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Cardiovascular Research 1999 43(1):192-199; doi:10.1016/S0008-6363(99)00055-3
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Copyright © 1999, European Society of Cardiology

Hypertensive left ventricular remodeling and ACE-gene polymorphism

Francesco Perticone*, Raffaele Maio, Carmela Cosco, Roberto Ceravolo, Saverio Iacopino, Massimo Chello, Pasquale Mastroroberto, Donatella Tramontano and Pier L Mattioli

Department of Medicina Sperimentale e Clinica ‘G. Salvatore’, Policlinico Mater Domini, Via T. Campanella 88100, Catanzaro, Italy

* Corresponding author. Tel.: +39-0961-712-264; fax: +39-0961-775-373 perticone{at}unicz.it

Received 17 August 1998; accepted 17 December 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Objective:To evaluate the relationship between ACE-gene polymorphism and left ventricular geometry in never treated hypertensives. Methods: We enrolled 200 hypertensive outpatients that underwent clinical and ambulatory blood pressure measurements, echocardiographic evaluation and analysis for insertion (I)/deletion (D) polymorphism by PCR. Patients with normal or increased (>125 g/m2 in males and >110 g/m2 in females) left ventricular mass were considered to have concentric remodeling or concentric left ventricular hypertrophy if their relative wall thickness was ≥0.45. Results: The left ventricular mass index values (g/m2) were 136±30 in DD genotype, 124±26 in ID genotype, and 116±20 in II genotype (DD vs. ID P<0.005; DD vs. II P<0.05), and were unrelated to blood pressure. Ninety-six patients presented left ventricular hypertrophy (48.0%): 51 with concentric and 45 with eccentric hypertrophy. The eccentric left ventricular hypertrophy was detected in 32 (36.8%) DD patients, in ten (10.5%) ID patients (P<0.05), and in three (16.6%) II patients. The relative septal thickness was 0.43±0.09 in DD genotype, 0.45±0.08 in ID genotype, and 0.43±0.10 in II genotype. In DD and ID genotypes, the relative posterior wall thickness (0.37±0.07 vs. 0.41±0.07; P<0.0001) and the end-diastolic left ventricular internal dimension (52.8±3.3 mm vs. 48.3±2.8 mm; P<0.0001) were statistically different. Conclusions: The DD genotype of the ACE-gene is associated with an increased left ventricular mass and with a significantly higher prevalence of eccentric left ventricular hypertrophy, when compared to ID genotype.

KEYWORDS ACE-gene polymorphism; Left ventricular hypertrophy; Cardiac remodeling; Hypertension; Cardiovascular risk factors

This article is referred to in the Editorial by Y.M. Pinto and W.H. van Gilst (pages 192–199) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Left ventricular hypertrophy (LVH) represents a substantial risk for cardiovascular morbidity and mortality. Echocardiography has permitted the reliable noninvasive evaluation of left ventricular mass (LVM) and has been proved to be a more sensitive tool for the detection of LVH [1–3].

In hypertensives LVH develops as an adaptive process allowing the heart to normalize increased afterload and preserve systolic performance. However, clinical studies do not show a close relation between blood pressure (BP) values and degree of LVH. Besides, in humans left ventricular adaptation to high BP has been shown to be more complex. In fact, hypertensives with mild to moderate hypertension exhibit normal LVM and wall thickness [4–7]; other patients have eccentric LVH that is not related to systolic dysfunction, but rather to increased preload and cardiac output [6,8]. In hypertensive patients abnormal left ventricular geometry is also predictive of cardiovascular events [1,3,4].

The renin–angiotensin system (RAS) seems to be involved in the pathophysiology of high BP and in the cardiac adaptive process. The cloning of the ACE-gene has made it possible to identify an insertion (I)/deletion (D) polymorphism that appears to be associated with different levels of serum ACE activity [9–11]. Previous studies relating ACE genotype to myocardial infarction, dilated and hypertrophic cardiomyopathy and LVH have been conflicting [12–21].

