ARTHEROSCLEROSIS
Plasma leptin and prognosis in patients with established coronary atherosclerosis
Robert Wolk, MD, PhD*, ,
Peter Berger, MD, FACC*,
Ryan J. Lennon, MS ,
Emmanouil S. Brilakis, MD*,
Bruce D. Johnson, PhD* and
Virend K. Somers, MD, PhD, FACC*,,*
* Cardiovascular Diseases
Hypertension
Biostatistics, Mayo Clinic, Rochester, MinnesotaUSA
Manuscript received June 7, 2004;
accepted July 28, 2004.
* Reprint requests and correspondence: Dr. Virend K. Somers, Mayo Clinic, Saint Mary’s Hospital, 1216 Second Street SW, Rochester, Minnesota 55902
(Email: somers.virend{at}mayo.edu).
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Abstract
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OBJECTIVES: This study was designed to evaluate the relationship between plasma leptin and prognosis in patients with angiographically confirmed coronary atherosclerosis.
BACKGROUND: Experimental studies suggest that leptin, an adipose tissue-derived hormone, exerts important cardiovascular effects.
METHODS: Study subjects were recruited prospectively from a cohort of patients undergoing clinically indicated coronary angiography (n = 382). The median duration of follow-up was four years. Follow-up information was available for 361 patients.
RESULTS: The combined end point of cardiac death, myocardial infarction (MI), cerebrovascular accident, or re-vascularization occurred in 44 subjects. In the simple Cox model, leptin had a significant (p < 0.001) non-linear/cubic univariate relationship with the combined end point. Other variables associated with prognosis in the univariate analysis were body mass index (BMI), prior MI, insulin resistance, C-reactive protein (CRP), fibrinogen, and number of coronary vessels with >50% stenosis. A positive relationship between leptin and prognosis was also seen when leptin levels were split by quintiles, with a hazard ratio of 6.46 for the highest quintile. The only two variables significantly associated with the combined end point in the multivariate Cox model were leptin (p = 0.004) and number of coronary vessels with >50% stenosis (p < 0.001). A similar relationship between leptin and prognosis was observed when leptin was adjusted for BMI.
CONCLUSIONS: In patients with angiographically confirmed coronary atherosclerosis, leptin is a novel predictor of future cardiovascular events independent of other risk factors, including lipid status and CRP.
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Abbreviations and Acronyms
| | BMI = body mass index | | CABG = coronary artery bypass grafting | | CRP = C-reactive protein | | CVA = cerebrovascular accident | | HDL = high-density lipoprotein | | LDL = low-density lipoprotein | | MI = myocardial infarction | | PCI = percutaneous coronary intervention |
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The adipose tissue-related hormone leptin (1) has been increasingly implicated in increased cardiovascular risk. Although originally viewed as a mediator involved mainly in energy homeostasis, several cardiovascular actions of leptin (such as sympathetic activation, pressor effects, regulation of vascular function, insulin resistance, enhancement of platelet aggregation, and proangiogenic effects) (2–12) suggest that leptin may also play an important role in the development of cardiovascular disease. Consistent with this notion are the results of two nested case-referent studies indicating that leptin might be a risk factor for myocardial infarction (MI) and stroke (13,14).
In a large prospective study of leptin and cardiovascular risk, which utilized the West of Scotland Coronary Prevention Study (WOSCOPS)population, leptin was found to be a modest but independent predictor of coronary events during a five-year follow-up period (15). However, a smaller study on the Quebec Cardiovascular Study population found no association between leptin levels and coronary events (16). Both studies included only male subjects. Furthermore, relatively low-risk populations were investigated in both studies. In the Quebec study, only subjects free of ischemic heart disease were included. The WOSCOPS population consisted of moderately hypercholesterolemic men who had not had an MI and did not exhibit any other major manifestations of coronary artery disease. The pathophysiologic role and predictive value of leptin may be different in patients with established coronary atherosclerosis, with possible implications for secondary prevention and risk stratification.
We evaluated the prognostic value of plasma leptin levels in a large cohort of higher-risk patients with angiographically confirmed coronary atherosclerosis.
