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Importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction
Importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction Toshihiko Hattori, MD, Tsutomu Sumimoto, MD, Mutsuhito Kaida, MD, Fumio Yuasa, MD, Toshimitsu Jikuhara, MD, Makoto Hikosaka, MD, Tetsuro Sugiura, MD, and Toshiji Iwasaka, MD Osaka, Japan
Background Distribution of skeletal muscle perfusion during exercise is an important factor in determining exercise capacity and is markedly impaired in patients with cardiac disease. This study examined the importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction.
Methods We studied 19 patients with left ventricular dysfunction (left ventricular ejection fraction <45%) after myocardial infarction. All the patients underwent cardiopulmonary exercise testing with measurements of central hemodynamics, leg blood flow (LBF), and the percentage of cardiac output distributed to both legs (%LBF). Calf reactive hyperemic flow (RH) was measured by venous occlusive plethysmography at supine rest.
Results LBF at peak exercise was closely related to peak cardiac output and RH. Furthermore, %LBF at peak exercise had modest correlation with peak cardiac output and good correlation with RH. Although peak cardiac output and RH were independent determinants of LBF at peak exercise by multiple regression analysis, RH had higher correlation with %LBF at peak exercise than peak cardiac output. Despite marked changes in other hemodynamic variables, nonleg blood flow during exercise was constantly maintained at a level identical to resting value.
Conclusions Calf vasodilator capacity, which was the major determinant of distribution of skeletal muscle perfusion during exercise, may have contributed to maintaining perfusion of important nonexercising regions during exercise in patients with left ventricular dysfunction. (Am Heart J 1998;136:458-64.)
Distribution of skeletal muscle perfusion during exercise is an important factor determining exercise capacity and is markedly impaired in patients with cardiac disease.1-10 However, the pathophysiologic mechanism responsible for this impairment during exercise has not been clearly defined. Several investigators2,4,11 demonstrated that an increase in cardiac output during exercise was the major determinant of distribution of skeletal muscle perfusion during exercise in both cardiac patients and normal subjects. In contrast, other investigators1,3,12,13 observed that limb vasodilator response to various stimuli is markedly reduced in heart failure and suggested that the reduced intrinsic limb vasodila-
From the Second Department of Internal Medicine, Kansai Medical University. Submitted July 8, 1997; accepted Feb. 10, 1998. Reprint requests: Toshihiko Hattori, MD, CCU, Kansai Medical University, 10-15 Fumizonocho, Moriguchi-city Osaka 570, Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89606
tor capacity is the major factor determining impaired distribution of skeletal muscle perfusion. Thus the relative contribution of cardiac pump function and peripheral vasodilator capacity in determining distribution of skeletal muscle perfusion during exercise has not been completely defined in patients with cardiac disease. The present study was designed to measure calf reactive hyperemic flow as an index of intrinsic calf vasodilator capacity and to perform symptom-limited cardiopulmonary exercise testing with measurements of central hemodynamics and leg blood flow (LBF) response in patients with left ventricular dysfunction after myocardial infarction. Accordingly, we examined calf reactive hyperemic flow, LBF, and the percentage of cardiac output distributed to both legs (%LBF) during exercise to investigate the importance of intrinsic limb vasodilator capacity in determining distribution of skeletal muscle perfusion during exercise in patients with this disorder.
American Heart Journal Volume 136, Number 3
Hattori et al 459
Methods
Central hemodynamic and metabolic measurements
Patient population
Pulmonary and systemic arterial pressures were recorded continuously, and pulmonary arterial wedge pressure was recorded intermittently at rest and at each exercise stage with DS-3300 system (Fukuda Denshi). Blood samples were drawn simultaneously from the radial and pulmonary arteries at rest and within the last 30 seconds of each exercise stage. The blood samples were used for the immediate measurements of pH, PO2, and PCO2 (Radiometer Company ABL2), as well as oxygen saturation and hemoglobin concentration (Radiometer Company OSM2). Plasma norepinephrine concentration was determined in arterial samples.
We evaluated 57 consecutive patients with first Q-wave myocardial infarction who not only underwent both exercise test and coronary arteriography but also had patent infarctrelated coronary artery with negative exercise test. Each patient underwent a complete physical examination, and patients were excluded from the study if they had physical or radiographic signs of obstructive lung disease, atrial fibrillation or flutter, valvular disease evaluated by color Doppler echocardiography, or intermittent claudication that limited their exercise capacity. Of these, 19 men aged 34 to 63 years (mean 53 ± 9 years) with resting left ventricular ejection fraction <45% were selected for the purpose of this study. The resting left ventricular ejection fraction ranged from 17% to 44% (mean 34% ± 7%). All patients included in this study had their first acute Q-wave myocardial infarction 3 to 6 weeks before the study, and none of the patients had postinfarction angina, critical arrhythmia, or uncontrolled congestive heart failure for at least 2 weeks before the study. All medications were discontinued for >48 hours before the study. The risks of the study were fully explained and informed consent was obtained from each patient before the study. The research protocol was approved by the Ethics Committee of Kansai Medical University.
