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Effect of dobutamine on skeletal muscle metabolism in patients with congestive heart failure
CONGESTIVE
HEART FAILURE
Effect of Dobutamine on Skeletal Muscle Metabolism in Patients with Congestive Heart Failure Donna M. Mancini, MD, Mitchell Schwartz, MD, Nancy Ferraro, RN, Richard Seestedt, BS, Britton Chance, PhD, and John R. Wilson, MD
Dobutamine is known to htcrease leg blood flow during exercise in patients with heart failure. However, it is uncertain whether the increased fiow is deihfered to working skeletal musde. In 7 patients with heart failure, the effects of dobutamine were magnetic resooexamined on caif w-31 nance spectroscopy (MRS) spectra and femoral vein blood flow during rest and upright plantar flexion. During upright piantar ftexion every 3 seconds, dobutamine increased femoral venous Mood flow (control 1.7 f 0.1; dobutamine 2.1 f 1.0 liters/min; p
P
atients with heart failure are frequently limited by exertional fatigue, duein part to skeletalmuscle underperfusion.1,2Myccardial dysfunction coupled with an abnormality of arteriolar vasodilation during exercisehas been postulated to underlie the skeletal muscle underperfusionin heart failure. Therefore, pharmacologic agents with both positive inotropic and vasodilatory properties should alleviate muscle fatigue. Nevertheless,dobutamine, a drug that exhibits such desirable features,3-5has no effect on either the maximal exercise capacity of patients or their blood lactate responseto exercise,despite increasesin leg blood flo~.~,’ This could indicate that dobutamine does not improve oxygen availability within working skeletal muscle. Alternatively, dobutamine may in fact improve skeletal muscle perfusion and metabolism.Maximal exercisecapacity may not change becauseit is influenced by variables such as patient motivation and dyspneaand therefore doesnot representa reliable index of skeletal muscle function. Blood lactate may not change despite improved intracellular metabolism due to a dissociation between intracellular metabolism and blood lactate changes.8 Phosphorus-31 magnetic resonance spectroscopy (MBS) offers a noninvasive method of establishing whether or not dobutamine enhancesoxygen delivery to working skeletal muscle. Phosphocreatine, inorganic phosphate and pH are sensitive to changes in muscle oxygen delivery.9-11If dobutamine enhancesperfusion of a hypoxic, working muscle, one would expect an increase in phosphorcreatineand pH and a decreasein inorganic phosphate. Therefore, the present study was undertaken to determine if dobutamine alters these metabolic parameters in patients with chronic heart failure. To confirm that dobutamine improves leg blood flow, femoral venousblood flow and hemoglobin 02 saturation were also measured. METHODS Subpets: Seven patients with chronic heart failure
From the Cardiovascular Section, Department of Medicine, and the Department of Biochemistry and Biophysics,University of Pennsylvania, and the Department of Medicine, Veterans Administration Hospital, Philadelphia, Pennsylvania. This study was supported in part by ResearchAdministration grant support (Dr. Mancini) from the VeteransAdministration and by RO-1HL34834 and ResearchCareer Development Award HL01766 (Dr. Wilson) from the National Institutes of Health, Bethesda,Maryland. Manuscript receivedSeptember29,1989; revisedmanuscript receivedand acceptedDecember27, 1989. Address for reprints: Donna M. Mancini, MD, Cardiology, Third Floor, White Building, Hospital of the University of Pennsylvania,3400 Spruce Street, Philadelphia, Pennsylvania 19104.
were studied. The average age was 52 f 8 years. All patients were receiving digoxin, diuretics and vasodilator agents.None of the patients had peripheral edema, claudication, angina or valvular heart disease.All patients were screenedfor peripheral vascular disease.Etiology of heart failure was coronary artery diseasein 3 patients and cardiomyopathy in 4 patients. Left ventricular ejection fraction averaged 20 f 5% (range 10 to 24) and mean peak oxygen consumption averaged 16.7 f 3.6 ml/min/kg (range 11.7 to 23.7). THE AMERICAN JOURNAL OF CARDIOLOGY MAY 1, 1990
1121
TABLE
I Phosphorus-31
NMR
Reproducibility
Studies
P,/PCr
Rest PF every 9 seconds PF every 6 seconds PF every 3 seconds P, = inorganic
in Five Patients
Work Slope (min/ml) (P,/PCr vs VOg)
First
Second
First
Second
0.22 f 0.03
7.12i0.16
0.0070f0.0038
6.96 f 0.10
7.13 f0.19 7.02 f 0.20
0.0078~00044
1.15 f 0.24
1.52 f 0.72
1.03f0.31
6.94f 0.20
7.04f 0.07
1.63 f 0.52
1.85 f 0.54
6.78f0.18
6.78f0.20
First
Second
0.20 f 0.03 1.14 f 0.93
phosphorus;
0 I
PCr = phosphocreatine:
PF = plantar flexon;
\i02 = oxygen consumptm
CONTROL DOBUTAMINE
96”
q9”
REST
q3”
PLANTARFLEXION
s I
125
cl I
Failure
PH
The protocol was approved by the Committee on Studies Involving Human Beings at the University of Pennsylvania. Written informed consent was obtained. Leg flow rtudier: Leg blood flow measurements were performed in 5 patients using previously described techniques.I36In 2 patients receiving long-term anticoagulation, leg flow measurementswere not obtained. A 50 cm 5Fr thermodilution catheter with a thermistor at 2 cm and an injection port at 12 cm (Elecath) was inserted into the femoral vein and advanced in a retrograde fashion 18 cm. Flows were determined by rapid injection of a 2.5 ml iced dextrose bolus using a commercially available thermodilution computer. In 2 patients, a thermodilution Swan-Ganz catheter was also inserted.
