High plasma adiponectin is related to low functional capacity in patients with chronic heart failure

doi:10.1016/j.ijcard.2008.12.126

International Journal of Cardiology

Volume 144, Issue 2, 8 October 2010, Pages 230-231

https://doi.org/10.1016/j.ijcard.2008.12.126 Get rights and content

Abstract

We evaluated the association between plasma adiponectin and functional capacity in patients with chronic heart failure (CHF). Similarly to NT-proBNP, plasma adiponectin was elevated in CHF compared to healthy controls. Adiponectin correlated inversely with peak oxygen consumption and 6-minute walking distance and was able to identify CHF patients with impaired exercise capacity. Our findings support a role of adiponectin as an index of heart failure severity.

Introduction

In contrast to healthy individuals, plasma adiponectin (AD) is considered as a marker of wasting and is related to high mortality in patients with chronic heart failure (CHF) [1]. We assessed the potential association of AD with functional capacity.

Section snippets

Materials and methods

Fifty seven patients, aged 57.2 ± 11.9 years with mean LVEF 28.7 ± 8% and 17 healthy volunteers matched for age, sex and body mass index (BMI) were tested for plasma AD and N-terminal probrain natriuretic peptide (NT-proBNP). Exercise capacity was evaluated using cardiopulmonary exercise testing while the 6 min walk-test (6MWT) was conducted in 37 patients out of the 57. Dyspnea was assessed according to Borg scale (6–20) at the end of the 6MWT.

Results

AD correlated positively with NT-proBNP (r = 0.574 p < 0.001), while both AD (26.9 ± 19.8 vs. 14.2 ± 5.9 μg/ml, p < 0.01) and NT-proBNP (1059.2 ± 1109.1 vs. 360.5 ± 91 pg/ml, p < 0.001) levels were significantly higher in CHF patients compared to controls. Patients achieved a mean peakVO₂ of 16.5 ± 4.4 ml/kg/min. The 6MWT distance was 366 ± 73 m and dyspnea 10.8 ± 2.9. AD and NT-proBNP correlated positively with NYHA functional class and dyspnea, and inversely with exercise capacity and BMI (Table 1). Adjustment for

Discussion

We demonstrated an inverse, independent association of plasma AD with exercise capacity indices. We also showed that AD, like NT-proBNP, has the ability to identify CHF patients with impaired functional capacity below class A according to Weber classification system (peakVO₂ < 20 ml/kg/min), patients considered for heart transplantation (peakVO₂ < 14 ml/kg/min) [2] and patients with high mortality risk (peakVO₂ < 10 ml/kg/min, 6MWT < 300 m) [3], [4].

We have confirmed recent findings according to which

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [8].

