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VIEWPOINT

Exercise and cardiovascular risk reduction: Time to update the rationale for exercise?

¹Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom; ²School of Sport Science, Exercise and Health, The University of Western Australia; ³Advanced Heart Failure and Cardiac Transplant Service, Royal Perth Hospital, Perth; ⁴School of Medicine, University of Notre Dame, Fremantle, Australia; and ⁵Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota

ALTHOUGH IT IS GENERALLY ACCEPTED that the promotion of exercise accords with clinical best practice, the anecdotal experience of many primary care physicians, cardiologists, and exercise physiologists is that, even when exercise prescriptions are adhered to, risk factors often fail to demonstrate marked improvement. Since modification of traditional risk factors fails to fully explain the magnitude of exercise-mediated risk reduction (18), we propose that there are direct effects of exercise on the vascular wall, which confer cardioprotection via a "vascular conditioning" effect.

Magnitude of Risk Reduction With Exercise Training or Physical Fitness

The Health Professional's Study (25) included 44,452 men whose adjusted relative risk of myocardial infarction was 0.7 (P < 0.001), providing strong evidence for the cardiovascular benefits of exercise in primary prevention. Meta-analyses of exercise-based cardiac rehabilitation, including trials conducted in the contemporary medications/interventions era, estimate reduction in mortality of 20–32% (26), although the lack of impact on non-fatal infarction remains unexplained. Nonetheless, exercise is associated with 30% benefit in terms of decreased cardiac risk (27), a magnitude similar to that associated with antihypertensive and lipid lowering interventions (32, 35).

Does Risk Factor Modification Explain the Risk Reduction Associated with Exercise?

A recent American Heart Association expert statement (27) suggested that, in normocholesterolemic subjects, exercise decreases LDL cholesterol by 1–5%. The impact of exercise on blood pressure averages 3/2 mmHg in normotensive subjects and the impact of cardiac rehabilitation is similar (26). The impact of physical activity on glycometabolic control in healthy subjects appears small and transient (17, 30), although exercise is clearly an important intervention in diabetes/insulin resistance as its effects exceed those associated with the use of metformin (13a, 31).

A recent analysis of 27,000 subjects (18) reported that differences in risk factors explained 59% or less of the cardiovascular risk reduction associated with exercise. The impact of HbA1c, lipid subprofiles, lipoprotein(a), apolipoproteinA1, apolipoproteinB-100, creatinine, homocysteine, hs-CRP, fibrinogen, s-ICAM-1, weight, height, blood pressure, and diabetes were taken into account. Blood pressure and inflammatory/hemostatic markers were responsible for the major contributions to exercise-mediated risk reduction, while lipids, body mass index, and HbA1c contributed to a lesser degree. This statistical modeling suggests that at least 40% of the risk reduction associated with exercise cannot be explained by establish risk factors. Furthermore, a proportion of each of these risk factor contributions may be mediated through improvements in endothelial function (21, 22).

Although the impact of exercise may be greater in subjects with raised cholesterol, blood pressure, or glycated hemoglobin, the effects of exercise on risk factors are generally smaller than those achieved with pharmacological interventions (27, 32, 35) and less than that which would account for the impact of exercise on cardiovascular outcomes. It is, of course, probable that the small benefits in each risk factor summate, but other explanations for the cardioprotective benefits of exercise seem likely.

What Could Account for the Positive Effects of Exercise Beyond Traditional Risk Factors?

The endothelium produces numerous paracrine hormones, including nitric oxide (NO), which are anti-atherogenic. Endothelial dysfunction precedes and predicts the development of atherosclerotic disease and initially occurs at coronary branch points, as do atherosclerotic plaques. Interventions of known cardiovascular benefit improve endothelial function. Coronary and peripheral endothelial dysfunction predict cardiovascular events, and improvement in endothelial function improves prognosis. Endothelial dysfunction can be considered an early and integral manifestation of vascular disease and improvement in endothelial function should impact on CV risk (9).

An important physiological stimulus to endothelium-mediated vasodilation is shear stress. Removal of the endothelium abolishes flow- and pharmacological NO-mediated arterial dilatation and NO-dependent, flow-mediated, vasodilation normalizes endothelial shear (23). There is strong evidence that exercise training of small and large muscle groups is associated with improvement in NO-vasodilator function (9).

