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Serum Resistin Is Associated with High Risk in Patients with Congestive Heart Failure a Novel Link Between Metabolic Signals and Heart Failure

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Serum Resistin Is Associated with High Risk in Patients with Congestive Heart Failure a Novel Link Between Metabolic Signals and Heart Failure Circ J 2007; 71: 460–464 Serum Resistin is Associated With High Risk in Patients With Congestive Heart Failure A Novel Link Between Metabolic Signals and Heart Failure Yasuchika Takeishi, MD; Takeshi Niizeki, MD; Takanori Arimoto, MD; Naoki Nozaki, MD; Osamu Hirono, MD; Joji Nitobe, MD; Tetsu Watanabe, MD; Noriaki Takabatake, MD; Isao Kubota, MD Background Resistin is derived from fat tissue in rodents, and serum levels are elevated in animal models of obesity and insulin resistance. Recent studies have reported that resistin is correlated with markers of inflamma- tion and oxidative stress and is predictive of coronary atherosclerosis in humans. However, clinical significance of serum resistin has not been examined in heart failure. Therefore, the purpose of this study was to examine whether: (1) resistin is correlated with the severity of heart failure; and (2) resistin can predict clinical outcomes of patients with heart failure. Methods and Results Serum levels of resistin in 126 patients hospitalized for heart failure and 18 control sub- jects were measured. The patients were followed up with end-points of cardiac death and re-hospitalization caused by worsening of heart failure. The serum resistin level was higher in patients with heart failure than in control subjects and increased with advancing New York Heart Association functional class. The normal upper limit of the resistin level was determined as the mean +2standard deviation value of control subjects (14.1ng/ml). In heart failure patients, the cardiac event rate was higher in patients with a high resistin level than in those with a normal level. Among age, body mass index, serum levels of resistin, brain natriuretic peptide, loop diuretics selected by the univariate Cox regression hazard analysis, age and resistin were significant predictors of future cardiac events by multivariate Cox analysis. Conclusion Serum resistin was related to the severity of heart failure and associated with a high risk for adverse cardiac events in patients with heart failure. (Circ J 2007; 71: 460–464) Key Words: Adipocytokine; Heart failure; Resistin; Prognosis dipose tissue secretes bioactive peptides, called “adi- health problem that causes a high mortality rate because of pocytokines”, which act locally and distally through the increasing aging population and high prevalence of A autocrine, paracrine and endocrine effects.1–4 An heart failure in the elderly.11–13 However, the relationship increased production of adipocytokines impacts on multi- between adipocytokines and heart failure has not been ple functions such as energy balance, immunity, insulin previously examined. Despite the significant reduction in sensitivity, angiogenesis, blood pressure, lipid metabolism mortality achieved in recent clinical trials, heart failure and haemostasis, all of which are linked to cardiovascular patients still have a poor prognosis.14 Thus, the role of diseases. Resistin has been recently identified as a novel cardiac biomarkers in the evaluation and risk stratification adipose-specific cysteine-rich protein.5–8 It is a 12.5-kDa of patients with heart failure continues to increase in polypeptide, whose functions are not clearly established, importance. although it has been associated with insulin resistance in Therefore, the purpose of the present study was to ex- rodents. It has been reported that resistin potentially links amine whether: (1) serum levels of resistin, 1 of adipo- obesity to diabetes in mice with diet-induced obesity and in cytokines, were related to the severity of heart failure; and genetically obese mice.9 A recent study has demonstrated (2) serum resistin was useful to predict adverse clinical that plasma resistin levels are correlated with markers of outcomes in patients with heart failure. inflammation and are predictive of coronary atherosclerosis in humans.10 Congestive heart failure (CHF) is a major and increasing Methods Study Population (Received November 9, 2006; revised manuscript received December Between January 2001 and April 2004, we prospectively 26, 2006; accepted January 16, 2007) enrolled 126 consecutive CHF patients (76 men and 50 Department of Cardiology, Pulmonology, and Nephrology, Yamagata women, mean age 67±13 years, range 21–92 years) who University School of Medicine, Yamagata, Japan Mailing address: Yasuchika Takeishi, MD, Department of Cardiology, had been admitted to the Yamagata University Hospital for Pulmonology, and Nephrology, Yamagata University School of Medi- treatment because of worsening CHF, for the diagnosis and cine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. E-mail: takeishi pathophysiological investigations, or for therapeutic evalua- @med.id.yamagata-u.ac.jp tions of CHF. Baseline characteristics of the study popula- Circulation Journal Vol.71, April 2007 Serum Resistin in Heart Failure 461 tion are shown in Table1. Exclusion criteria in the present Table 1 Clinical