Published online before print March 19, 2007, doi: 10.1161/HYPERTENSIONAHA.106.083790
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2007;49:1000.)
© 2007 American Heart Association, Inc.
Original Articles |
Age-Related Changes in Echocardiographic Measurements
Association With Variation in the Estrogen Receptor-
Gene
From the Institute for Clinical Research and Health Policy Studies (I.P., C.H.S.) and Molecular Cardiology Research Institute (G.S.H., R.D.P., R.H.K., M.E.M.), Tufts-New England Medical Center, Boston, Mass; the Center for Cancer Research (A.M.S., D.E.H.), Massachusetts Institute of Technology, Cambridge; National Heart, Lung, and Blood Institute’s Framingham Heart Study (R.S.V., E.J.B.), Framingham, Mass; the Biostatistics Department (L.A.C., S.D.), Boston University School of Public Health, Mass; the Department of Preventive Medicine and Cardiology (R.S.V., E.J.B.), Boston University School of Medicine, Mass; and the Cardiology Department (A.P.), Hadassah–Hebrew University Medical Center, Jerusalem, Israel.
Correspondence to Inga Peter, Tufts-New England Medical Center, 750 Washington St, NEMC #63, Boston, MA 02111; e-mail ipeter{at}tufts-nemc.org
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Left ventricular (LV) mass and other LV measures have been shown to be heritable. In this study we hypothesized that functional variation in the gene coding for estrogen receptor-
(ESR1), known for mediating the effect of estrogens on myocardium, is associated with age-related changes in LV structure. Four genetic markers (ESR1 TA repeat; rs2077647, or +30T>C; rs2234693, or PvuII; and rs9340799, or XbaI) were genotyped in 847 unrelated individuals (488 women) from the Framingham Offspring Study, who attended 2 examination cycles 16 years apart (mean ages at first examination: 43±9 years; at follow-up: 59±9 years). ANCOVA was used to assess the association of polymorphisms and their haplotypes with cross-sectional measurements and longitudinal changes in LV mass, wall thickness, end-diastolic and end-systolic internal diameter, and fractional shortening after adjustment for factors known to influence these variables. Changes over time were detected for all of the LV measurements (P ranging from <0.0001 to 0.02), except for fractional shortening in men. The SS genotype of the ESR1 TA repeat polymorphism in the promoter region was associated with longitudinal changes in LV mass and LV wall thickness (P ranging from 0.0006 to 0.01). Moreover, the TA[S]–+30[T]–PvuII[T]–XbaI[A] haplotype (frequency: 47.5%) was associated with greater LV changes as compared with the TA[L]–+30[C]–PvuII[C]–XbaI[G] haplotype (frequency: 31.8%). Our results are consistent with the hypothesis that common ESR1 polymorphisms are significantly associated with age-related changes in LV structure. Understanding the mechanisms predisposing to unfavorable LV remodeling of the heart with advancing age may aid in the discovery of new therapeutic targets for the prevention of heart failure.
Key Words: echocardiography • left ventricular remodeling • estrogen receptor- • restriction fragment length • single nucleotide polymorphism
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
By the year 2035,
1 in 4 individuals in the United States will be 
65 years of age.1 Increasing age is associated with an exponential rise in cardiovascular morbidity and mortality, with heart failure (HF) being the most common cause of hospitalization in elderly individuals.2 Over the past 2 decades, significant progress has been made in characterizing the effects of healthy aging on multiple aspects of cardiovascular structure and function (reviewed in References 1 and 3). Cardiac morphological changes during aging include increasing left ventricular (LV) wall thickening, which can impair cardiac relaxation. In the absence of cardiac events, systolic function remains largely preserved. Although these aging changes are adaptive and interpreted as a "normal" response to a stiffer and less compliant arterial tree, the role of intrinsic factors in remodeling are unclear. The superimposition of additional age-related risk factors, such as hypertension or atherosclerosis, may render the heart more susceptible to overt failure.