Leg blood flow measurements Femoral venous flow was determined by thermodilution technique in triplicate at rest and at each exercise stage. Bolus injections of 3 ml iced or room temperature saline solution were used to obtain blood flow measurements with the use of a commercially available thermodilution computer (Edwards REF-1, Baxter). Output curves were displayed on a strip chart recorder to ensure an exponential decay curve. The validity of using the thermodilution technique to measure LBF during dynamic exercise has been confirmed by previous studies,7 and LBF determined by this system are comparable to leg flow measurements reported with other methods.14,15
Exercise protocol
Calf reactive hyperemic flow
Patients were studied while they were in the supine position at rest and during bicycle ergometric exercise. Supine bicycle exercise was performed to familiarize the patients with an isokinetic bicycle ergometer (Monark 881E ergometer, Solna) 2 or 3 days before the study. On the day of the study, a 7F balloon-tipped pulmonary artery catheter was inserted through the internal jugular vein and positioned in the pulmonary artery and a short polyethylene catheter was inserted into the radial artery. A 50 cm 5F thermodilution catheter with the thermistor at 2 cm and the injection port at 12 cm was inserted simultaneously into the femoral vein 2 cm below the inguinal ligament and advanced into the iliac vein under fluoroscopic guidance. After 30 minutes of rest, bicycle exercise testing was performed with ECG monitoring and expired gas analysis. Exercise began at a work load of 15 W with the pedal speed maintained at 60 rpm and increased by 15 W every 3 minutes until symptom-limited maximum.
Before exercise testing, calf blood flow was measured by using a mercury-in-Silastic polymeric silicone strain gauge placed around the upper calf and connected to an electronically calibrated plethysmograph (Medasonics SPG16). Reactive hyperemic flow was measured by inflating the cuff placed around the upper thigh to 40 mm Hg above the systolic pressure to occlude arterial flow to the calf for 5 minutes. To avoid the variation of calf blood flow values at various time points after release of arterial occlusion, we measured calf blood flow initially at 5 and 15 seconds after release of arterial occlusion and averaged these two flow measurements to estimate calf reactive hyperemic flow as previously described.9
Expired gas analysis Continuous expired gas analysis was performed with an Oxycon-4 (Mijnhardt Co.). Instruments were calibrated at the beginning of each study and before every measurements. From these data, oxygen consumption (VO2) was measured at supine rest on a bicycle and continuously during exercise. Averaged measurements during the last 30 seconds of each exercise stage were used for analysis.
Derived variables Mean arterial blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Cardiac output was determined by the Fick principle by use of systemic arteriovenous oxygen difference and directly measured VO2. To describe cardiac output distribution during exercise, nonleg blood flow (non-LBF) was calculated as cardiac output – (LBF × 2). The percentage of cardiac output distributed to the two legs (%LBF) was determined as (LBF × 2)/cardiac output.
Radionuclide angiography Radionuclide angiocardiography was performed at rest by use of a multicrystal gamma camera (Baird Atomic System 77)
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Table I. Baseline characteristics Calf vasodilator capacity <19.4 ml/min/100 ml (n = 9)
≥19.4 ml/min/100 ml (n = 10)
p Value
56 ± 8 31 ± 8
50 ± 9 37 ± 5
NS NS
8 1 107 ± 13 3.8 ± 0.6 0.23 ± 0.10 3.4 ± 0.6 12 ± 4
9 1 98 ± 12 4.2 ± 0.6 0.33 ± 0.11 3.6 ± 0.6 16 ± 5
NS
Age (yr) LVEF (%) Site of MI Anterior Inferior Mean BP (mm Hg) Cardiac output (L/min) LBF (L/min) Non-LBF (L/min) %LBF (%)
NS NS NS NS NS
LVEF, Left ventricular ejection fraction; MI, myocardial infarction; BP, arterial blood pressure.
Table II. Hemodynamic and metabolic responses to exercise
Mean BP VO2 Norepinephrine Cardiac output LBF Non-LBF %LBF
(mm Hg) (ml/min/kg) (pg/dl) (L/min) (L/min) (L/min) (%)
Rest
Peak exercise
103 ± 13 3.2 ± 0.4 269 ± 153 4.0 ± 0.6 0.28 ± 0.11 3.5 ± 0.7 14 ± 5
120 ± 19* 16.7 ± 4.0* 1519 ± 798* 9.2 ± 3.2* 2.8 ± 1.3* 3.7 ± 1.2 58 ± 10*
BP, Arterial blood pressure. *p < 0.001 vs resting value.
in the anterior projection 2 or 3 days before the study. Left ventricular ejection fraction was determined from the backgroundcorrected representative cardiac cycle as follows: (end-diastolic counts – end-systolic counts)/end-diastolic counts × 100.
Statistical analysis All data are presented as mean ± standard deviation. Student’s t test was used to compare the two groups and paired t test was used for paired samples. The least-squares regression was used to assess the relationship between the two variables. Multiple regression analysis was used to determine the important variables related to LBF and %LBF at peak exercise. Probability values of <0.05 were considered to be significant.
Results Calf vasodilator capacity Calf blood flow at rest was 3.4 ± 1.7 ml/min/100 ml tissue, which was markedly increased to 18.2 ± 4.4 ml/min/100 ml tissue (median 19.4 ml/min/100 ml tissue, range 10.8 to 25.8 ml/min/100 ml tissue) during reactive hyperemia. There were no significant differences in baseline and resting hemodynamic character-
istics between nine patients with calf vasodilator capacity below the median and 10 patients with calf vasodilator capacity above the median (Table I).
