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(Circulation. 1996;93:210-214.)
© 1996 American Heart Association, Inc.

Articles

Physical Training Improves Endothelial Function in Patients With Chronic Heart Failure

Burkhard Hornig, MD; Volker Maier, BS; Helmut Drexler, MD

From the Med Klinik III, University of Freiburg (Germany).

Correspondence to Helmut Drexler, MD, Med Klinik III, University of Freiburg, Hugstetterstr 55, 79106 Freiburg, Germany.

	Abstract

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Background Chronic heart failure is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). Since endothelial function is thought to play an important role in coordinating tissue perfusion and modulating arterial compliance, interventions to improve endothelial dysfunction are imperative.

Methods and Results To assess the potential of physical training to restore FDD, 12 patients with chronic heart failure were studied and compared with FDD of 7 age-matched normal subjects. With a recently developed high-resolution ultrasound system, diameters of radial artery were measured at rest, during reactive hyperemia (with increased flow causing endothelium-mediated dilation), and during sodium nitroprusside, causing endothelium-independent dilation. Determination of FDD was repeated after intra-arterial infusion of N^G-monomethyl-L-arginine (L-NMMA, 7 µmol/min) to inhibit endothelial synthesis and release of nitric oxide. The protocol was performed at baseline, after 4 weeks of daily handgrip training, and 6 weeks after cessation of the training program. FDD was impaired in heart failure patients compared with normal subjects. L-NMMA attenuated FDD, indicating that the endothelial release of nitric oxide is involved in FDD. Physical training restored FDD in patients with heart failure. In particular, the portion of FDD inhibited by L-NMMA (representing FDD mediated by nitric oxide) was significantly higher after physical training (8-minute occlusion: 8.0±1% versus 5.4±0.9%; P<.05; normal subjects: 9.2±1%).

Conclusions These results indicate that physical training restores FDD in patients with chronic heart failure, possibly by enhanced endothelial release of nitric oxide.

Key Words: heart failure • endothelium • exercise • endothelium-derived factor

	Introduction

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Systemic vasoconstriction and impaired peripheral perfusion are hallmarks in advanced CHF.¹ While a number of factors, including increased sympathetic tone and an activated renin-angiotensin system, have been proposed to be involved in the reduced arterial vasodilatory capacity in heart failure,¹ the pivotal role of the endothelium in coordinating tissue perfusion has now been recognized.² Several clinical studies have documented endothelial dysfunction of large conduit and small resistance vessels in patients with CHF.^{3 4 5} Endothelial dysfunction may affect the cardiovascular system in two ways: first, endothelial dysfunction of resistance vessels may impair peripheral perfusion, and, second, endothelial dysfunction of large conduit vessels may limit the increase in blood flow provided by the supplying large vessels and may increase impedance of the failing LV and consequently impair LV ejection.

An important functional consequence of endothelial dysfunction is the inability to release EDRF (nitric oxide) in response to physiological stimuli such as increases in flow,⁶ reflecting impaired FDD. Previous studies from our laboratory have shown that FDD is impaired in patients with CHF.⁴ Conversely, chronically increased blood flow enhances the release of EDRF in experimental models,^{7 8} ie, by upregulation of nitric oxide synthase, the enzyme that uses L-arginine to generate nitric oxide. The latter has been shown to account for the biological activity of EDRF.⁹ We hypothesized that intermittent increases of blood flow by physical training may increase the capability of the endothelium to release nitric oxide and therefore may restore endothelial function in patients with heart failure who are usually subjected to a limited degree of physical activity. To this end, FDD in the nondominant forearm was assessed at baseline, after 4 weeks of handgrip training, and 6 weeks after the training program was stopped and compared with FDD of normal subjects.

	Methods

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Twelve male patients with CHF in New York Heart Association functional class III with radiological and echocardiographic signs of cardiomegaly and 7 age-matched normal subjects (age, 41±8 years; 4 men) were studied. Characteristics of the heart failure patients are shown in Table 1. All patients were treated with digitalis, angiotensin-converting enzyme inhibitors, and diuretics, but none received other vasoactive drugs. Digoxin and captopril were stopped 24 hours, diuretics 12 hours, and enalapril 48 hours before measurements. Alcohol and caffeine were prohibited within 12 hours of the study. Patients with diabetes mellitus, hypercholesterolemia (LDL cholesterol >155 mg/dL), arterial hypertension, or significant hematologic, renal, or hepatic dysfunction were excluded by a careful history, physical examination, electrocardiogram, and laboratory analysis. All subjects were nonsmokers and none of the patients participated in an exercise program before the study. Written informed consent was obtained from all subjects, and the protocol was approved by the Ethics Committee of the University of Freiburg.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients With CHF

