- Email: [email protected]
Effects of Moderate Intensity Exercise on Serum Lipids in African-American Men With Severe Systemic Hypertension
Effects of Moderate Intensity Exercise on Serum Lipids in African-American Men With Severe Systemic Hypertension Peter F. Kokkinos, PhD, Puneet Narayan, MD, John Colleran, DO, Ross D. Fletcher, Raj Lakshman, PhD, and Vasilios Papademetriou, MD
MD,
The prevalence of systemic hypertension and its cardiovascular consequences is higher in African-Americans than in whites. Low to moderate intensity aerobic exercise lowers blood pressure (BP) in African-American patients with severe hypertension. It is not known whether such exercise can improve lipid metabolism in these patients. Thirty-six African-American men with established essential hypertension, aged 35 to 76 years, were randomly assigned to an exercise (n 5 17) or no exercise (n 5 19) group. The exercise group exercised for 16 weeks, 3 times/week, at 60% to 80% of maximum heart rate. After 16 weeks, peak oxygen uptake in the exercise group improved (21 6 4 vs 23 6 3 ml/kg/min; p <0.001). Body weight did not change. Exercise intensity correlated with high-density lipoprotein (HDL) cholesterol changes from baseline to 16
weeks (r 5 0.65; p <0.01) and was the strongest predictor of these changes (R2 5 0.4; p 5 0.009). Lipoprotein-lipid changes in the 2 randomized groups did not differ significantly. A 10% increase in HDL cholesterol—42 6 19 versus 46 6 19 mg/dl; p 5 0.003—noted in 10 patients who exercised >75% of maximal heart rate suggested the existence of an exercise intensity threshold. Thus low to moderate intensity aerobic exercise may not be adequate to modify lipid profiles favorably in patients with severe hypertension. However, substantial changes in HDL cholesterol were noted in patients exercising at intensities >75% of age-predicted maximum heart rate, suggesting an exercise-intensity threshold. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;81:732–735)
he prevalence of hypertension and its cardiovascular consequences are higher in African-AmerT icans than in whites. Thus, interventions to posi-
exercise program in the preceding 6 months. Inclusion criteria were age .21 years and history of essential hypertension with untreated diastolic BP $110 mm Hg or systolic BP $180 mm Hg. Patients were excluded from the study if they had a history of (1) congestive heart failure, (2) stroke, (3) evidence of coronary heart disease based on stress test and/or stress thallium, (4) insulin-dependent diabetes mellitus, (5) smoking, or (6) alcoholism, drug abuse, or psychiatric disease. All patients signed a consent form, approved by the local institutional review board, and were randomly assigned to the exercise (n 5 17) or no exercise (n 5 19) group. All patients were placed on antihypertensive medication to control BP. BP was measured with the patient sitting comfortably and the cuff arm supported at the heart level. BP was measured every 2 weeks and medication adjusted, until BP was achieved (BP #95 mm Hg or 10 mm Hg below pretreatment levels). Treatment was initiated with indapamide 2.5 mg/day. If this was not effective in controlling BP, sustained release verapamil 120 mg/ day was added. Verapamil was increased as necessary to a maximum dose of 480 mg/day, depending on patient’s requirement and tolerability. If target BP was not achieved with this combination, enalapril was added. The dose of enalapril ranged from 2.5 to 40 mg/day. Patients were evaluated on 3 different occasions to ensure that they had persistently controlled BP. All patients achieved target BP control. Patients were advised and frequently reminded not to alter their dietary habits through the duration of the study. Nonexercising patients were also advised to maintain the
1
tively modify the cardiac risk profile of these patients is particularly important. Recently, we reported that low to moderate aerobic exercise significantly lowers blood pressure (BP) and reduces left ventricular mass in African-American patients with severe hypertension.2 Low to moderate intensity exercise is preferable for the severely hypertensive patient for it is less likely to raise exercise BP to abnormally high levels, frequently observed in these patients.3 It is also better tolerated by patients and carries a lower risk for musculoskeletal injuries4 and acute cardiac complications.5 Whether low to moderate intensity aerobic exercise improves lipid metabolism in African-American patients with severe hypertension is not known. Thus, we sought to determine if the lipoprotein-lipid profiles of African-American patients with severe hypertension would improve after 16 weeks of moderate intensity aerobic exercise.
METHODS Thirty-six African-American men with established essential hypertension, aged 35 to 76 years (mean 58 6 11), were recruited for this study. All patients were sedentary, defined as not engaging in a regular From the Cardiology Division, Veterans Affairs Medical Center, Washington; and Cardiology Division, Georgetown University Medical Center, Washington, DC. Manuscript received August 27, 1997; revised manuscript received and accepted December 15, 1997. Address for reprints: Vasilios Papademetriou, MD, Veterans Affairs Medical Center, Hypertension Research Clinic, 50 Irving Street, N.W., Washington, DC 20422.
