Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure

Background Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype. Methods We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months. Genotype for the insertion/deletion polymorphism of the ACE gene was determined by polymerase chain reaction. An echocardiographic examination was performed at baseline and at the end of the 12 months. Results The mean (± SD) age of the 93 patients was 62 ± 9 years, and the mean New York Heart Association class was 2 ± 1. The genotype was DD in 26 patients (28%). Forty-seven patients were assigned to spironolactone treatment (mean dose, 32 ± 16 mg). In the treated group, only patients with a non-DD genotype showed significant improvement in left ventricular ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to 4.8%; P = 0.002), end-systolic volume (–23 mL; 95% CI: –36 to –11; P = 0.0005), and end-diastolic volume (–27 mL; 95% CI: –43 to –12; P = 0.001). In the multivariate analysis, the estimated net effect of treatment was 29 mL better (95% CI: –20 to 78 mL) for end-diastolic volume, 20 mL better (95% CI: –18 to 58 mL) for end-systolic volume, but 1.4% worse (95% CI: –3.4% to 6.2%) for left ventricular ejection fraction in patients with non-DD versus DD genotypes. Conclusion The effects of spironolactone treatment on left ventricular systolic function and remodeling may in part depend on ACE genotype.