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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0646
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 7 2806-2810
Copyright © 2008 by The Endocrine Society

Low-Plasma Insulin-Like Growth Factor-I Levels Are Associated with Impaired Endothelium-Dependent Vasodilatation in a Cohort of Untreated, Hypertensive Caucasian Subjects

Francesco Perticone, Angela Sciacqua, Maria Perticone, Irma Laino, Sofia Miceli, Ilaria Care', Giulia Galiano Leone, Francesco Andreozzi, Raffaele Maio and Giorgio Sesti

Department of Experimental and Clinical Medicine, University Magna Graecia, 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Francesco Perticone, M.D., Department of Experimental and Clinical Medicine, Policlinico Mater Domini-Viale Europa, Campus Germaneto, 88100 Catanzaro, Italy. E-mail: perticone{at}unicz.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Accumulating evidence suggests that IGF-I has protective vascular effects, supporting the possibility that IGF-I deficiency may contribute to atherosclerosis. However, the relationship between plasma IGF-I levels and endothelium-dependent vasodilatation is still unsettled.

Objective: We designed this present study to test the hypothesis that low-plasma IGF-I levels are associated with reduced endothelial function independently classical cardiovascular risk factors.

Setting: Outpatients were included in the study.

Patients: A total of 100 never-treated hypertensive Caucasian subjects participating in the CAtanzaro MEtabolic RIsk factors Study was recruited.

Interventions: Subjects underwent forearm blood flow (FBF) evaluation by strain-gauge plethysmography in response to increasing doses of acetylcholine (ACh) (Sigma, Milan, Italy) and sodium nitroprusside (Malesci, Florence, Italy). Insulin sensitivity was estimated by the homeostasis model assessment index.

Results: Plasma IGF-I levels were significantly correlated with age (r = –0.300; P = 0.001), high-density lipoprotein serum cholesterol (r = 0.211; P = 0.017), homeostasis model assessment index (r = –0.355; P <0.0001), systolic blood pressure (r = –0.174; P = 0.042), glomerular filtration rate (r = 0.228; P = 0.011), and ACh-stimulated FBF (r = 0.565; P <0.0001). In a stepwise forward multivariate regression analysis, the strongest predictors of ACh-stimulated FBF response were plasma IGF-I levels, accounting for 31.9% of its variation.

Conclusions: These results demonstrate, for the first time, that low-plasma IGF-I levels are highly associated with reduced endothelial function, an early step in atherogenesis process.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Accumulating evidence suggests that IGF-I plays an important role in the development of cardiovascular diseases (1, 2). Low-circulating IGF-I levels have been previously associated with angiographically documented coronary artery disease (3). An inverse relationship between plasma IGF-I concentrations and the prevalence of atherosclerotic plaques has been reported in healthy elderly subjects (4), whereas another cross-sectional study of elderly men identified an inverse linear relation between IGF-I levels and carotid intima media thickness (IMT) (5). Several population-based prospective studies have suggested that low-circulating levels of IGF-I within the normal range may predict an increased risk of ischemic heart disease (6, 7), ischemic stroke (8), and nonfatal myocardial infarction (9). In patients with acute myocardial infarction, circulating IGF-I concentrations on admission to hospital are markedly decreased compared with healthy controls and are significantly lower in those with a worse prognosis, independent of infarct size (10). GH-deficient adults, who have low-circulating IGF-I levels, are characterized by increased IMT (11), and a higher risk of mortality attributable to cardiovascular disease (12, 13). Together, these observations uniformly support the possibility that IGF-I deficiency may contribute to atherothrombotic diseases.

It is now established that endothelial dysfunction is an early event in atherogenesis that precedes the thickening of the intima and the formation of atherosclerotic plaques (14, 15). It has been reported that forearm endothelial dysfunction predicts cardiovascular events in individuals at risk for atherosclerosis, such as hypertensive patients (16). A characteristic feature of endothelial dysfunction is a reduction in the bioavailability of the antiatherosclerotic molecule nitric oxide (NO). There is evidence that IGF-I is a potent vasodilator; iv administration of IGF-I increases blood flow through a NO-dependent mechanism (17, 18). In endothelial cells, IGF-I, interacting with its receptor (19), stimulates NO production contributing to the regulation of vascular tone (20, 21). Moreover, liver-specific IGF-I knockout mice showed impaired acetylcholine (ACh)-induced vasorelaxation of resistance vessels (22). Although these results suggest that IGF-I may favorably influence vascular function, the relationship between plasma IGF-I levels and endothelium-dependent vasodilatation is still unsettled. On the other hand, cardiovascular risk factors, including low-density lipoprotein (LDL) cholesterol (23), insulin resistance (24), glucose intolerance (25), central obesity (26), and smoking (27), which are considered promoters of ischemic diseases by causing endothelial dysfunction, have been associated with low serum IGF-I levels. Thus, the investigation of the relative role of low IGF-I vs. well-established cardiovascular risk factors on endothelial function requires measurements of endothelium-dependent vasodilatation by gold standard techniques and the use of multivariate statistical models, including classical and emerging cardiovascular risk factors. Therefore, the present study was designed to test the hypothesis that low-plasma IGF-I levels are associated with reduced endothelial function independently of cardiovascular risk factors in a cohort of untreated, hypertensive Caucasian subjects.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