732
©1998 by Excerpta Medica, Inc. All rights reserved.
0002-9149/98/$19.00 PII S0002-9149(97)01020-5
same level of physical activity. Patients were followed at least monthly in our clinic. Blood collection: Blood samples for lipids and lipoprotein measurements were obtained from the patient’s antecubital vein after they were stabilized with the study medication. Samples were drawn at baseline and within 24 hours from the last exercise session. All blood samples were collected in the morning and after 12 to 14 hours of fasting. After separation, the plasma was stored in cryovils at 280°C in the central lipid laboratory at the Veterans Affairs Medical Center, where plasma lipid and lipoprotein analyses were performed. Plasma lipid measurements: All lipid measurements were obtained with the Abbott VP Super System Analyzer using Abbott Agent Enzymatic Reagents (Abbott Diagnostics, Irving, Texas). The system was set up and standardized with the Center for Disease Control quality control samples. If any control sample was not within 2 SDs of its mean, the entire batch of analyses was repeated. Previous experience revealed that control pools stored at 280°C were stable for $1 year. Cholesterol and lipoprotein determination: Plasma total cholesterol was determined using Abbott Agent Enzymatic Reagents. Precipitation for the determination of high-density lipoprotein (HDL)3 cholesterol and HDL cholesterol was performed according to the established methods.6,7 No patient had highly lipemic plasma. The intra- and interassay coefficients of variation for the various lipid parameters were: total cholesterol, 2.5% and 3.2%, respectively; HDL cholesterol, 3.5% and 6.7%, respectively; HDL3 cholesterol, 3.5% and 6.9%, respectively; and triglycerides, 2.2% and 4.3%, respectively. Plasma apolipoprotein A1 and B determinations:
Apolipoproteins were determined by highly specific and sensitive immunorate-nephelometric methods using the Beckman ICS Nephelometer system (Palo Alto, California) for the quantitative measurement of apolipoprotein A1 and B.8,9 The central lipid laboratory is standardized by the Center for Disease Control, Atlanta, Georgia. The intra- and interassay coefficients of variation for the various apoprotein parameters were: apolipoprotein A1, 3.5% and 7.2%, respectively; apolipoprotein B, 4.3% and 7.8%, respectively. Peak oxygen uptake and blood pressure: Peak oxygen uptake was assessed in the exercise group. Assessments were obtained at baseline and after 16 weeks of training. Each patient walked/ran on a treadmill at a speed that elicited 75% of the agepredicted maximal heart rate, at 0% grade. The grade was increased from 0% to 4% at the beginning of the fourth minute, and by 2% every minute after the end of the fifth minute. Oxygen uptake values were recorded every 30 seconds (Medical Graphics Cardiopulmonary Exercise System 2001, St. Paul, Minnesota). Peak oxygen uptake was established when the patient reached volitional fatigue. Peak oxygen uptake was not assessed in the
control group, because it is well established that it does not change in the control group. Exercise program: Patients in the exercise group participated in an aerobic exercise program for 16 weeks. Exercise training consisted of stationary cycling 3 times per week. Exercise sessions consisted of a 5-minute warm-up period (slow cycling) before the prescribed aerobic exercise and ending with an appropriate cooling off period. The duration and intensity of the actual exercise phase was maintained for 20 to 50 minutes at 60% to 80% of predicted maximum heart rate. Heart rate was measured continuously with a portable heart rate monitor. BP was monitored periodically during each workout to ensure that it was within safe limits (systolic BP ,220 mm Hg and diastolic BP ,110 mm Hg). The workload was adjusted to maintain target heart rate within the prescribed criteria throughout the exercise session. Patients exercised for an average of 44 6 9 minutes. Height and weight were measured on a standard physician’s scale. Body mass index and body surface area were computed by standardized formulas. Data analysis: Multivariate analysis of variance was performed to identify differences between groups. The paired t test was used to assess within-group changes. Simple and multiple regression analyses were performed to determine the association between lipids and age, body mass index, exercise intensity, and exercise duration. The 0.05 level of significance was applied for all tests.
