Effect of aerobic and resistance exercise training on vascular function ...

Am J Physiol Heart Circ Physiol 279: H1999–H2005, 2000.

Effect of aerobic and resistance exercise training on vascular function in heart failure ANDREW MAIORANA,1,3 GERARD O’DRISCOLL,3,4 LAWRENCE DEMBO,3 CRAIG CHEETHAM,1 CARMEL GOODMAN,1 ROGER TAYLOR,2,3 AND DANIEL GREEN1,3,4 1 Department of Human Movement and Exercise Science and 2Medicine, The University of Western Australia, Nedlands 6907; and 3Department of Cardiology and 4Cardiac Transplant Unit, Royal Perth Hospital and West Australian Heart Research Institute, Perth 6000, Western Australia Received 11 November 1999; accepted in final form 25 May 2000

Maiorana, Andrew, Gerard O’Driscoll, Lawrence Dembo, Craig Cheetham, Carmel Goodman, Roger Taylor, and Daniel Green. Effect of aerobic and resistance exercise training on vascular function in heart failure. Am J Physiol Heart Circ Physiol 279: H1999–H2005, 2000.—Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 ⫾ 1.8 to 10.9 ⫾ 2.1 ml 䡠 100 ml⫺1 䡠 min⫺1 for the highest dose, P ⬍ 0.05 by ANOVA), forearm vascular resistance (21.5 ⫾ 5.0 to 15.3 ⫾ 3.9 ml 䡠 100 ml forearm⫺1 䡠 min⫺1, P ⬍ 0.01), or FBF ratios (P ⬍ 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training (P ⬍ 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 ⫾ 2.7 to 33.5 ⫾ 3.1 ml 䡠 100 ml⫺1 䡠 min⫺1, infused limb; P ⬍ 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus. endothelium; nitric oxide; acetylcholine; blood flow; chronic heart failure

(CHF) exhibit impaired exercise capacity and depressed peak O2 uptake ˙O (V 2 peak). Along with hemodynamic variables such as cardiac output, left ventricular ejection fraction, and ˙O pulmonary capillary wedge pressure, V 2 peak correlates with prognosis (32). Although cardiac abnormality initiates and underlies CHF, a major limitation to exercise capacity is of peripheral origin, involving impaired O2 transport and utilization (6). Elevated peripheral resistance is a consistent finding in CHF (5, 13, 17, 21, 27) and is associated with increased ventricular afterload and myocardial O2 dePATIENTS WITH CHRONIC HEART FAILURE

Address for reprint requests and other correspondence: D. Green, Dept. of Human Movement and Exercise Science, The Univ. of Western Australia, Nedlands 6907, Western Australia. http://www.ajpheart.org

mand. Decreased skeletal muscle perfusion and O2 delivery may directly limit exercise capacity (46) and, in addition, may initiate hypoxia-induced changes in skeletal muscle histology and metabolism that hasten fatigue (31). Several studies indicate that exercise training reverses peripheral vascular abnormalities in CHF and improves exercise capacity, although the contribution of improved vascular function is unclear (14, 31). Previous studies have reported improved vascular endothelial function in the upper limb after hand-grip exercise training in CHF subjects (17, 22), and another recent study reported improved basal and stimulated nitric oxide (NO)-dependent endothelial function in the lower limb to result from a program of cycle ergometer training in CHF patients (13). However, because the vascular beds assessed were those subjected to the training stimulus in these studies on subjects with CHF, it is not clear whether a training effect would be localized or generalized to other vascular beds. The purpose of the present study was, therefore, to examine whether an exercise training program targeted at improving peripheral skeletal muscle function improves resistance vessel function in the forearm vasculature, a vascular bed specifically excluded from the training stimulus. METHODS

Subjects and screening measures. Twelve males were recruited after undertaking a screening program consisting of a medical history and examination and a hematological and biochemical profile, including measurement of serum electrolytes, urea and creatinine, uric acid, liver function, and serum lipids. The following were excluded: smokers; those with renal impairment or proteinuria; those with hepatic impairment, gout, or hyperuricemia; and those with hypercholesterolemia (total cholesterol ⬎ 6.0 mmol/l) or hypertension (blood pressure ⬎ 160/90 mmHg). The characteristics of those enrolled are presented in Table 1. Eight subjects had coronary heart disease, four had idiopathic dilated cardiomyopathy, and all were between New York Heart Association (NYHA) class I and class III and did not have overt evidence 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.

