Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure.
We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor alpha and estrogen receptor beta (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status.
In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia.
The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.
"Emerging data have suggested that inherited traits might also play a role in this regard. For instance, polymorphisms of the estrogen receptor β gene were associated with LV mass and wall thickness solely in women , while variation at the androgen receptor gene showed significant association with LV hypertrophy in males with hypertrophic cardiomyopathy . Our study provided novel evidence that TLR4 Asp299Gly polymorphism is associated with lower LV mass exclusively in hypertensive women. "
[Show abstract][Hide abstract] ABSTRACT: Background: This study investigated the impact of a putative functional TLR4 polymorphism (Asp299Gly) on left ventricular (LV) structure in hypertensive subjects. Methods: A sample of 443 patients (266 women and 177 men) was evaluated by clinical history, physical examination, anthropometry, analysis of inflammatory and metabolic parameters, echocardiography and TLR4 Asp299Gly genotyping. In addition, the relationship between the polymorphism and in vitro lipopolysaccharide responsiveness of peripheral blood monocytic cells was also assessed. Results: Women carrying the 299Gly allele presented lower posterior wall thickness (p = 0.01), interventricular septum thickness (p = 0.04), LV mass (p = 0.01) and LV mass index (p = 0.03), as well as a reduced prevalence of LV hypertrophy (p = 0.002), in comparison to women with the wild-type genotype. These results were confirmed by stepwise and logistic regression analyses adjusted for potential confounders. Conversely, the 299Gly allele did not influence LV structure in men. Furthermore, in vitro assays revealed that monocytes of either men or women heterozygous for the 299Gly allele presented a lower lipopolysaccharide-induced production of interleukin-6, compared to non-carriers. Conclusions: The functional TLR4 Asp299Gly polymorphism is associated with lower LV mass in hypertensive women. These findings suggest that interactions among gender, LV remodeling and TLR4 gene variants may occur in hypertensive subjects.
"However, in the same cohort, rs1271572 and rs1256049 polymorphisms were found to be linked to MI, but not IS, in women but not in men. A potential gender-specific variation in the ERβ gene was also observed with rs1256031 and rs1256059 SNPs, which showed an association with left ventricular mass and wall thickness in women but not in men according to the Framingham Heart Study [Peter, I. et al. 2005a]. "
[Show abstract][Hide abstract] ABSTRACT: Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) alpha and beta. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERalpha polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERbeta in order to provide a functional perspective with potential pharmacogenomic implications.
"Interestingly, Peter et al.  showed that in women, but not men, two polymorphisms in ER-β (ERS2 rs1256031 and ERS2 rs1256059) were associated with increased LV mass and LV wall thickness. The protective effects of estrogen with regard to cardiac hypertrophy also appear to be age-dependent . "
[Show abstract][Hide abstract] ABSTRACT: Pre-menopausal women have reduced risk for cardiovascular disease, and cardiovascular disease rises after menopause. Studies in animal models have also suggested that females have reduced injury following ischemia and reperfusion (I/R). However, a large clinical trial, the Women's Health Initiative, found an increase in cardiovascular incidents in women on hormone replacement therapy. Taken together, these data suggest that we need a better understanding regarding the mechanisms for the protection observed in the animal studies. In some studies, particularly in the rat, females show less I/R injury; however, in many animal studies no gender difference in I/R injury is observed. Under conditions where calcium is elevated or contractility is increased just prior to ischemia, females have been reported to have less I/R injury than males. Also, estrogen administration has been shown to reduce I/R injury. The protection observed under conditions of increased contractility has been shown to involve an increase in nitric oxide signaling leading to S-nitrosylation of the L-type calcium channel, which reduces calcium loading during ischemia and early reperfusion thereby reducing I/R injury. Estrogen binding to nuclear estrogen receptors results in altered expression of a number of cardioprotective genes such as nitric oxide synthase and heat shock proteins. Estrogen also alters a number of genes involved in metabolism such as lipoprotein lipase, prostaglandin D2 synthase, and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1-alpha). The effects of these alterations in gene expression may depend on the context of other hormonal stimuli and gene expression as well as physiological stimuli. Furthermore, addition of estrogen has acute non-genomic responses that involve activation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, which has been shown to be protective, at least when activated for short durations. This review will summarize the data showing protection in females in animal studies and will summarize the data on possible mechanisms of cardioprotection in females.
Cardiovascular Research 09/2007; 75(3):478-86. DOI:10.1016/j.cardiores.2007.03.025 · 5.94 Impact Factor
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