Distribution of cardiac output during exercise In all 19 patients, the bicycle exercise was limited by exercising muscle fatigue and not by dyspnea. None of the patients had either chest pain or significant ST changes suggestive of active ischemia during exercise. The maximal work load was 59 ± 24 W and the exercise duration was 720 ± 293 seconds. Hemodynamic and metabolic responses to exercise are summarized in Table II. Cardiac output and LBF increased significantly during exercise. %LBF also increased as a result of relative increase in the proportion of LBF to cardiac output during exercise. However, non-LBF during exercise was constantly maintained at a level identical to the resting value.
Determinants of LBF at peak exercise LBF at peak exercise was not related to peak mean arterial blood pressure or to norepinephrine concen-
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Figure 1
Left panel: Relation between LBF at peak exercise and cardiac output (CO) at peak exercise. Right panel: Relation between LBF at peak exercise and calf reactive hyperemic flow induced by arterial occlusion for 5 minutes at spine rest. LBF at peak exercise had close correlation with these variables.
tration. However, LBF at peak exercise had close correlations with peak cardiac output and calf reactive hyperemic flow (r = 0.94, p < 0.001; r = 0.80, p < 0.001) (Fig. 1). To determine the important factor determining LBF at peak exercise, multiple regression analysis was performed by using peak cardiac output and calf reactive hyperemic flow. As a result, peak cardiac output (regression coefficient = 0.30, p < 0.001) and calf reactive hyperemic flow (regression coefficient = 0.08, p = 0.019) were independent determinants of LBF at peak exercise.
Determinants of %LBF at peak exercise %LBF at peak exercise was not related to peak mean arterial blood pressure or to norepinephrine concentration. However, %LBF at peak exercise had modest correlation with peak cardiac output (r = 0.56, p = 0.02) and good correlation with calf reactive hyperemic flow (r = 0.75, p < 0.001) (Fig. 2). To determine the important factor determining %LBF at peak exercise, multiple regression analysis was performed with peak cardiac output and calf reactive hyperemic flow. The multiple regression analysis demonstrated that only calf reactive hyperemic flow (regression coefficient = 1.68, p = 0.008) was significantly related to %LBF at peak exercise.
Relation between peak VO2 and peripheral hemodynamic measurements Peak VO2 had a fair correlation with calf reactive hyperemic flow (r = 0.68, p = 0.002), good correlation with LBF (r = 0.81, p < 0.001), and modest correlation with %LBF at peak exercise (r = 0.48, p = 0.04) (Fig. 3).
Discussion The present study is one of the first to examine the direct relation between peripheral hemodynamics during exercise and intrinsic limb vasodilator capacity. The findings of the present study demonstrate that calf vasodilator capacity is a more important determinant of cardiac output local flow during exercise than is peak cardiac output. Furthermore, this may have contributed to maintaining perfusion of the important nonexercising regions during exercise in patients with left ventricular dysfunction after myocardial infarction. Cardiac output response to exercise has been reported to be an important determinant of LBF and, therefore, of peak aerobic performance in patients with heart failure and in normal subjects.2,4,11 In contrast, several other studies3,9,12,13 demonstrated that intrinsic limb vasodilator response to a number of stimuli is impaired in patients with cardiac disease and suggested that the impaired limb vasodilator response
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462 Hattori et al
Figure 2
Left panel: Relation between %LBF at peak exercise and cardiac output (CO) at peak exercise. Right panel: Relation between %LBF at peak exercise and calf reactive hyperemic flow induced by arterial occlusion for 5 minutes at spine rest. %LBF at peak exercise had modest correlation with peak CO and good correlation with calf reactive hyperemic flow.
may have contributed to skeletal muscle hypoperfusion and exercise intolerance. Limb reactive hyperemic response to 5 minutes of ischemia represents maximal peripheral vasodilation independent of central hemodynamics or sympathetic tone in patients with heart failure and in normal subjects.9 In the present study, we found that cardiac output had a close correlation with LBF at peak exercise, emphasizing that cardiac output response was an important determinant of LBF response during exercise. Conversely, calf reactive hyperemic flow had fair correlations with peak LBF and peak VO2, which demonstrate the importance of intrinsic vasodilator capacity of resistance vessels within the exercising skeletal muscle in determining skeletal muscle perfusion during exercise and, therefore, reflect exercise capacity. Our findings, that peak cardiac output and calf reactive hyperemic flow were independent determinants of LBF at peak exercise, underline the contribution of maximal calf vasodilator capacity as well as cardiac output in determining skeletal muscle perfusion during exercise. Previous studies2,3,16-19 demonstrated that %LBF as well as cardiac output and LBF are lower during exercise in patients with heart failure than in normal subjects. These studies reported that %LBF at peak
exercise was only 50% to 60% in heart failure but >80% in normal subjects. In contrast, non-LBF was continuously maintained at identical levels during exercise in patients with heart failure and in normal subjects. These findings suggest that impaired skeletal muscle vasodilation contributed to the redistribution of cardiac output to the nonexercising vital regions in a setting of inadequate cardiac output response to exercise in heart failure. In the present study, our patients demonstrated a similar reduction in %LBF at peak exercise, but non-LBF during exercise was constantly maintained at a level identical to the resting value. Furthermore, calf reactive hyperemic flow was a better determinant of %LBF at peak exercise than peak cardiac output, indicating that distribution of skeletal muscle perfusion during exercise was not determined primarily by cardiac output response but rather by intrinsic limb vasodilator capacity. Therefore, calf vasodilator capacity, the major determinant of distribution of skeletal muscle perfusion during exercise, may have contributed to maintaining perfusion of important nonexercising regions during exercise in patients with left ventricular dysfunction. This is consistent with the previous studies2,3 of patients with heart failure, suggesting that intrinsic abnormalities of exercising leg blood
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Figure 3
Relation between peripheral hemodynamic variables and peak VO2. Each peripheral hemodynamic variable had positive correlation with peak VO2.
