European Heart Journal Advance Access originally published online on April 5, 2008
European Heart Journal 2008 29(10):1307-1315; doi:10.1093/eurheartj/ehn135
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Atherogenic dyslipidaemia but not total- and high-molecular weight adiponectin are associated with the prognostic outcome in patients with coronary heart disease
1 Department of Medicine I and Clinical Chemistry, Ruprecht-Karls-University of Heidelberg, Germany
2 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
Received 13 September 2007; revised 3 March 2008; accepted 10 March 2008; online publish-ahead-of-print 5 April 2008.
* Corresponding author. Department of Nephrology, Technical University Munich, Ismaningerstr. 22, 81675 Munich, Germany. Tel: +49 89 4140 6701, Fax: +49 4140 4878, Email: maximilian.eynatten{at}lrz.tum.de or meynatten{at}yahoo.de
See page 1221 for the editorial comment on this article (doi:10.1093/eurheartj/ehn185)
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Abstract |
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Aims: Adiponectin is closely related to atherogenic dyslipidaemia and may be a clinical important mediator of recurrent coronary heart disease (CHD). However, studies with emphasis on secondary disease prevention are rare. We report data from a prospective study investigating the prognostic value of adiponectin, its high-molecular weight (HMW) form, and of markers of lipid metabolism in patients after their first acute CHD event.
Methods and results: We measured baseline total- and HMW-adiponectin in 1051 patients aged 30–70 years with incident CHD and a prospective follow-up was conducted [median: 56.6 months (interquartile range: 53.2; 57.5)]. During this period, 95 patients (incidence: 22.3/1000 patient years) experienced a secondary cardiovascular disease (CVD) event. After adjustment by Cox proportional hazard models, neither total- nor HMW-adiponectin was associated with secondary CVD events. In contrast, LDL-cholesterol and markers of atherogenic dyslipidaemia were independently associated with secondary CVD events (relative risk per unit increase: LDL-cholesterol: 1.54; 95%CI 1.18–2.01; P = 0.001, triglycerides: 1.58; 95%CI 1.31–1.90; P < 0.0001 and HDL-cholesterol: 0.34; 95%CI 0.14–0.79; P = 0.01).
Conclusion: Measurement of total- and HMW-adiponectin may add no significant value to risk stratifications in patients with incident CHD. In contrast, approaching atherogenic dyslipidaemia may represent a promising target in secondary prevention programs for high-risk patients.
Key Words: Coronary heart disease • Epidemiology • Secondary disease prevention • Adiponectin • Dyslipoproteinaemia
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Introduction |
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Circulating adiponectin is particularly low in patients with prevalent coronary heart disease (CHD)1 and serum levels are related to the extent of coronary atherosclerosis.2 Since prospective epidemiological studies have suggested that decreased adiponectin levels may be associated with the risk of type 2 diabetes,3,4 adiponectin is suggested to be a major mechanistic link between diabetes and increased CHD risk. Adiponectin, a 30 kDa protein also known as ACRP30, GBP28, apM1, and AdipoQ, is the most abundant adipocytokine and has insulin sensitizing, anti-inflammatory, and anti-atherogenic effects (reviewed in ref.5). Adiponectin was emerging as an important mediator of future risk for primary CHD in apparently healthy men as well as in patients with type 2 diabetes enrolled in the Health Professionals Study.6,7 Subsequent investigations in a large population-based cohort with an 18-year follow-up8 and in additional populations with pre-existing disease (such as type 1 diabetes and end-stage renal disease)9,10 confirmed the significant relationship between adiponectin and CHD risk. However, recent studies have not reported significant associations between adiponectin levels and primary CHD risk, thus suggesting that the use of adiponectin for cardiovascular risk stratification is much more complex.11–13 So far, it has not been elucidated whether adiponectin is a useful prognostic predictor in patients in advanced stages of CHD.
