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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4284-4288
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

Relation among Left Ventricular Mass, Insulin Resistance, and Blood Pressure in Nonobese Subjects1

Robert A. Phillips, Lawrence R. Krakoff, Andrea Dunaif, Diane T. Finegood2, Richard Gorlin3 and Seiichi Shimabukuro

Mount Sinai Medical Center (R.A.P., L.R.K., R.G.), New York, New York 10029; Brigham and Women’s Hospital (A.D.), Boston, Massachusetts 00000; Simon Fraser University (D.T.F.), Burnaby, British Columbia, Canada; and Hirano General Hospital (S.S.), Gifu, Japan

Address all correspondence and requests for reprints to: Robert A. Phillips, M.D., Ph.D., Section of Hypertension, Prevention, and Rehabilitation, Zena and Michael A. Wiener Cardiovascular Institute, Box 1085, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029. E-mail: robert_phillips{at}smtplink.mssm.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Because left ventricular (LV) mass (LVM) is a powerful predictor of future cardiovascular events, it is important to identify hemodynamic and nonhemodynamic factors that increase LVM. We studied the separate contribution to LVM of daily arterial blood pressure (BP) and insulin resistance in a consecutive series of 29 (mean ± SD age, 43 ± 13 yr) nonobese (body mass index, 24 ± 1.8 kg/m2), nondiabetic, glucose-tolerant subjects with untreated borderline or mild hypertension. The insulin sensitivity index (SI) was quantitatively determined from the frequently sampled iv glucose tolerance test. BP was characterized by ambulatory 24-h BP monitoring, and LVM index (LVMI) was determined by two-dimensional directed M-mode echocardiography. LVMI was directly related to 24-h mean BP (r = 0.47; P = 0.01). LMVI was also significantly related to SI (r = -0.43; P = 0.02). In this nonobese group, neither LVMI nor SI was related to body mass index or age. After adjustment for the influence of BP on LVMI, a significant relation remained between LVMI and SI (P < 0.05).

We conclude that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP and may be an important modulator of LV growth. In addition to a reduction of arterial BP, optimal prevention of LV hypertrophy in hypertensives may require improved insulin sensitivity.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
A RELATIVELY continuous relationship exists between the absolute amount of left ventricular (LV) mass as determined by echocardiography and cardiovascular risk. In the Framingham study, each 50 g/m increase in LV mass (LVM) was associated with a 1.49 relative risk of cardiovascular disease in men and a 1.57 relative risk in women (1). The effect on cardiovascular mortality was even more striking, with a 1.73 relative risk for each 50 g/m for men and a 2.12 relative risk for each 50 g/m for women. Fortunately, regression of LVM with drug treatment is associated with decreased risk for subsequent cardiovascular events (2). Because of the impact of LVM on cardiovascular morbidity and mortality, determining the factors that increase LVM is especially important.

Increased blood pressure (BP) and other hemodynamic factors are signals for myocardial growth (3). However, for the same level of BP there is wide variation among individuals in both the degree of left ventricular mass and vascular damage. Careful hemodynamic evaluations indicate that differences in BP, stroke index, and contractility account for only about 66% of the variation in LVM in hypertensives (4). This implies that LVM may be partly determined by nonhemodynamic factors (5). For example, genetic (6), acquired (e.g. obesity) (7, 8), and dietary factors, such as alcohol (9) and sodium intake (10), influence mass independently from their effect on BP.

Because myocardial protein degradation is inhibited during hyperinsulinemia in insulin-resistant subjects, it has been suggested that insulin resistance could be a contributing factor to LVM (11). Cross-sectional epidemiological studies have demonstrated that insulin resistance occurs in nonobese, nondiabetic, glucose-tolerant hypertensives (12). To test the hypothesis that insulin resistance might be related to myocardial mass independent of the effect of arterial BP or obesity, we studied a nonobese, glucose-tolerant, and previously untreated population of subjects with high normal or stage I hypertension.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject selection

This population is a consecutive sample of all subjects between 18–67 yr of age who met criteria and agreed to participate in the protocol. They had all been referred because of a previous diagnosis of high normal or stage I hypertension (13). Before referral, subjects had an office diastolic BP of 90 mm Hg or greater on at least two occasions, but had never been treated. None had a history of glucose intolerance, diabetes mellitus, or any other endocrine disorder. None of the subjects was a trained athlete. Subjects were excluded from this study if they were obese based on criteria used in the National Health and Nutrition Surveys I and II (27.8 kg/m2 for men and 27.3 kg/m2 for women) (14). Causes of secondary hypertension were excluded in all subjects by history and physical exam, and by biochemical testing to exclude elevated levels of plasma catecholamines or PRA. All subjects signed informed consent for the protocol that was approved by the institutional review board of the Mount Sinai Medical Center.

