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(Circulation. 1999;100:1802-1807.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Circulating Insulin and Insulin Growth Factor-1 Are Independent Determinants of Left Ventricular Mass and Geometry in Essential Hypertension
Presented in part at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13–16, 1995, and published in abstract form (Circulation. 1995;92[suppl I]:I-154).
From the Ospedale Generale Regionale Raffaello Silvestrini, Unità Operativa di Malattie Cardiovascolari, Perugia (P.V., C.B., A.C., M.P.T., C.P.); Ospedale Beato G. Villa, Città della Pieve (G.S.); and Dipartmento di Medicina Interna e Scienze Endocrine e Metaboliche, Università di Perugia (G.R., F.S., P.B.), Italy.
Correspondence to Dr Paolo Verdecchia, Ospedale R. Silvestrini, Dipartimento di Discipline Cardiovascolari, Località Ponte della Pietra, 06156 Perugia PG, Italy. E-mail verdec{at}tin.it
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Abstract |
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Background—It is unclear whether insulin and insulin-like growth factor-1 (IGF-1) are independent determinants of left ventricular (LV) mass in essential hypertension.
Methods and Results—We studied 101 never-treated nondiabetic subjects with essential hypertension. All had 24-hour noninvasive ambulatory blood pressure (ABP) monitoring and a 75-g oral glucose tolerance test. We determined fasting glucose, insulin, and IGF-1 and postload glucose and insulin 2 hours after glucose. Insulin resistance was estimated by the homeostasis model assessment (HOMAIR) formula. LV mass showed an association with body mass index (BMI) (r=0.47; P<0.01), postload insulin (r=0.54; P<0.01), HOMAIR (r=0.39; P<0.01), and IGF-1 (r=0.43; P<0.01) and a weaker association with average 24-hour systolic and diastolic ABPs (r=0.29 and r=0.26; P<0.05) and basal insulin (r=0.31; P<0.05). Relative wall thickness was positively related to IGF-1 (r=0.39; P<0.01) but not to fasting or 2-hour postload insulin, HOMAIR, and glucose. In a multiple regression analysis, the final LV mass model (R2=0.64) included IGF-1, postload insulin, average 24-hour systolic ABP, sex, and BMI. IGF-1 and postload insulin accounted for >40% of variability of LV mass. The final model (R2=0.36) for relative wall thickness included IGF-1 (16% total explained variability), average 24-hour systolic ABP, sex, BMI, and age but not insulin and HOMAIR.
Conclusions—These data indicate that insulin and IGF-1 are powerful independent determinants of LV mass and geometry in untreated subjects with essential hypertension and normal glucose tolerance.
Key Words: hypertension • hypertrophy • echocardiography • insulin • growth substances
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Introduction |
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Left ventricular (LV) mass determined at echocardiography in 1 single session is a potent independent predictor of cardiovascular morbidity and mortality in essential hypertension,1 2 3 and its reduction during treatment has a favorable prognostic impact.4 5 However, despite its growing use in clinical practice for cardiovascular risk stratification, the pathophysiological mechanisms underlying the LV structural abnormalities in essential hypertension are still incompletely known.6
Blood pressure (BP) overload explains only in part the changes in LV structure in subjects with hypertension, because the proportion of LV mass variability accounted for in these subjects by BP, either clinic or ambulatory, is small.6
Insulin could be involved in the pathogenesis of essential hypertension.7 An inverse association has been noted between insulin sensitivity, measured by the glucose clamp technique, and LV wall thickness in subjects with essential hypertension.8 Insulin may exert a direct growth-promoting effect on cardiomyocytes.9 Insulin growth factor-1 (IGF-1) may induce cardiac hypertrophy,10 and insulin could stimulate muscle cell growth by binding to the IGF-1 receptors because of the structural similarity between the 2 molecules.11 Also, in subjects with essential hypertension, IGF-1 may be increased and associated with LV mass.12
The above considerations prompted us to plan a study to ascertain the role of insulin and IGF-1 as possible independent determinants of LV mass in uncomplicated, never-treated, and nondiabetic subjects with essential hypertension.
