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(Circulation. 1998;98:2652-2655.)
© 1998 American Heart Association, Inc.
Editorial |
Endothelium as a Therapeutic Target in Heart Failure
From the Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Hannover, Germany.
Correspondence to Helmut Drexler, MD, Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neubergstraße 1, 30625 Hannover, Germany. E-mail drexler.helmut{at}mh-hannover.de
Key Words: Editorials • nitric oxide • exercise • heart failure
Patients with chronic heart failure are characterized by systemic vasoconstriction and reduced peripheral perfusion, which are thought to contribute to the impaired exercise capacity in this disorder. Whereas an increased sympathetic tone and an activated renin-angiotensin system have been proposed to be involved in the reduced vasodilator capacity in heart failure, the important role of the endothelium in coordinating tissue perfusion has not been recognized until recently. Recent clinical studies have documented impaired endothelium-dependent relaxations of peripheral resistance and conduit arteries in patients with chronic heart failure, most likely due to impaired availability of nitric oxide (NO). On the other hand, the endothelial production of vasoconstricting factors1 such as angiotensin II or endothelin appears to be increased in severe heart failure. Whereas numerous important functions of the endothelium have been recognized in the past, many recent experimental and clinical studies have focused on endothelium-derived NO, probably because one of its main functions, vascular relaxation, can easily be assessed in humans in vivo. NO is a potent endogenous vasodilator and appears to be responsible for the maintenance of basal vascular tone; it is also thought to exert other important effects, such as inhibition/modulation of platelet aggregation, leukocyte adhesion, cell respiration, and apoptosis. The mechanisms of the actions of NO include activation of second messengers such as cGMP, direct effects on redox-sensitive regulatory proteins, and interactions with reactive oxygen species.
Impaired endothelium-dependent vascular relaxation has been documented in virtually all cardiovascular disorders and appears to occur early in the course of cardiovascular disorders such as arteriosclerosis, diabetes mellitus, hypercholesterolemia, or hypertension. Impaired endothelium-dependent relaxation may be associated with alterations of other endothelial functions, such as adhesion of leukocytes or altered balance of profibrinolytic to prothrombotic activity; however, whether or not impaired endothelium-dependent relaxation always reflects a more general "endothelium dysfunction" remains to be established.
Experimental and some clinical studies indicate that impaired endothelium-dependent relaxation is, at least to a large extent, related to impaired availability of NO. On the basis of the assumption that endothelium-derived NO is vasoprotective in many ways in vivo in humans, preservation or restoration of normal endothelial function has become a target for therapy and may even be considered as a surrogate for clinical events at later stages of cardiovascular disorders. Improvements in endothelium-dependent relaxation have been observed with a variety of interventions, such as supplementations of the precursor of NO (L-arginine), estrogens, ACE inhibition, lipid lowering, radical scavenging by antioxidants, and physical activity (for review, see Reference 11 ).
Although prevention or amelioration of endothelial dysfunction represents an attractive goal for therapeutic interventions to reduce symptoms or clinical events, the clinical benefit of the remarkable improvements in endothelial function per se has not been conclusively demonstrated in patients with cardiovascular disease. Experimental studies have indicated that the endothelium modulates vascular remodeling in response to injury and other stimuli. Preservation of endothelial function, ie, NO availability, has been shown to be protective against the development of vascular alterations in experimental arteriosclerosis or graft vasculopathy. However, clinical studies in this respect are lacking. The most convincing circumstantial evidence for the functional importance of endothelial NO in patients has been provided by intervention studies in patients with hypercholesterolemia. Marked reduction of serum cholesterol was associated with rapid recovery of endothelial function,2 improvement of myocardial perfusion,3 and reduction of myocardial ischemia.4 These observations would be consistent with the notion that the reversal of impaired endothelium-dependent relaxation contributes to improved myocardial tissue perfusion and attenuation of myocardial ischemia in patients with hypercholesterolemia.