Radial artery diameters were measured by a recently developed high-resolution A-mode ultrasonic echo-tracking device (ASULAB) that allows measurements of arterial diameter with a precision of ±2.5 µm^{4 10} by using a novel oversampling technique. Recordings of arterial diameters (10 cm proximal to the wrist) were obtained with a 10-MHz transducer positioned perpendicularly to the vessel without direct skin contact by using ultrasonic gel as transmitting medium. Stereo Doppler guidance was used to ensure a correct vertical position of the probe over the artery. Each diameter measurement represents data digitized over 4 seconds (three to five beats).

Forearm blood flow velocity was measured continuously by an 8-MHz Doppler probe (Vasoscope III, Kranzbühler) 5 cm proximal to the 10-MHz probe. Arterial blood flow (mL/min) at the mid-forearm level was calculated as the product of blood flow velocity and cross-sectional area obtained from simultaneous measurements of mean arterial diameter, with a circular vessel area assumed. For each velocity value, at least 15 beats were averaged. Upper-arm or wrist occlusion was performed by inflating an occlusion cuff to 40 mm Hg above systolic blood pressure for 4 or 8 minutes. After release of arterial occlusion, arterial diameter was determined at 20-second intervals for 2 minutes and then every 30 seconds until the diameter returned to baseline. Arterial blood pressure and heart rate were measured on the contralateral arm with a commercially available automatic blood pressure cuff.

After insertion of a polyethylene catheter in the left brachial artery (nondominant arm), blood flow velocity was recorded continuously and arterial diameter determined every 30 seconds until stable baseline conditions were obtained (approximately 30 minutes). Thereafter, a 4- and 8-minute, upper-arm arterial occlusion was performed and FDD assessed in the forearm. Since this approach assessed the vascular responses within the ischemic circulatory bed, a subset of 5 patients and 5 normal subjects underwent wrist occlusion (8 minutes) with determination of the vascular response of the radial artery proximal to the ischemic circulatory bed. Determination of FDD was performed at baseline and after intra-arterial infusion of L-NMMA (Calbiochem; 7 µmol/min over 5 minutes). Dose determination was based on recent publications¹¹ and our earlier observations in normal subjects and patients with CHF³ demonstrating that this dose of L-NMMA attenuated the acetylcholine-induced increase in forearm blood flow by 65±7%. To assess endothelium-independent vasodilatory capacity, subjects received an intra-arterial infusion of SNP (0.3, 3, and 10 µg/min over 5 minutes each). Blood flow and diameter data reported for L-NMMA and SNP represent the measurement during the last minute of each infusion. In a subset of 5 patients, FDD in the dominant arm that was not exposed to training was determined and served as an internal control. In patients with heart failure, this protocol was repeated after 4 weeks of training and 6 weeks after the end of the training program for the patients with CHF. The heart failure patients were asked to perform a handgrip training program with the nondominant hand using a handgrip exerciser (Ultra Grip hand exerciser BK 5299, Sammens) as recently established by Sinoway et al.¹² This device is precalibrated to resistances between 0.9 and 37.3 kg over a distance of 45 mm, and these resistances are accurate within 10%. The maximal amount of work that the subjects could perform (at a rate of 30 contractions per minute) for 3 minutes was determined. They were then asked to perform the workload closest to 70% of the maximal workload for 30 minutes daily for 4 weeks. Patient compliance was achieved by weekly telephone contact during the training period.

Statistical Analysis
All data are expressed as mean±SEM. Statistical analysis was performed by ANOVA for repeated measures followed by the Student-Newman-Keuls test. A value of P<.05 was considered statistically significant.