0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society

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EXERCISE TRAINING AND VASCULAR FUNCTION IN CHF

Table 1. Subject baseline characteristics Subject

Age, yr Ejection fraction, % Peak oxygen uptake, ml 䡠 kg⫺1 䡠 min⫺1 Plasma lipids, mmol/l Total cholesterol LDL-C HDL-C Triglycerides Mean arterial pressure, mmHg Resting heart rate, beats/min

Baseline Characteristics

60 ⫾ 2 26 ⫾ 3 19.5 ⫾ 1.2 4.8 ⫾ 0.3 2.8 ⫾ 0.2 1.1 ⫾ 0.1 2.0 ⫾ 0.3 84 ⫾ 3 69 ⫾ 4

Values are means ⫾ SE. LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

of congestive cardiac (right heart) failure at the time of study. Nine patients were in sinus rhythm, and the remaining three were in atrial fibrillation. Eleven patients were taking angiotensin-converting enzyme inhibitors, eight were taking aspirin, seven took warfarin, six were on a diuretic, four took digoxin, five were on lipid-lowering therapy, three were taking a nitrate, three took a potassium supplement, two were taking carvedilol, and two took an antiarrhythmic. Medications were not altered in any patient during the course of the trial. The study protocol was approved by the Royal Perth Hospital Ethics Committee, and subjects gave written informed consent. Study design. Subjects were randomized to an 8-wk exercise training program or a nontraining period during which they were instructed not to undertake any formal exercise (see Fig. 1). Forearm vascular function was assessed after 8 wk, after which point crossover occurred with reassessment 16 wk after entry. Each vascular function assessment involved measurement of the forearm blood flow (FBF) response to an ischemic challenge and to intra-arterial infusion of endothelium-dependent and -independent vasodilators into the nondominant forearm. Exercise training regime. The 8-wk training regime consisted of three l-h sessions of whole body exercise each week. Each of these sessions commenced and concluded with a l0-min warm-up/cooldown and stretching period. Each training session involved an exercise “circuit” consisting of seven resistance exercises alternated with eight aerobic exercise (cycling) stations, each performed for 45 s, at which point a timer sounded and subjects had 15 s to move to the next station. To conclude the circuit, subjects spent 5 min walking on a treadmill. Of the seven resistance exercises, five concentrated on the lower limbs or trunk: dual seated leg press, left and right hip extension, seated abdominal flexion, and dual leg flexion. Two resistance exercises concentrated on the torso or upper limb: dual pectoral flexion and dual shoulder extension. Subjects were specifically instructed to avoid hand gripping during all exercises, including shoulder extension and pectoral flexion, and were monitored to ensure compliance with this instruction. Cycle ergometry and treadmill walking were maintained at 70–85% of peak heart rate, which was determined during a graded incremental exercise test performed to peak endur˙O ance capacity (V 2 peak) before entry to the study. Resistance training intensity was maintained at 55–65% of pretraining maximum voluntary contraction, which was determined for all seven exercises in the circuit. During resistance exercise, subjects were instructed to perform one complete lift every 3 s so that 15 repetitions of an exercise were performed per