Oral glucose tolerance test (OGTT)

A standard OGTT was performed in all subjects to assess glucose tolerance. After ingesting a 1.67-mol carbohydrate diet for 3 days and fasting for 10–12 h overnight, subjects received a 0.42-mol glucose load. Blood samples were obtained at 0, 30, 60, 90, and 120 min for determination of plasma glucose and insulin levels.

Insulin sensitivity

Within 1 month of the OGTT, insulin action was quantitatively determined using Bergman’s minimal model, a method equivalent to the euglycemic glucose clamp for assessment of overall insulin sensitivity (15). In preparation for the tolbutamide-modified, frequently sampled, iv glucose tolerance test (FSIGT), subjects ate a 1.67-mol carbohydrate diet for 3 days and fasted overnight (12 h). After placement of two iv catheters, four basal samples were collected over 15 min, after which glucose (1.7 mmol/kg, iv bolus) was injected over 1 min. Twenty minutes after glucose, tolbutamide was given as a 1.1 mmol iv bolus. Blood specimens (5 cc) were collected at various time points (0, 2, 3, 4, 5, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100, 120, 160, and 180 min) to allow glucose levels to return to baseline.

The insulin sensitivity index (SI) was calculated by application of the minimal model of glucose kinetics (MINMOD computer program version NUDEMM1, copyright R. N. Bergman) to the dynamics of plasma glucose and insulin during the FSIGT. The adequacy of the minimal model fits was judged by the criteria suggested by Prigeon et al. (16) All reported parameters had a fractional SD below those suggested as upper limits (6.9% for SI).

BP

To accurately characterize BP (17), 24-h BP monitoring was performed using the SpaceLabs 90202 device (SpaceLabs, Redmond, WA). Subjects were monitored on a day chosen for typical weekly activity; most were employed in work outside their home. For calibration, the device was connected to an aneroid or mercury sphygmomanometer with a Y-tube. Three consecutive "office BPs" were taken by sphygmomanometer, 2–3 min apart, in a seated position and were calibrated to the monitor readings. A device was used only if measurements differed by 5 mm Hg or less from the sphygmomanometer. To characterize the pattern of awake and nocturnal BPs, subjects recorded in a diary the time at which they went to sleep and awoke. Ambulatory BP recordings were made every 20 min during waking hours and every 60 min during sleep. After completion of the recording, data were transferred by software to an IBM-compatible computer and processed for deletion of errors and predefined outliers (systolic, <70 or >260; diastolic, <40 or >150; heart rate, <20 or >200). Hand editing for outliers was not performed to avoid bias. Means and SDs were calculated using SpaceLabs PC Interface Software for IBM. The patient’s nocturnal (sleep) BP was characterized as normal ("dippers") if their sleep pressure was between 10% and 20% lower than awake BP and as abnormal ("nondippers") if sleep pressure was less than 10% lower than awake BP (18).

Echo cardiography

Two-dimensionally guided M-mode echocardiography was performed with an ATL Mark 600 or ATL Ultramark 6 scanner (Advanced Technology Laboratories, Inc., Bothell, WA) using a 2.5- or 3.0-MHz transducer. Studies were either recorded on videotape or directly stored in digital form on floppy disks. Echo cardiographic tracings were coded and interspersed with other ongoing studies to reduce the chance of reader bias. The studies were analyzed with a commercially available digitizer (ColorVue II, Nova MicroSonics, Allendale, NJ) in a random order by two independent observers who were unaware of the subject’s insulin resistance and BP status. We have previously shown (19) that this method of blinded and digitized echo cardiographic analysis of LVM is associated with a high degree of interobserver concordance (r = 0.93; P = 0.0001). End-diastolic measurements of LV dimensions were made according to the Penn Convention protocol to measure LVM (20). LVM was calculated by the formula: LVM = 1.04[(IVS + LVID + PWT)3 - (LVID)3] - 13.6. The sum of the interventricular septum and LV posterior wall defined LV wall thickness. To correct for the effect of body size on heart mass (21), LVM was indexed by body height2.

Assays

Insulin was measured by RIA (22). The intraassay coefficient of variation for the insulin assay at 50% binding was 3%. The interassay coefficient of variation was 8%. The assay was parallel over a range of plasma sample volumes, and all fasting insulin levels were run at a sample volume of 200 µL instead of 100 µL and were thus on a reliable portion of the standard curve (23). Plasma glucose was measured by the glucose oxidase technique with a Beckman Coulter, Inc. Glucose Analyzer II (Fullerton, CA).