_ 150 .E c .
with Heart
CONTROL DOBUTAMINE
After catheter insertion, resting flow was determined in triplicate with the patient standing. Femoral venous blood was obtained for lactate and hemoglobin 02 saturation. The patient then performed upright plantar flexion (toe-ups) at 3 different frequencies:every 9,6 and 3 seconds. The higher the frequency, the greater the workload. Contractions were sustainedfor approximately 1 second.Each workload was performed for 5 minutes with continuous monitoring of heart rate and respiratory gases (SensorMedics metabolic cart) and measurement of cuff blood pressure at the end of each workload. During the last 2 minutes of exercise, flows were determined in triplicate and femoral venousblood samples were obtained. Each workload was separated by a 15-minute rest period. Each patient performed the exercisesequencetwice, once during the control state and once while receiving dobutamine. The 2 sequenceswere separatedby at least a 90-minute rest period. The sequenceof administration of dobutamine was randomized. Dobutamine was infused at an initial rate of 3 pg/kg/min for 10 minutes. The dose was then increasedby 3 pg/kg/min every 10 minutes until a maximal dose of 15 pg/kg/min was reachedor a 20%increasein heart rate, 20% decreasein systolic arterial pressure or an increase in ventricular ectopic beats was noted. The peak dose achieved averaged 9.0 f 2.4 pg/kg/ min. Exercise was then performed on the maximally tolerated dose. Blood for lactate measurementswas deproteinized with cold perchloric acid and assayedwith a spectrophotometric technique. Hemoglobin 02 saturation was measured with an Instrumentation Laboratories 282 Co-Oximeter. Phosphorus-31
0
REST
q3”
q9” PLANTARFLEXION
mstandddngexerciseincentrelend
<0.0!5 cenhl vs ddnhimine). 1122
THE AMERICAN
JOURNAL
debutaminsstudies (*p
OF CARDIOLOGY
VOLUME
65
magnetic
resonance
spectra
stud-
Calf MRS studies were performed on a separate day from the flow studies. The MRS protocol has been previously described.12In brief, the patient was brought to the MRS laboratory. The leg was positioned in an 11.5 inch bore 1.9 tesla superconducting magnet (Oxford ResearchSystem). The calf was placed over a 4.5 cm diameter surface coil. Following optimization of field homogeneity, a 4-minute rest scan was recorded using radiofrequency pulses (pulse width 25 to 35 ps) applied every 5 seconds.The patient was then withdrawn from the magnet and, outside the magnet, performed upright plantar flexion. Exercise was performed ies:
at 3 different frequencies: every 9, 6 and 3 seconds. Each workload was performed for 5 minutes with continuous monitoring of heart rate and expired respiratory gases(SensorMedics metabolic cart) and measurement of cuff blood pressureat the end of the workload. After 5 minutes of exerciseat a given workload, a rapidly inflating pneumatic cuff (D.E. Hokanson, Inc.) was inflated around the upper thigh to 250 mm Hg to “freeze” metabolism. The patient’s leg was then rapidly repositioned within the magnet (
limb perfusion. No significant change in femoral venous lactate concentration was noted (Figure 2). Phosphorus-31 magnetic resonance spectroscopy: Control exercise resulted in a progressive increase in the PJPCr ratio and a decrease in intracellular PH.
