Cardiac Hypertrophy/Remodeling

Left Ventricular Hypertrophy, Subclinical Atherosclerosis,

and Inflammation
Sameer K. Mehta, J. Eduardo Rame, Amit Khera, Sabina A. Murphy, Russell M. Canham,
Ronald M. Peshock, James A. de Lemos, Mark H. Drazner

AbstractTo elucidate mechanisms by which left ventricular (LV) hypertrophy (LVH) increases the risk of atherosclerotic
heart disease, we sought to determine whether LVH is independently associated with coronary artery calcium (CAC)
and serum C-reactive protein (CRP) levels in the general population. The Dallas Heart Study is a population-based
sample in which 2633 individuals underwent cardiac MRI to measure LV structure, electron beam CT to measure CAC,
and measurement of plasma CRP. We used univariate and multivariable analyses to determine whether LV mass and
markers of concentric LV hypertrophy or dilation were associated with CAC and CRP. Increasing quartiles of LV mass
indexed to fat-free mass, LV wall thickness, and concentricity, but not LV volume, were associated with CAC in both
men and women (P0.001). After adjustment for traditional cardiovascular risk factors and statin use, LV wall
thickness and concentricity remained associated with CAC in linear regression (P0.001 for each). These associations
were particularly robust in blacks. LV wall thickness and concentricity were also associated with elevated CRP levels
(P0.001 for both) in gender-stratified univariate analyses, although these associations did not persist in multivariable
analysis. In conclusion, concentric LVH is an independent risk factor for subclinical atherosclerosis. LVH is also
associated with an inflammatory state as reflected in elevated CRP levels, although this relationship appears to be
mediated by comorbid conditions. These data likely explain in part why individuals with LVH are at increased risk for
myocardial infarction. (Hypertension. 2007;49:1385-1391.)
Key Words: left ventricular hypertrophy atherosclerosis inflammation myocardial infarction
coronary artery disease

L eft ventricular (LV) hypertrophy (LVH), whether deter-

mined by the ECG19 or echocardiogram,6 8,10 18 has
been associated with various adverse cardiovascular out-
comes, including mortality, myocardial infarction, and heart
failure. Although there has been considerable speculation as
to why LVH is such an important marker of risk,19,20 the basic
mechanisms that predispose patients with LVH to develop
atherosclerotic heart disease (ASHD) are not known. Previ-
ous hypotheses have included abnormalities in the coronary
vasculature2125 or platelets,26 increased blood viscosity,27
and a prothrombotic state.28 In addition to these factors,
which may contribute to reduced myocardial oxygen supply,
myocardial oxygen demand is also increased in patients with
LVH.20 Another simple explanation for the association of
LVH and ASHD is that LVH reflects target organ damage
from concomitant risk factors, such as hypertension, thus
providing a noninvasive barometer of the extent of ASHD.
The association of LVH with atherosclerosis in other vascular
territories, for example, the carotid artery,29 supports this
hypothesis. There are scant data as to whether LVH is
associated with the burden of coronary atherosclerosis as
estimated by coronary artery calcium (CAC).30 32 Yet another
emerging hypothesis is that LVH itself is a low-level inflam-
matory state, as has been suggested recently from animal33
and human studies.34,35 If this is the case, one could postulate
that the proinflammatory state associated with LVH may
increase the risk of ASHD and incident myocardial infarction.
The Dallas Heart Study is a large, ethnically diverse,
population-based sample of Dallas County, Tex, in which
subjects underwent cardiac MRI and coronary electron beam CT
(EBCT) and had serum C-reactive protein (CRP) measured,
affording an ideal opportunity to determine the mechanisms by
which LVH increases the risk of ASHD. In this study we tested
the following 2 hypotheses: LVH is independently associated
with extent of subclinical atherosclerosis as measured by CAC,
and LVH is independently associated with an elevation in CRP.
Measures of LVH included elevated LV mass, wall thickness,
and concentricity (the ratio of LV mass:volume).
Methods
Study Population
The Dallas Heart Study is a multiethnic, population-based, proba-
bility based sample of 6101 residents of Dallas County designed to

