Serum Insulin-like Growth Factor I and Risk for Heart Failure in Elderly Individuals without a Previous Myocardial Infarction: The Framingham Heart Study

Context Biological research and retrospective clinical studies show that insulin-like growth factor I (IGF-I) promotes salutary left ventricular modeling. Contribution This community-based study followed 717 elderly people without known myocardial infarction or heart failure for 5 to 9 years. Participants with higher levels of IGF-I developed heart failure less often than did those with lower levels. Implications High IGF-I levels are associated with decreased risks for heart failure. Cautions High IGF-I levels are also associated with increased risks for cancer. Future research should confirm these associations and explore mechanisms to increase IGF-I levels in people at risk for heart failure without increasing the risk for cancer. The Editors Considerable experimental and clinical evidence supports a key role of insulin-like growth factor I (IGF-I) in the pathogenesis of left ventricular remodeling and heart failure (1). In basic science studies, IGF-I promotes myocardial hypertrophy, increases cardiac contractility, and attenuates myocyte necrosis and apoptosis in models of ischemic, hemodynamic, and toxic cardiac injury (2-7). In clinical reports, patients with congestive heart failure have lower levels of serum IGF-I that correlate with the degree of left ventricular systolic dysfunction, presence of cachexia and skeletal muscle weakness, and indices of neurohormonal and cytokine activation (8, 9). Furthermore, administering IGF-I has been reported to improve left ventricular contractility indices in small clinical case series (10) and experimental models of heart failure (4). Epidemiologic investigations have shown an increasing incidence of congestive heart failure with age (11). Serum IGF-I levels have been reported to decrease with age in community-based investigations (12, 13). These parallel observations suggest that a decrease in serum IGF-I level with age may increase the incidence of heart failure in the elderly (14). However, no previous investigation has prospectively examined the relationship of serum IGF-I level to the incidence of heart failure. We hypothesized, on the basis of the body of scientific evidence noted, that a low serum IGF-I level may be associated with an increased risk for congestive heart failure. Accordingly, we examined the relationship of serum IGF-I levels to the risk for congestive heart failure in an elderly, community-based sample. Methods Study Sample The Framingham Heart Study began in 1948 as a prospective longitudinal epidemiologic investigation of 5209 women and men who are examined every 2 years (15). The 1167 participants who were alive at the time of the 22nd biennial examination cycle (between 1992 and 1994) were eligible for the present investigation. We excluded 450 participants (39%) for the following reasons: prevalent congestive heart failure (84 participants) or myocardial infarction (106 participants) and insufficient blood specimen for IGF-I analyses (260 participants). Participants with a myocardial infarction were excluded because low serum IGF-I level is a risk factor for myocardial infarction (16), which in turn is a powerful risk factor for heart failure (11). After the exclusions, 717 participants (mean age, 78.4 years; 479 women) were eligible. At the baseline examination, all participants underwent a medical history, routine physical examination (including anthropometry and blood pressure measurement), 12-lead electrocardiography, and laboratory assessment of cardiovascular disease risk factors. The institutional review board at Boston Medical Center approved the study, and all participants gave written informed consent. Measurement of Serum IGF-I At the baseline examination, 3 mL of serum from each participant was obtained in the early afternoon (with the participant in a supine position and a nonfasting state). Specimens were immediately transported by courier from Framingham, Massachusetts, to the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, and stored at 80 C. Serum on dry ice was then shipped to Endocrine Sciences, Inc. (Calabasas Hills, California). Serum IGF-I was measured by radioimmunoassay after acid ethanol extraction (17) in 3 batches; the intrassay coefficient of variation was less than 4%. Insulin-like growth factorbinding proteins were not measured. Outcome All participants were under continuous surveillance for the development of cardiovascular disease events, including congestive heart failure. Three experienced investigators reviewed all suspected congestive heart failure events by examining hospital records, information from physicians, and pathology reports by using previously described methods (18). Congestive heart failure was diagnosed on the basis of the previously detailed Framingham Heart Study criteria (19); these criteria, which require