minute. Subjects were instructed in the correct lifting technique and in how to prevent the Valsalva maneuver. Intensity and duration of the exercise program were progressively increased during the first 2–3 wk of the program, as individually tolerated, initially by increasing the number of exercise circuits from one to three and then by increasing resistance or cycling load. Vascular function assessment protocol. Vascular function assessments were conducted 4 h after medication use and, for individual subjects, at the same time of the day for repeat studies after crossover. Subjects were required to refrain from drinking alcohol or caffeinated beverages for 12 h before the procedure. At each visit, biochemical and hematological parameters were repeated. Investigations were conducted in a quiet, temperaturecontrolled laboratory. Subjects lay supine while pneumatic pressure cuffs (SC10 and SC5; D. E. Hokanson, Bellevue, WA) and strain gauges (SG24; Medasonics, Mountain View, CA) were positioned for the measurement of FBF by the technique of strain-gauge plethysmography. The cuffs on both wrists were connected to a flow-regulated source of compressed air, and arm cuffs were connected to a rapid inflation device (E20, D. E. Hokanson). The strain gauges were placed 8–10 cm from the olecranon process of each forearm, and care was taken to ensure that they were at the same level on each arm. Output from the gauges passed through an amplifier (SPG16, Medasonics) and was sampled by an online microcomputer at a rate of 75 Hz before being displayed on a monitor in real time. A software program coordinated the acquisition, storage, and display of data as well as inflation and deflation of the arm cuffs, ensuring that blood flow measures were synchronized with cuff inflation during recording periods. Measurement of peak forearm vasodilator capacity. Five minutes after subject preparation was completed, the arm cuffs were inflated to a pressure of ⬎220 mmHg for a period of 10 min to provide a stimulus for reactive hyperemic blood flow in each forearm, the maximal flow recorded after deflation of the arm cuffs (RHBF10) being peak vasodilator capacity (36). In all cases, RHBF10 occurred within the first 30 s after cuff release. Measurement of vasodilator dose-response curves. After measurement of RHBF10, a 10-min rest period was observed to allow FBFs to return to baseline. A 20-gauge arterial

Fig. 1. Study design. Subjects undertook a randomized, controlled crossover trial of 8 wk of exercise and nonexercise training periods.


cannula (Arrow, Reading, PA) was then introduced into the brachial artery of the nondominant arm under local anesthesia with ⬍2 ml of 1% lidocaine (Astra PharmaceuticalsAustralia) to transduce pressure for the infusion of drugs or physiological saline and for sampling of arterial blood. Intraarterial pressure was measured continuously (Transpac, Abbot Laboratories) throughout the study. Drug infusions were administered using a constant-rate-infusion pump (IVAC 770). Acetylcholine (ACh; Miochol, Ciba Vision-Australia) was infused at 10, 20, and 40 ␮g/min, each for 3 min, followed by sodium nitroprusside (SNP; David Bull Laboratories-Australia) at 2, 4, and 8 ␮g/min, each for 3 min. All solutions were prepared aseptically from sterile stock solutions or ampoules immediately before infusion into the brachial artery. The study protocol and time frame were identical for every subject. Baseline measurements started 25 min after cannulation of the brachial artery. Blood flow measurements were taken by inflating the wrist cuffs to 220 mmHg, to exclude the hands from the circulation, and by rapidly inflating the upper arm cuffs to 45 mmHg for 10 out of every 15 s throughout the baseline and drug-infusion periods. Output from the strain gauges was stored, and the average of the last five flow measurements from each period was used for analysis. Between infusions, the cuffs were deflated, allowing at least 15 min for FBF to recover from the preceding infusion before further baseline measures were recorded. Analysis. All blood flow measures were analyzed by an investigator who was blinded with respect to subject identification. Although the low doses of drugs infused in the study produce negligible systemic effects and showed no effect on blood pressure or heart rate, it is still desirable to exclude an alteration in overall hemodynamics as a cause of the flow changes seen in the infused forearm. Thus FBF was measured simultaneously in both arms, although only one arm was infused, and the noninfused arm served as a control. As in earlier studies (11, 12, 34, 35), FBF in the infused arm is described as a ratio to that in the noninfused arm. Changes in the ratio during ACh and SNP infusions are expressed as percent changes from the baseline immediately preceding each drug administration (1). In addition, FBF is expressed in absolute units (ml 䡠 100 ml⫺1 䡠 min⫺1), and vascular resistance was calculated in the infused arm as the ratio of mean arterial pressure to FBF (expressed as mmHg 䡠 ml⫺1 䡠 100 ml tissue⫺1 䡠 min⫺1). Results are expressed as means ⫾ SE. The responses after exercise training were compared with nontraining responses using two-way ANOVA, with repeated measures performed on the three dose levels of ACh and SNP. All other comparisons of training and nontraining periods, including post hoc analysis of ANOVA results, were undertaken using Student’s paired two-tailed and one-tailed t-tests. P ⬍ 0.05 was considered significant.

