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Exercise-Induced Hypertension, Endothelial Dysfunction, and Coronary Artery Disease in a Marathon Runner
Exercise-Induced Hypertension, Endothelial Dysfunction, and Coronary Artery Disease in a Marathon Runner Radha Goel, MDa, Farhan Majeed, MDb, Robert Vogel, MDb, Mary C. Corretti, MDb, Matthew Weir, MDb, Charles Mangano, RDMSb, Charles White, MDc, Gary D. Plotnick, MDb, and Michael Miller, MDb,d,* Aerobic activity performed on a regular basis is 1 of several lifestyle recommendations endorsed to reduce risk of coronary disease. However, 1 potential concern of arduous aerobic activity is exercise-induced hypertension. This is the first case to our knowledge, of accelerated coronary calcification in an otherwise asymptomatic middle-aged male marathon runner devoid of traditional cardiovascular risk factors. As a consequence of exerciseinduced hypertension and associated oxidative stress, improvement of endothelial dysfunction occurred after antioxidant supplementation. In conclusion, vigorous aerobic activity in susceptible individuals may promote oxidative stress and coronary atherosclerosis. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:743–744) Like other forms of systemic hypertension, exercise-induced hypertension is associated with endothelial dysfunction. However, although cardiologists often recommend aerobic activity to their patients, screening for exercise-induced hypertension is rarely, if ever, performed. Jurva et al1 recently demonstrated that impairment of endothelial-mediated vasodilation occurs after acute exposure to exercise-induced hypertension. Case Description To determine the effect of chronic exposure to exercise-induced hypertension, we recently evaluated a 51-yearold physician with no traditional cardiovascular risk factors. His body mass index was 23.5 kg/m2, and his systolic blood pressure at rest ranged from 110 to 120 mm Hg. He jogged 1 hour/day beginning at age 21 and ran 2 marathons yearly. Physical examination results were normal. Fasting biochemical measurements included total cholesterol of 5.6 mmol/L (218 mg/dl), triglycerides of 0.87 mmol/L a Department of Medicine, Duke University School of Medicine, Durham, North Carolina; and Departments of bMedicine, cRadiology, and d Epidemiology and Preventive Medicine, University of Maryland Medical Center, Baltimore, Maryland. Manuscript received August 29, 2006; revised manuscript received and accepted September 19, 2006. *Corresponding author: Tel: 410-328-6299; fax: 410-328-4382. E-mail address: [email protected]. edu (M. Miller).
(77 mg/dl), low-density lipoprotein cholesterol of 3.3 mmol/L (127 mg/ dl), high-density lipoprotein of 2.0 mmol/L (76 mg/dl), high-sensitivity C-reactive protein of 0.5 mg/L, homocysteine of 10 mol/L, and lipoprotein(a) of 7 mg/dl (all within normal ranges). During follow-up stress testing, the patient completed stage 5 of the Bruce protocol, achieving 17 METs. However, his blood pressure increased from 118/78 mm Hg at baseline to 230/78 mm Hg. Review of 2 previous stress test results disclosed similar elevations in systolic blood pressure (i.e., ⬎200 mm Hg) during and beyond stage 5 of the Bruce protocol. On the basis of running duration and intensity, it was estimated that the subject spent approximately 20 to 30 minutes/day at a systolic blood pressure ⬎200 mm Hg. A 40-slice coronary computed tomography angiogram demonstrated severe 3-vessel coronary calcium and diffuse, nonobstructive 3-vessel coronary artery disease (Figure 1). Myocardial perfusion imaging results were normal. To evaluate endothelial function in response to exercise, brachial artery reactivity testing was performed using 7.5-MHz ultrasound and expressed as percentage diameter change from baseline to hyperemia (1 minute after 5-minute upper-arm blood pressure cuff occlusion). Normal flow-mediated dilation was found at baseline, but impaired flow-mediated dilation occurred immediately and 1 hour after exercise. In contrast, we also studied 10 healthy men aged 41 ⫾ 10 years
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.09.127
and found similar acute reductions in flow-mediated dilation immediately after exercise that improved 1 hour after activity (from 9.0 ⫾ 4.2% to 17.8 ⫾ 5.7%; Figure 2). Repeat stress brachial artery reactivity testing performed in our patient several weeks later, after antioxidant administration of an oral bolus of vitamin C (2 g) and vitamin E (800 IU) 1 hour before exercise showed partial reversal of the flow-mediated dilation response at 1 hour and normalization by 2 hours. Comments Aerobic exercise is associated with a number of beneficial effects, including decreased blood pressure, enhanced insulin sensitivity, weight loss, favorable lipid and lipoprotein alterations, and improved endothelial function.2– 4 However, excessive activity may result in deleterious effects related to increased oxidative stress and endothelial dysfunction.5,6 Although mild impairment in flow-mediated dilation occurs immediately after exercise, presumably because of acute oxidative stress, rapid improvement occurs in normal subjects ⬍1 hour after exercise is completed (Figure 2). Our patient showed impaired flow-mediated dilation that persisted for 1 hour after exercise but partially reversed after antioxidant vitamin administration. Previously, antioxidant supplementation was shown to reverse an impaired flow-mediated dilation response after a fatty meal, another factor associated with endothelial dysfunction.7 www.AJConline.org
744
The American Journal of Cardiology (www.AJConline.org)
thereby leading to endothelial dysfunction8 and coronary disease9 in an otherwise healthy man devoid of conventional atherosclerotic risk factors.
