Myocardial Free Fatty Acid and Glucose Use After
Carvedilol Treatment in Patients With Congestive
Heart Failure
Thomas R. Wallhaus, MD; Michael Taylor, PhD; Timothy R. DeGrado, PhD;
Douglas C. Russell, MD, PhD; Peter Stanko, MD; Robert J. Nickles, PhD; Charles K. Stone, MD
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Background—Use of ␤-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial
oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a
shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation.
Methods and Results—We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with
stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction
ⱕ35%) using myocardial positron emission tomography studies and resting echocardiograms before and 3 months after
carvedilol treatment. Myocardial uptake of the novel long chain fatty acid metabolic tracer 14(R, S)-[18F]fluoro-6-thiaheptadecanoic acid ([18F]-FTHA) was used to determine myocardial FFA use, and [18F]fluoro-2-deoxy-glucose
([18F]-FDG) was used to determine myocardial glucose use. After carvedilol treatment, the mean myocardial uptake rate
for [18F]-FTHA decreased (from 20.4⫾8.6 to 9.7⫾2.3 mL · 100 g–1 · min–1; P⬍0.005), mean fatty acid use decreased
(from 19.3⫾7.0 to 8.2⫾1.8 ␮moL · 100 g–1 · min–1; P⬍0.005), the mean myocardial uptake rate for [18F]-FDG was
unchanged (from 1.4⫾0.4 to 2.4⫾0.8 mL · 100 g–1 · min–1; P⫽0.14), and mean glucose use was unchanged (from
11.1⫾3.1 to 18.7⫾6.0 ␮moL · 100 g–1 · min–1; P⫽0.12). Serum FFA and glucose concentrations were unchanged, and
mean left ventricular ejection fraction improved (from 26⫾2% to 37⫾4%; P⬍0.05).
Conclusions—Carvedilol treatment in patients with heart failure results in a 57% decrease in myocardial FFA use without
a significant change in glucose use. These metabolic changes could contribute to the observed improvements in energy
efficiency seen in patients with heart failure. (Circulation. 2001;103:2441-2446.)
Key Words: fatty acids 䡲 glucose 䡲 metabolism 䡲 heart failure
ignificant evidence has demonstrated that ␤-adrenoreceptor blockade in the setting of stable, chronic heart failure
can result in a dramatic improvement in left ventricular
function and prognosis in patients with both ischemic and
nonischemic cardiomyopathy.1– 4 The pathophysiological basis for these clinical benefits, perhaps surprisingly, is not
clearly established. A potential rationale for the use of
␤-adrenoreceptor blockade in heart failure is its effect to
counteract the adverse metabolic effects of long-term sympathetic adrenergic system activation5 and the resulting increased myocardial oxygen consumption.6
In heart failure, myocardial energy efficiency is reduced.7
It can be hypothesized that myocardial energy efficiency is
reduced as a result of inappropriate, catecholamine-induced,
enhanced free fatty acid (FFA) use secondary to elevated
levels of serum FFAs acting as a metabolic substrate for the
myocardium and within the myocardium itself by wasteful
S
cycling of FFAs through intramyocardial lipolysis, reesterification, and suppression of glucose metabolism.6,8 –10 ␤-Adrenoreceptor blockade in patients with heart failure improves myocardial energy efficiency,11–16 and a shift in myocardial substrate
use from FFA to glucose oxidation12 could contribute to the
energy-sparing effects of this treatment.
In the present study, we evaluated the effect of a 3-month
period of carvedilol treatment on regional myocardial FFA
and glucose uptake in patients with stable New York Heart
Association (NYHA) functional class III ischemic cardiomyopathy using positron emission tomography (PET) imaging
with both the long-chain fatty acid tracer 14(R, S)-[18F]fluoro6-thia-heptadecanoic acid ([18F]-FTHA) and [18F]fluoro-2deoxy-glucose ([18F]-FDG). We hypothesized that a switch in
myocardial energy substrate use from FFAs to glucose may
be one potential mechanism for the improved energy efficiency seen in the treatment of patients with heart failure.
Received December 5, 2000; revision received February 23, 2001; accepted March 1, 2001.
