Effects of ACE Gene Insertion/Deletion
Polymorphism on Response to Spironolactone in
Patients with Chronic Heart Failure
Mariantonietta Cicoira, MD, Andrea Rossi, MD, Stefano Bonapace, MD, Luisa Zanolla, MD, Andreas Perrot, MSc, Darrel P. Francis, MRCP, Giorgio Golia, MD, Lorenzo Franceschini, MD, BACKGROUND: Angiotensin-converting enzyme (ACE) is
tients were assigned to spironolactone treatment (mean dose, involved in the pathophysiology of chronic heart failure, and its 32 Ϯ 16 mg). In the treated group, only patients with a non-DD activity is determined in part by a polymorphism of the ACE genotype showed significant improvement in left ventricular gene. We hypothesized that the benefits of spironolactone, ejection fraction (3.0%; 95% confidence interval [CI]: 1.2% to which inhibits downstream elements of ACE-mediated abnor- 4.8%; P ϭ 0.002), end-systolic volume (–23 mL; 95% CI: –36 to malities, may depend on ACE genotype.
–11; P ϭ 0.0005), and end-diastolic volume (–27 mL; 95% CI: METHODS: We randomly assigned 93 chronic heart failure
– 43 to –12; P ϭ 0.001). In the multivariate analysis, the esti- patients to treatment with spironolactone (n ϭ 47) or to a con- mated net effect of treatment was 29 mL better (95% CI: –20 to trol group (n ϭ 46) and followed them for 12 months. Genotype 78 mL) for end-diastolic volume, 20 mL better (95% CI: –18 to for the insertion/deletion polymorphism of the ACE gene was 58 mL) for end-systolic volume, but 1.4% worse (95% CI: determined by polymerase chain reaction. An echocardio- –3.4% to 6.2%) for left ventricular ejection fraction in patients graphic examination was performed at baseline and at the end CONCLUSION: The effects of spironolactone treatment on
RESULTS: The mean (Ϯ SD) age of the 93 patients was 62 Ϯ 9
left ventricular systolic function and remodeling may in part years, and the mean New York Heart Association class was 2 Ϯ depend on ACE genotype. Am J Med. 2004;116:657– 661.
1. The genotype was DD in 26 patients (28%). Forty-seven pa- Neurohormonalactivationinchronicheartfailure (RALES) showed that the aldosterone antagonist spi- is associated with the progression of the disease ronolactone, when added to ACE-inhibitor therapy, re- and increased levels of hormones are closely duces the risk of death in patients with severe chronic associated with poor outcomes in these patients An- heart failure One of the underlying mechanisms tagonism of the renin-angiotensin-aldosterone system is might be the improvement of left ventricular systolic therefore one of the main goals in the treatment of heart function and volumes Nevertheless, the response af- failure patients, and it can be achieved with angiotensin- ter treatment varies among patients, with some showing converting enzyme (ACE) inhibitors. Nevertheless, reac- no clear effect. We hypothesized that the beneficial car- tivation of the renin-angiotensin-aldosterone system diac effects of spironolactone might vary among chronic during ACE inhibitor treatment occurs frequently heart failure patients with different ACE genotypes.
owing to a genetic basis. In fact, an insertion/deletionpolymorphism of the ACE gene has been associated withthe failure of aldosterone suppression despite ACE- inhibitor administration in patients with chronic heart This study is part of a randomized trial of spironolactone in chronic heart failure patients; details of the study pro-tocol are given elsewhere In brief, 106 outpatients From Dipartimento di Scienze Biomediche e Chirurgiche (MC, AR, SB, with chronic heart failure were randomly assigned to spi- LZ, GG, LF, PZ), Sezione di Cardiologia, Universita` degli Studi di Ve- ronolactone treatment (25 to 50 mg/d) or a control group rona, Verona, Italy; Universitaetsklinikum Charite (AP, KJO), Kardi- for 12 months. Patients were undergoing chronic ACE- ologie am Campus Buch & Campus Virchow-Klinikum, und Max-Del-brueck-Centrum fuer Molekulare Medizin, Berlin, Germany; and St.
inhibitor treatment at the maximum tolerated dose. At Mary’s Hospital (DPF), London, United Kingdom.