If dobutamine augmented blood flow to active skeletal muscle, one would anticipate improvement in muscle metabolism. At each level of exercise the Pi/PCr ratio should be lower and pH higher. Dobutamine had no effect on the slope of the relation between systemic VOz and the Pi/PCr ratio (control 0.0054 f 0.0039 vs dobutamine 0.0056 f 0.0032 [difference not significant]) or on muscle pH (Figure 3, Table II). Representative phosphorus-31 MRS spectra from patient no. 2 are shown in Figure 4. This patient also
2 3.0IL
E
~
O I
CONTROL DOBUTAMINE
i
II q9”
ii 96”
T I1-
Leg bleed flow: Systemic 902 increasedsignificantly throughout exercise (Figures 1 and 2, Table II). Heart rate and blood pressure measured during each q6” 99” REST workload at the time of leg flow and spectroscopicstudies were comparable; no difference was significant. During control and dobutamine sequences,femoral venous oxygen saturation decreased significantly (p <0.05) from resting values during plantar flexion at rates of every 6 and 3 seconds.Similarly, leg blood flow increased significantly over resting flow during exercise at rates of every 6 and every 3 seconds(p
1123
TABLE II NMR Metabolic Measurements Dobutamine
P,/PCr Workload
PH
C
DB
C
Rest PF every 9 seconds PF every 6 seconds PF every 3 seconds
During Control and
Infusion
D8
0.20f 0.06 0.17 f 0.05 0.82 f 0.19 0.92 f 0.32
7.02 f 0.06 7.04 f 0.05 6.98h 0.07 7.04 f 0.19
0.98f0.29
6.94
1.22kO.51*
f 0.09
6.99
f 0.06
6.86 f 0.12 6.93 f 0.09
.5Oh 0.51 1.39f 0.42
* p CO.05 control versus dobutamine. C = control: DB = dobutamine; other abbreviations
as in Table I.
had systemic hemodynamic measurementsperformed. Twelve pg/kg/min of dobutamine increasedhis resting heart rate from 86 to 95 beats/mm, mean arterial blood pressurefrom 80 to 83 mm Hg, cardiac index from 1.49 to 3.59 liters/min/m2 and pulmonary artery saturation from 46 to 68%. Pulmonary capillary wedge remained unchanged at 30 mm Hg. Resting femoral venous oxygen saturation increasedmarkedly from 50 to 80% and remained significantly increased throughout exercise. Leg blood flow was significantly higher at rest (control 0.8 liters/min; dobutamine 1.26 liters/mm) and the
2.0 -
I
1.5-
2 5 a
1.0.
O-0 l -
.
highest workload (control 1.83 liters/min; plantar flexion every 3 seconds3.46 liters/mm). Despite this impressivehemodynamic effect, no substantial change in MRS spectrawas observedeither at rest or during exercise (Figure 4). DISCUSSION During exercise in the presence of normal blood flow, muscle oxidative metabolism is stimulated by an increase in adenosinediphosphate, the level of which is linearly related to cellular VOZ. Muscle glycolysis is also stimulated, resulting in a decreasein pH. Muscle underperfusion produces an upward shift in the adenosine diphosphateto VOz relation. Concurrently, glycolysis is augmentedand muscle pH drops. Thesemetabolic changes can be noninvasively assessedusing phosphorus-31 MRS by monitoring intramuscular PCr, Pi and the shift betweenthese2 peaks.The Pi/PCr ratio parallels changes in adenosine diphosphate. Therefore, the relation between Pi/PCr and VO2 can be used to estimate changesin the adenosinediphosphateto VO2 relation. The shift between Pi and PCr is proportional to cellular pH. In the present study, we used phosphorus-31MRS to investigate the effect of dobutamine on muscle blood flow. During control exercise,we monitored Pi/PCr and
CONTROL DOBUTAMINE p=NS
0.5 FIGURE 3. Imrganic phoqhw to phorpbcredm rauo (Pirn) md intrPH vemus
p=NS
6.701
300
anddobdamhetudle8.
