Effect of Mild Aerobic Exercise on Serum Lipids and Apolipoproteins in Patients with Coronary Artery Disease

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1 Effect of Mild Aerobic Exercise on Serum Lipids and Apolipoproteins in Patients with Coronary Artery Disease Hidenori URATA, M.D.,* Jun SASAKI, M.D.,* Yoichi TANABE, M.D.,* Akira KIYONAGA, M.D.,* Toyokazu YOSHIDA, M.D.,* Hiroaki TANAKA, M.D.,** Munehito SHINDO, Ph.D.,** and Kikuo ARAKAWA, M.D.* SUMMARY The effects of mild aerobic exercise on serum lipids, apolipoproteins and lecithin-cholesterol acyltransferase (LCAT) activity were examined in 11 male patients with coronary artery disease and 4 healthy male controls. The mild aerobic exercise program involved exercise intensity at 50% of maximal oxygen uptake, as determined from the blood lactate threshold, for 60min periods 3 times per week for 10 weeks. Following mild aerobic exercise, serum levels of high density lipoprotein cholesterol (HDL-C) were increased significantly from 50 }7mg/dl to 59 }11mg/dl (p<0.05) with a simultaneous increase in apolipoprotein A-I (apo A-I) in normal controls. The LCAT activity was significantly increased from 65 } 22nmol/ml/hr to 99 }30nmol/ml/hr in normal controls (p<0.05). Furthermore, maximal oxygen uptake (VO2max) was significantly increased in normal controls. In contrast, no significant changes were found in HDL-C, apo A-I, apo B, VO2max and body weight in patients with coronary artery disease. There was significant correlation between the initial HDL-C level and the change in HDL-C level following the exercise program in the combined group of normal controls and patients with coronary artery disease. Additional Indexing Words: Aerobic exercise therapy HDL Apoprotein Lipoprotein Ischemic heart disease HE relation between low HDL-C and increased risk for ischemic heart disease has been suggested from epidemiological studies.1)-3) It has also From the Second Department of Internal Medicine* and Physical Education,** Fukuoka University, Fukuoka. Address for reprint: Jun Sasaki, M.D., Second Department of Internal Medicine, School of Medicine, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka , Japan. Received for publication February 3, Manuscript revised July 21,

2 28 URATA, ET AL. Jpn. Heart J. January 1987 been suggested that regular physical exercise increases the concentration of high density lipoproteins and thereby decreases the risk of ischemic heart disease.4)-8) In fact many studies, primarily in patients with coronary artery disease, report that beneficial changes in lipoprotein metabolism occur following regular exercise therapy. 7),9)-13) Although cross-sectional studies with mild exercise and a number of longitudinal studies with moderate or severe exercise have been performed and the serum lipid and lipoprotein profiles reported, there are little or no data that examined the effect in longitudinal studies of mild aerobic exercise on serum lipids and lipoproteins. We report here the results of a longitudinal study designed to examine the effect of mild aerobic exercise on changes in serum lipids, lipoproteins and apolipoproteins in middle aged men with no coronary artery disease and male patients with coronary artery disease. MATERIALS AND METHODS Eleven male patients with coronary artery disease aged 45 to 64 (average 57 years) and 4 control men (average 51 years) participated in this study. The patients with coronary artery disease were assessed by selective coronary angiography. All patients had more than 75% stenosis of at least one main coronary artery. Five patients had old myocardial infarction without severe complication. At the end of the control period, the patients were subjected to a multistage test of submaximal exercise on an electric bicycle ergometer (Lode, Holland) according to the method described elsewhere.14) The exercise intensity of each subject was estimated for each patient from a plot of blood lactate concentration against exercise work load in watts. This break point reflects the blood lactate threshold, which corresponds to approximately 50% of VO2max. Since our graded exercise was submaximal, VO2max was calculated using work load, heart rate and the volume of oxygen uptake (ml/kg/min) during the graded exercise test by the method of Astrand.15) All patients were subjected to mild aerobic exercise 3 times a week for 10 weeks. Training began with a 5 to 10 min "warm up" period of light calisthenics and stretching exercise followed by a 60min exercise at 50% of VO2max using a bicycle ergometer (Monark, Sweden) at a steady speed. This in turn was followed by a 5 to 10min "cooling off" period. The exercise sequence was supervised by physical education instructors. The pulse rate, blood pressure and EGG were monitored during the training period by a physician. Intellectual work (e.g., speaking, reading, listening to the radio, watching television) was permitted during the exercise. A caloric expenditure