Figure 1. Forty-slice coronary computed tomographic angiography (CTA) demonstrated severe 3-vessel coronary calcium and diffuse, nonobstructive 3-vessel coronary artery disease.
Figure 2. Stress brachial artery reactivity testing demonstrated impaired flow-mediated dilation (FMD) immediately and 1 hour after exercise. Repeat stress brachial artery reactivity testing with a preexercise bolus of the antioxidants vitamin C and vitamin E demonstrated the partial reversal of FMD 1 hour after exercise. In contrast, healthy subjects evidenced improved FMD 1 hour after exercise.
In extending the acute effects of exertional hypertension made by Jurva et al,1 it is likely that chronic exposure
to exercise-induced hypertension (estimated as 20 to 30 minutes/day over 30 years) resulted in oxidative stress,
1. Jurva JW, Phillips SA, Syed AQ, Syed AY, Pitt S, Weaver A, Gutterman DD. The effect of exertional hypertension evoked by weight lifting on vascular endothelial function. J Am Coll Cardiol 2006;48:588 –589. 2. Corretti M, Plotnick GD, Vogel RA. Effect of treadmill exercise on flow-mediated brachial artery vasoactivity. J Am Coll Cardiol 1996; 27:130A. 3. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, Froelicher VF, Leon AS, Pina IL, Rodney R, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104: 1694 –1740. 4. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, Seals DR. Regular aerobic exercise prevents and restores age-related decline in endothelial-dependent vasodilation in healthy men. Circulation 2000; 102:1351–1357. 5. Mastaloudis A, Leonard SW, Traber MG. Oxidative stress in athletes during extreme endurance exercise. Free Radical Biol Med 2001;31: 911–922. 6. Goto C, Higashi Y, Kimura M, Noma K, Hara K, Nakagawa K, Kawamura M, Chayama K, Yoshizumi M, Nara I. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans. role of endotheliumdependent nitric oxide and oxidative stress. Circulation 2003;108:530 –535. 7. Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA 1997;278:1682–1686. 8. Inoue N, Ramasamy S, Fukai T, Nerem RM, Harrison DG. Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells. Circ Res 1996;79:32– 37. 9. Allison TG, Cordeiro MAS, Miller TD, Daida H, Squires RW, Gau GT. Prognostic significance of exercise-induced systemic hypertension in healthy subjects. Am J Cardiol 1999; 83:371–375.