Although extensive evidence supports the existence of environmental factors affecting longitudinal changes in cardiac structure, genetic contributions to myocardial aging remain largely unknown. Indication that genetic factors influence cardiac structure and function comes mainly from cross-sectional studies. The proportion of total variability in LV mass (LVM) explained by genetic factors, or heritability, has been estimated to be 17% to 69% in humans.4,5 Recent data on other echocardiographic measurements have shown heritability estimates ranging between 9% and 33%.6 However, the role of genetics in age-related changes in myocardial LV wall thickness (LVWT) and dimensions has not been defined. Several studies have estimated the contribution of genetic effects to intraindividual variation over time in other cardiovascular risk factors, including changes in adiposity,7,8 cholesterol levels,9 and blood pressure,9 whereas, to our knowledge, no data on myocardial aging are available.
Cardiac remodeling after myocardial infarction,10 HF progression,11,12 and LV hypertrophy13 are significantly different between men and women. In particular, age-associated increases in LVM and LVWT are seen more commonly in women than in men.14 Moreover, LV hypertrophy and HF with preserved LV function are more common in women after menopause. Estrogen regulates gene expression by binding to estrogen receptors (gene designation ESR1) and ß (ESR2; reviewed in Reference 15). Estrogen receptors are expressed in cardiomyocytes and fibroblasts.16 Genetic variation in ESR1 has been shown to be associated with phenotypic variation in LVM cross-sectionally.17 Given previous studies that have analyzed the association of genetic differences with LVM at a single time point, or within a short follow-up, and considering the important role of estrogen receptor- in mediating the effect of estrogens on the heart, we hypothesized that age-related LV remodeling in healthy men and women is associated with variation in ESR1.
To test this hypothesis, we selected the single nucleotide polymorphisms (SNPs) that were of most relevance to cardiovascular disease based on previous literature, in particular, those that were part of a haplotype block studied intensively in relation to blood pressure.18,19 Here, we present the association of LV changes over a 16-year period with 4 members of ESR1 that include a thymine–adenine (TA) dinucleotide repeat polymorphism in the promoter region, a synonymous coding region SNP in exon 1 (ESR1 30T>C), and 2 SNPs in the first intron (ESR1 PvuII and XbaI).
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Cohort
The sample was derived from the longitudinal community-based Framingham Heart Study offspring cohort of unrelated individuals of European descent and is described elsewhere.20 Participants included in the present investigation attended examination cycles 2 and 6 (1979–1982 and 1995–1998) and underwent routine medical history, physical examination, and echocardiography. Participants were excluded if they had a history of myocardial infarction, HF, or significant valvular disease; had no ESR1 TA repeat data; or had unavailable echocardiograms at either examination. The total sample contained 847 individuals.
All of the subjects gave written informed consent. The Framingham Heart Study protocol is approved by the Boston University Medical Center Institutional Review Board.
Echocardiography
Measurements were performed using 2D-guided M-mode echocardiography in accordance with American Society of Echocardiography recommendations.21 For examination 2, M-mode measurements were made with hand-held calipers off printed strip charts.22 For examination 6, echocardiographic measurements were made with commercially available software (Tomtec) averaging 3 digitized beats. The measurements obtained at examinations 2 and 6 included LVWT [posterior wall thickness+ventricular septal thickness], LV internal diameter end diastole (LVIDD), LV internal diameter end systole (LVIDS), LVM indexed to height (LVM/ht2.7),23,24 and fractional shortening (FS; relative wall thickness). Changes in LVM, LVM/ht2.7, LVWT, relative wall thickness, LVIDD, LVIDS, and FS were presented as subtracted values between the examination cycles 6 and 2, as well as by percent changes.
SNP Genotyping
Participants’ genomic DNA was extracted from peripheral blood leukocytes using standard methods. Four polymorphic markers at the ESR1 gene were genotyped for this study (Figure 1). The dinucleotide TA repeat in the 5' promoter region at 1174 bp upstream of exon 1 was amplified by PCR, as described previously.25 The 3 SNPs: c.30T>C (rs2077647; a synonymous substitution, Ser
Ser); intron 1 c.454 to 397C > T (also known as PvuII, rs2234693), and intron 1 c.454 to 351A>G (also known as XbaI, rs9340799) were genotyped as described previously.26
|
Statistical Analysis
Observed genotype frequencies were compared with those expected under Hardy–Weinberg equilibrium using a 
2 test. Given multiple alleles observed for the ESR1 microsatellite (number of the TA repeats ranged between 9 and 31; median: 18), and their bimodal distribution, the genotype for this polymorphism was coded as LL if both alleles contained at least the median number of repeats (18 repeats), SS if both alleles were "short" (<18), and LS if 1 allele had 18 and the other allele had <18 repeats.