baseline and after 12 months, a complete echocardio- Dr. Cicoira is supported by a grant from the Italian Society of Cardi- graphic examination was performed in all patients. The Requests for reprints should be addressed to Mariantonietta Cicoira, present study includes all 93 patients from the original MD, Divisione di Cardiologia, Ospedale Civile Maggiore, p.le Stefani, 1 study sample (47 assigned to spironolactone treatment) 37126 Verona, Italy, or [email protected]
who completed the 12-month follow-up. The protocol Manuscript submitted June 11, 2003, and accepted in revised form was approved by the Ethics Committee of the Azienda Spironolactone and ACE Gene Polymorphism/Cicoira et al Table 1. Baseline Characteristics of the Study Sample
* Serum creatinine: to convert to mg/dL, divide by 88.4; plasma aldosterone: to convert to ng/dL, divide by 0.03.
NYHA ϭ New York Heart Association.
Ospedaliera of Verona, and patients provided written in- sion analysis. A P value Ͻ0.05 was considered statistically formed consent for the genetic analysis.
significant. Data were analyzed using Statview 5.0 (Aba-cus Concepts Inc, Cary, North Carolina) and Stata (SAS The echocardiographic evaluation was performed by aphysician who was blinded to the treatment group. Leftventricular end-diastolic and end-systolic diameters, wall thickness, and left atrial diameter were measured by M-mode echocardiography from the parasternal long-axis The mean (Ϯ SD) age of the 93 patients was 61.6 Ϯ 8.9 view, as recommended by the American Society of Echo- years Most were men and had chronic heart cardiography Left ventricular end-diastolic and end- failure of ischemic origin. Treatment with beta-blockers systolic volumes and ejection fraction were measured was relatively common, and was used in 69% of patients.
from the apical four-chamber view using the monoplane The mean spironolactone dose in the treated group was The genotype was DD in 26 patients (28%), ID in 51 (55%), and II in 16 (17%). The frequencies of the two Genotyping was performed with the DNA of circulating alleles were 55% for D and 45% for I. The genotype dis- leukocytes obtained from peripheral whole blood. Poly- tribution did not differ significantly between the spirono- merase chain reaction was used to establish ACE geno- lactone and control groups (DD: 32% vs. 24%; ID: 47% type Putative DD genotypes were confirmed using vs. 64%; II: 21% vs. 13%; P ϭ 0.27). The mean spirono- the ACE-2 primer which eliminates the likelihood lactone dose was similar in patients with different geno- of mistyping that can occur with a two-primer system.
types (DD: 33.0 Ϯ 15.9 mg; ID: 30.1 Ϯ 13.2 mg; II: 32.5 Ϯ Results were scored by two independent investigators 15.8 mg; P ϭ 0.82). Thirteen patients did not complete who were unaware of patient identity or treatment group.
the study: 4 (31%) had a DD genotype, 6 (46%) had an ID genotype, and 3 (23%) had an II genotype, which was According to previous findings from our center pa- similar to the distribution among patients who com- tients were grouped by genotype: DD or non-DD. Inter- pleted the study (P ϭ 0.81).
group comparisons were made using the Student t test, Baseline echocardiographic characteristics, including analysis of variance, or chi-squared test, as appropriate.
left ventricular ejection fraction, were similar in patients Comparisons between baseline and follow-up values in with different genotypes except for the inter- patients with the same genotype were made using the ventricular septum, which was thicker in patients with Student t test for paired data. The estimated net effect of the DD genotype compared with those with a non-DD treatment between DD and non-DD genotypes was de- genotype in the control group (both P Ͻ0.05), as well as termined from an interaction term in the multiple regres- left ventricular volumes, which were also larger in pa- THE AMERICAN JOURNAL OF MEDICINE௡ Volume 116 Spironolactone and ACE Gene Polymorphism/Cicoira et al Table 2. Baseline Echocardiographic Characteristics of the Study Sample, by Treatment Group and Genotype*
* Intergroup comparisons were made using the Student t test for unpaired data.
tients with the DD genotype in the control group (all P sis showed that the estimated net effect of treatment was 29 mL better (95% confidence interval [CI]: –20 to Changes in Echocardiographic Measurements 78 mL; P ϭ 0.24) for end-diastolic volume, 20 mL better(95% CI: –18 to 58 mL; P ϭ 0.31) for end-systolic vol- At the end of 12 months, there was a significant increase ume, but 1.4% worse (95% CI: –3.4% to 6.2%; P ϭ 0.3) in fractional shortening in the spironolactone group for ejection fraction in patients with non-DD versus DD among patients with a non-DD genotype, whereas there was no change among those with the DD genotype There was only a trend towards improvement in leftventricular end-systolic diameter in patients with a DISCUSSION
non-DD genotype who were treated with spironolactone.