400
500
i/O,
1124
oxygen
conrunp#on
restandhrhgexerdse&eingcenbd
600
(ml/min)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
700
(-2)
a
pH responses.We then reevaluatedresponsesduring the infusion of dobutamine. We reasoned that if dobutamine improves muscle blood flow, this should result in a downward shift in the Pi/PCr to VOz slope and an increasein muscle pH. During control exercise, our patients exhibited increasesin the Pi/PCr ratio and decreasesin intramuscular pH that were more marked than changes previously observedby us in normal subjects,‘* indicating an abnormal metabolic responseto exercise.At peak exercise, femoral venous hemoglobin 02 saturation decreasedto 23 f 5% associatedwith an increasein blood lactate levels, consistent with muscle underperfusion. Metabolic abnormalities during submaximal exercise that are unrelated to grossreductions in limb blood flow have been described in forearm muscle in patients with heart failure.14-I6 Calf exercise results in substantially greater increasesin systemicVO2 than doesforearm exercise and thus exhausts circulatory reservemore readily than does forearm exercise. Administration of dobutamine to our patients increased leg blood flow and decreasedfemoral venous hemoglobin oxygen saturation, consistent with prior observations.6The changesin femoral venousoxygen saturation produced by dobutamine were more dramatic than the changesin leg flow, due most likely to difficulties in accurately measuring small changesin leg blood flow during plantar flexion. With each plantar flexion, calf muscle contraction ejects blood into the veins. This
results in pulsatile changesin femoral vein flow that are variably sampledby the bolus thermodilution technique. Despite the change in leg blood flow, no evidenceof improved oxygen delivery to working skeletal muscle was observed.The degree of increase in the PJPCr ratio and decreasein muscle pH with exercise remained comparable to control exercise. Femoral venous blood lactate levels were unchanged. Results of this study therefore suggestthat dobutamine doesnot increaseoxygen delivery to working skeletal muscle. Presumably, the dobutamine-induced increase in leg blood flow was directed to other tissues within the leg. This finding is consistentwith the observation of Drexler et al*’ that dobutamine does not increaseskeletal muscle blood flow in the rat. A lesslikely explanation is that dobutamine improved muscle blood flow but that the musclewas unable to use the delivered blood. Alternately, muscle metabolism may have improved minimally but not to an extent detectable by phosphorus-31 MRS. Maintenance of oral vasodilator therapy may also have attenuated the effect of dobutamine. Results of this study explain the previously observed failure of short-term dobutamine therapy to improve the maximal exercise capacity of patients with heart failure. This study also illustrates how a noninvasive methodologycan be usedto assessthe effect of pharmacologic agents on exercising skeletal muscle in patients with heart failure. Phosphorus-31MRS provides infor-
Control
Dobutamine (12 ucglkglmin)
PCr-,
FIGURE 4. Ptmspbw31 NMR spectra fremarepmenMvepatient((no.2)~ restaaddwingexerciseduirrg~ andddnltadneinfurion.
q9’
J I 10 5
I . . I , 0 -5 -10 -15 -20 10 5 0 -5 -10 -15 :20 PPm PPm THE AMERICAN JOURNAL OF CARDIOLOGY MAY 1. 1990
1125
mation about the effect of the intervention on intracellular metabolism. Such an approach could potentially be used to evaluate both short- and long-term therapeutic interventions, since studies can be repeated multiple times with minimal discomfort to patients. REFERENCES
1. 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;69:1079-1087. 2. Weter KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982,65:1213-1223. 3. Sonnenblick E, Frishman W, LeJemtel TH. Dobutamine: a new synthetic cardioactive sympathetic amine. N Engf J Med 1979;30@17-22. 4. Mikulic E, Cohn J, Franciosa J. Comparative hemodynamiceffccts of inotropic and vasodilator drugs in severe heart failure. Circulation 1977;56:528-533. 5. Robie N, Goldberg L. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine. Am Heart J 1975,90;340m345. 6. Wilson JR, Martin J, 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; 53:1308-1315. 7. Maskin C, Forman R, Sonnenblick E, Frishman W, LeJemtel T. Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983;51:177-182.
1126
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JOURNAL
OF CARDIOLOGY
VOLUME
65
8. Jorfeldt L, Juhlin-Dannfelt A, Karlsson J. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J Appl Physiol 1978;44:350352. 9. Chance B, Eleff S, Leigh J. Noninvasive, non-destructive approaches to cell bioenergetics. Proc Nat1 Arad Sci USA 1980:77:7430-7434. 10. Chance B, Eleff S, Leigh JS, Sokolow D, Sapega A. Mitochondrial regulation of phosphccreatine/inorganic phosphate ratios in exercising human muscle: a gated “P NMR study. Pm Nat1 Acad Sci USA 1981;78:6714-6718. 11. Chance B, Clark B, Nioka S, Subramanian H, Maris J, Argov Z, Bode H. Phosphorus nuclear magnetic resonance spectroscopy in viva. Circulation 1985;72:IV-103-W-110. 12. Mancini DM, Ferraro N, Tuchler M, Chance B, Wilson JR. Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus31 nuclear magnetic resonance. Am J Cardiol 1988,62:1234-1240. 13. Moon RB, Richards JR. Determination of intracellular pH by “P NMR. J Biol Chem 1973;248:7276-7278. 14. Wiener DH, Maris J, Chance B, Wilson JR. Detection of skeletal muscle hypoperfusion during exercise using phosphorus-3 1 nuclear magnetic resonance spectroscopy. JACC 1986;7:793-799. 15. Weiner D, Fink L, Maris J, Jones R, Chance B, Wilson JR. Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: role of reduced muscle blood flow. Circulation 1986;73:1127-1136. 16. Massie B, Conway M, Yonge R, Frostick S, Lcdingham J, Sleight P, Radda G, Rajagopalan B. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation 1987:76:10091019. 17. Drexler H, Banhardt U, Meinhertz T, Wollschliiger H, Lehmann M, Just H. Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure: a double-blind, placebo-controlled trial. Circulation 1989;79:491-502.