flow and reactive hyperemic response may prevent hypoperfusion and, possibly, ischemia in vital nonexercising regions. The contribution of relative arterial hypotension and increased sympathetic vasoconstriction to reduced distribution of skeletal muscle perfusion during exercise has been reported in patients with heart failure.3,20 However, mean arterial blood pressure and norepinephrine concentration were not related to LBF responses during exercise in our patients. Although the role of arterial hypotension and sympathetic vasoconstriction in determining reduced distribution of skeletal muscle perfusion during exercise cannot be completely excluded, the present study demonstrated that arterial blood pressure and norepinephrine concentration were not primarily determinants of LBF response to exercise. In contrast, contribution of chronic muscular21-28 and vascular12,13,29 deconditioning to exercise intolerance or skeletal muscle hypoperfusion have been observed in patients with chronic heart failure. Although the present study did not define the primary factor causing peripheral hemodynamic abnormalities in patients with left ventricular dysfunction after myocardial infarction, a rapid vascular deconditioning within a few weeks rather than muscle deconditioning may have contributed, in part, to a decrease in limb
vasodilator capacity and distribution of skeletal muscle perfusion during exercise. Vascular fluid retention, a reduction in peripheral capillary formation, and other factors that impair endothelial function may have affected calf reactive hyperemic flow. Two limitations of our study should be addressed. First, all the patients included in this study had recent onset of left ventricular dysfunction (acute myocardial infarction 3 to 6 weeks before the study). Therefore, it is possible that calf reactive hyperemic flow may vary in patients with other causes of left ventricular dysfunction. It remains to be seen whether different causes can in any way affect calf reactive hyperemic flow. Second, previous studies29,30 have described that exercise training enhances limb reactive hyperemic flow. Because patients in the present study did not participate in an exercise training program, we could not determine the effect of exercise training on limb reactive hyperemic flow in this study. In conclusion, noninvasive measurement of calf reactive hyperemic flow at supine rest can predict LBF responses to exercise and, therefore, exercise tolerance in patients with left ventricular dysfunction. Furthermore, calf vasodilator capacity may play an important role in maintaining perfusion of nonexercising vital organs during exercise.
464 Hattori et al
References 1. Zelis R, Longhurst J, Capone RJ, Mason DT. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 1974;50:137-43. 2. Sullivan MJ, Knight JD, Higginbotham MB, Cobb FR. Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Circulation 1989;80:769-81. 3. Zelis R, Flaim SF. Alteration in vasomotor tone in congestive heart failure. Prog Cardiovasc Dis 1982;24:437-59. 4. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: role of impaired nutritive flow to skeletal muscle. Circulation 1984;69:1079-87. 5. Wilson JR, Martin JL, Schwartz D, Ferraro N. Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: role of cardiac pump dysfunction as determined by the effect of dobutamine. Am J Cardiol 1984;53:1308-15. 6. Longhurst J, Gifford W, Zelis R. Impaired forearm oxygen consumption during static exercise in patients with congestive heart failure. Circulation 1976;54:477-80. 7. Wilson JR, Martin JL, Ferraro N, Weber KT. Effect of hydralazine on perfusion and metabolism in the leg during upright bicycle exercise in patients with heart failure. Circulation 1983;68:425-32. 8. LeJemtel TH, Maskin CS, Lucido D, Chadwick BJ. Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation 1986; 74:245-51. 9. Zelis R, Mason DT, Braunwald E. A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure. J Clin Invest 1968;47:960-70. 10. Franciosa JA, Ziesche S, Wilen M. Functional capacity of patients with chronic left ventricular failure. Am J Med 1979;67:460-6. 11. Sumimoto T, Kaida M, Yuasa F, Hattori T, Jikuhara T, Hikosaka M, et al. Skeletal muscle hypoperfusion during recovery from maximal supine bicycle exercise in patients with heart failure. Am J Cardiol 1996;78:841-4. 12. Hattori T, Sumimoto T, Yuasa F, Kaida M, Jikuhara T, Hikosaka M, et al. Influence of intrinsic limb vasodilator capacity on exercise tolerance in patients with recent myocardial infarction. Am Heart J 1996;132:593-8. 13. Jondeau G, Katz SD, Toussaint JF, Dubourg O, Monrad ES, Bourdarias JP, et al. Regional specificity of peak hyperemic response in patients with congestive heart failure: correlation with peak aerobic capacity. J Am Coll Cardiol 1993;22:1399-402. 14. Jorfeldt L, Jublin-Dannfelt A, Pernow B, Wassen E. Determination of human leg blood flow: a thermodilution technique based on femoral venous bolus injection. Clin Sci Mol Med 1968;54:517-23.