Improvement in tissue perfusion is an important goal in patients with chronic heart failure, in terms of both the peripheral and the coronary circulation. Although impaired endothelium-dependent relaxation has been demonstrated in the coronary and peripheral circulations in patients with chronic heart failure, the functional significance of this observation needs to be established, particularly with respect to its importance during exercise. Initial studies6 have reported a positive correlation between peak oxygen uptake and endothelium-dependent peripheral vasodilation in patients with heart failure and claim that endothelial function may be one of the factors contributing to exercise intolerance in such patients. However, endothelium-independent vasodilation was not assessed in the study by Nakamura et al,5 and the coefficient value was low; therefore, a cause-effect relationship remained uncertain. Conceivably, the impairment of endothelium-dependent relaxation in heart failure could be a marker rather than a functionally important factor.
Recent data demonstrated that expression of endothelial NO synthase is reduced in an experimental model of heart failure.6 Conversely, a 10-day training program resulted in an increase in the expression of endothelial NO synthase.7 The expression of endothelial NO synthase is increased by shear stress in isolated endothelial cells.8 Thus, impaired endothelium-dependent relaxation in heart failure may be related to reduced peripheral blood flow, which in turn may be restored by repetitive increases in blood flow by physical training, resulting in intermittent enhanced shear stress and, consequently, increased expression and activity of endothelial NO synthase. In this respect, we have previously shown that a training protocol confined to 1 extremity in patients with heart failure results in enhanced flow-dependent, endothelium-mediated dilation, whereas endothelial function of the untrained extremity remains unchanged.9 These observations suggest that local mechanical forces play a key role in the beneficial effect of training. In addition to the regulation of endothelial NO synthase, other shear-dependent mechanisms may be involved as well; ie, shear stress upregulates the expression of Cu/Zn superoxide dismutase, a radical-scavenging enzyme,10 but suppresses the expression of ACE.11 There is evidence that chronic heart failure is associated with increased oxidative stress.12 Thus, increased expression and activity of endothelial superoxide dismutase may be protective via the scavenging of radicals, thereby reducing the inactivation of NO. The local activity of radical-scavenging enzymes and radical-producing enzymes in the periphery has not been assessed in patients with heart failure. However, Mohazzab and coworkers13 have recently shown that the basal release of superoxide anion (O2-) is increased in failing human cardiac myocytes, apparently due to increased O2- production by mitochondria and NADH oxidoreductases. Do we have evidence that increased radical formation is operative in vivo in patients with heart failure? There is evidence that endothelial dysfunction in patients with congestive heart failure can be improved and normalized by the antioxidant vitamin C, which supports the notion that chronic heart failure is associated with increased radical formation that in turn affects endothelium-mediated vasomotor tone.14
Shear-stress–mediated suppression of ACE may have an impact on endothelium-dependent relaxation by affecting local concentrations of bradykinin because ACE is identical to kininase II, which degrades bradykinin into inactive products. Bradykinin is a strong stimulus for the release of NO from the endothelium. Experimental and clinical data suggest that bradykinin or the B2 receptor is involved in flow-dependent, endothelium-mediated dilation.15 16 Moreover, ACE inhibition improves endothelium-dependent relaxation by bradykinin/bradykinin B2 receptor–mediated mechanisms.17 Taken together, impaired endothelium-dependent relaxation in heart failure may be a secondary event in response to alterations in peripheral hemodynamics. Alterations in shear stress related to impaired blood flow may play an important role in the development of endothelial dysfunction in this setting, although other factors such as increased levels of cytokines should not be dismissed.
In the present issue of Circulation, Hambrecht et al18 evaluate the effects of physical training on endothelial function and exercise capacity in patients with chronic heart failure. An association of improvement in endothelial function by physical training and an increase in exercise capacity in patients with heart failure was noted. Similarly, endothelium-dependent peripheral vasorelaxation improved after recovery from heart failure by mitral and/or aortic valve replacement, and this improvement was related to increases in exercise capacity.6 This observation raises several important questions. Does impaired exercise-induced release of NO contribute to reduced aerobic exercise capacity in patients with chronic heart failure? Does enhanced endothelial function by physical training contribute to increased exercise capacity in heart failure? Do other interventions known to improve endothelial function in heart failure increase exercise capacity in this disorder? If so, the endothelium would indeed represent an important therapeutic target in patients with chronic heart failure.
