The European Journal of Heart Failure 8 (2006) 355 – 360

www.elsevier.com/locate/ejheart

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

Received 5 May 2005; received in revised form 22 May 2005; accepted 10 October 2005
Available online 7 February 2006

Abstract

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.
D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Apelin; Chronic heart failure

1. Introduction and rats and show significant similarities in amino acid

sequence and tissue distribution with angiotensinogen and
Although considerable advances have been made in our the angiotensin II receptor type 1 (AT1), respectively [6–
understanding of the pathogenesis and treatment of heart 12]. On the basis of these findings, several experimental
failure over the past two decades, morbidity and mortality studies have contributed to unravelling the physiological
remain high [1,2]. One potential explanation for this is that role of apelin in the cardiovascular system.
there are as yet, unknown biologically active molecules In contrast to angiotensin, a potent vasopressor and anti-
which exacerbate disease progression. diuretic hormone, apelin both lowers blood pressure (via a
Apelin, the novel endogenous ligand for the G-protein- nitric oxide-dependent mechanism) [13 –16] and produces
coupled receptor APJ, was first isolated from bovine diuresis by inhibition of arginine vasopressin activity and
stomach extracts by Tatemoto et al. in 1998 [3,4]. Apelin release [17]. Apelin, at least in animal studies, is the most
is secreted as a 77-amino acid pre-proprotein, which is then potent endogenous inotrope yet identified on the basis that
cleaved to active peptides of 12-, 13- and 36-amino acid significant positive inotropic effects are noted even in the
moieties [5]. Both apelin and APJ mRNA are highly subnanomolar range [18].
expressed in the cardiovascular system in both humans Several groups have attempted to measure plasma apelin
concentrations in patients with heart failure. These studies
* Corresponding author. Tel.: +44 141 420 3680; fax: +44 141 211 4950. only involved small numbers of patients and have produced
E-mail address: [email protected] (K.S. Chong). conflicting results. Chen et al. measured plasma concen-
1388-9842/$ - see front matter D 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2005.10.007
356 K.S. Chong et al. / The European Journal of Heart Failure 8 (2006) 355 – 360

trations of apelin in eighty heart failure patients with a broad 2.3. Statistical analysis
spectrum of disease severity and noted a rise in plasma
apelin concentrations compared to normal subjects [19]. A All data analysis was performed using the Statistical
Finnish study of only 38 patients with CHF found decreased Package for Social Sciences (SPSS 11.5) software. Normal-
plasma apelin concentrations in patients with CHF of ly distributed, continuous data, unless otherwise stated, are
ischaemic aetiology [20]. expressed as mean values (T SD). Non-normally distributed
The aim of this study was therefore to evaluate plasma continuous data are expressed as medians [25th and 75th
apelin concentrations in a large cohort of patients with percentile]. Differences between mean values were analysed
chronic heart failure (CHF) and to investigate the associa- using the Student’s t-test and those between median values
tion of plasma apelin concentrations with various clinical by the Mann –Whitney U-test. To compare the apelin values
and laboratory parameters of left ventricular dysfunction. 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
2. Methods data.
Pearson’s Correlation coefficients were computed with
2.1. Patients log transformed values for apelin to assess the strength of
association between apelin and other variables. Spearman
We studied 202 patients with CHF secondary to left Correlation was used for categorical variables. Variables
ventricular systolic dysfunction. 186 of the patients were
recruited following their referral to the Scottish Cardiopul-
monary Transplant unit for cardiac transplant assessment Table 1
between April 2001 and May 2004 (left ventricular ejection General characteristics in 22 normal controls and 202 patients with chronic
heart failure
fraction < 35% measured by radionuclide ventriculography).
The remaining 16 patients in New York Heart Association Demographic Controls (n = 22) Patients (n = 202) p
(NYHA) functional class I were recruited from the Heart Age (years) 51.3 T 9.2 51.7 T 11.6 ns
Function Clinics of the Glasgow Royal Infirmary and Male sex (%) 16 (59%) 157 (77.7%) 0.05
Weight (kg) 75.4 T 13.2 85.2 T 16.5 0.004
Western Infirmary. Height (cm) 168.6 T 9.8 172.9 T 10.1 ns
Twenty-two subjects, who had no history of cardiac events, Body mass index 26.4 T 3.0 28.8 T 5.0 0.003
had normal echocardiograms, electrocardiograms and N- (kg/m2)
Terminal pro-brain natriuretic peptide (NT-proBNP) concen- NYHA class – 55 (27.2%)/147 –
trations acted as controls. The exclusion criteria were age less (I and II/III and IV) (72.8%)
Aetiology – 48%/44.4%/7.6% –
than 16 years, pregnancy or known concurrent malignancy. (IHD/DCM/other)
The study received local research ethics committee approval QRS duration (ms) 87 T 10 132 T 38 <0.001
and informed consent was obtained from all participants. Heart rate (/min) 62 T 11 76 T 17 0.001
The study complies with the Declaration of Helsinki. Atrial fibrillation (%) 0% 38 (19.7%) <0.001
All patients had an echocardiogram and electrocardio- Systolic blood pressure 117 T 14 111 T19 ns
(mm Hg)
gram. Blood samples were taken for measurement of plasma Mean arterial pressure 90 T 8 66 T 11 <0.001
apelin and NT-proBNP concentrations as described below. (mm Hg)
In patients with advanced CHF, radionuclide ventriculog- Serum creatinine 90.5 T 12.3 126.4 T 42.8 <0.001
raphy (RNVG) and peak VO2 were also performed. (Amol/l)
LVEDd (mm) 51.6 T 5.7 65.4 T 9.1 <0.001
LVESd (mm) 32.4 T 4.7 54.9 T 10.2 <0.001
2.2. Measurement of plasma Apelin and NT-proBNP levels Fractional shortening 37.2 T 5.3 16.9 T 7.0 <0.001
(%)
Venous blood samples were collected in ethylene- LVEF (%) – 15.6 T 8.0a –
diamine-tetra-acetic acid-containing tubes. The samples RVEF (%) – 22.2 T 10.4a –
were then spun at 3000 rpm for 10 min at 0 -C and plasma Peak VO2 (ml/kg/min) – 11.3 T 3.6a –
Apelin (ng/ml)T 3.76 [0.85 – 5.13]T 0.85 [0.53 – 2.04]T <0.001
extracted and frozen in aliquots at 70 -C until analysis. NT-proBNP (pg/ml)T 29 [19 – 51]T 1370 [466 – 3925]T <0.001
Apelin assays were performed using the Apelin-12 micro- Medication (%)
plate ELISA assay kit (Phoenix Pharmaceuticals) according ACE inhibitor – 78.8
to the manufacturer’s instructions. The antibody used in this Angiotensin receptor – 15.2
apelin assay cross-reacts 100% with Apelin-12, 13 and 36. blocker
Beta-blocker – 71.1
The assay therefore includes all of the above peptides if Spironolactone – 54.9
present in the plasma. NT-proBNP was measured using a Digoxin – 40.9
chemiluminescent immunoassay kit (Roche Diagnostics) on Values are expressed as mean T SD or %, except non-normally distributed
an Elecsys 2010 analyser. The clinicians involved with the variablesT which are expressed as the median [interquartile range].
a
patients’ care were blinded to the apelin values obtained. Excludes patients in NYHA I.
 K.S. Chong et al. / The European Journal of Heart Failure 8 (2006) 355 – 360 357

