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(Circulation. 2001;103:1644.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Pharmacogenetic Interactions Between ß-Blocker Therapy and the Angiotensin-Converting Enzyme Deletion Polymorphism in Patients With Congestive Heart Failure

Dennis M. McNamara, MD; Richard Holubkov, PhD; Karen Janosko, RN, MSN; Amy Palmer, MA; Jue J. Wang, MS; Guy A. MacGowan, MD; Srinivas Murali, MD; Warren D. Rosenblum, MD; Barry London, MD, PhD; Arthur M. Feldman, MD, PhD

From the Cardiovascular Institute, University of Pittsburgh Medical Center (D.M.M., R.H., K.J., A.P., J.J.W., G.A.M., S.M., W.D.R., B.L., A.M.F.), and the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (R.H.), Pittsburgh, Pa.

Correspondence to Dennis M. McNamara, MD, Heart Failure Section, University of Pittsburgh Medical Center, S-558 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail mcnamaradm{at}msx.upmc.edu

	Abstract

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Background—Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele (ACE D) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with ß-blocker therapy have not been previously evaluated.

Methods and Results—We prospectively followed 328 patients (age, 56.1±11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24±0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n=120) and those without ß-blocker therapy (n=208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D allele (1-year percent survival II/ID/DD=94/77/75; 2-year=78/65/60; ordered log-rank test, P=0.044). In patients not treated with ß-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P=0.005). In contrast, in patients receiving ß-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD=91/80/86; 2-year=70/71/77; P=0.73).

Conclusions—In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with ß-blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with ß-blockers in the determination of heart failure survival.

Key Words: receptors, adrenergic, beta • angiotensin • survival • genetics • heart failure

	Introduction

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Neurohormonal activation plays an important role in heart failure progression. In patients with systolic dysfunction, activation of the renin-angiotensin system¹ and elevation of circulating catecholamines² both contribute to left ventricular remodeling and worsening of the heart failure syndrome. Inhibition of ACE leads to reduction in circulating catecholamines,³ suggesting complex interactions exist in these two important reflex pathways.

As early as 1892, Sir William Osler⁴ recognized that after myocardial injury, patients transition from compensation to decompensation at highly variable rates. The observed clinical diversity in heart failure may be in part the result of genetic heterogeneity. A significant portion of the variability in ACE activity is genetically based⁵ and has been linked to a common biallelic polymorphism in intron 16 of the ACE gene.⁶ The two alleles differ on the presence or absence of a 287-base period insertion (I, insertion; D, deletion). The D allele has been consistently associated with higher ACE activity or angiotensin II levels across distinct patient populations, including normal control subjects,⁷ hypertensive subjects,⁸ and patients with congestive heart failure.⁹ Despite this association, its role as a cardiac risk factor remains controversial,^{10 11 12 13} and few studies have evaluated its impact on heart failure survival.¹⁴

ß-Adrenergic receptor antagonists (ß-blockers) have an increasing role in the treatment of patients with systolic dysfunction and may reduce the adverse effects of renin-angiotensin activation. We sought to evaluate the impact of the ACE D/I polymorphism on survival in a population of patients with congestive heart failure caused by systolic dysfunction and the potential pharmacogenetic interactions with ß-blocker therapy.

	Methods

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Study Population
This study was approved by the Institutional Review Board of the University of Pittsburgh Medical Center. A series of 328 patients with heart failure caused by systolic dysfunction referred to the Cardiomyopathy Clinic at the University of Pittsburgh Medical Center were recruited into a study of Genetic Risk Assessment of Cardiac Events (GRACE) between April 1996 and March 1999. Informed consent was obtained and peripheral blood was drawn for DNA isolation and genotyping. At the time of study entry, demographic information, New York Heart Association class, previous cardiovascular evaluation, and medical therapy were recorded. Patients were prospectively followed to an end point of either death or heart transplantation. Medical therapy was reassessed at 1-year follow-up or at the time of event for those patients who died or were given transplantation before 1 year. Medical personnel participating in management and follow-up were blinded to the genotype status of individual subjects.