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Clinical observations demonstrate that increased plasma APN levels are associated with poor cardiac function, symptomatic clinical status, and high mortality in this patient population [56–58]. Moreno et al. employed a Mendelian randomization technique to evaluate this counterintuitive data and demonstrated that the paradoxical association between high plasma APN level and increased cardiovascular congestive heart failure (CHF) mortality is based on a cause–effect relationship, suggesting an unexpected deleterious role for APN’s action on metabolism and atherosclerotic processes [59–61]. CHF failure is a complex disease, often a consequence of MI, when the heart is unable to effectively pump blood to meet physiologic demands.
For the past two decades, a great deal of research has been published concerning adiponectin (APN), an abundant protein responsible for regulating numerous biologic functions including antioxidative, antinitrative, anti-inflammatory, and cardioprotective effects. A review of APN and its two major receptors is timely because of new findings concerning the mechanisms by which APN signaling may be altered in pathologic processes such as diabetes and heart failure. In this review we elaborate on currently known information regarding the physiologic role of APN and the known mechanisms underlying pathologic APN resistance − namely, APN receptor downregulation and phosphorylation − and provide insight regarding the future directions of APN research including an assessment of the clinical applicability of preventing pathologic post-translational modification of the APN receptor.
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Moreover, there is no significant change in the expression levels of signaling molecules involved in APN vascular function, indicating the involvement of an unknown molecular mechanism. Interestingly, numerous recent epidemiological studies report elevated circulating APN levels in patients with heart failure, suggesting the onset of APN resistance with heart failure[3,8,14]. However, whether the metabolic derangements in pre-diabetes cause APN resistance (and are causatively related to subsequent endothelial dysfunction) has not been elucidated.
Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN's anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN's anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.
Sudden cardiac death and diabetes mellitus
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The excess risk of CHD in obese patients may be related to low serum concentrations of adiponectin, which has insulin-sensitizing and anti-atherogenic properties (Arita et al., 1999). In one of our studies we reported a relationship between high plasma adiponectin and low functional capacity in patients with chronic HF (Laoutaris et al., 2010). The association between BMI and cause-specific mortality was reported in the Prospective Studies Collaboration analysis (Prospective Studies Collaboration et al., 2009).
Plasma adiponectin in heart failure with and without cachexia: Catabolic signal linking catabolism, symptomatic status, and prognosis
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In healthy subjects, high ADPN levels are associated with a protective cardiovascular effect, low blood pressure, lower total and LDL-cholesterol, low body mass index (BMI) as well as with high insulin sensitivity and high HDL-cholesterol [7,10]. Recently, several studies on the role of ADPN in CHF have been focused on mortality [11,12], functional capacity [13], or metabolism [14]. Impaired metabolic balance, reduced symptomatic status, and poor prognosis culminate in cardiac cachexia.
Adiponectin (ADPN) as an adipose tissue hormone contributes to regulation of energy metabolism and body composition and is associated with cardiovascular risk profile parameters. Cardiac cachexia may develop as a result of severe catabolic derangement in chronic heart failure (CHF). We aimed to determinate an abnormal ADPN regulation as a link between catabolic signalling, symptomatic deterioration and poor prognosis.
We measured plasma ADPN in 111 CHF patients (age 65 ± 11, 90% male, left ventricular ejection fraction (LVEF) 36 ± 11%, peak oxygen consumption (peakVO₂) 18.1 ± 5.7 l/kg*min, body mass index (BMI) 27 ± 4 kg/m², all mean ± standard deviation) and 36 healthy controls of similar age and BMI. Body composition was assessed by dual energy X-ray absorptiometry, insulin sensitivity was evaluated by homoeostasis model assessment, exercise capacity by spiroergometry. Plasma ADPN did not differ between CHF vs. controls (13.5 ± 11.0 vs. 10.5 ± 5.3 mg/l, p > 0.4), but increased stepwise with NYHA functional class (I/II/III: 5.7 ± 1.4/10.7 ± 8.3/19.2 ± 14.0 mg/l, ANOVA p < 0.01). Furthermore, ADPN correlated with VO₂ at anaerobic threshold (r = −0.34, p < 0.05). ADPN was highest in cachectic patients (cCHF, 16%) vs. non-cachectic (ncCHF) (18.7 ± 15.0 vs. 12.5 ± 9.9 mg/l; p < 0.05). ADPN indicated mortality risk independently of established prognosticators (HR: 1.04 95% CI: 1.02–1.07; p < 0.0001). ADPN above the mean (13.5 mg/l) was associated with a 3.4 times higher mortality risk in CHF vs. patients with ADPN levels below the mean.
Circulating ADPN is abnormally regulated in CHF. ADPN may be involved in impaired metabolic signalling linking disease progression, tissue wasting, and poor outcome in CHF.
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Letter to the EditorHigh plasma adiponectin is related to low functional capacity in patients with chronic heart failure

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Acknowledgement

Am Heart J

J Heart Lung Transplant

Int J Cardiol

Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure

Circulation

Letter to the Editor
High plasma adiponectin is related to low functional capacity in patients with chronic heart failure