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(Circulation. 2009;120:42-49.)
© 2009 American Heart Association, Inc.

Hypertension

Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension

M.L. Handoko, MD^*; F.S. de Man, MSc^*; C.M. Happé, BSc; I. Schalij, BSc; R.J.P. Musters, PhD; N. Westerhof, PhD; P.E. Postmus, MD, PhD; W.J. Paulus, MD, PhD; W.J. van der Laarse, PhD; A. Vonk-Noordegraaf, MD, PhD

From the Departments of Physiology (M.L.H., F.S.d.M., R.J.P.M., N.W., W.J.P., W.J.v.d.L.) and Pulmonology (M.L.H., F.S.d.M., C.M.H., I.S., N.W., P.E.P., A.V.N.), VU University Medical Center/Institute for Cardiovascular Research, Amsterdam, the Netherlands.

Correspondence to Dr Anton Vonk-Noordegraaf, Department of Pulmonology, VU University Medical Center, Boelelaan 1117, 1081 BV Amsterdam, the Netherlands. E-mail a.vonk{at}vumc.nl

Received November 4, 2008; accepted May 8, 2009.

Background— Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment. However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training.

Methods and Results— Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25±3.9 to 62±3.9 minutes; P<0.001). Moreover, capillary density increased significantly (from 1.21±0.12 to 1.51±0.07 capillaries per cardiomyocyte; P<0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135±14 to 276±18 leukocytes per 1 mm²; P<0.001).

Conclusions— In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings.

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CLINICAL PERSPECTIVE

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