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Methods |
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Study Subjects
The present study was conducted in 115 subjects who consecutively entered the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) registry and fulfilled the following admission criteria: (1) never-treated essential hypertension with sitting BP
140 mm Hg systolic or 90 mm Hg
diastolic in 3 visits in the previous 3 weeks, (2) no
diabetes mellitus, (3) good-quality echocardiographic
tracings, (4) 1 valid ambulatory BP reading per hour, (5) absence of
heart failure or valvular defects, and (6) normal liver and
kidney function. Details of the PIUMA protocol have been reported
previously.3 5 For this project, a 75-g oral glucose
tolerance test was performed in all subjects. The study was conducted
in accordance with the declarations of Helsinki and Tokyo, and all
subjects gave informed consent.
BP Measurement
Clinic BP was measured by a physician in the outpatient hospital
clinic with a mercury sphygmomanometer, with the subject sitting for
10 minutes. The average of 3 measurements was considered for the
analysis. Ambulatory BP was recorded with an oscillometric
device (models 90202 and 90207, SpaceLabs) set to take a reading every
15 minutes throughout the 24 hours. Normal daily activities were
allowed and encouraged, and patients were told to keep their
nondominant arm still and relaxed to the side during measurements.
Reading, editing, and analysis of data were done as previously
described.3 5 The spontaneous day-to-day variability of
ambulatory BP was assessed in some of these patients.13
Daytime and nighttime periods were defined according to the so-called
"narrow fixed clock intervals"14 (day, from 10
AM to 8 PM; night, from midnight to 6
AM) to mirror the actual patients' waking-sleeping
rhythms.
Echocardiography
The echocardiographic study was performed with
commercially available machines according to standard laboratory
procedures. The M-mode echocardiographic study of the
LV was performed under 2-dimensional control according to the American
Society of Echocardiography
recommendations.15 Only frames with optimal visualization
of interfaces and simultaneously showing septum, LV ID, and
posterior wall were used for readings. Tracings were read by 2
observers who were unaware of patients' clinical data, and the mean
value from at least 5 measurements per observer was computed. The
intraobserver and intratracing variability in our laboratory has been
reported elsewhere.5 LV mass was calculated according to
Devereux et al16 and normalized by both body surface area
and by height2.7(see Reference 17 )
to correct for the effect of overweight. Relative wall thickness was
calculated as (posterior wall thickness)/LV internal radius, and
concentric remodeling or concentric LV hypertrophy was
defined by a relative wall thickness >0.45.
Hormone and Metabolic Investigations
All participants were instructed to follow a weight-maintaining
diet of 300 g of carbohydrates per day for the 3 days before the
study. On the morning of the study, patients were admitted to the
outpatient clinic at 7:30 AM after an overnight fast. A
plastic catheter was inserted into a forearm vein for blood sampling
and kept patent by a slow saline drip. At 8 AM, a standard
oral glucose load (75 g glucose monohydrate) in 300 mL water was given
to all subjects. Neither food nor water was allowed during the test.
Blood samples were taken immediately before and 2 hours after load for
glucose and insulin determinations. IGF-1 levels were determined only
in basal samples.
Plasma glucose was immediately determined by the glucose oxidase method (Glucose Analyzer, Beckman; intra-assay coefficient of variation [CV] 2.2%, interassay CV 3.8%). Plasma insulin was determined in duplicate by a highly specific (cross-reactivity: intact proinsulin <0.2%; Des-31,32-HPI <0.2%; Des-64,65-HPI <0.2%; IGF-1 undetectable) and sensitive (2 µU/mL) radioimmunoassay (Linco Research; intra-assay CV 3.3%, interassay CV 4.2%; internal reference values in healthy subjects: 11.6±3.4 [mean±SD] µU/mL). Circulating IGF-1 was determined in duplicate by 2-site specific (cross-reactivity: human insulin undetectable; intact proinsulin undetectable) and sensitive (2.06 ng/mL) immunoradiometric assay (Diagnostic System Laboratories; intra-assay CV 4.4%, interassay CV 4.8%; internal reference values in healthy subjects 50 to 70 years old: 180.4±48.3 [mean±SD] ng/mL).