RESULTS Two of the patients from the exercise group were excluded from the study. Alcohol consumption was suspected and confirmed in 1 patient and the other patient was on lipid-lowering medication before his enrollment in the study. Comparisons of the exercise and nonexercise groups revealed no baseline differences in any of the variables examined. Baseline and 16-week comparisons of peak oxygen uptake in the exercise group revealed significant improvements (21 6 4 vs 23 6 3 ml/kg/min; p ,0.001). Changes from baseline to week 16 in body weight, body surface area, and body mass index did not differ between the 2 randomized groups (Table I). The lipoprotein-lipid and apolipoprotein profiles of the patients in the 2 randomized groups at baseline and 16 weeks are presented on Table I. There were no significant differences between the 2 groups in any of the variables examined. Exercise intensity correlated well with HDL cholesterol changes from baseline to 16 weeks (r 5 0.65; p ,0.01). Multivariate analysis (stepwise) with HDL cholesterol changes from baseline to 16 weeks as the dependent variables disclosed intensity as the only predictor of HDL cholesterol changes (R2 5 0.42; p 5 0.009). A separate analysis in 10 patients who exercised $75% of the age-predicted maximal heart rate revealed a 10% increase in HDL cholesterol (41.8 6 19 vs 46.0 6 19 mg/dl) and a 7%
SYSTEMIC HYPERTENSION/SEVERE SYSTEMIC HYPERTENSION EXERCISE LIPIDS
733
gest that such a threshold may be approximately 75% of maximal heart rate. However, larger exercise studExercise (n 5 15) No Exercise (n 5 19) ies are needed to assess the role of exercise intensity on HDL cholesBaseline 16 Weeks Baseline 16 Weeks terol metabolism. Weight (kg) 96 6 14 97 6 15 95 6 18 94 6 19 The length of the exercise trainBody mass index 30 6 4 30 6 4 31 6 5 31 6 5 ing period may also play a role in Body surface area 2.1 6 0.1 2.2 6 0.1 2.1 6 0.2 2.1 6 0.2 Triglycerides (mg/dl) 147 6 66 143 6 71 116 6 74 112 6 70 HDL cholesterol metabolism. In Total cholesterol (mg/dl) 220 6 50 231 6 62 219 6 26 216 6 28 general, studies of .12 weeks’ duLDL cholesterol (mg/dl) 149 6 43 157 6 50 149 6 22 150 6 25 ration have reported some favorHDL cholesterol (mg/dl) 43 6 16 45 6 17 47 6 11 47 6 9 able changes in HDL cholesterol HDL2 cholesterol (mg/dl) 15 6 14 14 6 11 16 6 7 15 6 7 HDL3 cholesterol (mg/dl) 26 6 6 31 6 7 31 6 6 32 6 7 levels.10 However, not all changes Total cholesterol/ 5.5 6 1.7 5.3 6 1.2 4.9 6 1.2 4.8 6 1.2 reported were statistically signifiHDL cholesterol cant (p ,0.05) and the association Apo AI 143 6 30 143 6 31 141 6 15 139 6 12 is not consistent.10 Apo B 131 6 34 143 6 32 132 6 22 140 6 38 Finally, it is likely that exerciseApo 5 apolipoprotein; HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein. induced changes in lipid metabolism are the result of the interaction among duration of each exercise decrease in total cholesterol-to-HDL cholesterol ra- session, and intensity, frequency, and length of the exercise training period. Future exercise training tio (5.8 6 0.8 vs 5.4 6 1.2). studies should be designed to address the independent and interactive effects of the exercise compoDISCUSSION The results of the present study do not support the nents on lipid and lipoprotein metabolism. hypothesis that low to moderate intensity exercise (60% to 80% of predicted maximum heart rate) is adequate to alter lipid profiles favorably in AfricanAmerican patients with severe hypertension. Although 1. Subcommittee on Definition and Prevalence of the 1984 Joint National an explanation for the failure of exercise to alter lipid Committee on Detection, Evaluation, and Treatment of High Blood Pressure. prevalence, and the status of awareness, treatment, and control profiles in these patients is not immediately available, Hypertension, in the United States: final report of the Subcommittee on Definition and several possibilities exist. Approximately half of the Prevalence of the 1984 Joint National Committee. Hypertension 1985;7:457– studies report favorable HDL cholesterol changes af- 468. Kokkinos PF, Narayan P, Colleran JA, Pittaras A, Notargiacomo A, Reda D, ter exercise, whereas the rest do not.10 Although the 2. Papademetriou V. Effects of regular exercise on blood pressure and left ventricreasons for this inconsistency are not clear, several ular hypertrophy in African-American men with severe hypertension. N Engl factors have been implicated. Some investigators sug- J Med 1995;333:1462–1467. 3. Kokkinos PF, Narayan P, Fletcher RD, Tsagadopoulos D, Papademetrioum V. gest a threshold for the length of the exercise training Effects of aerobic training on exaggerated blood pressure response to exercise in period11–14; the weekly amount of exercise10,11,13–15 african-americans with severe systemic hypertension treated with indapamide 6 enalapril. Am J Cardiol 1997;79:1424 –1426. and exercise intensity16 –19 must be met or exceeded verapamil 4. Friedewaid VE Jr, Spence DW. Sudden cardiac death associated with exercise: before significant favorable changes in HDL choles- the risk-benefit issue. Am J Cardiol 1990;66:183–188. 