Download Age-Related Changes in Echocardiographic

Age-Related Changes in Echocardiographic Measurements
Association With Variation in the Estrogen Receptor-␣ Gene
Inga Peter, Gordon S. Huggins, Amanda M. Shearman, Arthur Pollak, Christopher H. Schmid,
L. Adrienne Cupples, Serkalem Demissie, Richard D. Patten, Richard H. Karas, David E. Housman,
Michael E. Mendelsohn, Ramachandran S. Vasan, Emelia J. Benjamin
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
Abstract—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. (Hypertension. 2007;49:1000-1006.)
Key Words: echocardiography 䡲 left ventricular remodeling 䡲 estrogen receptor-␣ 䡲 restriction fragment length
䡲 single nucleotide polymorphism
y the year 2035, ⬇1 in 4 individuals in the United States
will be ⱖ65 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.
B
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.
Received October 31, 2006; first decision November 19, 2006; revision accepted February 21, 2007.
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 [email protected]
© 2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/HYPERTENSIONAHA.106.083790
1000
Peter et al
Genetic Variation in Age-Related Echo Changes
1001
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
Figure 1. Location of ESR1 polymorphisms relative to exons 1 and 2 and their quantitative characteristics. Numbered boxes indicate
exons; solid black lines indicate introns; vertical arrows indicate SNPs; (TA)n indicates promoter region polymorphism; rs2077647, or
30T⬎C, is a coding synonymous SNP; and rs2234693, or PvuII, and rs9340799, or XbaI, are intronic SNPs.
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
␤ (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 phenoTABLE 1.
typic 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
Participant Characteristics at Examination Cycles 2 and 6 (16 Years Apart)
Examination Cycle 2*
Study Characteristics
Age, y
BMI, kg/m2
Examination Cycle 6*
P of Change Between
Cycles†
Men (N⫽359)
Women (N⫽488)
Men (N⫽359)
Women (N⫽488)
Men
Women
42⫾9
43⫾9
58⫾9
59⫾9
26.1⫾3.2
24.1⫾4.2
28.0⫾4.1
26.9⫾5.1
䡠䡠䡠
⬍0.0001
䡠䡠䡠
⬍0.0001
6
2
13
8
0.004
⬍0.0001
22
15
43
41
⬍0.0001
⬍0.0001
9
7
30
26
⬍0.0001
0.004
30
31
17
16
⬍0.0001
⬍0.0001
䡠䡠䡠
123⫾14
33
128.8⫾19.7
䡠䡠䡠
⬍0.0001
⬍0.0001
118⫾17
䡠䡠䡠
129.2⫾17.8
76
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
80⫾9
75⫾10
77.0⫾9.0
74.4⫾9.1
⬍0.0001
185.0⫾2.1
125.3⫾4.8
192.4⫾1.2
142.3⫾6.3
0.0002
⬍0.0001
LVM/ht2.7‡
40.4⫾1.5
34.6⫾2.8
42.0⫾1.2
39.4⫾3.4
0.0002
⬍0.0001
LVWT, cm‡
1.91⫾0.05
1.62⫾0.07
2.02⫾0.03
1.83⫾0.07
⬍0.0001
⬍0.0001
RWT, ratio‡
0.37⫾0.01
0.35⫾0.02
0.41⫾0.01
0.40⫾0.02
⬍0.0001
⬍0.0001
LVIDD, cm‡
5.12⫾0.05
4.62⫾0.05
5.02⫾0.03
4.55⫾0.01
⬍0.0001
⬍0.0001
Diabetes mellitus, %
Hypertension, %
Hypertension treatment, %
Current smokers, %
Postmenopausal women, %
LVM, g‡
LVIDS, cm‡
FS, ratio‡
⬍0.0001
0.09
3.30⫾0.05
2.88⫾0.05
3.24⫾0.05
2.81⫾0.02
0.02
⬍0.0001
0.357⫾0.003
0.377⫾0.005
0.356⫾0.007
0.382⫾0.004
0.70
0.02
RWT indicates relative wall thickness.
*Study characteristics are mean⫾SD for continuous measures, % for categorical variables.
†Calculated using Mantel–Haenszel ␹2 test for change for categorical variables, t-test otherwise.
‡Age adjusted.
1002
Hypertension
May 2007
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
Figure 2. Cross-sectional echocardiographic measurements at the examination cycles 2 and 6. Means and SEs are presented after
adjustment for age, BMI, systolic and diastolic blood pressure, antihypertension treatment, and diabetes status. A and B, LVM in men
and women, respectively (overall P for difference in men and women combined between SS and LS and LL at examination 2⫽0.11, at
examination 6⫽0.03). C and D, LVWT (P⫽0.17 and 0.07). E and F, LVIDD (P⫽0.09 and 0.32). G and H, LVIDS (P⫽0.001 and 0.99).
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
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, Ser3 Ser); intron
1 c.454 to 397C ⬎ T (also known as PvuII, rs2234693), and intron
Peter et al
Genetic Variation in Age-Related Echo Changes
1003
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
Figure 2. (Continued)
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 (ⱖ18
repeats), SS if both alleles were “short” (⬍18), and LS if 1 allele had
ⱖ18 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. Repeatedmeasures 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
The characteristics of the 359 male and 488 female unrelated
Framingham Heart Study Offspring participants from 2 ex-
amination 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
1004
Hypertension
May 2007
TABLE 2.