Received January 22, 2007; first decision February 5, 2007; revision accepted March 10, 2007.
From the Donald W. Reynolds Cardiovascular Clinical Research Center and Divisions of Cardiology (S.K.M., J.E.R., A.K., R.M.C., R.M.P., J.A.d.L.,
M.H.D.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas; and the TIMI Study Group (S.A.M.), Boston, Mass.
Correspondence to Mark H. Drazner, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9047. E-mail
Mark.Drazner@UTSouthwestern.edu
2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/HYPERTENSIONAHA.107.087890

1385
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1386 Hypertension June 2007

study cardiovascular disease. A description of the study design,
sample description, and variable definitions has been described
previously.36 The initial visit for all 6101 participants included an
interview for demographic and health-related data, as well as 5 blood
pressure measurements. Subjects between the ages of 30 and 65
years were invited to participate in 2 additional visits, which
included blood and urine sampling, as well as imaging procedures.
Of these, a total of 2744 participants underwent cardiac MRI and
EBCT, as measurement of CRP from stored plasma specimens.
Participants with a previous history of myocardial infarction were
excluded from the present analysis, leaving 2633 individuals in the
final study cohort.
EBCT Protocol and CAC Classification
Gated EBCT image acquisition was performed using an Imatron
C-150 XP EBCT scanner. Details of image acquisition and scanner
properties have been described previously.38 A focus was defined as
a region of 3 continuous voxels with a computed tomography
number 130. The voxel size was 0.5860.5863 mm, so that 3
voxels would be a volume of 3.08 mm. Scans were read blindly by
a single individual at 2 different settings, and only foci within the
coronary arteries were scored. Results were reported in Agatston
units,39,40 and the mean of the 2 scores was used as the final CAC
score. CAC-positive individuals were defined as individuals with a
mean CAC score 10 Agatston units.

Blood Pressure Cardiac MRI

Five sets of blood pressure measurements were obtained using an
automatic oscillometric device (Welch Allyn, series 52 000) with an
appropriately sized blood pressure cuff at each of 3 visits. This
device has been validated against catheter measurement of arterial
pressure.37 The blood pressure was considered the average of
measurements 3 through 5 at each visit (total 9 readings: n2596;
total 6 readings: n36; total 3 readings: n1).
Multiple breath-hold electrocardiographic-gated cine magnetic reso-
nance images were obtained from 2 similar 1.5-T MRI systems. The
details of this protocol have been described previously.8,41 Mean LV
wall thickness was determined via short axis slices. The wall
thickness was computed for each slice excluding the apical slice and
then averaged to determine the mean LV wall thickness. Concen-
tricity was defined as the ratio of LV mass/LV end-diastolic volume.

TABLE 1. Baseline Characteristics of the Study Subjects Stratified by Gender-Specific

