CLINICAL STUDY: ACUTE CORONARY SYNDROME
Angiotensin-converting enzyme gene polymorphism interacts with left ventricular ejection fraction and brain natriuretic peptide levels to predict mortality after myocardial infarction
Barry R. Palmer, PhD*,
Anna P. Pilbrow, BSc (Hons)*,
Tim G. Yandle, PhD*,
Chris M. Frampton, PhD*,
A. Mark Richards, MD*,
M. Gary Nicholls, MD, FACC* and
Vicky A. Cameron, PhD*,*
* Christchurch Cardioendocrine Research Group, Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand
Manuscript received July 31, 2002;
revised manuscript received October 28, 2002,
accepted November 19, 2002.
* Reprint requests and correspondence: Dr. Vicky A. Cameron, Department of Medicine, Christchurch School of Medicine and Health Sciences, P.O. Box 4345, Christchurch, New Zealand.
vicky.cameron{at}chmeds.ac.nz
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Abstract
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OBJECTIVES: The goal of this study was the exploration of the associations between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and post-myocardial infarction (MI) outcomes, especially any interaction with the accepted clinical prognostic markers brain natriuretic peptide (BNP) and left ventricular ejection fraction (LVEF).
BACKGROUND: The ACE gene I/D polymorphism has been implicated in the development of MI, hypertension, and left ventricular hypertrophy. We examined the association of ACE I/D and prognosis after acute MI.
METHODS: Patients incurring acute MI were genotyped for the ACE I/D polymorphism. Clinical data included assays of neurohormones, radionuclide ventriculography, and mortality over a mean 2.6 years of follow-up.
RESULTS: Patients (n = 978) had a mean age of 62.1 years, and 78% were male. Overall genotype frequencies were II 23.2%, ID 49.5%, and DD 27.3%. Chi-square analysis revealed an association between the ACE D allele and death after MI (88 of 103 who died were DD or ID; p < 0.05), with an odds ratio for mortality of 8.03 (95% confidence interval, 2.16 to 29.88). Patients with the DD genotype had higher (p < 0.05) plasma BNP, N-terminal BNP (N-BNP), and endothelin-1 levels within 96 h after MI than grouped ID/II patients. Multivariate analysis indicated ACE genotype, age, and previous MI were independent predictors of death (p < 0.05). Patients with an ACE D allele in combination with either a lower than median LVEF or greater than median BNP had a higher mortality (p < 0.001 and p < 0.025, respectively) than the risk associated with the D allele itself.
CONCLUSIONS: Angiotensin-converting enzyme genotyping may provide additional prognostic information in patients after MI in combination with the proven utility of LVEF, plasma BNP, and N-BNP measurements.
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Abbreviations and Acronyms
| | ACE | | angiotensin-converting enzyme | | AII | | angiotensin II | | ANP | | atrial natriuretic peptide | | ApoE | | apolipoprotein E | | BMI | | body mass index | | BNP | | brain natriuretic peptide | | DNA | | deoxyribonucleic acid | | I/D | | insertion/deletion | | LV | | left ventricle/ventricular | | LVEF | | left ventricular ejection fraction | | MI | | myocardial infarction | | N-BNP | | N-terminal brain natriuretic peptide | | PCR | | polymerase chain reaction | | PMI | | Christchurch Post-Myocardial Infarction study | | RAAS | | renin-angiotensin-aldosterone system |
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Angiotensin-converting enzyme (ACE) (kinase II, EC 3.4.15.1
[EC]
, CD 143) is a membrane-bound, zinc metalloendopeptidase involved in the metabolism of many small peptides, notably the conversion of the biologically inactive decapeptide angiotensin I to the bioactive octapeptide angiotensin II (AII). The enzyme is expressed on the surface of cells in many tissues, but its richest source is the lung (1). Angiotensin-converting enzyme also circulates in a soluble form produced by proteolytic cleavage of the extracellular portion from endothelial cells. A common polymorphism in the ACE gene consists of a 287 base pair Alu insertion/deletion (I/D) in intron 16 (2), and comparison with the homologous region of the genomes of other primates suggests that the D allele is ancestral (3). The I/D polymorphism itself is not believed to be directly responsible for inherited variation in plasma ACE levels in humans (4). However, it has been shown to be closely linked to one or more functional polymorphisms that determine approximately 50% of the variation in plasma ACE levels between individuals (2,5). The polymorphism is also associated with the level of ACE gene expression in the left ventricle (LV) (6).
