(Hypertension. 1996;27:729-734.)
© 1996 American Heart Association, Inc.
Articles |
Hyperinsulinemia and Left Ventricular Geometry in a Work-Site Population in Japan
From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, and Cardiovascular Center, Fukuoka Red Cross Hospital, Japan.
Correspondence to Yusuke Ohya, MD, PhD, Second Department of Internal Medicine, Kyushu University, Faculty of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan. E-mail ohya@intmed2.med.kyushu-u.ac.jp.
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Abstract |
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Abstract The present study was designed to test whether hyperglycemia or hyperinsulinemia influences left ventricular mass and geometry. An echocardiogram and 75-g oral glucose tolerance test were performed in 210 normotensive and 180 mildly to moderately hypertensive male workers in a bus company who were free from cardiac diseases and were not taking medication for hypertension and diabetes mellitus. When we divided subjects into four groups according to the left ventricular geometric pattern using left ventricular mass index of 110 g/m2 and relative wall thickness (ratio of 2x posterior wall thickness to end-diastolic left ventricular diameter) of 0.44, body mass index and systolic blood pressure were higher in those with concentric hypertrophy and eccentric hypertrophy. In addition, hemoglobin AIc level and the sum of fasting and 2-hour postload serum glucose levels were higher in subjects with concentric hypertrophy. In subjects without diabetes mellitus (n=336), 2-hour postload serum insulin level and the sum of fasting and 2-hour postload serum insulin levels tended to be higher in those with concentric hypertrophy and concentric remodeling. In multiple regression analysis, the sum of glucose levels (or hemoglobin A1c level) in all subjects and the sum of insulin (or 2-hour postload insulin) levels in subjects without diabetes mellitus significantly correlated with relative wall thickness independent of age, systolic blood pressure, and body mass index. Neither glucose nor insulin levels correlated with left ventricular mass index. Our results suggest that hyperglycemia and hyperinsulinemia may promote concentric changes in the left ventricle in normotensive and mildly to moderately hypertensive men.
Key Words: echocardiography • obesity • hypertrophy, left ventricular • hyperinsulinism • hyperglycemia
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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It has been determined that LV hypertrophy is an independent predictor of cardiovascular morbidity and mortality.1 2 In a recent study, the relationship between the cardiovascular prognosis and LV hypertrophy was further evaluated with consideration of LV geometric patterns3 ; an increase in LV wall thickness relative to LV cavity size (relative wall thickness) with and without an increase in LV mass further added to the risk for cardiovascular complications in patients with essential hypertension. Thus, attention should be paid to relative wall thickness as well as to LV mass. Predictive factors for increases in LV mass are high BP, obesity, aging, female sex, a high hematocrit, diabetes mellitus, and a high salt intake.4 5 6 7 8 9 Possible contributions of hyperinsulinemia and insulin resistance to LV mass have also been suggested, but the results reported are not consistent.10 11 12 13 14 15 In contrast, predictive factors for increases in relative wall thickness have not yet been fully clarified; however, high BP, high peripheral resistance, aging, black race, obesity, and low plasma renin activity have been reported to be associated with relative wall thickness.4 5 6
The purpose of the present study was to evaluate the possible contribution of hyperinsulinemia and hyperglycemia to LV mass and geometry. Subjects in the present study comprised a relatively large number of normotensive and mildly to moderately hypertensive male subjects in a work-site population in Japan. We attempted to analyze LV mass and geometry using LV mass index and relative wall thickness. We used the insulin level at 2 hours after glucose administration and the sum of insulin levels during a 75-g OGTT as markers of hyperinsulinemia, both of which were demonstrated to correlate well with insulin sensitivity.16 17
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Methods |
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Subjects
The study group was part of a cohort of 8639 workers in a bus and railway company in the Fukuoka area of Japan. The 577 workers underwent echocardiography and a 75-g OGTT conducted in the healthcare center of the company. These subjects were healthy volunteers or subjects who had either hypertension (BP
160/100 mm Hg) or any ECG abnormality on an annual health
examination. Subjects with a fasting serum glucose level of 7.8
mmol/L on an annual health examination were not included. The study
protocol was approved by committees in the healthcare center and our
department, and informed consent was obtained from all subjects. The following subjects were excluded from the analysis: (1) women, because they constituted only a small portion of the population; (2) subjects with coronary heart disease, congestive heart failure, cardiomyopathy, athlete's heart, valvular heart disease, cerebrovascular disease, or renal failure (serum creatinine >0.18 mmol/L); (3) subjects taking medication for hypertension or diabetes mellitus; and (4) subjects with an echocardiogram of inadequate quality to estimate LV mass and geometry. Cardiac diseases were diagnosed on review of clinical history, physical examination, rest and exercise ECG, Holter ECG, chest roentgenogram, echocardiogram, and hospitalization records. Any subjects suspected of having cardiovascular diseases were referred to cardiovascular centers located in the Fukuoka area for further evaluation, including a radionuclide study and coronary angiography. Consequently, 390 male workers remained for the analysis (age, 50±8 years; BMI, 23.8±2.8 kg/m2; BP, 130±19/81±11 mm Hg [mean±SD]).