Characteristics of 126 Patients With Chronic Heart study included: patients with clinical or electrocardio- Failure graphic evidence suggestive of acute coronary syndrome n=126 within 3 months preceding admission, those with renal failure characterized by a serum creatinine concentration Age (years) 67±13 ≥ M/F 76/50 1.5mg/dl, and those with active hepatic or pulmonary dis- NYHA class (I/II/III/IV) 33/44/43/6 15–19 ease. Informed consent was obtained from all patients Hypertension (%) 71 (56%) before participation in this study, and the study protocol DM (%) 32 (16%) was approved by the Human Investigations Committee of Hyperlipidemia (%) 24 (19%) our institution. Smoking (%) 31 (29%) Blood samples were obtained at admission for measure- BMI (kg/m2) 23.5±3.8 Etiology of heart failure (%) ments of serum resistin levels. A 2-dimensional echocar- Dilated cardiomyopathy 48 (38%) diography was performed by an experienced cardiologist, Ischemic heart disease 34 (27%) who did not have knowledge of the biochemical data, Valvular heart disease 20 (15%) within 1 week after admission. Clinical data, including age, Hypertensive heart disease 12 (10%) sex and New York Heart Association (NYHA) functional Others 12 (10%) class at admission were obtained from patient interviews Blood examinations Glucose (mg/dl) 131±62 and hospital medical records. The diagnosis of CHF was HbA1c (%) 6.2±1.3 based on a history of dyspnea and symptomatic exercise in- Hb (g/dl) 12.8±2.1 tolerance with signs of pulmonary congestion or peripheral Total cholesterol (mg/dl) 187±44 edema or documentation of left ventricular enlargement or Triglyceride (mg/dl) 113±63 dysfunction by chest X-ray film, echocardiography, or HDL-C (mg/dl) 50±15 radionuclide ventriculography.15–19 The etiologies of CHF LDL-C (mg/dl) 113±38 Creatinine (mg/dl) 0.9±0.3 were dilated cardiomyopathy in 48 patients, ischemic heart Resistin (ng/ml) 12.1±8.5 disease in 34 patients, valvular heart disease in 20 patients, BNP (pg/ml) 495±647 and hypertensive heart disease in 12 patients. A diagnosis of Echocardiography hypertension, diabetes, and hyperlipidemia were obtained LVEDD (mm) 53±10 from medical records or patient history of currently or pre- LVEF (%) 49±20 viously received medical therapy. E/A ratio 2.2±7.8 DcT (ms) 203±85 Physicians were kept blinded to the results of the bio- Medications (%) chemical markers, and optimal medical therapy was per- ACEI/ARB 86 (68%) formed independently based on improvement of symptoms, β-blockers 50 (40%) physical examination findings, and pulmonary congestion Ca channel blockers 40 (32%) on chest X-rays. Loop diuretics 74 (59%) Spironolactone 31 (25%) Digoxin 40 (32%) End-Points and Follow up Statins 22 (17%) No patients were lost to follow up (mean follow up 645±644 days, range 29–1,080 days) after discharge. The NYHA, New York Heart Association; DM, diabetes mellitus; BMI, body mass end-points were: (1) cardiac death, defined as death from index; Hb, hemoglobin; HDL-C, high-density lipoprotein-cholesterol; LDL- worsening CHF or sudden cardiac death; and (2) worsening C, low-density lipoprotein-cholesterol; BNP, brain natriuretic peptide; 15–19 LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejec- CHF requiring readmission. Sudden cardiac death was tion fraction; DcT, deceleration time; ACEI, angiotensin-converting enzyme- defined as death without definite premonitory symptoms or inhibitors; ARB, angiotensin II receptor blocker. signs and was confirmed by the attending physician. A re- view of medical records and follow-up telephone interviews were conducted to survey cardiac events by 2 cardiologists, value below the lower detection limit of the assay was who were blinded to blood examination data. Cardiac defined as zero. A Cox proportional hazard analysis was events were adjudicated using medical records, electrocar- performed to determine the independent predictor of car- diograms, chest X-ray reports, autopsy reports, death cer- diac events for the entire population. Independent pre- tificates and witness statements. dictors selected in the univariate analysis were entered into the multivariate analysis. A cardiac event-free curve was Measurement of Serum Resistin Levels computed according to the Kaplan – Meier method and Blood samples obtained at admission for measurement compared by a log-rank test. A p value of less than 0.05 was of serum levels of resistin were drawn and centrifuged at considered as statistically significant. Statistical analysis 2,500G for 15min at 4°C within 30min of collection, and was performed with a standard statistical program package the serum obtained was stored at –70°C until analysis. (StatView, version 5.0, SPSS version 10.0 Institute Inc). Serum resistin concentration was measured by using a sandwich enzyme-linked immunosorbent assay (ELISA, Phoenix Pharmaceutical, Inc, Belmont, CA, USA) as pre- Results viously reported.7 Intra- and inter-assay coefficients of varia- Serum Resistin Levels in Study Subjects tion were 3.4 and 6.3%, respectively. Serum resistin levels were measured in 126 patients with heart failure and in 18 control subjects. As shown in Fig1, Statistical Analysis serum resistin levels increased with advancing NYHA Data are presented as mean±standard deviation (SD). functional class.
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