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Original Studies |
Division of Cardiology, Department of Medicine, Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Veterans General Hospital, Taichung (W-L.L., C.-T.T.), and Taipei (J.-W.C., S.-J.L.), Taiwan; and the Departments of Medicine and Biological Chemistry, Division of Endocrinology, Diabetes, and Metabolism, University of California (P.H.W.), Irvine, California 92697
Address all correspondence and requests for reprints to: Ping H. Wang, M.D., Department of Medicine, Medical Science Building I, C240, University of California, Irvine, California 92697. E-mail: phwang{at}uci.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite ample experimental data indicating that IGF-I plays an important role in the regulation of myocardial structure and function, the clinical significance of IGF-I in human heart disease is not clear. This is in part because the changes in the IGF-I system, which includes IGF-I and its binding proteins (IGFBPs), in cardiovascular diseases largely remain unknown. To this end, we have determined the changes in circulating IGF-I and IGFBPs in human acute myocardial infarction and explored the clinical significance of IGF-I levels in AMI.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From July 1996 to June 1997, all patients admitted for AMI were screened with the following criteria: 1) typical chest pain, 2) Q-wave in 2 or more leads on 12-lead surface electrocardiogram, and 3) elevation of serum creatine kinase (CK) and CK MB fraction at least double the upper limit of the normal range. Patients with insulin-requiring diabetes, hypertension with systolic blood pressure over 180 mm Hg, previous myocardial infarction, previous congestive heart failure, thyroid diseases, liver diseases, or serious medical disease (i.e. cancer, sepsis, etc.) were excluded. In addition, patients with cardiogenic shock on admission were excluded. Patients with atrial fibrillation, complete left bundle branch block on electrocardiogram, or poor echocardiographic window that precluded adequate echocardiographic measurements were also excluded from this study.
Study protocol
All qualified patients were treated by regimens suggested by the American College of Cardiology/American Heart Association guidelines for management of AMI (20). On admission, patients were not treated with angiotensin-converting enzyme (ACE) inhibitor unless there was post-AMI angina or congestive heart failure refractory to non-ACE inhibitor therapy. Patients with post-AMI angina or congestive heart failure were treated with standard heart failure therapies that included ACE inhibitor and/or revascularization. Most patients received elective coronary arteriogram before hospital discharge in accordance with the current standard of practice. Coronary angioplasty was not performed during the study unless it was indicated by the American College of Cardiology/American Heart Association guidelines for coronary angioplasty in AMI (21).
All blood samples were collected on fasting from antecubital vein between 0800–0900 h. Blood was collected on the first (day 1, the morning after being admitted), second (day 2), third (day 3), and seventh (week-1) hospital days and again 3 weeks after the onset of AMI (week 3). Seventeen apparently healthy age- and sex-matched subjects (14 males and 3 females) were selected from patients admitted for routine health exam, and no significant medical problem was found. These healthy subjects served as controls for serum IGF-I, IGFBP-1, and IGFBP-3. Their mean age was 59 ± 2 yr (range, 49–72 yr). The protocol was approved by the institutional review board on human research and experiments. Informed consent was obtained from every patient enrolled in this study.
Laboratory assays
Total IGF-I was determined by a two-site immunoradiometric assay (IRMA) using commercially available kit from Diagnostic Systems Laboratories, Inc. (Webster, TX). Free IGF-I was determined by a direct assay method using the free IGF-I IRMA kit from Diagnostic Systems Laboratories, Inc., and both IGFBP-1 and IGFBP-3 were analyzed with IRMA kits from Diagnostic Systems Laboratories, Inc. Serum free T4, GH, and aldosterone were measured with RIA kits from INCSTAR Corp. (Stillwater, MN), Corning Nichols Institute Diagnostics (San Juan Capistrano, CA), and Diagnostic Systems Laboratories, Inc.
Echocardiographic measurements
Echocardiography was performed with Hewlett-Packard Co. SONOS 2000 or 2500 (Hewlett-Packard Co., Andover, MA) on day 1, week 1, and 1 month (month 1), and 2 months (month 2) after myocardial infarction. The LV anterior septum and posterior wall thickness, and chamber diameters were measured according to the standards of the American Society of Echocardiography (22, 23). The two-dimensional and Doppler echocardiographic measurements and on-line analyses were stored on S-VHS tapes and reviewed by the same cardiologist. The LV end-diastolic and end-systolic volumes (EDV and ESV, respectively) were calculated by modified Simpson’s method (24). Cardiac output was calculated as (EDV - ESV)/1000 x heart rate; the LV ejection fraction was determined as (EDV - ESV)/EDV x 100%. LV mass at end diastole was measured by the method described by Schiller NB et al. (23) and corrected with body surface area. All of these calculations were performed on-line using HP-SONOS 2000/2500 system software.
