Published online before print August 5, 2002, doi: 10.1161/01.CIR.0000027563.44593.CC
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(Circulation. 2002;106:939.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Low Serum Insulin-Like Growth Factor I Is Associated With Increased Risk of Ischemic Heart Disease
A Population-Based Case-Control Study
From the Department of Growth and Reproduction, Rigshospitalet (A.J., J.G.); Department of Biostatistics, Panum Institute (T.S.); and Centre for Preventive Medicine, Medical Department M, and Glostrup County Hospital (M.D., T.J.), University of Copenhagen, Denmark.
Correspondence to Anders Juul, MD, PhD, Department of Growth and Reproduction, Rigshospitalet section 5064, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail ajuul{at}dadlnet.dk
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Abstract |
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Background— Insulin-like growth factor I (IGF-I) has been suggested to be involved in the pathogenesis of atherosclerosis. We hypothesize that low IGF-I and high IGFBP-3 levels might be associated with increased risk of ischemic heart disease (IHD).
Methods and Results— We conducted a nested case-control study within a large prospective study on cardiovascular epidemiology (DAN-MONICA). We measured IGF-I and IGFBP-3 in serum from 231 individuals who had a diagnosis of IHD 7.63 years after blood sampling and among 374 control subjects matched for age, sex, and calendar time. At baseline when all individuals were free of disease, subjects in the low IGF-I quartile had significantly higher risk of IHD during the 15-year follow-up period, with a relative risk (RR) of 1.94 (95% CI, 1.03 to 3.66) of IHD compared with the high IGF-I quartile group, when IGFBP-3, body mass index, smoking, menopause, diabetes, and use of antihypertensives were controlled for. Conversely, individuals in the high IGFBP-3 quartile group had an adjusted RR of 2.16 (95% CI, 1.18 to 3.95) of having IHD. Identification of a high-risk population with low IGF-I and high IGFBP-3 levels resulted in markedly higher risk of IHD (RR 4.07; 95% CI, 1.48 to 11.22) compared with the index group.
Conclusions— Individuals without IHD but with low circulating IGF-I levels and high IGFBP-3 levels have significantly increased risk of developing IHD during a 15-year follow-up period. Our findings suggest that IGF-I may be involved in the pathogenesis of IHD.
Key Words: atherosclerosis • epidemiology • myocardial infarction • growth substances
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Introduction |
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Insulin-like growth factor I (IGF-I), which is a mitogenic peptide that circulates in plasma, has endocrine effects in numerous target tissues. Most plasma IGF-I originates from the liver. IGF-I production is stimulated by growth hormone (GH) secretion, and IGF-I mediates many of the anabolic actions of GH. Because IGF-I is important for tissue repair and cell proliferation, it has been suggested that it may be
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involved in the pathogenesis of atherosclerosis,1 although this has not been previously documented. The biological activity of IGF-I is strongly influenced by specific IGF binding proteins (IGFBP-1 to -6), of which the major IGFBP-3 carries >80% of circulating IGF-I. The circulating pool of IGF-I, which is primarily complexed to the high-molecular-weight IGFBP-3, is inhibited from transendothelial transport. It is generally believed that IGF-I can leave the circulating reservoir only in its free (biologically active) form or bound to the small-molecular-weight IGFBP-1 and -2. Because of methodological difficulties in measuring the free fraction of IGF-I, the total concentration of IGF-I is determined after elimination of interfering IGFBPs in most studies. In serum stored frozen for many years, determination of free IGF-I is most likely not possible. Consequently, it is important to measure IGFBP-3 and take it into account when total IGF-I is determined and related to a biological outcome. IGF-I levels decrease with increasing age throughout adulthood.2 Furthermore, the molar ratio between IGF-I and IGFBP-3 decreases with increasing age in adults, resulting in decreasing levels of free, biologically active IGF-I.3 Because atherosclerosis is more prevalent with increasing age, theoretically, decreasing IGF-I levels could be involved in the development of atherosclerosis. Patients with low IGF-I due to GH deficiency are characterized by increased mortality attributable to cardiovascular disease,4,5 which supports the hypothesis of IGF-I being involved in the pathogenesis of ischemic heart disease (IHD).6–9 In most cross-sectional studies, serum IGF-I levels are low in patients with manifest coronary artery disease,6–8 although not in all studies.10–12 However, these studies are all cross-sectional and thus give no information on causality. Because IGF-I levels are generally low in patients in a catabolic state, no information as to whether or not IGF-I could be involved in the pathogenesis of IHD can be deducted. To our knowledge, no previous prospective studies on IGF-I and IGFBP-3 in relation to development of IHD exist. We therefore evaluated the role of serum IGF-I levels for the development of IHD in a large prospective nested case-control study of healthy subjects.
