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European Journal of Heart Failure 1999 1(4):363-369; doi:10.1016/S1388-9842(99)00045-8
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© 1999 European Society of Cardiology

Angiotensin-II type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure

Bert Anderssona,*, Irina Blangeb and Christer Sylvénb

a Department of Cardiology, Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital 413 45 Göteborg, Sweden
b Department of Cardiology, Karolinska Institute at Huddinge Hospital Stockholm, Sweden

* Corresponding author. Tel.: +46-31-342-10-00; fax: +46-31-82-37-62. E-mail address: bert.andersson{at}hjl.gu.se


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: It has been suggested that a genetic polymorphism in the angiotensin II type 1 receptor gene (ATRG) and the ACE gene DD genotype might have a synergistic influence on the risk of developing cardiovascular disease.

Aims: To study the possible interaction between polymorphisms in the ACE gene and the ATRG, regarding survival and left ventricular function.

Methods: Polymorphism of the two genes was studied in a population-based cohort of 194 patients with idiopathic heart failure, recruited from the western part of Sweden 1985–1988. The patients were investigated by echocardiography. The survival status was checked during the 7-year follow-up period.

Results: Although there was no statistically significant additive risk of the ATRG polymorphism, patients carrying the ACE gene DD genotype in combination with a C allele of the ATRG tended to have a poorer prognosis. DD + AA, OR 1.24 (95% CI 0.67–2.32, P = 0.49); DD + AC, OR 1.64 (95% CI 0.95–2.83, P = 0.08); DD + CC, OR 3.54 95% CI 0.78–16.1, P = 0.10); DD + AC/CC, OR 1.84 (95% CI 1.10–3.08, P = 0.02). Patients with the DD + AC/CC genotypes tended to have lower ejection fraction and increased left ventricular mass.

Conclusions: There was a trend toward a worse prognosis in patients with the combination of a C-allele in the ATRG and the ACE gene DD genotype, suggesting an interaction of these two genetic polymorophisms on disease severity.

Key Words: Polymorphism (genetics) • Heart failure, congestive • Cardiomyopathy, congestive • Ventricular function, left • Prognosis • Epidemiology, molecular

Received February 15, 1999; Revised July 26, 1999; Accepted August 9, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
A genetic polymorphism in the angiotensin converting enzyme (ACE) gene has been identified, and the homozygous deletion (DD) genotype has been associated with an increased risk of developing coronary artery disease [1] and myocardial hypertrophy [2]. Although important negative studies have been published, [3,4] a meta-analysis has shown a statistically significant increase in the risk of developing coronary artery disease in patients with the DD genotype [5]. The most important implication of this genetic variation might be that individuals who develop a cardiovascular disease and possessing the DD genotype might be at an increased risk of disease progression. We recently reported an association between the DD genotype and an increased mortality in patients with idiopathic CHF [6].

A polymorphism in the angiotensin II type 1 receptor gene (ATRG) was discovered more recently. Angiotensin II exerts cellular effects through two receptor subtypes, AT1 and AT2. The AT1, a G protein-coupled receptor, is probably responsible for the major part of the intracellular effects of angiotensin II. A polymorphism in the 3' untranslated region of the ATRG has been described, corresponding to an A–C transversion at nucleotide position 1166 of the mRNA sequence [7]. The polymorphism consists of an A or C variant, giving three different possible genotypes: AA, AC, or CC. In association studies the C allele has been related to coronary vasoconstriction and stenosis [8,9]. Tiret and coworkers [10,11] found an association with the risk of developing hypertension and ischemic heart disease, whereas others have been unable to confirm these findings [12,13]. Furthermore, it has been suggested that the C allele is linked with higher serum levels of ACE in patients with sarcoidosis [14]. There are no previous studies regarding survival related to the ATRG polymorphism. A possible interaction between functionally important polymorphisms might have implications for the combination of treatment with ACE inhibitors and AT1 receptor blockade. It has been suggested that AT1 receptor blockers have effects similar to ACE inhibitors, or additive effects on top of ACE inhibitor treatment [15,16].