Multivariable ANCOVA was performed to detect associations of the cross-sectional values and changes in quantitative echocardiography measures over time with ESR1 TA genotypes. Repeated-measures ANCOVA was used to examine the rate of change in LV sizes associated with ESR1 TA genotypes exploring effects on change as interaction term. Lewontin’s D' 27 was calculated to assess the linkage disequilibrium between the ESR1 TA repeat and the 3 SNPs of interest. Haplotype analysis including all 4 of the genotyped markers was carried out.
All of the analyses were performed using SAS/STAT and SAS/Genetics (including the proc haplotype procedure; SAS 9.1, SAS Institute, Inc). A 2-sided P<0.05 was considered statistically significant. An expanded Methods section is available online at http://hyper.ahajournals.org.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The characteristics of the 359 male and 488 female unrelated Framingham Heart Study Offspring participants from 2 examination cycles 16 years apart are shown in Table 1. Both men and women had significantly higher body mass index (BMI), systolic blood pressure, and more treatment for hypertension and diabetes at examination cycle 6; however, diastolic blood pressure was lower in men, and fewer men and women smoked. For both sexes, the LVM and LVWT were significantly greater at the later examination. Significant changes in echocardiographic measures over time were detected in both men and women in all of the tested features, except for FS in men (Table 1).
|
Significant sex-specific differences in longitudinal changes for all of the studied variables were detected (Table 1). Women had a greater increase in BMI and systolic blood pressure than men (12.0% versus 7.3%, P<0.0001; 9.2% versus 4.7%, P=0.01, respectively, for sex difference). Women showed a greater increase compared with their male counterparts in LVM (13.8% increase versus 4.4%; P<0.0001) and LVWT (12.3% increase versus 5.8%; P=0.0008). LV diameters were smaller for both sexes at examination cycle 6.
The genotype frequencies for the 4 polymorphisms under study (Figure 1) conformed to those expected under the Hardy–Weinberg equilibrium. All 4 of the genetic markers were in strong linkage disequilibrium. Given a potential functional importance of the ESR1 TA repeat because of its location in the promoter region of the gene, and its previous association with LVM, we chose to study the association between this variant and changes in cardiac structure with aging first.
No significant differences were observed between the 3 ESR1 TA genotype groups (SS, LS, and LL) in age, sex, hypertension, and incidence of diabetes (data not shown). In multivariable-adjusted cross-sectional analysis, ESR1 TA SS carriers, compared with individuals with LL and LS, had lower LVM, LVIDD, and LVIDS at examination 2 but higher LVM and LVWT 16 years later (Figure 2
; Table S1, available online at http://hyper.ahajournals.org). Also, carriers of both short alleles (SS) were shown to have a greater increase in LVM and LVWT than carriers of other genotypes (general and recessive models) in both males and females in adjusted (Table 2) and unadjusted analyses (Table S2). Similar trend was observed for another SNP under study, rs2234693, or PvuII (data not shown).
|
|
|
Secondary Analyses
The reported association between ESR1 TA genotypes and changes in LVM persisted if the study sample was stratified by the change in health status with regard to diabetes and menopause in women. Individuals with diabetes at both examination cycles (N=34) had a more marked mean increase in LVM (36.4±13.2 g, or 23%) if they carried ESR1-TA SS; the mean increase was more modest (12.9±4.9 g, or 7%) if they carried ESR1-TA LS, and they had a mean decrease of 7.5±10.3 g (–4.3%) if they carried ESR1-TA LL. Neither menopausal status nor hormone replacement therapy explained the observed change in the echocardiographic traits in women (data not shown).
