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(Circulation. 2001;103:102.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Type 2 Diabetes Mellitus on Left Ventricular Geometry and Systolic Function in Hypertensive Subjects
Hypertension Genetic Epidemiology Network (HyperGEN) Study
From the Weill Medical College of Cornell University (V.P., J.N.B., J.E.L., M.-Y.S., R.B.D.), New York, NY; University of Minnesota (D.K.A.), Minneapolis, Minn; University of Alabama at Birmingham (A.O.), Birmingham, Ala; Wake Forest University School of Medicine (D.W.K.), Winston-Salem, NC; University of Utah School of Medicine (P.N.H.), Salt Lake City, Utah; and Washington University Medical School (D.M., D.C.R.), St. Louis, Mo.
Correspondence to Vittorio Palmieri, MD, Weill Medical College of Cornell University, Division of Cardiology (Box 222), 525 E 68th Street, New York, NY 10021. E-mail: vpalmier{at}med.cornell.edu
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Abstract |
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Background—Type 2 diabetes is a cardiovascular risk factor. It remains to be elucidated in a large, population-based sample whether diabetes is associated with changes in left ventricular (LV) structure and systolic function independent of obesity and systolic blood pressure (BP).
Methods and Results—Among 1950 hypertensive participants in the HyperGEN Study without overt coronary heart disease or significant valve disease, 20% (n=386) had diabetes. Diabetics were more likely to be women, black, older, and have higher BMI and waist/hip ratio than were nondiabetics. After adjustment for age and sex, diabetics had higher systolic BP, pulse pressure, and heart rate; lower diastolic BP; and longer duration of hypertension than nondiabetics. LV mass and relative wall thickness were higher in diabetic than nondiabetic subjects independent of covariates. Compared with nondiabetic hypertensives, diabetics had lower stress-corrected midwall shortening, independent of covariates, without difference in LV EF. Insulin levels and insulin resistance were higher in non–insulin-treated diabetics (n=195) than nondiabetic (n=1439) subjects (both P<0.01). Insulin resistance positively but weakly related to LV mass and relative wall thickness.
Conclusions—In a relatively healthy, population-based sample of hypertensive adults, type 2 diabetes was associated with higher LV mass, more concentric LV geometry, and lower myocardial function, independent of age, sex, body size, and arterial BP. structural and functional abnormalities in addition to, and independent of, atherosclerosis.13 14 In the Framingham cohort, diabetes was associated with higher LV mass in women but not men.15 High blood pressure (BP), obesity, and abnormal lipid profile, which often coexist with diabetes, tend to be associated with preclinical cardiovascular abnormalities16 and may contribute to the association of diabetes with cardiovascular events. Cardiac features of diabetic and nondiabetic hypertensive subjects remain incompletely described in population-based samples. Therefore, we compared clinical and metabolic characteristics, LV geometry, and systolic function between diabetic and nondiabetic hypertensive participants in the Hypertension Genetic Epidemiology Network (HyperGEN) Study.
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Methods |
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Population
The HyperGEN Study is part of the National Heart, Lung, and Blood Institute Family Blood Pressure Program to assess the genetic basis of hypertension in the population. Hypertension was defined by antihypertensive treatment or recorded (BP) measurements
140 mm Hg systolic and/or 90 mm Hg diastolic on 2 occasions. To
be eligible, hypertensive subjects were required to have onset of
hypertension by age 60 years and 1 hypertensive sibling who was
willing to participate. Individuals with type I diabetes were excluded
because of high risk of hypertension due to nephropathy. Four of 5
field centers in HyperGEN participated in the ancillary
echocardiographic study. Study participants were recruited from
existing populations previously defined, including the Atherosclerosis
Risk in Communities (ARIC) study (Minneapolis and Forsyth County, North
Carolina), the Minnesota Heart Study, and the Utah Healthy Family Tree
Study. Selected participants from these parent studies previously
participated in the NHLBI Family Heart
Study,17 from which a large
proportion of the hypertensive sibships were sampled for HyperGEN. Many
of the Birmingham patients (all black) were selected from the
community. The target population was 50% each black and white in
Winston-Salem and 100% white in Minnesota and Utah.
The first HyperGEN examination began in 1996 to obtain
standardized measurements of BP at rest and its reactivity to several
stimuli. Standardized anthropometric measurements included body mass
index (BMI), body surface area, and waist/hip ratio. Fasting serum
glucose, insulin, and lipid and lipoprotein concentrations were
obtained. Diabetes mellitus was diagnosed by American Diabetes
Association criteria18
(fasting glucose 126 mg/dL or use of hypoglycemic medication).