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Methods
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The study was approved by the Mayo Clinic Institutional Review Board. All subjects with clinical indications for angiography were recruited prospectively in a cardiac catheterization laboratory at the Mayo Clinic, Rochester, Minnesota, between June and December 1998. The most common indications for angiography included chest pain, an abnormal imaging study, or dyspnea on exertion. Exclusion criteria included diabetes, smoking history >50 pack-years, history of organ transplantation, prior coronary re-vascularization, bleeding disorders, blood transfusion within 30 days, human immunodeficiency virus infection, renal failure, prior chest radiation therapy, and pregnancy.
Blood samples were drawn at baseline after an overnight fast. Insulin resistance was calculated using the homeostasis model assessment (HOMA) (17). Leptin was measured by the Human Leptin double-antibody radioimmunoassay kit (Linco Research Inc., St. Louis, Missouri) and high-sensitivity C-reactive protein (CRP) was measured on the Hitachi 912chemistry analyzer (Roche Diagnostics Corp., Indianapolis, Indiana) by a polystyrene particle enhanced immunoturbidimetric assay from DiaSorin (Stillwater, Minnesota).
Of the original consecutively recruited 504 subjects, we included in this analysis patients with one or more coronary artery stenoses on angiography of >10% (n = 382). Of these subjects, 41% had an unstable coronary syndrome on admission and the remaining 59% had stable coronary artery disease. The angiograms were assessed by one or two observers (blind to leptin levels or other risk factors) by visual estimate or hand-held calipers. In addition to calculating the number of coronary vessels with >50% stenosis, the angiograms were also analyzed according to the segmental classification proposed in the Coronary Artery Surgery Study (CAGE coronary extent scores) (18). Although the CAGE scores correlated well with the number of coronary vessels with >50% stenosis (Pearson correlation coefficient = 0.81, p < 0.0001), we found that they did not improve the model's ability to predict events. The model using the number of diseased vessels actually appeared to be better (the global likelihood ratio test statistic for the model with the CAGE scores was 44.9 [14 df], whereas for the model with number of diseased vessels it was 56.9 [14 df]). Therefore the CAGE scores were not used in the final analysis.
All 382 subjects were followed up for the presence of any of the following events: cardiac death, new MI, cerebrovascular accident (CVA), and revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]). Readmission for restenosis followed by re-vascularization was considered an end point. Within the first month after the index angiography, 107 patients were re-vascularized by CABG and 99 were re-vascularized by PCI. These procedures were not "new events" and did not count as adverse events occurring during follow-up because they were dictated by the results of the index angiography.
Statistical analysis.
Continuous variables with little to mild skewness were summarized as mean values ± SD and continuous variables with skewed distributions were summarized as median values (first, third quartile). Discrete variables are summarized as frequencies and percentages. The association between leptin and continuous variables was assessed using Spearman's correlation coefficient; for discrete variables a rank-sum test was employed.
Hazard ratios were calculated using simple (univariate) and multiple (multivariate) Cox models. The combined end point of cardiac death, MI, CVA, or re-vascularization was used. If a subject had several different events, only the first event and the time to this first event were considered in the analysis. Noncardiac mortality was treated as a right-censored event time (n = 8). The following variables were selected for covariance adjustment, based on clinical significance: age, gender, smoking status, prior MI, unstable angina or acute MI on admission, mean blood pressure, CRP, low-density lipoprotein (LDL) to high-density lipoprotein (HDL) ratio, insulin resistance, fibrinogen, and number of coronary vessels with significant stenoses ( 50% reduction in luminal diameter). Because of skewness, log transformations of CRP, leptin, leptin to body mass index (BMI) ratio, insulin resistance, and LDL/HDL ratio were used. A cubic polynomial function of leptin was used due to the evidence of a nonlinear/cubic relationship between leptin and follow-up events. A likelihood ratio test with three degrees of freedom was used to test the hypothesis of no overall leptin association with events.
Missing values for leptin (n = 2), CRP (n = 2), insulin (n = 1), glucose (n = 1), and the LDL/HDL ratio (n = 10) were replaced with sample medians.
All continuous variables were standardized to have zero mean and an SD of 1 in the models so that the presented hazard ratio is for a 1-SD change in the variable. Skewed variables were standardized after the logarithmic transformation. The quadratic and cubic leptin terms represent squared and cubed values of the standardized log-leptin variable. All hypothesis tests were two-tailed with a 0.05 type I error rate. SAS version 8.2 (Cary, North Carolina) software was used for data analysis. PROC PHREG was used to analyze long-term survival, PROC CORR was used to estimate correlations, and PROC NPAR1WAY was used to calculate rank sum tests. PROC STDIZE was used to standardize continuous variables.
