(Circulation. 1999;99:60-64.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Sustained Improvement in Flow-Mediated Vasodilation After Short-Term Administration of Dobutamine in Patients With Severe Congestive Heart Failure
From the Department of Medicine, Division of Cardiology, The Albert Einstein College of Medicine, Bronx, NY.
Correspondence to Thierry H. Lejemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461.
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Abstract |
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Background—In patients with severe congestive heart failure (CHF), short-term administration of dobutamine exerts sustained clinical benefits that are partially mediated by a training-like effect on skeletal muscle. Recently, physical training has been shown to enhance endothelial function in the skeletal muscle vasculature by improving endothelial function. Whether the dobutamine-induced training effect is also associated with an improvement in endothelial function in the skeletal muscle vasculature is currently unknown.
Methods and Results—Flow-mediated vasodilation in response to
peak reactive hyperemia was evaluated in the forearms of 9
patients with severe CHF who were treated with dobutamine
for 72 hours. Resting and peak hyperemic brachial artery blood
flow and diameter (BABF [mL/min] and BAD [mm], respectively) were
measured by 2-dimensional and Doppler ultrasonography at baseline,
at 3 and 72 hours during dobutamine infusion, and at 2 and
4 weeks after discontinuation of dobutamine therapy. In
addition, the brachial artery response to sublingual (SL)
administration of nitroglycerin (NTG) was evaluated at
baseline and at 2 and 4 weeks after discontinuation of
dobutamine therapy. Ten patients with severe CHF who did
not receive dobutamine served as control subjects. Resting
BABF was significantly increased at 3 and 72 hours (391.2±31.8 and
366.8±31.0 mL/min, respectively, compared with 289.8±18.6 mL/min at
baseline; P<0.05). Peak hyperemic BABF was not
altered by dobutamine infusion compared with baseline
values. The increase in BAD during peak hyperemic response was
greater after infusion of dobutamine for 72 hours
(15.2±2.7% versus 9.1±1.8%, P<0.05) and remained
significantly greater for 
2 weeks after discontinuation of
dobutamine (12.3±2.2% versus 9.1±1.8%,
P<0.05). In contrast to the peak hyperemic
response, the increase in BAD (%) induced by SL NTG was unchanged by
administration of dobutamine for 72 hours. Two and 4 weeks
after discontinuation of dobutamine, NTG-induced increases
in BAD were similar to the BAD noted at baseline.
Conclusions—In patients with severe CHF, short-term
administration of dobutamine for 72 hours selectively
improves vascular endothelial function for 2 weeks.
Key Words: heart failure • nitroglycerin • vasodilation
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Introduction |
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Treatment of compliant patients with severely symptomatic congestive heart failure (CHF) despite therapy with drugs such as ACE inhibitors, loop diuretics, long-acting nitrates, and cardiac glycosides remains a therapeutic challenge. Short-term administration of dobutamine has been shown to produce sustained clinical effects in these patients.1 The persistence of the clinical effects after discontinuation of dobutamine has been attributed to 2 mechanisms: a sustained improvement in myocardial contractility–left ventricular performance and a training-like effect on the skeletal muscles.2 3 Physical training has recently been shown to specifically enhance flow-mediated vasodilation in patients with CHF.4 5 Whether dobutamine-induced training also involves the vascular endothelium is currently unknown.
Accordingly, the present study was undertaken to serially assess endothelium-dependent vasodilation (brachial artery dilatation in response to 5 minutes of occlusion) and endothelium-independent vasodilation (regional response to sublingual [SL] administration of nitroglycerin [NTG]) in patients with severe CHF who were treated for 72 hours with dobutamine. Patients with severe CHF who were not treated with dobutamine served as control subjects.
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Methods |
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Patient Population
Twelve men and 7 women with CHF and symptoms compatible with New York Heart Association functional class IV were studied. Extensive coronary artery disease was documented in all patients by coronary angiography. In addition, 8 patients had type II diabetes mellitus, and 5 had a history of hypertension. None of the patients were smokers. All patients were treated with furosemide (80 to 240 mg/d), digoxin (mean serum level, 0.9 ng/mL), captopril (25 to 75 mg/d), or enalapril (10 to 30 mg/d). Long-acting nitrates were discontinued 48 hours before the study. Nine of 19 patients were treated with dobutamine at a mean infusion rate of 3.5 µg · kg-1 · min-1 (range, 2.5 to 5.0 µg · kg-1 · min-1) for 72 hours. The rate of infusion of dobutamine was adjusted according to clinical response during the first 2 hours of administration, as evidenced by an increase in urinary output, enhanced peripheral perfusion, and relief of symptoms. The remaining 10 patients were not treated with dobutamine and served as control subjects. The clinical characteristics of the 9 patients who received dobutamine and the 10 who did not receive dobutamine are summarized in Table 1
. All patients who were treated with
dobutamine remained ambulatory during the 4 weeks after
discontinuation of dobutamine therapy. All patients gave
written, informed consent. The study protocol was approved by the
Albert Einstein College of Medicine Committee of Clinical
Investigations.