The aim of this study was to evaluate in a group of never treated hypertensive patients: (1) the possible relationship between ACE-gene polymorphism and BP; (2) the possible interaction between ACE DD genotype alone or in association with other factors (age, gender and BP values) on cardiac mass and left ventricular geometry.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 References
 
2.1 Study population
The study included 237 consecutive outpatients, 113 men and 124 women, referred at Catanzaro University Hospital to evaluate their hypertensive status. All patients were white, and their families had been living in Calabria (South Italy) at least two generations. Causes of secondary hypertension were excluded by the appropriate clinical and biochemical examination. Patients enrolled in this study had not been evaluated before regarding the association of the ACE-gene polymorphism with LVH, and none had received antihypertensive drugs.

Local ethical committee approved the protocol study, and all participants gave written informed consent for all procedures.

2.2 Echocardiograms
Echocardiographic tracings were taken with the patient in partial left decubitus position, using a Vingmed Sound CFM-800C (Horten-Norway) with an annular phased-array 2.5 MHz transducer. Reproducibility of measurements was optimized by having the same experienced sonographer (CC) perform all studies. In our laboratory, the intra-observer coefficients of variation are 4.65% for posterior wall (PW) thickness, 4.60% for inter-ventricular septal (IVS) thickness, 1.50% for left ventricular internal dimension (LVID) and 6.33% for LVM. Echocardiographic readings were made in random order by investigator who had no knowledge of patients BP and other clinical data. The mean values from at least five measurements for each parameter for patients were computed.

Beat-to-beat LVM variability, expressed as the S.D. of five measurements, ranged from 0 to 23 g, with a mean of 9.8 g.

2.2.1 M-mode measurements
Tracings were recorded under two-dimensional guidance and measurements were taken at the tip of the mitral valve or just below. Measurements of IVS thickness, PW thickness and left ventricular internal dimensions were made at end-diastole and end-systole as recommended by the American Society of Echocardiography and the Penn Convention [22,23]. LVM was calculated using the formula introduced by Devereux and co-workers. Individual values for LVM were indexed by body surface area (LVMI), and expressed as g/m2 [23].

2.2.2 Patterns of left ventricular geometry
Relative wall thickness (RWT) was measured at end-diastole as the ratio of twice the thickness of PW/LVID [1] or, as recently reported by Verdecchia et al. [3], as the ratio of twice the thickness of IVS/LVID. The value of 0.45 was considered the cutpoint of RWT.

Categorizing patients according to values of LVMI and end-diastolic RWT identified four different patterns of left ventricular geometry. Upper normal limits of LVMI were 125 g/m2 in men and 110 g/m2 in women. Patients with normal LVMI were considered to have normal left ventricular geometry if their RWT was normal (<0.45) or concentric remodeling if their RWT was elevated (≥0.45). Those with increased LVMI were considered to have concentric or eccentric LVH if their RWT was ≥0.45 or normal (<0.45).

2.3 Blood pressure measurements
Clinic BP was measured with patients supine after 5 min of rest with a mercury sphygmomanometer. A minimum of three BP readings were taken on three separate occasions at least 2 weeks apart. Patients with a clinic BP≥160 mmHg systolic and/or 95 mmHg diastolic were defined as hypertensive.

Ambulatory BP monitoring was obtained using an A&D TM 2420 recorder (model 7, Takeda, Tokyo, Japan). Recordings were taken every 10 min during the day (from 07:00 a.m. to 11:00 p.m.) and every 20 min during the night (from 11:00 p.m. to 07:00 a.m.). We considered the cut-point for hypertension BP values >140/90 mmHg.

2.4 Detection of ACE polymorphism
The ACE genotypes were determined in duplicate by polymerase chain reaction (PCR) using the primers and methods described by Rigat et al. [24]. The genotype was verified using an insertion specific primer, according to Shanmugan et al. [25]. For further details see the method previously described [17].

2.5 Statistical analysis
Analysis of variance for clinical and biological data was performed and differences between means were compared by unpaired Student’s t-test, as appropriate. Allele frequencies were estimated by the gene counting method, and Hardy–Weinberg’s equilibrium was verified by a {chi}2 test. Multiple linear regression was used to compare quantitative data on LVM and end-diastolic LVID among patients with the DD, ID and II genotypes. Each group was analyzed separately according to the gender and together, with and without adjustments for covariates (age, BMI, systolic and diastolic ambulatory BP). LVH (presence or absence) was analyzed as categorical variable by a stepwise multiple logistic regression with forward selection; ACE genotypes, age, sex, BMI, systolic and diastolic ambulatory BP were considered as independent variables. Finally, the statistical analysis was based on the calculation of odds ratios to provide an estimate of the risk of LVH using Yates’s corrected {chi}2 test, or Fisher’s test as appropriate, after ANCOVA correction for age, BMI and BP; the Bonferroni/Holt correction was used for P values. Analysis was performed in all patients, and for men and women separately. Significant differences were assumed to be present at P<0.05. All group data are reported as mean±S.D.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 References
 
