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European Journal of Heart Failure 2004 6(1):11-16; doi:10.1016/j.ejheart.2003.07.009
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© 2004 European Society of Cardiology

Does angiotensin-converting enzyme gene polymorphism affect blood pressure? Findings after 6 years of follow-up in healthy subjects

Pietro Di Pasqualea,*, Sergio Cannizzaroa and Salvatore Paternab

a Division of Cardiology ‘Paolo Borsellino’, G.F. Ingrassia Hospital, Via Val Platani 3, 90144 Palermo, Italy
b Department of Emergency Medicine University of Palermo, Palermo, Italy

* Corresponding author. Tel./fax: +39-91-7033742. E-mail address: lehdi{at}tin.it


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: There has been an increase in research into the association between angiotensin-converting enzyme (ACE) gene deletion polymorphism and cardiovascular disease, with conflicting results. The present prospective long-term study was conducted to evaluate whether the DD genotype could also be associated with a higher prevalence of hypertension in healthy subjects, over 6 years of follow-up.

Methods: Population: 684 healthy volunteers (aged, 25–55 years): normotensive and free of cardiovascular diseases, with acceptable echocardiographic window. All subjects had to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at entry.

Study protocol: All subjects underwent a complete physical examination, 12-lead ECG and ECHO, and venous blood samples were drawn for DNA analysis and cholesterol. All subjects had a clinical evaluation each year for the 6 year duration of the study.

Results: All 684 subjects completed 6 years of follow-up. We identified three genetically distinct groups. The ACE-DD group (n=225, 80F/145M, mean age 43.4±7.6 years) had 42 hypertensive subjects (18.3%), 5 heart failure (HF) subjects and 6 subjects with acute coronary syndromes (ACS). There was no association between family history, smoking habit, hypercholesterolemia and events. The ACE-ID group (n=335, 116F/219M, mean age 43.6±7 years) had 16 hypertensive subjects (4.7%) and 3 subjects with ACS. The ACE-II group (n=124, 45F/79M, mean age 42.5±6.9 years) had 2 hypertensive subjects (1.6%) and 1 HF subject. The incidence of hypertension and cardiovascular events was significantly higher in the ACE-DD group (53 cases, 23%) than in the ACE-ID and ACE-II groups (20 and 3 cases, 5.9 and 2.4%, respectively), P=0.0001. The higher incidence of hypertension was observed in the older age groups (36–45 and 46–55 years) with ACE-DD and ACE-ID genotypes.

Conclusion: Our data suggest that ACE-DD polymorphism is associated with a higher incidence of hypertension in baseline healthy subjects, irrespective of other risk factors. The higher incidence of hypertension was apparent predominantly in the older age groups.

Key Words: ACE-I/D gene polymorphism • Healthy subjects • Hypertension

Received June 27, 2003; Revised July 8, 2003; Accepted July 8, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
There has been an increase in research into the angiotensin-converting enzyme (ACE) gene deletion polymorphism, and there is continuing interest in the link between a variant deletion of the gene for ACE and an increased incidence of myocardial infarction (MI) [1]. Many studies have reported an association between the ACE-D allele and both coronary heart disease [2–4] and other cardiovascular diseases [5,6], although other studies have failed to confirm this result [7]. The mechanism underlying this positive association is not yet clear. There is increasing evidence linking the renin–angiotensin–aldosterone system with the regulation of cardiac and vascular growth. ACE circulates in the plasma and is present on the surface of endothelial cells, where it stimulates the conversion of the inactive angiotensin I to the highly active angiotensin II. Angiotensin II is a potent vasoconstrictor. An attractive hypothesis is that the effects of the ACE-D allele polymorphism are mediated by altered expression of tissue and/or circulating ACE. Recently, two large prospective studies have shown a positive association between the DD genotype and hypertension [8,9]. The study of this association is very important because hypertension is a major risk factor in the development of heart failure (HF).

