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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

J Clin Hypertens (Greenwich).

Adiponectin is a cardioprotective adipocytokine. Serum adiponectin concentration decreases in patients who are obese but increases in patients with chronic heart failure (CHF). The aim of this study was to explore the temporal changes in serum adiponectin concentration following treatment for acute decompensated heart failure (ADHF). Serum adiponectin was measured on admission and at discharge in 95 patients who were admitted to our hospital with ADHF. Ten patients without heart failure (HF) served as controls. Serum adiponectin concentration was higher on admission in HF patients than in the controls (22.6±13.3 μg/mL vs 9.3±3.9 μg/mL, P<.01). Serum adiponectin concentration decreased after treatment in HF patients (18.0±11.7 μg/mL vs 22.6±13.3 μg/mL, P<.01). The larger temporal decrease in adiponectin level in ADHF was associated with the lower incidence of cardiac death or HF hospitalizations (log-rank, P<.05). Serum adiponectin concentration was elevated in ADHF and decreased following the treatment. How much serum adiponectin decreases in response to treatment in ADHF is an important determinant of the prognosis. J Clin Hypertens (Greenwich). 2010;12:900–904.

Adiponectin is one of the adipocyte-derived cytokines (adipocytokines), and it decreases in conditions such as obesity and type 2 diabetes mellitus.1,2 Adiponectin concentrations negatively correlate with body mass index (BMI), percentage of body fat, waist to hip ratio, and intra-abdominal fat.1,3,4 Clinical studies have shown that high levels of adiponectin are associated with reduced risk of cardiovascular disease.5,6 However, increased levels of adiponectin have been reported in patients with chronic heart failure (CHF) and are associated with the severity of heart failure (HF),7 cachexia,8 and higher mortality9–13 in CHF patients. Since experimental studies have suggested that adiponectin has a cardioprotective effect,14–16 adiponectin is supposed to increase for compensating HF. Acute decompensated HF (ADHF) is a dynamic process of decompensation of HF and recompensation by intensive treatment. We have shown that interleukin 6 exhibits different patterns of temporal changes than interleukin 18 and tumor necrosis factor α (TNF-α) in ADHF.17 Serum adiponectin concentration may reflect damage or a protective signal depending on the context. The aim of the present study was to determine the role of temporal changes in serum adiponectin concentration as a potential marker of outcome in ADHF.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Patients

We studied 95 consecutive HF patients who were admitted to our hospital and fulfilled the Framingham criteria of acute decompensation from April 2005 to December 2007. The mean length of stay was 22±3 days. The diagnosis of acute decompensation was based on the worsening of dyspnea on effort or the development of orthopnea within a few days just before admission and radiographic findings of pulmonary congestion on admission. There were 61 men and 34 women, ranging in age from 28 to 91 years (Table I). We excluded patients with significant concomitant diseases such as acute coronary syndrome (ACS), infections, severe renal failure (serum creatinine >2.0 mg/dL), malignancy, and autoimmune disease. We also excluded patients for whom cardiac surgery was indicated. Creatinine clearance was calculated by the Cockcroft–Gault equation.18 All patients were treated with standard medication for HF, including intravenous diuretics, human atrial natriuretic peptide, catecholamines, and phosphodiesterase inhibitors, as appropriate. We also evaluated 10 control patients who had no signs or symptoms of HF. Control patients were admitted for coronary angiography, and only those with no evidence of coronary artery stenosis were included. All controls had no signs or symptoms of HF. All patients gave informed consent in advance for their participation, and the ethics committee at our institution approved the protocol. The study end points were cardiac death or hospitalizations caused by HF. Patients were followed up for 14 months on average (range, 0.7–41 months). No patients were lost to follow-up.

Table I.   Patient Characteristics
 ADHF PatientsControls
  1. Abbreviations: ADHF, acute decompensated heart failure; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVDd, left ventricular end-diastolic dimension; NYHA, New York Heart Association; SBP, systolic blood pressure;. Values are expressed as mean ± standard deviation. aP<.01 vs controls.

Sample size, No.9510
Age, y70±1270±7
Sex, men/women61/347/3
Body mass index, kg/m224.1±4.521.5±2.7
NYHA class, II/III/IV12/54/28 
Etiology of heart failure, %
 Ischemic heart disease37
 Dilated cardiomyopathy21
 Hypertensive27
 Others15
Diabetes mellitus, %3733
SBP, mm Hg144±34a127±7
DBP, mm Hg84±1981±6
Heart rate, beats per min93±26a78±10
Ejection fraction, %40±15a66±8
LVDd, mm58±10a45±8
Creatinine clearance, mL/min63±1465±17
Adiponectin, μg/mL22.6±13.3a9.3±3.9
Total cholesterol, mg/dLl75±43199±30
HDL cholesterol, mg/dL47±1652±10
LDL cholesterol, mg/dL102±34117±33
Triglycerides, mg/dL111±73117±58

Measurement of Adiponectin and BNP

Peripheral venous blood was transferred to nonheparinized tubes and centrifuged at 1750 g for 15 minutes at 4°C. The obtained serum samples were stored at −80°C until they were assayed. Serum adiponectin and plasma brain natriuretic peptide (BNP) were measured on admission and just before discharge. Serum adiponectin concentration was determined by a commercially available enzyme-linked immunosorbent assays kit (Otsuka Pharmaceuticals, Tokyo, Japan) as previously described.1 Plasma BNP concentration was measured using noncompetitive immunoradiometric assays for human BNP (Shionogi, Osaka, Japan).