Homeostasis Model Assessment of Insulin Resistance
In each subject, the degree of insulin resistance was estimated
by the homeostasis model assessment (HOMAIR) as
described by Matthews et al18 and validated by
Bonora.19 Briefly, HOMAIR was
calculated by taking into account fasting insulin and blood glucose
levels according to the equation HOMAIR=fasting
insulin (µU/mL)/[22.5xe-ln(glucose
[mmol/L])]. Low HOMAIR values
denote normal insulin sensitivity, whereas high values denote insulin
resistance. In our laboratory, the mean value for age-matched, white,
normotolerant, normotensive subjects (n=42) was 2.83±0.7 (95th
percentile 3.99).
Statistical Analysis
Results are given as mean±SD unless otherwise specifically
stated. Statistical analyses were performed by use of SAS/STAT
(SAS Institute) release 6.12 and JMP (SAS Institute) release 3.2.
Two-tailed unpaired t test was used to compare study
response variables between subject categories. Correlation
coefficients were calculated according to Pearson's method. Stepwise
multivariate linear regression analysis was
used to determine the significant independent predictors of LV mass or
relative wall thickness. Office and ambulatory BP, plasma insulin,
HOMAIR, IGF-1, and the
echocardiographic parameters were
analyzed as continuous variables, body mass index (BMI) was
considered as presence versus absence of overweight or obesity (25
versus <25 kg/m2), and sex was considered as
male versus female. Stepwise logistic regression analysis was
used to determine the independent predictors of LV
hypertrophy (LV mass index 125 versus <125
g/m2). Office and ambulatory BP, insulin,
HOMAIR, IGF-1, and BMI were analyzed as
continuous variables, and sex was considered as male versus female.
The Spearman test (rS) was used for the
correlation of LV mass to the night/day BP ratio in either sex to
obviate for possible imbalances in the gaussian distribution in the
smaller samples. Probability values <0.05 were considered
statistically significant in all analyses.
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Results |
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Patients
Of 113 subjects examined initially, 8 were excluded for impaired glucose tolerance (2-hour postload plasma glucose >140 and <200 mg/dL) and 4 for diabetes (2-hour postload plasma glucose >200 mg/dL). The remaining 101 subjects entered the study.
The main demographic and clinical characteristics of these subjects are
reported in Tables 1
and 2. As expected, fasting and postload
insulin, HOMAIR, triglycerides, uric
acid, and LV mass were increased in the subset with BMI 25
kg/m2 (all P<0.05), and the increase
in LV mass in these subjects was accounted for by an increase in both
wall thicknesses and internal diameter (all P<0.05). IGF-1
and office and ambulatory BP did not differ between the 2 groups.
HOMAIR exceeded 3.99 in 51% of subjects, in
agreement with the prevalence rate reported by
Bonora.19
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Determinants of LV Mass and Geometry
As reported in Table 3, LV mass
showed a significant association with ambulatory BP (r=0.30
for systolic, 0.27 for diastolic) but not with
office BP. There was also a direct association between LV mass and the
night/day ratio of systolic BP in the overall population
(r=0.25), which held in the female
(rS=0.32; P=0.04) but not in the
male (rS=0.20; P=0.14) sex. LV
mass also showed a direct association with fasting (r=0.31)
and postload (r=0.55) insulin, HOMAIR
(r=0.39), and IGF-1 (r=0.42). Relative wall
thickness showed a significant association with office systolic
BP (r=0.21), ambulatory systolic (r=0.42)
and diastolic (r=0.29) BP, and IGF-1
(r=0.39) but not with fasting insulin, postload insulin, and
HOMAIR.