Statistics

All data are expressed as the mean ± SD. All statistical analyses were performed with programs of the SAS Institute, Inc. (Cary, NC). The relations between the variables were analyzed by simple correlation and by multiple regression analysis using the SAS Proc Reg procedures.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The subjects studied (21 men and 8 women) were middle-aged, nonobese, nondiabetic, and glucose tolerant. The group (17 whites, 6 African Americans, 3 Hispanics, and 3 Asians) is representative of subjects with high normal and mild hypertension that are referred to our clinic for evaluation. BP ranged from normal to mildly hypertensive levels (Table 1Go). The insulin sensitivity index (SI) was not different between women and men (8.9 ± 3 vs. 6.8 ± 3 x 10-5 min-1/pmol/L) or between African Americans and other subjects (6.3 ± 2.5 vs. 7.7 ± 3.3 x 10-5 min-1/pmol/L). The LVM index (LVMI) did not differ between women and men (49 ± 10 vs. 52 ± 11 g/m2) or between African Americans and other subjects (51 ± 10 vs. 52 ± 10 g/m2). In this nonobese group there was no relation between body mass index and any measure of insulin or glucose metabolism (SI, fasting insulin, fasting glucose, or area under the insulin curve of the FSIGT).


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  		Table 1. Characteristics of subjects

 
In univariate analysis, there was a direct relation between the LVMI and BP. Of the BP variables measured, 24-h mean arterial pressure had the closest relation to LVMI (Fig. 1Go) and was directly related to wall thickness (r = 0.41; P < 0.05). There was an inverse relation between 24-h diastolic BP and SI that was of borderline significance (r = -0.31; P = 0.09). An abnormal LVMI was inversely related to the SI (Fig. 2Go). The SI was also inversely related to wall thickness (r = -0.53; P < 0.01). There was a trend toward a direct relationship between the LVMI and fasting insulin (r = 0.33; P = 0.07) and the insulin area under the curve of the FSIGT (r = 0.34; P = 0.06). There was no relationship between fasting glucose and LVMI. In this nonobese group, neither LVMI nor LV wall thickness was related to body mass index or age.



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  		Figure 1. Relation between 24-h mean arterial BP and LVMI.

 


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  		Figure 2. Relation between SI and LVMI.

 
When 24-h mean BP and SI were considered together in a multivariate analysis, both variables remained independently related to LVMI (P < 0.05 for each variable). An additional multivariate analysis (Proc Reg/Selection = Stepwise) was performed that included the following variables, entered in order and evaluated for independent contribution to LVMI: SI, 24-h mean BP, body mass index, race, gender, and pattern of nocturnal BP. In this analysis, only SI and 24-h mean BP remained independently related to LVMI (P < 0.05 for each variable). Similarly, when considered together in multivariate analysis, SI and 24-h mean BP were independently related to LV wall thickness (P < 0.05 for each variable).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
There have been several reports examining the relationships between hyperglycemia, hyperinsulinemia, or insulin resistance and either BP or LVM in different populations. These have included, in various combinations, known treated or untreated hypertensives, known diabetics, and obese or nonobese subjects. The current study is unique because it found a significant independent correlation between LVM and both BP and insulin resistance in nonobese subjects with early hypertension who are neither diabetic nor have glucose intolerance. Thus, it is free of the possible influences of prior hypertension and its treatment, diabetes, excess weight, or impaired glucose tolerance.

Insulin resistance measured by euglycemic clamp has been related to LV wall thickness in a population of mild to moderate hypertensives that included obese subjects (24). Insulin levels and other less specific indexes of insulin resistance have been directly related to LVM in obese normotensives and in studies of hypertensives that have included obese subjects (25, 26, 27, 28). In the Techumseh Blood Pressure Study of normotensive subjects, higher fasting insulin levels were found in men whose LVM was in the upper 10th percentile of the population (29). A study of untreated Japanese men that predominantly included nonobese subjects found a relationship between 24-h excretion of C-peptide and LVM (30). In patients with type 1 diabetes, those with insulin resistance were more likely to have LV hypertrophy than those who were insulin sensitive (31). In a study of patients with type 2 diabetes and hypertension, the level of fasting glucose was directly related to the LVM (32).

Three studies in hypertensive subjects failed to demonstrate a relationship between insulin levels and LVM. Several features of these studies might account for these negative results. For example, the insulin level or the area under the insulin curve from an OGTT are relatively imprecise measures of insulin sensitivity and presume an adequate ß-cell response to insulin resistance. These surrogate measures of insulin sensitivity were used in each of these negative studies, and this might obscure a relation between insulin resistance and LVM. In two of the studies, patients with moderate and severe hypertension were included; hemodynamic influences on LVM might predominate over nonhemodynamic factors (33, 34). One study included previously treated hypertensives. As antihypertensive treatment often regresses LVM, it would be less likely that a relationship would be found between insulin resistance and LVM in a population of previously treated patients (34).

