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

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Abstract

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.

Section snippets

Study sample

This study is part of a randomized trial of spironolactone in chronic heart failure patients; details of the study protocol are given elsewhere (7). In brief, 106 outpatients with chronic heart failure were randomly assigned to spironolactone treatment (25 to 50 mg/d) or a control group for 12 months. Patients were undergoing chronic ACE-inhibitor treatment at the maximum tolerated dose. At baseline and after 12 months, a complete echocardiographic examination was performed in all patients. The

Results

The mean (± SD) age of the 93 patients was 61.6 ± 8.9 years (Table 1). Most were men and had chronic heart failure of ischemic origin. Treatment with beta-blockers was relatively common, and was used in 69% of patients. The mean spironolactone dose in the treated group was 31.1 ± 15.6 mg.

The genotype was DD in 26 patients (28%), ID in 51 (55%), and II in 16 (17%). The frequencies of the two alleles were 55% for D and 45% for I. The genotype distribution did not differ significantly between the

Discussion

We found that the previously known effects of spironolactone on cardiac function are at least in part genetically based. We observed an improvement in left ventricular systolic function and volumes only in patients with the II or ID genotypes of the ACE gene who had undergone 12 months of treatment with spironolactone. These results further support the evidence that a genetic polymorphism might contribute to the effects of a drug treatment on cardiac function in chronic heart failure patients.

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      As the response of ACE DD patients to the ACE inhibitor therapy did not statistically differ from that of ID and II patients, there was a statistical relevant difference on the response to the beta-blocker therapy [32,33]; in fact, not only ACE DD patients did show a better response to this treatment, but the lack of it was associated with an increased transplant need and a poorer transplant-free survival [33]. As concerns mineralocorticoid receptor antagonists, ACE ID and ACEII patients treated with spironolactone responded better than ACE DD patients in terms of left ventricular systolic function and volume [34]. Another polymorphism in the in the 5′ region of the transcription start site of ACE gene, the − 240A > T substitution (rs4340), has been suggested to influence ACE plasma levels.

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      Data regarding the pharmacogenomics of spironolactone in HF is also limited. Only 4 studies have focused on spironolactone,44-47 each including less than 100 patients and investigating only a limited number of genes or SNPs. Thus far, no genetic association has been replicated in any these studies.

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      Patients who were AA homozygous appeared more sensitive to treatment, suggesting that patients carrying the C allele may benefit from higher doses of candesartan. In addition, this gene variant may affect the degree of left ventricular remodeling with angiotensin II receptor blockers (ARBs).39–41 Although these exploratory studies have limitations with small sample sizes, they may suggest a candidate gene association for future studies with ARBs.

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    Dr. Cicoira is supported by a grant from the Italian Society of Cardiology for Cardiovascular Research.

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