5. Fletcher GF, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein S, terol can occur. H, Sivarajan Froelicher ES, Froelicher VF, Pina IL. Benefits and The existence of a minimum exercise intensity Falls recommendations for physical activity programs for all Americans. A statenecessary for improvements in HDL cholesterol levels ment for health professionals by the Committee on Exercise and Cardiac has been suggested by epidemiologic16,18 and inter- Rehabilitation of the Council on Clinical Cardiology, American Heart AssoCirculation 1992;86:340 –344. ventional19 studies. Stein et al19 reported significant ciation. 6. Gidez LI, Miller GJ, Burstein M, Eder HA. Analysis of plasma high density improvement in HDL cholesterol levels in subjects lipoprotein subclasses by a precipitation procedure: correlation with preparand analytical ultracentrifugation. In: Report of High Density Lipoprowho exercised at 75% of maximal heart rate for 12 ative tein Methodology Workshop, Section V. Part 28 (NIH publication no. 79 – weeks, but no changes in those who exercised at 65% 1661). Bethesda, Md.: US Dept. of Health and Human Services 1984:328 – 342. of maximal heart rate. 7. Friedwalt WT, Levy RI, Fredrickson DS. Estimation of the concentration of Indications of an exercise intensity threshold were low-density lipoprotein cholesterol in plasmas without the use of preparative also noted in the present study. Exercise intensity ultracentrifuge. Clin Chem 1972;18:499 –508. correlated significantly with HDL cholesterol changes 8. Lopex-Virella MF, Virell G. Immunonephelometric determination of apolipoIn: Lippel K, ed. Proceedings of the Workshop on Apoprotein Quantififrom baseline to 16 weeks and was the only predictor roteins. cation. Bethesda, MD: National Institutes of Health 1983;289 –313. of these changes. Furthermore, a separate analysis in 9. Chirtel SJ, Coutlakis PJ, Chambers LL, Lakshman MR. Use of end-point to standardize the rate of nephelometric assay of human and rat patients exercising $75% of their maximal heart rate nephelometry apolipoprotein A1. J Lab Clin Med 1989;113:632– 641. (n 5 10) revealed a 10% increase in HDL cholesterol 10. Haskell WL, Superko R. Influence of exercise on plasma lipids and lipoproand a 7% decrease in total cholesterol-to-HDL cho- teins. In: Horton ES, Terjung RL, eds. Exercise, Nutrition and Energy MetaboNew York: Macmillan, 1988:213–227. lesterol ratio. Although these findings were not statis- lism. 11. Wood PD, Stefanick ML, Dreaon DM, Frey-Hewitt B, Garay SC, Williams tically significant, they suggest that a minimum exer- PT, Superko HR, Fortmann SP, Albers JJ, Vranizan KM, et al. Changes in plasma cise intensity threshold may be required before favor- lipids and lipoproteins in overweight men during weight loss through dieting as compared to exercise. N Engl J Med 1988;319:1173–1179. able HDL cholesterol changes are realized. Our 12. Wood PD, Haskell WL, Blair SN, Williams PT, Krauss RM, Lindgren FT, observations and those reported by Stein et al19 sug- Albers JJ, Ho PH, Farguhar JW. Increased exercise level and plasma lipoprotein TABLE I Lipoprotein-Lipid Profiles for Patients in the Exercise and No Exercise Groups at Baseline and at 16 Weeks
734 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 81
MARCH 15, 1998
concentrations: A one-year, randomized study in sedentary, middle-aged men. Metabolism 1983;32:31–38. 13. Williams PT, Wood PD, Haskell WL, Vranizan K. The effects of running mileage and duration on plasma lipoprotein levels. JAMA 1982;247:6274 –2679. 14. Superko RH. Exercise training, serum lipids, and lipoprotein particles: is there a change threshold? Med Sci Sports Exerc 1991;23:667– 685. 15. Kokkinos PF, Holland JC, Narayan P, Colleran JA, Dotson CO, Papademetriou P. Miles run per week and high-density lipoprotein cholesterol levels in healthy, middleaged men: a dose-response relationship. Arch Intern Med 1995;155:414 – 420.
16. Lakka TA and Salonen JT. Physical activity and serum lipids: A cross-sectional population study in eastern Finnish Men. Am J Epidemiol 1992;136:806 – 818. 17. Leclerc S, Allard C, Talbot J, et al. High density lipoprotein cholesterol, habitual activity and physical fitness. Atherosclerosis 1985;57:43–51. 18. Drygas W, Jegler A, Kunski H. Study on threshold dose of physical activity and coronary risk factors. Int J Sports Med 1988;9:275–278. 19. Stein RA, Michielli DW, Glantz MD, et al. Effects of different exercise training intensities on lipoprotein cholesterol fractions in healthy middle-aged men. Am Heart J 1990;119:277–283.