Since cardiovascular risk factors are associated with impaired endothelial function, which is reversible via pharmacological treatment (21, 22), it is conceivable that exercise training improves endothelial function by virtue of its impact on risk factors. However, exercise training improves endothelial function in the absence of changes in lipid levels (10, 15), blood pressure (10, 13), glucose tolerance (10), or BMI (34). Improvement in risk factors is therefore not an obligatory requirement for improvement in endothelial function as a result of exercise training.

How Does Exercise Training Directly Affect the Vascular Wall?

Vascular function.   Hambrecht and colleagues (11) studied the impact of 4 wk of cycle exercise on the internal mammary artery of CAD patients. Training significantly increased endothelium-dependent dilation. From analysis of a section of artery harvested during bypass surgery, the authors concluded that exercise increases NO-synthase protein expression and phosphorylation, effects consistent with a shear-stress mechanism for enhanced NO bioactivity.

Another mechanism may relate to the impact of exercise on oxidative stress. Repeated NO production as a result of exercise may reduce its degradation by free radicals, directly decrease free radical production, or increase the expression of antioxidant enzymes. Goto and colleagues (5) observed improvement in endothelial function after moderate-intensity training, which did not alter oxidative stress, whereas high-intensity training increased oxidative stress and endothelial function did not improve. The impact of exercise on endothelial function may depend on the balance between reactive oxygen species, antioxidant defenses, and their impact on NO bioavailability.

Vascular structure.   Autopsy and angiographic studies suggest that physical conditioning increases arterial cross-sectional area (2, 16) and athletes consistently exhibit enlarged skeletal muscle conduit (3, 19) and resistance (8) arteries, compared with controls. Longitudinal studies provide further support for an arteriogenic impact of exercise training (3, 7, 19). Arterial remodeling is shear stress and NO (endothelium)-dependent (33) and acts in a manner that homeostatically regulates wall shear (28).

Exercise Training, Heart Rate Variability, and Vascular Adaptation

Fatal arrhythmias can occur in conjunction with ischemia, in tissue previously damaged by ischemia, and as primary events. Emerging evidence suggests that low heart rate variability (HRV) at rest or during exercise is an independent predictor of cardiovascular mortality (29). Exercise training/physical activity are associated with enhanced HRV (14, 24). There are several possible explanations. As described above, exercise training is associated with increased compliance and arterial remodeling of great vessels, including those in barosensitive areas. This may increase baroreceptor afferent activity, evoking increased reflex parasympathetic outflow. In addition, recent studies indicate that endurance training remodels cardiorespiratory centers, thereby reducing sympathetic, and enhancing parasympathetic, outflow (1, 20). Whether these adaptations occur in humans is not known, but seems likely. Increased parasympathetic, and decreased sympathetic, outflow to the heart would typically be cardioprotective (1).

Clinical Relevance of the Direct Effects of Exercise Training on the Vasculature

A recent study compared the effects of stenting to exercise training. After 12 mo, the "stent" group exhibited decreased stenosis diameter (8112%), whereas exercise training had no impact (7877%) (12). Nonetheless, significantly higher event-free survival occurred with exercise training (88 vs. 70%). Coronary interventions treat a short segment of the diseased coronary tree, whereas exercise exerts beneficial effects on endothelial function and disease progression in the entire arterial bed. In contrast to exercise training, interventional cardiology represents palliative care with respect to the underlying atherosclerotic disease process (12). Exercise training should be the cornerstone of prevention efforts.

Summary

Exercise training reduces cardiovascular events. The effects of exercise on traditional risk factors do not fully account for the magnitude of risk reduction. Exercise exerts direct effects on the vasculature via the impact of repetitive increases in shear stress on the endothelium, which transduce functional and structural adaptations that decrease atherosclerotic risk. Direct effects of exercise on the vasculature therefore provide a plausible contribution to the reduction in cardiac events associated with exercise training. Since different forms of exercise are associated with different patterns of shear stress and arterial adaptation, future studies should focus on the direct impacts of exercise on vasculature function and structure rather than on surrogate measures of vascular health.

GRANTS

D. J. Green received research funding support from the National Heart Foundation of Australia. M. J. Joyner was supported by National Institute of Health Grants HL-46493, NS-32352, and HL-83947.