Quartiles of Concentricity
Quartile of LV Concentricity

Variable Quartile 1 Quartile 2 Quartile 3 Quartile 4 P

Age, y 42 43 45 49 0.001
IQ 35 to 48 35 to 49 37 to 52 42 to 56
Race, % 0.001
Non-Hispanic black 35 44 52 64
Non-Hispanic white 43 34 29 21
Hispanic 19 19 17 13
BMI, kg/m2 28 29 30 31 0.001
IQ 23 to 30 24 to 32 25 to 34 26 to 35
Smoker, % 24 27 27 33 0.003
Family history of MI, % 27 30 32 38 0.001
Diabetes, % 5 6 11 21 0.001
Hypertension, % 15 17 28 55 0.001
On statin, % 4 4 7 9 0.001
SBP, mm Hg 119 122 126 138 0.001
IQ 111 to 126 113 to 129 117 to 134 124 to 149
DBP, mm Hg 75 77 79 84 0.001
IQ 70 to 79 72 to 82 74 to 84 78 to 90
Total cholesterol, mg/dL 175 180 182 187 0.001
IQ 148 to 197 157 to 202 156 to 204 159 to 211
LDL cholesterol, mg/dL 101 106 108 113 0.001
IQ 79 to 121 82 to 127 86 to 129 85 to 135
HDL cholesterol, mg/dL 53 50 50 49 0.001
IQ 42 to 60 40 to 58 40 to 57 40 to 58
Triglycerides, mg/dL 113 108 114 102 0.001
IQ 63 to 127 67 to 139 69 to 150 72 to 164
Fat-free mass, kg 53.4 54.7 55.7 57.0 0.001
IQ 43.6 to 62.1 45.5 to 63.0 46.7 to 63.8 47.2 to 65.7
Fat mass, kg 24.6 25.9 28.1 29.3 0.001
IQ 16.5 to 29.8 17.7 to 32.1 19.4 to 34.4 21.3 to 36.6
IQ indicates interquartile range; MI, myocardial infarction; LDL, low-density lipoprotein; HDL, high-density
lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure. Quartiles of LV concentricity (g/mL) were 0.8
to 1.5, 1.5 to 1.69, 1.69 to 1.89, and 1.89 (men) and 0.7 to 1.31, 1.31 to 1.48, 1.48 to 1.69, and 1.69 (women).

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 Mehta et al LVH, CAC, and CRP 1387

High-Sensitivity CRP Assay
Blood samples were obtained after an overnight fast in ethylenedi-
amine tetra-acetic acid, centrifuged at 1000g for 15 minutes at 4C
and stored at 80C before the assay was performed. CRP measure-
ments were performed on thawed samples using the Roche/Hitachi
912 System, Tina-quant assay, as described previously.42 The min-
imal detectable range of this assay is 0.1 mg/L, and the upper limit
is 20 mg/L.
Statistical Analysis
Categorical data are reported as proportions and continuous data as
median values and interquartile ranges. Baseline demographic vari-
ables, including coronary artery disease risk factors, were compared
among gender-specific quartiles of LV concentricity. The 2 test was
used for categorical variables and the Wilcoxon rank sum test for
continuous variables, because many were nonparametric. Univariate
analyses between variables and CAC were performed by analyzing
the log of CAC1 to transform CAC to a continuous variable, as
well as by analyzing CAC as a categorical variable (presence or
absence of CAC). A test for trend across ordered groups was
performed for the association between quartiles of LV structure and
CAC and CRP. Multivariable logistic regression models were con-
structed in which prevalent CAC was the dependent variable. Linear
regression models were constructed using log CAC1 as the depen-
dent variable. In addition to a measure of LV structure, these models
included adjustment for traditional risk factors for the development
of coronary artery disease, including diabetes, hypertension, systolic
blood pressure, smoking, cholesterol levels, and age, as well as fat
mass, fat-free mass, the use of statin medications, and the use of oral
estrogens. These analyses were repeated in the following subgroups:
blacks, whites, and in patients not on antihypertensive treatment
(n1973). We also performed formal analyses testing the interaction
between race (black or white) and LV mass, wall thickness, and
concentricity on CAC with multiplicative interaction terms using
multivariable linear (outcome: log CAC1) and logistic (outcome:

Figure 1. Association between gender-specific quartiles of LV structure and CAC. Note that increasing LV wall thickness (A), concen-
tricity (B), and LVM mass indexed to fat-free mass (C) were associated with increasing CAC, whereas LV end-diastolic volume indexed
to body surface area (D) was not. P values are for trend across interquartile ranges.

