Adiponectin, an adipocytokine, is secreted by adipocytes and mediates antihypertrophic and anti-inflammatory effects in the heart. Plasma concentrations of adiponectin are decreased in the presence of obesity, insulin resistance, and obesity-associated conditions such as hypertension and coronary heart disease. However, a paradoxical increase in adiponectin levels is observed in human systolic heart failure (HF). We sought to investigate the determinants of adiponectin levels in patients with chronic systolic HF. Total adiponectin levels were measured in 99 patients with stable HF and a left ventricular (LV) ejection fraction of <40%. The determinants of adiponectin levels on univariate analysis were included in a multivariate linear regression model. At baseline, 62% of the patients were black, 63% were men, the mean age was 60 ± 13 years, the LV ejection fraction was 21 ± 9%, and the body mass index was 30.6 ± 6.7 kg/m 2 . The mean adiponectin level was 15.8 ± 15 μg/ml. Beta-Blocker use, body mass index, and blood urea nitrogen were significant determinants of adiponectin level on multivariate analysis. The LV mass, structure, and LV ejection fraction were not related to adiponectin levels on multivariate analysis. The effect of β-blocker therapy was most marked in nonobese patients with a body mass index <30 kg/m 2 . In conclusion, in patients with chronic systolic HF, β-blocker therapy correlated with lower adiponectin levels, especially in nonobese patients. This relation should be taken into account when studying the complex role of adiponectin in patients with chronic systolic HF.
Adiponectin, an adipocyte-derived cytokine, is abundantly present in human plasma and mediates favorable actions in cardiovascular and metabolic-associated diseases. Adiponectin exerts a plethora of effects, including antihypertrophic and anti-inflammatory effects, in addition to improving vascular function and modulating pathologic cardiac remodeling. Depressed adiponectin levels are evident in the presence of obesity, coronary artery disease (CAD), hypertension, and insulin resistance and might reflect greater cardiovascular risk and inflammation. However, increased adiponectin levels are seen in patients with systolic heart failure (HF). The release of adiponectin into the circulation is associated with the severity of HF symptoms, disease severity, and mortality. Elevated adiponectin levels likely reflect an attempt to mitigate pro-inflammatory or impaired metabolic states and demonstrates a balance between the protective and harmful pathways in left ventricular (LV) systolic dysfunction and HF. Interactions among various factors can alter the adiponectin levels in patients with HF, making it difficult to interpret adiponectin levels in the development and progression of HF. We, therefore, sought to investigate the determinants of adiponectin levels in a cohort of patients with HF and chronic systolic dysfunction.
Methods
A total of 104 patients with chronic HF and a LV ejection fraction <40% were recruited from an ambulatory HF Clinic at the Boston Medical Center (Boston, Massachusetts) from 2001 to 2005. Of the 104 patients, 5 had end-stage renal disease and required dialysis. They were excluded because adiponectin levels are elevated in renal dysfunction. The data were recorded at enrollment, and the analysis reflected the measurements from 99 patients. The medical history was obtained to document the etiology, the severity of HF symptoms according to the New York Heart Association functional class, and co-morbid disease. Routine laboratory results (e.g., electrolytes and blood count) and concomitant cardiac medications were recorded. The body mass index (BMI) was calculated as the ratio of the weight in kilograms to the height in squared meters. The Boston Medical Center institutional review board approved the study, and all patients gave written informed consent. An ischemic etiology was defined by a history of myocardial infarction (electrocardiographic findings or positive troponin levels) and/or positive results from a noninvasive stress test or cardiac catheterization. A hypertensive etiology was defined by a documented history of pharmacologically treated hypertension and no known CAD (electrocardiographic, noninvasive stress test, or cardiac catheterization findings). An idiopathic etiology was defined as no identifiable cause found for the cardiomyopathy and included primary valvular disease, alcohol-induced, and familial.