	Results

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Baseline Measurements
After upper-arm and wrist occlusion, a significant increase in radial arterial diameter was noted during reactive hyperemia. FDD, defined as percent increase in vessel diameter, was attenuated in patients with CHF (8 minutes of occlusion in upper arm/wrist: +8.6±0.9%/10.3±0.7%) compared with normal subjects (+13.5±0.7%/13.0±0.9%; P<.05) (Fig 1). The impairment of FDD was similar in patients with dilated and ischemic cardiomyopathy (data). FDD was significantly higher in the dominant arm compared with the nondominant forearm (Table 2). L-NMMA did not affect radial artery diameter at baseline but attenuated FDD after both upper-arm (Fig 2) and wrist occlusion. Infusion of SNP caused a dose-dependent increase of the radial arterial diameter. Infusion of L-NMMA decreased forearm blood flow significantly at baseline (31±5 versus 20±4 mL/min; P<.05). L-NMMA did not alter the peak blood flow responses during reactive hyperemia (4 and 8 minutes of occlusion; baseline: 101±20/110±23 mL/min; L-NMMA: 95±19/103±18 mL/min) but reduced the area under the curve (59.6±5.5 versus 41.8±24 arbitrary units; P<.05). Thus, despite a similar peak increase in flow, L-NMMA reduced total reactive hyperemia.

View larger version (12K): [in this window] [in a new window]   Figure 1. Bar graph shows percentage change in diameter during reactive hyperemia (FDD) in the nondominant forearm after 4 minutes of upper-arm occlusion at baseline, after 4 weeks of training, and 6 weeks after the end of the training (n=12).

View this table: [in this window] [in a new window]   Table 2. FDD and Maximal Reactive Hyperemic Blood Flow in the Dominant and Nondominant Forearms: Effect of Training of the Nondominant Arm (n=5)

View larger version (20K): [in this window] [in a new window]   Figure 2. Bar graph shows percentage change of diameter (FDD) during reactive hyperemia after 8 minutes of upper-arm occlusion in normal individuals (n=7) and patients with CHF (n=12) at baseline and after 4 weeks of training. ] denotes the portion of FDD inhibited by L-NMMA (P<.05 vs CHF for CHF training and Normals); *P<.05 vs corresponding value before L-NMMA.

Effect of Physical Training
After 4 weeks of handgrip training (nondominant arm), radial artery diameters (before reactive hyperemia) were similar to those at baseline before training (2.86±0.1 versus 2.90±0.1 mm) and values determined in normal subjects (2.87±0.1 mm). The percentage change in diameter during FDD after upper-arm and wrist occlusion was significantly increased after training (+13.6±0.9%/15.5±1% after 8 minutes of upper-arm and wrist occlusion, respectively). In the nontrained, dominant forearm, however, FDD was similar to the values before the training program (Table 2). Infusion of SNP caused a dose-dependent vasodilation that did not significantly differ from the dilator response observed at baseline (SNP, 10 µmol: 3.32±0.1 versus 3.28±0.1 mm at baseline). After training, the portion of FDD inhibited by L-NMMA (representing the percentage change of diameter that is mediated by nitric oxide) was significantly increased compared with baseline and was similar to values observed in normal subjects (Fig 2). After wrist occlusion, the portion of FDD inhibited by L-NMMA increased from 4.6±0.7% at baseline to 8.6±1.0% after training (P<.05).

Peak blood flow and the area under the curve during reactive hyperemia were similar before and after the training program (data not shown). Infusion of L-NMMA decreased forearm blood flow significantly and to a similar extent before and after training. SNP caused a similar dose-dependent increase of blood flow compared with baseline measurements before training (SNP, 10 µmol: 37±7 mL/min after training versus 36±7 mL/min at baseline).

Withdrawal Period
Six weeks after cessation of physical training, radial artery diameters (before reactive hyperemia) were similar to those at baseline before training (2.92±0.1 versus 2.90±0.1 mm). FDD was similar compared with values before training (8-minute upper-arm/wrist occlusion: 8.6±0.9%/10.1±1%) (Fig 1). The maximal blood flow response during reactive hyperemia in response to upper-arm and wrist occlusion was similar compared with the values at baseline and after physical training (wrist occlusion: baseline/training/withdrawal: 105±22/116±12/111±12 mL/min).

	Discussion

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The results of the present study lead to three major conclusions: (1) arterial FDD in the human forearm is to a large extent mediated by endothelial release of nitric oxide; (2) the impaired FDD in patients with CHF is restored by physical training, most likely by increased endothelial release of nitric oxide; and (3) the beneficial effect of physical training on endothelial function is restricted to the trained extremity and is lost 6 weeks after cessation of training.