3.1 Study population
Of the 237 patients, 200 (84.3%) were included in the analysis because of the good quality of the echocardiograms that were made before genotypes were available. Demographic and humoral characteristics are summarized in Table 1. The groups did not differ significantly with regard to age, height, weight, body-mass index, systolic and diastolic BP and heart rate.


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  		Table 1 Characteristics of the subjects according to ACE genotype and sex

 
3.2 Frequencies of alleles and genotypes
The frequencies of the ACE D and I alleles were 0.672 and 0.328 respectively, similar to those observed in a normal population from the same area [26].

The observed frequencies of 0.435 (n=87), 0.475 (n=95), and 0.090 (n=18) for the DD, ID and II genotypes, respectively, were in Hardy–Weinberg’s equilibrium ({chi}2=0.049, P=0.825). No significant differences were found between men and women ({chi}2=1.749; P=0.417) (Table 1).

3.3 ACE genotypes and blood pressure
Systolic and diastolic clinic BP values were 163/98±17/7 mmHg and 157/98±12/9 mmHg in DD and II homozygous, respectively; in ID group BP was 161/99±16/7, but these differences were not statistically significant.

The monitored BP values were 150/92±13/9 mmHg and 147/91±10/6 mmHg in DD and II homozygous, respectively; in ID group BP was 147/90±11/7 mmHg. These differences were not statistically significant.

Thus, both clinic and monitored BP values were similar in the three genotypes and resulted unrelated to ACE-gene polymorphism.

3.4 ACE genotypes and LVM
The LVMI values are reported in Fig. 1 Comparison between groups revealed that DD genotype was associated with a significantly increased LVM when compared with ID (P<0.005) and II (P<0.05) genotype. Gender analysis demonstrated that I/D polymorphism of ACE-gene significantly affects the LVMI only in hypertensive males, while the cardiac mass values did not differ significantly in hypertensive females (Fig. 2).


Figure 1
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  		Fig. 1 Values of left ventricular mass index (LVMI) in ACE-gene genotypes are graphically reported. The LVMI is significantly increased in DD genotype in comparison with ID (P<0.005) and II (P<0.05) genotypes. No differences were observed between ID and II genotypes.

 

Figure 2
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  		Fig. 2 Left ventricular mass index (LVMI) values, obtained according to gender analysis, in the three genotypes are graphically reported. LVMI is significantly higher in DD and ID genotype males than females; no significantly differences are present in II group. Besides, the cardiac mass values did not significantly differ in females, while the significant differences between genotypes are found in males.

 
An excess of patients homozygous for the D allele characterized the group with LVH. In particular, patients with cardiac hypertrophy were 52 (31 men and 21 women) (26.0%) in DD genotype, 39 (18 men and 21 women) (19.5%) in ID genotype, and five (2.5%) in II genotype (three men and two women) (Table 2). The analysis, adjusted for covariates (age, BMI and BP), revealed that the DD genotype was associated with a significantly increased risk of LVH; when analysis was performed separately for gender, significant differences were observed in men, but not in women (Table 3).


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  		Table 2 Echocardiographic characteristics of the hypertensive patients according to ACE genotypea

 

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  		Table 3 Adjusted odds ratios and 95% CI for left ventricular hypertrophy according to ACE genotype and sex

 
When we tested the effects of other factors by a stepwise multiple linear regression, we observed that gender, ACE genotype and systolic ambulatory BP were each significantly related to LVMI (Table 4).


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  		Table 4 Effects of variables associated with left ventricular mass index (LVMI) and left ventricular internal dimension (LVID) tested by multiple linear regressiona

 
Successively, the analysis in which LVM was included as a dichotomous variable (presence or absence of LVH) revealed that only the ACE was independently related to LVH (Table 5).