HEART FAILURE
Effect of Dobutamine on Skeletal Muscle Metabolism in Patients with Congestive Heart Failure Donna M. Mancini, MD, Mitchell Schwartz, MD, Nancy Ferraro, RN, Richard Seestedt, BS, Britton Chance, PhD, and John R. Wilson, MD
Dobutamine is known to htcrease leg blood flow during exercise in patients with heart failure. However, it is uncertain whether the increased fiow is deihfered to working skeletal musde. In 7 patients with heart failure, the effects of dobutamine were magnetic resooexamined on caif w-31 nance spectroscopy (MRS) spectra and femoral vein blood flow during rest and upright plantar flexion. During upright piantar ftexion every 3 seconds, dobutamine increased femoral venous Mood flow (control 1.7 f 0.1; dobutamine 2.1 f 1.0 liters/min; p
P
atients with heart failure are frequently limited by exertional fatigue, duein part to skeletalmuscle underperfusion.1,2Myccardial dysfunction coupled with an abnormality of arteriolar vasodilation during exercisehas been postulated to underlie the skeletal muscle underperfusionin heart failure. Therefore, pharmacologic agents with both positive inotropic and vasodilatory properties should alleviate muscle fatigue. Nevertheless,dobutamine, a drug that exhibits such desirable features,3-5has no effect on either the maximal exercise capacity of patients or their blood lactate responseto exercise,despite increasesin leg blood flo~.~,’ This could indicate that dobutamine does not improve oxygen availability within working skeletal muscle. Alternatively, dobutamine may in fact improve skeletal muscle perfusion and metabolism.Maximal exercisecapacity may not change becauseit is influenced by variables such as patient motivation and dyspneaand therefore doesnot representa reliable index of skeletal muscle function. Blood lactate may not change despite improved intracellular metabolism due to a dissociation between intracellular metabolism and blood lactate changes.8 Phosphorus-31 magnetic resonance spectroscopy (MBS) offers a noninvasive method of establishing whether or not dobutamine enhancesoxygen delivery to working skeletal muscle. Phosphocreatine, inorganic phosphate and pH are sensitive to changes in muscle oxygen delivery.9-11If dobutamine enhancesperfusion of a hypoxic, working muscle, one would expect an increase in phosphorcreatineand pH and a decreasein inorganic phosphate. Therefore, the present study was undertaken to determine if dobutamine alters these metabolic parameters in patients with chronic heart failure. To confirm that dobutamine improves leg blood flow, femoral venousblood flow and hemoglobin 02 saturation were also measured. METHODS Subpets: Seven patients with chronic heart failure
From the Cardiovascular Section, Department of Medicine, and the Department of Biochemistry and Biophysics,University of Pennsylvania, and the Department of Medicine, Veterans Administration Hospital, Philadelphia, Pennsylvania. This study was supported in part by ResearchAdministration grant support (Dr. Mancini) from the VeteransAdministration and by RO-1HL34834 and ResearchCareer Development Award HL01766 (Dr. Wilson) from the National Institutes of Health, Bethesda,Maryland. Manuscript receivedSeptember29,1989; revisedmanuscript receivedand acceptedDecember27, 1989. Address for reprints: Donna M. Mancini, MD, Cardiology, Third Floor, White Building, Hospital of the University of Pennsylvania,3400 Spruce Street, Philadelphia, Pennsylvania 19104.
were studied. The average age was 52 f 8 years. All patients were receiving digoxin, diuretics and vasodilator agents.None of the patients had peripheral edema, claudication, angina or valvular heart disease.All patients were screenedfor peripheral vascular disease.Etiology of heart failure was coronary artery diseasein 3 patients and cardiomyopathy in 4 patients. Left ventricular ejection fraction averaged 20 f 5% (range 10 to 24) and mean peak oxygen consumption averaged 16.7 f 3.6 ml/min/kg (range 11.7 to 23.7). THE AMERICAN JOURNAL OF CARDIOLOGY MAY 1, 1990
1121
TABLE
I Phosphorus-31
NMR
Reproducibility
Studies
P,/PCr
Rest PF every 9 seconds PF every 6 seconds PF every 3 seconds P, = inorganic
in Five Patients
Work Slope (min/ml) (P,/PCr vs VOg)
First
Second
First
Second
0.22 f 0.03
7.12i0.16
0.0070f0.0038
6.96 f 0.10
7.13 f0.19 7.02 f 0.20
0.0078~00044
1.15 f 0.24
1.52 f 0.72
1.03f0.31
6.94f 0.20
7.04f 0.07
1.63 f 0.52
1.85 f 0.54
6.78f0.18
6.78f0.20
First
Second
0.20 f 0.03 1.14 f 0.93
phosphorus;
0 I
PCr = phosphocreatine:
PF = plantar flexon;
\i02 = oxygen consumptm
CONTROL DOBUTAMINE
96”
q9”
REST
q3”
PLANTARFLEXION
s I
125
cl I
Failure
PH
The protocol was approved by the Committee on Studies Involving Human Beings at the University of Pennsylvania. Written informed consent was obtained. Leg flow rtudier: Leg blood flow measurements were performed in 5 patients using previously described techniques.I36In 2 patients receiving long-term anticoagulation, leg flow measurementswere not obtained. A 50 cm 5Fr thermodilution catheter with a thermistor at 2 cm and an injection port at 12 cm (Elecath) was inserted into the femoral vein and advanced in a retrograde fashion 18 cm. Flows were determined by rapid injection of a 2.5 ml iced dextrose bolus using a commercially available thermodilution computer. In 2 patients, a thermodilution Swan-Ganz catheter was also inserted.