SYSTEMIC HYPERTENSION/SEVERE SYSTEMIC HYPERTENSION EXERCISE LIPIDS
735
MD,
The prevalence of systemic hypertension and its cardiovascular consequences is higher in African-Americans than in whites. Low to moderate intensity aerobic exercise lowers blood pressure (BP) in African-American patients with severe hypertension. It is not known whether such exercise can improve lipid metabolism in these patients. Thirty-six African-American men with established essential hypertension, aged 35 to 76 years, were randomly assigned to an exercise (n 5 17) or no exercise (n 5 19) group. The exercise group exercised for 16 weeks, 3 times/week, at 60% to 80% of maximum heart rate. After 16 weeks, peak oxygen uptake in the exercise group improved (21 6 4 vs 23 6 3 ml/kg/min; p <0.001). Body weight did not change. Exercise intensity correlated with high-density lipoprotein (HDL) cholesterol changes from baseline to 16
weeks (r 5 0.65; p <0.01) and was the strongest predictor of these changes (R2 5 0.4; p 5 0.009). Lipoprotein-lipid changes in the 2 randomized groups did not differ significantly. A 10% increase in HDL cholesterol—42 6 19 versus 46 6 19 mg/dl; p 5 0.003—noted in 10 patients who exercised >75% of maximal heart rate suggested the existence of an exercise intensity threshold. Thus low to moderate intensity aerobic exercise may not be adequate to modify lipid profiles favorably in patients with severe hypertension. However, substantial changes in HDL cholesterol were noted in patients exercising at intensities >75% of age-predicted maximum heart rate, suggesting an exercise-intensity threshold. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;81:732–735)
he prevalence of hypertension and its cardiovascular consequences are higher in African-AmerT icans than in whites. Thus, interventions to posi-
exercise program in the preceding 6 months. Inclusion criteria were age .21 years and history of essential hypertension with untreated diastolic BP $110 mm Hg or systolic BP $180 mm Hg. Patients were excluded from the study if they had a history of (1) congestive heart failure, (2) stroke, (3) evidence of coronary heart disease based on stress test and/or stress thallium, (4) insulin-dependent diabetes mellitus, (5) smoking, or (6) alcoholism, drug abuse, or psychiatric disease. All patients signed a consent form, approved by the local institutional review board, and were randomly assigned to the exercise (n 5 17) or no exercise (n 5 19) group. All patients were placed on antihypertensive medication to control BP. BP was measured with the patient sitting comfortably and the cuff arm supported at the heart level. BP was measured every 2 weeks and medication adjusted, until BP was achieved (BP #95 mm Hg or 10 mm Hg below pretreatment levels). Treatment was initiated with indapamide 2.5 mg/day. If this was not effective in controlling BP, sustained release verapamil 120 mg/ day was added. Verapamil was increased as necessary to a maximum dose of 480 mg/day, depending on patient’s requirement and tolerability. If target BP was not achieved with this combination, enalapril was added. The dose of enalapril ranged from 2.5 to 40 mg/day. Patients were evaluated on 3 different occasions to ensure that they had persistently controlled BP. All patients achieved target BP control. Patients were advised and frequently reminded not to alter their dietary habits through the duration of the study. Nonexercising patients were also advised to maintain the
1
tively modify the cardiac risk profile of these patients is particularly important. Recently, we reported that low to moderate aerobic exercise significantly lowers blood pressure (BP) and reduces left ventricular mass in African-American patients with severe hypertension.2 Low to moderate intensity exercise is preferable for the severely hypertensive patient for it is less likely to raise exercise BP to abnormally high levels, frequently observed in these patients.3 It is also better tolerated by patients and carries a lower risk for musculoskeletal injuries4 and acute cardiac complications.5 Whether low to moderate intensity aerobic exercise improves lipid metabolism in African-American patients with severe hypertension is not known. Thus, we sought to determine if the lipoprotein-lipid profiles of African-American patients with severe hypertension would improve after 16 weeks of moderate intensity aerobic exercise.
METHODS Thirty-six African-American men with established essential hypertension, aged 35 to 76 years (mean 58 6 11), were recruited for this study. All patients were sedentary, defined as not engaging in a regular From the Cardiology Division, Veterans Affairs Medical Center, Washington; and Cardiology Division, Georgetown University Medical Center, Washington, DC. Manuscript received August 27, 1997; revised manuscript received and accepted December 15, 1997. Address for reprints: Vasilios Papademetriou, MD, Veterans Affairs Medical Center, Hypertension Research Clinic, 50 Irving Street, N.W., Washington, DC 20422.
732
©1998 by Excerpta Medica, Inc. All rights reserved.