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 statistical-
ly significant.

3. Results

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
Fig. 1. Box plot graph depicting Apelin concentrations in 202 patients with
index, QRS duration, heart rate, mean arterial pressure, chronic heart failure according to NYHA class and 22 controls.
serum creatinine, left ventricular echo dimensions and
fractional shortening compared to the patient population. versus 3.76 [0.85 –5.13] ng/ml, p < 0.001) (Table 1 and Fig.
In contrast to NT-proBNP concentrations, which were 1). A similar finding was also noted when patients were
significantly higher in patients with CHF compared to divided according to quartiles of left ventricular ejection
controls, plasma apelin concentrations were significantly fraction: although there was a significant difference in
lower (both p < 0.001). apelin concentration between controls and patients with CHF
Table 2 shows the demographics along with clinical ( p < 0.001), plasma apelin concentrations did not alter
characteristics of the 202 patients according to NYHA class. significantly with diminishing left ventricular function
In contrast to plasma NT-proBNP concentrations, there were (Fig. 2).
no significant differences in plasma apelin concentrations Age, sex, body mass index and serum creatinine had no
between the functional classes. significant effect on plasma apelin concentrations (Table 3).
Plasma apelin levels were significantly lower in all There was no significant correlation between plasma apelin
patients with left ventricular dysfunction, irrespective of levels and plasma NT-proBNP. However, there were weak
NYHA class, when compared to controls (0.85 [0.53 – 2.04] but significant positive correlations with LVEF (R = 0.154,