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1.1 min (P ⬍ 0.001). Details of the effect of the exercise program on body composition, functional capacity, and strength have been published elsewhere (30). Forearm vascular function. RHBF10, an index of peak vasodilator capacity induced by ischemia, was significantly increased by exercise training in the infused limb (nondominant arm), from 27.9 ⫾ 2.7 to 33.5 ⫾ 3.1 ml 䡠 100 ml⫺1 䡠 min⫺1, and in the noninfused limb, from 31.9 ⫾ 2.8 to 40.9 ⫾ 3.6 ml 䡠 100 ml⫺1 䡠 min⫺1 (each P ⬍ 0.05, paired t-test; Fig. 2). Absolute FBF data recorded in the infused and noninfused limbs at baseline and during the infusion of ACh and SNP at three dose levels, after the nontraining and training periods, are presented in Table 2. The baseline FBF values preceding the two drugs in both the trained and untrained state were not different, indicating adequate washout periods between infusions. Absolute FBF responses to ACh were significantly augmented after training (P ⬍ 0.05, 2-way ANOVA). When analyzed with either one- or two-tailed post hoc t-tests, differences were evident between trained and untrained paired data at the 10- and 20␮g/min dose level (P ⬍ 0.05). ACh also reduced forearm vascular resistance (FVR) more after training than after the nontraining period (P ⬍ 0.01 by ANOVA, Table 3), with significance levels of P ⬍ 0.001 at doses of 10 and 20 ␮g/min by paired t-test. Although absolute FBF responses to SNP increased after training, statistical significance by ANOVA was not achieved (P ⫽ 0.06, Table 2). FVR responses to SNP were not significantly different by ANOVA (P ⫽ 0.09). However, as described in METHODS, it is optimal to analyze the data in terms of FBF ratios, that is, the ratio of flow in the infused arm to that in the noninfused arm. When analyzed in this way, the ratios at the three dose levels of ACh were significantly greater after training (P ⬍ 0.01, 2-way ANOVA; Table 4), with significance levels of P ⬍ 0.05 at doses of 20 and 40 ␮g/min by either one- or two-tailed t-tests. Responses

RESULTS

General effects of exercise training. Resting heart rate and mean arterial pressure were not significantly different after the trained and untrained periods: 69 ⫾ 4 and 70 ⫾ 4 beats/min and 84 ⫾ 3 and 83 ⫾ 3 mmHg, respectively. There were also no significant differences in body weight, plasma total, or high-density lipoprotein or low-density lipoprotein cholesterol. ˙O V 2 peak increased as a result of training from 19.5 ⫾ 1.2 to 22.0 ⫾ 1.5 ml 䡠 kg⫺1 䡠 min⫺1 (P ⬍ 0.01), and exercise test duration improved from 15.2 ⫾ 0.9 to 18.0 ⫾

Fig. 2. Peak reactive hyperemic blood flow after 8 wk of inactivity (untrained) or 8 wk of circuit weight training (trained). Values are means ⫾ SE. Peak vasodilator responses in both limbs were enhanced after training (P ⬍ 0.05).

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Table 2. Absolute blood flows in infused and noninfused forearms after untrained and trained periods Infused Arm Flows Untrained

Resting FBF ACh infusion 10 ␮g/min 20 ␮g/min 40 ␮g/min Pre-SNP baseline SNP infusion 2 ␮g/min 4 ␮g/min 8 ␮g/min