It is now well established that the diameter of large arteries is influenced by changes in blood flow. An increase in flow results in transient dilation of the vessel that is dependent on the integrity of vascular endothelium.^{13 14} Experimental and clinical data suggest that this vasodilation is to a large extent mediated by the endothelial release of nitric oxide,^{15 16 17} which accounts for the biological activity of EDRF.⁹

CHF is characterized by peripheral vasoconstriction¹ and abnormal vascular compliance,¹⁸ both of which may be related in part to endothelial dysfunction of peripheral resistance and conduit vessels. Indeed, endothelial dysfunction of both large conduit and small resistance vessels has been demonstrated in animal models and patients with CHF, including impaired flow-mediated dilation of conduit vessels.^{3 5 19 20} In the present study, FDD in patients with heart failure was impaired compared with normal individuals, similar to our previous findings.⁴ Consistent with recent observations,¹⁷ our data demonstrate that FDD in the human forearm is substantially inhibited by L-NMMA, suggesting that the release of nitric oxide is involved in FDD. The reduced portion of FDD inhibited by L-NMMA in heart failure (compared with normal subjects) suggests that the endothelial release of nitric oxide is significantly impaired in patients with CHF.

The training program of the nondominant arm resulted in a significantly increased FDD in that extremity, normalizing FDD compared with normal subjects. The extent of FDD was not affected in the dominant arm, which was not exposed to the training program. Thus, the beneficial effect of training was confined to the extremity exposed to regular, daily, intermittent exercise. Notably, comparable exercise programs of one forearm in patients with heart failure did not alter systemic cardiac output, heart rate, or plasma norepinephrine or lactate levels.²¹ Thus, the beneficial effect of physical training on FDD in the trained extremity (but not in the untrained) suggests a local mechanism. In this respect, it is noteworthy that the portion of FDD inhibited by L-NMMA was significantly higher after training (and nearly normalized compared with the normal subjects), suggesting that the improvement in FDD with training was attributed to enhanced release of nitric oxide. Recent experimental data demonstrated that the nitric oxide synthase gene expression in endothelial cell cultures is increased after exposure to increased shear stress²² and that chronic increased blood flow causes an increased endothelial release of nitric oxide.^{7 8} Moreover, a 10-day training program increased the vascular nitric oxide production and nitric oxide synthase gene expression in a dog model²³ and was associated with increased FDD of coronary arteries.²⁴ These experimental observations would support the notion that repetitive increases in flow by physical training exert an upregulation of the nitric oxide synthase, which in turn provides enhanced synthesis and release of nitric oxide, resulting in an improvement of endothelial function in our patients with heart failure. Vice versa, chronic immobilization (or lack of adequate activity) may be associated with reduced expression of the nitric oxide synthase and consequently, decreased synthesis of nitric oxide. Indeed, FDD at baseline was significantly higher in the dominant compared with the nondominant arm, consistent with this hypothesis.

One might argue that FDD measured in the forearm after upper-arm occlusion assesses vascular responses within the ischemic circulatory bed and therefore may not be representative. However, FDD was also determined in a subset of patients after wrist occlusion with determination of the vascular response of the radial artery proximal to the ischemic circulatory bed. This approach yielded similar results supporting the principal findings of the present study. The extent of FDD is influenced by the magnitude of reactive hyperemia. It should be noted that neither the training program nor L-NMMA altered the maximal reactive hyperemic response to upper-arm or wrist occlusion. This finding may be surprising, since previous studies using similar training programs observed an increased hyperemic response in normal individuals.¹² It should be noted, however, that our approach assessed forearm blood flow including the hand circulation, which may not respond to the present training program. In contrast, Sinoway et al¹² used plethysmography to determine skeletal muscle blood flow of the forearm, which is the primary target of this type of exercise. The present study was specifically designed to evaluate FDD. Because enhanced reactive hyperemia with physical training would affect the extent of FDD, the present approach was applied intentionally to avoid confounding effects of training-induced changes in reactive hyperemia.