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  		Table 5 Effects of covariates on left ventricular hypertrophy tested by multiple logistic regression

 
3.5 Patterns of left ventricular geometry
The prevalence of LVH was 48.0% (n=96); particularly, patients showing concentric and eccentric LVH were 51 (25.5%) and 45 (22.5%), respectively. Normal LVM was observed in 104 (52.0%) patients; 57 (28.5%) of them had normal left ventricular geometry, and 47 (23.5%) showed concentric left ventricular remodeling: 30 patients (15.0%) had isolated relative increase in the septal or in the PW thickness, and 17 patients (8.5%) had combined relative increase of septum and PW (Table 2).

LVMI was greater in the subset with concentric left ventricular remodeling than in that with normal ventricular geometry (103.6±10.1 g/m2 vs. 98.1±11.6 g/m2; P<0.05). Diastolic IVS and PW thickness were greater in the group with concentric remodeling than in that with normal geometry: 12.0±1.1 mm vs. 9.2±0.9 mm (P<0.0001), and 10.3±1.4 mm vs. 8.5±1.1 mm (P<0.0001). End-diastolic LVID was greater in the group with normal geometry than in that with concentric remodeling: 49.5±3.1 mm vs. 47.1±3.1 mm (P<0.0001).

3.6 Genotypes and left ventricular geometry
When left ventricular geometry was analyzed according to genotypes in patients with LVH, we observed: in DD group, concentric and eccentric LVH was present in 20 (23.0%) and 32 (36.8%) patients, respectively; in ID group, patients with concentric and eccentric LVH were 29 (30.5%) and 10 (10.5%), respectively; in II group, concentric and eccentric LVH was detected in two (11.1%) and three (16.6%) patients, respectively ({chi}2=11.900; P=0.002) (Fig. 3 and Table 2).


Figure 3
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  		Fig. 3 Diagrams were divided into four fields by the upper limit of left ventricular mass index (LVMI)>110 g/m2 in females ({blacksquare}) and>125 g/m2 in males ({square}), and relative wall thickness (RWT)≥0.45. The four patterns of left ventricular geometry were plotted: normal left ventricle (bottom left), concentric remodeling (top left), concentric hypertrophy (top right) and eccentric hypertrophy (bottom right). It is evident that in DD genotype the prevalence of patients with eccentric hypertrophy is greater than ID genotype ({chi}2=11.900; P=0.002). See text for further explanation.

 
In patients with normal LVMI we observed: in DD genotype, normal left ventricular geometry and concentric remodeling were detected in 18 (20.6%) and 17 (19.5%) patients, respectively; in ID genotype, patients showing normal geometry and concentric left ventricular remodeling were 31 (32.6%) and 25 (26.3%), respectively; in II genotype, eight (44.4%) patients had normal left ventricular geometry and five (27.8%) had concentric left ventricular remodeling (Fig. 3 and Table 2). No significant differences between groups were observed ({chi}2=0.406; P=0.816).

A multiple linear regression demonstrated that gender, ACE genotype and systolic ambulatory BP were each significantly related to end-diastolic LVID (Table 4).

The RWT values, calculated using both the IVS and PW, and the end-diastolic LVID are graphically reported in Fig. 4; other echocardiographic parameters are listed in Table 2. Any significant relation was found when we tested the effects of age, gender, ACE genotypes and BP values on RWT by both a linear and logistic regression.


Figure 4
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  		Fig. 4 (Top) Mean values of the relative wall thickness (RWT) of the interventricular septum (IVS) and posterior wall (PW) in ACE-gene genotypes are graphically showed. The mean value of RWT of PW of the DD genotype was significantly (P<0.0001) lower than ID genotype. (Bottom) Values of the end-diastolic left ventricular internal diameter (EDLVID) into the three genotypes of ACE-gene polymorphism are graphically reported. The value of EDLVID of the DD genotype was significant (P<0.0001) higher than ID or II genotype.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 References
 
Findings obtained in this study are unable to detect any relationship between BP values and ACE-gene polymorphism in hypertensive patients, even if O’Donnel, recently, demonstrated in the Framingham population an association between ACE DD genotype and increased risk for hypertension in men but not in women [27]. Our data also confirm the first observation that hypertensives homozygous for the short allele (DD) of ACE-gene have a higher LVMI than ID or II genotypes [17]; but, by comparison to our previously published findings, we detected at present that gender and monitored SBP too may affect cardiac mass. In fact, in our population the LVMI is higher by 10.4 g/m2 in men than in women; and it increases of 4.5 g/m2 for each 10 mmHg. Moreover, it is very interesting that I/D polymorphism of ACE-gene significantly affects the echocardiographic cardiac mass only in hypertensive males, while the LVMI values did not significantly differ in hypertensive females. Probably, a larger study population collected may explain these results.