_ 150 .E c .
with Heart
CONTROL DOBUTAMINE
After catheter insertion, resting flow was determined in triplicate with the patient standing. Femoral venous blood was obtained for lactate and hemoglobin 02 saturation. The patient then performed upright plantar flexion (toe-ups) at 3 different frequencies:every 9,6 and 3 seconds. The higher the frequency, the greater the workload. Contractions were sustainedfor approximately 1 second.Each workload was performed for 5 minutes with continuous monitoring of heart rate and respiratory gases (SensorMedics metabolic cart) and measurement of cuff blood pressure at the end of each workload. During the last 2 minutes of exercise, flows were determined in triplicate and femoral venousblood samples were obtained. Each workload was separated by a 15-minute rest period. Each patient performed the exercisesequencetwice, once during the control state and once while receiving dobutamine. The 2 sequenceswere separatedby at least a 90-minute rest period. The sequenceof administration of dobutamine was randomized. Dobutamine was infused at an initial rate of 3 pg/kg/min for 10 minutes. The dose was then increasedby 3 pg/kg/min every 10 minutes until a maximal dose of 15 pg/kg/min was reachedor a 20%increasein heart rate, 20% decreasein systolic arterial pressure or an increase in ventricular ectopic beats was noted. The peak dose achieved averaged 9.0 f 2.4 pg/kg/ min. Exercise was then performed on the maximally tolerated dose. Blood for lactate measurementswas deproteinized with cold perchloric acid and assayedwith a spectrophotometric technique. Hemoglobin 02 saturation was measured with an Instrumentation Laboratories 282 Co-Oximeter. Phosphorus-31
0
REST
q3”
q9” PLANTARFLEXION
mstandddngexerciseincentrelend
<0.0!5 cenhl vs ddnhimine). 1122
THE AMERICAN
JOURNAL
debutaminsstudies (*p
OF CARDIOLOGY
VOLUME
65
magnetic
resonance
spectra
stud-
Calf MRS studies were performed on a separate day from the flow studies. The MRS protocol has been previously described.12In brief, the patient was brought to the MRS laboratory. The leg was positioned in an 11.5 inch bore 1.9 tesla superconducting magnet (Oxford ResearchSystem). The calf was placed over a 4.5 cm diameter surface coil. Following optimization of field homogeneity, a 4-minute rest scan was recorded using radiofrequency pulses (pulse width 25 to 35 ps) applied every 5 seconds.The patient was then withdrawn from the magnet and, outside the magnet, performed upright plantar flexion. Exercise was performed ies:
at 3 different frequencies: every 9, 6 and 3 seconds. Each workload was performed for 5 minutes with continuous monitoring of heart rate and expired respiratory gases(SensorMedics metabolic cart) and measurement of cuff blood pressureat the end of the workload. After 5 minutes of exerciseat a given workload, a rapidly inflating pneumatic cuff (D.E. Hokanson, Inc.) was inflated around the upper thigh to 250 mm Hg to “freeze” metabolism. The patient’s leg was then rapidly repositioned within the magnet (
limb perfusion. No significant change in femoral venous lactate concentration was noted (Figure 2). Phosphorus-31 magnetic resonance spectroscopy: Control exercise resulted in a progressive increase in the PJPCr ratio and a decrease in intracellular PH.