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In a stepwise multivariate linear regression
analysis (Table 4), the
independent determinants of LV mass were postload insulin, sex, IGF-1,
BMI, and average 24-hour ambulatory systolic BP. Office BP, BP
load, the night/day ratio of systolic BP, and
HOMAIR did not achieve significance to enter the
model. Postload insulin accounted for 30% of total variability of LV
mass; a further 12% was accounted for by sex, 9% by IGF-1, 9% by
BMI, and finally, 5% by average 24-hour ambulatory systolic
BP. The multiple r was 0.81, which indicates that the whole
model accounted for 65% of total variability of LV mass. Figure 1 shows that the association between LV
mass and postload insulin held in the normal-weight (r=0.32,
P<0.05) as well in the overweight (r=0.48,
P<0.001) subjects. Figure 2
shows that the closeness of the association between LV mass and IGF-1
did not differ in the normal-weight (r=0.49,
P<0.01) compared with overweight (r=0.49,
P<0.01) subjects.
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Figure 3 shows the values of fasting
insulin, 2-hour postload insulin, HOMAIR, and
IGF-1 in the presence and absence of echocardiographic
LV hypertrophy. In a stepwise logistic regression
analysis, the independent predictors of LV
hypertrophy were IGF-1 (P<0.01), postload
insulin (P<0.01), average 24-hour systolic BP
(P<0.01), and BMI (P<0.05). The adjusted odds
ratio of LV hypertrophy was 1.68 (95% CI 1.21 to 2.33) for
every 10-µU/mL increase in postload insulin, 1.27 (95% CI 1.12 to
1.44) for every 10-ng/mL increase in IGF-1, 1.64 (95% CI 1.16 to 2.30)
for every 5–mm Hg increase in average 24-hour systolic BP,
and 1.91 (95% CI 1.02 to 3.56) for each 3-kg/m2
increase in BMI. Office BP, BP load, the night/day ratio of
systolic BP, and HOMAIR did not enter the
model.
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The independent determinants of relative wall thickness are reported in
Table 5. Relative wall thickness was
accounted for by average 24-hour ambulatory systolic BP, IGF-1,
age, BMI, and sex. Average 24-hour ambulatory systolic BP
accounted for 17% of total variability of relative wall thickness; a
further 11% was accounted for by IGF-1, 3% by age, 3% by BMI, and
2% by sex. The whole model accounted for 36% of total variability
of LV mass (multiple r=0.60). As shown in Figure 4, the univariate association between LV mass and IGF-1 was
comparable in the normal-weight (r=0.35, P<0.05)
and overweight (r=0.45, P<0.01) subjects.
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When subjects were subdivided by LV geometry (Figure 5), postload plasma insulin did
not differ between the subset with normal LV geometry and that with
concentric remodeling, whereas it was increased in the group with
eccentric hypertrophy compared with that with concentric
hypertrophy (P<0.001). In contrast, IGF-1 did
not differ between the group with eccentric and that with concentric
hypertrophy, whereas it was increased in the subjects with
concentric LV remodeling compared with those with normal LV geometry
(P<0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Insulin and IGF-1 were powerful independent determinants of LV mass in never-treated subjects with essential hypertension and normal glucose tolerance. Together, these 2 hormones accounted for 39% of variability of LV mass, and a further 26% of variability was explained by overweight, sex, and average 24-hour ambulatory systolic BP, leading to 65% of LV variability being explained by these factors. Moreover, IGF-1, but not insulin, independently accounted for 11% of variability of relative wall thickness, with a further 25% of variability explained by 24-hour ambulatory systolic BP, age, sex, and overweight. These findings have been obtained in a population of nondiabetic subjects with normal glucose tolerance, thus removing the potential objection that hyperinsulinemia might have been an obvious relevant confounder.
It is well established that peripheral hyperinsulinemia in subjects with essential hypertension is a marker of insulin resistance.7 8 The HOMAIR was calculated to obtain a better quantitative estimate of insulin resistance.18 19 Although this index was increased in subjects with LV hypertrophy, it was not an independent predictor of LV mass after control for postload insulin, IGF-1, sex, overweight, and ambulatory BP. Because HOMAIR reflects fasting insulin levels, our data suggest that postload insulin is more important than fasting insulin as a potential determinant of LV mass.