Noninfused Arm Flows

Trained

P

Untrained

Trained

P Value

2.4 ⫾ 0.3

3.0 ⫾ 0.4

0.11

2.6 ⫾ 0.3

3.6 ⫾ 0.4

0.19

3.2 ⫾ 0.7 3.9 ⫾ 1.2 7.0 ⫾ 1.8 2.5 ⫾ 0.3

5.3 ⫾ 1.5 8.5 ⫾ 2.4 10.9 ⫾ 2.9 2.6 ⫾ 0.2

0.03 0.01 0.04 0.27

3.0 ⫾ 0.4 3.0 ⫾ 0.4 3.2 ⫾ 0.4 3.0 ⫾ 0.5

3.2 ⫾ 0.4 3.4 ⫾ 0.5 2.9 ⫾ 0.4 3.3 ⫾ 0.4

0.33 0.13 0.15 0.27

7.8 ⫾ 1.1 9.8 ⫾ 1.4 14.1 ⫾ 1.9

9.3 ⫾ 1.0 12.4 ⫾ 1.2 17.8 ⫾ 1.9

0.08 0.04 0.03

3.1 ⫾ 0.6 2.8 ⫾ 0.4 3.4 ⫾ 0.8

3.2 ⫾ 0.3 2.8 ⫾ 0.4 3.0 ⫾ 0.4

0.43 0.46 0.26

Arm flow values are means ⫾ SE in ml 䡠 100 ml forearm⫺1 䡠 min⫺1. P values are for paired 1-tailed t-test for trained vs. untrained. Absolute forearm blood flow (FBF) responses to ACh in the infused arm were enhanced by exercise training (P ⬍ 0.05 by 2-way ANOVA). Changes in response to sodium nitroprusside (SNP) did not achieve statistical significance by ANOVA (P ⫽ 0.06 by 2-way ANOVA) but were different at higher doses when analyzed by 1-tailed t-test (P ⬍ 0.05).

to SNP were not different by ANOVA (P ⫽ 0.08) or by paired t-test. When these ratios were analyzed as percent changes from their preceding baselines, a form of analysis that is considered most appropriate (1, 11, 12, 33, 35), the response to both ACh (P ⬍ 0.05 by ANOVA, Fig. 3) and SNP (P ⬍ 0.05 by ANOVA, Fig. 4) improved after training. Post hoc t-tests revealed significant differences at 20 and 40 ␮g/min for ACh (P ⬍ 0.05) and at doses of 4 and 8 ␮g/min for SNP (P ⬍ 0.05). These statistical results were similar regardless of whether one- or two-tailed t-tests were used. The responses were not dependent on the order of training and nontraining periods. DISCUSSION

The results of this study indicate that exercise training improves indexes of vascular function in patients with CHF. Endothelium-dependent vasodilation to ACh, largely NO dependent, and endothelium-independent vasodilation to SNP significantly increased when absolute blood flows and flow ratios were assessed. Reactive hyperemia, an index of peak vasodiTable 3. FVR responses in infused arm after untrained and trained periods

Resting FVR ACh infusion 10 ␮g/min 20 ␮g/min 40 ␮g/min Pre-SNP baseline SNP infusion 2 ␮g/min 4 ␮g/min 8 ␮g/min

Table 4. FBF ratios after untrained and trained periods

Untrained

Trained

39.1 ⫾ 4.2

32.3 ⫾ 3.2

0.08

34.4 ⫾ 4.2 31.2 ⫾ 3.9 21.5 ⫾ 5.0 42.0 ⫾ 6.1

23.4 ⫾ 3.1 18.3 ⫾ 3.5 15.3 ⫾ 3.9 34.8 ⫾ 3.2

⬍0.01 ⬍0.01 ⬍0.05 0.07

13.4 ⫾ 2.0 10.9 ⫾ 1.6 7.3 ⫾ 1.1

10.4 ⫾ 1.3 7.5 ⫾ 0.9 5.5 ⫾ 0.9

0.07 0.03 0.08

⫺1

lator capacity and resistance vessel structure (36), also improved after exercise training. A principle finding is that these improvements occurred in the forearm resistance bed despite the substantial avoidance of forearm exercise, suggesting that the beneficial effect of exercise training on vascular function may be generalized and not specific to the vascular bed of the trained skeletal muscle. Several previous studies have investigated the effects of exercise training in patients with CHF. Four weeks of local forearm training improved forearm conduit arterial flow-dependent vasodilation, an effect attenuated by infusion of the inhibitor of NO synthesis, NG-monomethyl-L-arginine (L-NMMA) (17). In other studies, 8 wk of forearm training improved forearm flow responses to ACh, whereas endothelium-independent responses were unaltered (22), and 6 mo of cycle training improved basal and stimulated endotheliumdependent NO-related responses in the lower limb (13). These studies are consistent with literature indicating that exercise training in animals improves NO-dependent vasodilation (4, 24, 29, 45) and upregulates expression of the constitutive NO synthase (NOS) (40,

P Value

⫺1

Values are means ⫾ SE in ml 䡠 100 ml forearm 䡠 min . P values are for paired 1-tailed t-test for trained vs. untrained. Forearm vascular resistance (FVR) responses to ACh in the infused arm were reduced by exercise training (P ⬍ 0.01 by 2-way ANOVA). Changes in response to SNP did not achieve statistical significance by ANOVA (P ⫽ 0.09 by 2-way ANOVA) but were different at 4 ␮g/min when analyzed by 1-tailed t-test (P ⬍ 0.05).

