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J Am Coll Cardiol, 2001; 37:175-182
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY: HYPERTENSION

Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans

Roland E. Schmieder, MD, FACC*, Jeanette Erdmann, PhD{dagger}, Christian Delles, MD*, Johannes Jacobi, MD*, Eckart Fleck, MD{dagger}, Karl Hilgers, MD* and Vera Regitz-Zagrosek, MD{dagger}

* Department of Medicine IV/Nephrology, University of Erlangen-Nürnberg, Nürnberg, Germany
{dagger} Department of Internal Medicine and Cardiology, Charité, Campus Virchow-Klinikum, Humboldt University and Deutsches Herzzentrum Berlin, Berlin, Germany

Manuscript received October 14, 1999; revised manuscript received July 13, 2000, accepted September 11, 2000.

Reprint requests and correspondence: Dr. Roland E. Schmieder, Department of Medicine IV, University Erlangen-Nürnberg, Breslauer Str. 201, 90471 Nürnberg, Germany
Roland.Schmieder{at}rzmail.uni-erlangen.de


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

Our study goal was to analyze whether gene variants of angiotensin II type 2-receptor (AT2-R) modulate the effects of angiotensin II on the left ventricle (LV).

BACKGROUND

Experimental data suggest that angiotensin II modifies ventricular growth responses via angiotensin II type 1-receptors (AT1-R) and AT2-R.

METHODS

In 120 white, young male subjects with normal or mildly elevated blood pressure, we assessed plasma angiotensin II and aldosterone concentrations (RIA), 24-h urinary sodium excretion, 24-h ambulatory blood pressure and LV structure (two-dimensional guided M-mode echocardiography). The intronic +1675 G/A polymorphism of the X-chromosomal located AT2-R gene was investigated by single-strand conformational polymorphism analysis and DNA-sequencing.

RESULTS

Hypertensive subjects with the A-allele had a greater LV posterior (11.0 ± 1.3 vs. 9.9 ± 1.3 mm, p < 0.001), septal (11.8 ± 1.4 vs. 10.1 ± 1.2 mm, p < 0.001) and relative wall thickness (0.44 ± 0.06 vs. 0.39 ± 0.06, p < 0.01) as well as LV mass index (138 ± 23 vs. 120 ± 13 g/m2, p < 0.001) than those with the G-allele. Confounding factors (i.e., body mass index and surface area, plasma angiotensin II, sodium excretion, systolic and diastolic ambulatory blood pressure) were similar between the two genotypes. In normotensive subjects, relative wall thickness (0.36 ± 0.05 vs. 0.35 ± 0.05) and LV mass index (115 ± 21 vs. 112 ± 17 g/m2) were nearly identical across the two genotypes, with similar confounding variables.

CONCLUSIONS

Our data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.

Abbreviations and Acronyms
  AT1-R = angiotensin II type 1-receptor
  AT2-R = angiotensin II type 2-receptor
  BP = blood pressure
  LV = left ventricle
  PCR = polymerase chain reaction
  RAS = renin angiotensin system

Left ventricular (LV) structure and function are important predictors of cardiovascular morbidity and mortality in cardiac patients and in the general population (1,2). Echocardiographic LV hypertrophy increases the risk of cardiovascular morbid events in primary and secondary hypertension (3–5) but also indicates a higher risk for the development of arterial hypertension in normotensive subjects (6,7). Constitutional and environmental factors have been identified that influence cardiac structural adaptation to an increased preload and afterload imposed on the LV (8–11). Studies of monozygotic and dizygotic twins have suggested that inherited factors are also of pathogenic relevance (12,13).

The activity of the renin angiotensin system (RAS) profoundly influences blood pressure (BP) and cardiovascular disease (14–17). Experimental studies have documented the growth stimulating and regulating effects of angiotensin II on myocardial cells (14,15). In hypertensive subjects impaired suppression of the RAS or, conversely, increased sensitivity to angiotensin II appeared to act as a stimulus for LV hypertrophy (18,19).