Recently, increasing attention has been paid to the relationship between multimeric isoforms of adiponectin and metabolic variables. In the circulation, adiponectin exists at least in three multimeric isoforms, a low-molecular weight (LMW), a medium molecular weight (MMW), and the high molecular weight (HMW) form.14 These different oligomeric forms of adiponectin might activate different signalling pathways and exert distinct functions on its target tissues. HMW adiponectin may be the major active form of this protein.14 Thus, primarily HMW quantity rather than total adiponectin was associated with insulin sensitivity and was shown to be superior as predictor of the metabolic syndrome.15,16 Since patients with type 2 diabetes and CHD showed a significant and selective reduction of HMW adiponectin,17 it has been speculated that HMW adiponectin rather than total adiponectin may provide prognostic information beyond that obtained from established cardiovascular risk factors. However, large prospective studies investigating the role of HMW adiponectin in CHD prevention are not published so far.
We, therefore, studied the prognostic values of both total adiponectin and HMW adiponectin for the subsequent risk of secondary cardiovascular disease (CVD) events in a large cohort of patients with incident CHD. Since recent studies suggested that a significant proportion of the increased risk for CHD associated with low serum adiponectin may be attributable to associated changes in elevated plasma triglyceride and low HDL cholesterol levels referred to as atherogenic dyslipidaemia,18–20 we further compared the values of adiponectin and HMW for secondary risk stratification with the prognostic role of markers of atherogenic dyslipidaemia.
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Methods |
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Study population
Patients with incident CHD (International Classification of Diseases, 9th Rev. codes 410–414) aged 30–70 years and participating in an in-hospital rehabilitation program between January 1999 and May 2000 in two co-operating clinics (Schwabenland-Klinik, Isny and Klinik am Südpark, Bad Nauheim, Germany) were enrolled in the study (the total response during baseline recruitment was 58%, resulting in the total number of 1206 patients included at baseline).
Data collection and endpoint definition
In all patients, active follow-up was conducted 1, 3, and about 4.5 years after discharge from the rehabilitation centre and follow-up information was completed for 1051 patients (87.2%). Information was obtained from the patients using a mailed standardized questionnaire. Information regarding secondary cardiovascular events and treatment since discharge from the in-hospital rehabilitation clinic was obtained from the primary care physician also by means of a standardized questionnaire. If a patient had died during follow-up, the death certificate was obtained from the local Public Health Department and the main cause of death was coded according to the International Classification of Diseases (9th Revision). Secondary cardiovascular events were defined either as CVD as the main cause of death (as stated in the death certificate), non-fatal myocardial infarction (MI), or ischaemic cerebrovascular event (stroke). All non-fatal secondary events were reported by the primary care physicians (the last follow-up information was obtained 21 June 2005). The design and methods of the study have previously been reported.21,22 Information on left ventricular function was derived as previously described23 and was documented on a four-point semiquantitative scale as normal [ejection fraction (EF), >65%], as mild depression (EF, 50–65%), moderate depression (EF, 35–50%), or severe depression (EF, <35%). We censored patients with unknown follow-up status at the date of the last contact. From the variables of interest, we had missing values for total adiponectin (n = 1), HMW adiponectin (n = 1), HDL-cholesterol (n = 5), LDL-cholesterol (n = 13), and triglycerides (n = 1). We replaced missing values by the mean of the population sample.
The study complied with the Declaration of Helsinki and all subjects gave written informed consent. The study was approved by the Ethics Boards of the Universities of Ulm and Heidelberg and of the Physicians’ chamber of the States of Baden-Wuerttemberg and Hessen (Germany).
Laboratory methods
Blood was drawn at baseline at the end of rehab [mean time from the acute event was 43 days (first quartile 36 days, third quartile 51 days)] in a fasting state under standardized conditions and stored at –80°C until analysis. Serum total adiponectin and HMW adiponectin concentrations were measured by enzyme-linked immunosorbant assay ELISA (ALPCO, Salem, NH, USA). Recent studies have demonstrated the ELISA system as appropriate method for the quantification of adiponectin multimers in large cohorts.15–17 The intra- and inter-assay variations were 5.4%, 5.0%, and 5.0%, 5.7% for total adiponectin and HMW adiponectin, respectively. C-reactive protein was determined by a high-sensitivity assay (N Latex CRP mono, Dade Behring, Marburg, Germany). N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured by means of a one-step enzyme immunoassay based on electrochemiluminescence (Roche Diagnostics, Mannheim, Germany). Interleukin-6 (IL-6) was measured by a high-sensitivity assay (R&D Systems, Wiesbaden, Germany). Fasting plasma glucose (FPG) was measured by a glucose oxidase method. Triglyceride, total cholesterol, and HDL-cholesterol levels were quantified by standard laboratory methods (all markers measured before rehab discharge) and LDL-cholesterol levels were calculated by using the Friedewald formula. All markers were measured in a blinded fashion.