The functional significance of the beneficial effects of improved endothelial function of large conduit vessels in patients with heart failure remains to be fully determined. It should be noted, however, that large arteries are more than passive conduits.²⁵ Nitric oxide may well be directed toward adjusting the passive elastic properties of the arterial wall, thereby controlling the local mechanical properties of the arterial wall and contributing to the dynamic control of cardiac performance. Previous studies have shown reduced arterial compliance in patients with CHF.¹⁷ There is some evidence that endothelial maintenance of conduit artery distensibility is impaired in patients with CHF.²⁶ Although our determination of impaired endothelial dysfunction was limited to the radial artery, one might speculate that if similar changes were found to be present throughout the large arterial tree, it is possible that they could increase impedance to LV performance. Moreover, the endothelium appears to protect large vessels against constrictor effects of endogenous catecholamines during exercise.²⁷ Future studies need to address the impact of physical training on endothelial dysfunction in the coronary circulation of patients, given the recent observations that endothelial function of the aorta and coronary arteries was enhanced by exercise training in animal models.^{23 28}

	Selected Abbreviations and Acronyms

 

CHF = chronic heart failure EDRF = endothelium-derived relaxing factor FDD = flow-dependent dilation L-NMMA = NG-monomethyl-L-arginine LV = left ventricle, left ventricular SNP = sodium nitroprusside

	Acknowledgments

 
This study was supported in part by the Deutsche Forschungsgemeinschaft (Dr 148/7-1 and 5-2).

Received July 27, 1995; revision received October 23, 1995; accepted November 1, 1995.

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				W Doehner and S D Anker Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure? Heart, June 1, 2005; 91(6): 707 - 709. [Abstract] [Full Text] [PDF]

				T. Kishi, Y. Hirooka, A. Masumoto, K. Ito, Y. Kimura, K. Inokuchi, T. Tagawa, H. Shimokawa, A. Takeshita, and K. Sunagawa Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure Circulation, May 31, 2005; 111(21): 2741 - 2747. [Abstract] [Full Text] [PDF]

				I. T Moe, H. Hoven, E. V Hetland, O. Rognmo, and S. A Slordahl Endothelial function in highly endurance-trained and sedentary, healthy young women Vascular Medicine, May 1, 2005; 10(2): 97 - 102. [Abstract] [PDF]

				H. Zheng, Y.-F. Li, K. G. Cornish, I. H. Zucker, and K. P. Patel Exercise training improves endogenous nitric oxide mechanisms within the paraventricular nucleus in rats with heart failure Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2332 - H2341. [Abstract] [Full Text] [PDF]

				D. Fischer, S. Rossa, U. Landmesser, S. Spiekermann, N. Engberding, B. Hornig, and H. Drexler Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death Eur. Heart J., January 1, 2005; 26(1): 65 - 69. [Abstract] [Full Text] [PDF]

				D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor Effect of exercise training on endothelium-derived nitric oxide function in humans J. Physiol., November 15, 2004; 561(1): 1 - 25. [Abstract] [Full Text] [PDF]

				U. Landmesser, N. Engberding, F. H. Bahlmann, A. Schaefer, A. Wiencke, A. Heineke, S. Spiekermann, D. Hilfiker-Kleiner, C. Templin, D. Kotlarz, et al. Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase Circulation, October 5, 2004; 110(14): 1933 - 1939. [Abstract] [Full Text] [PDF]

				V. M. Conraads, P. Beckers, J. Vaes, M. Martin, V. Van Hoof, C. De Maeyer, N. Possemiers, F. L. Wuyts, and C. J. Vrints Combined endurance/resistance training reduces NT-proBNP levels in patients with chronic heart failure Eur. Heart J., October 2, 2004; 25(20): 1797 - 1805. [Abstract] [Full Text] [PDF]

				P. C. E. de Groot, F. Poelkens, M. Kooijman, and M. T. E. Hopman Preserved flow-mediated dilation in the inactive legs of spinal cord-injured individuals Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H374 - H380. [Abstract] [Full Text] [PDF]

				U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]

				K. F. Harris and K. A. Matthews Interactions Between Autonomic Nervous System Activity and Endothelial Function: A Model for the Development of Cardiovascular Disease Psychosom Med, March 1, 2004; 66(2): 153 - 164. [Abstract] [Full Text] [PDF]

				E. J. Benjamin, M. G. Larson, M. J. Keyes, G. F. Mitchell, R. S. Vasan, J. F. Keaney Jr, B. T. Lehman, S. Fan, E. Osypiuk, and J. A. Vita Clinical Correlates and Heritability of Flow-Mediated Dilation in the Community: The Framingham Heart Study Circulation, February 10, 2004; 109(5): 613 - 619. [Abstract] [Full Text] [PDF]

U. Laufs, N. Werner, A. Link, M. Endres, S. Wassmann, K. Jurgens, E. Miche, M. Bohm, and G. Nickenig Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis Circulation, January 20, 2004; 109(2): 220 - 226.