ACKNOWLEDGMENTS

The authors thank Dr. David Dunstan of the International Diabetes Institute for his helpful discussion and advice regarding exercise and glycometabolic control.

FOOTNOTES

Address for reprint requests and other correspondence: D. Green, Research Institute for Sport and Exercise Sciences, Liverpool John Moores Univ., Henry Cotton Campus, 15-21 Webster St., Liverpool L3 2ET, UK (e-mail: d.j.green{at}ljmu.ac.uk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

REFERENCES

1. Billman GE, Kukielka M. Effect of endurance exercise training on heart rate onset and heart rate recovery responses to exercise in animals susceptible to ventricular fibrillation. J Appl Physiol 102: 231–240, 2007.[Abstract/Free Full Text]
2. Currens JH, White PD. Half century of running: Clinical, physiological and autopsy findings in the case of Clarence De Mar, "Mr. Marathoner". N Engl J Med 265: 988–993, 1961.[Web of Science][Medline]
3. Dinenno FA, Tanaka H, Monahan KD, Clevenger CM, Eskurza I, DeSouza CA, Seals DR. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol 534: 287–295, 2001.[Abstract/Free Full Text]
5. 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 endothelium-dependent nitric oxide and oxidative stress. Circulation 108: 530–535, 2003.[Abstract/Free Full Text]
6. Green DJ, Bilsborough W, Naylor LH, Reed C, Wright J, O'Driscoll G, Walsh JH. Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide. J Physiol 562: 617–628, 2005.[Abstract/Free Full Text]
7. Green DJ, Cable NT, Fox C, Rankin JM, Taylor RR. Modification of forearm resistance vessels by exercise training in young men. J Appl Physiol 77: 1829–1833, 1994.[Abstract/Free Full Text]
8. Green DJ, Fowler DT, O'Driscoll JG, Blanksby BA, Taylor RR. Endothelium-derived nitric oxide activity in forearm vessels of tennis players. J Appl Physiol 81: 943–948, 1996.[Abstract/Free Full Text]
9. Green DJ, Maiorana AJ, O'Driscoll G, Taylor R. Topical Review: Effects of exercise training on vascular endothelial nitric oxide function in humans. J Physiol 561: 1–25, 2004.[Abstract/Free Full Text]
10. Green DJ, Walsh JH, Maiorana A, Best M, Taylor RR, O'Driscoll JG. Exercise-induced improvement in endothelial dysfunction is not mediated by changes in CV risk factors: a pooled analysis of diverse patient populations. Am J Physiol Heart Circ Physiol 285: H2679–H2687, 2003.[Abstract/Free Full Text]
11. Hambrecht R, Adams V, Erbs S, Linke a Krankel N, Shu Y, Baither Y, Geilen S, Thiele H, Gummert JF, Mohr FW, Schuler G. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107: 3152–3158, 2003.[Abstract/Free Full Text]
12. Hambrecht R, Walther C, Möbius-Winkler S, Gielen S, Linke A, Conradi K, Erbs S, Kluge R, Kendziorra K, Sabri O, Sick P, Schuler G. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: a randomized trial. Circulation 109: 1371–1378, 2004.[Abstract/Free Full Text]
13. Higashi Y, Sasaki S, Kurisu S, Yoshimizu A, Sasaki N, Matsuura H, Kajiyama G, Oshima T. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects. Circulation 100: 1194–1202, 1999.[Abstract/Free Full Text]
13. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393–403, 2002.[Abstract/Free Full Text]
14. Levy WC, Cerqueira MD, Harp GD, Johannessen KA, Abrass IB, Schwartz RS, Stratton JR. Effect of endurance exercise training on heart rate variability at rest in healthy young and older men. Am J Cardiol 82: 1236–1241, 1998.[CrossRef][Web of Science][Medline]
15. Lewis TV, Dart AM, Chin-Dusting JPF, Kingwell BA. Exercise training increases basal nitric oxide production from the forearm in hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 19: 2782–2787, 1999.[Abstract/Free Full Text]
16. Mann GV, Spoerry A, Gray M, Jarashow D. Atherosclerosis in the Masi. Am J Epidemiol 95: 26–37, 1972.[Abstract/Free Full Text]
17. Mensink M, Blaak EE, Corpeleijn E, Saris WH, de Bruin TW, Feskens EJ. Lifestyle intervention according to general recommendations improves glucose tolerance. Obesity Res 11: 1588–1596, 2003.[Web of Science][Medline]
18. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms. Circulation 116: 2110–2118, 2007.[Abstract/Free Full Text]
19. Naylor L, O'Driscoll G, Fitzsimons M, Arnolda L, Green DJ. Effects of training resumption on conduit arterial diameter in elite rowers. Med Sci Sports Exerc 38: 86–92, 2006.[CrossRef][Web of Science][Medline]
20. Nelson AJ, Juraska JM, Musch TI, Iwamoto GA. Neuroplastic adaptations to exercise: neuronal remodeling in cardiorespiratory and locomotor areas. J Appl Physiol 99: 2312–2322, 2005.[Abstract/Free Full Text]
21. O'Driscoll G, Green D, Rankin J, Stanton K, Taylor R. Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 100: 678–684, 1997.[Web of Science][Medline]
22. O'Driscoll G, Green D, Taylor R. Simvastatin, an HMG-Coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 95: 1126–1131, 1997.[Abstract/Free Full Text]
23. Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 8: 37–44, 1986.[Abstract/Free Full Text]
24. Rennie KL, Hemingway H, Kumari M, Brunner E, Malik M, Marmot M. Effects of moderate and vigorous physical activity on heart rate variability in a British study of civil servants. Am J Epidemiol 158: 135–143, 2003.[Abstract/Free Full Text]
25. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Exercise type and intensity in relation to coronary heart disease in men. JAMA 288: 1994–2000, 2002.[Abstract/Free Full Text]
26. Taylor RS, Brown A, Ebrahim S, Jolliffe J, Noorani H, Rees K, Skidmore B, Stone JA, Thompson DR, Oldridge N. Exercise-based rehabilitation for patients with coronary disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 116: 682–692, 2004.[CrossRef][Web of Science][Medline]
27. Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, Berra K, Blair SN, Costa F, Franklin B, Fletcher GF, Gordon NF, Pate RR, Rodriguez BL, Yancey AK, Wenger NK. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease. A statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 107: 3109–3116, 2003.[Free Full Text]
28. Tronc F, Wassef M, Esposito B, Henrion D, Glagov S, Tedgui A. Role of NO in flow-induced remodeling of rabbit common carotid artery. Arterioscler Thromb Vasc Biol 16: 1256–1262, 1996.[Abstract/Free Full Text]
29. Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D. Reduced heart rate variability and mortality risk in an elderly cohort. Framingham Heart Study. Circulation 90: 878–883, 1994.[Abstract/Free Full Text]
30. Tsukui S, Kanda T, Nara M, Nishino M, Kondo T, Kobayashi I. Moderate-intensity regular exercise decreases serum tumour necrosis factor-a and HbA1c levels in healthy women. Int J Obes 24: 1207–1211, 2000.[CrossRef][Web of Science][Medline]
31. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Aunola S, Cepaitis Z, Moltchanov V, Hakumaki M, Mannelin M, Martikkala V, Sundvall J, Uusitupa MG, the Finnish Diabetes Prevention Study. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344: 1343–1350, 2001.[Abstract/Free Full Text]
32. Turnbull F. Blood pressure lowering treatment trialists' collaboration: effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362, 2003.
33. Tuttle JL, Nachreiner RD, Bhuller AS, Condict KW, Connors BA, Herring BP, Dalsing MC, Unthank JL. Shear level influences artery remodelling, wall dimension, cell density and eNOS expression. Am J Physiol Heart Circ Physiol 281: H1380–H1389, 2001.[Abstract/Free Full Text]
34. Watts K, Beye P, Siafarikas A, Davis EA, Jones TW, O'Driscoll G, Green DJ. Exercise training normalises vascular dysfunction and improves central adiposity in obese adolescents. J Am Coll Cardiol 43: 1823–1827, 2004.[Abstract/Free Full Text]
35. Wilt TJ, Bloomfield HE, MacDonald R, Nelson D, Rutks I, Ho M, Larsen G, McCall A, Pineros S, Sales A. Effectiveness of statin therapy in adults with coronary disease. Arch Intern Med 164: 1427–1436, 2004.[Abstract/Free Full Text]

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