The observation that individuals carrying two copies of the D allele of the ACE gene had an increased risk of myocardial infarction (MI) (7) and other heart disease events (8) has resulted in enormous interest and extensive experimentation. Although several studies have confirmed and extended the original results (9–11), other investigators have made contrary observations (12–14), and the subject remains an area of controversy (8,15). A recent review of the prolific literature on ACE I/D heart disease association studies (1) concludes that the D allele confers a modestly increased risk of MI, especially that of fatal MI, particularly in specific geographical areas (Europe, regions of the U.S., and Japan). This risk appears to be pronounced in patient subgroups that would usually be considered low risk (low body mass index [BMI] and low apolipoprotein E [ApoE]) (7). By comparison, only a few studies have examined the association between ACE genotype and outcome after MI and have found either no association (12,13) or an association of the D allele with greater mortality (16) and increased LV remodelling after MI.
Because reports indicate that possession of the D allele increases tissue levels of ACE, and is associated with LV hypertrophy (6,11), we hypothesized that the D allele lowers the threshold of the heart to activation of ventricular remodelling in response to cardiac injury. This would lead to a greater rate of adverse events in post-MI patients. The present study, in a large MI cohort from a single center, explores the associations between the ACE gene I/D polymorphism and post-MI outcomes. This is the first study to examine whether any interaction exists between the recognized postinfarct prognostic markers circulating brain natriuretic peptide (BNP) levels, LV imaging indexes, and ACE I/D genotype.
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Methods
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Patients.
Patients were recruited to the Christchurch Post-Myocardial Infarction (PMI) study (17,18) beginning in November 1994 and followed for up to five years (mean, 2.6 years or 937 days). The study was approved by the Canterbury Ethics Committee, and participating patients all provided written, informed consent. Christchurch Hospital gives tertiary coronary care services to a population of approximately 500,000 on the South Island of New Zealand. This population is predominantly (approximately 85%) of Western European ancestry, with the current Maori population estimated to be approximately 8%. Patient ethnicity in this study was self-declared.
Clinical measurements
Acute MI (including ST-segment elevation and non–ST-segment elevation infarction) was defined by the presence of typical cardiac ischemic symptoms, ischemic change on the electrocardiogram in two or more contiguous leads, and peak elevation of plasma creatine kinase to at least twice normal (400 U/l). Although not an inclusion criterion, all patients were troponin T positive. Inclusion criteria included age <80 years, absence of cardiogenic shock, and survival for at least 24 h after MI. Blood samples were taken 24 to 96 h after the onset of symptoms, in the morning (07:00 to 13:00), from an indwelling intravenous cannula placed at least 30 min before sampling and with the patient resting quietly while semirecumbent. Samples were taken into chilled EDTA evacuated tubes, placed immediately on ice, centrifuged within 20 min at 4°C, and the plasma stored at –80°C before assay. Hormones were measured as previously described (atrial natriuretic peptide [ANP] [19], BNP [19], N-terminal brain natriuretic peptide [N-BNP] [20], guanosine 3'-5' cyclic monophosphate [19], adrenomedullin [21], and endothelin-1 [19]) and catecholamines by high performance liquid chromatography with electrochemical detection (22). Creatine kinase and troponin T were measured using commercial enzyme-linked immunosorbent assay kits (Boehringer Mannheim, Germany).
Left ventricular function was assessed by radionuclide ventriculography within 24 h of blood sampling. Each study was performed using a General Electric 400AC gamma camera interfaced to a General Electric 3000I computer system (General Electric Medical Systems, Milwaukee, Wisconsin) after standard in vivo technetium-99m red blood cell labeling.
Mortality was followed over a mean follow-up period of 2.6 years (median, 2.4 years; range, 3 to 2,119 days). Death was confirmed by consultation with the hospital specialist or family physician in attendance, and a copy of the death certificate was obtained in each case.
Deoxyribonucleic acid (DNA) isolation
Deoxyribonucleic acid was isolated from whole blood samples by the method of Ciulla et al. (23) (1988) or a rapid alkaline lysis method. The latter protocol used 480 µl of fresh or thawed whole blood that was added to 900 µl of 0.17 M NH4Cl, mixed on a rotary mixer for 25 min, and then spun for 30 s at 13,000 rpm in a microfuge to sediment the white blood cells. The white blood cells were washed in two changes of 500 µl of 10 mM NaCl, 10 mM EDTA pH 8.0, before resuspending in 400 µl of 50 mM NaOH with thorough vortexing and incubating at 95°C for 20 min. The extracted DNA solution was neutralized with 100 µl of 1 M Tris pH 7.5 and stored at –20°C.