Table 2
Patient characteristics in 202 patients with chronic heart failure dichotomized according to NYHA class
Demographic NYHA I NYHA II NYHA III NYHA IV
n 16 39 113 34
Age (years) 60.9 T 17.6 51.0 T 10.7 52.1 T 9.4 46.9 T 13.5
Male sex 68.8% 66.7% 79.6% 88.2%
Weight (kg) 90.0 T 17.3 85.2 T 17.1 86.6 T 16.3 78.3 T 14.6
Height (cm) 169.0 T 11.0 174.0 T 11.0 172.3 T 10.1 174.0 T 8.9
Body Mass Index (kg/m2) 32.2 T 8.1 29.0 T 4.4 29.4 T 4.8 25.9 T 4.7
Aetiology (% IHD) 62.5% 38.9% 48.2% 52.9%
QRS duration (ms) 109 T 34 133 T 36 130 T 35 144 T 46
Atrial fibrillation (%) 33.3% 20.0% 18.3% 17.6%
Peak VO2 (ml/kg/min) – 13.6 T 4.2 11.2 T 3.2 9.4 T 2.8
LVEF by RNVG (%) – 18.3 T 7.5 15.3 T 6.9 10.1 T 6.0
LVEDd (mm) 60.3 T 7.5 64.2 T 7.8 65.7 T 9.6 68.1 T 8.6
Fractional shortening (%) 20.6 T 8.4 18.3 T 6.5 16.7 T 6.8 14.8 T 7.0
Systolic blood pressure (mm Hg) 122.4 T 15.4 122.0 T 23.9 111.2 T 16.1 94.9 T 10.9
Serum sodium (mmol/l) 140.86 T 2.12 139.83 T 3.00 139.29 T 2.85 135.97 T 5.16
Serum creatinine (Amol/l) 116.2 T 28.6 117.6 T 32.1 128.0 T 46.9 131.7 T 43.3
Loop diuretic (%) 62.6% 85.3% 92.7% 96.9%
ACE Inhibitor (%) 81.2% 88.2% 76.9% 75.8%
Angiotensin II receptor blocker (%) 18.8% 8.8% 18.2% 9.1%
Beta blocker (%) 75.0% 88.2% 74.3% 42.1%
Spironolactone (%) 25.0% 44.1% 63.1% 55.9%
NT-proBNP (pg/ml)T 579 [196 – 2961] 1005 [372 – 2025] 1160 [433 – 2573] 7036 [2375 – 11843]
Apelin (ng/ml)T 0.95 [0.55 – 5.10] 0.88 [0.46 – 1.55] 0.84 [0.56 – 2.10] 0.80 [0.48 – 2.03]
Values are expressed as mean T SD or %, except non-normally distributed variablesT which are expressed as the median [interquartile range].
358 K.S. Chong et al. / The European Journal of Heart Failure 8 (2006) 355 – 360

been shown to have diuretic properties through counter-

acting 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 hypoth-
esize that inhibition of apelin breakdown, or its augmen-
Fig. 2. Box plot graph depicting Apelin concentrations in 202 patients with tation by exogenous administration might have therapeutic
chronic heart failure according to quartiles of left ventricular ejection potential in the treatment of chronic heart failure. This
fraction, and 22 controls.
theory is supported by the recent finding that an infusion
of apelin reduces left ventricular preload and afterload, and
p < 0.05), RVEF (R = 0.192, p < 0.05) and VO2 (R = 0.163, increases contractile reserve in mice [29].
p < 0.05), but only peak VO2 was significant on multivariate Given the low and suppressed plasma apelin concen-
analysis. trations 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
4. Discussion unlikely to be a useful predictor of prognosis in patients
with chronic heart failure.
This is the largest study to date reporting the character- The effect of medical therapy on plasma apelin
istics of plasma apelin concentrations in patients with concentrations is unknown. It has been reported that after
chronic heart failure across a broad spectrum of disease ventricular offloading with left ventricular assist device
severity. (LVADs) in humans, tissue levels of apelin and expression
We have shown that plasma apelin concentrations are levels of the APJ receptor increase [33]. Studies have also
significantly lower in patients with CHF due to left shown that beta-blockers can lead to a substantial increase
ventricular systolic dysfunction compared to normal con- in left ventricular ejection fraction in patients with heart
trols. Our results concur with those of Földes et al. [21], failure due to left ventricular systolic dysfunction [34].
although they only included 38 patients with coronary heart These findings imply that further longitudinal studies are
disease and the patients were not divided according to warranted to test the hypothesis that plasma apelin
NYHA class. We further established that plasma apelin concentrations might rise especially in those who are
concentrations are not dependent on the aetiology of heart
failure, age, sex, body mass index (BMI) and renal Table 3
function. Pearson’s correlation coefficients (R) for different variables with log
In contrast to our results, Chen et al. demonstrated higher transformed values for apelin
plasma apelin concentrations in patients with CHF, com- Variables R p
pared to normal controls, and this was more noticeable in Age 0.113 0.11
those with less symptomatic heart failure. Indeed, from their Gender 0.067 (q) 0.35
data there was no significant difference in apelin concen- Body Mass Index 0.091 0.24
trations between the normal controls and patients with Aetiology 0.002 (q) 0.97
advanced heart failure [22]. In contrast, we found that QRS duration 0.116 0.14
Heart rate 0.038 0.61
irrespective of the NYHA class or ejection fraction, plasma Atrial fibrillation 0.001 (q) 0.99
apelin concentrations were significantly lower in patients Systolic blood pressure 0.078 0.29
with CHF than in normal controls. These differences may be Mean arterial pressure 0.051 0.49
due to varied clinical features in the two groups of patients Diastolic blood pressure 0.020 0.79
studied, especially with regards to the aetiology of the heart Serum creatinine 0.032 0.66
Serum sodium 0.043 0.57
failure and the differences in medication between the two LVEF 0.154 <0.05
studies. RVEF 0.192 <0.05
Animal studies have demonstrated that apelin is not Peak VO2 0.163 <0.05
only a vasodilator [16,23,25] but that it also has potent NT-proBNP 0.049 0.49
positive inotropic effects [26]. More recently, apelin has Spearman correlation was used for categorical variables (q).
 K.S. Chong et al. / The European Journal of Heart Failure 8 (2006) 355 – 360 359

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