Resting FBF ACh infusion 10 ␮g/min 20 ␮g/min 40 ␮g/min Pre-SNP baseline SNP infusion 2 ␮g/min 4 ␮g/min 8 ␮g/min

Untrained

Trained

P Value

1.0 ⫾ 0.1

0.9 ⫾ 0.1

0.14

1.1 ⫾ 0.2 1.2 ⫾ 0.2 2.3 ⫾ 0.5 0.9 ⫾ 0.1

1.7 ⫾ 0.3 2.3 ⫾ 0.4* 3.5 ⫾ 0.6* 0.8 ⫾ 0.1

3.1 ⫾ 0.5 4.1 ⫾ 0.6 5.8 ⫾ 1.0

3.1 ⫾ 0.4 4.9 ⫾ 0.6 6.6 ⫾ 0.8

0.03 ⬍0.01 0.02 0.20 0.47 0.17 0.19

Values are means ⫾ SE. P values are for paired 1-tailed t-test for trained vs. untrained. FBF ratio responses to ACh in the infused arm were enhanced by exercise training (* P ⬍ 0.01 by 2-way ANOVA). Changes in response to SNP did not achieve statistical significance by ANOVA (P ⫽ 0.08 by 2-way ANOVA).


Fig. 3. Forearm blood flow (FBF) response to 3 doses of ACh after 8 wk of inactivity (E) or 8 wk of circuit weight training (■). FBF is expressed as the %change in the ratio of infusion arm to noninfusion arm flows relative to the baseline period preceding the administration of ACh. Values are means ⫾ SE. Vasodilatation to ACh was significantly increased (P ⬍ 0.05, 2-way ANOVA).

43). However, the vascular beds examined in the previous studies of CHF patients were those directly involved in the training stimulus (13, 17, 22). This is the first demonstration that a clinically relevant exercise program induces generalized beneficial vascular adaptation, although a previous study of cycle training in normal volunteers suggested some improvement in basal NO function (23). The beneficial effects of an exercise program on vascular function probably relate to the effect of increased flow on the endothelium, although general metabolic effects might also be operative. Acutely increasing blood flow in conduit vessels increases flow-mediated stress on the vessel wall, which, in turn, liberates NO from the endothelium (8, 26, 37); flow-dependent vasodilation is attenuated by coinfusion of L-NMMA, indicating that conduit vessel dilation during exercise is, at least in part, NO dependent (17, 19). The vasodilator response in resistance vessels during exercise, and hence exercise-induced hyperemia, is also partly NO dependent (7, 9, 38). Furthermore, experimentally, repeated exercise induces a sustained increase in the expression of endothelial constitutive NOS (ecNOS) (40, 43). It seems, therefore, that repetitive increases in flow, as a result of exercise training, induce a chronic adaptation of the NO vasodilator system. However, several previous studies of forearm exercise training in healthy volunteers have failed to improve NO-mediated vascular function in the trained musculature (10– 12). It might be expected that the endothelial response to exercise would result not only from increased blood flow but also from changes in other hemodynamic variables such as increased heart rate and blood pressure, as well as metabolic effects, which would be imposed throughout the vasculature. This is the likely explanation for what appears to be a general improvement in endothelial function rather than one restricted to the vascular bed exercised. We cannot, however, exclude the possibility that decreased sympathetic nervous