ACE genotyping
Angiotensin-converting enzyme genotyping was performed in 20 µl reactions in 96-well plates, using a two primer polymerase chain reaction (PCR) protocol (24) and the addition of 5% DMSO to eliminate misamplification of heterozygous templates (25). Amplimers were electrophoresed on large format 1%, 0.5 x TBE gels stained with ethidium bromide and visualized with a BIO-RAD Fluor-S imaging system (Hercules, California). To ensure that the insertion (I) alleles had been correctly amplified by this protocol, 100 DNA samples were also genotyped by a three-primer PCR protocol using two flanking primers and a third primer that anneals to the Alu repeat sequence that makes up the insertion within intron 16 of the ACE gene (26). The genotypes were 100% concordant using the two and three primer genotyping assays.
Statistical analysis
The primary hypothesis was to explore the associations between the ACE I/D polymorphism and post-MI outcomes including any synergistic effects of the polymorphism with other accepted "clinical" prognostic indicators including left ventricular ejection fraction (LVEF) and plasma BNP levels. Dominant, recessive, and incremental models of risk were tested. Univariate analysis comparing the three genotype groups and comparing the DD genotype group with the combined ID and II groups was performed using chi-square and analysis of variance analyses. Kaplan-Meier survival curves were compared between genotype and risk groups using log-rank tests. Multivariate analysis of survival status was performed using a Cox proportional hazards model to determine independent association between genotype, and other risk factors with mortality. All statistical analyses were performed using SPSS version 10 (SPSS Inc., Chicago, Illinois). Of approximately 1,000 patients recruited, it would be expected that 75% would be DD or ID. The overall mortality rate post-MI was 10% for the duration of the study, with 4% expected in the II group and 12% in the DD or ID group. To determine whether in the ID/DD group there was elevated mortality in those with LVEF <median or BNP >median levels, there would be 375 in each subgroup. If the relative risk was 2.0, the mortality would be 8% versus 16%, respectively, for each low-risk versus high-risk cohort. In a sample of 1,000 patients, there would be sufficient power (>90%) to detect this difference at p < 0.05.
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Results
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Genotypes were obtained for 978 of the PMI cohort. Demographic characteristics and clinical background did not differ between genotype groups (Table 1). Treatment with ACE inhibitors and beta-blockers did not differ between genotype groups, and mortality in genotype groups did not differ with or without these treatments. There was a significant difference in mortality between genotypes. Mortality was lowest in the II group (15/227, 6.61%) and similarly increased in both ID and DD groups (54/484, 11.2%; 34/267, 12.7%, respectively). The association between mortality and ACE genotype was most marked when DD and ID individuals were grouped and compared with those with II genotype (chi-square = 4.8, p < 0.05). There was a significant association between the ACE D allele and death after MI (88 of 103 who died were DD or ID; p < 0.05) (Fig. 1). Because it has been reported that the ACE genotype has a particularly pronounced influence on mortality in low-risk groups (7), we examined this relationship using BMI and total cholesterol levels (ApoE measurements were not available). However, there was no difference in the association of mortality or other end points with ACE genotype in these risk-stratified groups (data not shown).
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Figure 1 Kaplan-Meier survival curves for the three angiotensin-converting enzyme genotype groups. Solid line = DD genotype; dotted line = ID genotype; dashed line = II genotype.
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Neurohumoral and hemodynamic measurements are shown in Table 2. Left ventricular volumes tended to be greatest in DD patients, followed by ID patients compared with II patients.
When DD individuals were compared with grouped ID and II patients, LV end-diastolic volume was significantly greater (p = 0.027), and increased LV end-systolic volume bordered on significance (p = 0.051). Plasma ANP, BNP, N-BNP, and endothelin-1 levels were all significantly elevated in the DD group compared with grouped ID and II levels (ANP, p = 0.016; BNP, p = 0.001; N-BNP, p = 0.007; endothelin-1, p = 0.010).