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15. Jorfeldt L, Wahren J. Leg blood flow during exercise in men. Clin Sci 1971;41:459-73. 16. Wade OL, Bishop JM. Cardiac output and regional blood flow. Oxford: Blackwell Scientific; 1962. 17. Astrand P, Rodahl K. Textbook of work physiology. New York: McGraw-Hill; 1970. 18. Davis JO. The physiology of congestive heart failure. In: Hamilton WF, Dow P, editors. Handbook of physiology. Vol III. Baltimore: Williams & Wilkins; 1972. 19. Donald KW. Exercise and heart disease. A study in regional circulation. BMJ 1959;1:985-94. 20. Wilson JR, Wiener DH, Fink LI, Ferrano N. Vasodilatory behavior of skeletal muscle arterioles in patients with nonedematous chronic heart failure. Circulation 1986;74:775-9. 21. Massie BM, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P, et al. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation 1987; 76:1009-19. 22. Massie BM, Conway M, Rajagopalan, Yonge R, Frostick S, Ledingham J, et al. Skeletal muscle metabolism during exercise under ischemic conditions in congestive heart failure: evidence for abnormalities unrelated to blood flow. Circulation 1988;78:320-6. 23. Mancini DM, Coyle E, Coggan A, Beltz J, Ferrano N, Montain S, et al. Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation 1989;80:1338-46. 24. Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992;85:1364-73. 25. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992;85:1751-9. 26. Lipkin D, Jones D, Round J, Poole-Wilson P. Abnormalities of skeletal muscle in chronic heart failure. Int J Cardiol 1988;18:187-95. 27. Miyagi K, Asanoi H, Ishizaka S, Kameyama T, Sasayama S. Loss of skeletal muscle mass is a major determinant of exercise intolerance in chronic heart failure [abstract]. Circulation 1991;84(suppl II):II-74. 28. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81:518-27. 29. Sinoway LI. Effect of conditioning and deconditioning stimuli on metabolically determined blood flow in humans and implications for congestive heart failure. Am J Cardiol 1988;62:45E-8E. 30. Martin WH, Kohrt WM, Malley MT, Korte E, Stolts S. Exercise training enhances leg vasodilatory capacity of 65-y-old men and women. J Appl Physiol 1990;69:1804-9.
Background Distribution of skeletal muscle perfusion during exercise is an important factor in determining exercise capacity and is markedly impaired in patients with cardiac disease. This study examined the importance of intrinsic calf vasodilator capacity in determining distribution of skeletal muscle perfusion during supine bicycle exercise in patients with left ventricular dysfunction.
Methods We studied 19 patients with left ventricular dysfunction (left ventricular ejection fraction <45%) after myocardial infarction. All the patients underwent cardiopulmonary exercise testing with measurements of central hemodynamics, leg blood flow (LBF), and the percentage of cardiac output distributed to both legs (%LBF). Calf reactive hyperemic flow (RH) was measured by venous occlusive plethysmography at supine rest.
Results LBF at peak exercise was closely related to peak cardiac output and RH. Furthermore, %LBF at peak exercise had modest correlation with peak cardiac output and good correlation with RH. Although peak cardiac output and RH were independent determinants of LBF at peak exercise by multiple regression analysis, RH had higher correlation with %LBF at peak exercise than peak cardiac output. Despite marked changes in other hemodynamic variables, nonleg blood flow during exercise was constantly maintained at a level identical to resting value.
Conclusions Calf vasodilator capacity, which was the major determinant of distribution of skeletal muscle perfusion during exercise, may have contributed to maintaining perfusion of important nonexercising regions during exercise in patients with left ventricular dysfunction. (Am Heart J 1998;136:458-64.)
Distribution of skeletal muscle perfusion during exercise is an important factor determining exercise capacity and is markedly impaired in patients with cardiac disease.1-10 However, the pathophysiologic mechanism responsible for this impairment during exercise has not been clearly defined. Several investigators2,4,11 demonstrated that an increase in cardiac output during exercise was the major determinant of distribution of skeletal muscle perfusion during exercise in both cardiac patients and normal subjects. In contrast, other investigators1,3,12,13 observed that limb vasodilator response to various stimuli is markedly reduced in heart failure and suggested that the reduced intrinsic limb vasodila-
From the Second Department of Internal Medicine, Kansai Medical University. Submitted July 8, 1997; accepted Feb. 10, 1998. Reprint requests: Toshihiko Hattori, MD, CCU, Kansai Medical University, 10-15 Fumizonocho, Moriguchi-city Osaka 570, Japan. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/89606
tor capacity is the major factor determining impaired distribution of skeletal muscle perfusion. Thus the relative contribution of cardiac pump function and peripheral vasodilator capacity in determining distribution of skeletal muscle perfusion during exercise has not been completely defined in patients with cardiac disease. The present study was designed to measure calf reactive hyperemic flow as an index of intrinsic calf vasodilator capacity and to perform symptom-limited cardiopulmonary exercise testing with measurements of central hemodynamics and leg blood flow (LBF) response in patients with left ventricular dysfunction after myocardial infarction. Accordingly, we examined calf reactive hyperemic flow, LBF, and the percentage of cardiac output distributed to both legs (%LBF) during exercise to investigate the importance of intrinsic limb vasodilator capacity in determining distribution of skeletal muscle perfusion during exercise in patients with this disorder.