Insulin levels were assessed by immunoassay (Sanofi Access; reference
range, 1.9 to 23 µU/mL). Insulin resistance was calculated by use of
the previously validated homeostasis model assessment
(HOMA).19 Myocardial
infarction, coronary bypass, and percutaneous coronary angioplasty were
identified by participant reports. Type and number of antihypertensive
medications used were recorded at clinical evaluation.
Clinical and echocardiographic information was available for
2161 hypertensive subjects. We excluded subjects without technically
satisfactory LV measurements (3.1% of the cohort) or with 2+ aortic
or mitral disease; dialysis treatment; history of myocardial
infarction, coronary bypass, or percutaneous coronary angioplasty; or
severe hypokinesis, akinesis, or dyskinesis on
echocardiogram.
Echocardiographic Methods
Echocardiograms were performed by use of methods
previously
described.20 21 22
A standardized protocol was followed, under which parasternal and
apical acoustic windows were used to record 10 consecutive beats per
each projection. All elements of the protocol were recorded on
videotape; additional strip-chart recordings were made in 1 center.
Principal sonographers received training, including written material
and didactic and hands-on training at the Reading Center in New York
City, NY. Additionally, test tapes were sent to each center as
part of sonographer training, and feedback on echocardiographic studies
was provided to monitor compliance with the protocol. Parasternal
long-axis and apical views were used to detect valvular regurgitation
by color Doppler.
Echocardiographic Measurements
Correct orientation of planes for imaging and Doppler
recordings was verified with standard
procedures.23 LV internal
dimension and interventricular septal and posterior wall thicknesses
were measured at end-diastole and end-systole by American Society of
Echocardiography
recommendations24 on 
3
cardiac cycles at or just below the tips of mitral leaflets in
parasternal long-axis and short-axis views. When optimal orientation of
LV M-mode readings could not be obtained, correctly oriented linear
2-dimensional measurements were made by use of the American Society of
Echocardiography leading-edge
convention.25 Wall motion
was assessed in parasternal long-axis and short-axis views and apical
2-, 3-, and 4-chamber views, with the LV divided into 5 segments at the
base, 5 at the papillary muscles, and 4 at the
apex.26 Echocardiograms were
preliminarily read by a first reader and subsequently reread by highly
experienced readers. All readers were blinded to subjects’ clinical
data. We reported excellent reliability of LV mass measurement
(intraclass correlation coefficient=0.93) and good reliability of LV
systolic function assessment (intraclass correlation coefficient=0.61
to 0.71) in a previous
study,27 in which an
echocardiographic methodology similar to that used in this study was
employed.
Calculation of Derived Variables
End-diastolic LV dimensions were used to calculate LV
mass by a formula that yields values closely related
(r=0.90) to necropsy LV
weight28 and has proven
valuable for cardiovascular risk
stratification.29 30 31 32
LV mass was indexed by height2.7 to identify
LV hypertrophy with partition values of
46.7g/m2.7 in women and
49.2g/m2.7 in
men.33 Relative wall
thickness (RWT), an estimate of LV geometric concentricity, was
calculated as twice posterior wall thickness divided by internal
dimension. End-diastolic and end-systolic LV volumes were calculated by
the Teichholz method,34
which uses linear measurements of LV internal diastolic and systolic
diameters, as has been validated by invasive and Doppler reference
standards.21 35 36
Linear-measurement–derived ejection fraction (EF) was calculated as
the percentage reduction of LV volume from diastole to end-systole. To
estimate global LVEF, accounting for the contribution of each LV
segment to systolic reduction of LV volume, we assigned a score of 4.5
to each segment with normal wall motion (which yielded global EF of
63%); scores of 3.5, 2.5, and 1.5 to mildly, moderately, and severely
hypokinetic segments, respectively; 0 to akinetic; and -1 to dyskinetic
segments.