In the present study we intended to extend our previous investigation, including a longer follow-up period and an evaluation of interaction between the ATRG and the ACE gene polymorphisms in a population-based cohort of patients with idiopathic CHF. It was hypothesised that the DD polymorphism and the C allele of the ATRG might synergistically influence survival and myocardial hypertrophy.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients and controls
At the time of investigation, the western region of Sweden comprised five counties and had 1.64 million inhabitants, and the population was served by 19 hospitals. A survey of all patients, aged 16–65, hospitalised due to CHF or cardiomyopathy from 1980 to 1987, was performed between 1985 and 1988 (n=2711). Besides a diagnosis of CHF made by the responsible doctor, one of the following six findings of CHF was required for inclusion in the study: pulmonary rales; pulmonary congestion on chest X-ray; peripheral edema of probable cardiac origin; significant weight loss following diuretic treatment; cardiogenic shock; or autopsy findings of congestion and CHF. From the hospital records all possible causes of CHF were identified, including ischemic heart disease, hypertension, valvular heart disease, alcoholism, insulin treated diabetes mellitus, systemic diseases, serious infections and myocarditis, hypertrophic cardiomyopathy, cancer treatment, and pericardial diseases. The background population and definition of excluded conditions have been presented in detail previously [17]. Patients with no obvious cause of heart failure were invited to a clinical investigation. Out of 584 eligible patients with apparently idiopathic CHF, 411 of whom were alive, 293 accepted the investigation. Results of this investigation have been described previously [18,19]. The present investigation was performed at seven of the regional hospitals and blood samples for central analysis at the coordinating center were obtained at four of these seven hospitals, comprising the present study population (n=194). A random sample from the general population of individuals free from cardiovascular disorders and age-matched to the patient group was used as controls (n=77). Blood samples were drawn and stored until further analysis at –70°C.

2.2. Investigations
All patients and controls were investigated by M-mode and two-dimensional echocardiography and had a clinical examination including ECG, chest radiographs and routine laboratory tests. Echocardiography was performed according to the recommendations of the American Society of Echocardiography [20,21]. M-mode tracings were used to calculate left ventricular ejection fraction [22] and left ventricular mass [23]. Coronary angiography or autopsy was evaluated in 33 patients who presented with left ventricular dilatation and reduced ejection fraction. The diagnosis of dilated cardiomyopathy was confirmed in 31 of these patients who had normal coronary arteries.

2.3. Follow-up
Survival status was checked repeatedly during the 7-year follow-up period with the County population register and the Swedish national death registry, where all deaths in the country are registered. Patients who underwent a cardiac transplant were considered to have had an endpoint.

2.4. Laboratory investigation
Peripheral blood was separated in plasma and blood cells and stored in a freezer at –70°C until further analysis. DNA was extracted from frozen EDTA whole blood with the QIAmp blood kit (QIAGEN Inc, Chatsworth, CA, USA). ATRG polymorphism was determined using PCR with following DdeI digestion of PCR products, as described by Katsuya et al. [24]. The primers used to amplify the AT1 receptor region of 350 bp encompassing the A1166-C1166 polymorphism were 5'-ATAATGTAAGCTCATCCACC and 5'-GAGATTGCATTTCTGTCAGT. Forty cycles of PCR, consisting of 94°C for 1 min, 55°C for 1 min and 72°C for 1 min, were performed (Taq polymerase; Promega, Medison, USA). PCR products were digested with 5 U Dde I (Amersham, Life Science, UK) at 37°C for 2 h and then separated on 2% agarose gel. Polymerase chain detection of the insertion/deletion polymorphism of the human ACE gene was performed as described previously [25]. Blinded genotyping was undertaken after the samples had been separated with electrophoresis on a 2% agarose gel and stained with ethidium bromide (0.5 mg/ml).