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Methods |
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Denmark has a homogenous population of
5 million inhabitants. All inhabitants are included in the Danish National Civil Registration system in which they are registered with a unique 10-digit number, enabling follow-up of an individual from birth throughout life. Linked to this system there is systematic registration of diseases (discharge diagnoses according to the WHO International Classification of Diseases [ICD]) in the Danish National Patient register, and causes of death are registered in The Danish Register of Causes of Death.
Participants
In 1982 to 1984, an age- and sex-stratified random sample of 4807 individuals aged 30, 40, 50, and 60 years was drawn from a background population of 320 000 people, which is considered representative of the Danish population. The subjects who were living in the southwestern part of Copenhagen County participated in a study on risk factors for cardiovascular diseases, DAN-MONICA I (which is part of the WHO MONICA project), and 3785 of these accepted to participate (79%). The participants filled in a questionnaire on lifestyle, social factors, and former and present heart diseases and symptoms. The participants were examined, and fasting blood samples were drawn from an antecubital vein. Serum was kept at -20°C until analysis. The study took place at the Center for Preventive Medicine (former Glostrup Population studies). The study population has previously been described in detail.13 Of the 3785 individuals, 57 were excluded because of previous IHD, leaving 3728 free of IHD for additional analysis.
In the Danish National Patient Register and The Danish National Register of Causes of Death, all individuals with IHD in the subsequent follow-up period (beginning in 1982 to 1984 and ending in 1998) were recorded (ICD8 410 to 414 and ICD10 DI20 to DI25), resulting in 231 cases with IHD (82 hereof had died from IHD) (Table 1). Of the 231 patients with IHD, 143 suffered a myocardial infarction (MI). Each IHD case was assigned 2 controls who were at risk at the time of IHD. Controls were matched for age, sex, and season of the year, resulting in a total of 693 individuals on whom analyses were based. Because 88 of these subjects were randomly selected twice, blood samples taken in 1982 to 1984 from 605 individuals (176 females) were analyzed for IGF-I and IGFBP-3 and compared between the groups. No serum was available in 9 individuals (hereof 3 cases).
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Measurements
Questions on smoking concerned current and previous habits (yes, occasionally, no/never) and the kinds and average daily quantities of tobacco consumed (1 cigarette converted to 1 g of tobacco, and 1 cigar converted to 5 g of tobacco) based on the mean tobacco content in cigarettes available in 1980. Smoking habits were stratified into the following 5 categories: (1) never smoker; (2) ex-smoker; (3) 1 to 15 g/day; (4) 16 to 25 g/day; and (5) >25 gram per day. Alcohol consumption was recorded as weekly consumption of wine, beer, and alcohol and transformed into drinks per week. Physical activity was recorded and stratified into the following: (1) mostly sedentary; (2) walking, bicycling, or otherwise active at least 4 hours per week; (3) jogging or demanding sports or doing heavy activity during leisure hours for at least 3 hours per week; and (4) long-distance running or competitive sports several times per week. Categories 3 and 4 were combined into one category (because there were only 6 individuals in category 4), leaving 3 categories for analysis. Subjective health was recorded in 4 groups. Social classes (1 through 5) were calculated with 1 as the highest class. Menopausal age was registered for the women. Body weight of the participants wearing only light indoor clothes and without shoes was measured to the nearest 0.1 kg with a calibrated lever balance, and height was measured to the nearest 0.5 cm on a wall-mounted stadiometer. Body mass index (BMI) was calculated as body weight in kilograms divided by the square of height in meters. Blood pressure was measured with a sphygmomanometer and determined as the mean of two measurements on the left arm of the subjects having rested 5 minutes in the supine position. Diastolic blood pressure was determined as Korotkoff fifth-phase level.