Over the last 5 years various genes of the RAS have been associated with cardiovascular disease (20–25). However, these studies yielded conflicting results: some found a positive association of the risk for myocardial infarction with the angiotensin-converting enzyme D-allele, whereas others did not (20,21). Similarly, the T235-variant of the angiotensinogen gene was found to be associated with essential hypertension, but subsequent studies in monozygotic and dizygotic twin pairs did not confirm the earlier observation (22,23). More recent studies have focused on variants of genes downstream of the angiotensinogen and angiotensin-converting enzyme in the RAS cascade.

The angiotensin II type 1-receptor (AT1-R) appears to be the primary receptor that mediates the vasoconstrictor and growth promoting effects of angiotensin II in humans (15). The gene that encodes AT1-R has been intensively investigated as a risk factor for hypertension and cardiovascular disease (23,26). The nucleotide substitution (A/C in position +1166) in the gene of the AT1-R is located in the 3' untranslated part of the gene, and increased frequency of the C-allele has been reported in patients with arterial hypertension, increased aortic stiffness, LV hypertrophy and coronary vasoconstriction (24,25). However, other reports did not confirm such an association between the +1166 A/C polymorphism and cardiovascular disorders (23).

Up to now, most of the studies have been carried out with respect to AT1-R genotypes and related effects. In contrast, function, regulation and signal transduction of the angiotensin II type 2-receptor (AT2-R) are only partly known (27). Angiotensin II type 2-receptor expression is restricted to a few tissues in adults. It is upregulated in the endothelium under pathological circumstances, such as new intima formation after vascular injury and in the heart after myocardial infarction or during cardiac remodeling (28–30). The expression patterns and regulation of the angiotensin II receptors differ among species with the AT2-R being the predominant receptor subtype in the human heart (30–32). The AT2-R gene is located on the X-chromosome and spans about 5 kb (33). The gene structure and the complete nucleotide sequence of the human AT2-R gene, which includes the promoter region, was elucidated in 1995 (33). Regulatory elements are located in the first intron in addition to the promoter region (34). The AT2-R decreases BP, exerts antiproliferative effects on endothelial and vascular smooth muscle cells (15,35–38) and modifies LV fibrogenic (39) and growth responses (40). The signaling via AT2 is essential for the development of pressure overload-mediated cardiac hypertrophy in transgenic mice (41), whereas in isolated adult rat hearts AT2 inhibition amplifies the LV growth response to angiotensin II (40).

The pathogenic effects of the AT2-R for cardiac structural processes in humans are far from being understood. To the best of our knowledge no data have been reported in humans so far. We thought that the functional characterization of the human AT2-R genotypes is an attractive approach to elucidate the pathogenic role of AT2-R in cardiovascular diseases, particularly since no AT2-R agonist or antagonist is available for human use, and, thus, no pharmacological experiments have been carried out to elucidate the physiological and pathophysiological role of AT2-R. Therefore, we tested whether the +1675G/A polymorphism is associated with cardiac structural adaptation to an increased afterload in a homogeneous study cohort of young male white subjects.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study population.   By advertising we elicited the participation of young white male students at the campus of the University Erlangen-Nürnberg. One-hundred twenty subjects were consecutively enrolled in the study up to a number of 60 subjects in the normotensive range and 60 subjects with mildly elevated BP. According to the World Health Organization/International Society of Hypertension (WHO/ISH) criteria, an average BP of ≥140 mm Hg systolic or ≥90 mm Hg diastolic was said to be hypertensive (42). The study protocol was approved by the clinical investigation and ethics committees of the University Erlangen-Nürnberg, Germany, and informed consent was given before study inclusion.