0002-9149/98/$19.00 PII S0002-9149(97)01020-5
same level of physical activity. Patients were followed at least monthly in our clinic. Blood collection: Blood samples for lipids and lipoprotein measurements were obtained from the patient’s antecubital vein after they were stabilized with the study medication. Samples were drawn at baseline and within 24 hours from the last exercise session. All blood samples were collected in the morning and after 12 to 14 hours of fasting. After separation, the plasma was stored in cryovils at 280°C in the central lipid laboratory at the Veterans Affairs Medical Center, where plasma lipid and lipoprotein analyses were performed. Plasma lipid measurements: All lipid measurements were obtained with the Abbott VP Super System Analyzer using Abbott Agent Enzymatic Reagents (Abbott Diagnostics, Irving, Texas). The system was set up and standardized with the Center for Disease Control quality control samples. If any control sample was not within 2 SDs of its mean, the entire batch of analyses was repeated. Previous experience revealed that control pools stored at 280°C were stable for $1 year. Cholesterol and lipoprotein determination: Plasma total cholesterol was determined using Abbott Agent Enzymatic Reagents. Precipitation for the determination of high-density lipoprotein (HDL)3 cholesterol and HDL cholesterol was performed according to the established methods.6,7 No patient had highly lipemic plasma. The intra- and interassay coefficients of variation for the various lipid parameters were: total cholesterol, 2.5% and 3.2%, respectively; HDL cholesterol, 3.5% and 6.7%, respectively; HDL3 cholesterol, 3.5% and 6.9%, respectively; and triglycerides, 2.2% and 4.3%, respectively. Plasma apolipoprotein A1 and B determinations:
Apolipoproteins were determined by highly specific and sensitive immunorate-nephelometric methods using the Beckman ICS Nephelometer system (Palo Alto, California) for the quantitative measurement of apolipoprotein A1 and B.8,9 The central lipid laboratory is standardized by the Center for Disease Control, Atlanta, Georgia. The intra- and interassay coefficients of variation for the various apoprotein parameters were: apolipoprotein A1, 3.5% and 7.2%, respectively; apolipoprotein B, 4.3% and 7.8%, respectively. Peak oxygen uptake and blood pressure: Peak oxygen uptake was assessed in the exercise group. Assessments were obtained at baseline and after 16 weeks of training. Each patient walked/ran on a treadmill at a speed that elicited 75% of the agepredicted maximal heart rate, at 0% grade. The grade was increased from 0% to 4% at the beginning of the fourth minute, and by 2% every minute after the end of the fifth minute. Oxygen uptake values were recorded every 30 seconds (Medical Graphics Cardiopulmonary Exercise System 2001, St. Paul, Minnesota). Peak oxygen uptake was established when the patient reached volitional fatigue. Peak oxygen uptake was not assessed in the
control group, because it is well established that it does not change in the control group. Exercise program: Patients in the exercise group participated in an aerobic exercise program for 16 weeks. Exercise training consisted of stationary cycling 3 times per week. Exercise sessions consisted of a 5-minute warm-up period (slow cycling) before the prescribed aerobic exercise and ending with an appropriate cooling off period. The duration and intensity of the actual exercise phase was maintained for 20 to 50 minutes at 60% to 80% of predicted maximum heart rate. Heart rate was measured continuously with a portable heart rate monitor. BP was monitored periodically during each workout to ensure that it was within safe limits (systolic BP ,220 mm Hg and diastolic BP ,110 mm Hg). The workload was adjusted to maintain target heart rate within the prescribed criteria throughout the exercise session. Patients exercised for an average of 44 6 9 minutes. Height and weight were measured on a standard physician’s scale. Body mass index and body surface area were computed by standardized formulas. Data analysis: Multivariate analysis of variance was performed to identify differences between groups. The paired t test was used to assess within-group changes. Simple and multiple regression analyses were performed to determine the association between lipids and age, body mass index, exercise intensity, and exercise duration. The 0.05 level of significance was applied for all tests.