IGF-I was determined by radioimmunoassay.14 Briefly, serum was extracted by acid-ethanol and cryoprecipitated before analysis to remove interfering IGF binding proteins. Interassay and intra-assay coefficients of variation were <9% and <6%, respectively. Details regarding determination of IGF-I in our laboratory have been presented previously.2 IGFBP-3 was determined by a radioimmunoassay, as previously described.15 Reagents for the assay were obtained from Mediagnost GmbH. Sensitivity was 0.29 µg/L (defined as 3 SD from the mean of the zero standard). In our hands, interassay and intra-assay coefficients of variation were 10.7% and 2.4% (at bound to free ratios of 0.4 to 0.5), respectively. Details regarding determination of IGFBP-3 in our laboratory have been presented previously.16 Total cholesterol was measured in the CHOD-PAP enzymatic method (Monotest R Cholesterol, Boehringer Mannheim) and triglyceride by using the GPO-PAP enzymatic method (Peridochrom R Triglycerides, Boehringer Mannheim). HDL cholesterol was measured using the CHOD-PAP method after precipitating apolipoprotein B containing lipoproteins with a magnesium-phosphotungstic reagent.17
Statistical Analysis
The relation between plasma IGF-I and IGFBP-3 and IHD was analyzed on the basis of a nested in-cohort case-control study design. Each case and two controls that were matched for age, sex, and calendar time were analyzed using the Cox proportional hazard model. We controlled for menopause, BMI, smoking, alcohol intake, blood pressure, serum lipids, physical activity, social class, self-evaluated health, and family history of IHD. Some of these possible confounders were not significant and were left out in subsequent analyses. The continuous risk factors IGF-I and IGFBP-3 were grouped in quartiles. For IGF-I, the risk was calculated relative to the highest quartile group, whereas for IGFBP-3 the risk was calculated relative to in the lowest quartile group, because IGFBP-3 had an inverse risk profile compared with that of IGF-I. Trend test was based on model with linear effect of the risk factors. To compare the impact of different risk factors measured in different units, continuous risk factors were standardized by their standard deviation. Thus, regression coefficients reflect the relative risk (RR) for the change of 1 in the standardized risk factor. The proportional hazards models were investigated for interactions, appropriateness of linearity of effects, and time-varying effects. Continuous variables for different groups were compared by Wilcoxon tests and ordinal variables by 
2 tests.
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Results |
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Baseline characteristics of the cases and controls are shown in Table 2. The mean time (SD) between blood sampling and diagnosis of IHD was 7.63 (3.92) years, ranging from 0.10 to 15.16 years. Mean age at baseline was 53.6 years, ranging from 30.5 to 61.9 years. Of the 176 participating women, 123 were postmenopausal. Individuals who develop IHD had higher BMI, blood pressure, and cholesterol compared with controls. Furthermore, smoking and use of antihypertensives were more prevalent among cases versus controls (Table 2). IGF-I and IGFBP-3 were negatively associated with age (r=-0.318 and r=-0.166, both P<0.0001), and men had significantly higher IGF-I levels (202 [SD 52] ng/mL) compared with women (172 [52] ng/mL, P<0.0001). Body mass index, smoking, and alcohol intake were not associated with IGF-I and IGFBP-3 in adjusted ANOVAs. In addition, calendar time of year had no influence on IGF-I or IGFBP-3 levels. The influence of time between blood sampling and diagnosis on the risk estimates was analyzed by stratification of patients according to time between blood sampling and diagnosis (0 to 2 years, 2 to 4 years, 4 to 6 years, and 6 to 15 years). No interaction between these strata existed, and the risk estimates were of similar size except for individuals having IHD <2 years from blood sampling. Consequently, the 21 patients with