In all patients, the most recent clinical assessment demonstrated left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) 0.45 (n=305) or qualitative assessment documenting moderate to severe left ventricular dysfunction (n=23). Left ventricular systolic function was estimated by radionuclide scan in 143 patients (43.6%), left ventricular angiography in 20 (6.1%), and by echocardiography in 165 (50.3%). Patients with a previous myocardial infarction, coronary artery bypass surgery, or angiographic evidence of coronary disease (defined as >50% stenosis of a major epicardial coronary artery) were classified as ischemic.

Genotyping of ACE Polymorphism
Genomic DNA was extracted from peripheral blood with a Pure Gene Kit, Gentra Systems, Inc. ACE genotyping was performed by the method of Lindpaintner et al¹⁵ ; primers 5'GCC CTG CAG GTG TCT GCA GCA TGT 3' and 5' GGA TGG CTC TCC CCG CCT TGT CTC 3' were used to amplify the D and I alleles, resulting in 319-bp and 597-bp products, respectively. Polymerase chain reactions (PCR) were run for 35 cycles: 30 seconds at 94°, 45 seconds at 56°, and 2 minutes at 72°. The product was subjected to electrophoresis in a 1.5% agarose gel and stained with ethidium bromide. Given preferential amplification of the D allele in heterozygous samples, samples found to have the DD genotype were reamplified with insertion-specific primers 5' TGG GAC CAC AGC GCC CGC CAC TAC 3' and 5' TCG CCA GCC CTC CCA TGC CCA TAA 3' and identical PCR conditions, except for an annealing temperature of 67°. Evaluation of these products on a 1.5% agarose gel revealed a 335-bp product in the presence of an I allele.

Statistical Analysis
Results are presented as mean±SD. Continuous baseline characteristics were compared nonparametrically on the basis of ordered genotype status with the Jonckheere-Terpstra test¹⁶ ; these comparisons were made between ß-blocker users and nonusers by the Wilcoxon rank-sum test. Categorical outcomes were compared by genotype status with the Mantel-Haenszel ² test and by ß-blocker status with the ² test or Fisher’s exact test in the case of expected small cell sizes. For outcome analysis, Kaplan-Meier event-free survival curves were analyzed for the entire study population and separately in patients with and those without ß-blocker therapy on entry. For the outcome of survival alone, transplanted patients were censored at the time of transplantation. The log-rank test was used for comparison of survival curves; for comparison by genotype status, a linear trend across genotype levels was tested. Cox regression analysis was used to quantify the relative risk of an event over time according to genotype and ß-blocker use; significance of coefficients was assessed by the Wald test.

	Results

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Baseline Demographics and Clinical Characteristics
The mean age of the cohort was 56.1±11.9 years; 75% were men, 52% ischemic, and 91% white. The mean LVEF was 0.24±0.08. Eighty-seven percent of patients were treated with an ACE inhibitor, 9% with an angiotensin receptor blocker, and 37% with a ß-blocker at the time of study entry. Genotyping classified 21% of patients as homozygous for the I allele, 47% as heterozygous, and 32% as homozygous for the D allele. The demographics and baseline clinical characteristics by genotype are listed in Table 1. No significant differences were detected among the 3 genotype subgroups.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics by Genotype

ß-Blocker Therapy
In comparisons of patients by the presence (n=120) versus absence (n=208) of ß-blocker therapy on entry, NYHA class distribution was similar between groups (number of patients receiving therapy with class I/II/III/IV=3/43/72/2; no ß-blockers, NYHA class I/II/III/IV= 5/74/116/13; P=0.47), and no significant differences in age, race, cause, sex, or baseline ACE inhibitor therapy were noted (Table 2). Patients receiving ß-blocker therapy had a slightly higher mean LVEF (0.26±0.09 versus 0.24±0.08, P=0.04). Of the patients receiving ß-blocker therapy at entry, 53% were taking carvedilol (mean daily dose, 42±27 mg), 33% metoprolol (mean daily dose, 56±29 mg), and 14% others (atenolol, propranolol). At entry, the mean heart rate of patients receiving carvedilol was significantly lower than patients not receiving any ß-blocker therapy (heart rate with carvedilol, 75±18 bpm; no therapy, 83±16; P=0.005). In contrast, the mean heart rate of patients receiving metoprolol was not significantly different from those not receiving therapy (metoprolol, 84±20 bpm), probably because of a lower mean equivalent dose. Of patients receiving ß-blocker at study entry, 84% continued to receive therapy at 1 year (mean dose carvedilol, 47±28 mg; metoprolol, 70±43 mg).