Statistical methods
The distribution (median) of total adiponectin, HMW adiponectin, HDL-cholesterol, LDL-cholesterol, and triglyceride levels according to sociodemographic characteristics and various cardiovascular risk factors were analysed by Kruskal–Wallis test. Partial Spearman correlation coefficients, adjusted for age and sex, were used to analyse the associations between total adiponectin and HMW adiponectin with cardiovascular risk factors. The relation of total adiponectin and HMW adiponectin, HDL-cholesterol, LDL-cholesterol, and triglyceride levels (categorized in quintiles) with CVD events during follow-up was assessed by the Kaplan–Meier method and tested for significance by means of the log-rank test. The Cox proportional hazards model was employed to assess the independent association of total adiponectin and HMW adiponectin (continuously per unit increase) with the risk of secondary CVD events. The proportional hazards assumption was assessed graphically and the assessment was based on the multivariable model.
Beside the model adjusted for age and sex, the following potential confounders were considered in multivariable analyses: body mass index, smoking status, history of diabetes, family status, severity of CVD, intake of ACE-inhibitors and lipid lowering drugs, initial management of CHD, and NT-proBNP (the latter was previously found to be associated with prognosis in this study23). To avoid over-adjustment, the latter covariates were added only if they were significant predictors of a secondary event at an 
-level of 0.1 or if their inclusion changed the parameter estimates for the main variables (adiponectin/HMW) by more than 10%. To compare their prognostic value with that of total adiponectin or HMW adiponectin, either HDL-, LDL-cholesterol, or triglyceride levels (continuously) were included instead of total adiponectin or HMW adiponectin in separate analyses in the fully adjusted model. Finally all parameters, total adiponectin, or HMW adiponectin (continuous), as well as HDL-cholesterol, LDL-cholesterol, and triglyceride levels (continuous) were included simultaneously.
Significance tests were two-tailed, and P-values <0.05 were considered as statistically significant. All statistical procedures were carried out with the SAS® statistical software package (release 8.2, Cary, NC, USA, SAS Institute Inc., 1999).
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Results |
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Baseline characteristics
The initial management of CHD in the 1051 included patients in the acute clinic was non-invasive for 191 patients (18.2%), included percutaneous coronary intervention (PCI) (including stents) for 361 patients (34.4%), and coronary artery bypass grafting (CABG) for 499 patients (47.5%). Table 1 shows main characteristics of the study population. The mean age was 59.0 ± 8.0 years, and 84.9% of the patients were male. During follow-up [median: 56.6 months (interquartile range: 53.2; 57.5)], 95 patients experienced a secondary CVD event (incidence: 22.3/1000 patient years); (30 patients died from CVD, 35 patients suffered from a non-fatal MI, and for 30 patients an ischaemic cerebrovascular event was reported).
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Table 2 shows the relationship between various sociodemographic- and cardiovascular risk factors with the median of total adiponectin and HMW adiponectin and markers of lipid metabolism. We found a significant lower median of the total adiponectin and HMW adiponectin distribution in male patients, in the age group 30–39, subjects with a BMI >30 kg/m2, and in those with current lipid lowering therapy. In addition, never smokers had a significantly increased median of total adiponectin and HMW adiponectin, whereas patients with current intake of ACE-inhibitors had higher total adiponectin levels only. HDL-cholesterol was lower in male patients, subjects with a BMI >30 kg/m2, and current smokers and was also associated with age. Triglyceride levels were significantly increased in male patients, were higher in the younger, subjects with a BMI >30 kg/m2, current smokers, and in patients with a history of diabetes, whereas LDL-cholesterol levels were lower in those with current lipid lowering therapy.
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Spearman partial correlation coefficients between cardiovascular risk factors and total adiponectin and HMW adiponectin are presented in Table 3. After adjustment for sex and age, both total adiponectin and HMW adiponectin were positively correlated with LDL-cholesterol, HDL-cholesterol, and NT-proBNP. Negative correlations were found for both with BMI, creatinine clearance, triglyceride levels and FPG. Markers of systemic inflammation, such as high-sensitive C-reactive protein and IL-6, were significantly associated with HMW adiponectin, but not with total adiponectin levels.
