RESUMEN
The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE-insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important modulating factor in this relationship. ACE-I/D allele and genotype distribution was determined in 3 groups: 104 men with a first MI at a young age (≤45 years old), 271 healthy young men (≤30 years old), and 28 healthy elderly men (>65 years old). All participants were French descendants from Quebec City, Canada. Frequency distribution of the ACE alleles and genotypes was similar among the healthy young, the healthy elderly, and the MI patients (P > .05). However, when considering the age at the time of the MI (≤40, ≤35, or ≤30 years old), a significant age-dependent effect with the prevalence of the ACE-DD genotype was found, as it increased by 22%, 61%, and 157%, respectively, compared with the healthy young group (P < .05). Similar observations were obtained versus the healthy elderly men (P < .05). The ACE-I/D polymorphism seems to be a genetic risk factor for MI in young men and becomes an important modulator of MI risk at a young age.
Asunto(s)
Envejecimiento/genética , Estudios de Asociación Genética , Infarto del Miocardio/enzimología , Infarto del Miocardio/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutagénesis Insercional/genética , Factores de Riesgo , Eliminación de Secuencia/genética , Adulto JovenRESUMEN
A simple, specific, sensitive, inexpensive and rapid HPLC method for enantioselective quantification of carvedilol in human plasma was developed in this study. S(-)- and R(+)-carvedilol and R(+)-propranolol as the internal standard were extracted from human plasma by liquid-liquid extraction using methyl tert-butyl ether. Enantioseparation was performed on a reverse-phase C18 Phenomenex Luna 5micron 150mmx2mm column after chiral derivatization with 2,3,4,6-tetra-O-acetyl-beta-d-glucopyranosyl isothiocyanate. The mobile phase was a mixture of water and acetonitrile. The peaks were detected using a fluorescence detector, where the excitation and emission wavelengths were set at 242 and 344nm, respectively. The limits of quantification for the S(-)- and R(+)-carvedilol enantiomers were both 0.5ng/ml. Combined intra- and inter-day variations for both enantiomers were less than 8.3%. The combined accuracy for both enantiomers ranged from 91.7 to 104.7%. This method was used to assay the carvedilol enantiomers in human plasma samples obtained from heavily medicated heart failure patients within the framework of a clinical trial.
Asunto(s)
Carbazoles/sangre , Carbazoles/química , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/tratamiento farmacológico , Propanolaminas/sangre , Propanolaminas/química , Carbazoles/administración & dosificación , Carvedilol , Cromatografía Líquida de Alta Presión/métodos , Humanos , Propanolaminas/administración & dosificación , EstereoisomerismoRESUMEN
BACKGROUND: The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB. OBJECTIVE: To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor. METHODS: We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan. RESULTS: Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (-9.1 +/- 4.7 vs 1.1 +/- 3.3 mm Hg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (-5.1 +/- 1.5 vs 1.9 +/- 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (-151.4 [-207; -19.8] ng/L vs 147.3 [-61.3; 882.9] ng/L; p = 0.03) and hsCRP (-0.8 [-2.2; -0.03] mg/L) vs 0.2 [-1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found. CONCLUSIONS: The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bencimidazoles/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/genética , Receptor de Angiotensina Tipo 1/genética , Tetrazoles/uso terapéutico , Anciano , Análisis de Varianza , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Proteína C-Reactiva/efectos de los fármacos , Método Doble Ciego , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/efectos de los fármacos , Fragmentos de Péptidos/efectos de los fármacos , Polimorfismo GenéticoRESUMEN
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The progression and pharmacological response of heart failure-affected patients are subject to interindividual variability. It is also acknowledged that the genotype frequency of certain gene polymorphisms varies across different ethnic groups and that a difference in gene polymorphism frequencies between healthy and heart failure patients seems to exist. WHAT THIS STUDY ADDS: This study investigated associations between 10 gene polymorphisms of RAAS-related genes with an individual's susceptibility to heart failure. Our data suggest that the angiotensinogen (AGT) 235 single nucleotide polymorphism (SNP) may be associated with heart failure in our population and that the AGT(M174)-AGT(T235) haplotype, as well as the AGT/angiotensin-converting enzyme (ACE) gene combination, may play an important role in disease predisposition. AIMS: Racial differences in survival outcomes point towards a genetic role in the pathophysiology of heart failure. Furthermore, contemporary evidence links genetics to heart failure (HF) predisposition. We tested for a difference in prevalence of 10 renin-angiotensin-aldosterone system (RAAS)-related gene polymorphisms between a homogenous population of HF patients and healthy controls. METHODS: One hundred and eleven healthy volunteers and 58 HF patients were included in this study. The healthy control group consisted of males aged between 18 and 35 years old. The HF group consisted of patients (89.7% male) who were 63.8 +/- 7.9 years old, were in New York Heart Association (NYHA) class II-III and had a documented left ventricular ejection fraction (LVEF) Asunto(s)
Insuficiencia Cardíaca/genética
, Polimorfismo Genético
, Sistema Renina-Angiotensina/genética
, Población Blanca/genética
, Adolescente
, Adulto
, Anciano
, Canadá/epidemiología
, Método Doble Ciego
, Femenino
, Frecuencia de los Genes/genética
, Predisposición Genética a la Enfermedad/genética
, Insuficiencia Cardíaca/sangre
, Humanos
, Masculino
, Persona de Mediana Edad