From the William S. Middleton Veterans Hospital, Madison, Wis (T.R.W., D.C.R.); the Department of Medical Physics, University of
Wisconsin—Madison, Madison, Wis (M.T., R.J.N.); the Department of Medical Physics, Duke University, Durham, NC (T.R.D.); and the Department
of Medicine, University of Wisconsin—Madison, Madison Wis (T.R.W., D.C.R., P.S., C.K.S.).
Dr Wallhaus has received funding support from Smith-Kline Beecham.
Correspondence and reprint requests to Thomas R. Wallhaus, MD, 600 Highland Ave, H6/349, University of Wisconsin Hospital and Clinics,
Department of Medicine, Cardiology Section, Madison, WI 53792-3248. E-mail [email protected]
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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Circulation
May 22, 2001
TABLE 1.
Patient Characteristics
Age, y
64⫾14
Race, white/black
9/0
Patients taking an ACE inhibitor, n
8/9
Patients taking digoxin, n
8/9
Patients taking cholesterol-lowering agents, n
6/9
Values are mean⫾SEM or No. of patients.
Methods
Patient Population
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This study was reviewed and approved by the Human Subjects
Committee at the University of Wisconsin at Madison. Nine patients
were recruited from the University of Wisconsin Hospital and
Clinics and the Madison Veterans Hospital (Table 1). All patients
gave informed consent. All patients had left ventricular ejection
fractions ⱕ35% and were on active treatment with an ACE inhibitor
(if tolerated) and digitalis (unless contraindicated), with stable
NYHA functional class III congestive heart failure at least 3 months
before study entry. Left ventricular ejection fraction was determined
by resting echocardiograms. No patient was taking ␤-adrenoreceptor
blocking agents at the time of study entry. Exclusion criteria
included a history of diabetes mellitus, severe or unstable angina,
recent myocardial infarction (⬍3 months), and active alcohol/drug
abuse.
Carvedilol Treatment Regimen
All patients completed baseline initial [18F]-FTHA and [18F]-FDG
PET scans (Figure 1). Patients then received carvedilol starting at a
dose of 3.125 mg orally twice a day for 1 week. Thereafter, dosage
was titrated every 2 weeks to a target dose of 25 mg twice a day.
Patients were treated for a total of 3 months at the target dose of 25
mg twice a day before returning for follow-up [18F]-FTHA and
[18F]-FDG PET scans. During this time, patients were evaluated in
the clinic every 2 weeks to assess tolerance and compliance with
carvedilol therapy.
[18F]-FTHA and [18F]-FDG Tracer Production
Nucleophilic aqueous [18F]-fluoride was produced by using the
11.4-MeV beam of the University of Wisconsin Radiopharmaceutical Delivery System 112 cyclotron and the high-pressure Au/Ag or
Ag body [18O]H2O targets, which are described in detail elsewhere.17
[18F]-FTHA was synthesized as previously described.18 [18F]-FDG
was produced using a microwave cavity-based adaptation of the
Hammacher synthesis, as previously described.19
PET Scanning Procedures Before and
After Carvedilol
All patients completed [18F]-FTHA and [18F]-FDG PET scans on
consecutive days, both before and after completion of a 3-month
course of carvedilol. After an overnight fast (12 hours), patients
underwent a brief history and physical examination. Intravenous
access was obtained with 20-gauge angiocatheters in the dorsum of
the right hand and the left antecubital fossa. Blood samples were
drawn to determine glucose and FFA concentrations at the beginning, midpoint, and at end of the PET scan. Serum norepinephrine
and epinephrine samples were drawn just before the PET scans in the
supine position, after 30 minutes of rest. Blood samples were stored
at ⫺70°C until analyzed. Patients were positioned supine in the GE
Advance PET scanner (General Electric Inc), which was set to the
following parameters: 15.6 cm axial field of view, 35 slices, 3.8 mm
in-plane resolution, and whole body tomograph. After optimization of
subject position for visualization of the entire heart, transmission scans
were performed for 15 minutes using 3 rotating 68Ge pin sources.
For the [18F]-FTHA scans, patients received a programmed infusion of 2.5 mCi of [18F]-FTHA over 10 minutes from a Harvard
syringe pump using a standard 10-mL syringe. For the [18F]-FDG
scans, patients received a 10 mCi bolus infusion of [18F]-FDG.
