RESUMO
Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.
Assuntos
Citocromo P-450 CYP3A/genética , Genótipo , Insuficiência Cardíaca/genética , Citrato de Sildenafila/uso terapêutico , Volume Sistólico/genética , Vasodilatadores/uso terapêutico , Idoso , Tolerância ao Exercício/efeitos dos fármacos , Tolerância ao Exercício/genética , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Citrato de Sildenafila/sangue , Citrato de Sildenafila/farmacologia , Volume Sistólico/efeitos dos fármacos , Vasodilatadores/sangue , Vasodilatadores/farmacologiaRESUMO
We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.
Assuntos
Apolipoproteínas/genética , Furosemida/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Lipoproteínas HDL/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Administração Intravenosa , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína L1 , Ensaios Clínicos como Assunto , Feminino , Deslocamentos de Líquidos Corporais/efeitos dos fármacos , Genótipo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Fatores de Tempo , Resultado do Tratamento , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
BACKGROUND: Dilated cardiomyopathy is characterized by an imbalance between left ventricular performance and myocardial energy consumption. Experimental models suggest that oxidative stress resulting from increased xanthine oxidase (XO) activity contributes to this imbalance. Accordingly, we hypothesized that XO inhibition with intracoronary allopurinol improves left ventricular efficiency in patients with idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Patients (n=9; ejection fraction, 29+/-3%) were instrumented to assess myocardial oxygen consumption (MVO(2)), peak rate of rise of left ventricular pressure (dP/dt(max)), stroke work (SW), and efficiency (dP/dt(max)/MV O(2) and SW/MVO(2)) at baseline and after sequential infusions of intracoronary allopurinol (0.5, 1.0, and 1.5 mg/min, each for 15 minutes). Allopurinol caused a significant decrease in MVO(2) (peak effect, -16+/-5%; P<0.01; n=9) with no parallel decrease in dP/dt(max) or SW and no change in ventricular load. The net result was a substantial improvement in myocardial efficiency (peak effects: dP/dt(max)/MVO(2), 22+/-9%, n=9; SW/MVO(2), 40+/-17%, n=6; both P<0.05). These effects were apparent despite concomitant treatment with standard heart failure therapy, including ACE inhibitors and beta-blockers. XO and its parent enzyme xanthine dehydrogenase were more abundant in failing explanted human myocardium on immunoblot. CONCLUSIONS: These findings indicate that XO activity may contribute to abnormal energy metabolism in human cardiomyopathy. By reversing the energetic inefficiency of the failing heart, pharmacological XO inhibition represents a potential novel therapeutic strategy for the treatment of human heart failure.