Statistical analysis
All data of continuous variables were expressed as the mean ± SEM. Student’s t test and ANOVA were used to compare between-group differences, and paired Student’s t test was used to compare within-group differences in means. The serial measurements of a factor were tested by the general linear model repeated measures with simple contrast (SPSS for Windows, release 7.5.2, SPSS, Inc., Chicago, IL), interacting with AMI site and revascularization therapy (primary PTCA or thrombolytic therapy). Correlation analysis was performed with the least squares method. Statistical significance was accepted at two-tailed P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 34 consecutive patients who met inclusion criteria were
enrolled in this study. There were 29 males and 5 females, with a mean
age of 62 ± 1 yr. The demographic data of all patients with AMI
are shown in Table 1
. Among them, 15
patients received thrombolytic therapy. Immediate coronary angioplasty
was performed in 6 patients, and successful revascularization was
achieved in all of them. Five patients presented with Killip functional
class III heart failure, and 7 patients presented with functional class
II heart failure.
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The mean levels of total IGF-I and IGFBP-3 in our control subjects
are similar to the mean normal IGF-I levels in this age group (25, 26).
Compared to the controls, patients with AMI showed a trend toward
higher total IGF-I levels, as shown in Fig. 1 (day 1, 280.8 ± 35.3
vs. 207.0 ± 29.5 ng/mL; P = 0.17), but
this did not reach statistical significance, possibly due to the
limited patient number. In contrast, serum free IGF-I levels were
significantly increased in patients with AMI (day 1, 1.10 ± 0.16
vs. 0.56 ± 0.28 ng/mL; P =
0.004). The levels of morning GH (1.3 ± 0.3 vs.
0.9 ± 0.4) did not differ between AMI and control patients.
IGFBP-1 levels were lower (day 1, 39.9 ± 8.5 vs.
69.5 ± 10.5 ng/mL; P = 0.035) and IGFBP-3 levels
were higher (1091 ± 169 vs. 2397 ± 144 ng/mL;
P = 0.02) in patients with AMI. Lower IGFBP-1 levels
might have contributed to higher free IGF-I levels in AMI patients.
These data for total and free IGF-I levels did not change significantly
when the patients were stratified according to sex, sites of
infarction, types of treatments, or peak CK levels.
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. Total IGF-I
levels slightly decreased on days 2 and 3, then bounced back to levels
higher than the control values. Free IGF-I levels decreased to control
levels by the end of the first week. IGFBP-1 levels also decreased
significantly by the end of first week, whereas IGFBP-3 generally
paralleled the changes in total IGF-I. These results show that the
IGF-I system was significantly altered after AMI.
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LV remodeling occurs immediately after AMI, and poor ventricular
remodeling is associated with poor clinical outcome (15, 16). In our
patients, anterior septum and posterior wall became thinner after AMI,
and LV end-systolic diameter was significantly increased during the
first month (Fig. 2). LV end-systolic
diameter was partially restored by the end of the second month. These
results are consistent with remodeling changes in the LV after AMI. The
relationship between the total IGF-I level and ventricular remodeling
is shown in Fig. 3; day 2 total IGF-I
levels correlated well with remodeling of LV on day 7. Moreover, day 2
total IGF-I levels were positively related to day 7 ejection fraction.
Similar relationships were found between day 3 and day 7 total IGF-I
level, and day 7 LV remodeling/ejection fraction (Table 3). When the patients were evenly divided
into three tertiles according to their IGF-I levels, we found that
higher total IGF-I levels on days 2 and 3 were associated with smaller
LV mass, less ventricular dilatation, and better ventricular function
on day 7 after AMI (Fig. 4). Age, sex,
peak CK, and use of revascularization did not differ among these three
groups. These results suggest that IGF-I could have been involved in
the regulation of myocardial remodeling and cardiac function in these
patients. No significant correlation was found between free IGF-I
levels and myocardial remodeling or ejection fraction.