2.5. Statistical analysis
Owing to the small number of ATRG CC homozygotes, AC heterozygotes and CC homozygotes were pooled in this analysis. A multivariate stepwise Cox proportional hazard model was used to evaluate the influence of the ACE gene and the ATRG polymorphisms on mortality. The DD genotype and the AC/CC genotype were tested. Further, the following clinical variables were also correlated with mortality: ejection fraction, age, gender, NYHA functional class, duration of heart failure symptoms, LV end-diastolic diameter, LV mass, heart rate, and systolic blood pressure. A multivariate procedure for independent predictors of mortality was performed, including genotypes and clinical variables with a P value<0.10 in the univariate correlation. Similar to the mortality analysis, a univariate and multivariate logistic correlation was done for evaluation of the impact of genotypes and clinical variables on LV mass. The statistical analyses were performed on SAS statistical software (SAS Inc, Cary, NC, USA). All values are expressed as mean±S.D. A P value<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Genotype distribution
The C/A allele frequencies was 0.29/0.71 among the patients, and 0.30/0.70 among the control subjects (not significant). In patients with dilated cardiomyopathy and negative coronary angiography the corresponding allele frequencies were 0.44/0.56 (P=0.089 vs. controls). Baseline characteristics are given for the patients according to the three ATRG polymorphisms in Table 1, and the distribution of the ACE and ATRG genotypes is given in Table 2.


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  		Table 1 Baseline characteristics in 194 patients with idiopathic congestive heart failure and different ATRG genotypesa

 


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  		Table 2 Distributions of ATRG and ACE gene polymorphisms in 194 patients with congestive heart failure

 
3.2. Survival data
During the 7-year follow-up there were 92 endpoints in the study, 10 of which were due to cardiac transplantations. Survival curves for the three different ATRG genotypes are presented in Fig. 1. Survival curves for the combination of genotypes DD+AC/CC, DD+AA, ID/II+AC/CC, ID/II+AA show a trend towards a poorer survival in patients with genotypes DD and AC/CC (Fig. 2). Using a univariate Cox analysis the combination of DD+AC/CC genotypes was associated with the poorest outcome. Odds ratio (OR) for mortality was 1.87 (95% CI 1.21–2.90, P=0.005) for DD+AC/CC; 1.58 (95% CI 1.06–2.33, P=0.02) for DD; and 1.28 (95% CI 0.87–1.89, P=0.21) for AC/CC. Risk evaluation of different ATRG genotypes, related to the presence of DD genotype are shown in Fig. 3. In a multivariate analysis, including only the two genotypes DD and AC/CC, only the DD genotype was independently associated with mortality, OR 1.56 (95% CI 1.06–2.32, P=0.03). In the multivariate analysis that corrected for the influence of other variables, neither the ACE nor the ATRG genotype was independently associated with survival. An interaction test between the two genotypes was not statistically significant (P=0.11). Including all clinical, echocardiographic and genetic variables in the analysis, LV mass, blood pressure and NYHA class were independently correlated with long-term survival (Table 3).


Figure 1
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  		Fig. 1 Mortality curves constructed by the Kaplan–Meier procedure in 194 patients according to the three ATRG genotypes AA, AC, CC. In a univariate Cox regression analysis, there was no significant difference in survival between the three groups.

 


Figure 2
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  		Fig. 2 Mortality curves constructed by the Kaplan–Meier procedure in 194 patients according to different ATRG and ACE gene polymorphisms: DD+AC/CC, DD+AA, ID/II+AC/CC, ID/II+AA. In a univariate Cox regression analysis, there was a significant difference in survival between the four groups (P=0.04).

 


Figure 3
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  		Fig. 3 Risk of death according to ATRG genotype (AA, AC, AC/CC and CC) in the presence of ACE gene DD polymorphism in 194 patients with idiopathic heart failure. Number of cases at risk are given in each subgroup. Odds ratio (95% CI) was calculated as the risk of death during a 7-year follow-up and the P values are given below group frequencies.