Previous studies have established the beneficial effects of physical training in patients with chronic heart failure. Several mechanisms have been proposed, including improvement in left ventricular diastolic function, autonomic balance, ventilatory function, and/or skeletal muscle function. In particular, skeletal muscle atrophy, impaired metabolism, and reduced oxidative capacity appear to contribute to the reduced exercise capacity in chronic heart failure. Exercise training has been shown to improve the force of contraction, metabolism, and oxidative capacity of skeletal muscle. Force of contraction in skeletal muscle is modulated by NO through impaired Ca2+ activation of actin filaments, resulting in decreased myofibrillar calcium sensitivity.19 Skeletal muscle fibers express 2 isoforms of NO synthases, a neuronal and endothelial NO synthase. However, expression of inducible NO synthase has been shown to emerge in skeletal muscle of patients with heart failure,20 and therefore, increased NO availability within skeletal muscle may affect contractile force in these patients. Moreover, there is evidence that endogenous NO released from the microvascular endothelium plays an important role in the modulation of cellular respiration in skeletal muscle.21 The suppression of tissue O2 consumption in response to bradykinin (presumably stimulating the endothelial release of NO) is blunted in skeletal muscle from dogs with heart failure,22 which indicates a defective endogenous NO-mediated modulation of tissue O2 consumption in skeletal muscle after the development of heart failure. Whether or not defective NO biosynthesis in skeletal muscle blood vessels can be improved by physical training remains to be determined, but preservation of endothelial NO synthase expression in aortic endothelium by physical training has been shown recently.23 Interestingly, preservation of endothelial vasodilator function by physical training was associated with preserved resting hemodynamics and alleviation of clinical manifestations of heart failure,23 which suggests that the beneficial effects of physical training in heart failure are mediated in part by endothelial mechanisms. In the present study by Hambrecht et al,18 a significant relationship was observed between improvement of endothelial function and exercise capacity, which suggests that improved endothelial function contributed to increased exercise capacity. Obviously, a significant correlation does not prove a cause-effect relationship. Moreover, because the coefficient value was moderate, the improved endothelial function can only account for a small incremental increase in exercise capacity.
How can an improvement in peripheral endothelium-mediated vasodilation contribute to exercise capacity? A complex physiology exists for hyperemia, exercise, and NO. The role of NO in exercise-induced increases in blood flow or reactive hyperemia remains controversial, and the effects of inhibition of NO synthesis in this respect are modest at best. Increases in flow during exercise or after arterial occlusion are mediated by several mechanisms, and blockade of several systems is necessary to attenuate reactive hyperemia. In normal individuals, peak vasodilatory capacity can be increased by physical training without influencing basal or stimulated activity of the NO dilator system,24 although exercise training undoubtedly augments endothelial NO synthesis and flow-dependent dilation of skeletal muscle arterioles through NO and prostaglandins.25 After physical training, an increase in flow reserve or reactive hyperemia has been observed in both animals and humans. In fact, physical training in patients has been associated with increases in skeletal muscle blood flow during exercise, reactive hyperemia, and peak oxygen consumption, possibly due to enhancement of vascular conduction and growth.26
In the present study by Hambrecht et al,18 the endothelium-independent increase in femoral blood flow did not change after training, although the absolute values were slightly higher after training (1785 versus 1587 mL). However, only 1 dose of nitroglycerin was administered, and the increase in flow was only 270% despite a medium- to high-level training protocol, which indicates that maximal vasodilation was not obtained by this dose of nitroglycerin. Thus, Hambrecht et al did not determine maximal reactive hyperemia or maximal endothelium-independent increases in peripheral blood flow (maximal flow reserve). Therefore, the importance of increased exercise hyperemia cannot be appreciated from the present study. However, increases in metabolic vasodilation in response to arterial occlusion may not necessarily be associated with increased training-induced endothelium-dependent vasodilation during exercise in heart failure and vice versa. Indeed, a recent study observed that the increased vasodilatory responses after arterial occlusion and endothelium-dependent stimuli after physical training in patients with heart failure do not correlate, which suggests that the determinants of peak reactive hyperemia and endothelium-dependent vasodilation may be distinct.27 However, increased NO availability during exercise provided by physical training may contribute to exercise capacity without affecting total increases in skeletal muscle blood flow, ie, by affecting the distribution of blood flow within skeletal muscle. In heart failure, skeletal muscle underperfusion emerges predominantly in oxidative working muscle.28 Inhibition of NO synthesis and release by NG-nitro-L-arginine methyl ester (L-NAME) is most effective in limiting blood flow to oxidative working muscle, but the inhibitory effect of L-NAME on blood flow in these muscle fibers appears to be attenuated in chronic heart failure.29 Thus, redistribution of blood flow within skeletal muscle appears to emerge in heart failure owing to endothelial dysfunction, possibly secondary to chronic deconditioning. Improved oxygen delivery with physical training may be related in part to the reversal of impaired endothelium-dependent relaxation within oxidative muscle fibers.