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We wished to further explore the relationship between IGF-I levels
and the outcomes of AMI. To this end, we have compared IGF-I levels in
healthy survivors and patients with poor clinical outcomes. As shown in
Table 4, the mean total IGF-I level was significantly
lower in the patients who died (n = 2) or developed severe
congestive heart failure (functional classes III and IV; n = 4)
during 3 months of post-AMI follow-up. In those patients with poor
outcomes, a borderline reduction of IGFBP-3 was observed on day 2. Day
2 and day 3 levels of morning GH, supine aldosterone, and
T4 levels did not differ between healthy survivors and
patients with poor outcomes. Similar to a lack of correlation between
the free IGF-I level and myocardial remodeling, the levels of free
IGF-I did not differ between healthy survivors and patients with poor
outcomes. The day 2 total IGF-I levels in healthy survivors and
patients with poor outcomes are shown in Fig. 5. Total IGF-I levels were less than 137
ng/mL in all patients with poor outcomes; only 14% of healthy
survivors had total IGF-I levels less than 137 ng/mL (100% sensitivity
and 74% specificity). These results suggest that after the onset of
AMI, those patients with low total IGF-I level were at increased risk
of adverse outcomes.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, we have characterized the changes in IGF-I and IGFBPs during and after AMI and found that total IGF-I levels could be used to stratify postinfarction myocardial remodeling and function. These results support the current hypothesis that IGF-I protects the viability of uninfarcted myocardium. Whether total IGF-I represents an independent determinant of myocardial remodeling and function is not clear, because the size of our study does not allow us to perform valid multivariate analysis. However, the relationship between IGF-I and myocardial remodeling did not change when the patients were stratified according to age, sex, peak CK level, or mode of treatment. Our data also showed that total IGF-I levels were lower in those patients with poor clinical outcome (mortality or severe heart failure), thus raising the possibility that during the first few days of AMI, the total IGF-I level may be used to predict the patient’s prognosis.
The changes in free IGF-I were somewhat different from the changes in total IGF-I. Upon AMI, free IGF-I increased significantly and then decreased to control levels by the end of the first week. The initial rise in free IGF-I can be partly explained by a reduction of IGFBP-1, but the reduction in free IGF-I by the end of the first week cannot be explained by the changes in IGFBP-1. We were surprised by the finding that free IGF-I levels were not related to myocardial remodeling, and that free IGF-I did not differ between healthy survivors and patients with poor outcome. These results suggest that the effects of IGF-I on the heart are dependent on the total pool of circulating IGF-I rather than the concentration of free IGF-I. IGFBP-3 changes in the same direction as total IGF-I, consistent with the previous observation that IGFBP-3 generally reflects the level of total IGF-I (30). However, the reduction of IGFBP-3 in patients with poor outcome is not as significant as the total IGF-I. One possible explanation may be that the biologically active IGFBP-3 level was decreased, but degraded IGFBP-3 fragments were still present in the blood.
Postinfarction myocardial remodeling is associated with stretching and thinning of myocardium and increased wall stress. Higher total IGF-I levels at the beginning of AMI were accompanied by less ventricular dilatation, smaller LV mass, and better ventricular function. This suggests that IGF-I prevents undesirable remodeling of myocardium after AMI. In an animal model of experimental ischemia, exogenous IGF-I administration suppressed apoptosis of cardiomyocytes in viable myocardium (13). In another study that investigated the effects of ischemia in wild-type mice and transgenic mice overexpressing IGF-I in myocardium (12), infarction produced less cardiomyocyte apoptosis and less ventricular dilatation in transgenic mice. As apoptosis of cardiomyocytes in viable myocardium may contribute to the extension of infarction and remodeling of myocardium, the beneficial effects of IGF-I on ischemic heart may be mediated in part through its antiapoptotic effects.
Systemic circulatory levels of IGF-I are regulated by complex mechanisms that are not well understood. IGF-I levels can be increased by GH and nutritional intake (29). In addition, some data suggest that other hormones, such as T4 and PRL, can modulate the systemic serum level of IGF-I (31, 32). Moreover, there is evidence suggesting that IGF-I levels can be down-regulated by cytokines (33). As increased cytokine production has been observed upon the occurrence of myocardial infarction and reperfusion (34, 35), it is possible that cytokines may contribute to the transient reduction of total IGF-I levels 2–3 days after myocardial infarction. Alternatively, low IGF-I levels might have resulted from poor tissue perfusion in liver. As liver is a major site of IGF-I production (25), poor cardiac function could lead to inadequate liver perfusion and, in turn, reduce IGF-I production. The exact mechanisms underlying the changes in the IGF-I system during and after AMI will have to be elucidated by further study.
In summary, we have described significant changes in circulating total IGF-I, free IGF-I, IGFBP-1, and IGFBP-3 during and after AMI. The results also suggest that the levels of total IGF-I at the initial stages of AMI might be used to predict later remodeling of myocardium and myocardial function, and that a low circulating IGF-I level is associated with poor patient prognosis. Although the exact relationship between the total IGF-I level and patient outcome will have to be verified with a larger study, our findings suggest that lower total IGF-I levels upon AMI are associated with higher mortality and morbidity. Whether the relationship between low IGF-I and poor post-AMI survival represents a direct causal relationship should be further defined in future studies of human AMI.
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Footnotes |
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Received September 1, 1998.
Revised January 11, 1999.
Accepted January 30, 1999.
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References |
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of the insulin-like
growth factor I messenger ribonucleic acid response to growth hormone
in rat hepatocyte primary culture. Endocrinology. 138:1078–1084.This article has been cited by other articles:
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