However, in the spironolactone group, there was a sig- We found that the previously known effects of spirono- nificant improvement in left ventricular ejection fraction lactone on cardiac function are at least in part genetically in patients with a non-DD genotype (mean change: 3.0% based. We observed an improvement in left ventricular Ϯ 4.9%; P ϭ 0.002); the change after treatment (0.2% Ϯ systolic function and volumes only in patients with the II 5.0% P ϭ 0.85) was not significant in those with the DD or ID genotypes of the ACE gene who had undergone 12 genotype Similarly, left ventricular volumes months of treatment with spironolactone. These results decreased significantly after treatment only in patients further support the evidence that a genetic polymor- with a non-DD genotype (end-diastolic volume: –27 Ϯ phism might contribute to the effects of a drug treatment 39 mL, P ϭ 0.001; end-systolic volume: –23 Ϯ 31 mL, P ϭ on cardiac function in chronic heart failure patients.
0.0005), but did not change in those with the DD geno- How might the ACE gene insertion/deletion polymor- type (end-diastolic volume: –10 Ϯ 50 mL, P ϭ 0.46; end- phism influence the effect of spironolactone on cardiac systolic volume: –2 Ϯ 36 mL, P ϭ 0.79).
function and volumes? Interindividual variability in the In comparison, there were no significant changes in response to antagonism of the renin-angiotensin aldoste- ejection fraction or left ventricular volumes in the control group at the end of the 12-month period among both is evidence that activation of the renin-angiotensin- patients with the DD genotype (ejection fraction: –2.9% aldosterone system is genetically determined Pa- Ϯ 5.8%, P ϭ 0.12; end-diastolic volume: –11 Ϯ 56 mL, tients who are homozygous for the DD allele have higher P ϭ 0.57; end-systolic volume: 1 Ϯ 47 mL, P ϭ 0.96) and serum and tissue ACE levels and activity, and conse- those with a non-DD genotype (ejection fraction: 1.3% Ϯ quently have greater activation of the renin-angiotensin- 5.2%, P ϭ 0.16; end-diastolic volume: 1 Ϯ 54 mL, P ϭ aldosterone system than do patients with the ID or II 0.88; end-systolic volume: –1 Ϯ 43 mL, P ϭ 0.97) genotypes Furthermore, we have recently shown that patients with aldosterone “escape” despite chronic Changes from baseline in ejection fraction and end- ACE inhibition are more likely to have the DD genotype diastolic and end-systolic volumes between patients with than are patients with normal aldosterone levels We DD and non-DD genotypes were greater in the control have also found that patients with the II genotype have adequate aldosterone suppression with chronic ACE in- The interaction term in the multiple regression analy- hibition Other investigators have reported that the THE AMERICAN JOURNAL OF MEDICINE௡ Volume 116 659
Spironolactone and ACE Gene Polymorphism/Cicoira et al Table 3. Changes in Echocardiographic Parameters from Baseline to 12-Month Follow-up, by Treatment Group and Genotype*
* Comparisons between follow-up and baseline measurements were made using the Student t test for paired data. Comparisons between DD andnon-DD genotype were made using the Student t test for unpaired data.
extent of exercise-induced left ventricular growth in DD genotype have a significantly lower response to treat- healthy subjects is strongly influenced by the insertion/ ment than patients with the II genotype How- deletion polymorphism of the ACE gene and that ever, the endpoints in these studies were renal function the DD genotype in patients with dilated cardiomyopathy and blood pressure, and no previous studies have ana- is associated with poorer systolic function and greater left lyzed the role of ACE gene polymorphisms on cardiac ventricular size in comparison with the II or ID genotype function and remodeling after aldosterone antagonism in These findings are consistent with a role of the para- patients with chronic heart failure.