IHD <2 years from blood sampling were excluded in the final analyses. At baseline, IGF-I levels were 199 (54) ng/mL in the controls and 194 (49) ng/mL in the cases (P=0.131). IGFBP-3 levels were 3546 (782) ng/mL in the controls and 3636 (836) ng/mL in the cases (P=0.737). To allow quartile analyses, IGF-I were stratified into the following quartiles: 48 to 161, 162 to 192, 193 to 226, and 227 to 462 ng/mL, and IGFBP-3 was stratified into the following quartiles: 1043 to 3041, 3042 to 3526, 3527 to 4034, and 4035 to 8568 ng/mL, respectively. Using this approach, low IGF-I was significantly associated with increased risk of IHD, the lower IGF-I quartile group having a RR of IHD of 2.17 (95% CI, 1.20 to 3.94) compared with the high IGF-I quartile group, when IGFBP-3 was controlled for. Conversely, individuals in the high IGFBP-3 quartile group had a RR of 2.00 (95% CI, 1.09 to 3.68) of having IHD, when IGF-I was controlled for. Thus, in our cohort, increasing risk of IHD was observed with each IGF-I quartile (after controlling for IGFBP-3) (Table 3). We then controlled for known risk factors like BMI, smoking, alcohol intake, physical activity, social class, previous diabetes, family history of IHD, self-evaluated health, and menopausal status, but this did not significantly alter the associations between IGF-I and IHD (Table 3). Although subjects were matched for sex, we carried out sex-specific analyses and found similarly sized risk estimates for men and women. None of these analyses gained statistical significance. Table 4 shows the univariate standardized parameter estimates of IGF-I and IGFBP-3 in comparison with the estimates of other well-known risk factors for IHD. The standardized parameter estimates indicate the change in RR of IHD with a change corresponding to 1 SD in the corresponding risk factor, hereby enabling direct comparison of risk factors regardless of units. It can be deducted from Table 4 that the parameter estimates of standardized IGF-I, (-0.28 [0.127]) (estimate [SE]) is of the same order of magnitude compared with a well-known risk factor for IHD like HDL cholesterol (-0.47 [0.10]), resulting in RR for IHD of 0.75 (95% CI, 0.59 to 0.97) for one IGF-I SD unit change and 0.63 (95% CI, 0.52 to 0.76) for one HDL cholesterol SD unit change, respectively. The Figure shows the adjusted RRs of IHD for the 4 IGF-I quartiles versus the 4 IGFBP-3 quartiles, giving 16 different risk groups whose risk were calculated using data from Table 3. No interaction between IGF-I and IGFBP-3 was found (P=0.68). It is clearly seen that the RR increases with decreasing IGF-I quartile at a given IGFBP-3 quartile and that the RR increases with increasing IGFBP-3 quartile at a given IGF-I quartile. Furthermore, it can be seen from the Figure that the high-risk individuals, ie, individuals in the low IGF-I quartile group and at the same time in the high IGFBP-3 quartile group, have a RR of IHD of 4.07 (95% CI, 1.48 to 11.22) after adjustment for confounders compared with the index group.
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Discussion |
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In this 15-year prospective study of 231 cases and 374 matched controls, all without IHD at entry of study, individuals with baseline IGF-I levels in the lowest quartile had a 2-fold increased risk of IHD compared with the reference group, when the major IGF-binding protein, IGFBP-3, was controlled for. To our knowledge, no previous prospective studies exist on the possible association between IGF-I and development of IHD.
Interestingly, we found opposite effects of IGF-I and IGFBP-3 on the risk of future development of IHD. This phenomenon makes sense and can be explained by the fact that IGFBP-3 inhibits the bioactivity of IGF-I by sequestering IGF-I into a circulating reservoir, hereby reducing the free fraction of IGF-I in the circulation. The relatively large study size and collection of blood samples before diagnosis when all individuals were free of disease are major strengths of this investigation.