To evaluate LV mass and LV geometry, echocardiography (two-dimensional targeted M mode) was performed with an ultrasound imager (SSA-160A, Toshiba Medical Co Ltd) with either a 2.5- or 3.75-MHz transducer by expert physicians (Y.O., I.A., K.F., S.O., and K.K.). Patients were examined in the left lateral decubitus position. End-diastolic and end-systolic LV diameters and thickness of the interventricular septum and LV posterior wall were obtained according to the Penn convention. LV mass was calculated by use of the formula of Devereux and Reichek.18 LV mass index was obtained by dividing LV mass by body surface area. In some analyses, LV mass was also normalized for the allometric power of its relationship to height (LV mass/height2.7).19 20 Relative wall thickness was calculated as the ratio of two times posterior wall thickness to end-diastolic LV diameter. LV volume was calculated with the use of Teichholz's formula,21 and ejection fraction was obtained by the conventional method. The mean value from at least three cardiac cycles was used for data analysis, which had been measured by one physician (Y.O.) blinded to the patients' information.
Four different LV geometric patterns were identified
according to
relative wall thickness and LV mass index (Figure
).
Relative wall thickness of 0.44 and LV mass index of 110
g/m2 were used as cutoff points, which were mean+2 SD of
normal subjects in the present study.
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Clinical Measurements
BMI (body weight divided by squared
height) was used as a marker
of obesity. We measured BP in the subject's right arm using the first
and fifth phases of Korotkoff sounds by mercury sphygmomanometer after
at least 5 minutes of rest in the sitting position. Measurements were
repeated three times, and the average of the two lower values was used
for analysis. Subjects were normotensive (n=210; BP <140/90 mm
Hg) or hypertensive (n=180; BP 140/90 mm Hg; WHO stage I or II).
Metabolic Investigations
The 75-g OGTT was performed after
overnight fasting; blood
samples were taken before (fasting) and 2 hours after oral glucose
administration (2-hour postload level) to measure serum glucose and
insulin levels. The sum of fasting and 2-hour postload glucose levels
or HbA1c level was used as a marker of hyperglycemia or
glucose intolerance. The 2-hour postload insulin level or the sum of
fasting and 2-hour postload insulin levels was used as a marker of
hyperinsulinemia or insulin resistance.
Diabetes mellitus was diagnosed by the criteria of the WHO.22 Subjects who had a fasting glucose level of 7.8 mmol/L or higher and/or a 2-hour postload glucose level of 11.1 mmol/L or higher were diagnosed with diabetes mellitus. Fifty-four subjects were diagnosed as having diabetes mellitus by 75-g OGTT but did not manifest any diabetic complications, which were evaluated by the neurological examination, ophthalmoscopic examination, and proteinuria.
Statistical Analysis
Data are expressed as mean±SD.
Statistical analysis was
performed with the use of SAS version 6.07 (SAS Inc). Differences
between groups were assessed by ANOVA with the multiple comparison test
(Scheffé's test). Simple and stepwise regression
analyses were performed by CORR and STEPWISE programs,
respectively. A value of P<.05 was regarded as
statistically significant.
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Results |
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The characteristics of our study subjects (n=390) are shown in Table 1
. There was no significant difference in age or
body surface area among the groups. BMI and systolic BP were
significantly higher in the concentric hypertrophy and
eccentric hypertrophy groups. Glucose levels (fasting,
2-hour postload, and their sum) and HbA1c level were higher
in the concentric hypertrophy group than in other groups.
Values of interventricular septum thickness, LV
posterior wall thickness, and relative wall thickness in the four
groups were in the following order (highest to lowest): concentric
hypertrophy, concentric remodeling, eccentric
hypertrophy, and normal geometry, except there was no
difference between concentric hypertrophy and eccentric
hypertrophy groups in interventricular
septum thickness (Table 2). The LV diastolic
dimension and LV mass index were larger in concentric
hypertrophy and eccentric hypertrophy groups.
Heart rate was higher in concentric hypertrophy and
concentric remodeling groups than in the eccentric
hypertrophy group.