crine renin-angiotensin-aldosterone system in the con- Our study has several limitations. First, the sample was trol of cardiac growth The tissue expression of an- small. Second, the treatment-genotype interaction term giotensin and aldosterone at the cardiac level, which has was not statistically significant. Although for ejection been associated with ACE gene polymorphisms is fraction the estimated net effect of treatment was better particularly important, since elevated ACE levels in car- for patients with the DD genotype, the confidence inter- diac tissue may eventually lead to increased production of val suggests that the response could be up to 3.4 times cardiac angiotensin II and aldosterone, which are in- worse in this group of patients. On the other hand, the volved in regulating cardiac remodeling and function estimated net effect of treatment for left ventricular vol- umes was worse in patients with the DD genotype, thus These observations suggest that ACE gene polymor- supporting our hypothesis. Third, the study was not a phisms are involved in determining the response to aldo- double-blind, placebo-controlled trial. Nevertheless, the sterone antagonism in terms of cardiac function. Previ- physician performing the echocardiographic examina- ous studies of ACE inhibitors found that patients with the tion was blinded to the treatment group and genotype.
THE AMERICAN JOURNAL OF MEDICINE௡ Volume 116 Spironolactone and ACE Gene Polymorphism/Cicoira et al Finally, an improvement in left ventricular function rep- tolerance in chronic heart failure patients. J Am Coll Cardiol. 2002; resents only a surrogate endpoint in patients with chronic 8. Sahn DJ, DeMaria AD, Kisslo J, Weyman A. Recommendations heart failure, which does not necessarily imply a prognos- regarding quantitation in M-mode echocardiography: result of a tic benefit. This question might be answered by larger survey of echocardiographic measurement. Am J Cardiol. 1978;58: prospective studies specifically designed to assess the ef- fect of aldosterone antagonism on outcome in relation to 9. Tiret L, Rigat B, Visvikis S, et al. Evidence from combined segrega- tion and linkage that a variant of the angiotensin I-converting en-zyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. It seems, therefore, that patients with the II genotype not only have a less activated renin-angiotensin-aldoste- 10. Walsh PS, Metzger DA, Higuchi R. Chelex 100 as a medium for rone system at baseline, but also a better response to en- simple extraction of DNA for PCR-based typing from forensic ma- docrine antagonism at different levels of the system. Fur- terial. Biotechniques. 1991;10:506 –513.
thermore, these patients have a lower risk of developing 11. Evans AE, Poirer O, Kee F, et al. Polymorphism of the ACE gene in subjects who die from coronary heart disease. QJM. 1994;87:211– chronic heart failure and ischemic heart disease The opposite is true for patients with the DD genotype.
12. Exner DV, Dries DL, Domanski MJ. Lesser response to angiotensin- Still, patients with the DD genotype probably should not converting-enxyme inhibitor therapy in black as compared with be considered nonresponders to aldosterone antagonism white patients with left ventricular dysfunction. N Engl J Med. 2001;3:1351–1357.
for several reasons. In our study, patients in the control 13. Roig E, Perez-Villa F, Morales M, et al. Clinical implications of group with the DD genotype showed a trend towards increased plasma angiotensin II despite ACE inhibitor therapy in worsening of left ventricular systolic function and left patients with congestive heart failure. Eur Heart J. 2000;21:53–57.
ventricular remodeling, while patients with the same ge- 14. Jorde UP, Ennezta PV, Lisker J, et al. Maximally recommended notype in the spironolactone group remained stable over doses of angiotensin-converting enzyme (ACE) inhibitors do notcompletely prevent ACE-mediated formation of angiotensin II in time. Furthermore, the difference in changes in ejection chronic heart failure. Circulation. 2000;101:844 –846.
fraction between DD and non-DD genotype was even 15. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion larger in the control group than in the spironolactone polymorphism in the angiotensin I-converting enzyme gene ac- group. We wish to emphasize that the hypothesized ef- counting for half the variance of serum enzyme levels. J Clin Invest. fects of ACE gene polymorphisms on drug efficacy and 16. Zhu X, Bouzekri N, Southam L, et al. Linkage and association anal- cardiac function in patients with chronic heart failure ysis of angiotensin I-converting enzyme (ACE)-gene polymor- should be confirmed in larger randomized studies.
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