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1388 Hypertension June 2007

TABLE 2. Association of LV Structure and CAC

Logistic (CAC10) Linear (log CAC1)

Unadjusted Adjusted Unadjusted Adjusted

LV Parameter OR (CI)* P OR (CI)* P P P

LV mass 1.79 (1.58 to 2.04) 0.001 1.18 (0.91 to 1.5) 0.21 0.64 0.001 0.32 0.001
LV end-diastolic volume 1.00 (0.88 to 1.13) 0.98 1.03 (0.85 to 1.23) 0.8 0.087 0.05 0.06 0.21
LV wall thickness 2.43 (2.10 to 2.80) 0.001 1.23 (0.97 to 1.55) 0.09 0.83 0.001 0.27 0.001
Concentricity 1.91 (1.71 to 2.13) 0.001 1.14 (0.99 to 1.32) 0.06 0.60 0.001 0.16 0.001
Odds ratios are for interquartile ranges: LV mass, 57 g; LV volume, 31 mL; LV wall thickness, 2.4 cm; and concentricity, 0.4 g/mL. Models adjusted for race, age,
sex, family history of early myocardial infarction, systolic blood pressure, fat mass, fat-free mass, total cholesterol, high-density lipoprotein, diabetes, smoking,
antihypertensive therapy, use of statin medications, and oral estrogen use.
*Odds ratio (95% CIs).
LV mass/end-diastolic volume.

prevalent CAC) regression with the same covariates as above.
Multivariable linear regression models were constructed where log
CRP was the dependent variable as well. Analyses were performed
using Stata version 8.2 (Stata Corp).
Results
Baseline characteristics of the cohort are shown, stratified by
gender-specific quartiles of LV concentricity (mass/volume).
Increasing concentricity was associated with increasing age,
body mass index, blood pressure, cholesterol, fat mass, and
fat-free mass (Table 1). Higher concentricity was also asso-
ciated with black ethnicity, diabetes, smoking history, and use
of statins.
Measures of concentric LVH, including wall thickness
(Figure 1a), concentricity (Figure 1b), or LV mass indexed to
fat-free mass (Figure 1c), were associated with an increased
prevalence of CAC in both men and women (P0.001 for
each). In contrast, there was no significant association be-
tween LV end-diastolic volume indexed to body surface area
and CAC for either gender (Figure 1d). After adjusting for
important potential confounders, LV mass, wall thickness,
and concentricity each remained associated with the quantity
of CAC in multivariable linear (outcome log CAC1)
regression analyses (Table 2). There was a strong trend for an
independent association of concentricity (P0.06) and wall
thickness (P0.09) with the presence of CAC in multivari-
able logistic regression analyses as well (Table 2). LV
end-diastolic volume was not associated with CAC in similar
multivariable models. When restricting the multivariable
linear regression analysis to the subgroup of participants who
were not on antihypertensive treatment, the significant rela-
tionships between LV mass (P0.008), wall thickness
(P0.006), concentricity (P0.01), and CAC persisted.
We sought to determine whether the association of con-
centric LVH and CAC differed between blacks and whites. In
subgroup analyses (Table 3), the association of concentric
remodeling and subclinical atherosclerosis appeared particu-
larly robust in blacks. In formal interaction testing in multi-
variable linear regression using the same covariates as in
Table 2, however, the multiplicative interaction term between
race (black or white) and measure of LVH (LV mass, LV wall
thickness, or LV concentricity) on the outcome of log
CAC1 was not significant (P0.8, P0.2, and P0.16,
respectively). Similar results were seen in interaction testing
in multivariable logistic regression (P0.2, P0.8, and
P0.3, respectively).
In gender-specific analyses,42 measures of concentric hy-
pertrophy, including increasing wall thickness (Figure 2a)
and concentricity (Figure 2b), were associated with increased
CRP, whereas LV mass indexed to fat-free mass was not
(P not significant). In contrast to the findings with CAC,
multivariable analysis demonstrated that measures of concen-
tric hypertrophy were not independently associated with CRP
after adjusting for important confounders (Table 4).
Discussion
Although LVH is an important risk factor for incident adverse
cardiovascular events, the mechanisms behind this associa-