View this table: [in this window] [in a new window]   Table 2. Patient Characteristics by ß-Blocker Therapy

Outcomes: Event-Free Survival
The median follow-up time for all patients was 21 months (range, 3 to 38 months for patients alive and transplant free at last follow-up). During the course of follow-up, 119 events occurred, including 76 deaths and 43 transplants, which are listed by ACE genotype in Table 3. For the entire cohort, the presence of the D allele was associated with poor transplant-free survival (1-year percent transplant-free survival by genotype II/ID/DD=94/77/75; 2-year=78/65/60; P=0.044, Figure 1). A corresponding Cox regression analysis in patients with the II genotype as the reference category found a borderline increase in relative risk (RR) of events among heterozygotes (RR, 1.61; 95% CI, 0.95 to 2.73; P=0.08) and a significantly increased risk among patients with the DD genotype (RR, 1.80; 95% CI, 1.03 to 3.12; P=0.04).

View this table: [in this window] [in a new window]   Table 3. Study Events by Genotype in All Patients

View larger version (13K): [in this window] [in a new window]   Figure 1. Transplant-free survival compared by ACE genotype. Overall cohort, n=328. Ordered log-rank test, P=0.044.

The adverse impact of ACE D allele on transplant-free survival was dramatically increased when analysis was limited to patients not treated with ß-adrenergic antagonists (1-year percent transplant-free survival II/ID/DD=95/75/67; 2-year=81/61/48; Figure 2; P=0.005). This effect in this subset approached significance when survival alone was used as an end point, censoring patients at the time of heart transplantation (1-year percent survival=98/86/80; 2-year=83/76/64; P=0.054). In contrast, among patients treated with ß-blockers, no influence of ACE genotype on transplant-free survival was seen (1-year percent transplant-free survival=91/80/86; 2-year=70/71/77; P=0.73; Figure 3). In a similar fashion, evaluation of survival as a single end point in this subset demonstrated no significant association of ACE genotype with survival (1-year percent survival II/ID/DD=91/84/95; 2-year=75/77/92; P=0.15).

View larger version (13K): [in this window] [in a new window]   Figure 2. Transplant-free survival by ACE genotype. Patients not treated with ß-blockers at time of study entry, n=208. Ordered log-rank test, P=0.005.

View larger version (13K): [in this window] [in a new window]   Figure 3. Transplant-free survival by ACE genotype. Patients receiving ß-blocker therapy, n=120. Ordered log-rank test, P=0.73.

For the overall cohort, there was a trend for improved transplant-free survival in patients receiving ß-blockers that failed to reach statistical significance (P=0.065). When the effect of ß-blocker therapy on survival was evaluated within a given genotype class, no difference in event-free survival was seen for patients with the II (P=0.74) or ID (P=0.59) genotype. However, among patients homozygous for the D allele, treatment with ß-blockers was associated with a significant improvement in transplant-free survival (Figure 4, P=0.007). The benefits of ß-blockers remained highly significant in this subset for the outcome of survival alone (P=0.004).

View larger version (12K): [in this window] [in a new window]   Figure 4. Transplant-free survival compared by ß-blocker use for patients with ACE DD genotype only, n=105. Event-free survival was significantly better for patients treated with ß-blockers (n=43) compared with those not receiving therapy (n=62) (P=0.007 by log-rank test).