RESULTS Two of the patients from the exercise group were excluded from the study. Alcohol consumption was suspected and confirmed in 1 patient and the other patient was on lipid-lowering medication before his enrollment in the study. Comparisons of the exercise and nonexercise groups revealed no baseline differences in any of the variables examined. Baseline and 16-week comparisons of peak oxygen uptake in the exercise group revealed significant improvements (21 6 4 vs 23 6 3 ml/kg/min; p ,0.001). Changes from baseline to week 16 in body weight, body surface area, and body mass index did not differ between the 2 randomized groups (Table I). The lipoprotein-lipid and apolipoprotein profiles of the patients in the 2 randomized groups at baseline and 16 weeks are presented on Table I. There were no significant differences between the 2 groups in any of the variables examined. Exercise intensity correlated well with HDL cholesterol changes from baseline to 16 weeks (r 5 0.65; p ,0.01). Multivariate analysis (stepwise) with HDL cholesterol changes from baseline to 16 weeks as the dependent variables disclosed intensity as the only predictor of HDL cholesterol changes (R2 5 0.42; p 5 0.009). A separate analysis in 10 patients who exercised $75% of the age-predicted maximal heart rate revealed a 10% increase in HDL cholesterol (41.8 6 19 vs 46.0 6 19 mg/dl) and a 7%
SYSTEMIC HYPERTENSION/SEVERE SYSTEMIC HYPERTENSION EXERCISE LIPIDS
733
gest that such a threshold may be approximately 75% of maximal heart rate. However, larger exercise studExercise (n 5 15) No Exercise (n 5 19) ies are needed to assess the role of exercise intensity on HDL cholesBaseline 16 Weeks Baseline 16 Weeks terol metabolism. Weight (kg) 96 6 14 97 6 15 95 6 18 94 6 19 The length of the exercise trainBody mass index 30 6 4 30 6 4 31 6 5 31 6 5 ing period may also play a role in Body surface area 2.1 6 0.1 2.2 6 0.1 2.1 6 0.2 2.1 6 0.2 Triglycerides (mg/dl) 147 6 66 143 6 71 116 6 74 112 6 70 HDL cholesterol metabolism. In Total cholesterol (mg/dl) 220 6 50 231 6 62 219 6 26 216 6 28 general, studies of .12 weeks’ duLDL cholesterol (mg/dl) 149 6 43 157 6 50 149 6 22 150 6 25 ration have reported some favorHDL cholesterol (mg/dl) 43 6 16 45 6 17 47 6 11 47 6 9 able changes in HDL cholesterol HDL2 cholesterol (mg/dl) 15 6 14 14 6 11 16 6 7 15 6 7 HDL3 cholesterol (mg/dl) 26 6 6 31 6 7 31 6 6 32 6 7 levels.10 However, not all changes Total cholesterol/ 5.5 6 1.7 5.3 6 1.2 4.9 6 1.2 4.8 6 1.2 reported were statistically signifiHDL cholesterol cant (p ,0.05) and the association Apo AI 143 6 30 143 6 31 141 6 15 139 6 12 is not consistent.10 Apo B 131 6 34 143 6 32 132 6 22 140 6 38 Finally, it is likely that exerciseApo 5 apolipoprotein; HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein. induced changes in lipid metabolism are the result of the interaction among duration of each exercise decrease in total cholesterol-to-HDL cholesterol ra- session, and intensity, frequency, and length of the exercise training period. Future exercise training tio (5.8 6 0.8 vs 5.4 6 1.2). studies should be designed to address the independent and interactive effects of the exercise compoDISCUSSION The results of the present study do not support the nents on lipid and lipoprotein metabolism. hypothesis that low to moderate intensity exercise (60% to 80% of predicted maximum heart rate) is adequate to alter lipid profiles favorably in AfricanAmerican patients with severe hypertension. Although 1. Subcommittee on Definition and Prevalence of the 1984 Joint National an explanation for the failure of exercise to alter lipid Committee on Detection, Evaluation, and Treatment of High Blood Pressure. prevalence, and the status of awareness, treatment, and control profiles in these patients is not immediately available, Hypertension, in the United States: final report of the Subcommittee on Definition and several possibilities exist. Approximately half of the Prevalence of the 1984 Joint National Committee. Hypertension 1985;7:457– studies report favorable HDL cholesterol changes af- 468. Kokkinos PF, Narayan P, Colleran JA, Pittaras A, Notargiacomo A, Reda D, ter exercise, whereas the rest do not.10 Although the 2. Papademetriou V. Effects of regular exercise on blood pressure and left ventricreasons for this inconsistency are not clear, several ular hypertrophy in African-American men with severe hypertension. N Engl factors have been implicated. Some investigators sug- J Med 1995;333:1462–1467. 3. Kokkinos PF, Narayan P, Fletcher RD, Tsagadopoulos D, Papademetrioum V. gest a threshold for the length of the exercise training Effects of aerobic training on exaggerated blood pressure response to exercise in period11–14; the weekly amount of exercise10,11,13–15 african-americans with severe systemic hypertension treated with indapamide 6 enalapril. Am J Cardiol 1997;79:1424 –1426. and exercise intensity16 –19 must be met or exceeded verapamil 4. Friedewaid VE Jr, Spence DW. Sudden cardiac death associated with exercise: before significant favorable changes in HDL choles- the risk-benefit issue. Am J Cardiol 1990;66:183–188. 