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Two-Dimensional and Doppler Ultrasonography
This method has been described previously.6 7
Ultrasound examination of the brachial artery in the dominant forearm
was performed with the use of a high-resolution 5- to 10-MHz ultrasonic
transducer connected to an ATL HDI 3000cv Ultrasound System that allows
measurement of arterial diameter with a precision of
0.1 mm. With the patient supine, the transducer was positioned 5
to 10 cm above the antecubital fossa. The brachial artery was
identified and carefully scanned to determine its origin, course, and
the presence and extent of atheroma. Exclusion criteria
included extensive arterial wall
atheromatous changes, arterial narrowing,
or a Doppler signal consistent with proximal
arterial stenosis. The origin of the vessel was
avoided because of changes in velocity profile at the branching point.
Once the optimal portion of the artery was visualized, the position of
the transducer was marked on the skin. The center of the vessel was
identified when the clearest images of the anterior and posterior walls
of the artery were obtained, and the transmit zone was set to the level
of the anterior wall. Depth and gain settings were optimized to
identify the lumen-to–vessel wall interface and were kept constant
during each study. Before any Doppler measurements were attempted,
great care was taken to visualize the vessel at its largest diameter
with the vessel walls parallel in the 2-dimensional sector image. When
the vessel walls are parallel, one can assume that the ultrasound beam
is directed parallel to the longitudinal axis of the
vessel.8 Transducer position was then adjusted to minimize
the incident angle of the ultrasound beam. An angle of <60° was
obtained in all instances and was kept constant in each subject.
Automatic internal correction for the Doppler angle was used with
the aid of an on-screen cursor. A 2- to 3-mm sample volume was placed
in the center of the vessel, and fine adjustments of its position were
made until a narrow Doppler spectrum was obtained. Under these
conditions, the maximal velocity, corresponding to the central position
in a parabolic velocity profile, was recorded. Even though this
variable tended to overestimate the actual velocity across the
whole cross section of the vessel, this approach maximized
reproducibility of the Doppler signal. Two-dimensional and
Doppler studies were recorded on commercially available
videocassettes for later analysis.
Flow-Mediated Vasodilation and Response to NTG
Flow-mediated vasodilation was measured in the response of the
brachial artery after peak reactive hyperemia. Peak reactive
hyperemia was induced by inflation of a blood pressure cuff
around the forearm to a pressure of 200 mm Hg for 5 minutes,
followed by release. The wrist was not occluded during the final minute
of forearm occlusion.
The brachial artery was scanned at rest and for 30 seconds before and 180 seconds after cuff deflation. The maximum increase in brachial artery diameter (BAD) occurred at 90 seconds after release of cuff occlusion. The scan was performed at 5 time points: baseline (before dobutamine), at 3 and 72 hours after administration of dobutamine was begun, and at 2 and 4 weeks after discontinuation of dobutamine therapy. In the control patients, the scan was performed at baseline (day 1), day 3, 2 weeks, and 4 weeks.
The brachial artery response to NTG was assessed before treatment with dobutamine and at 2 and 4 weeks after discontinuation of dobutamine therapy. After optimal visualization of the brachial artery, a dose of 0.4 mg of NTG was administered, and the brachial artery was scanned over the next 5 minutes. The brachial artery response to SL administration of NTG was not assessed in patients who did not receive dobutamine.
Data Analysis
Arterial diameters were measured by 2 observers
using ultrasonic calipers (NovaMicrosonics) from the
anterior-to-posterior interface between the media and adventitia, at a
fixed distance from an anatomic marker such as a vein or fascial plane.
The mean diameter was calculated from 8 cardiac cycles (4 from each
observer) incident with the R wave on a continuously recorded ECG.
We performed analysis of Doppler velocity by integrating
the darkest portion of the spectral display throughout systole and
diastole and dividing by the R-R interval. The results of 5
cardiac cycles were averaged. In case of arrhythmias, beats
were excluded from analysis. Blood flow was calculated by
multiplying the velocity-time integral by the heart rate and artery
cross-sectional area. During the peak hyperemic response, BAD,
blood flow velocity, and heart rate were obtained at 30, 60, 90, 120,
and 180 seconds after release of arterial occlusion.
Statistical Analysis
All data are presented as mean±SD.
Hemodynamic parameters were
analyzed by 1-way ANOVA with repeated measures, followed by
Scheffé's post hoc test for statistical significance.
Statistical significance was accepted at the 95% confidence interval
(P<0.05).
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Results |
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Resting Brachial Artery Blood Flow
During administration of dobutamine at an average infusion rate of 3.5 µg · kg-1 · min-1, resting brachial artery blood flow (BABF) increased from 289.8±18.6 mL/min at baseline to 391.2±31.8 mL/min at 3 hours and 366.8±31.0 mL/min at 72 hours (both P<0.05 versus baseline). At 2 and 4 weeks after discontinuation of dobutamine, resting BABF returned to 310.8±20.2 and 296±17.6 mL/min, respectively, values that were not statistically different from baseline (Figure 1
).