Two-dimensional and Doppler echocardiography were performed at baseline using the Vingmed Vivid Five System (GE Vingmed, Milwaukee, Wisconsin), as previously described. Echocardiograms were performed and analyzed in a blinded manner. As previously described, measurements of the systolic and diastolic chamber dimensions and wall thickness were obtained from 2-dimensional imaging according to the recommendations of the American Society of Echocardiography. Similarly, the standard cube formula was used to calculate the LV mass. The relative wall thickness was calculated as (2 × PWT) / LVEDD, where PWT was the posterior wall thickness and LVEDD, the LV end-diastolic diameter.
The vital signs were recorded, and 35 ml fasting blood samples were collected from the antecubital vein after the patient had rested 10 minutes in the supine position. The plasma/serum was decanted and immediately stored at −80°C. The adiponectin and brain natriuretic peptide (BNP) levels were determined by enzyme-linked immunosorbent assay (Otsuka Pharmaceutical, Tokyo, Japan) and the ADVIA Centaur assay (Siemens Healthcare Diagnostics, Deerfield, Illinois), respectively. The minimal detection limit for adiponectin was 0.12 μg/ml, and the intra- and interassay coefficients of variation were both <10%. The C-reactive protein levels were measured by a commercial laboratory (Quest Diagnostics, Cambridge, Massachusetts).
The summary statistics are presented as the mean ± standard deviation for continuous variables and as the number (percentages) for categorical variables. We examined the relation between each marker and adiponectin using Pearson’s correlation. In these analyses, the skewed variables were analyzed after log transformation. The adiponectin levels were divided into tertiles, and the relation among adiponectin, clinical characteristics, and echocardiographic parameters were examined using analysis of variance or the chi-square test, as appropriate. For medication use, we compared the adiponectin levels between patients “using” or “not using” each class of medication by Student’s t test. We specified a priori that a factor must show a potential association (ie, p <0.15) with adiponectin on bivariate analysis to be tested in a multivariate regression model. A p value of <0.05 was considered statistically significant. All reported p values are 2-tailed, and all confidence intervals were computed at the 95% level. All analyses were conducted using the Statistical Package for Social Sciences software, version 11.5 (SPSS, Chicago, Illinois).
Results
A total of 99 patients with chronic, systolic HF completed the present study. Most patients were black and male and had hypertension ( Table 1 ). Patients were maintained on evidence-based therapy for systolic HF, and most were New York Heart Association class II or III. At enrollment, the mean duration with the diagnosis of HF for these patients was 4 years (range 1 to 237 months). Most patients had a mean BMI of >30 kg/m 2 . The mean creatinine was 1.7 ± 2.3 mg/dl, with a Modification of Diet in Renal Disease glomerular filtration rate of 63.3 ± 31 ml/min/1.73 m 2 . The mean adiponectin level was 15.8 ± 15 μg/ml.
| Characteristics | n = 99 |
|---|---|
| Age (years) | 60 ± 13 |
| Men | 62 (63%) |
| Race | |
| Black | 61 (62%) |
| White | 35 (35%) |
| Hispanic | 3 (3%) |
| Body mass index (kg/m 2 ) | 30.6 ± 6.7 |
| Duration of heart failure at enrollment (months) | 48 ± 50 |
| Systolic blood pressure (mm Hg) | 125 ± 23 |
| Diastolic blood pressure (mm Hg) | 72 ± 13 |
| Heart rate (beats/min) | 75 ± 16 |
| Etiology of heart failure | |
| Ischemic | 38 (38%) |
| Idiopathic | 31 (32%) |
| Hypertension | 30 (30%) |
| Diabetes mellitus | 39 (39%) |
| Hypertension | 84 (85%) |
| Chronic renal insufficiency | 45 (45%) |
| Gout | 25 (25%) |
| Alcohol use | |
| Active | 40 (40%) |
| Inactive | 59 (60%) |
| Smoker | 22 (22%) |
| New York Heart Association functional class | |
| I | 17 (18%) |
| II | 40 (40%) |
| III | 34 (34%) |
| IV | 8 (8%) |
| Medication use | |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 87 (88%) |
| β Blocker | 82 (83%) |
| Digoxin | 51 (52%) |
| Spironolactone | 13 (13%) |
| Nitrates | 31 (31%) |
| Hydralazine | 9 (9%) |
| Statin | 50 (50%) |
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