 


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  		Table 3 Univariate and multivariate correlation with mortality in 194 patients with idiopathic congestive heart failurea

 
3.3. Left ventricular mass
The DD and the ID genotypes were significantly correlated with LV mass in the univariate analysis. The ATRG genotypes were not significantly associated with LV mass. The influence of other variables is shown in Table 4. In the multivariate logistic analysis, the DD genotype showed a trend towards a connection with LV mass, OR 1.76 (95% CI 0.94–3.31, P=0.08). Incorporating all other variables resulted in only the male sex having an independent association with LV mass. There was a trend towards increasing LV mass in the combined groups of DD and AC/CC genotypes: DD+AC/CC, 156±53 g/m2; DD+AA, 149±62 g/m2; ID/II+AC/CC, 137±50 g/m2; ID/II +AA, 131±39 g/m2 (P=0.072, DD+AC/CC vs. the other genotypes combined). Similarly, ejection fraction was lower in the DD+AC/CC group (36±16%) as compared with the other genotypes combined (P=0.048): DD+AA, 42±20%; ID/II+AC/CC, 46±16%; ID/II+AA, 39±16%.


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  		Table 4 Univariate and multivariate logistic correlations with LV mass in 194 patients with idiopathic congestive heart failurea

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
This is the first study to evaluate the influence of the ATRG genotype on long-term survival. The advantages of the present study were that the patients were extracted from a population-based cohort, and that we possessed complete 7-year survival data. Furthermore, the patient group constituted a clinically homogeneous group of patients with regard to etiology, in that all were considered to have CHF of unknown cause. This is a common group in clinical practice and constituted 22% of the total CHF population. We were not able to perform coronary angiography in all study patients. Coronary angiography was done in a subset of the patients and the frequency of concealed coronary artery disease was estimated to be 6%.

Most previous epidemiological studies have been studying the risk for development of coronary artery disease, and some major studies have been negative [4]. On the other hand, when the neurohormonal systems are significantly activated, such as in congestive heart failure, certain genotypes might predispose for an altered neurohormonal response. This might explain why effects of genetic polymorphism could be found in patient populations with heart failure, but not in patients and controls without activated neurohormonal systems. We have previously demonstrated that the DD genotype of the ACE gene was independently associated with a poorer 5-year survival in this patient group, also in a multivariate analysis, OR 1.69 (95% CI 1.01–2.82, P=0.04) [6]. In the present 7-year analysis, the ACE gene polymorphism was not independently associated when other variables had been introduced in the regression analysis. A reason for the differing results might be that in the present longer follow-up there were fewer patients at risk. Progression of cardiac dysfunction could also possibly make markers of disease severity successively more important. Nevertheless, the patients with the DD polymorphism still had the poorest survival among the different genotypes.

4.1. Possible pathophysiological mechanisms
The ACE gene DD polymorphism has been associated with increased concentrations of angiotensin II. On the other hand, a possible physiological mechanism of the presence of a C allele in the ATRG has not been clarified. Several G protein–coupled receptors exhibit down-regulation due to increased agonist stimulation [26–28]. Tiret [10] suggested that the ATRG C allele is in linkage disequilibrium with a functional variant that could alter the down-regulation of the ATRG in response to angiotensin II. Thus, an altered receptor sensitivity could be responsible for an interaction between the two polymorphisms. Neurohormonal activation of systemic or tissue renin–angiotensin system may participate in disease progression by means of inducing myocardial hypertrophy, precipitate myocyte damage, and by fibroblast stimulation [29–31]. An interaction of gene expression might contribute to the observed interaction in treatment effects of combined ACE inhibition and angiotensin II receptor blockade, such as in the recent RESOLVD study [16].

4.2. Limitations
Homozygotes with the CC genotype are infrequent in the general population, and to establish a possible increase in the risk of death larger studies are needed. The trend toward increased mortality with the combination of DD and CC genotypes was not statistically significant in an interaction analysis. However, the inability to show a significant contribution of the ATRG genotype in the mortality estimate may also be falsely negative in that the homozygous CC group was too small. A combined analysis with other study populations might be of value, but to our knowledge no other population has been subject to as long a follow-up as in our study.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In patients with idiopathic heart failure, a non-significant trend toward poorer survival was found in patients possessing the DD polymorphism in combination with the ATRG C allele.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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