Mean 16-Year Changes in the Echocardiographic Measurements by ESR1 TA Repeat
P
Men Mean
Change⫾SE* (N)
Women Means
Change⫾SE* (N)
ANCOVA
Echo
Phenotype
SS (99)
LS (180)
LL (80)
SS (125)
LS (244)
LL (117)
LVM, g
15.4⫾2.0
5.4⫾1.4
4.5⫾2.3
24.3⫾1.2
15.2⫾1.0
14.4⫾1.2
2.7
LVM/ht
LVWT, cm
RWT, ratio
LVIDD, cm
LVIDS, cm
FS, ratio
Repeated-Measures
ANCOVA
General Recessive† General Recessive†
0.002
0.0006
0.0008
0.0003
3.6⫾0.1
1.1⫾0.1
1.1⫾0.1
6.4⫾0.1
4.4⫾0.1
4.1⫾0.1
0.001
0.0002
0.002
0.0008
0.15⫾0.02
0.09⫾0.01
0.11⫾0.02
0.25⫾0.01
0.18⫾0.01
0.21⫾0.01
0.01
0.003
0.01
0.004
0.06⫾0.001
0.15
䡠䡠䡠
0.15
⫺0.05⫾0.02
0.04⫾0.001
⫺0.09⫾0.01
⫺0.14⫾0.02
⫺0.03⫾0.01
⫺0.06⫾0.01
⫺0.14⫾0.01
0.07
䡠䡠䡠
0.01
䡠䡠䡠
0.07
⫺0.01⫾0.01
⫺0.08⫾0.01
⫺0.06⫾0.01
⫺0.02⫾0.01
⫺0.08⫾0.01
⫺0.10⫾0.01
0.34
䡠䡠䡠
0.05
0.02
0.36
䡠䡠䡠
0.13
⫺0.006⫾0.002
0.03⫾0.001
0.04⫾0.001
0.06⫾0.001
0.004⫾0.001 ⫺0.005⫾0.002 0.0002⫾0.002
0.05⫾0.001
0.009⫾0.001
0.006⫾0.002
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
䡠䡠䡠
RWT indicates relative wall thickness.
*Predicted means after adjustment for sex, age, echocardiographic measurement at examination cycle 2; BMI at examination cycle 2 (weight for LVM/ht2.7); changes
in systolic and diastolic blood pressure, BMI (weight for LVM/ht2.7), and diabetes status between the examination cycles; and current antihypertensive treatment.
†Comparison between ESR1 TA SS carriers and LL and LS carriers. Recessive model is not shown if P for the genotype effect in general model was ⬎0.05. For
trait definition see Methods section.
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 multivariableadjusted 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 im-
provement over the individual ESR1-TA repeat analyses in
terms of the explained variance.
Discussion
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 ⱖ1 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
Peter et al
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
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 crosssectional 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.
Genetic Variation in Age-Related Echo Changes
1005
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.
Sources of Funding
This study was supported by National Institutes of Health National
Heart, Lung, and Blood Institute program project grants P01HL077378 (to M.E.M), 6R01-NS 17950, and 2K24HL04334 (to
R.S.V.).
1006
Hypertension
May 2007
Disclosures
None.
References
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
1. Lakatta EG, Sollott SJ. Perspectives on mammalian cardiovascular aging:
humans to molecules. Comp Biochem Physiol A Mol Integr
Physiol. 2002;132:699 –721.
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.
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.
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.
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.
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.
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.
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.
15. Mendelsohn ME. Genomic and nongenomic effects of estrogen in the
vasculature. Am J Cardiol. 2002;90:3F– 6F.
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.
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.
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.
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 crosssectional and longitudinal blood pressure in the Framingham Heart Study.
J Hypertens. 2005;23:2193–2200.
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.
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.
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.
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.
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.
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.
32. Hees PS, Fleg JL, Lakatta EG, Shapiro EP. Left ventricular remodeling
with age in normal men versus women: novel insights using threedimensional magnetic resonance imaging. Am J Cardiol. 2002;90:
1231–1236.
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.
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.
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.
Age-Related Changes in Echocardiographic Measurements: Association With Variation in
the Estrogen Receptor- α Gene
Inga Peter, Gordon S. Huggins, Amanda M. Shearman, Arthur Pollak, Christopher H. Schmid,
L. Adrienne Cupples, Serkalem Demissie, Richard D. Patten, Richard H. Karas, David E.
Housman, Michael E. Mendelsohn, Ramachandran S. Vasan and Emelia J. Benjamin
Downloaded from http://hyper.ahajournals.org/ by guest on May 8, 2017
Hypertension. 2007;49:1000-1006; originally published online March 19, 2007;
doi: 10.1161/HYPERTENSIONAHA.106.083790
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2007 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/49/5/1000
Data Supplement (unedited) at:
http://hyper.ahajournals.org/content/suppl/2007/02/28/HYPERTENSIONAHA.106.083790.DC1
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/