Dynamic imaging was performed with a frame rate of 2 minutes for
5 scans, 5 minutes for 6 scans, and 10 minutes for 1 scan. After
injecting the tracer, 2 mL of arterialized venous blood was drawn
from the heated-hand intravenous catheter for 18F activity every 2
minutes for the first 20 minutes and every 5 minutes for the last 40
minutes of the scanning procedure. Samples were placed on ice and
centrifuged. Standard aliquots of plasma were used to determine the
time course of radioactivity concentration.
Biochemical Analysis
Serum epinephrine and norepinephrine concentrations were determined by high-pressure liquid chromatography with electrochemical
detection.20 Nonesterified (free) fatty acid concentrations were measured by spectrophotometric enzymatic assay (Wako Chemicals).
Plasma glucose concentrations were measured by a glucose oxidation assay (CX3-Delta Analyzer, Beckman Instruments, Inc).
Region of Interest Definition
To determine radiotracer time course, regions of interest were drawn
within the myocardial borders in 3 contiguous midventricular transaxial slices of each subject. Myocardial slices were aligned between
PET scans taken before and after carvedilol treatment, and identical
regions of interest were pasted onto myocardial segments on [18F]FTHA and [18F]-FDG scans. All 9 patients had thinned, akinetic left
ventricular wall segments on echocardiography, which corresponded
to metabolically inactive segments on PET images, suggesting
infarcted myocardium. Regions of interest did not include these wall
segments. Regions of interest were restricted to myocardial segments
demonstrating relatively preserved contractility by echocardiography.
PET myocardial transaxial slices were matched with the apical long-axis
echocardiographic wall segments used to assess resting wall motion.
Data Analysis
Estimation of uptake rates from the PET time course data were
performed with graphical analysis.21 The myocardial uptake rates
(Ki) for [18F]-FTHA and [18F]-FDG were first estimated from the
following relation:
冕
(1)
Cpdt
0
Ci(T)
⫹Vd
⫽ Ki
Cp(T)
Cp(T)
where Ci indicates myocardial radioactivity; dt, derivative time; and
Cp, plasma [18F] radioactivity concentration at time T. Plots of
Ci(T)/Cp(T) versus Cp(T)dt/Cp(T) are fitted to straight lines by
conventional least-squares methods, and the slopes of the best-fit
lines are taken as estimates of Ki. The myocardial metabolic uptake
(MUR) rates for each region of interest were then calculated from the
Ki values using the following formula:
(2)
Figure 1. Schematic of imaging protocol.
冢 冣
T
PKi
LC
MUR⫽
where P indicates the plasma glucose or FFA concentration and LC
is the lumped constant. The mean serum fatty acid and glucose
values obtained during the PET scanning procedure were used to
determine P. A lumped constant of 0.67 was assumed for [18F]-FDG,
and 1.0 was assumed for [18F]-FTHA.
Wallhaus et al
TABLE 2.
Fatty Acid and Glucose Metabolism in Heart Failure
2443
Laboratory and Clinical Data
Before Carvedilol
Serum glucose, mmol/L
After Carvedilol
P
5.5⫾0.3
5.72⫾0.4
0.08
Serum FFA, mmol/L
0.96⫾0.10
0.91⫾0.10
0.71
Serum norepinephrine concentration, pg/mL
467⫾36
535⫾117
0.50
Serum epinephrine concentration, pg/mL
Rate-pressure product, mm Hg 䡠 bpm
Minute work, mm Hg 䡠 bpm/cm2
Left ventricular ejection fraction, %
39⫾8
40⫾8
0.47
9077⫾531
7594⫾585
0.05
221 500⫾2700
25⫾2
234 300⫾3700
37⫾3
0.58
0.002
Values are mean⫾SEM.
Myocardial oxygen consumption related to FFA use was estimated
before and after carvedilol treatment using the following formula:
(3)
FFA O2 consumption⫽[FFA utilization rate
(␮moL 䡠 100 g⫺1 䡠 min⫺1)*130 ATP/mole FFA]/
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2.83 ATP yield per O2 atom
where 130 ATP/mole FFA is the amount of ATP produced per mole
of FFA consumed, and 2.83 ATP yield per O2 atom is the amount of
ATP produced per mole of oxygen consumed.22
Echocardiographic Evaluation
Echocardiograms were obtained using a Hewlett Packard Sonos
5500 ultrasound system before and after the completion of carvedilol
treatment. Left ventricular regional wall motion was assessed by an
experienced echocardiographer who was blinded to the carvedilol
status of the patient. Two-dimensional echocardiographic estimation
of left ventricular ejection fraction was calculated using Simpson’s
biplane method 23 with the Nova Microsonics ImageVue
Workstation.