3 Vol.28 No.1 EFFECT OF MILD AEROBIC EXERCISE ON LIPID METABOLISM 29 of about 300kcal/60min was estimated. The blood sampling was done in the morning following the exercise day. The blood samples were collected by venipuncture from an antecubital vein following 12 hours of fasting. The serum was recovered following centrifugation at 3,000 rpm for 15 min and stored at 4 Ž. All analyses were completed within 48 hours. The concentrations of both cholesterol and triglyceride in the serum were measured using enzymatic assays.16),17) The HDL-C in serum was quantitated by heparin-manganese precipitation.18) Low density lipoprotein cholesterol (LDL- C) was calculated according to the method of Friedewald et al.19) The concentrations of serum apoproteins, apo A-I and apo B, were determined by rocket immunoassay as described previously.20) LCAT activity was measured using the method of Nagasaki and Akanuma.21) The patients in the study were asked to maintain their normal casual lifestyle during the study including diet, sleeping, alcohol, smoking and other exercise. Student's t-test was used to evaluate the statistical significance of the data. RESULTS After 10 weeks of mild aerobic exercise a significant increase in VO2max was observed in normal controls, whereas no significant changes were observed in patients with coronary artery disease (Table I). The increase in VO2max indicates that a substantial improvement in aerobic exercise capacity was observed in the normal group. No significant changes in body weight Table I. Comparison of the Characteristics of Normal Subjects and Patients with Coronary Artery Disease * p<0.05 compared to initial value. ** p<0.05 compared to the value of normal group. All values are mean }standard deviation.

4 30 URATA, ET AL. Jpn. Heart J. J anuary 1987 Table II. Changes in Lipids, Apolipoproteins and LCAT Activity Following Mild Aerobic Exercise in Normal Subjects (n=4) * p<0.05 compared to initial value. ** p<0.1 compared to initial value. All values are mean }standard deviation. Table III. Changes in Lipids, Apolipoproteins and LCAT Activity Following Mild Aerobic Exercise in Patients with Coronary Artery Disease (n=11) All values are mean }standard deviation. were observed in either group during this study. The concentrations of serum lipids and apolipoproteins as well as LCAT activity observed during this study are tabulated in Tables II (normal) and III for patients with coronary artery disease. In normal controls two significant changes were noted; the concentration of HDL-C and the LCAT activity were increased significantly (p<0.05 for both). Apo A-I levels tended to increase (p<0.1) and free fatty acids levels tended to decrease following 10 weeks of mild aerobic exercise, but these changes were not significant (Table II). No significant changes in TC, TG, PL and apo B were observed (Table II). In patients with coronary artery disease no significant changes were observed in HDL-C or any of the other parameters measured (Table III). A significant correlation between the initial HDL-C levels and the changes in HDL-C levels following exercise program was observed (Fig.1).

