European Heart Journal Advance Access published online on September 30, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp398
Long- but not short-term multifactorial intervention with focus on exercise training improves coronary endothelial dysfunction in diabetes mellitus type 2 and coronary artery disease
1 Department of Cardiology, Heart Centre, University of Leipzig, Leipzig, Germany
2 Department of Medicine, University of Leipzig, Leipzig, Germany
3 Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
4 Internal Medicine, Cardiology, Sports Medicine, Chair and Full Professor of Medicine, Institute of Sports Medicine, Prevention and Rehabilitation, Paracelsus Medical University Salzburg, Lindhofstr. 20, Salzburg 5020, Austria
Received 21 February 2009; revised 7 April 2009; accepted 9 August 2009 * Corresponding author. Tel: +43 662 4482 4270, Fax: +43 662 4482 4274, Email: j.niebauer{at}salk.at
Aims: Patients with type 2 diabetes mellitus (T2DM) suffer from accelerated coronary artery disease. We assessed the effects of a multifactorial intervention with focus on exercise training on coronary endothelial function, vascular structure, and inflammation in serum and skeletal muscle biopsies, including mRNA expression of diabetes candidate genes.
Methods and results: Twenty-three patients were randomized to either 4 weeks in-hospital exercise training (6 x 15 min bicycle/day, 5 days/week) and a hypocaloric diet, followed by a 5 months ambulatory program (30 min ergometer/day, 5 days/week, plus 1 h group exercise/week), or a control group. At the beginning of the study, at 4 weeks, and after 6 months changes in diameter of coronary arteries in response to acetylcholine and mean peak flow velocity were invasively measured; intramural plaques were assessed by intravascular ultrasound. Six months of intervention led to significant improvement of coronary endothelial function, whereas intramural plaque burden remained unchanged. After 4 weeks, endothelial function remained unchanged, however, lowest values for fasting glucose, HbA1c, high-sensitive C-reactive protein, total and LDL-cholesterol, and highest values for mRNA expression in skeletal muscle of p22, gp91, haem oxygenase 1, peroxisome proliferator activator receptor (PPAR) 
and 
were observed. There was a continuous increase for AdipoR1, AdipoR2, Glut4, interleukin-6, endothelial nitric oxide synthase, and PPAR-coactivator-1 mRNA expression in skeletal muscle.
Conclusion: This is the first study to demonstrate improvement in coronary endothelial function by a multifactorial intervention which focused on exercise training in patients with T2DM. This coincided with improved markers of hyperglycaemia, insulin sensitivity, and inflammation both in serum and skeletal muscle biopsies.
Key Words: Exercise training • Coronary endothelial function • Diabetes mellitus • Skeletal muscle • Intracoronary ultrasound