We find it very exciting that the effects of IGF-I and IGFBP-3 on the risk of developing IHD are sizeable and of the same magnitude as well-known risk factors for IHD like cholesterol and blood pressure. Although several cross-sectional studies exist on the possible association between the IGF-IGFBP system and known cardiovascular risk factors in healthy subjects free of disease, some controversies exist.18–20 Caution has to be taken when interpreting the results, because these studies, in addition to their cross-sectional nature, were based on a smaller number of subjects. Patients with IHD have low IGF-I levels, as demonstrated in several cross-sectional studies in patients who already have manifest heart disease.7,8 Furthermore, IGF-I seems to influence the progression of atherosclerosis and cardiac function in these patients.21 Albeit low IGF-I levels were found in patients with IHD in most of these studies, they were all cross-sectional, which makes it impossible to draw any conclusions on causality. More likely, low IGF-I levels in patients with manifest IHD reflect the presence of the disease.
Importantly, the subjects of the present study were all free of disease at the time of blood sampling and followed prospectively until they were diagnosed as having IHD. Thus, we believe that IGF-I may influence the development of IHD rather than be a consequence of the disease. Theoretically, low IGF-I levels in individuals who develop IHD could be explained by coexisting obesity, low physical activity, and insulin resistance. Recently, reduced IGF-I levels were found in patients with effort angina pectoris and no evidence of cardial artery spasm on angiography (cardiac syndrome X).22 In these insulin-resistant patients, IGF-I correlated with baseline insulinemia, and the authors suggest that IGF-I may play a role for the impaired insulin sensitivity in syndrome X.22 Furthermore, IGFBP-1, which is regulated by insulin and decreases the free fraction of IGF-I, correlates negatively with several established cardiovascular risk factors and positively with insulin sensitivity in healthy subjects.12 Clearly, obesity, physical activity, and overt diabetes are well-known risk factors for IHD and were also found to be significantly associated with risk of IHD in our study. Importantly, inclusion of these variables in the statistical models did not change the independent association between IGF-I and risk of IHD. In adults with type 1 diabetes, IGF-I as well as IGFBP-3 were lower than in control subjects,23 whereas IGF-I levels were normal in subjects with type 2 diabetes.23,24 Thus, although insulin resistance was not determined in our study population, insulin resistance could theoretically influence IGF-I and IGFBP-3 and hereby affect cardiovascular risk.
Our data are interesting in light of studies showing that untreated patients with GH deficiency, who have low IGF-I levels, are characterized by premature mortality attributable to cardiovascular disease.4,5 Although no causal link between IGF-I and cardiovascular disease can be deducted from these studies, they lend support to our hypothesis of IGF-I being involved in the development of cardiovascular disease.
In theory, IGF-I could mediate the atherosclerotic process by affecting the hepatic cholesterol synthesis and regulation. Alternatively, IGF-I may influence endothelial function, because higher IGF-I levels were found in hypertensive patients7 in whom IGF-I was a positive determinant of left ventricular wall mass.25 Furthermore, IGF-I correlated positively with aortic distensibility in healthy subjects.26 Based on the present results, we suggest that IGF-I may indeed be involved in the pathogenesis of IHD, although the exact mechanism remain unknown.
In conclusion, our prospective study of healthy individuals showed that low circulating IGF-I levels and high IGFBP-3 levels are associated with increased risk of IHD during a 15-year follow-up period. The increased risk of IHD for individuals having low IGF-I levels was sizeable and comparable to other well-known risk factors, like cholesterol and blood pressure. Thus, we hypothesize that IGF-I may be involved in the pathogenesis of IHD.
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Acknowledgments |
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This study was supported by the National Research Council (grant No. 22-00-0174). We are grateful for the skilled technical assistance of Karen Grunnet, Kirsten Jorgensen, Ulla Højelse, and Ole Nielsen.
Received March 29, 2002; revision received June 5, 2002; accepted June 7, 2002.