Strong linkage disequilibrium detected between the 4 ESR1 markers resulted in 3 common haplotypes (Figure 1). The TA[S]–+30[T]–PvuII[T]–XbaI[A] haplotype was associated with LVM (8.7±3.3 g difference in change associated with each copy of this haplotype; P=0.008), LVWT (0.04±0.02 cm; P=0.06), and LVIDD (0.08±0.04 cm; P<0.05) change if compared with the TA[L]–+30[C]–PvuII[C]–XbaI[G] haplotype. However, the haplotype analysis provided no improvement over the individual ESR1-TA repeat analyses in terms of the explained variance.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study we report significant longitudinal changes in LV structure measured by M-mode echocardiography in ambulatory community-based individuals from the Framingham Heart Study over a period of 16 years. The changes include an increase in LVM and LVWT and a reduction in LV diameter at end systole and end diastole. However, the nature and magnitude of changes in LV structure has not been consistent across previously published studies. LVM, an important indicator of ventricular remodeling, in cross-sectional studies has been associated with advancing age in some28,29 but not all studies.30–32 Given considerable heritability estimates reported for LVM and other measures of LV structure and function, it is reasonable to suggest that the discrepancies between studies may be because of genetic factors, in addition to study design.
The ESR1 TA polymorphism is located in the regulatory region of the ESR1 gene, 1174 bp upstream of the first proposed transcribed site in exon 1,33 between promoters B and C,34 and is more likely to drive this effect than other ESR1 SNPs under study. The long allele has been associated with increased cardiovascular risk factor profile in previous reports. Namely, compared with short allele carriers, the TA L polymorphism has been linked with more severely diseased coronary arteries35,36 and a higher risk of myocardial infarction.35 At baseline (examination cycle 2), our results are consistent with a previous report that 1 long TA allele is associated with higher LVM.17 However, in our study, TA SS carriers demonstrated substantial LV remodeling consistent with a pattern of age-associated concentric hypertrophy. Intriguingly, this association maintained after the adjustment for longitudinal changes in other risk factors, such as BMI, systolic and diastolic blood pressure, occurrence of diabetes, hypertension, or menopause in women. For example, in individuals with diabetes mellitus at both exams, there was, on average, a 27.3% difference in the change in LVM between carriers of 2 short alleles (SS) versus no short alleles (LL), suggesting a significant disadvantage in developing LV hypertrophy. A similar trend was observed in women regardless of the change in their menopausal status and/or hormone replacement therapy over a period of 16 years. The fact that TA S allele carriers had greater LVM 16 years later, whereas the L carriers showed the least change, suggests that ESR1 TA SS genotype is associated with greater age-dependent LV remodeling.
Pollak et al36 have reported association between the ESR1 TA S allele and narrowed coronary segments in older individuals, while showing reverse relation in younger individuals. Significant associations with numerous cardiovascular outcomes have been reported for other ESR1 SNPs that are in strong linkage disequilibrium with the ESR1 TA repeat polymorphism. The common ESR1 PvuII T allele that is linked with the ESR1 TA S allele has been shown to interact with cigarette smoking, resulting in significantly higher concentrations of small low-density lipoprotein particles among female smokers.37 We observed that the TA[S]–+30[T]–PvuII[T]–XbaI[A] haplotype, although strongly linked with LV remodeling, did not improve the explained variance over the ESR1-TA polymorphism.
To our knowledge, this is the first report of a candidate gene approach to assess genetic susceptibility to myocardial aging. Previously, we found that the association between ESR1 SNPs and longitudinal blood pressure was stronger at older compared with younger ages.19 The previous blood pressure data and the associations that we report here support the hypothesis that genetic effects have age-dependent penetrance resulting in a difference of cross-sectional relations at 2 different ages. Despite the adjustment for age, our cross-sectional data suggest that there must be an age when the ESR1 TA genotype and LV relations are flat (Figure 2
).
It has been suggested that changes in cardiovascular risk factors with advancing age reflect gene–environmental interactions.9 Also, reductions in the cellular RNA concentrations, the rate of protein synthesis, and changes in gene expression have been shown to occur with aging.38 Estrogen receptor–dependent changes may occur indirectly through their effect on lipoprotein metabolism and blood vessel stiffness or directly by modulating gene expression in cardiac muscle and fibroblast cells. The TA repeat is located in the regulatory region of ESR1; therefore, modified ESR1 may alter expression of a number of genes, including endothelial NO synthase, prostacyclin synthase, inducible NO synthase, endothelin 1, progesterone receptor, and others.15
HF with a normal ejection fraction is more common with increasing age, particularly in women.39 Typically, persons with HF and normal LV function have thickened ventricular walls and smaller cavity dimensions. These changes render the ventricle less compliant, which, in concert with increased vascular stiffness, can contribute importantly to HF. The greater increase of LVM and LVWT found in TA[S]/PvuII[T] haplotype carriers over 16 years suggests that carriers of this haplotype may have a greater susceptibility to HF with preserved cardiac function.