The present prospective long-term study was conducted to evaluate whether the DD genotype was associated with a higher prevalence of hypertension in healthy subjects over 6 years of follow-up. The end point of the study was to observe the incidence of hypertension in healthy subjects with ACE-I/D polymorphism after 6 years of follow-up.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
The study was done through our public epidemiology screening clinic for healthy individuals, where every year thousands of subjects undergo medical evaluation. Between May and July 1995, the first 1280 consecutive healthy subjects presenting at the above clinic were invited to participate in our study. Of these 1280 subjects, 185 were receiving drugs, 105 had a BMI >25 and 36 refused to participate. The remaining 954 healthy subjects (aged 25–55 years) were, therefore, suitable for the study and were sent to our Division of Cardiology, Ingrassia Hospital (Italy) for preliminary evaluation and enrollment. The follow-up was completed between May and July 2001, when the all subjects completed the last clinical and physical evaluations. All subjects were white Caucasians and Italian citizens.

2.1. Inclusion criteria
All subjects had to be normotensive (systolic blood pressure (SBP) <=120–125 mmHg and diastolic <=80 mmHg) at entry, free of cardiovascular disease, with normal body weight and a body mass index <25. The subjects had to have an acceptable echocardiographic window, with no symptoms of CAD, no history of HF, angina, MI, diabetes, hypertension, obesity, hypercholesterolemia (>240 mg/dl), or other clinical disorders which could determine cardiovascular alterations (e.g. collagen and respiratory diseases, metabolic alterations, etc.). All subjects had to be clinically healthy and not receiving drugs before or after entry into the study. All individuals were required to have a normal electrocardiogram (ECG) and echocardiogram (ECHO) at study admission. Subjects with hypercholesterolemia (>200 and <240 mg/dl) agreed not to receive drugs and to follow a modified diet only. Subsequent annual monitoring of plasma cholesterol levels showed good control in this group (187±25 mg/dl after 6 years). All the other subjects showed cholesterol values <200 mg/dl throughout the 6 years of follow-up. Subjects with cholesterol levels >240 mg/dl were excluded from the study.

2.2. Study protocol
Prior to enrollment, all subjects underwent a complete physical examination, and height, weight, blood pressure (mean of three measurements after 5-min supine rest, each 1 min apart), 12-lead ECG and ECHO recordings were obtained. Venous blood samples were drawn for analysis of DNA and cholesterol (values of cholesterol <200 mg/dl were considered normal, with HDL >45 mg/dl). Subjects were instructed to avoid any drug treatments (non-steroidal anti-inflammatory drugs, diuretics, antihypertensive drugs) without previously informing the research team.

The molecular biologist evaluating the ACE gene polymorphism was blinded to the clinical history of the subjects. The samples of blood sent to the laboratory were only identified by a number. Another independent physician was responsible for correlating the numbered laboratory data with the subjects identity. The results of gene determination were seen after 6 years and these results were related to the subjects identity. We obtained a complete association between ACE-gene and subjects before unblinding of the data.

All data were analysed by an independent physician and submitted to the person responsible for the research. The local ethics committee approved the study, and all subjects gave informed consent to supply peripheral blood for DNA analysis.

2.3. Follow-up (6 years)
All subjects were contacted every 6 months by a member of the research team for a telephone interview and each year attended for a clinical visit. We also obtained information from family doctors, who were informed about the study endpoints. Any of the subjects experiencing hypertension or other cardiovascular disorders according to the family doctor were invited to attend hospital for evaluation and initiation of treatment as necessary. ECG, ECHO and when necessary computed tomography and other investigations were performed as appropriate. Subjects were defined as hypertensive when repeated controls showed SBP and DBP values >140 and 90 mmHg, respectively. HF was defined when patients showed a reduction of ejection fraction (EF) <40–45% on ECHO and ECG changes related to left ventricular enlargement. Myocardial infarction or acute coronary syndromes (ACS) were defined when the patients experienced chest pain with elevation or depression of ST segment on ECG, concomitant alterations of segmentary kinetics on the ECHO and showed evidence of critical coronary stenosis by coronarography. All subjects underwent the final evaluation (complete physical and clinical examination) between May and July 2001.