Table 3 relates patient ethnicity to ACE genotype. Patients were predominantly European (85.9%), followed by a group whose ethnicity was not stated (10.7%), Maori (2.4%), and a small number of other non-European ethnic groups (Indian, Asian, and Pacific Islanders) (1.0%). The European group was made up of New Zealand European (74.5% of total) and other European (11.4% of total). Despite the small sample sizes of the Maori and other non-European ethnic groups, the frequency of the I allele was much higher for these groups compared with the Europeans (chi-square analysis: European vs. Maori, p < 0.001; European vs. other non-European, p = 0.026). Notably, no DD individuals were identified in the Maori or other non-European ethnic groups.
Multivariate analysis revealed that ACE genotype, LVEF, BNP, a history of previous MI, and age were all independent predictors of death (p < 0.05) (Table 4). The ACE genotype groupings were strong independent predictors of mortality with ID or DD genotypes conferring increased risk corrected for the other risk factors in the analysis (odds ratio = 8.03; 95% confidence interval, 2.16 to 29.88; p = 0.002). Figure 2 illustrates interactions between ACE genotype and both LVEF and BNP in prediction of post-MI mortality. Patients with an ACE D allele in combination with either a lower than median LVEF or greater than median BNP had a significantly greater mortality (p < 0.001 and p < 0.025, respectively) than either of these risk factors alone. In contrast, for those with the II genotype, the prognostic ability of LVEF particularly, or BNP, was reduced.
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Table 4 Results of a Cox Proportional Hazards Model Analysis of Factors Predictive of Death as an End Point for the MI Cohort
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Figure 2 Kaplan-Meier survival curves illustrating the interaction between angiotensin-converting enzyme genotype (ID/DD vs. II) and (a) left ventricular ejection fraction (LVEF) and (b) brain natriuretic peptide (BNP) below or above overall median values. Medians: LVEF, 48%; BNP, 22 pmol/l. *p < 0.05; **p < 0.01;  p < 0.001.
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Discussion
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ACE genotype and prognosis.
In this study the ACE I/D genotype was demonstrated to be a stronger prognostic indicator of death after MI than in any previous study, with an odds ratio (corrected for other risk factors) of 8.03. Patients with either DD or ID genotype died at a significantly higher rate during the study period compared with the II group. Interestingly, the Kaplan-Meier survival curve in Figure 1 shows that death dynamics were very similar for the DD and ID genotype groups, and divergence from the II curve was observed from the 1,000 days post-MI point onwards.
Comparison with previous studies
Three previous studies have examined post-MI survival in relation to ACE genotype (12,13,16). Keavney et al. (12) and Samani et al. (13) found no association of ACE genotype with mortality after MI. Keavney et al. (12) reported follow-up of five years for 4,629 patients in a multicenter study and observed no difference in mortality between II, ID, and DD genotype groups. While it is difficult to discern a single factor to explain the disparity between that study and the present findings, differences in the patient sample groups may contribute to the differing outcomes. In the Keavney et al. (12) study, male patients were aged 30 to 54 years and female patients 30 to 64 years (compared with 20 to 79 years for both male and female patients in the present study). Despite the fact that in the Keavney et al. (12) study patients were predominantly younger, the overall mortality was higher (approximately 15% compared with 10.5% in the present study), and, hence, other factors may have contributed to a greater mortality in the Keavney study. A two-center study by Samani et al. (13) also found no difference in mortality between DD and ID/II genotype groups. However, this study followed only 684 patients for a shorter follow-up period (median, 15 months). Conversely, Yoshida et al. (16) found ACE genotype to be a risk factor for secondary cardiac events, including fatal events, in a study following 176 MI patients for five years. This is also supported by the Regression Growth Evaluation Statin Study (REGRESS), which found events including death and MI occurred more frequently in subjects with DD genotype among 885 male coronary artery disease patients (27). Consistent with our findings, ventricular dilation was shown to be increased in ACE DD patients after anterior MI (n = 96) at one-year follow-up (28). Others (7) have found that ACE genotype is associated with a greater risk of MI and subsequent mortality in those with low BMI and ApoE levels, but those in our study in a similar risk stratum showed no difference in the association of mortality or other end points with ACE genotype.
