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European Journal of Heart Failure 2006 8(4):355-360; doi:10.1016/j.ejheart.2005.10.007
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© 2006 European Society of Cardiology

Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure

Kwok Shiong Chong*, Roy S. Gardner, James J. Morton, Euan A. Ashley and Theresa A. McDonagh

Glasgow Royal Infirmary, Scottish Cardiopulmonary Transplant Unit 10 Alexandra Parade, G31 2ER Glasgow, Scotland, United Kingdom

* Corresponding author. Tel.: +44 141 420 3680; +44 141 211 4950. E-mail address: vchong{at}doctors.org.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Background: Apelin, the novel endogenous ligand for the G-protein-coupled receptor APJ, has shown positive inotropic, vasodilatory and diuretic properties in animal studies. Differential expression and synthesis of apelin and APJ receptors have been observed in normal and failing human hearts, suggesting a possible role in cardiovascular homeostasis. Changes in plasma apelin concentrations in relation to heart failure have been described in small studies with conflicting results. Our aim was to evaluate plasma apelin concentrations in a large cohort of patients with chronic heart failure (CHF) across a broad spectrum of disease severity.

Method and results: Plasma apelin concentrations were measured in 202 patients with CHF secondary to left ventricular systolic dysfunction and 22 age-matched controls. Plasma apelin concentrations were significantly lower in patients with CHF, irrespective of NYHA class, ejection fraction or aetiology when compared to age-matched controls (0.85 [0.53–2.04] versus 3.76 [0.85–5.13] ng/ml, p<0.001). Apelin concentrations were correlated with peak VO2 and right ventricular ejection fraction, but not with age, sex, body mass index, renal function or NT-proBNP concentrations.

Conclusions: Plasma apelin concentrations are decreased in patients with CHF. The Apelin-APJ signaling pathway may be a potentially important mediator in the pathophysiological processes of heart failure and may therefore have potential therapeutic implications.

Key Words: Apelin • Chronic heart failure

Received May 5, 2005; Revised May 22, 2005; Accepted October 10, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 
Although considerable advances have been made in our understanding of the pathogenesis and treatment of heart failure over the past two decades, morbidity and mortality remain high [1,2]. One potential explanation for this is that there are as yet, unknown biologically active molecules which exacerbate disease progression.

Apelin, the novel endogenous ligand for the G-protein-coupled receptor APJ, was first isolated from bovine stomach extracts by Tatemoto et al. in 1998 [3,4]. Apelin is secreted as a 77-amino acid pre-proprotein, which is then cleaved to active peptides of 12-, 13- and 36-amino acid moieties [5]. Both apelin and APJ mRNA are highly expressed in the cardiovascular system in both humans and rats and show significant similarities in amino acid sequence and tissue distribution with angiotensinogen and the angiotensin II receptor type 1 (AT1), respectively [6-12]. On the basis of these findings, several experimental studies have contributed to unravelling the physiological role of apelin in the cardiovascular system.

In contrast to angiotensin, a potent vasopressor and anti-diuretic hormone, apelin both lowers blood pressure (via a nitric oxide-dependent mechanism) [13-16] and produces diuresis by inhibition of arginine vasopressin activity and release [17]. Apelin, at least in animal studies, is the most potent endogenous inotrope yet identified on the basis that significant positive inotropic effects are noted even in the subnanomolar range [18].

Several groups have attempted to measure plasma apelin concentrations in patients with heart failure. These studies only involved small numbers of patients and have produced conflicting results. Chen et al. measured plasma concentrations of apelin in eighty heart failure patients with a broad spectrum of disease severity and noted a rise in plasma apelin concentrations compared to normal subjects [19]. A Finnish study of only 38 patients with CHF found decreased plasma apelin concentrations in patients with CHF of ischaemic aetiology [20].

The aim of this study was therefore to evaluate plasma apelin concentrations in a large cohort of patients with chronic heart failure (CHF) and to investigate the association of plasma apelin concentrations with various clinical and laboratory parameters of left ventricular dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Study limitations
 References
 
2.1. Patients
We studied 202 patients with CHF secondary to left ventricular systolic dysfunction. 186 of the patients were recruited following their referral to the Scottish Cardiopulmonary Transplant unit for cardiac transplant assessment between April 2001 and May 2004 (left ventricular ejection fraction < 35% measured by radionuclide ventriculography). The remaining 16 patients in New York Heart Association (NYHA) functional class I were recruited from the Heart Function Clinics of the Glasgow Royal Infirmary and Western Infirmary.