Study inclusion criteria were: age between 20 and 40 years, male gender, white, no current or previous treatment for arterial hypertension, no cardiovascular disease (with the exception of mildly elevated BP) and no secondary hypertension or WHO stage III hypertensive disease. Therefore, exclusion criteria were: advanced hypertensive fundoscopic changes, myocardial infarction or any other evidence of coronary artery disease, congestive heart failure or previous cerebrovascular event and hepatic or renal insufficiency. Each participant underwent a thorough clinical work-up described elsewhere in detail (19).

BP measurements.   To obtain correct BP readings a standard sphygmomanometer was used, and the cuff size was adjusted according to the participant’s arm circumference. Four casual BP readings were taken in our outpatient clinic on at least two different occasions (at least four weeks apart) after 5 min of rest in a standardized fashion. Subjects who had been allocated to one of the two groups according to the screening BP, but later failed to fulfill all study entry criteria, were replaced.

Ambulatory 24-h BP measurements were taken with an automatic portable device (Spacelab No. 90207, Redmont, California). Measurement intervals were every 15 min during the day (defined from 7:00 to 22:00 h) and every 30 min during the night (43). In parallel, a 24-h urinary sodium excretion, which represents a rough but valuable estimate of daily sodium intake, was measured (18,19).

Parameters of the RAS.   Blood samples for the determination of plasma angiotensin II and serum aldosterone levels were collected from patients who were in the supine position after 1 h of complete rest. For plasma angiotensin II measurements, blood was collected into prechilled 10 ml syringes, prepared with EDTA 125 mmol and phenantroline 26 mmol (Merck, Darmstadt, Germany) to inhibit the angiotensin-converting enzyme. The samples were centrifuged for 10 min at 4°C immediately after collection and rapidly stored after centrifugation at –21°C, but analyzed within three months. Plasma samples were extracted, and, after purification of the samples, immunoreactive angiotensin II was measured in duplicate by radioimmunoassay with antiserum, as previously described (19). The coefficient of variation was <5%. Serum aldosterone was measured by a commercially available radioimmunoassay kit (Aldosterone Maia, Serono, Freiburg, Germany).

Echocardiography.   Two-dimensional guided M-mode echocardiography was performed using an ultrasonoscope (Picker-Hitachi CS 192; Tokyo, Japan) with a 2.5 MHz probe (for details see [18,19]). All echocardiographic readings were evaluated by two investigators independently. The echocardiographic reading was done blindly with respect to other clinical data and, in particular, to the genotyping of our subjects (as indicated by different locations of the echocardiographic and genetic evaluation). Relative wall thickness taken as a parameter for concentric LV hypertrophy was calculated as two times posterior wall thickness divided by end-diastolic diameter. Left ventricular mass was calculated according to the American Society of Echocardiography recommendations (44) but was then corrected according to the suggestions of Devereux and coworkers (45). Coefficients of variation for all structural parameters were less than 10%.

Mutation screening and genotyping.   Genomic DNA was extracted from 2 to 5 ml of whole blood by standard methods using a commercially available kit (QIAamp Blood Midi Kit, QIAGEN GmbH, Hilden, Germany). In a previous study the complete coding region of the human AT2-R gene (1,092 base pair [bp]) as well as intron 1 (152 bp) were screened in 92 patients with cardiovascular diseases. Eight overlapping PCR-fragments of 142 to 297 bp were used. SSCP was run at 4°C and room temperature on 10% polyacrylamide gels (49:1; acrylamide: bisacrylamide). Two variants significantly altered the migration pattern of the corresponding PCR-products. Sequencing of aberrant products revealed one frequently occurring intronic polymorphism (+1675 G/A) (Fig. 1) and one rare amino acid substitution (Gly-21-Val).