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Results
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Of the original 382 subjects, follow-up information was available in 361 patients (95%). Baseline demographic and clinical characteristics of this cohort are shown in Table 1.
Leptin values were skewed to the right with a median of 9.2 ng/ml and a range of 0.7 to 90.6 ng/ml. Leptin was positively correlated with female gender (p < 0.001); BMI (p < 0.001); HDL cholesterol; HDL/LDL ratio and triglycerides (p = 0.002, p = 0.004, and p < 0.001, respectively); glucose, insulin, and insulin resistance (p = 0.002, p < 0.001, and p < 0.001, respectively); CRP (p < 0.001); fibrinogen (p = 0.001); hypertension (p < 0.001); mean blood pressure (p = 0.003); and systolic blood pressure (p < 0.001). There was no difference in baseline plasma levels of leptin between the patients originally admitted with an unstable coronary syndrome and those with stable coronary artery disease (median [Q1, Q3]: 8.3 [5.3, 17.1] ng/ml vs. 9.9 [5.6, 19.1] ng/ml, respectively; p = 0.53).
The patients were followed up for a median of four years (the 25th and 75th percentiles were 3.9 and 4.2 years, respectively). During the follow-up, the combined end point of cardiac death, MI, CVA, or re-vascularization was seen in a total of 44 subjects (5 cardiac deaths, 12 MIs, 12 PCIs, 9 CABGs, 6 CVAs). The adverse follow-up events were evenly distributed between patients originally admitted with an unstable coronary syndrome (20 events) and those with stable coronary artery disease (24 events).
In the simple Cox model, leptin had a significant (p < 0.001) nonlinear/cubic univariate relationship with the combined end point (Fig. 1, Table 2). Other variables associated with prognosis in the univariate analysis were BMI, prior MI, insulin resistance, CRP, fibrinogen, and number of coronary vessels with >50% stenosis (Table 2). When leptin was analyzed as a categorical variable split by quintiles, a similar positive relationship was seen between leptin and worse prognosis, with a hazard ratio of 6.46 (95% confidence intervals 1.45 to 28.7) for the highest quintile of leptin (Fig. 2). Figure 3 shows the Kaplan-Meier estimated survival curves for the leptin quintile groups.
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Figure 1 The cubic relationship between leptin levels and hazard ratios for the combined end point. The leptin value of 4 ng/ml was taken as reference. Leptin is plotted on a logarithmic scale.
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Figure 2 Association between leptin (determined by the sample quintiles) and hazard ratios for the combined end point. The bars indicate 95% confidence intervals. The reference level is the first quintile.
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Figure 3 Kaplan-Meier survival free of cardiac death, myocardial infarction, cerebrovascular accident, and revascularization for the leptin quintile groups. Note the truncated ordinate axis.
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The only two variables significantly associated with the combined end point in the multiple Cox model were leptin (p = 0.004) and number of coronary vessels with >50% stenosis (p < 0.001) (Table 3). The relationship between leptin levels and hazard ratios in Cox regression analyses is shown in Figure 1.
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Table 3. Multivariate Hazard Ratios for the Combined End Point Using Uncorrected (Absolute) Leptin Values or Leptin Values Corrected for BMI (i.e., Leptin/BMI ratio)
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When leptin was corrected for BMI and expressed as leptin/BMI ratio, a similar cubic relationship was observed between BMI-corrected leptin and the combined end point, both in univariate (p < 0.001) and multivariate (p = 0.003) analyses (Tables 2 and 3).
In a separate model we also considered only the "hard" end points (cardiac death, MI, and CVA). Also in this case, we found significant multivariate associations between cardiovascular events and leptin (p = 0.026) as well as leptin/BMI ratio (p = 0.007). These hard end points were also significantly linked to number of coronary vessels with >50% stenosis (multivariate analysis: p = 0.053 with uncorrected leptin in the model, and p = 0.032 with leptin/BMI ratio in the model).
Because 41 out of 44 follow-up events occurred in patients with >50% coronary artery stenosis (262 subjects), we also performed a subanalysis in this subgroup. Similar to the results in the entire study group, the only two independent multivariate predictors of prognosis in this subgroup were leptin (p = 0.01) and the number of diseased vessels (p < 0.001).