Nevertheless, the most important findings of our study are that the DD genotype of the ACE-gene is associated with a significantly higher prevalence of patients showing eccentric LVH than ID genotype (36.8% vs. 10.5%; P<0.005). Thus, present data may support the conclusion that DD genotype of ACE-gene polymorphism affects the adaptive cardiac remodeling in hypertensive patients. Our results seem to be in conflict with data recently reported by Gharavi et al. [28] and Montgomery et al. [29] that found the evidence of association between DD genotype and concentric LVH in hypertensive patients and in normotensive trained military males, respectively. However, this contrast is only apparent because our patients were all hypertensive and never treated, whereas Gharavi et al. studied a small number of patients and included treated hypertensives in whom antihypertensive medications were discontinued two weeks before ambulatory BP measurements and echocardiographic evaluations. The disagreement with Montgomery et al. may be explained by differences in study population selection, and in the time of appearance (10 weeks) and in the type of cardiac adaptive modifications. In fact, in hypertensives the cardiac adaptive response to pressure overload is surely different from that observed in normotensive trained subjects in whom physical training induces a decrease in vascular resistance and an increase in volume overload.

Our study does not provide any explanation of mechanism by which homozygosity for the short allele (DD) may affect the structural changes of left ventricle in hypertensives with increased cardiac mass. Pressure overload and duration of hypertension seems to be unrelated to concentric or eccentric hypertrophy. An increase of interstitial and perivascular deposition of fibrillar collagen has been shown in the hypertrophied left ventricle of SHR [30] and human hypertensives [31]. It has been reported by several groups [9–11] that I/D polymorphism is associated with elevated serum ACE activity that may mediate cardiac growth by a possible alteration in tissue kinin metabolism or by effects on angiotensin II synthesis [32]. Thus, present data account for the strong association between ACE-gene polymorphism and hypertensive cardiac mass, but further studies are needed to clarify the relationship between I/D polymorphism of ACE-gene and adaptive cardiac remodeling in hypertensive patients. Perhaps ACE is not the rate-limiting step in basal angiotensin II production but becomes so with hypertrophic stimulation. More important, cardiac RAS may have little basal effect but may transduce hypertrophic stimuli that may support the strong association between ACE genotype and LVM in patients exposed to growth stimuli such as hypertensive status [16]. Finally, the ACE polymorphism does not seem to exert its effects through differences in growth hormone activity despite the proximity of the two genes [33].


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
References
 
LVH represents a substantial risk for the hypertensive patients. In fact, previous reports have clearly demonstrated that LVM has a continuous and graded association with cardiovascular outcomes [2]. Similarly, other prospective studies have investigated the independent contribution of cardiac geometry to prognosis, but it did not provide a closing prognostic information beyond that available from LVM and traditional cardiovascular risk factors [1,3]. In a 10-year follow-up study including patients with uncomplicated hypertension, the incidence of all-cause mortality increase from 1% in hypertensives with normal ventricular geometry to 10% and 24% in hypertensives with eccentric and concentric LVH [1].

The main findings of this study are that: (1) men are at increased risk of developing LVH; (2) hypertensive patients homozygous for the short allele (DD) of ACE-gene polymorphism are at risk of the developing LVH; (3) the eccentric LVH is more prevalent in DD than ID genotype, (4) the impact of I/D polymorphism of the ACE-gene on LVM may act only under specific conditions, suggesting an interaction between genetic factors and altered hemodynamic conditions in the modulation of hypertensive cardiac mass.

Finally, it is reasonable to conclude that the DD genotype is associated with a much higher prevalence of LVH and a higher risk of subsequent adverse cardiovascular outcomes. Even if a more prevalence of cardiac eccentric remodeling could attenuate this risk, the LVH represents per se the most important morphological predictor of adverse cardiovascular outcomes.

Time for primary review 28 days.


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

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