Study Limitations
This study was strengthened by the long period of time between echocardiograms, community-based setting, and comprehensive measurement of cardiac function. However, because of the lack of persons of diverse ethnic backgrounds, the generalizability to other ethnicities is unknown. We acknowledge that, to assess the genetic contribution to LV remodeling, one must account for environmental and extracardiac influences. Although we adjusted for numerous risk factors, we cannot exclude residual confounding by other factors not included in the multivariable models. To limit the artifact of multiple testing, we began our study with the TA repeat polymorphism that has been linked previously with LVM and then confirmed our findings using haplotype analysis. In addition, because of advances in echocardiography technology, the equipment evolved from largely M-mode examination to 2D guided M-mode at the later examination. Although no data directly comparing the 2 techniques are available, improvements in technology potentially reduced both measurement error and random misclassification of LV measurements at examination 6, which would introduce a conservative bias. Moreover, the measurements could not have been biased by genotype, which was the primary exposure examined in this study. We also acknowledge the possibility of depletion of susceptibilities if carriers of the TA LL genotype who had the highest LVM at examination 2 died because of cardiovascular disease over the 16-year period and never came back to get DNA at examination cycle 6. Because we did not account for specific classes of antihypertensive medications, such as diuretics, although unlikely, it is possible that more individuals with the TA LL genotype were nonrandomly on diuretics at the follow-up visit. However, in an observational cohort, confounding by medications is inevitable.
Conclusions
The findings of this study are consistent with the hypothesis that longitudinal changes in LVM, as assessed by M-mode echocardiography, differ not only by sex, age, and body size but also by a regulatory region polymorphism in ESR1. Carriers of the common ESR1 TA[SS] genotype demonstrated an increase in LVM and LVWT. These findings will need to be replicated in other cohorts.
Perspectives
Quantitative data on age-related changes in myocardial structure and function in the absence of major cardiovascular disease are essential to identify the specific characteristics of the aging process in the heart. Knowledge that a specific carrier status may predispose to significant disadvantage in the development of cardiovascular risk factors may lead to targeted intervention strategies to reduce age-associated risk among genetically susceptible individuals.
|
Acknowledgments |
|---|
Sources of Funding
This study was supported by National Institutes of Health National Heart, Lung, and Blood Institute program project grants P01-HL077378 (to M.E.M), 6R01-NS 17950, and 2K24HL04334 (to R.S.V.).
Disclosures
None.
Received October 31, 2006; first decision November 19, 2006; accepted February 21, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Lakatta EG, Sollott SJ. Perspectives on mammalian cardiovascular aging: humans to molecules. Comp Biochem Physiol A Mol Integr Physiol. 2002; 132: 699–721.[CrossRef][Medline] [Order article via Infotrieve]
2. American Heart Association. Heart Disease and Stroke Statistics. Statistical Supplement. Dallas: American Heart Association; 2005.
3. Lakatta EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail Rev. 2002; 7: 29–49.[CrossRef][Medline] [Order article via Infotrieve]
4. Post WS, Larson MG, Myers RH, Galderisi M, Levy D. Heritability of left ventricular mass: the Framingham Heart Study. Hypertension. 1997; 30: 1025–1028.
5. Sharma P, Middelberg RP, Andrew T, Johnson MR, Christley H, Brown MJ. Heritability of left ventricular mass in a large cohort of twins. J Hypertens. 2006; 24: 321–324.[Medline] [Order article via Infotrieve]
6. Bella JN, MacCluer JW, Roman MJ, Almasy L, North KE, Best LG, Lee ET, Fabsitz RR, Howard BV, Devereux RB. Heritability of left ventricular dimensions and mass in Am Indians: the Strong Heart Study. J Hypertens. 2004; 22: 281–286.[Medline] [Order article via Infotrieve]
7. Coady SA, Jaquish CE, Fabsitz RR, Larson MG, Cupples LA, Myers RH. Genetic variability of adult body mass index: a longitudinal assessment in Framingham families. Obes Res. 2002; 10: 675–681.[Medline] [Order article via Infotrieve]
8. Hunt MS, Katzmarzyk PT, Perusse L, Rice T, Rao DC, Bouchard C. Familial resemblance of 7-year changes in body mass and adiposity. Obes Res. 2002; 10: 507–517.[Medline] [Order article via Infotrieve]
9. Friedlander Y, Austin MA, Newman B, Edwards K, Mayer-Davis EI, King MC. Heritability of longitudinal changes in coronary-heart-disease risk factors in women twins. Am J Hum Genet. 1997; 60: 1502–1512.[Medline] [Order article via Infotrieve]
10. Shlipak MG, Angeja BG, Go AS, Frederick PD, Canto JG, Grady D. Hormone therapy and in-hospital survival after myocardial infarction in postmenopausal women. Circulation. 2001; 104: 2300–2304.
11. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, Murabito JM, Vasan RS. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002; 347: 1397–1402.
12. Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation. 2002; 105: 1585–1591.
13. Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, Douglas PS, Lorell BH. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol. 1999; 34: 264–273.
14. Shub C, Klein AL, Zachariah PK, Bailey KR, Tajik AJ. Determination of left ventricular mass by echocardiography in a normal population: effect of age and sex in addition to body size. Mayo Clin Proc. 1994; 69: 205–211.[Medline] [Order article via Infotrieve]
15. Mendelsohn ME. Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol. 2002; 90: 3F–6F.[CrossRef][Medline] [Order article via Infotrieve]
16. Grohe C, Kahlert S, Lobbert K, Stimpel M, Karas RH, Vetter H, Neyses L. Cardiac myocytes and fibroblasts contain functional estrogen receptors. FEBS Lett. 1997; 416: 107–112.[CrossRef][Medline] [Order article via Infotrieve]
17. Leibowitz D, Dresner-Pollak R, Dvir S, Rokach A, Reznik L, Pollak A. Association of an estrogen receptor-alpha gene polymorphism with left ventricular mass. Blood Press. 2006; 15: 45–50.[CrossRef][Medline] [Order article via Infotrieve]
18. Ellis JA, Infantino T, Harrap SB. Sex-dependent association of blood pressure with oestrogen receptor genes ERalpha and ERbeta. J Hypertens. 2004; 22: 1127–1131.[CrossRef][Medline] [Order article via Infotrieve]
19. Peter I, Shearman AM, Zucker DR, Schmid CH, Demissie S, Cupples LA, Larson MG, Vasan RS, D’Agostino RB, Karas RH, Mendelsohn ME, Housman DE, Levy D. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens. 2005; 23: 2193–2200.[Medline] [Order article via Infotrieve]
20. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol. 1979; 110: 281–290.
21. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978; 58: 1072–1083.
22. Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1987; 59: 956–960.[CrossRef][Medline] [Order article via Infotrieve]
23. de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O, Alderman MH. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol. 1992; 20: 1251–1260.[Abstract]
24. Gardin JM, McClelland R, Kitzman D, Lima JA, Bommer W, Klopfenstein HS, Wong ND, Smith VE, Gottdiener J. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am J Cardiol. 2001; 87: 1051–1057.[CrossRef][Medline] [Order article via Infotrieve]
25. Demissie S, Cupples LA, Shearman AM, Gruenthal KM, Peter I, Schmid CH, Karas RH, Housman DE, Mendelsohn ME, Ordovas JM. Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study. Atherosclerosis. 2006; 185: 210–218.[CrossRef][Medline] [Order article via Infotrieve]
26. Shearman AM, Cupples LA, Demissie S, Peter I, Schmid CH, Karas RH, Mendelsohn ME, Housman DE, Levy D. Association between estrogen receptor alpha gene variation and cardiovascular disease. JAMA. 2003; 290: 2263–2270.
27. Lewontin RC. The interaction of selection and linkage. II. Optimum models. Genetics. 1964; 50: 757–782.
28. Devereux RB, Roman MJ, de Simone G, O’Grady MJ, Paranicas M, Yeh JL, Fabsitz RR, Howard BV. Relations of left ventricular mass to demographic and hemodynamic variables in American Indians: the Strong Heart Study. Circulation. 1997; 96: 1416–1423.