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Total adiponectin and high-molecular weight adiponectin and risk of secondary cardiovascular disease events
The incidence of an event was 20.1 in the top quintile of the total adiponectin distribution compared to 22.5, 24.6, 21.3, and 23.0 per 1000 patient years in the first, second, third, and fourth quintile of the adiponectin distribution (P = 0.98) (Figure 1A). Of the patients in the top quintile of the HMW adiponectin distribution, 18.7 experienced an event compared to 21.2, 24.0, 19.1, and 28.9 per 1000 patient years in the first, second, third, and fourth quintile (P = 0.63) (Figure 1B).
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HDL-cholesterol, LDL-cholesterol, and triglyceride levels and risk of secondary cardiovascular disease events
Of the patients in the top quintile of the HDL-cholesterol distribution, 15.9 experienced an event compared to 22.5, 31.9, 22.3, and 19.1 per 1000 patient years in the first, second, third, and fourth quintile (P = 0.27) (Figure 1C). The incidence of an event was 34.3 in the top quintile of the LDL-cholesterol distribution compared to 18.1, 15.7, 34.5, and 12.0 per 1000 patient years in the first, second, third and fourth quintile (P = 0.002) (Figure 1D). Of the patients in the top quintile of triglyceride distribution 39.4 experienced an event compared to 16.0, 18.6, 18.4, and 20.1 per 1000 patient years in the first, second, third, and fourth quintile (P = 0.01) (Figure 1E).
Multivariable Cox proportional regression analyses
Results of the multivariable analyses are shown in Table 4. For total adiponectin and HMW adiponectin, no statistically significant association with secondary CVD events was evident. LDL-cholesterol levels significantly correlated with the risk of secondary CVD in multivariate adjusted models: {middle column: hazard ratio [HR] per unit increase: 1.54 [95% confidence interval (CI) 1.18–2.01; P = 0.001]}. Furthermore, both HDL-cholesterol as well as triglyceride concentrations showed significant associations with the risk of secondary CVD events in the multivariable model adjusted for multiple covariates [HDL-cholesterol: middle column: HR per unit increase: 0.34 (95%CI 0.14–0.79; P = 0.01); triglycerides: middle column: HR per unit increase: 1.58 (95%CI 1.31–1.90; P < 0.0001). Further adjustment for the intake of lipid-lowering drugs did not substantially affect the results. We finally included all independent variables simultaneously in one model (Table 4, last column). The HR for secondary CVD event per unit increase remained statistically significant for LDL-cholesterol: 1.40 (95%CI 1.07–1.84, P = 0.012), and triglycerides: 1.50 (95%CI 1.22–1.84, P = 0.002) but not for HDL-cholesterol: 0.42 (95%CI 0.17–1.06, P = 0.06). In addition, the association of adiponectin levels with total mortality was assessed. In the bivariate analysis (Kaplan–Meier estimate), the P-value of the log-rank was 0.37 and there was no difference among the categorized groups (according to quintiles, data not shown). The HR for an increase per unit of total adiponectin was 0.99 (95%CI 0.87–1.13, P = 0.92) after adjustment for age and gender (HR = 0.99, 95%CI 0.86–1.13 in fully adjusted model) and also showed no association with general mortality (n = 54 fatalities).
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Discussion |
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This prospective study including 1051 patients with stable CHD at baseline showed that although high total adiponectin and HMW adiponectin levels were associated with a more favourable CHD risk profile, they were not significantly associated with future secondary CVD events. In contrast, LDL-cholesterol as well as plasma triglycerides and HDL-cholesterol levels were significantly associated with subsequent secondary CHD risk independent of other established cardiovascular risk factors. These observations suggest that use of either total adiponectin or HMW adiponectin may add no prognostic value to that gained by established cardiovascular risk factors for the occurrence of secondary CVD events. However, management of common lipid disorders beyond elevated LDL-cholesterol, such as increased triglycerides and low HDL-cholesterol levels, may emerge as additional treatment targets in high-risk patients for CHD.