If dobutamine augmented blood flow to active skeletal muscle, one would anticipate improvement in muscle metabolism. At each level of exercise the Pi/PCr ratio should be lower and pH higher. Dobutamine had no effect on the slope of the relation between systemic VOz and the Pi/PCr ratio (control 0.0054 f 0.0039 vs dobutamine 0.0056 f 0.0032 [difference not significant]) or on muscle pH (Figure 3, Table II). Representative phosphorus-31 MRS spectra from patient no. 2 are shown in Figure 4. This patient also
2 3.0IL
E
~
O I
CONTROL DOBUTAMINE
i
II q9”
ii 96”
T I1-
Leg bleed flow: Systemic 902 increasedsignificantly throughout exercise (Figures 1 and 2, Table II). Heart rate and blood pressure measured during each q6” 99” REST workload at the time of leg flow and spectroscopicstudies were comparable; no difference was significant. During control and dobutamine sequences,femoral venous oxygen saturation decreased significantly (p <0.05) from resting values during plantar flexion at rates of every 6 and 3 seconds.Similarly, leg blood flow increased significantly over resting flow during exercise at rates of every 6 and every 3 seconds(p
1123
TABLE II NMR Metabolic Measurements Dobutamine
P,/PCr Workload
PH
C
DB
C
Rest PF every 9 seconds PF every 6 seconds PF every 3 seconds
During Control and
Infusion
D8
0.20f 0.06 0.17 f 0.05 0.82 f 0.19 0.92 f 0.32
7.02 f 0.06 7.04 f 0.05 6.98h 0.07 7.04 f 0.19
0.98f0.29
6.94
1.22kO.51*
f 0.09
6.99
f 0.06
6.86 f 0.12 6.93 f 0.09
.5Oh 0.51 1.39f 0.42
* p CO.05 control versus dobutamine. C = control: DB = dobutamine; other abbreviations
as in Table I.
had systemic hemodynamic measurementsperformed. Twelve pg/kg/min of dobutamine increasedhis resting heart rate from 86 to 95 beats/mm, mean arterial blood pressurefrom 80 to 83 mm Hg, cardiac index from 1.49 to 3.59 liters/min/m2 and pulmonary artery saturation from 46 to 68%. Pulmonary capillary wedge remained unchanged at 30 mm Hg. Resting femoral venous oxygen saturation increasedmarkedly from 50 to 80% and remained significantly increased throughout exercise. Leg blood flow was significantly higher at rest (control 0.8 liters/min; dobutamine 1.26 liters/mm) and the
2.0 -
I
1.5-
2 5 a
1.0.
O-0 l -
.
highest workload (control 1.83 liters/min; plantar flexion every 3 seconds3.46 liters/mm). Despite this impressivehemodynamic effect, no substantial change in MRS spectrawas observedeither at rest or during exercise (Figure 4). DISCUSSION During exercise in the presence of normal blood flow, muscle oxidative metabolism is stimulated by an increase in adenosinediphosphate, the level of which is linearly related to cellular VOZ. Muscle glycolysis is also stimulated, resulting in a decreasein pH. Muscle underperfusion produces an upward shift in the adenosine diphosphateto VOz relation. Concurrently, glycolysis is augmentedand muscle pH drops. Thesemetabolic changes can be noninvasively assessedusing phosphorus-31 MRS by monitoring intramuscular PCr, Pi and the shift betweenthese2 peaks.The Pi/PCr ratio parallels changes in adenosine diphosphate. Therefore, the relation between Pi/PCr and VO2 can be used to estimate changesin the adenosinediphosphateto VO2 relation. The shift between Pi and PCr is proportional to cellular pH. In the present study, we used phosphorus-31MRS to investigate the effect of dobutamine on muscle blood flow. During control exercise,we monitored Pi/PCr and
CONTROL DOBUTAMINE p=NS
0.5 FIGURE 3. Imrganic phoqhw to phorpbcredm rauo (Pirn) md intrPH vemus
p=NS
6.701
300
anddobdamhetudle8.