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tone after training may have contributed to the increased vasodilation evident. In the present study, the responses not only to ACh but also to SNP were enhanced after training, which would indicate that both endothelial and smooth muscle components of the NO-related dilator system improved. This is not surprising, because several studies have found that, in addition to endothelium-dependent responses (5, 21, 27, 44), endothelium-independent responses such as those to SNP can be impaired in patients with CHF (13, 18, 20). However, our finding contrasts with previous studies of patients with CHF in which improvement was limited to the endothelial component and the response to donated NO was unchanged (13, 17, 22). The finding of increased peak vasodilator capacity after an exercise training program is also novel in subjects with CHF. It is intriguing that the response was seen in both forearms after training, especially in view of the nature of the exercises. It is well established that exercise training in humans can improve peak vasodilator capacity of the exercised vascular bed (15, 41, 42), an effect suggesting a structural change involving enhanced cross-sectional area of the vasculature (3, 15, 36). Experimental studies have concluded that vessel wall architecture is modified to maintain constant wall stress (25, 28, 39). These studies include a recent finding that poststenotic dilation of the rabbit femoral artery, which is a chronic structural response to increased shear stress associated with turbulent flow, is NO dependent (2). Chronic structural vessel changes can, therefore, probably be regarded as an extension of the sustained changes in endothelial function resulting from exercise and may also be dependent largely on NO-related mechanisms. Because the nontrained data did not differ between the group training first or second, it does not appear that the effect of exercise training on the vasculature persisted for 8 wk. This is consistent with the time course of deconditioning associated with other physiological adaptations to exercise training, such as skele-

Fig. 4. FBF response to 3 doses of sodium nitroprusside (SNP) after 8 wk of inactivity (E) or 8 wk of circuit weight training (■). FBF is expressed as the %change in the ratio of infusion arm to noninfusion arm flows relative to the baseline period preceding the administration of SNP. Values are means ⫾ SE. Vasodilatation to SNP was significantly increased (P ⬍ 0.05, 2-way ANOVA).

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tal muscle metabolic changes (16), which reverse within 4–6 wk of exercise cessation. In addition, it accords with the reversal of improvement in flow-mediated dilatation observed 6 wk after the cessation of forearm hand-grip exercise in the brachial artery of CHF patients (17). The data suggest, therefore, that an exercise program, at some level as yet undetermined, would be necessary to maintain the vascular benefits of exercise. The nature of the training program has been described in great detail in the METHODS, because a program such as this, combining aerobic and resistance exercises and examining the vascular effects in patients with CHF, has not been previously described. Data indicating that this program significantly in˙O creased V 2 peak (from 19.5 ⫾ 1.2 to 22.0 ⫾ 1.5 ml 䡠 kg⫺1 䡠 min⫺1, P ⬍ 0.01), exercise test duration, and composite muscle strength were also obtained and are published separately (30). The exercise program is not, in fact, complicated, and a similar one could be used routinely in comparable patients and even adapted for a home-based program. In summary, this study extends previous reports regarding the beneficial effect of exercise training on vascular function in CHF. Importantly, for the first time, it found evidence that a relatively short program is associated with structural as well as functional changes and that the vascular benefit may be generalized to the circulation rather than limited to the skeletal muscle bed directly involved in the training stimulus. This study was supported by the National Heart Foundation of Australia and the Medical Research Fund of Western Australia (MEDWA). REFERENCES 1. Benjamin N, Calver A, Collier J, Vallance P, and Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 25: 918–923, 1995. 2. Calvo WJ, Hajduczok G, Russell JA, and Diamond SL. Inhibition of nitric oxide but not prostacyclin prevents poststenotic dilatation in rabbit femoral artery. Circulation 99: 1069– 1076, 1999. 3. Currens JH and 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. 4. Delp MD. Effects of exercise training on endothelium-dependent peripheral vascular responsiveness. Med Sci Sports Exerc 27: 1152–1157, 1995. 5. Drexler H, Hayoz D, Munzel T, Hornig B, Just H, Brunner HR, and Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol 69: 1596–1601, 1992. 6. Drexler H, Reide U, Munzel T, Konig H, Funke E, and Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 85: 1751–1759, 1992. 7. Dyke CK, Proctor DN, Deitz NM, and Joyner MJ. Role of nitric oxide during prolonged rythmic handgripping in humans. J Physiol (Lond) 448: 259–265, 1995. 8. Friebel M, Klotz KF, Ley K, Gaehtgens P, and Pries AR. Flow-dependent regulation of arteriolar diameter in rat skeletal muscle in situ: role of endothelium-derived relaxing factor and prostanoids. J Physiol (Lond) 483: 715–726, 1995. 9. Gilligan DM, Panza JA, Kilcoyne CM, Waclawiw MA, Casino PR, and Quyyumi AA. Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation. Circulation 90: 2853–2858, 1994.

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