Statistical Analysis

Values are expressed as means ± standard deviation (SD). All statistical analyses were performed using a commercially available statistical software program (STATVIEW version 5.0; SAS Institute Inc, Cary, NC). Differences between groups were assessed with the chi-square test for categoric data. Differences in continuous variables between groups were assessed with unpaired Student t test. Differences between admission and discharge values were assessed with paired Student t test. Adiponectin and BNP data were not normally distributed; therefore, these data were subjected to logarithmic transformation (log). Pearson’s correlation coefficient was used to assess the correlation between log adiponectin and log BNP and BMI and then between changes in log adiponectin and changes in log BNP. Kaplan–Meier analysis indicated differences in event-free survival for the composite of cardiac death and CHF hospitalization when the group was divided into the 3 groups, according to the tertile of the size of the treatment-induced changes in log adiponectin concentration. A P value <.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Table I summarizes the demographics of the patients with ADHF (n=95) and the controls (n=10). There was no significant difference in age, sex, BMI, or serum cholesterol level between the patients with ADHF and controls.

Serum adiponectin level was higher in patients with ADHF on admission than in controls (Table I). Log adiponectin was positively correlated with log BNP and inversely correlated with BMI on admission (r=0.42, P<.01; r=−0.35, P<.01, respectively). Both plasma BNP and serum adiponectin levels decreased in HF patients after treatment (Table II). Treatment-induced changes in log adiponectin did not correlate with changes in log BNP, which was a variable considered to be potentially associated with adiponectin in HF (r=0.22, P=.07). There was no difference in serum adiponectin concentration at discharge (the mean length of stay was about 3 weeks) between patients with and those without atrial natriuretic peptide (ANP) infusion (17.1±9.9 μg/mL vs 18.1±12.0 μg/mL). Left ventricular ejection fraction was not associated with adiponectin level on admission and treatment-induced changes in adiponectin (R=0.11, P=.4; R=0.10, P=.4, respectively). Kaplan–Meier analysis of the 95 patients were stratified into 3 groups according to the tertile of the size of the treatment-induced changes in adiponectin concentration (group 1: n=32, 9% to 20%; group 2: n=32, 2% to 9%; group 3: n=31, −12% to 2%) and in log BNP concentration (group 1: n=32, 20% to 60%; group 2: n=10% to 20%; group 3: n=31, −29% to 10%). Kaplan–Meier analysis showed that the higher event-free survival rate was associated with the larger treatment-induced changes in log adiponectin concentration (group 1 vs groups 2 and 3, log-rank: P<.05) (Figure A). On the other hand, the higher event-free survival rate was not associated with the larger treatment-induced changes in log BNP concentration (Figure B). In other words, the better prognosis was associated with the larger decrease in adiponectin concentration but not with the larger decrease in BNP in ADHF. Mean adiponectin level (SD) was 16.1 (7.7) in group 1, 26.3 (16.9) in group 2, and 19.7 (10.1) in group 3 at the end of study. Patients in group 3 did not show high adiponectin levels. The prognosis did not relate to adiponectin level at the end of study.

Table II.   Serum Adiponectin and Plasma BNP Levels
 AdmissionDischarge
  1. Abbreviation: BNP, brain natriuretic peptide. Values are medians (25th–75th percentile). aP<.01 vs admission.

Adiponectin, μg/mL18.0 (11.8-26.8)14.6 (9.1-24.1)a
BNP, pg/mL635 (352-1110)259 (100-517)a
image

Figure Figure.  Kaplan–Meier event: hospitalizations caused by heart failure (or cardiac death)–free survival curves according to tertiles of treatment-induced changes in log adiponectin concentration (group 1: n=32, 9% to 20%; group 2: n=32, 2% to 9%; group 3: n=31, −12% to 2%) (A) and brain natriuretic peptide concentration (group 1: n=32, 20% to 60%; group 2: n=32, 10% to 20%; group 3: n=31, −29% to 10%) (B).

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

The present study has revealed that a larger decrease in adiponectin level in response to conventional treatment is associated with a better prognosis in patients with ADHF.