Measures of Myocardial Function
Studies have documented that the traditional practice
of relating endocardial shortening to mean meridional end-systolic
stress across the LV wall may yield misleading results in individuals
with concentric LV
geometry37 or LV
dilatation.38 Therefore,
primary reliance was placed on the relation of midwall shortening (MWS)
to midwall circumferential end-systolic stress (cESS) at the level of
the LV minor
axis.37 39 40 41
MWS was calculated by taking into account epicardial migration of the
midwall during systole. Estimates of end-systolic stress by the
described method were closely related to values calculated by
substituting central BP estimated by applanation tonometry for cuff BP
(r=0.95).37
In another sample of 418 hypertensive adults with or without diabetes,
cuff systolic BP correlated closely to central BP estimated by
tonometry (r=0.93), and the
difference between brachial and central aortic systolic BP did not
differ between diabetic and nondiabetic hypertensives (12±7 versus
13±9 mm Hg, respectively;
P=0.9; M.J. Roman and R.B.D.,
personal communication, 2000). To evaluate LV performance while
taking cESS into account, shortening calculated from echocardiographic
measurements was expressed as a percentage of value predicted from cESS
with equations from previously studied normal
subjects37 and called
"stress-corrected MWS," a measure of myocardial systolic
function.41
Statistical Analyses
Continuous variables are expressed as mean±SD.
Unadjusted differences for clinical variables between diabetic and
nondiabetic subjects were assessed by
t test. Difference in
laboratory data and LV systolic function were adjusted for age and sex
by use of ANCOVA. Differences in LV structure and geometry were
adjusted for age, sex, BMI, and systolic BP as their major established
covariates,22 with further
adjustment for duration of hypertension. Fisher’s Exact Test and odds
ratios with 95% confidence intervals were used to test differences for
categorical variables in 2x2 tables. Logistic regression analysis was
used to derived odds ratio and 95% confidence intervals adjusted for
covariates. Multiple regression analyses were performed to assess
relation of diabetes to higher LV mass independent of established
covariates and duration of hypertension. Two-tailed
P<0.05 was considered
significant.
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Results |
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General Characteristics of the Study Population
A total of 1950 participants in the HyperGEN Study met selection criteria. Mean age was 54±11 years; BMI was 32.0±7.0 kg/m2; 63% were women; 35% were white, non-Hispanic; and 65% were black. Of the participants, 20% (n=386) had type 2 diabetes, of whom 45% were treated with insulin, 43% with oral hypoglycemics, and 12% with diet only. On average, duration of diabetes was 10 years. Age at diagnosis of diabetes was 48±12 years, whereas age at diagnosis of hypertension was 39±12 years (P<0.001).
Clinical and Metabolic Features of Diabetic and
Nondiabetic Hypertensive Subjects
Subjects with diabetes were older; had higher BMI,
waist/hip ratio, systolic BP, pulse pressure, and heart rate; had lower
diastolic BP; and were slightly more likely to be female than subjects
without diabetes
Table 1
. The proportion of subjects who had smoked
>100 cigarettes was similar between the groups, as was age at
diagnosis of hypertension. Duration of hypertension was longer among
diabetics (19±12 versus 14±11 years;
P<0.001). Diabetic patients
more frequently were on antihypertensive treatment than nondiabetics
(94% versus 89%; P<0.01) and
more frequently received ACE inhibitors (48% versus 27%;
P<0.01), whereas no
between-group differences were seen in ß-blocker (16% versus 20%),
calcium channel blocker (45% versus 37%), or diuretic (50% versus
47%) use (all P=NS). Diabetics
were more frequently on 2 medications than nondiabetics (47% versus
34%; P<0.01), which yielded,
on average, a higher number of antihypertensive medications in
diabetics than nondiabetics (1.6 [range, 0 to 6] versus 1.3 [range,
0 to 5];
P<0.001).
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Laboratory Data
After adjustments were made for age and sex, diabetic
patients had higher fasting plasma glucose, triglyceride, and
creatinine levels
(Table 2). Total cholesterol did not differ between groups,
but HDL cholesterol was lower and total cholesterol/HDL cholesterol and
triglyceride/HDL cholesterol ratios were higher in diabetics. Insulin
(11.2 versus 9.7 µU/mL) and HOMA (4.5 versus 2.5) levels were higher
in non–insulin-treated diabetics (n=195) than nondiabetic (n=1439)
subjects (both
P<0.01).