Among the limitations of the current study is that it shows a relation between insulin resistance and LVM, but it does not demonstrate causality. This association may be due to a hypertropic factor that is common to both borderline hypertension and insulin resistance. One such factor might be increased sympathetic nervous system activity. Hyperinsulinemia is associated with increased norepinephrine levels and increased sympathetic nervous system activity (35, 36). Elevated plasma norepinephrine levels in the absence of hypertension cause left ventricular hypertrophy in dogs (37). Significant increases in LVM occur after several weeks of diet-induced elevated endogenous catecholamine levels in normotensive offspring of hypertensive parents (38). These observations may be explained by the ability of catecholamines to elevate intracellular calcium, which initiates a calcineurin-dependent transcriptional pathway that results in cardiac hypertrophy (39). Insulin resistance is also associated with an elevation of intracellular calcium (40).

Another limitation of this study is the ethnic heterogeneity of the subjects. It is controversial whether all racial and ethnic groups demonstrate a relation between insulin resistance and BP (41, 42). In this study we did not find differences in insulin sensitivity or LVM among the different ethnic groups, but a thorough investigation of this issue would involve a very large sample size for each ethnic group.

The implications of this study derive from epidemiological observations that suggest that insulin resistance/hyperinsulinemia (43, 44) and LVM (1, 45, 46) are predictors of future cardiovascular morbidity and mortality. This study suggests that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP. In addition to the reduction of arterial BP, optimal prevention of increased LVM may require improved insulin sensitivity in the hypertensive patient. These data also suggest that the effect of insulin-sensitizing agents on LVM in hypertensive patients may be worthy of detailed study.


   Acknowledgments
 
We thank the following: the nursing staff of the Mount Sinai School of Medicine General Clinical Research Center for superb care of the study participants; Teresa Licholai for her assistance in performing certain hormone assays; Advanced Technology Laboratories, Inc. (Bothell, WA), for extended loan of ultrasound equipment; Nova Microsonics (Allendale, NJ) for extended loan of the Color Vue II analyzer; SpaceLabs, Inc. (Redmond, WA), for ambulatory BP-monitoring equipment; and The Upjohn Co. (Kalamazoo MI) for the iv tolbutamide.


   Footnotes
 
1 This work was supported by NIH Grant 5-M01-RR-00071 to the General Clinical Research Center and grants from the Heart Research Foundation (New York, NY) and the Sosnoff Foundation (New York, NY). Back

2 Medical Scientist of the Medical Research Council of Canada. Back

3 Deceased. Back

Received June 11, 1998.

Revised August 19, 1998.

Accepted August 25, 1998.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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D. C. Goff Jr, D. J. Zaccaro, S. M. Haffner, and M. F. Saad
Insulin Sensitivity and the Risk of Incident Hypertension: Insights from the Insulin Resistance Atherosclerosis Study
Diabetes Care, March 1, 2003; 26(3): 805 - 809.
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A. Ilercil, R. B. Devereux, M. J. Roman, M. Paranicas, M. J. O'Grady, E. T. Lee, T. K. Welty, R. R. Fabsitz, and B. V. Howard
Associations of Insulin Levels With Left Ventricular Structure and Function in American Indians : The Strong Heart Study
Diabetes, May 1, 2002; 51(5): 1543 - 1547.
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A. Q. Galvan, F. Galetta, A. Natali, E. Muscelli, A. M. Sironi, G. Cini, S. Camastra, and E. Ferrannini
Insulin Resistance and Hyperinsulinemia : No Independent Relation to Left Ventricular Mass in Humans
Circulation, October 31, 2000; 102(18): 2233 - 2238.
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R. Kuperstein and Z. Sasson
Effects of Antihypertensive Therapy on Glucose and Insulin Metabolism and on Left Ventricular Mass : A Randomized, Double-Blind, Controlled Study of 21 Obese Hypertensives
Circulation, October 10, 2000; 102(15): 1802 - 1806.
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P. Verdecchia, G. Reboldi, G. Schillaci, C. Borgioni, A. Ciucci, M. P. Telera, F. Santeusanio, C. Porcellati, and P. Brunetti
Circulating Insulin and Insulin Growth Factor-1 Are Independent Determinants of Left Ventricular Mass and Geometry in Essential Hypertension
Circulation, October 26, 1999; 100(17): 1802 - 1807.
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