1. Exercise improves coronary endothelial function in patients with coronary artery disease By Jordan Gauder Faculty of Health Sciences and Medicine, Bond University, QLD 4220 Methods: 19 patients with coronary endothelial dysfunction were randomly assigned to either the exercise group (10 patients) or to the control group (9 patients). To reduce confounding, patients with coronary risks that could be influenced by exercise training (such as diabetes, hypertension, hypercholesterolemia and smoking) were excluded. Patients assigned to the exercise program stayed in the hospital for four weeks of the study period. Their program consisted of 10 minutes on the cycle ergometer six times a day (in addition to 5 mins warm up and warm down). The cycling work rate was consistent with 80% of the heart rate they had achieved during a VO2 max test. The study was conducted over 4 weeks and results were gathered at the end of the fourth week. Data analysis: Titles and abstracts of all identified articles were screened for relevant trials and tests made on coronary artery disease patients. The relevant articles were up to date and were no longer than 10 years old; however studies on the physiological principles of endothelial function were older. Results: In the initial study the patients in the exercise group and control group revealed similar responses to the intracoronary Ach dosages. In the exercise group, the mean decreases in luminal diameter after infusions of 0.072, 0.72 and 7.2µg of Ach per minute were 5.3±1.5, 11.0±2.4, 15.22.2 respectively. Control group expressed similar results. After the four weeks of exercise training the coronary artery constriction was reduced by 48%, from 0.29±0.06 to 0.15±0.05 (shown in Fig.2). Introduction: Cornary artery disease (CAD) is a severe cardiovascular disease which can lead to death if untreated. Its prevalence in Australia alone from 2004-05 was 637,900.3 CAD is the build up of plaque in the coronary arteries which can cause inflammation and stenosis. Over time if undiagnosed it can cause serious obstruction to the blood flow of the heart and may cause a myocardial infarction, cardiac arrest or sudden death. An important modulator of blood vessels is the vascular endothelium which can act as a vasomotor tone and function. This is done by synthesizing and using the up regulation of nitric oxide.1The coronary vascular response to acetylcholine (Ach) depends on the state of the endothelium and endothelial nitric oxide pathway.2In patients with CAD, endothelial dysfunction is associated with coronary atherosclerosis and demonstrates that severe endothelial dysfunction in patients with CAD is associated with increased cardiac events.8This is represented in the figure below: After four weeks of exercise training, the change in CBF in response to Ach administration increased in a dose dependant manner. At 7.2µg the mean CBF increased from 27±11 percent above baseline at the initial study to 110±24 percent above baseline at four weeks (from 36±18 to 185±38ml/min) (Fig.3) Figure 3. Changes in CBF in response to Ach at a dose of 7.2µg/min at the initial study and after four weeks (P<0.01). Negative values indicate decreases in CBF. Exercise training led to a significant increase in flow dependant dilatation from 0.19±0.06 to 0.39±0.07mm, a 105% change; P<0.01 for the comparison between both groups. In the control group the changes in vessel diameter and blood flow velocity in response to Ach infusion were not significantly different from those in the initial study. Also flow dependant dilation in this group showed no significant change to adenosine infusion. Conclusions: Four weeks of vigorous exercise training improved coronary endothelial function in patients with coronary atherosclerosis. Coronary vasoconstriction in response to Ach was significantly attenuated after exercise training, indicating that exercise had beneficial effects on the endothelium in epicardial conduit vessels. Adenosine induced flow dependant vasodilatation was also markedly improved. Recent studies have shown that this improved effect on endothelial function is accompanied by an increased eNOS protein expression and eNOSphosphorylation thus attenuating the premature breakdown of NO by ROS. These increases in both local NO production and half life improve endothelium vasodilation in response to flow or Ach.6,9,10However this study did not restore endothelial response to normal levels, suggesting that the restoration of normal endothelial function may require a more extended training intervention. A Cochrane meta-analysis showed CAD patients in the exercise only group had a 27% reduction in all cause mortality when participated in moderate physical activity, 5 times a week. This suggests that the improvement of endothelial dysfunction helps to reduce cardiac morbidity and mortality in coronary artery disease patients, showing exercise can be used as an improvement in the rehabilitation of CAD patients. Figure1. A, Mean percentage change in CBF in response to acetylcholine among 3 groups, *P<0.0001 (Group 1 with the least and group 3 with the most severe endothelial function). B, Cardiac events (myocardial infarction percutaneous revascularizations, CABG, and/or cardiac death). †P<0.05. Management of CAD and reducing future adverse cardiac events exercise can be used as a form of treatment. Recent studies have shown evidence that exercise not only improves vascular function but also induced generalized improvement in endothelial function, possible as a result of hemodynamic and shear stress associated with exercise.4, 6Cost effectiveness over 12months shows that exercise expenses were significantly cheaper than percutaneous coronary intervention in rehabilitation for patients with coronary artery disease. Aim:The objective of this study is to determine whether aerobic exercise training has the potential to correct endothelial dysfunction and improve myocardial perfusion in patients with coronary artery disease. Figure 2. Individual changes in ccoronary-vessel luminal diameter in response to Ach at a dose of 7.2µg per minute at the initial study and after four weeks. Mean percentage differed significantly between the groups at four weeks, P<0.05. References: Furchgott RF, Zawadzki JV, Jothiananda D. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-6. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia,and hypertension. J Clin Invest 1993;92:652-62. Australian Government 2010, Coronary artery disease statistics, [Online] Available: http://www.aihw.gov.au/cvd/coronary_disease.cfm (30/7) Rainer Hambrecht, M.D., Anamaria Wolf, M.D, Stephen Gielen, M.D, et al. ‘Effect of exercise on Coronary endothelial function in patients with coronary artery disease’, N Eng J Med, Vol. 342, no. 7, pp. 454-460. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Eng J Med. 2;315:1046–1051 Jenifer H Walsh, William Bilsborough, Andrew Maiorana, et al. Exercise training improves conduit vessel function in patients with coronary artery disease. J Appl Physiol. 2003; 95:20-25 Ricardo J Esper, Roberto A Nordaby, Jorge O Vilariño, et al. Endothelial dysfunction: a comprehensive appraisal. Cardiovascular Diabetology 2006; pg 1-18 Jassim Al Suwaidi, MB, ChB; Shuichi Hamasaki, MD. Et al. Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction. American heart association. 2000;101;948-954 R. Hambrecht, MD; V. Adams, PhD; S. Erbs, MD. Et al. Regular physical activity improved endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. American heart association. 2003; 3153-3158 S. Gielen, MD; G. Schuler, MD; R. Hambrecht, MD. Exercise Training in Coronary Artery Disease and coronary vasomotion. American heart association 2001. January 10/3 Jolliffe J, Rees K, Taylor RRS. Et al. Exercise-based rehabilitation for coronary heart disease. Cochrane review. 2009 Exercise training led to significantly greater increases in coronary blood flow (CBF) velocity from base line in all respective doses, 0.072µg, 0.72µg, 7.2µg. The increase was 96% (from 4.6±2.8cm per second at the initial study to 9.0±3.6cm per second at the four weeks) with acetylcholine at a dose of 0.072µg per minute (P<0.05).