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Peak Hyperemic BABF and Diameter
Peak hyperemic BABF occurred 30 seconds after release of
the 5-minute arterial occlusion and was similar at baseline
and during and after administration of dobutamine (Figure 2A). Similarly, the increase in peak
blood flow velocity was identical at baseline and during and after
administration of dobutamine (Figure 2B). The
increase in BAD (%) during peak hyperemic response was maximal
at 90 seconds after release of the 5-minute arterial
occlusion. During administration of dobutamine, the
increase in BAD was only significantly greater at 72 hours when
compared with baseline (15.2±2.7% versus 9.1±1.8%,
P<0.05; Figure 3). Two weeks
after discontinuation of dobutamine, the increase in BAD
remained significantly greater than BAD noted at baseline (12.3±2.2%
versus 9.1±1.8%, P<0.05; Figure 3).
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Brachial Artery Responses to SL NTG
Administration of SL NTG resulted in a significant increase in
BABF. The increases in BABF were similar before and at 2 and 4 weeks
after discontinuation of dobutamine (Figure 4). SL NTG–induced increases in BAD were
also similar before and at 2 and 4 weeks after discontinuation of
dobutamine (Figure 5).
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Control Subjects
Resting and peak hyperemic BABF and increase in BAD during
hyperemic response are detailed in Table 2 for the 10 patients with severe CHF who
did not receive dobutamine. These parameters
remained unchanged at baseline, at 3 and 72 hours of
dobutamine therapy, and at 2 and 4 weeks after therapy was
discontinued.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present data indicate that in patients with severe CHF, flow-mediated vasodilation remains improved for
2 weeks after
short-term administration of dobutamine for 72 hours.
During administration of dobutamine, resting BABF steadily
increased at 3 and 72 hours, whereas flow-mediated vasodilation was
only improved at 72 hours. The lag between the increase in blood flow
and the improvement in flow-mediated vasodilation is similar to that
reported with physical training.4 Flow-mediated dilatation in response to 5 minutes of arterial occlusion tended to be greater in our patients with severe CHF than in healthy subjects studied by Celermajer et al (9.2% versus 8.2%).9 However, the peak increase in BAD occurred at 90 seconds after the release of occlusion in our patients, whereas Celermajer et al reported the increase in BAD at 60 seconds. Our data are within the range reported by Hornig et al,4 who observed an increase in arterial diameter of 6.8% and 12% after arterial occlusion for 4 and 8 minutes, respectively. Peak hyperemic BABF only increased by a factor of 2 in our patients. This substantially depressed peak hyperemic response probably reflects the severe symptoms experienced by our patients, because peak reactive hyperemia and functional capacity are closely correlated in patients with CHF.10 The lack of improvement in peak hyperemic response after administration of dobutamine for 72 hours is in agreement with the data of Khan and colleagues.11 These investigators reported that peak reactive hyperemia is not immediately improved despite restoration of cardiac output to near normal values after insertion of a left ventricular assist device.11
The selective improvement in flow-mediated but not in NTG-induced vasodilation points to a specific effect of dobutamine on the vascular endothelium. Flow-mediated vasodilation can be enhanced by either increased release of endothelium-derived relaxing substances or increased sensitivity of the vascular smooth muscle cells to relaxing substances. Because the response to NTG was left unchanged by short-term administration of dobutamine, an increased release of endothelium-derived relaxing substances rather than increased vascular smooth muscle cell sensitivity to relaxing substances probably accounts for the improvement in flow-mediated vasodilation. How short-term administration of dobutamine persistently increases the release of endothelium-derived relaxing substances is not fully understood.
Short-term administration of dobutamine may promote release of endothelium-derived relaxing substances by exposing the vasculature to increases in blood flow and thereby in shear stress.12 13 Physical training, which also transiently increases blood flow, has been reported to enhance constitutive NO synthase (cNOS) gene expression and NO production in experimental models of CHF.14 In contrast, cNOS gene expression was found to be unchanged in the skeletal muscle vasculature of patients with CHF who experienced a 20% increase in peak aerobic capacity after physical training.15
Elevated levels of cytokines in patients with severe CHF may activate the inducible form of NOS, which in turn increases NO production.16 However, the inducible pathway of NO production was most likely lessened by the short-term administration of dobutamine, which lowers cytokine levels in patients with CHF.17
Last, short-term administration of dobutamine may have altered vasomotor tone in patients with CHF by lowering neurohormonal activation. In turn, alterations in vasomotor may affect flow-mediated vasodilation. However, the steadiness of the NTG and peak hyperemic responses before and after short-term administration of dobutamine argues against alterations in vasomotor tone.
Limitations of Study
All of our patients were extremely symptomatic, and
thus, medications such as ACE inhibitors and cardiac
glycosides, which affect endothelial function, could
not be discontinued. The etiology of vascular
endothelial function was probably multifactorial in our
patients because many were diabetics and/or had a history of
hypertension. Moreover, all had extensive coronary artery
disease. Nevertheless, the improvement in flow-mediated vasodilation
induced by short-term administration of dobutamine suggests
that CHF was at least partially responsible for the impaired
flow-mediated vasodilation.
Received August 10, 1998; accepted September 16, 1998.
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