American Heart Journal Volume 136, Number 3
Hattori et al 459
Methods
Central hemodynamic and metabolic measurements
Patient population
Pulmonary and systemic arterial pressures were recorded continuously, and pulmonary arterial wedge pressure was recorded intermittently at rest and at each exercise stage with DS-3300 system (Fukuda Denshi). Blood samples were drawn simultaneously from the radial and pulmonary arteries at rest and within the last 30 seconds of each exercise stage. The blood samples were used for the immediate measurements of pH, PO2, and PCO2 (Radiometer Company ABL2), as well as oxygen saturation and hemoglobin concentration (Radiometer Company OSM2). Plasma norepinephrine concentration was determined in arterial samples.
We evaluated 57 consecutive patients with first Q-wave myocardial infarction who not only underwent both exercise test and coronary arteriography but also had patent infarctrelated coronary artery with negative exercise test. Each patient underwent a complete physical examination, and patients were excluded from the study if they had physical or radiographic signs of obstructive lung disease, atrial fibrillation or flutter, valvular disease evaluated by color Doppler echocardiography, or intermittent claudication that limited their exercise capacity. Of these, 19 men aged 34 to 63 years (mean 53 ± 9 years) with resting left ventricular ejection fraction <45% were selected for the purpose of this study. The resting left ventricular ejection fraction ranged from 17% to 44% (mean 34% ± 7%). All patients included in this study had their first acute Q-wave myocardial infarction 3 to 6 weeks before the study, and none of the patients had postinfarction angina, critical arrhythmia, or uncontrolled congestive heart failure for at least 2 weeks before the study. All medications were discontinued for >48 hours before the study. The risks of the study were fully explained and informed consent was obtained from each patient before the study. The research protocol was approved by the Ethics Committee of Kansai Medical University.
Leg blood flow measurements Femoral venous flow was determined by thermodilution technique in triplicate at rest and at each exercise stage. Bolus injections of 3 ml iced or room temperature saline solution were used to obtain blood flow measurements with the use of a commercially available thermodilution computer (Edwards REF-1, Baxter). Output curves were displayed on a strip chart recorder to ensure an exponential decay curve. The validity of using the thermodilution technique to measure LBF during dynamic exercise has been confirmed by previous studies,7 and LBF determined by this system are comparable to leg flow measurements reported with other methods.14,15
Exercise protocol
Calf reactive hyperemic flow
Patients were studied while they were in the supine position at rest and during bicycle ergometric exercise. Supine bicycle exercise was performed to familiarize the patients with an isokinetic bicycle ergometer (Monark 881E ergometer, Solna) 2 or 3 days before the study. On the day of the study, a 7F balloon-tipped pulmonary artery catheter was inserted through the internal jugular vein and positioned in the pulmonary artery and a short polyethylene catheter was inserted into the radial artery. A 50 cm 5F thermodilution catheter with the thermistor at 2 cm and the injection port at 12 cm was inserted simultaneously into the femoral vein 2 cm below the inguinal ligament and advanced into the iliac vein under fluoroscopic guidance. After 30 minutes of rest, bicycle exercise testing was performed with ECG monitoring and expired gas analysis. Exercise began at a work load of 15 W with the pedal speed maintained at 60 rpm and increased by 15 W every 3 minutes until symptom-limited maximum.
Before exercise testing, calf blood flow was measured by using a mercury-in-Silastic polymeric silicone strain gauge placed around the upper calf and connected to an electronically calibrated plethysmograph (Medasonics SPG16). Reactive hyperemic flow was measured by inflating the cuff placed around the upper thigh to 40 mm Hg above the systolic pressure to occlude arterial flow to the calf for 5 minutes. To avoid the variation of calf blood flow values at various time points after release of arterial occlusion, we measured calf blood flow initially at 5 and 15 seconds after release of arterial occlusion and averaged these two flow measurements to estimate calf reactive hyperemic flow as previously described.9
Expired gas analysis Continuous expired gas analysis was performed with an Oxycon-4 (Mijnhardt Co.). Instruments were calibrated at the beginning of each study and before every measurements. From these data, oxygen consumption (VO2) was measured at supine rest on a bicycle and continuously during exercise. Averaged measurements during the last 30 seconds of each exercise stage were used for analysis.
Derived variables Mean arterial blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Cardiac output was determined by the Fick principle by use of systemic arteriovenous oxygen difference and directly measured VO2. To describe cardiac output distribution during exercise, nonleg blood flow (non-LBF) was calculated as cardiac output – (LBF × 2). The percentage of cardiac output distributed to the two legs (%LBF) was determined as (LBF × 2)/cardiac output.