NO is also involved in the central regulation of sympathetic outflow, which suggests that both neuronal and endothelial NO synthesis may contribute to the regulation of vasomotor tone.30 It might be possible that the sympathoinhibitory effects of NO play a role in disease states such as heart failure with impaired baroreceptor function by contributing to sustained sympathetic activation. In this respect, it is noteworthy that neuronal NO synthase activity can be upregulated by endurance training.31
Taken together, although some observations are still controversial, these data indicate that endothelial dysfunction plays a significant role in redistribution of blood flow during exercise and adversely affects exercise capacity. Conditions such as heart failure that reduce endothelium-derived NO availability disturb the exercise-induced blood flow response and are associated with an impaired exercise capacity. Interestingly, an impaired hyperemic response to exercise and a reduced exercise capacity have been observed in other conditions associated with endothelial dysfunction. Thus, endothelial dysfunction may be a target for therapy to improve exercise capacity in patients with chronic heart failure as well as other cardiovascular disorders associated with endothelial dysfunction. Indeed, several clinical studies have been conducted to evaluate potential methods to improve endothelial dysfunction in heart failure besides physical training. There is evidence that supplementation of L-arginine, the precursor of NO, is associated with improvement in endothelial function and a moderate increase in exercise capacity.32 ACE inhibition has been shown to improve endothelium-dependent vasodilation,9 and it is conceivable that the delayed beneficial effect of ACE inhibitors on exercise-induced blood flow and exercise capacity in heart failure33 is in part related to improved endothelium-dependent vasodilation. Antioxidants such as vitamin C are very effective in restoring endothelium-dependent vasodilation14 ; however, their potential for improving exercise capacity has not been evaluated thus far. On the basis of the present observations, reversal of endothelial dysfunction by selective improvement of endothelial function may represent an attractive approach to test the notion that endothelial function contributes to the functional capacity of patients.
Acknowledgments
Dr Drexler is supported in part by the Deutsche Forschungsgemeinschaft (Dr 148/7-2).
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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M. de Lorgeril, P. Salen, M. Accominotti, M. Cadau, J.-P. Steghens, F. Boucher, and J. de Leiris Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure Eur J Heart Fail, December 1, 2001; 3(6): 661 - 669. [Abstract] [Full Text] [PDF]
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 M. Domanski, J. Norman, M. Wolz, G. Mitchell, and M. Pfeffer Cardiovascular Risk Assessment Using Pulse Pressure in the First National Health and Nutrition Examination Survey (NHANES I) Hypertension, October 1, 2001; 38(4): 793 - 797. [Abstract] [Full Text] [PDF]
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Recommendations for exercise training in chronic heart failure patients Eur. Heart J., January 2, 2001; 22(2): 125 - 135. [PDF]
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J. Bauersachs, D. Fraccarollo, P. Galuppo, J. Widder, and G. Ertl Endothelin-receptor blockade improves endothelial vasomotor dysfunction in heart failure Cardiovasc Res, July 1, 2000; 47(1): 142 - 149. [Abstract] [Full Text] [PDF]
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 M. Okuyama, S. Yamaguchi, M. Yamaoka, J. Nitobe, S. Fujii, T. Yoshimura, and H. Tomoike Nitric Oxide Enhances Expression and Shedding of Tumor Necrosis Factor Receptor I (p55) in Endothelial Cells Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1506 - 1511. [Abstract] [Full Text] [PDF]
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C. A. J. Farquharson and A. D. Struthers Spironolactone Increases Nitric Oxide Bioactivity, Improves Endothelial Vasodilator Dysfunction, and Suppresses Vascular Angiotensin I/Angiotensin II Conversion in Patients With Chronic Heart Failure Circulation, February 15, 2000; 101(6): 594 - 597. [Abstract] [Full Text] [PDF]
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