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  		Figure 1 (a) Part of the nucleotide sequence of the human angiotensin II type 2-receptor gene. The position of the G>A substitution at position +1675 is marked with an arrow. First row: DNA-sequence of a patient carrying the G-allele. Second row: DNA-sequence of a patient carrying both alleles (G/A). Third row: DNA-sequence of a patient carrying the A-allele. (b) Representative example of a SSCP-gel showing the characteristic band-pattern of the +1675 G/A polymorphism after denaturing and loading on a 10% PAA gel at 4°C. Lane 1: PCR-product of a heterozygote patient designated G/A. Lane 2: PCR-product of a patient carrying the G-allele (G). Lane 3: PCR-product of a patient carrying the A-allele (A). Lane 4 and 5: PCR-products of patients carrying the G-allele.

 
Since the +1675 G/A polymorphism does not alter any known enzyme restriction site, the genotyping in larger samples was based on repeated SSCP analysis. In brief, after amplification using primers AT2.intron 1F (5'-ATT ACG TCC CAG CGT CTG AG-3') and AT2.intron1R (5'-ATA AAT CAG CTT GCT TAG TGC C-3'), a PCR-fragment of 255 bp was produced. SSCP-gels were run for 16 to 18 h at 7 V/cm at 4°C. Bands were visualized by silver staining (46).

Three different DNA samples that represented the three genotypes (G-, A-, GA) were analyzed as controls on every gel (Fig. 1). All ambiguous samples were analyzed a second time, as proposed by others (47,48), and a second analysis was also performed for every 10th sample for control reasons.

Statistical analysis.   A power calculation was used to calculate the sample size with a 95% confidence (type I error: {alpha} = 0.05) and 90% power (type II error: ß = 0.10) assuming that a difference of {delta} = 12 g/m2 for LV mass index (with a standard deviation of {sigma} = 20 g/m2) is of clinical relevance (49).

All statistical analyses were carried out using SPSS software (SPSS for Windows, SPSS Inc., Chicago, Illinois). In particular, two-way analysis of variance was used to detect any significant difference between carriers of the A-allele vs. G-allele of the X-chromosomal located +1675 G/A polymorphism of the AT2-R gene in the normotensive versus the hypertensive group.

Finally, stepwise multiple linear regression analysis was used to examine the determinants of LV mass and septal and posterior wall thickness in the whole study cohort: the {alpha}-level for entry and removal of terms at each forward step was 0.10. All data in the text are given as x ± 1 standard deviation and in the figures as x ± 95% confidence interval. Two-tailed values of p < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
The clinical characteristics of our study population are given in Table 1. In our homogenous study cohort of young male white subjects, the frequency of the A-allele was 57% and of the G-allele 43%. When classified according to the WHO, the G-allele frequency was 46% in the hypertensive and 41% in the normotensive subjects, which was not significantly different ({chi}2 test: p > 0.20).


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  		Table 1 Characteristics of the Whole Study Cohort (n = 120), the Normotensive (n = 60) and Mildly Hypertensive Group (n = 60)

 
In the whole study group LV structural parameters were linked to the +1675 G/A polymorphism of the AT2-R gene (Table 2). Subjects with the A-allele of the AT2-R gene had a greater posterior (p < 0.025) and septal wall thickness (p < 0.001) than those with a G-allele of AT2-R gene. Relative wall thickness and LV mass were greater in subjects with the A-allele than they were in those with the G-allele of the AT2-R gene (p < 0.02). This difference in LV mass was not related to body surface area or body mass index, 24-h ambulatory systolic or diastolic BP, urinary sodium excretion, plasma angiotensin II or serum aldosterone concentrations since these potentially confounding cofactors were similar in the two genotypes of the AT2-R (Table 2). Accordingly, analysis of covariance revealed that the association of the +1675 G/A polymorphism of the AT2-R gene with LV mass (p = 0.003) and relative wall thickness (p = 0.014) were independent of body mass index, 24-h ambulatory systolic and diastolic BP, urinary sodium excretion, plasma angiotensin II and serum aldosterone concentrations.