Indeed the lack of an association between adiponectin and secondary CHD risk in this study is consistent with results observed in primary disease prevention settings in participants of the Strong Heart Study and both, females and males, in the British Regional Heart Study (BRHS).11–13 By contrast, two previous nested case–control studies reported a significant association between high adiponectin and lower risk of primary CHD in men,6,8 causing uncertainty about the association between circulating adiponectin and primary CHD risk. Adiponectin has anti-atherosclerotic properties that decrease vascular inflammation, foam-cell formation, and inflammatory cell adhesion to endothelial cells,5 which all play an important role in the very early atherogenic process. Hence, effects of adiponectin may be more of importance in these early phases of atherosclerosis, a pattern known from other inflammatory CHD risk factors such as C-reactive protein, which seems to be a better predictor in primary prevention.24 Therefore, the beneficial effects of adiponectin on CHD risk may not be readily reflected by its concentration in plasma among persons with manifest atherosclerosis and this may account, at least in part, for the missing association between adiponectin and secondary CHD risk in our study. This issue is further complicated by reports that the effects of adiponectin may depend on its quaternary structure in plasma.14 Our results suggest that HMW is not causally related to the progression of atherosclerosis in patients with advanced stages of the disease. However, additional studies are required to determine whether different multimeric isoforms vary in their effect on primary CHD risk in either women or men.
CVD still remains the leading cause of mortality in developed countries and control of the CVD epidemic requires a multifaceted strategy targeting modifiable risk factors for CHD. Although the link between low LDL-cholesterol and the prevention of CVD is well established, many patients remain at risk of CVD despite having LDL-cholesterol levels below recommended targets. Thus, increasing attention is being focused on other lipoprotein fractions, such as HDL and triglycerides, as potential targets of therapy. Elevated triglyceride levels combined with reduced HDL-cholesterol, referred to as atherogenic dyslipidaemia, are common lipoprotein abnormalities that affect up to 60% of high-risk patients and there is emerging evidence that combined abnormalities of the triglyceride-HDL axis are especially associated with adverse cardiovascular outcomes.18 We observed significant associations between plasma triglycerides and circulating HDL-cholesterol levels and secondary CVD events. After adjustment for adiponectin and HMW, however, HDL-cholesterol levels lost significance, whereas the statistical values of plasma triglycerides were only slightly attenuated. This finding further strengthens the hypothesis that the role of adiponectin in primary CHD may largely be explained by the association of adiponectin with HDL-cholesterol. Furthermore, previous data from the PROCAM and the Helsinki Heart studies suggested that hypertriglyceridaemia constitutes a predictor for CVD events that would escape attention if LDL-cholesterol levels alone were determined.25,26 Taken together, we believe that our findings may have important impact on planning secondary disease prevention programs and drug therapy targeted toward atherogenic dyslipidaemia may be considered in selected high-risk patients for CHD.
The following limitations of our study should be considered. We could successfully follow-up 87.2% of the patients, a fact that is important for the internal validity of this prospective study. Patients lost to follow-up were generally younger and had fewer CVD risk factors (i.e. lower BMI and lower C-reactive protein values). In addition, non-fatal secondary CVD events were reported by the primary care physician exclusively and were not further validated by additional enquiries. Although we had a large sample of patients with incident CHD, fatal CVD events were rare in this study population. This is explained by the fact that mortality of MI is highest during the pre- and early in-hospital phase. In the current study, only patients who were admitted within 3 months after their first acute event had been included. The mean interval from the acute event to recruitment was 43 days (first quartile 36 days, third quartile 51 days). Furthermore, not all patients are willing or able to participate in an in-hospital rehabilitation program. This may be a further reason for the slight underrepresentation of severely ill patients in our study sample, but more severely ill patients had been included too, almost half of patients had 3-vessel diseases. Underrepresentation of severely ill patients would though not explain the findings between adiponectin serum concentration, atherogenic dyslipidaemia, and CVD events.
In conclusion, total adiponectin and HMW adiponectin levels were not associated with secondary cardiovascular risk in patients with incident CHD and therefore will unlikely emerge as promising targets for secondary prevention measures. In contrast, plasma triglyceride, LDL-, and HDL-cholesterol levels were significantly related to secondary CHD risk independent of a broad range of covariates and traditional risk factors.
Conflict of interest: None declared.
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This work was supported by the German Federal Ministry of Education and Research (Grant 01GD9820/0) and by the Association of German Pension Fund Agencies (Grant 02 7 08).
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