400
500
i/O,
1124
oxygen
conrunp#on
restandhrhgexerdse&eingcenbd
600
(ml/min)
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
700
(-2)
a
pH responses.We then reevaluatedresponsesduring the infusion of dobutamine. We reasoned that if dobutamine improves muscle blood flow, this should result in a downward shift in the Pi/PCr to VOz slope and an increasein muscle pH. During control exercise, our patients exhibited increasesin the Pi/PCr ratio and decreasesin intramuscular pH that were more marked than changes previously observedby us in normal subjects,‘* indicating an abnormal metabolic responseto exercise.At peak exercise, femoral venous hemoglobin 02 saturation decreasedto 23 f 5% associatedwith an increasein blood lactate levels, consistent with muscle underperfusion. Metabolic abnormalities during submaximal exercise that are unrelated to grossreductions in limb blood flow have been described in forearm muscle in patients with heart failure.14-I6 Calf exercise results in substantially greater increasesin systemicVO2 than doesforearm exercise and thus exhausts circulatory reservemore readily than does forearm exercise. Administration of dobutamine to our patients increased leg blood flow and decreasedfemoral venous hemoglobin oxygen saturation, consistent with prior observations.6The changesin femoral venousoxygen saturation produced by dobutamine were more dramatic than the changesin leg flow, due most likely to difficulties in accurately measuring small changesin leg blood flow during plantar flexion. With each plantar flexion, calf muscle contraction ejects blood into the veins. This
results in pulsatile changesin femoral vein flow that are variably sampledby the bolus thermodilution technique. Despite the change in leg blood flow, no evidenceof improved oxygen delivery to working skeletal muscle was observed.The degree of increase in the PJPCr ratio and decreasein muscle pH with exercise remained comparable to control exercise. Femoral venous blood lactate levels were unchanged. Results of this study therefore suggestthat dobutamine doesnot increaseoxygen delivery to working skeletal muscle. Presumably, the dobutamine-induced increase in leg blood flow was directed to other tissues within the leg. This finding is consistentwith the observation of Drexler et al*’ that dobutamine does not increaseskeletal muscle blood flow in the rat. A lesslikely explanation is that dobutamine improved muscle blood flow but that the musclewas unable to use the delivered blood. Alternately, muscle metabolism may have improved minimally but not to an extent detectable by phosphorus-31 MRS. Maintenance of oral vasodilator therapy may also have attenuated the effect of dobutamine. Results of this study explain the previously observed failure of short-term dobutamine therapy to improve the maximal exercise capacity of patients with heart failure. This study also illustrates how a noninvasive methodologycan be usedto assessthe effect of pharmacologic agents on exercising skeletal muscle in patients with heart failure. Phosphorus-31MRS provides infor-
Control
Dobutamine (12 ucglkglmin)
PCr-,
FIGURE 4. Ptmspbw31 NMR spectra fremarepmenMvepatient((no.2)~ restaaddwingexerciseduirrg~ andddnltadneinfurion.
q9’
J I 10 5
I . . I , 0 -5 -10 -15 -20 10 5 0 -5 -10 -15 :20 PPm PPm THE AMERICAN JOURNAL OF CARDIOLOGY MAY 1. 1990
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mation about the effect of the intervention on intracellular metabolism. Such an approach could potentially be used to evaluate both short- and long-term therapeutic interventions, since studies can be repeated multiple times with minimal discomfort to patients. REFERENCES
1. 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;69:1079-1087. 2. Weter KT, Kinasewitz GT, Janicki JS, Fishman AP. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982,65:1213-1223. 3. Sonnenblick E, Frishman W, LeJemtel TH. Dobutamine: a new synthetic cardioactive sympathetic amine. N Engf J Med 1979;30@17-22. 4. Mikulic E, Cohn J, Franciosa J. Comparative hemodynamiceffccts of inotropic and vasodilator drugs in severe heart failure. Circulation 1977;56:528-533. 5. Robie N, Goldberg L. Comparative systemic and regional hemodynamic effects of dopamine and dobutamine. Am Heart J 1975,90;340m345. 6. Wilson JR, Martin J, 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; 53:1308-1315. 7. Maskin C, Forman R, Sonnenblick E, Frishman W, LeJemtel T. Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983;51:177-182.
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8. Jorfeldt L, Juhlin-Dannfelt A, Karlsson J. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J Appl Physiol 1978;44:350352. 9. Chance B, Eleff S, Leigh J. Noninvasive, non-destructive approaches to cell bioenergetics. Proc Nat1 Arad Sci USA 1980:77:7430-7434. 10. Chance B, Eleff S, Leigh JS, Sokolow D, Sapega A. Mitochondrial regulation of phosphccreatine/inorganic phosphate ratios in exercising human muscle: a gated “P NMR study. Pm Nat1 Acad Sci USA 1981;78:6714-6718. 11. Chance B, Clark B, Nioka S, Subramanian H, Maris J, Argov Z, Bode H. Phosphorus nuclear magnetic resonance spectroscopy in viva. Circulation 1985;72:IV-103-W-110. 12. Mancini DM, Ferraro N, Tuchler M, Chance B, Wilson JR. Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus31 nuclear magnetic resonance. Am J Cardiol 1988,62:1234-1240. 13. Moon RB, Richards JR. Determination of intracellular pH by “P NMR. J Biol Chem 1973;248:7276-7278. 14. Wiener DH, Maris J, Chance B, Wilson JR. Detection of skeletal muscle hypoperfusion during exercise using phosphorus-3 1 nuclear magnetic resonance spectroscopy. JACC 1986;7:793-799. 15. Weiner D, Fink L, Maris J, Jones R, Chance B, Wilson JR. Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: role of reduced muscle blood flow. Circulation 1986;73:1127-1136. 16. Massie B, Conway M, Yonge R, Frostick S, Lcdingham J, Sleight P, Radda G, Rajagopalan B. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation 1987:76:10091019. 17. Drexler H, Banhardt U, Meinhertz T, Wollschliiger H, Lehmann M, Just H. Contrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure: a double-blind, placebo-controlled trial. Circulation 1989;79:491-502.