Radionuclide angiography Radionuclide angiocardiography was performed at rest by use of a multicrystal gamma camera (Baird Atomic System 77)
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Table I. Baseline characteristics Calf vasodilator capacity <19.4 ml/min/100 ml (n = 9)
≥19.4 ml/min/100 ml (n = 10)
p Value
56 ± 8 31 ± 8
50 ± 9 37 ± 5
NS NS
8 1 107 ± 13 3.8 ± 0.6 0.23 ± 0.10 3.4 ± 0.6 12 ± 4
9 1 98 ± 12 4.2 ± 0.6 0.33 ± 0.11 3.6 ± 0.6 16 ± 5
NS
Age (yr) LVEF (%) Site of MI Anterior Inferior Mean BP (mm Hg) Cardiac output (L/min) LBF (L/min) Non-LBF (L/min) %LBF (%)
NS NS NS NS NS
LVEF, Left ventricular ejection fraction; MI, myocardial infarction; BP, arterial blood pressure.
Table II. Hemodynamic and metabolic responses to exercise
Mean BP VO2 Norepinephrine Cardiac output LBF Non-LBF %LBF
(mm Hg) (ml/min/kg) (pg/dl) (L/min) (L/min) (L/min) (%)
Rest
Peak exercise
103 ± 13 3.2 ± 0.4 269 ± 153 4.0 ± 0.6 0.28 ± 0.11 3.5 ± 0.7 14 ± 5
120 ± 19* 16.7 ± 4.0* 1519 ± 798* 9.2 ± 3.2* 2.8 ± 1.3* 3.7 ± 1.2 58 ± 10*
BP, Arterial blood pressure. *p < 0.001 vs resting value.
in the anterior projection 2 or 3 days before the study. Left ventricular ejection fraction was determined from the backgroundcorrected representative cardiac cycle as follows: (end-diastolic counts – end-systolic counts)/end-diastolic counts × 100.
Statistical analysis All data are presented as mean ± standard deviation. Student’s t test was used to compare the two groups and paired t test was used for paired samples. The least-squares regression was used to assess the relationship between the two variables. Multiple regression analysis was used to determine the important variables related to LBF and %LBF at peak exercise. Probability values of <0.05 were considered to be significant.
Results Calf vasodilator capacity Calf blood flow at rest was 3.4 ± 1.7 ml/min/100 ml tissue, which was markedly increased to 18.2 ± 4.4 ml/min/100 ml tissue (median 19.4 ml/min/100 ml tissue, range 10.8 to 25.8 ml/min/100 ml tissue) during reactive hyperemia. There were no significant differences in baseline and resting hemodynamic character-
istics between nine patients with calf vasodilator capacity below the median and 10 patients with calf vasodilator capacity above the median (Table I).
Distribution of cardiac output during exercise In all 19 patients, the bicycle exercise was limited by exercising muscle fatigue and not by dyspnea. None of the patients had either chest pain or significant ST changes suggestive of active ischemia during exercise. The maximal work load was 59 ± 24 W and the exercise duration was 720 ± 293 seconds. Hemodynamic and metabolic responses to exercise are summarized in Table II. Cardiac output and LBF increased significantly during exercise. %LBF also increased as a result of relative increase in the proportion of LBF to cardiac output during exercise. However, non-LBF during exercise was constantly maintained at a level identical to the resting value.
Determinants of LBF at peak exercise LBF at peak exercise was not related to peak mean arterial blood pressure or to norepinephrine concen-
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Figure 1
Left panel: Relation between LBF at peak exercise and cardiac output (CO) at peak exercise. Right panel: Relation between LBF at peak exercise and calf reactive hyperemic flow induced by arterial occlusion for 5 minutes at spine rest. LBF at peak exercise had close correlation with these variables.
tration. However, LBF at peak exercise had close correlations with peak cardiac output and calf reactive hyperemic flow (r = 0.94, p < 0.001; r = 0.80, p < 0.001) (Fig. 1). To determine the important factor determining LBF at peak exercise, multiple regression analysis was performed by using peak cardiac output and calf reactive hyperemic flow. As a result, peak cardiac output (regression coefficient = 0.30, p < 0.001) and calf reactive hyperemic flow (regression coefficient = 0.08, p = 0.019) were independent determinants of LBF at peak exercise.
Determinants of %LBF at peak exercise %LBF at peak exercise was not related to peak mean arterial blood pressure or to norepinephrine concentration. However, %LBF at peak exercise had modest correlation with peak cardiac output (r = 0.56, p = 0.02) and good correlation with calf reactive hyperemic flow (r = 0.75, p < 0.001) (Fig. 2). To determine the important factor determining %LBF at peak exercise, multiple regression analysis was performed with peak cardiac output and calf reactive hyperemic flow. The multiple regression analysis demonstrated that only calf reactive hyperemic flow (regression coefficient = 1.68, p = 0.008) was significantly related to %LBF at peak exercise.
Relation between peak VO2 and peripheral hemodynamic measurements Peak VO2 had a fair correlation with calf reactive hyperemic flow (r = 0.68, p = 0.002), good correlation with LBF (r = 0.81, p < 0.001), and modest correlation with %LBF at peak exercise (r = 0.48, p = 0.04) (Fig. 3).