2.4. Echocardiographic methods
Experienced physicians performed the ECHOs according to a strict protocol. All subjects lay in a standard left-lateral position to negate the influence of body position. Echocardiographic recordings were obtained at the end of the respiratory phase during normal breathing, and an apical four-chamber and two-chamber view was used. EF was obtained by the modified Simpson's rule, which uses two cross-section views (four- and two-chamber apical views) [10]. The end systolic and LV end diastolic dimensions were measured by two-dimensional left ventricular long and short axis views at the level of the mitral valve leaflet tips as recommended by American Society of Echocardiography protocols [11]. ECHOs were analysed unpaired and in random order. Measurements were expressed as the mean of three readings made independently by each of two observers blinded to ACE genotype.

2.5. DNA preparation
DNA was prepared from a small aliquot of whole blood collected in ethylenediaminetetraacetic acid, using a DNA extraction matrix. Genotypes were determined by polymerase chain reaction amplification of the ID region of the ACE gene using oligonucleotide primers and resolving the amplified products on 1.5% agarose gels containing ethidium bromide, with modification to prevent mistyping of the ID individuals as DD homozygotes (as previously reported) [7]. Blank controls were routinely included with each set of amplification to exclude contamination. Genotypes were determined without knowledge of the case control status and, as a further check, 30% of the subjects were chosen to undergo repeat genotyping using freshly prepared DNA, and all the cases were confirmed.

2.6. Statistical analysis
Results are expressed as the means±S.D. Data were analysed by two-tailed t-test in order to identify differences between the groups, and by ANOVA for repeated measures with Bonferroni correction for intragroup data. Nominal data were analysed by the {chi}2-test, P<0.05 was assumed to be statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
Of the 954 subjects, 45 did not undergo an ECHO, 55 had unacceptable echocardiographic windows, 65 had SBP ≥140 mmHg at entry, 30 were receiving drugs, 30 had ECG or echocardiographic abnormalities and 45 did not undergo follow-up assessment (first and second year), all were excluded from the study. These 270 subjects showed a similar distribution in genotypes of ACE-I/D (59 ACE-II, 91 ACE-DD, 120 ACE-ID) compared to the remaining subjects. The remaining 684 subjects met the entry criteria, agreed to be enrolled in the study and completed 6 years of follow-up. We identified 3 genetically distinct groups: (a) ACE-DD group: this group consisted of 225 subjects (80F/145M), mean age 43.4±7.6 years; (b) ACE-ID group: 335 subjects (116F/219M), mean age 43.6±7.6 years; (c) ACE-II group: 124 subjects (45F/79M), mean age 42.5±6.9 years. Characteristics of all the enrolled subjects are listed in Table 1. The observed distribution in genotypes of ACE-I/D was similar to that previously reported in a Sicilian population [12]. The groups were similar with regard to age, sex, smoking habits, family history and hypercholesterolemia.


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  		Table 1 Characteristics of all subjects enrolled according to genotypes

 
The incidence of events over the 6-year follow-up are shown in Table 2. In the ACE-DD group (n=225) five subjects had unsymptomatic HF (ECG changes in the QRS complex, ST segment and T wave related to ventricular enlargement and EF <45% on ECHO) and six subjects had myocardial ischemic events (4 AMI and 2 ACS). Hypertension was detected in 42 subjects (18.3%) with SBP/DBP values 152±12/91±9 mmHg, measured at first evidence of hypertension, these values were significantly higher compared to baseline values. The subsequent values were within the normal range (all patients received treatment with ACE-inhibitors). The 42 hypertensive patients did not show segmental hypertrophy on ECHO or EF reduction. There was no association between family history, smoking habit, hypercholesterolemia or hypertension and cardiovascular events. In fact, only 10 subjects with family history, hypercholesterolemia and smoking habit showed hypertension and/or cardiac events during the follow-up (Table 3).