In this study we included 100 previously untreated hypertensive patients, consecutively recruited at the Department of Experimental and Clinic of the University "Magna Graecia" of Catanzaro. All subjects were Caucasian and participating in the CAtanzaro MEtabolic RIsk factors Study, a metabolic disease prevention campaign for metabolic and cardiovascular risk factors. Recruitment mechanisms include word-of-mouth, fliers, and newspaper advertisements. Subjects were excluded if they had chronic gastrointestinal diseases associated with malabsorption, chronic pancreatitis, history of any malignant disease, history of alcohol or drug abuse, liver or kidney failure, and treatments able to modify glucose metabolism. Secondary forms of hypertension were excluded by systematic testing by a standard clinical protocol, including renal U.S. studies, computed tomography, renal scan, catecholamine, plasma renin activity, and aldosterone measurements.

We measured height, weight, and waist circumference with the subject standing. We calculated body mass index (BMI) as weight in kilograms divided by the square of height in meters. The institutional ethical Committee approved the study, and all participants gave written informed consent for all procedures.

Blood pressure (BP) measurements

Readings of clinic BP were obtained in the left arm of the supine patients, after 5-min quiet rest, with a mercury sphygmomanometer. A minimum of three BP readings was taken on three separate occasions at least 2 wk apart. Systolic and diastolic BP was recorded at the first appearance (phase I) and disappearance (phase V) of Korotkoff sounds. Baseline BP values were the average of last two of the three consecutive measurements obtained at intervals of 3 min. Patients with a clinic BP more than or equal to 140 mm Hg systolic and/or 90 mm Hg diastolic were defined as hypertensive (28).

Forearm blood flow (FBF) measurements

All studies were performed at 0900 h after overnight fasting, with the subjects lying supine in a quiet air-conditioned room (22–24 C). Subjects were instructed to continue their regular diet, but caffeine, alcohol, and smoking were stopped at least 24 h before the study. Forearm volume was determined by water displacement. Under local anesthesia and sterile conditions, a 20-gauge polyethylene catheter (Vasculon 2; BD, Franklin Lakes, NJ) was inserted into the brachial artery of the nondominant arm for evaluation of BP (Baxter Healthcare Corp., Deerfield, IL) and for drug’s infusion. This arm was elevated above the level of the right atrium, and a mercury-filled Silastic strain-gauge (Dow Corning, Corp., Midland, MI) was placed on the widest part of the forearm. The strain-gauge was connected to a plethysmograph (model EC-4; D. E. Hokanson, Inc., Bellevue, WA) calibrated to measure the percent change in volume; this was connected to a chart recorder to obtain the FBF measurements. A cuff placed on the upper arm was inflated to 40 mm Hg with a rapid cuff inflator (model E-10; D. E. Hokanson) to exclude venous outflow from the extremity. A wrist cuff was inflated to BP values 1 min before each measurement to exclude the hand blood flow. The antecubital vein of the opposite arm was cannulated. The FBF was measured as the slope of the change in the forearm volume. The mean of at least three measurements was obtained at each time point. Forearm vascular resistance (VR), as expressed in units, was calculated by dividing mean BP by FBF.

Vascular function

The protocol, previously described by Panza et al. (15), and subsequently used by our group (16), was used for the present study. All patients underwent measurement of FBF and BP during intra-arterial infusion of saline, ACh (Sigma, Milan, Italy), and sodium nitroprusside (SNP) (Malesci, Florence, Italy) at increasing doses. ACh was diluted with saline immediately before infusion. SNP was diluted in 5% glucose solution immediately before each infusion and protected from light with aluminum foil. All participants rested 30 min after artery cannulation to reach a stable baseline before data collection; measurements of FBF and VR were repeated every 5 min until stable. Endothelium-dependent and endothelium-independent vasodilation was assessed by a dose-response curve to intra-arterial ACh infusions (7.5, 15, and 30 µg/ml–1·min–1, each for 5 min) and SNP infusions (0.8, 1.6, and 3.2 µg/ml–1·min–1, each for 5 min), respectively. The sequence of administration of ACh and SNP was randomized to avoid any bias related to the order of drug infusion. The drug infusion rate, adjusted for forearm volume of each subject, was 1 ml/min.

