Effects of exercise training in patients with idiopathic pulmonary arterial hypertension F.S. de Man*, M.L. Handoko* ,# , H. Groepenhoff*, A.J. van ’t Hul " , J. Abbink + , R.J.H. Koppers 1 , H.P. Grotjohan e , J.W.R. Twisk**, H-J. Bogaard*, A. Boonstra*, P.E. Postmus*, N. Westerhof* ,# , W.J. van der Laarse # and A. Vonk-Noordegraaf* ABSTRACT: We determined the physiological effects of exercise training on exercise capacity and quadriceps muscle function in patients with idiopathic pulmonary arterial hypertension (iPAH). In total, 19 clinically stable iPAH patients (New York Heart Association II-III) underwent a supervised exercise training programme for the duration of 12 weeks. Maximal capacity, endurance capacity and quadriceps function were assessed at baseline and after 12 weeks. In 12 patients, serial quadriceps muscle biopsies were obtained. 6-min walk distance and peak exercise capacity did not change after training. However, endurance capacity improved significantly after training, demonstrated by a shift of the anaerobic threshold to a higher workload (from 32¡5 to 46¡6 W; p50.003) together with an increase in exercise endurance time (p,0.001). Moreover, exercise training increased quadriceps strength by 13% (p50.005) and quadriceps endurance by 34% (p50.001). Training enhanced aerobic capacity of the quadriceps, by increasing capillarisation (1.36¡0.10 to 1.78¡0.13 capillaries per muscle fibre; p,0.001) and oxidative enzyme activity, especially of the type-I (slow) muscle fibres. No changes were found in cross-sectional area and fibre type distribution. Exercise training in iPAH improves exercise endurance and quadriceps muscle function, which is also reflected by structural changes of the quadriceps. KEYWORDS: Biopsy, exercise training, pathophysiology, pulmonary hypertension, skeletal muscle dysfunction I diopathic pulmonary arterial hypertension (iPAH) is a life threatening disease, which eventually leads to right heart failure. A high pulmonary vascular resistance and right ventricu- lar dysfunction impair stroke volume, thereby limiting oxygen supply to the skeletal muscles, especially during exercise, resulting in lactic acidosis at low work rates and impaired functional capacity [1, 2]. Traditionally, exercise training in iPAH patients was contraindicated due to the risk of sudden cardiac death [3]. However, with the increase in medical treatment options in the last decennium, the prognosis has improved significantly, and the role of exercise training in patients with iPAH was reconsidered [3]. Recently, the first clinical trial on exercise training in patients with pulmonary arterial hypertension reported promising results of improved exercise capacity and quality of life [4]. Exercise training is a well-established adjunct therapy in several chronic diseases such as chronic obstructive pulmonary disease (COPD) and congestive heart failure [5, 6]. In patients with these chronic diseases, skeletal muscle dysfunction contributes to exercise intolerance [7–9]. The beneficial effects of exercise training in COPD and congestive heart failure are partially attributed to improved skeletal muscle efficiency [10, 11] and increased capillary density and oxidative enzyme activity in quadriceps muscle biopsies [11–13]. Also in iPAH patients, skeletal muscle dysfunc- tion has been reported. Respiratory muscle dys- function was found in two studies, both by voluntary and nonvoluntary techniques [14, 15]. More recently, forearm muscle dysfunction has been reported in these patients [16]. In a pilot study, examining voluntary strength of the AFFILIATIONS Depts of *Pulmonology, and # Physiology, Institute for Cardiovascular Research, and **Dept of Clinical Epidemiology and Biostatistics, The Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, " Breda Rehabilitation Center Foundation, Breda, + Rijnlands Rehabilitation Center, Leiden, 1 Dept of Pulmonology, Leeuwarden Medical Center, Leeuwarden, and e Dept of Pulmonology, Isala Clinics, Zwolle, The Netherlands. CORRESPONDENCE A. Vonk Noordegraaf Dept of Pulmonology VU University Medical Center Boelelaan 1117 1081 HV Amsterdam The Netherlands E-mail: a.vonk@vumc.nl Received: Feb 17 2009 Accepted after revision: March 13 2009 European Respiratory Journal Print ISSN 0903-1936 Online ISSN 1399-3003 Earn CME accreditation by answering questions about this article. You will find these at the back of the printed copy of this issue or online at www.erj.ersjournals.com/current.dtl EUROPEAN RESPIRATORY JOURNAL VOLUME 34 NUMBER 3 669 Eur Respir J 2009; 34: 669–675 DOI: 10.1183/09031936.00027909 CopyrightßERS Journals Ltd 2009 c