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  		Table 2 Events after 6 years of follow-up in all enrolled subjects

 


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  		Table 3 Association between hypertension, cardiovascular events and baseline risk factors in the three genotypes (number of patients)

 
In the ACE-ID group (n=335) 16 subjects were hypertensive (4.7%) (SBP/DBP 151±16/89±8 mmHg) measured at first evidence of hypertension and 3 subjects had myocardial ischemic events (1 AMI and 2 ACS). There was no association between family history, hypertension and cardiovascular events. Only seven subjects with family history, hypercholesterolemia and smoking habit showed hypertension and/or cardiac events during the follow-up (Table 3). After ACE-inhibitor treatment SBP/DBP were within the normal range.

In the ACE-II group (n=124) there were only two hypertensive subjects (1.6%) (SBP/DBP 144±6/88±4 mmHg at first evidence of hypertension), and one subject with HF (LBB on ECG and EF <45% on ECHO). No subjects with hypercholesterolemia, smoking habit or family history, presented with hypertension or cardiovascular events during the follow-up (Table 3). After ACE-inhibitor treatment SBP/DBP was within the normal range. ECG and ECHO data were normal in all subjects. The hypertensive subjects did not show significant alterations on ECG and ECHO (myocardial mass) because they had early diagnosis and treatment.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The healthy subjects with ACE-DD polymorphism enrolled into the study showed in the long term (6 years) a higher incidence of hypertension compared to those subjects with ACE-ID and ACE-II polymorphism. In addition, the higher incidence of hypertension was also observed when subjects were stratified into 10-year age groups (36–45 years, or 46–55 years) (Table 4). These observations suggest that the ACE-DD, by activation of the ACE system in the long term, can determine development of hypertension by endothelial dysfunction and neurohormonal activation [13,14]. Further, these results suggest that ACE-DD polymorphism could be considered a risk factor for hypertension per se. In fact, family history, smoking habit and hypercholesterolemia were not associated with a greater incidence of events in all three groups of subjects. ACE may play an important role in the proliferation of vascular smooth cells through activation of angiotensin II (an inducer of cell proliferation) and inhibition of bradykinin (an inhibitor of growth). The clinical observation of an increased incidence of malignant hypertension in certain ethnic groups supports a key role for genetic modifiers in determining susceptibility to malignant hypertension [15,16]. Subjects possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with arteriosclerosis [13]. Some studies, also on essential hypertension, have shown conflicting results, reporting both positive and negative associations [17–19]. Owing to the nature of the association studies, it is possible that the observed positive association is the result of linkage disequilibrium between the ACE-I/D polymorphism and another closely located functional polymorphic locus. However, there are several pieces of evidence supporting a functional role for the ACE-I/D polymorphism and hypertension. The ACE-DD genotype has been associated with increased serum and tissue concentrations of ACE [20–22]. The ratio of angiotensin I to angiotensin II is higher in the kidney than in serum, suggesting that the functional effects of the I/D polymorphism, in terms of the local production of angiotensin II, may be of particular importance in the kidney [23]. These effects are even more important following activation of RAS. Moreover, in animal models AII influences cell growth and matrix deposition, both of which are important in vascular wall remodelling [24,25]. Recently, two large prospective studies analysing different ethnic populations, the Japanese Suita study and the American Framingham heart study, have independently shown a positive association between the DD genotype and essential hypertension in men but not in women [8,9]. Echocardiography was used to include only healthy subjects into this study (all subjects showed normal ECG and ECHO). Since hypertension is a major risk factor for the development of HF, it is very important to identify which subjects are potentially at risk of HF, in order to be able to initiate treatment to prevent the development of hypertension and possible cardiac involvement.


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  		Table 4 Events according to stratification in 10-year age group and genotypes (number of subjects)

 
In conclusion, our data suggest that ACE-I/D polymorphism may determine an higher incidence of hypertension in healthy subjects, independent of other risk factors. The higher incidence of hypertension is apparent mostly in the age groups 36–45 and 46–55 years. This result suggests that if preventive treatment has to be started subjects aged 40–45 years appear the most suitable targets.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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