Analytical determinations

Plasma glucose was measured in duplicate by the glucose oxidation method (Beckman Glucose Analyzer II; Beckman Instruments, Milan, Italy). Total, LDL, and high-density lipoprotein (HDL) cholesterol and triglyceride concentrations were measured by enzymatic methods (Roche Diagnostics GmbH, Mannheim, Germany). Plasma insulin concentration was determined by a chemiluminescence-based assay (Roche Diagnostics). Plasma IGF-I concentrations were determined by chemiluminescent immunoassay (Nichols Institute Diagnostic, San Juan Capistrano, CA). Insulin sensitivity was estimated using the previously validated homeostasis model assessment (HOMA) index, calculated from the fasting glucose and insulin concentrations according to the formula: insulin (µU/ml) x glucose (mmol/liter)/22.5 (29). Creatinine measurements were performed within days of the initial baseline examination using Jaffe methodology and the uricase/peroxidase (Roche Molecular Biochemicals, Mannheim, Germany) method implemented in an autoanalyzer. Values of the estimated glomerular filtration rate (GFR) (ml/min/1.73 m2) were calculated using the modified Modification of Diet in Renal Disease equation involving creatinine concentrations as follows: 186.3 (serum creatinine)–1.154 (age)–0.203 0.742.

Statistical analysis

Continuous data are expressed as means ± SD (normally distributed data). Relationships between variables were determined by Pearson’s correlation coefficient (r). Relationships between variables were sought by stepwise multivariate linear regression analysis with forward selection to assess the magnitude of their individual effect on endothelial-dependent vasodilation. In the multivariate linear regression analysis, data are expressed as standardized regression coefficient (β) and P value. A P value less than 0.05 was considered statistically significant. All analyses were performed using SPSS software program version 12.0 for Windows (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All participants completed the protocol. Baseline clinical and biochemical characteristics of the study population are summarized in Table 1Go. Systolic and diastolic BP ranged from 120–180 and 64–120 mm Hg, respectively. Fasting insulin, HOMA, and IGF-I ranged from 5–28 µU/ml, 1.10–8.01, and 42–350 ng/ml, respectively.


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  		TABLE 1. Anthropometric and biochemical characteristics of the study population

 
Vascular function

Intra-arterial infusions of ACh caused a significant (P < 0.0001) dose-dependent increase in FBF and decrease in VR. The FBF increments from basal (2.9 ± 0.6/100 ml–1 tissue·min–1) at the three incremental doses of ACh were 2.7 ± 1.3 (+94%), 5.6 ± 3.2 (+193%), and 10.1 ± 5.5 (+352%) ml/100 ml–1 tissue·min–1. At the highest dose of ACh (30 µg/min), FBF increased to 13.1 ± 5.7 ml/100 ml–1 tissue·min–1, and VR decreased to 9.8 ± 3.9 U. Similarly, SNP infusions induced a significant increase in FBF (maximal increment from the basal, +306%; P < 0.0001) and a decrease in VR (maximal decrease from the basal, –77%; P < 0.0001). Intra-arterial infusion of vasoactive substances caused no changes in BP or heart rate values. For this analysis we used only the peak percent increase in ACh-stimulated FBF.

Correlational analysis

We detected an inverse and significant relationship between IGF-I and fasting insulin (r = –0.335; P < 0.0001). In addition, plasma IGF-I levels were significantly correlated with age (r = –0.300; P = 0.001), HDL serum cholesterol (r = 0.211; P = 0.017), HOMA (r = –0.355; P < 0.0001), systolic BP (r = –0.174; P = 0.042), GFR (r = 0.228; P = 0.011), and ACh-stimulated FBF (Fig. 1Go); the last relationship remained statistically significant also after adjusting for age, gender, and BMI (r = 0.522; P < 0.0001). There was no relationship between IGF-I levels and SNP-stimulated vasodilation (r = –0.040; P = 0.345). As reported in Table 2Go, ACh-stimulated FBF responses were significantly correlated with HDL serum cholesterol, GFR, and HOMA. To estimate the independent contribution of plasma IGF-I levels to ACh-stimulated FBF responses, we performed a stepwise forward multivariate regression analysis by a model, including age, gender, BMI, waist circumference, smoking status, systolic and diastolic BP, GFR, LDL and HDL serum cholesterol, triglyceride, plasma glucose, and insulin resistance measured by HOMA. The strongest predictor of ACh-stimulated FBF response was plasma IGF-I levels, accounting for 31.9% of its variation; the addition of HOMA explains another 3% of FBF variation (Table 3Go).