(77 mg/dl), low-density lipoprotein cholesterol of 3.3 mmol/L (127 mg/ dl), high-density lipoprotein of 2.0 mmol/L (76 mg/dl), high-sensitivity C-reactive protein of 0.5 mg/L, homocysteine of 10 mol/L, and lipoprotein(a) of 7 mg/dl (all within normal ranges). During follow-up stress testing, the patient completed stage 5 of the Bruce protocol, achieving 17 METs. However, his blood pressure increased from 118/78 mm Hg at baseline to 230/78 mm Hg. Review of 2 previous stress test results disclosed similar elevations in systolic blood pressure (i.e., ⬎200 mm Hg) during and beyond stage 5 of the Bruce protocol. On the basis of running duration and intensity, it was estimated that the subject spent approximately 20 to 30 minutes/day at a systolic blood pressure ⬎200 mm Hg. A 40-slice coronary computed tomography angiogram demonstrated severe 3-vessel coronary calcium and diffuse, nonobstructive 3-vessel coronary artery disease (Figure 1). Myocardial perfusion imaging results were normal. To evaluate endothelial function in response to exercise, brachial artery reactivity testing was performed using 7.5-MHz ultrasound and expressed as percentage diameter change from baseline to hyperemia (1 minute after 5-minute upper-arm blood pressure cuff occlusion). Normal flow-mediated dilation was found at baseline, but impaired flow-mediated dilation occurred immediately and 1 hour after exercise. In contrast, we also studied 10 healthy men aged 41 ⫾ 10 years
0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.09.127
and found similar acute reductions in flow-mediated dilation immediately after exercise that improved 1 hour after activity (from 9.0 ⫾ 4.2% to 17.8 ⫾ 5.7%; Figure 2). Repeat stress brachial artery reactivity testing performed in our patient several weeks later, after antioxidant administration of an oral bolus of vitamin C (2 g) and vitamin E (800 IU) 1 hour before exercise showed partial reversal of the flow-mediated dilation response at 1 hour and normalization by 2 hours. Comments Aerobic exercise is associated with a number of beneficial effects, including decreased blood pressure, enhanced insulin sensitivity, weight loss, favorable lipid and lipoprotein alterations, and improved endothelial function.2– 4 However, excessive activity may result in deleterious effects related to increased oxidative stress and endothelial dysfunction.5,6 Although mild impairment in flow-mediated dilation occurs immediately after exercise, presumably because of acute oxidative stress, rapid improvement occurs in normal subjects ⬍1 hour after exercise is completed (Figure 2). Our patient showed impaired flow-mediated dilation that persisted for 1 hour after exercise but partially reversed after antioxidant vitamin administration. Previously, antioxidant supplementation was shown to reverse an impaired flow-mediated dilation response after a fatty meal, another factor associated with endothelial dysfunction.7 www.AJConline.org
744
The American Journal of Cardiology (www.AJConline.org)
thereby leading to endothelial dysfunction8 and coronary disease9 in an otherwise healthy man devoid of conventional atherosclerotic risk factors.
Figure 1. Forty-slice coronary computed tomographic angiography (CTA) demonstrated severe 3-vessel coronary calcium and diffuse, nonobstructive 3-vessel coronary artery disease.
Figure 2. Stress brachial artery reactivity testing demonstrated impaired flow-mediated dilation (FMD) immediately and 1 hour after exercise. Repeat stress brachial artery reactivity testing with a preexercise bolus of the antioxidants vitamin C and vitamin E demonstrated the partial reversal of FMD 1 hour after exercise. In contrast, healthy subjects evidenced improved FMD 1 hour after exercise.
In extending the acute effects of exertional hypertension made by Jurva et al,1 it is likely that chronic exposure
to exercise-induced hypertension (estimated as 20 to 30 minutes/day over 30 years) resulted in oxidative stress,
1. Jurva JW, Phillips SA, Syed AQ, Syed AY, Pitt S, Weaver A, Gutterman DD. The effect of exertional hypertension evoked by weight lifting on vascular endothelial function. J Am Coll Cardiol 2006;48:588 –589. 2. Corretti M, Plotnick GD, Vogel RA. Effect of treadmill exercise on flow-mediated brachial artery vasoactivity. J Am Coll Cardiol 1996; 27:130A. 3. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, Froelicher VF, Leon AS, Pina IL, Rodney R, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104: 1694 –1740. 4. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, Seals DR. Regular aerobic exercise prevents and restores age-related decline in endothelial-dependent vasodilation in healthy men. Circulation 2000; 102:1351–1357. 5. Mastaloudis A, Leonard SW, Traber MG. Oxidative stress in athletes during extreme endurance exercise. Free Radical Biol Med 2001;31: 911–922. 6. Goto C, Higashi Y, Kimura M, Noma K, Hara K, Nakagawa K, Kawamura M, Chayama K, Yoshizumi M, Nara I. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans. role of endotheliumdependent nitric oxide and oxidative stress. Circulation 2003;108:530 –535. 7. Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high-fat meal. JAMA 1997;278:1682–1686. 8. Inoue N, Ramasamy S, Fukai T, Nerem RM, Harrison DG. Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells. Circ Res 1996;79:32– 37. 9. Allison TG, Cordeiro MAS, Miller TD, Daida H, Squires RW, Gau GT. Prognostic significance of exercise-induced systemic hypertension in healthy subjects. Am J Cardiol 1999; 83:371–375.