Previous studies have examined the relation of insulin8 20 21 22 or IGF-112 23 24 with LV mass in subjects with essential hypertension, but none of these studies assessed the independent association of these 2 hormones with LV mass in the same population.
The present study not only disclosed an independent relationship of insulin and IGF-1 to LV mass but also lent support to the view that such an association may be mediated by different mechanisms of action by these hormones on the concentric and eccentric components of LV geometry. In this setting, the potential clinical importance of the different patterns of LV geometry has been increasingly appreciated in the past few years, on the basis of longitudinal studies that examined the possibility that the different LV geometric patterns could provide prognostic information beyond the overwhelming contribution of LV mass in subjects with essential hypertension.1 25 26 27 28
Effects of Insulin and IGF-1 on LV Geometry
Experimental and clinical data suggest that insulin might
interfere with both the concentric and eccentric patterns of LV mass
growth. Stimulation of myocardial cell growth9 10 11 and
activation of the sympathetic nervous system29 30 might
preferentially lead to concentric LV hypertrophy through a
direct trophic effect and pressure overload, whereas sodium and
water retention31 could lead to eccentric LV
hypertrophy through volume overload. The direct effect of
insulin on myocardial cell growth could be mediated, at least in part,
by the IGF-1 receptors.9 10 Unfortunately, we did not
assess sympathetic nervous system activity or plasma volume; hence, we
were unable to quantify the impact of these mechanisms in our
population. Other potential nonhemodynamic determinants
of LV mass, including angiotensin, aldosterone,
atrial natriuretic peptide,32 33 34 and ACE
genotype,35 36 could not be assessed. Our findings
are partially in keeping with those of Paolisso et al,21
who found an impaired whole-body glucose disposal, determined with
euglycemic hyperinsulinemic clamp, in
hypertensive subjects with concentric LV remodeling or frank LV
hypertrophy compared with a group of subjects with normal
LV geometry. In a study carried out in nonobese and nondiabetic
hypertensive subjects, Phillips et al22 found an
independent relationship of mean 24-hour ambulatory BP and insulin
sensitivity index (frequently sampled intravenous glucose
tolerance test) to LV mass determined at
echocardiography.
As far as IGF-1 is concerned, some studies suggest that this 70-amino-acid peptide, synthesized primarily in the liver under the influence of growth hormone,37 could contribute to increasing LV mass in subjects with hypertension.12 23 24 IGF-1 directly stimulates the growth of cardiac myocytes through induction of cardiac protein synthesis.37 38 Unfortunately, we could not determine IGF-1 binding proteins in our study. More than 90% of total IGF-1 circulates bound to proteins,39 and the distribution of these binding proteins seems to be shifted from the high-molecular-mass forms (type 3) toward the low-molecular-mass forms (types 1 and 2) in hypertensive subjects with LV hypertrophy.12 23 This may have important implications because the low-molecular-mass forms may cross the capillary barrier, thus shuttling IGF-1 to myocardial and other target cells. However, a complex equilibrium seems to exists between insulin and IGF-1. In fact, the distribution of the IGF-1 binding proteins is also affected by insulin, because the low-molecular-mass forms, and hence the tissue availability of IGF-1, tend to decrease with increasing insulin resistance.40
Conclusions
There is growing evidence of a link between insulin and
cardiovascular risk,41 although the
independent role of insulin is still undetermined. This study suggests
that insulin and IGF-1 are important determinants of LV mass and
geometry in subjects with essential hypertension and normal glucose
tolerance and that this relation is independent of sex, overweight, and
office and ambulatory BP. Insulin and IGF-1 could lead to increased LV
mass through different basic effects on LV geometry.
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Acknowledgments |
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This study was supported in part by grants from the Associazione Umbria Cuore e Ipertensione, Perugia, Italy. Appreciation is expressed to Paolo de Luca and Mariano Cecchetti for nursing assistance.
Received May 3, 1999; revision received June 23, 1999; accepted July 2, 1999.
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