Background
Cardiac left ventricular hypertrophy (LVH) is an important risk factor for an adverse outcome in patients both with or without coronary artery disease [
1]. Furthermore, LVH represents an independent risk factor for sudden cardiac death, congestive heart failure, coronary heart disease and stroke, and it has been associated with diabetes mellitus (DM) and glucose intolerance in several epidemiological investigations [
2‐
6]. On the other hand, LVH can also be explained by genetic factors [
7‐
9] and its heritability has been estimated to be 0.17-0.69 [
10‐
12].
The beta-1 adrenergic receptor (β
1AR) has been considered to represent a potential candidate gene for LVH [
12‐
15]. This G protein-coupled receptor is the predominant beta adrenergic receptor in the heart (~ 70% β
1AR and 30% β
2AR), maintaining cardiac contractility in response to endogenous catecholamines [
16]. The β
1AR gene is localized to 10q24-26 [
17] and was cloned in 1987 [
18]. It encodes a 477-amino acid membrane protein that carries two common nonsynonymous single nucleotide polymorphisms, one in the extracellular amino terminus (Ser49Gly) and another in the proximal carboxyl terminus (Arg389Gly) [
19]. The Arg389Gly polymorphic site lies within the putative G
s coupling domain of the receptor [
20]. It has thus been considered to have functional significance, because the positively charged arginine residue differs markedly from neutral glycine. Accordingly, the polymorphism has been shown to have an effect on signalling properties of the receptor [
21].
The aim of our study was to investigate the possible association of the β1AR Arg389Gly polymorphism with various variables, including cardiac left ventricular parameters, among acute myocardial infarction (AMI) survivors in Northern Finland. We analyzed 452 patients, 20.6% of whom had diagnosed DM.
Discussion
The main finding of our study is the apparent association of the β
1AR Arg389 homozygotes with LVH among euglycemic AMI survivors, and that this association does not appear to exist among diabetic AMI survivors. Analyzing 452 Finnish patients who had undergone AMI, 79.4% of whom were euglycemic and 20.6% diabetic, we were able to show that the β
1AR Arg389 homozygotes had significantly higher LVMI when compared to the Gly389 carriers (either Gly389 homozygotes or Arg/Gly389 heterozygotes). The same applied also to IVSd, and this association was even stronger. Our result is logical based on previous reports on the functional properties of the two receptor variants. The β
1AR Arg389 variant has been shown to display markedly increased coupling to G
s and stimulation of adenylyl cyclase in response to the agonist isoproterenol
in vitro as compared to the Gly389 receptor form [
21]. Gly389 is thought to disrupt the predicted alpha-helical region of the cytoplasmic carboxyl terminus of the receptor, which may cause a less favorable receptor conformation for coupling to G
s [
28]. Thus, the β
1AR Arg389 variant can be considered as a "gain-of-function" receptor form.
It is well known that prolonged activation of the β
1AR leads to worsening of cardiac function. As a consequence, β
1AR expression is down-regulated and its coupling to adenylyl cyclase is desensitized [
29]. The Arg389Gly polymorphism appears to modulate this pathological situation: Mialet Perez
et al., who used transgenic mice, showed that the Arg389 variant is impaired in down-regulation, which most likely represents a protective event in the failing myocardium. Furthermore, the young Arg389 mice were found to have enhanced receptor function and heart contractility compared to the Gly389 carriers, whereas the older Arg389 mice displayed a phenotypic switch with decreased signalling to adenylyl cyclase and contractility compared to the corresponding Gly389 mice [
30]. In line with these
in vivo studies, Rathz
et al. have shown that the β
1AR Arg389 variant undergoes less agonist-promoted desensitization
in vitro compared to its allelic counterpart [
31]. Recently, Lewin and colleagues have thrown light on the mechanism underlying the β
1AR-induced cardiac damage by showing that inactivation of the cyclic AMP response element modulator (CREM) rescued the β
1AR-overexpressing mice from cardiomyocyte hypertrophy, fibrosis, and left ventricular dysfunction [
32]. It would be interesting to know, whether there is a difference in CREM expression and/or function between individuals carrying either the Arg389 or Gly389 variant - a highly speculative possibility worth investigating.
Our results support the notion that there is a direct genetic impact of the β
1AR Arg389 homozygosity on the left ventricular structure. We cannot, however, rule out the possibility that the observed increases in LVMI and IVSd among the β
1AR Arg389 homozygotes were related to hypertension because LVH partly represents an adaptive response to hypertension [
33]. In previous studies it has been shown that the β
1AR Arg389 homozygotes have an increased risk to develop essential hypertension among Scandinavians [
34] and Chinese [
35]. We, nevertheless, did not detect higher blood pressure values among the Arg389 homozygotes as compared to the Gly389 carriers in our study population (data not shown). This negative finding most likely results from the anti-hypertensive medication of the patients that took place after AMI and hospitalization and/or from the relatively small sample size.
To our knowledge, there are four previous studies concerning the β
1AR Arg389Gly polymorphism and left ventricular structure. In accordance with our study, Fu
et al. described a significant association between the β
1AR Arg389 variant and LVH in Chinese hypertensive individuals in two independent populations (n = 2417 and n = 327) [
13]. In contrast, no relationship between LVM and the β
1AR Arg389Gly polymorphism was found in a study population consisting of 110 healthy Caucasian twin pairs (n = 220) [
12]. In a third study by Stanton and colleagues, the Gly389 homozygotes were observed to have higher LVM when compared to the Arg389 homozygotes among 249 Caucasian patients suffering from renal failure [
14]. This study consisted of a very specific population: each individual had a proven renal disease, 37% of whom were on renal replacement therapy. This may explain the result that seems physiologically counter-intuitive. In the fourth study, Meyers
et al. who studied African American siblings suffering from hypertension found no significant association between the β
1AR Arg389Gly polymorphism and LVMI but reported that the Gly389 allele was significantly associated with a higher mean relative wall thickness compared to the Arg389 form [
15]. This association was not replicated in another study group consisting of a Hispanic cohort. It is important to note that the Gly389 allele is more frequent in black populations [
15,
25], which may explain the divergent findings.
When we analyzed the euglycemic and diabetic patients of our study group separately, we did not find any association between the β
1AR Arg389Gly polymorphism and LVH among the diabetic patients. The negative result can be considered to arise from an independent association between DM and LVH [
2‐
6], which is presumably stronger than the association of the β
1AR Arg389Gly polymorphism with LVH. Therefore the assumed stronger effect of DM can be expected to mask the weaker effect of the polymorphism on the left ventricular structure. Interestingly, the association between DM and LVH seems to be stronger in women than in men [
2,
5,
6]. In our study population the proportion of women was significantly higher among the diabetic subgroup as compared to the non-diabetics one (30.1/19.5%), supporting the hypothesis of the aforementioned "masking effect" of DM. Furthermore, the β
1AR expression has been shown to be markedly decreased in the hearts of diabetic patients (atrial appendages) [
36], which may also have had an impact on our results.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AEH carried out the genotyping of patients, performed the statistical analyses and drafted the manuscript. JMT performed the echocardiography. JMJ, KSK and HVH critically reviewed the manuscript. UEP-R critically reviewed the manuscript and helped to draft it. All authors read and approved the final manuscript.