Figure 1
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  		FIG. 1. Correlation between IGF-I levels and the peak increase in ACh-stimulated FBF in the study subjects.

 

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  		TABLE 2. Univariate correlations between peak percent increase in ACh-stimulated FBF and clinical and biochemical variables

 

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  		TABLE 3. Independent predictors of endothelium-dependent vasodilation by stepwise forward multivariate regression analysis on peak increase of FBF

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study demonstrate, for the first time, that plasma levels of IGF-I are significantly associated with the endothelium-mediated vasodilation in a cohort of untreated, hypertensive Caucasian subjects. Because endothelial dysfunction is considered an early event in atherogenesis (14, 15), present data further support the important role of IGF-I in the development of cardiovascular disease and the need to detect precociously this condition. In fact, an efficacious preventive strategy aimed at improving both insulin sensitivity and endothelial function through lifestyle changes and/or the use of appropriate drugs (molecules interfering with renin-angiotensin system, statins, insulin sensitizing substances) should be always performed to delay the progression of vascular damage. Interestingly, a polymorphism in the promoter region of the IGF-I gene is associated with low-circulating levels of IGF-I and increased carotid IMT (30), confirming its crucial role in the pathogenesis of vascular damage. Our results are also consistent with those observed in liver-specific IGF-I knockout mice, which showed impaired endothelium-dependent vascular response to ACh (22). Endothelial dysfunction is known to be associated with all traditional and emerging risk factors for atherosclerosis, which may cause vascular damage by reducing NO bioavailability. It is important to note that, in this study, plasma IGF-I levels are associated with endothelial function independently of classical cardiovascular risk factors, outlining the possibility of an alternative pathogenetic mechanism of the atherosclerotic process. In addition, the design of our study included only never-treated hypertensive subjects without the confounding effects of medical therapy, known to modulate endothelial function such as aspirin, statins, β-blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors.

IGF-I significantly interacts with and acts on endothelial physiology. Both human dermal microvascular endothelial cells and human aortic endothelial cells express more IGF-I receptors than insulin receptors (19). In endothelial cells, IGF-I stimulates NO production, contributing to the regulation of vascular tone and other antiatherosclerotic properties (20, 21). The effects of IGF-I on NO production are also mediated via regulation of endothelial NO synthase expression (31). Interestingly, it has been reported that atherosclerotic plaques express low-tissue IGF-I levels and reduced IGF-I receptors (32, 33, 34), and this may be consistent with the increased apoptotic rates of vascular cells from atherosclerotic plaques that contribute to its instability. This evidence has some clinical relevance because IGF-I and insulin are inversely related, as demonstrated also by us (24). Because insulin resistance status is frequent in hypertensive patients (35), it is evident that plasma insulin interferes with circulating IGF-I levels, underlining the role of metabolic alterations in the appearance and progression of the atherosclerotic cardiovascular diseases also in subjects with high BP.

Study limitations

The present study has some potential limitations. Metabolic and cardiovascular risk factors, including plasma IGF-I concentration, were measured once; therefore, intraindividual variation in the levels of these variables cannot be considered. In addition, the present findings are only based on Caucasian individuals, and different results might be observed in other ethnic groups. In fact, the genetic background could have an important role to determine the specific phenotype. Moreover, IGF-I binding protein 3 and free IGF-I levels were not measured, and this should be considered another limitation of the study. Finally, because IGF-I production is regulated by GH secretion, we cannot exclude that the impaired endothelium-dependent vasodilatation, observed in subjects with low IGF-I, is caused by increased levels of GH attributable to the loss of IGF-I-dependent feedback inhibition.


   Footnotes
 
Disclosure Statement: The authors have nothing to declare.

First Published Online April 22, 2008

Abbreviations: ACh, Acetylcholine; BMI, body mass index; BP, blood pressure; FBF, forearm blood flow; GFR, glomerular filtration rate; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IMT, intima media thickness; LDL, low-density lipoprotein; NO, nitric oxide; SNP, sodium nitroprusside; VR, vascular resistance.

Received March 20, 2008.

Accepted April 11, 2008.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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