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  		Table 2 Clinical and Echocardiographic Data Stratified According to the X-Chromosomal Located+1675 G/A Polymorphism of the Angiotensin II AT2-receptor Gene

 
Hypertensive subjects (according to WHO criteria) with the A-allele of the AT2-R gene had a greater posterior wall thickness (p < 0.001), septal wall thickness (p < 0.001), relative wall thickness (p < 0.001) and LV mass index (p < 0.01) than hypertensive subjects with the G-allele of the AT2-R (Tables 3 and 4, Fig. 2 and 3). Ambulatory and casual BP, body mass index, urinary sodium excretion, plasma angiotensin II and serum aldosterone concentrations were similar between the two genotypes of the AT2-R gene (Table 3). Analysis of covariance confirmed that the +1675 G/A polymorphism of the AT2-R gene was associated with LV mass (p < 0.001), relative wall thickness (p < 0.05), posterior (p < 0.01) and septal wall thickness (p < 0.001), independent of confounding factors. In contrast, no significant difference of LV structural parameters between the A- and G-allele carriers was found in the normotensive subgroups (Table 4).


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  		Table 3 Clinical Data Stratified According to the +1675 G/A Polymorphism of the Angiotensin II AT2-Receptor Gene

 

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  		Table 4 Echocardiographic Data Stratified According to the +1675 G/A Polymorphism of the Angiotensin II AT2-Receptor Gene

 


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  		Figure 2 Left ventricular mass in normotensive and hypertensive subjects classified according to the X-chromosomal located +1675 G/A polymorphism of the angiotensin II AT2-receptor gene. Solid circle= A-allele; solid square= G-allele. Data are given by means (symbols) ± 95% confidence interval.

 


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  		Figure 3 Posterior, septal and relative wall thickness in normotensive and hypertensive subjects classified according to the X-chromosomal located +1675 G/A polymorphism of the AT2-receptor gene. Solid circle= A-allele; solid square = G-allele. Data are given by means (symbols) ± 95% confidence interval.

 
Similarly, when our subjects were post hoc divided according to 24-h ambulatory BP criteria (≥130 mm Hg or ≥80 mm Hg [50]), the +1675 G/A polymorphism of the AT2-R modulated LV structure in the hypertensive (n = 46) but not in the normotensive individuals (n = 74). Hypertensive subjects with the A-allele of AT2-R revealed an increased LV mass index (132 ± 25 vs. 116 ± 14 g/m2, p = 0.011) and relative wall thickness (0.43 ± 0.06 vs. 0.37 ± 0.06, p = 0.004) with similar confounding factors such as 24-h ambulatory systolic and diastolic BP, body mass index, urinary sodium excretion, plasma angiotensin II and serum aldosterone concentrations (data not shown). Again, analysis of covariance indicated an independent association of the AT2-R gene with LV mass (p < 0.02), relative wall thickness (p < 0.05) and posterior (p < 0.02) and septal wall thickness (p < 0.001).

In the stepwise multiple regression analysis for posterior wall thickness, the +1675 G/A polymorphism of the AT2-R gene (p = 0.01), urinary sodium excretion (p = 0.002), body mass index (p < 0.001) and 24-h ambulatory systolic BP (p < 0.001) emerged as independent parameters. Similarly, determinants for septal wall thickness were the +1675 G/A polymorphism of the AT2-R (p < 0.001), urinary sodium excretion (p = 0.03), body mass index (p = 0.001) and 24-h ambulatory systolic BP (p < 0.001). Left ventricular mass was independently associated with the +1675 G/A polymorphism of the AT2-R gene (p = 0.006), body mass index (p < 0.001) and 24-h ambulatory systolic BP (p = 0.02).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
AT2-R gene and LV structure.   The principal finding of our study is that the +1675 G/A polymorphism of the X-chromosomal AT2-R gene is associated with LV structural changes in young male subjects with mildly elevated BP. The A-allele carriers had a greater LV mass and relative wall thickness than G-allele carriers, independent of other determinants of LV structure. The association of LV mass with the AT2-R gene polymorphism was most striking in hypertensive subjects, regardless of the definition used for arterial hypertension (Fig. 2 and 3). Elevated BP leads primarily to a thickening of the LV wall due to an increased afterload and, as a consequence, to a concentric remodeling of the LV indicated by an increased relative wall thickness and LV mass.

