Clinical studyEffects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure☆
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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Cited by (39)
A Physiologic Approach to the Pharmacogenomics of Hypertension
2016, Advances in Chronic Kidney DiseaseBiomarkers of activation of renin-angiotensin-aldosterone system in heart failure: How useful, how feasible?
2015, Clinica Chimica ActaCitation Excerpt :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.
Biomarker-guided therapies in heart failure: A forum for unified strategies
2013, Journal of Cardiac FailureCitation Excerpt :The basis for the apparent interaction of the β1 389 Arg/Gly polymorphism with bucindolol, which is not found with carvedilol or metoprolol, likely resides in the unique pharmacologic properties of bucindolol,16–18 but further studies are needed to elucidate this issue. Polymorphisms in the renin-angiotensin-aldosterone system (RAAS) have also been examined,23,24 and explorations aimed at identifying treatment selection and dosing with these genetic variations are in process.25–27 Other areas of nonpharmacologic investigation include pharmacogenetic associations with response to exercise,28 as well as implantable cardiac defibrillators29 and biventricular pacing in HF.
Pharmacogenomics and heart failure in congenital heart disease
2013, Canadian Journal of CardiologyCitation Excerpt :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.
Pharmacogenetics in Heart Failure Trials
2011, Heart Failure ClinicsCitation Excerpt :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.
Genomic Variation and Neurohormonal Intervention in Heart Failure
2010, Heart Failure ClinicsCitation Excerpt :The prevalence of aldosterone escape on ACE inhibitors is greatest in the ACE DD genotype.22 The impact of the aldosterone receptor antagonist spironolactone on left ventricular remodeling is also diminished in the ACE DD subset compared with the ID and II subsets23 in a manner that closely parallels the diminished clinical response to ACE inhibitors. The influence of the ACE D/I polymorphism on the effect of aldosterone receptor antagonists on survival remains to be determined.
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Dr. Cicoira is supported by a grant from the Italian Society of Cardiology for Cardiovascular Research.