High-intensity Interval Training after Percutaneous Coronary Intervention. A randomized controlled study evaluating the effect of exercise training on late luminal loss with relationship to inflammation and endothelial function
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Introduction: In spite of consistent scientific documentation of the beneficial effects of exercise training programs in coronary artery disease (CAD), exercise training is a remarkably underutilized (1) and probably also undervalued treatment option. CAD is an inflammatory disorder linking inflammation in the vessel wall to endothelial dysfunction and progression of disease (2). The aim of this study was to explore the effects of a high-intensity interval training program on the late luminal loss and the associated risk of restenosis, plasma levels of inflammatory markers, endothelial function and the cardiac autonomic nervous system. Further, percutaneous coronary intervention (PCI) can be regarded as a model for mechanical induced plaque rupture. An additionally objective was therefore the evaluation of the inflammatory response to PCI reflected by plasma levels of numerous inflammatory mediators. Methods: Subjects: Forty consecutive patients were included after successful PCI with stent implantation in one or several native coronary arteries because of angina pectoris. Patients were randomly assigned to an organized training program for 6 months or to usual care. Exercise Training: A high-intensity interval group training for 60 minutes three times a week was used, starting 11±4 days after PCI. Individual pulse watches allowed the patients to monitor their heart rate and exercise intensity during training. Quantitative coronary angiography: At 6 months follow-up, coronary reangiography with repetition of identical angiographic projections of the lesion was performed. A validated computer-assisted edge-detection algorithm was used to measure late luminal loss defined as the minimal lumen diameter immediately after the procedure minus the minimal lumen diameter at 6 months follow-up. Exercise Testing: Symptom-limited ergospirometry was performed on an upright, electrically braked cycle ergometer using a 20 Watt/minute ramp protocol. The patients were asked to exercise to exhaustion. Gas exchange data were collected continuously with an automated breath-bybreath system. Endothelial Function: Endothelium-dependent and endothelium-independent dilation of the brachial artery was measured using a 12-MHz ultrasound Doppler probe according to current guidelines (3). Inflammatory markers: High-sensitivity CRP concentrations were measured by a particle-enhanced immunoturbidimetric method with the use of Roche Modular P automated clinical chemistry analysers (Roche Diagnostics). Plasma concentrations of interleukin-(IL)-6, IL-10, pentraxin 3 (PTX3), tumor necrosis factor (TNF)α, vascular cell adhesion molecule (VCAM)-1, E-selectin, Pselectin, monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation, normal T cell expressed and secreted (RANTES/CCL5), CCL19, CCL21, IL-8/CXCL8 and CXCL16 were quantified by enzyme immunoassays (EIAs) obtained from R&D Systems (Minneapolis, MN). Plasma concentrations of von Willebrand factor (vWF) were analyzed by EIA using antibodies from DakoCytomation (Glostrup, Denmark). Plasma concentrations of CD40 ligand (CD40L) were analyzed by EIA provided by Bender MedSystems GmbH (Vienna, Austria). Heart Rate Variability: Heart rate variability (HRV) measures were obtained from a 3-channel portable Holter (Schiller MT-200, Switzerland) worn for 24 hours. The MT-210 Analysis Software Version 1.0.0 (Schiller) was used to analyse time and frequency domain measures of HRV. Results: At six months in-stent restenosis, measured as in-segment late luminal loss of the stented coronary area, was significant smaller in the training group compared to the control group. This effect was associated with a significant increased peak oxygen uptake and improved brachial artery reactivity in the training group only. In the training group all time domain indices and the frequency domain indices, total power and ultralow frequency of HRV, increased significantly during the training period, while mean heart rate decreased significantly. In the control group only one time domain measure index increased significantly. Plasma levels of CRP and PTX3 showed a significantly early increase after PCI peaking at 3 days and 3 hours, respectively. VCAM-1 increased significantly with a peak at 3 days, while E-selectin showed a significant gradual decrease. Markers of platelet mediated inflammation showed increasing (CD40 ligand) and decreasing (P-selectin) levels after PCI. While plasma levels of MCP, CCL21 and CXCL16 increased rapidly in response to PCI, IL-8, CCL19 and RANTES decreased. At 6 months, levels of the inflammatory markers CRP, IL-6 and IL-8 were significantly reduced and levels of the anti-inflammatory cytokine IL-10 were significantly increased in the training group only. The changes of CRP and IL-6 from baseline to 6 months were significantly correlated to late luminal loss in the stented segment at 6 months. In contrast to these anti-inflammatory effects, training had no effect on markers of platelet-mediated inflammation, and the effect of training on markers on endothelial cell activation were rather complex showing attenuating (vWF) and enhancing (E-selectin and VCAM-1) effects. Conclusion Regular high-intensity interval exercise training over 6 months resulted in a significant reduction in late luminal loss in the stented coronary segment after PCI for angina pectoris. This effect was associated with increased aerobic capacity, improved endothelium function and improved heart rate variability. PCI induced a complex response of plasma levels of inflammatory markers and cytokines during the first week post-PCI. Regular exercise training in non-acute stable angina patients following PCI may attenuate some, but not all inflammatory pathways, potentially contributing to the beneficial effects of exercise training on restenosis.
Paper I: American Heart Journal 158(5), Munk, P. S.; Staal, E. M.; Butt, N.; Isaksen, K.; Larsen, A. I., High-Intensity Interval Training May Reduce in-stent Restenosis Following Percutaneous Coronary Intervention with Stent Implantation: A randomized controlled trial evaluating the relationship to endothelial function and inflammation, pp. 734-741. Copyright 2009 Mosby. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1016/j.ahj.2009.08.021Paper II: International Journal of Cardiology 145(2), Munk, P. S.; Butt, N.; Larsen, A. I., High-Intensity Interval Exercise Training Improves Heart Rate Variability in Patients following Percutaneous Coronary Intervention for Angina Pectoris, pp. 312-314. Copyright 2009 Elsevier Ireland. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1016/j.ijcard.2009.11.015Paper III: Journal of Thrombosis and Thrombolysis 31(1), Munk, P. S.; Breland, U. M.; Aukrust, P.; Skadberg, Ø.; Ueland, T.; Larsen, A. I., Inflammatory Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease, pp. 92-98. Copyright 2010 Springer Science+Business Media. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1007/s11239-010-0471-7Paper IV: Munk, P. S.; Breland, U. M.; Aukrust, P.; Ueland, T.; Kvaløy, J. T.; Larsen, A. I., 2010, Exercise training reduces systemic inflammation in patients with stable coronary heart disease treated with percutaneous coronary intervention. Relationship to reduction of restenosis. Full text not available in BORA.