5. Fletcher GF, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein S, terol can occur. H, Sivarajan Froelicher ES, Froelicher VF, Pina IL. Benefits and The existence of a minimum exercise intensity Falls recommendations for physical activity programs for all Americans. A statenecessary for improvements in HDL cholesterol levels ment for health professionals by the Committee on Exercise and Cardiac has been suggested by epidemiologic16,18 and inter- Rehabilitation of the Council on Clinical Cardiology, American Heart AssoCirculation 1992;86:340 –344. ventional19 studies. Stein et al19 reported significant ciation. 6. Gidez LI, Miller GJ, Burstein M, Eder HA. Analysis of plasma high density improvement in HDL cholesterol levels in subjects lipoprotein subclasses by a precipitation procedure: correlation with preparand analytical ultracentrifugation. In: Report of High Density Lipoprowho exercised at 75% of maximal heart rate for 12 ative tein Methodology Workshop, Section V. Part 28 (NIH publication no. 79 – weeks, but no changes in those who exercised at 65% 1661). Bethesda, Md.: US Dept. of Health and Human Services 1984:328 – 342. of maximal heart rate. 7. Friedwalt WT, Levy RI, Fredrickson DS. Estimation of the concentration of Indications of an exercise intensity threshold were low-density lipoprotein cholesterol in plasmas without the use of preparative also noted in the present study. Exercise intensity ultracentrifuge. Clin Chem 1972;18:499 –508. correlated significantly with HDL cholesterol changes 8. Lopex-Virella MF, Virell G. Immunonephelometric determination of apolipoIn: Lippel K, ed. Proceedings of the Workshop on Apoprotein Quantififrom baseline to 16 weeks and was the only predictor roteins. cation. Bethesda, MD: National Institutes of Health 1983;289 –313. of these changes. Furthermore, a separate analysis in 9. Chirtel SJ, Coutlakis PJ, Chambers LL, Lakshman MR. Use of end-point to standardize the rate of nephelometric assay of human and rat patients exercising $75% of their maximal heart rate nephelometry apolipoprotein A1. J Lab Clin Med 1989;113:632– 641. (n 5 10) revealed a 10% increase in HDL cholesterol 10. Haskell WL, Superko R. Influence of exercise on plasma lipids and lipoproand a 7% decrease in total cholesterol-to-HDL cho- teins. In: Horton ES, Terjung RL, eds. Exercise, Nutrition and Energy MetaboNew York: Macmillan, 1988:213–227. lesterol ratio. Although these findings were not statis- lism. 11. Wood PD, Stefanick ML, Dreaon DM, Frey-Hewitt B, Garay SC, Williams tically significant, they suggest that a minimum exer- PT, Superko HR, Fortmann SP, Albers JJ, Vranizan KM, et al. Changes in plasma cise intensity threshold may be required before favor- lipids and lipoproteins in overweight men during weight loss through dieting as compared to exercise. N Engl J Med 1988;319:1173–1179. able HDL cholesterol changes are realized. Our 12. Wood PD, Haskell WL, Blair SN, Williams PT, Krauss RM, Lindgren FT, observations and those reported by Stein et al19 sug- Albers JJ, Ho PH, Farguhar JW. Increased exercise level and plasma lipoprotein TABLE I Lipoprotein-Lipid Profiles for Patients in the Exercise and No Exercise Groups at Baseline and at 16 Weeks
734 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 81
MARCH 15, 1998
concentrations: A one-year, randomized study in sedentary, middle-aged men. Metabolism 1983;32:31–38. 13. Williams PT, Wood PD, Haskell WL, Vranizan K. The effects of running mileage and duration on plasma lipoprotein levels. JAMA 1982;247:6274 –2679. 14. Superko RH. Exercise training, serum lipids, and lipoprotein particles: is there a change threshold? Med Sci Sports Exerc 1991;23:667– 685. 15. Kokkinos PF, Holland JC, Narayan P, Colleran JA, Dotson CO, Papademetriou P. Miles run per week and high-density lipoprotein cholesterol levels in healthy, middleaged men: a dose-response relationship. Arch Intern Med 1995;155:414 – 420.
16. Lakka TA and Salonen JT. Physical activity and serum lipids: A cross-sectional population study in eastern Finnish Men. Am J Epidemiol 1992;136:806 – 818. 17. Leclerc S, Allard C, Talbot J, et al. High density lipoprotein cholesterol, habitual activity and physical fitness. Atherosclerosis 1985;57:43–51. 18. Drygas W, Jegler A, Kunski H. Study on threshold dose of physical activity and coronary risk factors. Int J Sports Med 1988;9:275–278. 19. Stein RA, Michielli DW, Glantz MD, et al. Effects of different exercise training intensities on lipoprotein cholesterol fractions in healthy middle-aged men. Am Heart J 1990;119:277–283.
SYSTEMIC HYPERTENSION/SEVERE SYSTEMIC HYPERTENSION EXERCISE LIPIDS
735