the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria to diagnose heart failure, have been validated previously (20). Major criteria included paroxysmal nocturnal dyspnea or orthopnea, jugular venous distention, pulmonary rales, radiographic cardiomegaly, acute pulmonary edema, third heart sound, central venous pressure greater than 16 cm H2O, hepatojugular reflux, and weight loss of at least 4.5 kg in 5 days in response to treatment of heart failure. Minor criteria included bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, and heart rate of 120 beats/min or greater. Minor criteria were acceptable only if they were not attributed to another medical condition (such as chronic lung disease, cirrhosis, ascites, or nephrotic syndrome). Statistical Methods We used multivariable Cox proportional-hazards regression models (21) to examine the association of serum IGF-I with the incidence of congestive heart failure. Since there was no effect modification by sex, all analyses were performed for pooled sexes, with sex as a covariate. The distribution of serum IGF-I was slightly skewed positively, and raw values were log-transformed to reduce excessive influence of high values at the upper end of the distribution. Other investigators have used a similar approach (12, 22). Serum IGF-I was treated both as a continuous variable (raw value and with natural logarithmic transformation) and as a categorical variable (values below versus at or above the median value of 140 g/L). Age- and sex-adjusted probabilities of developing congestive heart failure on follow-up were estimated for individuals with serum IGF-I values below versus at or above the median value of 140 g/L from Cox regression models incorporating age and sex as covariates. In multivariable analyses, we adjusted for the following covariates (defined at the baseline examination): age, sex, ratio of serum total cholesterol to high-density lipoprotein (HDL) cholesterol, diabetes mellitus, systolic and diastolic blood pressure, antihypertensive treatment, smoking status, body mass index, clinical valve disease, prevalent atrial fibrillation, electrocardiographic left ventricular hypertrophy, and prevalent cardiovascular disease other than myocardial infarction (individuals with myocardial infarction were excluded, as noted). All 717 participants had complete information on these covariates. Criteria for these covariates have been described previously (18). We examined the following statistical models in hierarchical fashion: multivariable models with all covariates defined at baseline, as detailed, ignoring the occurrence of myocardial infarction on follow-up (model A); models adjusting for covariates at baseline and the occurrence of a myocardial infarction on follow-up (model B) (the latter adjustment is important because low serum IGF-I levels can predispose to the development of congestive heart failure by promoting myocardial infarction [16]); and models in which participants who experienced a myocardial infarction on follow-up were censored at the time of myocardial infarction (model C). Hazard ratios and their 95% CIs were estimated for each SD increase in the log IGF-I and raw IGF-I, and for levels at or above 140 g/L versus below (separately for each statistical model). Additional Analyses In the statistical models adjusting for covariates defined at the baseline examination and occurrence of an interim myocardial infarction (model B), we performed analyses incorporating several interaction terms (serum IGF-I level covariate) to examine for any variation in the effect of serum IGF-I on congestive heart failure hazard (effect modification) according to age, sex, body mass index, presence or absence of diabetes, and total cholesterolHDL cholesterol ratio. High IGF-I levels in conditions such as acromegaly may be associated with cardiac systolic and diastolic dysfunction (23). We therefore evaluated for any nonlinearity (U shape) in the relationship of serum IGF-I level to risk for congestive heart failure. Furthermore, since serum interleukin-6 has been reported to lower IGF-I levels (24) and cytokines have been implicated in the pathogenesis of congestive heart failure (25), we performed supplementary analyses adjusting for serum interleukin-6 in a subgroup of 525 individuals who had both serum interleukin-6 (enzyme-linked immunosorbent assay, R&D Systems, Minneapolis, Minnesota) and IGF-I measurements available. We performed secondary analyses in which death was modeled as a competing outcome to congestive heart failure (26), given the high mortality rate in our elderly cohort. Although left ventricular systolic function was not assessed at the baseline examination, routine echocardiography was done at examination cycle 20, approximately 4 years from the baseline examination. Additional analyses were performed on a subgroup of individuals who attended examination cycle 20 and had normal left ventricular systolic function at that examination. A 2-sided P