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In subjects without diabetes mellitus (n=336; Table
3),
there were no significant differences among groups in fasting insulin
level, 2-hour postload insulin levels, and the sum of both values.
However, 2-hour postload insulin and the sum of insulin levels tended
to be higher in the concentric hypertrophy and concentric
remodeling groups (ANOVA; 2-hour postload insulin, P=.08;
sum of insulin, P=.10). Results for LV mass index and
relative wall thickness were comparable to those observed in all
subjects.
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Simple correlations of LV mass index and relative wall thickness with
other variables are listed in Table 4. In all
subjects, BMI, systolic BP, and HbA1c significantly
correlated with LV mass index. Significant correlations were also
observed between these variables and LV mass normalized by
height2.7 (BMI, r=.418, P<.001;
systolic BP, r=.390, P<.001;
HbA1c, r=.108, P<.05). These
variables, along with age and all glucose values, significantly
correlated with relative wall thickness. In the subjects free from
diabetes, 2-hour postload insulin and the sum of insulin levels but not
fasting insulin level significantly correlated with relative wall
thickness. The LV mass index did not correlate with any insulin
variables.
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Table 5 shows the results from multiple regression
analysis. In all subjects, systolic BP and BMI were
selected as significant independent determinants of LV mass index when
age, systolic BP, BMI, and the sum of glucose levels were
included. Systolic BP and BMI were also selected as significant
determinants of LV mass normalized by height2.7
(systolic BP, partial r=.418, P=.0001;
BMI, partial r=.298, P=.0001). For relative
wall
thickness, systolic BP, BMI, and the sum of glucose levels were
selected as independent determinants. HbAIc also
significantly correlated with relative wall thickness independently
(partial r=.152, P=.0022) when used instead of
the sum of glucose levels.
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In subjects free from diabetes mellitus, the sum of insulin levels significantly correlated with relative wall thickness independently of age, BMI, and systolic BP in multiple regression analysis. The 2-hour postload insulin level also independently correlated with relative wall thickness when used instead of the sum of insulin levels (partial r=.130, P=.0318). Since BMI and insulin values were closely related (simple correlation; r=.313 versus fasting insulin; r=.379 versus 2-hour postload insulin; r=.401 versus sum of insulin; P<.0001), we divided nondiabetic subjects into two groups (high-BMI and low-BMI groups) at a median BMI of 23.7 kg/m2 to minimize the interference by BMI in multiple regression analysis. The 2-hour postload insulin level or sum of insulin levels was selected as a significant determinant of relative wall thickness in the high BMI group (sum of insulin levels, partial r=.198, P=.0136; 2-hour postload insulin, partial r=.214, P=.0077) but not in the low BMI group.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, we have demonstrated that hyperinsulinemia and hyperglycemia could be independent risk factors for concentric changes in LV geometry in normotensive and mildly to moderately hypertensive men. We also showed that both obesity and hypertension strongly contributed to LV hypertrophy in Japanese subjects, which had been reported for non-Asian subjects.4 6 7 23
Conflicting results regarding the possible contribution of hyperinsulinemia and insulin resistance to LV hypertrophy have been reported.10 11 12 13 14 15 One study observed a significant correlation between fasting insulin and LV mass in normotensive and hypertensive subjects,13 whereas other studies did not observe a significant relationship between LV mass and insulin levels during OGTT in hypertensive subjects10 11 and in atherosclerotic patients.12 In contrast, the insulin response during an intravenous glucose tolerance test independently correlated with LV mass in normotensive obese subjects.14 A study using the hyperinsulinemic euglycemic clamp technique revealed that insulin sensitivity is negatively correlated with LV wall thickness in hypertensive patients.15 The present study showed that postload insulin level and the sum of insulin levels during OGTT independently correlated with relative wall thickness but not with LV mass index. Inconsistent results between studies may be attributable to types of markers used to assess insulin sensitivity and LV hypertrophy. Differences in subjects also should be taken into account, because the influence of insulin resistance on the cardiovascular system might differ between races, sexes, and presence or absence of obesity.14 24 25 In addition, statistical power may be limited in studies with a small number of subjects.