In this study, serum TNF-α concentrations as associated with adipocytokines were higher in the ADHF group than in the control group (1.8±0.8 pg/mL vs 1.1±0.4 pg/mL, P<.01) but concentration of TNF-α did not appear to be elevated in our patients. Serum TNF-α concentrations did not change after about 3 weeks with conventional treatment (2.0±0.9 pg/mL vs 1.8±0.8 pg/mL, P=.33). A previous study reported that serum adiponectin levels were positively correlated with TNF-α,7 while another study reported lack of correlation in HF patients.10 We did not find any relationship between serum adiponectin and TNF-α levels (r=0.1, P=.45). The reason for the discrepancy is currently unknown. Serum adiponectin level responded more rapidly than TNF-α, and the changes of adiponectin with treatment indicated outcome in ADHF patients. Plasma BNP levels are established markers of prognosis in CHF. In this study, plasma BNP also decreased after treatment (Table II). Ang and colleagues19 reported that the changes in adiponectin and BNP are associated with prognosis in ACS. However, the changes of plasma BNP concentration did not relate with prognosis in our ADHF patients. These differences may have reflected the pathogenesis between CHF and ACS. The results of the present study suggest that the changes of serum adiponectin concentration treatment might be a better indicator of prognosis in patients with ADHF.

Experimental studies using adiponectin-deficient mice have shown that adiponectin protects the heart from ischemia reperfusion injury and pressure overload via several mechanisms, including 5’adenosine monophosphate–activated protein kinase signaling.14–16 These findings suggest that adiponectin is a cardioprotective factor like BNP. Circulating adiponectin may temporarily increase to protect the heart in ADHF and decrease when cardiac overload is ameliorated. A large decrease in adiponectin level in response to treatment may indicate a large increase in adiponectin levels in response to acute decompensation. Enhanced secretion of adiponectin would protect the cardiac injury in ADHF and improve prognosis. Previous studies have shown that serum adiponectin concentration positively correlates with the severity of congestive HF7 and with plasma levels of BNP or N-terminal BNP7,9–11,13 in stable CHF. In our study population, serum adiponectin concentration in ADHF positively correlates with plasma BNP such as that in stable CHF. A larger decrease in adiponectin level in response to treatment might indicate that ADHF was more successfully treated and more quickly improved. Faster improvement of ADHF might be associated with lesser cardiac injury and better prognosis.

Adiponectin is mainly expressed in adipose tissue, and its expression decreases in conditions such as obesity and type 2 diabetes mellitus. Serum adiponectin level corelates negatively with BMI7,9–11,13 in stable CHF. In our study population, serum adiponectin concentration in ADHF negatively correlated with BMI such as that in stable CHF and in a population without HF. Thus, major sources of circulating adiponectin are thought to be adipose tissue in ADHF. However, recent studies have shown that adiponectin mRNA and protein are expressed in cardiomyocytes of rodents and humans,20,21 and immunoreactive adiponectin was found in the myocardial tissues obtained from the autopsied heart.22 Adiponectin may be released from the heart in patients with HF.23 We have no data about the source of adiponectin in the present study; thus, further studies are necessary.

The mechanism of the increase in serum adiponectin level in ADHF remains unknown. Adipose tissue expresses natriuretic peptide receptors, and natriuretic peptides such as ANP and BNP induce lipolysis via a cyclic guanosine monophosphate (cGMP)–dependent pathway.24,25 Tsukamoto and colleagues26 have reported that natriuretic peptides promote adiponectin synthesis via the guanylyl cyclase A/cGMP/protein kinase G–dependent pathway by adipocytes. However, the treatment-induced changes in serum adiponectin level did not correlate with the treatment-induced changes in BNP. Another natriuretic peptide or other neurohumoral factors such as catecholamines or endothelin may stimulate adiponectin secretion in ADHF. Recently, plasma adiponectin levels have been shown to be increased with ANP infusion in patients with ADHF.26,27 In our study, there was no difference in serum adiponectin concentration at discharge between patients with and without ANP infusion. Failure to detect changes in adiponectin levels in patients treated for 1 week with ANP may be due to the fact that analysis of adiponectin was performed on plasma samples taken 2 weeks after cessation of ANP infusion.

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Three limitations of the study are noted. First, the present study consisted of a small number of patients. Second, the precise onset of acute decompensation was not necessarily determined in patients. Finally, we measured only the level of total adiponectin, not that of high molecular weight adiponectin, which is the true ligand of adiponectin receptor. However, Tsutamoto and colleagues13 have shown that total adiponectin was more useful in assessing mortality risk than high molecular weight adiponectin in patients with CHF with normal BMI.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Serum adiponectin level was elevated in ADHF and decreased following treatment with conventional therapy. The treatment-induced decrease in serum adiponectin concentration is an important determinant of positive outcome in ADHF.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Acknowledgments:  The authors are grateful to Noriko Kumon and Utako Kuze for their valuable assistance in the data management and for their excellent technical assistance.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References