In contrast to its effects on cardiovascular events, leptin was not a significant predictor of all-cause mortality.
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Discussion
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The novel finding of this prospective study was that plasma leptin level is an independent predictor of cardiovascular events among patients with coronary atherosclerosis confirmed by angiography. Using a multivariate Cox model, the only variables positively correlated with the combined end point were leptin (both uncorrected and corrected for BMI) and number of coronary vessels with significant stenoses.
The pathophysiologic mechanisms underlying the predictive value of leptin cannot be directly inferred from the present study and are probably multifactorial (2–12). However, in the present study the adverse prognostic effects of leptin were independent of inflammation (CRP), insulin resistance, dyslipidemia, fibrinogen, and blood pressure, as well as the angiographic severity of coronary artery disease. The negative prognostic association of hyperleptinemia is thus likely due to other factors such as increased sympathetic activity, enhanced platelet aggregation, increased oxidative stress, or paraoxonase-reducing effects (2,3,10,19,20). Possible explanations may also relate to the association of leptin with left ventricular hypertrophy (21–23), although the actual nature of this association requires further studies (24,25).
The balance between the potentially detrimental (2,3,8,9–12,22,23) and beneficial (4–7,26) actions of leptin may help explain our observation of a nonlinear relationship between leptin and prognosis (Fig. 1). We speculate that cardiovascular risk increases between the lowest leptin levels and the "plateau phase" owing to the detrimental effects of leptin. The risk then plateaus, perhaps because of the influence of some beneficial effects of leptin. With even greater levels of leptin, the risk increases further. Part of this imbalance may be related to the phenomenon of selective leptin resistance (27). Although this seems to be a plausible explanation, further studies are needed to clarify this question. It is important, however, that even in the plateau phase the risk is still greater than that for patients with the lower leptin values.
The finding of leptin as a prognostic factor in patients with coronary atherosclerosis may conceivably have important implications for novel cardiovascular therapies. Specifically, identification of those mechanisms underlying the deleterious effects of leptin on the cardiovascular system may provide a basis for new therapeutic and preventive interventions. In support of this proposition is the observation that a fish-rich diet (which has well-established beneficial cardiovascular effects) is associated with lower plasma leptin levels (28).
Study limitations.
Some limitations of the present study should be acknowledged. First, our patient sample consisted of subjects referred for coronary angiography with evidence of some coronary artery disease. We further excluded patients with other coexisting conditions associated with increased cardiovascular risk in their own right (including diabetes, significant smoking history, prior revascularization, prior radiation to the chest, and renal failure). These strict exclusion criteria decrease the complexity of the pathophysiologic processes involved and are therefore important to understand better any mechanistic interpretation of our data. Nevertheless, extrapolation of any conclusions from this study to other populations may be incorrect and future studies in other clinical cohorts are warranted. Second, this is an observational follow-up study, so no inferences can be made as to whether the modulation of leptin levels could affect cardiovascular risk. Finally, follow-up was unavailable in 5% of subjects, and it is possible that some events were not captured.
Conclusions.
In patients with established and angiographically confirmed coronary atherosclerosis, plasma leptin level is a novel predictor of future cardiovascular events. This association is independent of other traditional metabolic and cardiovascular risk factors, including lipid status and CRP. These findings may have important implications both for clinical risk stratification and for understanding the pathophysiologic mechanisms underlying cardiovascular morbidity and mortality.
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Footnotes
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This study was supported by Mayo Foundation grants HL-61560, HL-65176, HL-70302, and MO1-RR00585.
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R. Wolk and V. K. Somers
Leptin and vascular function: friend or foe?
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Adiponectin and Coronary Heart Disease: A Prospective Study and Meta-Analysis
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J M Gonzalez-Clemente, G Gimenez-Perez, C Richart, M Broch, A Caixas, A Megia, O Gimenez-Palop, I Simon, D Mauricio, and J Vendrell
The tumour necrosis factor (TNF)-{alpha} system is activated in accordance with pulse pressure in normotensive subjects with type 1 diabetes mellitus
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P. F. Bodary, S. Gu, Y. Shen, A. H. Hasty, J. M. Buckler, and D. T. Eitzman
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Arterioscler Thromb Vasc Biol,
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A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y.W. Lew, J. Narula, D. Sahn, et al.
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Abstract
Methods