The association of the +1675 G/A polymorphism of the AT2-R gene with LV mass was not affected by other confounding variables that are well known to modulate early structural processes of the LV to an increased pressure load (51). Similarly, body constitution known to modify the degree and pattern of LV hypertrophy in humans (11,52) did not bias our results.

Biological relevance of AT2-R gene.   Of the two 7-transmembrane angiotensin II receptor subtypes identified in humans up to now, most of the known effects of the renin angiotensin system are mediated by the AT1-R (53). In contrast, regulation and signal transduction of the AT2-R are still far from being understood. In the adult AT2-R expression is restricted to a few tissues. It is upregulated under circumstances such as cardiac remodeling and infarction (28–30). The single copy human AT2-R gene is located on the X-chromosome, spans about 5 kb and comprises two short noncoding exons (68 bp and 95 bp), 2 introns of 152 bp and 1,207 bp and exon 3 (>2,300 bp), which contains the entire protein coding region (33). Sequence elements located on the introns are necessary for efficient human AT2-R transcription (34). The newly detected intronic variant is located 29 bp before the start of exon 2, close to the region that is important for transcriptional activity of the human AT2-R gene (34).

Stimulation of the AT2-R has been shown to exert antiproliferative effects in rat coronary endothelial cells, vascular smooth muscle cells and adrenocortical cells (35–37). The signaling via AT2 is essential for the development of pressure overload-mediated cardiac hypertrophy in transgenic mice (41), whereas in adult hypertrophied rat hearts AT2-R blockade amplifies the immediate LV growth response to angiotensin II (40). In this study we observed that the AT2-R gene is associated with LV structural adaptive processes in hypertensive subjects prone to develop myocardial hypertrophy to an increased afterload. At the moment it is not yet understood whether the variant of the AT2-R gene directly affects the AT2-R function or gene expression or is in linkage disequilibrium with yet unknown polymorphisms in neighboring genes. However, since the 1675 G/A polymorphism is located in a gene region that is involved in transcriptional control of the AT2-R gene expression, it is tempting to speculate that it may affect gene expression and subsequently LV morphology. Interestingly, the antihypertrophic actions of AT2-R in experimental animals were more pronounced in hypertrophied hearts.

Study limitations.   Our results are restricted to young male white subjects. Therefore, we cannot extrapolate that the +1675 G/A polymorphism is associated with LV structure in older subjects or in subjects with more severe arterial hypertension, that is, excessive increase in afterload imposed on the LV. Conversely, since we examined a homogenous study population, our study clearly has some advantages. None of the subjects included had ever received or was on any current antihypertensive or cardiovascular medication, thereby ruling out any potential effect of previous antihypertensive therapy (55,56). Moreover, the results are extremely unlikely to be due to an unexpected mixture of population in our study center because the local German population is ethnically homogenous, and subjects of other nationality have been excluded. Finally, we did not fully account for the exercise-induced physiological hypertrophy as a potential underlying confounding element. However, there is no rationale why the +1675 A genotype of the AT2-R gene should exercise more than the G-allele carriers.

Conclusions.   The current data indicate that the +1675 G/A polymorphism of the AT2-R gene is associated with LV structure in young male subjects, in particular in those with mildly elevated BP. The influence of the G/A genotype of the AT2-R on the LV is independent of body size, plasma angiotensin II, serum aldosterone and the hemodynamic load as assessed by 24-h ambulatory BP monitoring. Thus, our data suggest first that the AT2-R subtype may be functional in humans and secondly that it may modulate LV morphology in mild essential hypertension (54).


   Footnotes
 
Supported, in part, by grants of DFG Schm 638/6-2 and DFG Re 662/4-1.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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