Various mechanisms of action of hyperinsulinemia on myocardial hypertrophy have been suggested. One possible mechanism is that insulin exerts a growth-stimulating effect.26 A second possible mechanism involves increasing blood volume through the effects of insulin on sodium reabsorption in the kidney.27 This action may be due to both direct and indirect effects through stimulation of the sympathetic nervous system.28 This third mechanism (ie, increased sympathetic nervous activity by insulin) may also directly stimulate proliferation of myocardial cells.29 In addition, it is also possible that increased sympathetic nervous activity may be associated with concentric change in the LV by increasing peripheral resistance, since subjects with concentric remodeling and concentric hypertrophy have been characterized hemodynamically by an increase in peripheral resistance.5 7
Recently, it has been reported that LV geometric patterns are strongly associated with cardiovascular prognosis in patients with essential hypertension.3 30 31 Morbidity in those with concentric hypertrophy was the highest of the four LV geometric patterns, and morbidity in those with concentric remodeling was higher than in those with normal geometry. If hyperinsulinemia is related to insulin resistance, the high risk in those with concentric hypertrophy and concentric remodeling may be explained in part by the presence of the insulin resistance syndrome.25
Obesity is known to be an independent determinant of LV mass and relative wall thickness.4 6 7 It has been reported that the relationship between obesity and LV mass could be made clearer by normalizing LV mass for the allometric power of its relationship to height (LV mass/height2.7) instead of normalizing for body surface area.19 20 We also observed that BMI was significantly correlated with LV mass index (LV mass/body surface area) as well as LV mass/height2.7 and relative wall thickness in all subjects in the univariate and multivariate analyses.
An obese state is characterized by insulin resistance and impaired glucose tolerance as well as other metabolic abnormalities. Thus, BMI is an important confounding factor in analysis of the influence of insulin on LV hypertrophy. In the subjects without diabetes mellitus, hyperinsulinemia but not BMI was selected as an independent significant determinant of relative wall thickness in multiple regression analysis, although both variables had a significant simple correlation with relative wall thickness. After we divided the subjects into high and low BMI groups by median value of BMI, hyperinsulinemia was a significant independent determinant of relative wall thickness in the high BMI group. It is thus likely that insulin correlates with relative wall thickness independently of BMI, even in a close relationship between insulin levels and BMI. In addition, since we observed a significant independent correlation between hyperinsulinemia and relative wall thickness only in the high BMI group, it is also likely that the influence of insulin on the left ventricle is more evident in obese subjects.
In previous studies, insulin resistance was evaluated with the use of the euglycemic clamp technique or the insulin-suppression test.15 16 17 25 However, these methods are not practical for studies dealing with a large number of subjects such as the general population or a work-site population. It has been reported that insulin sensitivity (measured by the euglycemic clamp technique) strongly correlated with insulin area and postload insulin levels during OGTT.16 17 In the present study we used postload insulin level and the sum of insulin levels as markers of insulin sensitivity, as in other epidemiological studies.24 32 Since postload insulin and the sum of insulin levels but not fasting insulin correlated with relative wall thickness in the present study, insulin resistance may underlie hyperinsulinemia and contribute to concentric change in LV geometry.
Several reports have shown that overt diabetes mellitus contributes to LV hypertrophy and deteriorates LV function in hypertensive patients.8 9 In these studies, the plasma glucose level significantly correlated with LV mass index in diabetic patients.8 Impaired glucose tolerance has also been reported to contribute to LV mass in hypertensive patients in one study,10 but another study did not observe such a contribution.11 In the present study, HbA1c and the sum of glucose levels during OGTT independently correlated with relative wall thickness but did not correlate with LV mass index. This association between diabetes and impaired glucose tolerance and increased relative wall thickness has recently been confirmed in Arizona Indians.33 The inconsistent results concerning LV mass may be attributed to the difference in the study populations. Our study population included subjects with mild diabetes mellitus, and most were newly diagnosed as diabetics. Thus, the influence of a high glucose level may be limited in the present study. If the study population included those with overt diabetes, the correlation between glucose level and LV mass might be detected.
One of the possible limitations of the present study is that the study population was not the general population; the study subjects were male workers who were selected from the work-site population. Therefore, the results in the present study may not be applicable to the general population. The second limitation is that the study subjects included only normotensive subjects and mildly to moderately hypertensive subjects (in WHO stages I and II) who were not taking antihypertensive medication. Therefore, this study could not discuss LV geometric alteration in the advanced stage of hypertensive heart disease, which manifests as eccentric hypertrophy.34 Early alteration of the left ventricle in response to high BP and other factors, including hyperinsulinemia, could be detected. The third limitation is that some subjects were excluded because of the poor quality of their echocardiograms. However, profiles of these excluded subjects did not differ from those of all included subjects (data not shown). Therefore, this may not directly influence the interpretation of our data.
In summary, we have demonstrated that hyperinsulinemia, which is possibly associated with insulin resistance, may promote concentric changes in LV geometry in normotensive and mildly to moderately hypertensive subjects without diabetes mellitus. Hyperglycemia also may be an independent risk factor for concentric changes in LV geometry when subjects with mild diabetes mellitus are included.
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Selected Abbreviations and Acronyms |
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References |
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