	Discussion

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In this study of patients with heart failure caused by systolic dysfunction, the presence of the D allele was associated with an increased risk of death or heart transplantation during subsequent follow-up. These findings are consistent with the previous report from Andersson et al,¹⁷ which demonstrated a poor survival in DD homozygotes in a Swedish cohort with idiopathic heart failure. Only 26% of patients in the Swedish cohort were treated with ACE inhibitors, which theoretically might decrease the impact of the D allele on heart failure progression. However, 95% of patients in the current study were treated with either ACE inhibitors or angiotensin receptor blockers, and this more generalized use of pharmacological inhibition of the renin-angiotensin system failed to eliminate the genetic heterogeneity of outcomes.

Case-control studies of the role of the ACE deletion as a risk factor for heart failure have led to conflicting results. Raynolds et al¹⁸ genotyped explanted tissue at the time of heart transplantation and found a much higher prevalence of DD homozygotes compared with control donor hearts. In contrast, studies of ambulatory patients with idiopathic dilated cardiomyopathy^{19 20 21} have not shown any significant increase in the prevalence of the D allele when compared with control populations. Although ACE genotype frequencies in the current study are similar to previously reported controls, a higher percentage of the patients progressing to transplantation were DD homozygotes (19 of 43, or 44%), consistent with the previous explant study. Overall, these studies suggest that the presence of ACE D allele does not increase the risk of myocardial injury, which initiates the heart failure syndrome, but instead may act as a disease modifier, altering the rate of disease progression.

Interestingly, whereas widespread use of ACE inhibitors failed to eliminate the effect of the ACE D allele on transplant-free survival, this genotype-dependent risk was not evident among patients treated with ß-blockers. In addition, the effects of ß-blocker therapy on transplant-free survival were markedly different among the 3 ACE genotype classes, with only patients within the DD class having apparent survival benefit. Therapy with ACE inhibitors has been shown to increase myocardial ß-receptor density,²² demonstrating the interdependence of sympathetic and renin-angiotensin activation. The results of the current study support this interaction and suggest a potentially important pharmacogenomic role of the ACE I/D polymorphism in the determination of ß-blocker utility.

Our study has a number of limitations. First, the use of the combined end point of death or transplantation as the timing of transplantation can be influenced by multiple factors and may not be equivalent to a cardiac "death." However, of the patients given transplantation during the study, 75% were UNOS status I and required either continuous intravenous inotropic therapy or left ventricular assist device support before transplantation, suggesting that in these patients, transplantation was the result of significant cardiac decompensation. In addition, when focusing on survival as a single end point and censoring patients at the time of transplantation, the effects of the ACE D allele on survival among patients not taking ß-blockers approached statistical significance (P=0.054), and the benefit of ß-blockers within the DD subset remained strongly statistically significant (P=0.004).

This study did not assess the effect of genotype on circulating markers of either renin-angiotensin or sympathetic activation. Although the association of the ACE deletion allele with increased plasma ACE activity has been consistently demonstrated in multiple previous studies,^{7 8 9 23} little is known about the influence of this allele on sympathetic activation. The increased effectiveness of ß-blocker therapy for DD subjects in the current study may suggest an increase in sympathetic activation in this genotype subset. Additional studies of the relation of ACE genotype to circulating catecholamine levels are needed to evaluate this hypothesis.

Despite similar demographics and functional class by ß-blocker therapy status, the absence of ß-blocker randomization at baseline makes the investigation of pharmacogenetics in the study exploratory in nature. However, the hypothesis suggested by this data that genetic heterogeneity influences the effect of ß-blocker therapy on survival can and should be reevaluated in the context of ongoing multicenter randomized trials. The results of these subsequent investigations may help to clarify the potential use of genetic background to target therapy for individual patients.

	Acknowledgments

 
This work was supported in part by a Career Development Award (K08-HL-02862) from the National Heart, Lung, and Blood Institute to Dr McNamara.

Received September 18, 2000; revision received December 1, 2000; accepted December 14, 2000.

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