Discussion The present study is one of the first to examine the direct relation between peripheral hemodynamics during exercise and intrinsic limb vasodilator capacity. The findings of the present study demonstrate that calf vasodilator capacity is a more important determinant of cardiac output local flow during exercise than is peak cardiac output. Furthermore, this may have contributed to maintaining perfusion of the important nonexercising regions during exercise in patients with left ventricular dysfunction after myocardial infarction. Cardiac output response to exercise has been reported to be an important determinant of LBF and, therefore, of peak aerobic performance in patients with heart failure and in normal subjects.2,4,11 In contrast, several other studies3,9,12,13 demonstrated that intrinsic limb vasodilator response to a number of stimuli is impaired in patients with cardiac disease and suggested that the impaired limb vasodilator response
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462 Hattori et al
Figure 2
Left panel: Relation between %LBF at peak exercise and cardiac output (CO) at peak exercise. Right panel: Relation between %LBF at peak exercise and calf reactive hyperemic flow induced by arterial occlusion for 5 minutes at spine rest. %LBF at peak exercise had modest correlation with peak CO and good correlation with calf reactive hyperemic flow.
may have contributed to skeletal muscle hypoperfusion and exercise intolerance. Limb reactive hyperemic response to 5 minutes of ischemia represents maximal peripheral vasodilation independent of central hemodynamics or sympathetic tone in patients with heart failure and in normal subjects.9 In the present study, we found that cardiac output had a close correlation with LBF at peak exercise, emphasizing that cardiac output response was an important determinant of LBF response during exercise. Conversely, calf reactive hyperemic flow had fair correlations with peak LBF and peak VO2, which demonstrate the importance of intrinsic vasodilator capacity of resistance vessels within the exercising skeletal muscle in determining skeletal muscle perfusion during exercise and, therefore, reflect exercise capacity. Our findings, that peak cardiac output and calf reactive hyperemic flow were independent determinants of LBF at peak exercise, underline the contribution of maximal calf vasodilator capacity as well as cardiac output in determining skeletal muscle perfusion during exercise. Previous studies2,3,16-19 demonstrated that %LBF as well as cardiac output and LBF are lower during exercise in patients with heart failure than in normal subjects. These studies reported that %LBF at peak
exercise was only 50% to 60% in heart failure but >80% in normal subjects. In contrast, non-LBF was continuously maintained at identical levels during exercise in patients with heart failure and in normal subjects. These findings suggest that impaired skeletal muscle vasodilation contributed to the redistribution of cardiac output to the nonexercising vital regions in a setting of inadequate cardiac output response to exercise in heart failure. In the present study, our patients demonstrated a similar reduction in %LBF at peak exercise, but non-LBF during exercise was constantly maintained at a level identical to the resting value. Furthermore, calf reactive hyperemic flow was a better determinant of %LBF at peak exercise than peak cardiac output, indicating that distribution of skeletal muscle perfusion during exercise was not determined primarily by cardiac output response but rather by intrinsic limb vasodilator capacity. Therefore, calf vasodilator capacity, the major determinant of distribution of skeletal muscle perfusion during exercise, may have contributed to maintaining perfusion of important nonexercising regions during exercise in patients with left ventricular dysfunction. This is consistent with the previous studies2,3 of patients with heart failure, suggesting that intrinsic abnormalities of exercising leg blood
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Figure 3
Relation between peripheral hemodynamic variables and peak VO2. Each peripheral hemodynamic variable had positive correlation with peak VO2.
flow and reactive hyperemic response may prevent hypoperfusion and, possibly, ischemia in vital nonexercising regions. The contribution of relative arterial hypotension and increased sympathetic vasoconstriction to reduced distribution of skeletal muscle perfusion during exercise has been reported in patients with heart failure.3,20 However, mean arterial blood pressure and norepinephrine concentration were not related to LBF responses during exercise in our patients. Although the role of arterial hypotension and sympathetic vasoconstriction in determining reduced distribution of skeletal muscle perfusion during exercise cannot be completely excluded, the present study demonstrated that arterial blood pressure and norepinephrine concentration were not primarily determinants of LBF response to exercise. In contrast, contribution of chronic muscular21-28 and vascular12,13,29 deconditioning to exercise intolerance or skeletal muscle hypoperfusion have been observed in patients with chronic heart failure. Although the present study did not define the primary factor causing peripheral hemodynamic abnormalities in patients with left ventricular dysfunction after myocardial infarction, a rapid vascular deconditioning within a few weeks rather than muscle deconditioning may have contributed, in part, to a decrease in limb
vasodilator capacity and distribution of skeletal muscle perfusion during exercise. Vascular fluid retention, a reduction in peripheral capillary formation, and other factors that impair endothelial function may have affected calf reactive hyperemic flow. Two limitations of our study should be addressed. First, all the patients included in this study had recent onset of left ventricular dysfunction (acute myocardial infarction 3 to 6 weeks before the study). Therefore, it is possible that calf reactive hyperemic flow may vary in patients with other causes of left ventricular dysfunction. It remains to be seen whether different causes can in any way affect calf reactive hyperemic flow. Second, previous studies29,30 have described that exercise training enhances limb reactive hyperemic flow. Because patients in the present study did not participate in an exercise training program, we could not determine the effect of exercise training on limb reactive hyperemic flow in this study. In conclusion, noninvasive measurement of calf reactive hyperemic flow at supine rest can predict LBF responses to exercise and, therefore, exercise tolerance in patients with left ventricular dysfunction. Furthermore, calf vasodilator capacity may play an important role in maintaining perfusion of nonexercising vital organs during exercise.
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