Renin-angiotensin-aldosterone system (RAAS) polymorphisms and heart disease
The importance of the RAAS in cardiovascular disease is evident from a number of lines of evidence (29), particularly the utility of ACE inhibitors in the treatment of MI (30) and congestive heart failure (31,32). While genetic influence on cardiovascular disease is recognized as being complex and multifactorial, it would not be unexpected if polymorphisms in genes encoding components of RAAS had significant effects on disease progression, given the reported effects on hemodynamics and cardiac remodelling (33). Reports of associations between heart disease and polymorphisms in genes affecting other components of the RAAS have also been published, including angiotensinogen (34), angiotensin II type I receptor (35), and aldosterone synthase (36). In addition, there have been reports of synergism between ACE I/D and some of these polymorphisms (37–40), along with contradictory studies that find no evidence for such multigene effects (41,42).
ACE genotypes and ethnicity
The relative frequencies of ACE genotypes recorded in the current study were similar to other studies where the subjects were predominantly European and virtually identical to one (34) of the two previous studies that have investigated the ACE polymorphism in cohorts of New Zealanders (34,43). Compared with European populations (7,12,34), Japanese have intermediate frequencies (44,45), and Polynesian ethnic groups have low frequencies of the D allele (43). African (46) and Indian (38,47) populations appear to have similar relative frequencies of the I and D alleles as Europeans. Ethnicity appears to have had little or no influence on the overall findings of this study. Although the number of patients who declared themselves to be Maori is very low, they display the low frequency of the D allele that had been noted previously in Polynesian populations (43). As a consequence of the extremely low frequency of the D allele in Maori populations, it seems unlikely that ACE genotype contributes to the high incidence of heart disease in Maori and their relatively poor prognosis (48,49).
ACE genotype and clinical measurements
In this study, ACE genotype was shown to be associated with plasma ANP, BNP, N-BNP, and endothelin-1 levels. Previously, BNP levels have been shown to be significantly associated with ACE genotype in a cohort of military recruits after, but not before, 10 weeks of physical training (50). The ANP levels after exercise were found to be significantly associated with ACE genotype in a cohort of 96 individuals with normal or impaired LV function (51). In our cohort, ANP levels were higher in DD patients compared with ID/II patients (p = 0.016)
The mechanism of the interactions between genotype and both LVEF and hormone levels is not clear. It is possible that higher tissue levels of ACE expression in the LV promote LV remodeling after MI, and the resultant LV dilation and cardiac hypertrophy enhances ANP and BNP secretion. Angiotensin II has also been reported to stimulate natriuretic peptide levels directly (52,53). To our knowledge, an association of ACE genotype with plasma endothelin-1 levels has not been previously reported. A number of studies have, however, described the interaction of endothelin-1 and AII, and increased levels of AII might well be expected to upregulate the expression of endothelin-1 (54,55). Both AII and endothelin-1 contribute to natriuretic peptide synthesis and secretion (56).
An association of ACE genotype with natriuretic peptide levels has been reported in 43 patients with blood samples taken at least a year after an anteroseptal MI (57). Nagashima et al. (57) found that levels of both ANP and BNP were elevated in grouped DD/ID individuals compared with II patients. This relationship between ACE genotype and the natriuretic peptide system may be of clinical relevance. Given the growing recognition of the utility of monitoring natriuretic peptide levels soon after MI (17,18,58) as a guide to prognosis and treatment (59,60), the Cox proportional hazards model multivariate analysis suggests determination of ACE genotype has potential as a prognostic tool for use in patients after acute MI. The interaction of ACE genotype and LVEF (as illustrated in Fig. 2) suggests that the additional burden of the ID/DD genotype contributes to mortality, possibly via increasing the degree of cardiac remodeling after MI (11).
Conclusions
Angiotensin-converting enzyme genotype was powerfully predictive of mortality in patients after acute MI. These findings reintroduce the potential of ACE genotype as a prognostic risk factor in contrast with the results of two previous studies (12,13). Our study differed from these earlier reports in that it was from a single New Zealand center and included patients up to age 80 years. After further investigation, ACE genotyping may also have potential in helping to elucidate which individuals with LV impairment might benefit from combined angiotensin receptor antagonist and ACE inhibitor therapy, which is far from clear at present (61).
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Acknowledgments
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The authors thank the participants in the study, Endolab staff, and cardiology outpatient staff.
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Footnotes
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Supported by the Health Research Council of New Zealand and the National Heart Foundation of New Zealand, Auckland, New Zealand. Ms. Pilbrow was the recipient of a Christchurch School of Medicine Summer Scholarship, and Prof. Richards holds the National Heart Foundation Chair of Cardiovascular Studies. Dr. Gottlieb Friesinger is the Guest Editor for this paper.
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