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T. Thum, F. Fleissner, I. Klink, D. Tsikas, M. Jakob, J. Bauersachs, and D. O. Stichtenoth Growth Hormone Treatment Improves Markers of Systemic Nitric Oxide Bioavailability via Insulin-Like Growth Factor-I J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4172 - 4179. [Abstract] [Full Text] [PDF]
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H. Holmer, J. Svensson, L. Rylander, G. Johannsson, T. Rosen, B.-A. Bengtsson, M. Thoren, C. Hoybye, M. Degerblad, M. Bramnert, et al. Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus in Hypopituitary Patients on Hormone Replacement Including Growth Hormone J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3560 - 3567. [Abstract] [Full Text] [PDF]
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M. A. Marini, E. Succurro, S. Frontoni, M. L. Hribal, F. Andreozzi, R. Lauro, F. Perticone, and G. Sesti Metabolically Healthy but Obese Women Have an Intermediate Cardiovascular Risk Profile Between Healthy Nonobese Women and Obese Insulin-Resistant Women Diabetes Care, August 1, 2007; 30(8): 2145 - 2147. [Full Text] [PDF]
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R. C. Kaplan, A. P. McGinn, M. N. Pollak, L. H. Kuller, H. D. Strickler, T. E. Rohan, A. R. Cappola, X. Xue, and B. M. Psaty Association of Total Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1), and IGFBP-3 Levels with Incident Coronary Events and Ischemic Stroke J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1319 - 1325. [Abstract] [Full Text] [PDF]
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M. Yazdanpanah, F. A Sayed-Tabatabaei, J. A M J L Janssen, I. Rietveld, A. Hofman, T. Stijnen, H. A P Pols, S. W J Lamberts, J. C M Witteman, and C. M van Duijn IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes. Eur. J. Endocrinol., November 1, 2006; 155(5): 751 - 756. [Abstract] [Full Text] [PDF]
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O. I. Okereke, J. H. Kang, J. Ma, J. M. Gaziano, and F. Grodstein Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4306 - 4312. [Abstract] [Full Text] [PDF]
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G. S. Johansson and H. J. Arnqvist Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1124 - E1130. [Abstract] [Full Text] [PDF]
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M. H. Rasmussen, A. Juul, L. L. Kjems, and J. Hilsted Effects of short-term caloric restriction on circulating free IGF-I, acid-labile subunit, IGF-binding proteins (IGFBPs)-1-4, and IGFBPs-1-3 protease activity in obese subjects. Eur. J. Endocrinol., October 1, 2006; 155(4): 575 - 581. [Abstract] [Full Text] [PDF]
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M. Bondanelli, M. R. Ambrosio, A. Onofri, A. Bergonzoni, S. Lavezzi, M. C. Zatelli, D. Valle, N. Basaglia, and E. C. degli Uberti Predictive Value of Circulating Insulin-Like Growth Factor I Levels in Ischemic Stroke Outcome J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3928 - 3934. [Abstract] [Full Text] [PDF]
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R. M. Martin, J. M. P. Holly, G. Davey Smith, and D. Gunnell Associations of Adiposity from Childhood into Adulthood with Insulin Resistance and the Insulin-Like Growth Factor System: 65-Year Follow-Up of the Boyd Orr Cohort J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3287 - 3295. [Abstract] [Full Text] [PDF]
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J. L. Menezes Oliveira, C. Marques-Santos, J. A. Barreto-Filho, R. Ximenes Filho, A. V. de Oliveira Britto, A. H. Oliveira Souza, C. M. Prado, C. R. Pereira Oliveira, R. M. C. Pereira, T. de Almeida Ribeiro Vicente, et al. Lack of Evidence of Premature Atherosclerosis in Untreated Severe Isolated Growth Hormone (GH) Deficiency due to a GH-Releasing Hormone Receptor Mutation J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2093 - 2099. [Abstract] [Full Text] [PDF]
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H. J. Schneider, B. Saller, J. Klotsche, W. Marz, W. Erwa, H.-U. Wittchen, and G. K. Stalla Opposite associations of age-dependent insulin-like growth factor-I standard deviation scores with nutritional state in normal weight and obese subjects. Eur. J. Endocrinol., May 1, 2006; 154(5): 699 - 706. [Abstract] [Full Text] [ |