Twenty-two subjects, who had no history of cardiac events, had normal echocardiograms, electrocardiograms and N-Terminal pro-brain natriuretic peptide (NT-proBNP) concentrations acted as controls. The exclusion criteria were age less than 16 years, pregnancy or known concurrent malignancy. The study received local research ethics committee approval and informed consent was obtained from all participants. The study complies with the Declaration of Helsinki.

All patients had an echocardiogram and electrocardiogram. Blood samples were taken for measurement of plasma apelin and NT-proBNP concentrations as described below. In patients with advanced CHF, radionuclide ventriculography (RNVG) and peak VO2 were also performed.

2.2. Measurement of plasma Apelin and NT-proBNP levels
Venous blood samples were collected in ethylene-diamine-tetra-acetic acid-containing tubes. The samples were then spun at 3000 rpm for 10 min at 0 °C and plasma extracted and frozen in aliquots at –70 °C until analysis. Apelin assays were performed using the Apelin-12 microplate ELISA assay kit (Phoenix Pharmaceuticals) according to the manufacturer's instructions. The antibody used in this apelin assay cross-reacts 100% with Apelin-12, 13 and 36. The assay therefore includes all of the above peptides if present in the plasma. NT-proBNP was measured using a chemiluminescent immunoassay kit (Roche Diagnostics) on an Elecsys 2010 analyser. The clinicians involved with the patients' care were blinded to the apelin values obtained.

2.3. Statistical analysis
All data analysis was performed using the Statistical Package for Social Sciences (SPSS 11.5) software. Normally distributed, continuous data, unless otherwise stated, are expressed as mean values (± SD). Non-normally distributed continuous data are expressed as medians [25th and 75th percentile]. Differences between mean values were analysed using the Student's t-test and those between median values by the Mann-Whitney U-test. To compare the apelin values within NYHA classes and ejection fraction quartiles, a non-parametric Kruskal-Wallis test was performed. These tests were repeated using one way ANOVA on log transformed data.

Pearson's Correlation coefficients were computed with log transformed values for apelin to assess the strength of association between apelin and other variables. Spearman Correlation was used for categorical variables. Variables achieving p<0.10 were included in a stepwise linear regression to further determine the association with plasma apelin concentrations. A p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Study limitations
 References
 
The demographic and clinical characteristics of the study subjects are shown in Table 1. The patient population was predominantly male (77.7%) with a mean age of 51.7 years. 73% were in NYHA class III/IV and the mean LVEF (excluding patients in NYHA class I) was 15.6%. A significant proportion of subjects with CHF was on appropriate disease modifying therapy. The controls were age-matched and had significantly lower weight, body mass index, QRS duration, heart rate, mean arterial pressure, serum creatinine, left ventricular echo dimensions and fractional shortening compared to the patient population.


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  		Table 1 General characteristics in 22 normal controls and 202 patients with chronic heart failure

 
In contrast to NT-proBNP concentrations, which were significantly higher in patients with CHF compared to controls, plasma apelin concentrations were significantly lower (both p<0.001).

Table 2 shows the demographics along with clinical characteristics of the 202 patients according to NYHA class. In contrast to plasma NT-proBNP concentrations, there were no significant differences in plasma apelin concentrations between the functional classes.


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  		Table 2 Patient characteristics in 202 patients with chronic heart failure dichotomized according to NYHA class

 
Plasma apelin levels were significantly lower in all patients with left ventricular dysfunction, irrespective of NYHA class, when compared to controls (0.85 [0.53-2.04] versus 3.76 [0.85-5.13] ng/ml, p<0.001) (Table 1 and Fig. 1). A similar finding was also noted when patients were divided according to quartiles of left ventricular ejection fraction: although there was a significant difference in apelin concentration between controls and patients with CHF (p<0.001), plasma apelin concentrations did not alter significantly with diminishing left ventricular function (Fig. 2).


Figure 1
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  		Fig. 1 Box plot graph depicting Apelin concentrations in 202 patients with chronic heart failure according to NYHA class and 22 controls.

 


Figure 2
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  		Fig. 2 Box plot graph depicting Apelin concentrations in 202 patients with chronic heart failure according to quartiles of left ventricular ejection fraction, and 22 controls.

 
Age, sex, body mass index and serum creatinine had no significant effect on plasma apelin concentrations (Table 3). There was no significant correlation between plasma apelin levels and plasma NT-proBNP. However, there were weak but significant positive correlations with LVEF (R=0.154, p<0.05), RVEF (R=0.192, p<0.05) and VO2 (R=0.163, p<0.05), but only peak VO2 was significant on multivariate analysis.


