Prognostic Usefulness of an Increase of N-Terminal Proatrial Natriuretic Peptide During Exercise in Patients With Chronic Heart Failure Alf Inge Larsen, MD, Christian Hall, MD, PhD, Pål Aukrust, MD, PhD, Torbjørn Aarsland, RN, Peter Faris, PhD, and Kenneth Dickstein, MD, PhD T his study shows that although patients with con- gestive heart failure (CHF) have elevated plasma levels of N-terminal (NT) proatrial natriuretic peptide (pro-ANP) compared with healthy persons, this neu- rohormone is further increased during exercise in such patients. Notably, such an increase is associated with long-term survival in this study population, suggesting a potential beneficial effect of the ability to increase ANP during exercise in patients with CHF. ••• Atrial natriuretic peptide (ANP) is a neurohormone found in increasing concentrations in relation to the severity of functional impairment in patients with CHF. 1 There are some studies that have reported en- hanced plasma ANP levels in response to dynamic exercise in patients with CHF, 2 but whether this is beneficial in such patients is unknown. Inactivity and deconditioning may be important factors aggravating the underlying pathophysiology in CHF. 3 Exercise training has been shown to improve exercise perfor- mance and to reduce symptoms in this population. 4 Results from studies on the effect of training on plasma levels of ANP in patients with CHF are not consistent. 5,6 This study evaluates the effect of a 12- week training program on levels of NT pro-ANP at rest and at maximal exercise, increases of NT pro- ANP during exercise, and the correlations between these values and cytokine levels, exercise perfor- mance, and mortality in patiens with CHF. Twenty-five men with stable CHF in New York Heart Association class II to III with a peak oxygen consumption 20 ml/kg/min and a 6-minute walk test 550 m were recruited for the study (Table l). Pa- tients were treated with conventional medical therapy; however, no patient was taking  blockers (Table l). The dosages of medical therapy remained constant during the training period, and there were no episodes of acute coronary syndromes or need for revascular- ization during this period. For comparison, the plasma concentrations of NT pro-ANP were measured in 19 controls (9 men and 10 women, mean age 66 years, range 54 to 83). These control subjects were recruited from an outpatient practice and were free from car- diopulmonary, renal, and infectious diseases accord- ing to questionnaire and clinical examination. The regional ethical committee approved the pro- tocol, and written informed consent was obtained from all patients. The study used an open trial de- signed for evaluating the effect of a 12-week exercise training program. The design, training protocol, and exercise testing protocols have previously been report- ed. 7 Patients were evaluated on an upright, electrically braked cycle ergometer (model KEM III, Mijnhardt, S.V. Bunnik, The Netherlands) using a 15 W/min ramp protocol to assess maximal exercise capacity. Gas exchange data were collected continuously with an automated breath-by-breath system (System 2001, Medical Graphics Corporation, St. Paul, Minnesota). To evaluate submaximal exercise capacity, the 6-minute walk test was performed according to con- ventional criteria, and the same investigator monitored all tests to ensure uniform instruction in a quiet exer- cise facility. 8 To assess endurance capacity, patients were in- structed to walk on a Star Track 3028 treadmill with a gradually increased speed and angle until a stable heart rate equal to 85% of the peak heart rate, as measured during maximal baseline bicycle testing, was reached. The patient was then instructed to con- tinue at a constant rate and angle until a total test time of 30 minutes. Capillary blood was collected before exercise, every 4 minutes during the test, at the end of test, and at 5 minutes into recovery for the assessment of lactate production. Before the maximal exercise test, an arterial can- nula (Viggo Spectramed, Helsingborg, Sweden) was placed in the radial artery and fixed to the arm with a continuous flush device (Intraflo II, 30 ml/hour, Ab- bott, Berkshire, United Kingdom) with heparinized saline solution connected to it. At baseline and at termination of the study, blood for analysis of NT pro-ANP and cytokines was collected from the arterial cannula into pyrogen-free vacuum blood collection ethylenediaminetetraacetic acid tubes (Becton Dickin- son, San Jose, California) after 5 minutes of supine rest. The tubes were immediately immersed in melting ice, centrifuged within 15 minutes at 1,000 g and 4°C for 10 minutes and then stored at -80°C. The plasma NT pro-ANP concentration was mea- sured in unextracted arterial plasma according to Sundsfjord et al. 9 The detection limit was 185 pmol/L and the between- and within-assay coefficients of vari- ation were 4.1% and 6.3%, respectively. Plasma levels of tumor necrosis factor (TNF)- From the Cardiology Division, Central Hospital in Rogaland, Stavanger; Research Institute for Internal Medicine, Medical Depart- ment, and Section of Clinical Immunology and Infectious Disease, Rikshospitalet, Oslo; and Hjertelaget Research Foundation, Stavanger, Norway; and the Department of Health Sciences, University of Cal- gary, Calgary, Alberta, Canada. Dr. Larsen’s address is: Cardiology Division, Central Hospital in Rogaland, N-4001 Stavanger, Norway. E-mail: al-i-lar@online.no. Manuscript received February 13, 2003; revised manuscript received and accepted March 27, 2003. 91 ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matter The American Journal of Cardiology Vol. 92 July 1, 2003 doi:10.1016/S0002-9149(03)00478-8