5 Vol.28 No.1 EFFECT OF MILD AEROBIC EXERCISE ON LIPID METABOLISM 31 Fig.1. The correlation between initial HDL-C levels and the change in HDL-C following a 10 week exercise program. Significant correlation between the initial HDL-C levels and the change in HDL-C levels following the exercise program was observed. =patients with coronary artery disease. =normal subjects. DISCUSSION The present study demonstrates that a quantitative mild aerobic exercise performed at approximately 50% of VO2max 3 times per week for 1 hour over 10 weeks increases VO2max, serum HDL-C level and LCAT activity in a group of randomly selected sedentary middle-aged men (control). In contrast, no significant changes were observed in those parameters in patients with coronary artery disease. Improvement in serum lipoprotein profiles that are associated with a decreased risk for the development of coronary artery disease has been reported following endurance exercise training programs.4)-8) From several retrospective studies, increased HDL-C levels in highly trained men and a positive correlation between the amount of exercise and HDL-C have been reported.22),23) However, there are no longitudinal studies that examined the effect of mild aerobic exercise on serum lipid and lipoprotein levels. Increased levels of HDL-C as a result of exercise training in patients with coronary artery disease have been reported. Huttunen et al9) reported a 11% increase in total HDL-C in patients with coronary artery disease who were exercised to 70% VO2max 3 times a week for 20 to 40 min over a 3 month period. Cowan10) reported a significant increase in HDL-C in patients exercised to 80% the maximal heart rate for 20min daily 5 days a week for 3 weeks. Ballantyne et al13) reported a significant increase in HDL2-C using

6 32 URATA, ET AL. Jpn. Heart J. January 1987 Fig.2. Changes in HDL-C, HDL2-C, HDL3-C following mild aerobic exercise for 20 weeks (in 1 case). HDL2 (1.063<d<1.125) and HDL3 (1.125< d<1.210) were separated by ultracentrifuge using KBr for density adjustment. The serum HDL2-C level increased and HDL3-C level decreased, yet no change was observed in the total HDL-C level. moderate physical exercise for 6 months in male myocardial infarction survivors. Streja et al11) reported only a very slight increase in HDL-C in sedentary men with coronary artery disease after jogging 2.8km, 3 times a week for a 13 week period. In the present study, even mild aerobic exercise, approximately 50% of VO2max, resulted in improved physical fitness and increased HDL-C levels in sedentary middle-aged men, although no improvement was observed in patients with coronary artery disease. From our studies we suggest that both a higher intensity and a longer duration of exercise than used in the present study are required to increase HDL-C levels in patients with coronary artery disease. In one of our patients followed for 5 months on the same exercise program, the serum HDL2-C level increased and HDL3-C was decreased (Fig. 2), yet no changes were observed in the total HDL-C level. Since a positive correlation between the initial HDL-C level and the increase in HDL-C after training was observed in the present study (Fig.1), one might expect no increase in HDL-C levels in patients with coronary artery disease and low initial HDL-C levels in response to this exercise program. A significant increase in LCAT activity was observed in the control subjects in response to the exercise regimen. Lopez-S et al24) also has reported an increase in LCAT activity after 7 weeks of moderate physical exercise performed in 30min sessions 4 times per week. The LCAT activity in the plasma results in the formation of cholesteryl esters. Cholesterol esterification occurs