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  		Table 3 Pearson's correlation coefficients (R) for different variables with log transformed values for apelin

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Study limitations
 References
 
This is the largest study to date reporting the characteristics of plasma apelin concentrations in patients with chronic heart failure across a broad spectrum of disease severity.

We have shown that plasma apelin concentrations are significantly lower in patients with CHF due to left ventricular systolic dysfunction compared to normal controls. Our results concur with those of Földes et al. [21], although they only included 38 patients with coronary heart disease and the patients were not divided according to NYHA class. We further established that plasma apelin concentrations are not dependent on the aetiology of heart failure, age, sex, body mass index (BMI) and renal function.

In contrast to our results, Chen et al. demonstrated higher plasma apelin concentrations in patients with CHF, compared to normal controls, and this was more noticeable in those with less symptomatic heart failure. Indeed, from their data there was no significant difference in apelin concentrations between the normal controls and patients with advanced heart failure [22]. In contrast, we found that irrespective of the NYHA class or ejection fraction, plasma apelin concentrations were significantly lower in patients with CHF than in normal controls. These differences may be due to varied clinical features in the two groups of patients studied, especially with regards to the aetiology of the heart failure and the differences in medication between the two studies.

Animal studies have demonstrated that apelin is not only a vasodilator [16,23,25] but that it also has potent positive inotropic effects [26]. More recently, apelin has been shown to have diuretic properties through counteracting the actions of arginine vasopressin (AVP) [27]. These unusual combinations of inotropy, vasodilatation and natriuresis imply that apelin has an important role is cardiovascular homeostasis. Szokodi et al. [28] found that apelin gene expression is markedly down regulated in cultured rat ventricular myocytes subjected to mechanical stretch and in models of chronic ventricular pressure overload in vivo. This suggests some yet unidentified mechanism that suppresses the apelin-APJ system, which might precipitate or perpetuate the pathophysiological process of heart failure. Considering the potentially favourable actions of apelin in heart failure, we hypothesize that inhibition of apelin breakdown, or its augmentation by exogenous administration might have therapeutic potential in the treatment of chronic heart failure. This theory is supported by the recent finding that an infusion of apelin reduces left ventricular preload and afterload, and increases contractile reserve in mice [29].

Given the low and suppressed plasma apelin concentrations across all NYHA classes and the lack of correlation with NT-proBNP concentration (a peptide that has been shown to correlate with prognosis) [30-32], apelin is unlikely to be a useful predictor of prognosis in patients with chronic heart failure.

The effect of medical therapy on plasma apelin concentrations is unknown. It has been reported that after ventricular offloading with left ventricular assist device (LVADs) in humans, tissue levels of apelin and expression levels of the APJ receptor increase [33]. Studies have also shown that beta-blockers can lead to a substantial increase in left ventricular ejection fraction in patients with heart failure due to left ventricular systolic dysfunction [34]. These findings imply that further longitudinal studies are warranted to test the hypothesis that plasma apelin concentrations might rise especially in those who are treated with beta-blockers. Unless apelin concentration changes with medical therapy, it is unlikely to be a useful marker to monitor response to therapy in heart failure.

We have found, for the first time, a positive correlation between plasma apelin concentrations and LVEF, RVEF and peak VO2 Max. The significance of these findings warrants further research.

In conclusion, our results suggest that apelin might play an important role in the pathophysiological processes of heart failure, a finding that may have potential therapeutic implications. Further research into the apelin-APJ signalling pathway might further develop the understanding of the pathogenesis and therapy in heart failure.


   5. Study limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
References
 
This study only involved patients with chronic heart failure secondary to left ventricular systolic dysfunction. Therefore, the findings of this study do not apply to patients with heart failure and preserved systolic function. Radionuclide ventriculography (RNVG) and peak VO2 were only performed in the 186 patients with advanced CHF referred for cardiac transplant assessment. In addition, 73% of the study population was in NYHA III/IV. This is therefore, primarily a study in advanced heart failure and further work involving more patients in NYHA classes I and II is necessary. Finally, the small number of controls might introduce statistical bias.


   Acknowledgements
 
We would like to acknowledge the help and support of Drs. Roger Carter PhD, Bill Martin PhD, Christina Yap PhD and Mrs. Lynn Ho and the patients and staff of the Scottish Cardiopulmonary Transplant Unit. We would also like to acknowledge the financial assistance of the British Heart Foundation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Study limitations
 References
 

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