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LV Mass and Geometry
Subjects with diabetes had higher LV wall thicknesses,
mass, and RWT than those without diabetes independent of age, systolic
BP, BMI, and sex, with no between-group difference in LV internal
diameter
(Table 3). After additional consideration of duration of
hypertension as covariate, between-group differences in LV mass (178
versus 173 g) and RWT (0.36 versus 0.35) were confirmed (both
P<0.05). LV mass (178 versus
172 g) and RWT (0.36 versus 0.35, both
P<0.01) remained higher in
diabetics after further adjustment for variables that indicated major
antihypertensive medication classes. Likelihood of LV hypertrophy was
higher in diabetic than nondiabetic subjects (38% versus 26%,
P=0.03; systolic BP and BMI
adjusted-odds ratio, 1.32; 95% CI, 1.02 to 1.70), but the difference
did not reach statistical significance when duration of hypertension
was included in the previous model (OR, 1.19; 95% CI, 0.9 to 1.6).
Subjects with LV hypertrophy versus those without had longer duration
of hypertension (18±12 versus 14±11 years;
P<0.01) and tended toward
longer duration of diabetes (11±10 versus 9±9 years;
P=0.055). A multiple linear
regression model showed significant association of diabetes with higher
LV mass (t=2.2, slope=5.9;
P=0.02) independent of
established covariates and duration of hypertension
(R=0.56;
P<0.001). Bivariate relations
of HOMA to LV mass (r=0.08;
P<0.01) and RWT
(r=0.19;
P<0.001) were relatively weak
and became weaker after adjustment for covariates
(r=0.003,
P=NS to LV mass;
r=0.06,
P=0.02 to RWT). Among subjects
not treated with insulin, a regression model that included HOMA instead
of BMI showed association of diabetes with LV mass
(t=3.6, slope 3.9;
P<0.001) independent of
covariates (R=0.46;
P<0.001).
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Myocardial Function and LV Chamber Systolic
Performance
Diabetics had similar EF (either from LV linear
dimension or from wall motion score) but lower MWS than did
nondiabetics independent of age, sex, and BMI
(Table 4). cESS, a measure of afterload, was higher in
diabetics. Stress-corrected MWS was lower in diabetic subjects
independent of covariates and variables that indicated major
antihypertensive medication classes (104% versus 106%;
P<0.05).
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LV Structure and Function in Diabetic Subjects
Divided According to Antidiabetic Treatment
Insulin-treated subjects (n=175) did not differ from
those not receiving insulin (n=211) in age (both mean of 57 years) or
proportion of women (69% versus 64%). Blacks more commonly received
insulin (83% versus 67%;
P<0.0005). Systolic BP was
higher in insulin-treated diabetics (141±25 versus 133±22 mm Hg;
P<0.01) as was fasting glucose
(180±80 versus 155±61 mg/dL;
P<0.01). Diastolic BP (both
72±11 mm Hg) and BMI (34.5±7.5 versus 33.1±6.7
kg/m2) did not differ. LV mass (184±42
versus 181±42 g; P>0.1) and
EF (62.4% versus 62.9%;
P>0.5) were similar in
insulin-treated and non–insulin-treated diabetics. RWT was higher
(0.37±0.05 versus 0.36±0.05;
P<0.05) and stress-corrected
MWS was lower in diabetics who received insulin (102±10% versus
105±10%, P<0.01) independent
of covariates.
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Discussion |
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TopAbstractMethodsResultsDiscussionReferences |
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In a large, population-based cohort of substantially clinically healthy diabetic and nondiabetic hypertensives, we found associations of type 2 diabetes with higher LV mass and concentric LV geometry. Effects of obesity and high BP did not completely account for higher LV mass and LV RWT in diabetics. Consideration of duration of hypertension or insulin resistance (HOMA) in addition to other covariates did not eliminated the association of diabetes with higher LV mass and RWT. Diabetic hypertensives had significantly lower stress-corrected MWS (myocardial systolic function) despite similar endocardial EFs versus nondiabetic hypertensives independent of age, sex, BMI, and afterload. Cardiovascular abnormalities found to be independently associated with diabetes in the present study are known to predict higher rates of cardiovascular events in both asymptomatic and symptomatic subjects.16
Clinical and Laboratory Data
Diabetes is associated with
hypertension.3 4 5 6 7 8 9 10 11 12
However, in the present population, hypertension was unlikely to be
consequence of type 2 diabetes, because mean age at diagnosis of
hypertension was younger by 8 years than age at diagnosis of diabetes.