TABLE 3. Association of Measures of LV Hypertrophy and CAC in Blacks and Whites in Multivariable Analysis
Logistic (CAC10) Linear (log CAC1)

Blacks (N1162) Whites (N808) Blacks (N1162) Whites (N808)

LV Parameter OR (CI)* P OR (CI)* P P P

LV mass 1.32 (0.95 to 1.8) 0.10 0.96 (0.6 to 1.6) 0.9 0.41 0.001 0.16 0.25
LV wall thickness 1.37 (1.0 to 1.9) 0.05 1.21 (0.8 to 1.9) 0.4 0.34 0.001 0.19 0.11
Concentricity 1.18 (0.98 to 1.42) 0.08 1.2 (0.92 to 1.5) 0.2 0.18 0.001 0.12 0.11
Odds ratios are for interquartile ranges: LV mass, 57 g; LV wall thickness, 2.4 cm; and concentricity, 0.4 g/mL. Models adjusted for age, sex, family history of early
myocardial infarction, systolic blood pressure, fat mass, fat-free mass, total cholesterol, high-density lipoprotein, diabetes, smoking, antihypertensive therapy, use
of statin medications, and oral estrogen use.
*Odds ratio (95% CIs).
LV mass/end-diastolic volume.

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 Mehta et al LVH, CAC, and CRP 1389

Figure 2. Association between gender-specific quartiles of LV structure and median CRP levels. Both increasing LV wall thickness (A)
and concentricity (B) were associated with increased median CRP levels. P values are for trend across interquartile ranges.