7 Vol.28 EFFECT OF MILD AEROBIC EXERCISE ON LIPID METABOLISM 33 No.1 in a complex that includes LCAT, HDL and apolipoprotein A-I. Since an increase in both LCAT activity and HDL-C levels were observed in control men following mild aerobic exercise, an increased metabolism of cholesterol, i.e., esterification of serum cholesterol to form cholesteryl esters, would be expected in these men in response to this mild aerobic exercise. ACKNOWLEDGMENTS The authors are grateful to Prof. Gene L. Cottam, University of Texas for his skillful revision of this paper. We thank Ms. Setsuko Matsumoto and Ms. Tomoko Tanaka for their technical assistance and Ms. Sayuri Morikawa, Ms. Miyoko Yamauchi, Mr. Tsunekazu Kouriyama and Mr. Yoshiaki Tanabe for their help in performing the exercise training. REFERENCES 1. Gofman JW, Young W, Tandy R: Ischemic heart disease, atherosclerosis and longevity. Circulation 34: 679, Medalie JH, Kahn HA, Neufeld HN: Five year myocardial infarction incidence. II. Association of single variables by age and birthplace. J Chronic Dis 26: 329, Gordon T, Castelli WP, Hjortland MC: High density lipoprotein as a protective factor against coronary heart disease. The Framingham study. Am J Med 62: 707, Bonnano JA, Lies JE: Effects of physical training on coronary risk factors. Am J Cardiol 33: 760, Farrell PA, Barborian J: The time course of alterations in plasma lipid and lipoprotein concentrations during eight weeks of endurance training. Atherosclerosis 37: 231, Gillian TB, Burke MB: Effect of exercise on serum lipids and lipoproteins in girls, aged 8 to 10 years. Artery 4: 203, Hartung GH, Squires WG, Gotto AM: Effect of exercise training on plasma high density lipoprotein cholesterol in coronary disease patients. Am Heart J 101: 181, Holloszy JO, Skinner JS, Toro G, Cureton TK: Effect of a six month program of endurance exercise in the serum lipids of middle-aged man. Am J Cardiol 14: 753, Huttunen JK, Lansimies E, Voutilainen E, Ehnholm C, Hictanen E, Penttila I, Siitonen O, Rauramaa R: Effect of moderate physical exercise on serum lipoproteins: a controlled clinical trial with special reference to serum high density lipoprotein. Circulation 60: 1220, Cowan GO: Influence of exercise on high-density lipoproteins. Am J Cardiol 52: 138, Streja D, Mymin D: Moderate exercise and high-density lipoprotein-cholesterol. JAMA 242: 2190, Erkenlens DW, Albers JJ, Hazzard WR, Frederrick RC, Bierman EL: High-density lipoprotein-cholesterol in survivors of myocardial infarction. JAMA 242: 2184, Ballantyne FC, Clark RS, Simpson HS, Ballantyne D: The effect of moderate physical exercise on the plasma lipoprotein subfractions of male survivors of myocardial infarction. Circulation 65: 913, Kiyonaga A, Arakawa K, Tanaka H, Shindo M: Blood pressure and hormonal responses to aerobic exercise. Hypertension 7: 125, Astrand PO, Ryhming I: A nomogram for calculation of aerobic capacity (physical fitness) from pulse rate during submaximal work. J Appl Physiol 7: 218, Allain CC, Poon LS, Chan CS, Richmond W, Fu PC: Enzymatic determination of total serum cholesterol. Clin Chem 20: 470, Eggstein M, Kreutz FH: Fine neue Bestimmung der Neutralfette im Blutserum und Gewebe,

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8 34 URATA, ET AL. Jpn. Heart J. J anuary 1987 I. Mitt. (Prinzip, Durchfuhrung und Besprechung der Methode.) Klin Wschr 44: 262, Warnick GR, Albers JJ: A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein. J Lipid Res 19: 65, Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 18: 499, Sasaki J, Kawano T, Sasaki Y, Ishihara Y, Sata T, Arakawa K: Serum lipid and apoprotein profiles after onset of acute myocardial infarction. Jpn Circ J 48: 546, Nagasaki T, Akanuma Y: A new colorimetric method for the determination of plasma lecithin-cholesterol acyltransferase activity. Clin Chim Acta 75: 371, Hartung GH, Foreyt JP, Mitchell RE, Vlasek I, Gotto AM Jr: Relationship of diet and HDL cholesterol in sedentary and active middle-aged men. Circulation 58: 204, Lehtonen A, Viikari J: Serum triglycerides and cholesterol and serum high-density lipoprotein cholesterol in highly physically active men. Acta Med Scand 204: 111, Lopez-S A, Vial R, Balart L, Arroyave G: Effect of exercise and physical fitness on serum lipids and lipoproteins. Atherosclerosis 20: 1, 1974

Katsuyuki Nakajima, PhD. Member of JCCLS International Committee

Katsuyuki Nakajima, PhD. Member of JCCLS International Committee Katsuyuki Nakajima, PhD Member of JCCLS International Committee Visiting Professor and Scientist Tufts University, Boston, MA & Framingham Offspring Study, Framingham, MA August 20 th, 2011, Tokyo Framingham