Although diabetics were more likely to be on antihypertensive
treatment, more frequently with 2 medications, systolic BP and pulse
pressure were greater in diabetic patients, a likely manifestation of
greater arterial
stiffness.42 Increase in
systolic stress, by increased arterial stiffness, is a stimulus for LV
wall thickening,43 thereby
potentially contributing to higher LV wall thickness, whereas lower
diastolic BP in diabetics probably negatively affects coronary
perfusion.44 Diabetics had a
worse lipid profile than nondiabetic subjects, which contributes to
atherosclerosis and coronary heart disease.
As expected from previous studies,45 insulin resistance was positively associated with LV mass and was higher in non–insulin-treated diabetics than in nondiabetic hypertensives in the present study.
LV Geometry
Diabetic hypertensives had higher LV mass and
concentric geometry independent of sex, age, obesity, BP, and duration
of hypertension or insulin resistance (HOMA) in alternative models as a
result of statistical collinearity of the latter variable with BMI.
Those findings were confirmed after further consideration of major
antihypertensive medication classes used. Notably, diabetics were more
frequently black, which may be an important additional finding.
However, race was not used as a covariate in multivariate models
because of collinearity with other independent variables in the present
population. In fact, an exploratory multiple linear regression analysis
in which race was included in addition to standard covariates and
diabetes resulted in a slightly lower multiple
R (0.55) and low tolerance
(0.79) for race.
Negative prognostic relevance of LV hypertrophy has been identified in clinical and population-based samples.16 29 30 31 32 Diabetics with LV hypertrophy had longer duration of diabetes and hypertension than those with normal LV mass. Likelihood of LV hypertrophy was 1.32-fold (95% CI, 1.02 to 1.70) higher in diabetic than nondiabetic hypertensives independent of most common clinically assessed conditions, such as sex, BP, and obesity. When duration of hypertension was further considered, relation of diabetes to LV hypertrophy became statistically insignificant, although a trend toward higher prevalence of LV hypertrophy in diabetic hypertensives was confirmed. Subjects with LV hypertrophy had longer duration of hypertension and a clear trend toward long duration of diabetes. These findings suggest that diabetes magnifies over time the alterations of the cardiovascular system induced by increased afterload of systemic hypertension and that the pathophysiological substrate for higher morbidity and mortality in diabetic subjects is multifactorial.
LV Systolic Function
Diabetic subjects, predominantly healthy due to
exclusion of individuals with ischemic or valvular heart disease or
renal failure, had lower myocardial systolic function than nondiabetic
subjects independent of covariates. The concern that
diabetes-associated atherosclerosis might affect noninvasive estimation
of myocardial function in diabetics by reducing systolic BP
augmentation between the central aorta (the BP to which the LV is
exposed) and the cuff BP used to calculate end-systolic stress (which
overestimates central BP in young individuals) is diminished by our
finding in a separate population of 418 hypertensive adults that the
difference between brachial and central systolic BP calculated by
applanation tonometry was similar between diabetics and nondiabetics
(12±7 versus 13±9; P=NS
[M.J. Roman, R.B.D., personal communication, 2000). Low
stress-corrected MWS is an independent predictor of cardiovascular
events in asymptomatic hypertensive patients with preserved
EF,46 but its prognostic
relevance in diabetic hypertensive individuals requires further
study.
Clinical Implications
The present report identifies diabetes-associated
increase in LV mass and RWT and decrease in LV midwall function, which
may contribute in part to high rates of overt coronary heart disease
and heart failure to which diabetic individuals are predisposed.
Although abnormalities of LV geometry and myocardial function were
mildly greater in diabetic than nondiabetic hypertensive patients, our
results suggest that those differences may amplify over time. Our
identification of a cluster of abnormalities of LV geometry and
function with factors associated with diabetes supports multifactorial
approach for preventing high rates of cardiovascular morbidity and
mortality in type 2
diabetics.2 47 48
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Acknowledgments |
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This work was supported in part by grant 5-R01-HL55673 and cooperative agreement grants 5-U10-HL54471, HL-54472, HL-54473, HL-54496, HL-54509, and HL-54515 from the National Heart, Lung, and Blood Institute, Bethesda, Md, and grant M-10RR0047-34 (GCRC) from the National Institutes of Health, Bethesda, Md. We thank the study center coordinators and the sonographers for expert performance of echocardiograms; Elizabeth A. Wood; Mary Paranicas, BA; and Dawn Fishman, BA, for design and maintenance of databases; and Virginia Burns for assistance in preparation of the manuscript.
Received May 30, 2000; revision received August 16, 2000; accepted August 16, 2000.
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