%) were independently predictive of mortality, conferring a 2-fold greater risk of dying during the follow-up period (odds ratio: 2.0; 95% CI: 1.3 to 3.0; P=0.001). This study suggested that angiotensinogen gene variants M235T and T174M may provide prognostic information for long-term survival in heart failure patients.

Asunto(s)

Angiotensinógeno/genética , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/mortalidad , Polimorfismo Genético , Anciano , Alelos , Femenino , Estudios de Seguimiento , Genotipo , Insuficiencia Cardíaca/fisiopatología , Homocigoto , Humanos , Masculino , Registros Médicos , Metionina , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Volumen Sistólico , Análisis de Supervivencia , Treonina

RESUMEN

BACKGROUND: The AMPD1 gene C34T polymorphism has previously been associated with prolonged survival in small cohorts of heart failure (HF) and coronary artery disease patients. This study aimed to corroborate the association of the AMPD1 C34T polymorphism with survival in larger myocardial infarction (MI) and HF cohorts. METHODS: Genotypes were obtained for 935 post-MI (PMI) and 433 patients with established HF, with median follow-up times of 5.4 and 3.1 years, respectively. At admission, cardiac function was assessed by nuclear ventriculography (PMI) and echocardiography (HF) and plasma cardiac neurohormones were assayed. RESULTS: Differences in mortality by AMPD1 genotype did not achieve significance, either for the overall HF (P = .07) or the overall PMI group (P = .28), but AMPD1 genotype predicted mortality in patients of both cohorts with a history of MI (HxMI). In contrast to previous studies, the mutant T allele was associated with poorer outcome. Mortality in HF HxMI patients was significantly different between genotype groups (n = 144, mortality CC 56.5%, CT/TT 77.8%, P = .027), but not in patients without HxMI. In PMI patients, the association of genotype with survival in the HxMI subgroup trended toward significance (n = 147, mortality CC 29.8%, CT/TT 45.5%, P = .093). Multivariate analysis of combined PMI and HF cohorts showed that HxMI patients with CT/TT genotype were at greater risk than all other groups (P < .001). CONCLUSION: This study suggests that AMPD1 C34T genotype is not a predictor of survival in heart disease patients, except possibly those with HxMI.

Asunto(s)

AMP Desaminasa/genética , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/mortalidad , Infarto del Miocardio/genética , Infarto del Miocardio/mortalidad , Anciano , Aldosterona/sangre , Angiotensina II/sangre , Factor Natriurético Atrial/sangre , Endotelina-1/sangre , Epinefrina/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Péptido Natriurético Encefálico/sangre , Norepinefrina/sangre , Polimorfismo Genético , Modelos de Riesgos Proporcionales , Estudios Retrospectivos

RESUMEN

The alpha-isoform of the glycosylphosphatidylinositol cell membrane tethered folate receptor (alpha-FR) is overexpressed in some carcinomas (notably ovarian carcinomas) relative to normal tissues. The nonpolyglutamatable folate-based thymidylate synthase (TS) inhibitor, CB300638 (TS K(i) = 0.24 nM) displayed an IC(50) of 0.0028 microM for the inhibition of the growth of human A431-FBP cells transfected with the alpha-FR. In contrast, the IC(50) for the neotransfected A431 cells was 0.81 microM (300-fold higher). Similarly, this compound inhibited the growth of human KB cells that constitutively overexpress the alpha-FR with an IC(50) of 0.0036 microM. These data were derived from cells grown in a physiological concentration of folate (20 nM R,S-leucovorin). Incubation of KB cells with a 1 microM excess of folic acid (FA), to selectively block uptake via the alpha-FR, increased the CB300638 IC(50) to 0.39 microM. The relatively low potency of CB300638 under these conditions, or in cell lines not expressing the alpha-FR, is ascribed to its low affinity for the ubiquitously expressed folate transporter, the reduced-folate carrier (K(i) for inhibition of [(3)H]methotrexate transport >100 microM). The high potency of CB300638 in alpha-FR-overexpressing cell lines is attributable to high affinity of the alpha-FR (53% of FA) and efficient endosomal trafficking mediated by the alpha-FR. Sixteen-h exposure to CB300638 inhibited the rate of (3)H(2)O release from 5-[(3)H]dUrd (in situ TS assay) in A431, A431-FBP, and KB cells with IC(50) values of 0.1 microM, 0.005 microM, and 0.002 microM, respectively. The coaddition of 1 micro M FA increased the IC(50)s for A431-FBP and KB cells to approximately 0.1 microM consistent with alpha-FR-mediated transport of CB300638. In conclusion, alpha-FR-mediated uptake of CB300638 leads to TS and growth inhibition that is highly selective for alpha-FR overexpressing tumor cell lines. The low expression of the alpha-FR in normal tissues, particularly those sensitive to TS inhibitors, together with the low affinity of CB300638 for the reduced-folate carrier, suggests that the compound may have potential as an antitumor agent with a high therapeutic index.

Asunto(s)

Antineoplásicos/farmacología , Proteínas Portadoras/metabolismo , Ciclopentanos/farmacología , Ácido Fólico/análogos & derivados , Ácido Fólico/farmacología , Quinazolinas/farmacología , Receptores de Superficie Celular , Timidilato Sintasa/antagonistas & inhibidores , Antineoplásicos/farmacocinética , Transporte Biológico , Carcinoma de Células Escamosas , División Celular/efectos de los fármacos , Ciclopentanos/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Receptores de Folato Anclados a GPI , Ácido Fólico/farmacocinética , Humanos , Cinética , Quinazolinas/farmacocinética , Proteínas Recombinantes/metabolismo , Transfección , Células Tumorales Cultivadas , Neoplasias de la Vulva