tion remain ill defined. In this large, population based-cohort,
we have demonstrated that markers of concentric ventricular
hypertrophy (LV wall thickness, concentricity, and indexed
LV mass) but not ventricular dilation were associated with
the burden of atherosclerosis as assessed by CAC. These
associations were particularly robust in blacks. Furthermore,
we have demonstrated that concentric hypertrophy (wall
thickness and concentricity) was associated with elevated
CRP, although this association appears to be mediated via the
risk factors for LVH rather than by LVH itself. Thus, patients
with concentric LVH may be at increased risk for incident
atherothrombotic events because of the synergistic combina-
tion of increased atherosclerotic burden43 47 in the setting of
coexisting risk factors associated with a proinflammatory
milieu.48 51
Previous data have suggested that LVH may be associated
with CAC. The initial description of such an association was
a convenience sample of 249 hypertensive patients in which
LVH was found to be associated with CAC in those over the
age of 60 years but not in younger patients.32 Subsequently,
LVH was found to be associated with CAC in 159 young-to-
TABLE 4. Association of LV Structure and (log) CRP
Unadjusted Adjusted*
LV Parameter P P
LV mass 0.037 0.06 0.02
LV end-diastolic volume ()0.031 0.09 ()0.05
LV wall thickness 0.092 0.001 0.025
Concentricity 0.074 0.001 0.025
*-Coefficients are for interquartile ranges, shown in Table 2. Models
adjusted for race, age, sex, family history of early myocardial infarction, systolic
blood pressure, fat mass, fat-free mass, total cholesterol, high-density
lipoprotein, diabetes, smoking, antihypertensive therapy, use of statin medi-
cations, and oral estrogen use.
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middle-aged blacks recruited from a longitudinal study as-
sessing HIV infection, cocaine use, and atherosclerosis.30
Because 55% of the subjects were HIV positive and 74%
were cocaine users, the generalizability of these findings was
uncertain. The Coronary Artery Risk Development In young
Adults (CARDIA) Study reported recently that echocardio-
graphic LVH was associated with the presence of CAC, but
this study was limited by a 10-year difference between the
index echocardiogram and the subsequent EBCT.31 Similarly,
recent data from the National Heart, Lung, and Blood Institute
Family Heart Study and HyperGen Study also reported that
echocardiographic LVH was also associated with the pres-
ence of CAC, particularly in black patients, but this study was
also limited by an average of 5 years between the index
echocardiogram and the evaluation for CAC.52 Thus, al-
though previous studies suggest that LVH was associated
with CAC, the applicability to the general population was
previously unknown. In addition, because of the much larger
sample size of our study and detailed phenotypic character-
ization of our study cohort, we have extended previous
studies by demonstrating that the association of LVH and
CAC is present in both men and women and is independent of
a number of important potential confounders, including
systolic blood pressure, hypertensive status, lipid levels,
statin use, and age. We also have demonstrated that the
association of LVH and CAC is particularly robust in blacks,
0.5 an important observation given the marked increase in the
0.02 prevalence of LVH in black as compared with white sub-
0.38 jects.8 Furthermore, we have been able to demonstrate that it
is concentric remodeling and not ventricular dilation that
0.15
drives the association of LVH and subclinical atherosclerosis,
an important distinction when assessing the underlying risk
associated with LVH.53
Recently, it has been hypothesized that LVH may itself be
an inflammatory state as assessed by elevations in CRP
1390 Hypertension June 2007
levels. This possibility was first raised in a study of patients
with end-stage renal disease undergoing hemodialysis.35 Sub-
sequently, 2 studies of hypertensive patients determined that
increased LV wall thickness (concentric remodeling) or
echocardiographic LVH were associated with elevations of
CRP.34,54 Herein, we found that increasing quartiles of LV
wall thickness and concentricity were associated with ele-
vated CRP in stepwise fashion in both men and women.
However, the association of LVH with CRP did not persist in
multivariable analysis after adjusting for body composition,
lipid levels, age, and other confounders, suggesting that CRP
was elevated in patients with LVH because of risk factors
common to the development of LVH and CRP elevation.
Thus, our data do not support the hypothesis that LVH itself
is a primary proinflammatory state.
There are important limitations of our study that should be
recognized. First, our study is cross-sectional. Thus, despite a
large sample size and diverse population, assigning causality
between LVH and CAC, or vice versa, is not possible.
Second, because 24-hour blood pressure recordings were not
performed, there may be residual confounding by an unmea-
sured effect of elevated blood pressure in the association
between concentric LVH and CAC despite multivariable
analysis. However, particular attention was paid to careful
blood pressure measurement in the Dallas Heart Study,
including the use of an automatic oscillometric device, which
has been validated against catheter measurement of arterial
pressure.36 Furthermore, we had 3 independent measurements
of blood pressure with 2 sets obtained in the home environ-
ment and 1 in an office setting. The inclusion of a home and
office measurement has been shown to provide additive
information compared with office measurement alone.55 Fi-
nally, we performed only a single measurement of CRP, and
variability in CRP measurements over time could influence
the association between LVH and CRP.56
Perspectives
Individuals in the general population with concentric LVH
have both increased coronary atherosclerotic burden as as-
sessed by CAC and evidence for an inflammatory state as
measured by CRP. Although the latter appears to be second-
ary to comorbid conditions, an increased coronary atheroscle-
rotic burden coupled with an inflammatory state, as suggested
by elevated CRP levels, may explain in part why LVH is a
risk factor for incident ASHD events, including myocardial
infarction.
Source of Funding
The Dallas Heart Study is funded by a center grant from the Donald
W. Reynolds Foundation.
Disclosures
J.A.d.L. has received significant support as research grants (Biosite
and Roche) or as a consultant/on an advisory board (Bayer) and
modest remuneration as honoraria or as a consultant/on an advisory
board (Biosite). The remaining authors report no conflicts.
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 Left Ventricular Hypertrophy, Subclinical Atherosclerosis, and Inflammation
Sameer K. Mehta, J. Eduardo Rame, Amit Khera, Sabina A. Murphy, Russell M. Canham,
Ronald M. Peshock, James A. de Lemos and Mark H. Drazner

Hypertension. 2007;49:1385-1391; originally published online April 2, 2007;

doi: 10.1161/HYPERTENSIONAHA.107.087890
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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