29. Gardin JM, Wagenknecht LE, Anton-Culver H, Flack J, Gidding S, Kurosaki T, Wong ND, Manolio TA. Relationship of cardiovascular risk factors to echocardiographic left ventricular mass in healthy young black and white adult men and women. The CARDIA study. Coronary Artery Risk Development in Young Adults. Circulation. 1995; 92: 380–387.
30. Nikitin NP, Loh PH, de Silva R, Witte KK, Lukaschuk EI, Parker A, Farnsworth TA, Alamgir FM, Clark AL, Cleland JG. Left ventricular morphology, global and longitudinal function in normal older individuals: a cardiac magnetic resonance study. Int J Cardiol. 2006; 108: 76–83.[CrossRef][Medline] [Order article via Infotrieve]
31. Ganau A, Saba PS, Roman MJ, de Simone G, Realdi G, Devereux RB. Ageing induces left ventricular concentric remodelling in normotensive subjects. J Hypertens. 1995; 13: 1818–1822.[Medline] [Order article via Infotrieve]
32. Hees PS, Fleg JL, Lakatta EG, Shapiro EP. Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol. 2002; 90: 1231–1236.[CrossRef][Medline] [Order article via Infotrieve]
33. Sano M, Inoue S, Hosoi T, Ouchi Y, Emi M, Shiraki M, Orimo H. Association of estrogen receptor dinucleotide repeat polymorphism with osteoporosis. Biochem Biophys Res Commun. 1995; 217: 378–383.[CrossRef][Medline] [Order article via Infotrieve]
34. Kos M, Reid G, Denger S, Gannon F. Minireview: genomic organization of the human ERalpha gene promoter region. Mol Endocrinol. 2001; 15: 2057–2063.
35. Kunnas TA, Laippala P, Penttila A, Lehtimaki T, Karhunen PJ. Association of polymorphism of human alpha oestrogen receptor gene with coronary artery disease in men: a necropsy study. BMJ. 2000; 321: 273–274.
36. Pollak A, Rokach A, Blumenfeld A, Rosen LJ, Resnik L, Dresner-Pollak R. Association of oestrogen receptor alpha gene polymorphism with the angiographic extent of coronary artery disease. Eur Heart J. 2004; 25: 240–245.
37. Shearman AM, Demissie S, Cupples LA, Peter I, Schmid CH, Ordovas JM, Mendelsohn ME, Housman DE. Tobacco smoking, estrogen receptor alpha gene variation and small low density lipoprotein level. Hum Mol Genet. 2005; 14: 2405–2413.
38. Meerson FZ, Javich MP, Lerman MI. Decrease in the rate of RNA and protein synthesis and degradation in the myocardium under long-term compensatory hyperfunction and on aging. J Mol Cell Cardiol. 1978; 10: 145–159.[CrossRef][Medline] [Order article via Infotrieve]
39. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 1999; 33: 1948–1955.
This article has been cited by other articles:
 |
|
 |
|
  W. Lieb, V. Xanthakis, L. M. Sullivan, J. Aragam, M. J. Pencina, M. G. Larson, E. J. Benjamin, and R. S. Vasan Longitudinal Tracking of Left Ventricular Mass Over the Adult Life Course: Clinical Correlates of Short- and Long-Term Change in the Framingham Offspring Study Circulation, June 23, 2009; 119(24): 3085 - 3092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Novotny, A. M. Simpson, N. J. Tomicek, T. S. Lancaster, and D. H. Korzick Rapid Estrogen Receptor-{alpha} Activation Improves Ischemic Tolerance in Aged Female Rats through a Novel Protein Kinase C{epsilon}-Dependent Mechanism Endocrinology, February 1, 2009; 150(2): 889 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Peter, A. Kelley-Hedgepeth, C. S. Fox, L. Adrienne Cupples, G. S. Huggins, D. E. Housman, R. H. Karas, M. E. Mendelsohn, D. Levy, and J. M. Murabito Variation in Estrogen-Related Genes Associated with Cardiovascular Phenotypes and Circulating Estradiol, Testosterone, and Dehydroepiandrosterone Sulfate Levels J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2779 - 2785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-a. B. Shih and D. T. O'Connor Hereditary Determinants of Human Hypertension: Strategies in the Setting of Genetic Complexity Hypertension, June 1, 2008; 51(6): 1456 - 1464. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||