Statistical Analysis
The clinical and laboratory data of the patients are presented as
mean⫾SEM. Uptake rate data are presented as mean⫾SEM. Comparing data before and after carvedilol treatment was done with a paired
Student’s t test. P⬍0.05 was considered statistically significant.
Results
Patient Characteristics
The study population was composed of 9 male patients with
ischemic cardiomyopathy (Table 1). All patients received
unchanged medical therapy for 3 months before enrollment.
Patients were maintained on ACE inhibitors (89%), digoxin
(89%), and diuretics (89%). Four patients (44%) were receiving hydroxymethylglutaryl coenzyme A reductase inhibitors
(statins), one (11%) was receiving gemfibrozil, and one was
receiving an angiotensin II receptor blocker (11%). No
patients were receiving ␤-adrenoreceptor blocking agents
before the study. All patients were maintained on carvedilol
treatment at 25 mg twice a day for at least 3 months (mean,
110⫾9 days).
Biochemical Data
The mean serum norepinephrine and epinephrine concentrations before carvedilol treatment were not significantly elevated and did not significantly change with carvedilol treatment (Table 2). The mean serum FFA concentration before
carvedilol treatment was elevated above the published normal
range (0.40 to 0.66 mmol/mL),24 and it did not significantly
change after carvedilol treatment (0.92⫾0.27 mmol/L versus
0.88⫾0.24 mmol/L; P⫽NS). The mean serum glucose con-
centration at baseline was within the normal range, and it did
not significantly change after carvedilol treatment
(5.4⫾0.3 mmol/L versus 5.6⫾0.3 mmol/L; P⫽NS).
Hemodynamic and Echocardiographic Data
The mean resting heart rate decreased with carvedilol treatment (78⫾5 bpm versus 66⫾5 bpm; P⬍0.05), but the mean
systolic blood pressure was unchanged (122⫾5 mm Hg
versus 114⫾4 mm Hg; P⫽NS). The rate-pressure product
was significantly lowered by carvedilol treatment
(9457⫾489 mm Hg · bpm versus 7185⫾478 mm Hg · bpm;
P⬍0.05); however, the calculated minute work was not
significantly changed by carvedilol (221 500⫾2700 mm Hg ·
bpm/cm3 versus 234 300⫾3700 mm Hg · bpm/cm3; P⫽0.58).
Left ventricular ejection fraction increased significantly
(from 26⫾2% to 37⫾4%; P⬍0.002) after carvedilol treatment, but left ventricular diastolic volume (195⫾34 mL
versus 170⫾33 mL; P⫽NS), systolic volume (142⫾29 mL
versus 116⫾19 mL; P⫽NS), end-diastolic dimension
(6.30⫾0.23 cm versus 6.14⫾0.53 cm; P⫽NS), and end-systolic
dimension (5.46⫾0.31 cm versus 5.23⫾0.50 cm; P⫽NS) were
not significantly changed by carvedilol treatment. The stroke
volume index was significantly increased by carvedilol
(24.1⫾3.1 mL/m2 versus 30.6⫾3.8 mL/m2; P⬍0.05).
PET Images and Kinetic Analysis
[18F]-FTHA
[18F]-FTHA uptake was seen in the heart within 90 seconds
after the start of the infusion, and it provided clear delineation
of myocardial borders. An example of parametric slope
images before and after carvedilol for [18F]-FTHA is shown in
Figure 2 (top). The mean Ki for [18F]-FTHA decreased (from
20.4⫾8.6 to 9.7⫾2.3 mL · 100g–1 · min–1; P⬍0.005), and the
mean myocardial fatty acid use in nonischemic segments
decreased (from 19.3⫾7.0 to 8.2⫾1.8 mmoL · 100g–1 · min–1;
P⬍0.005). The change in individual and mean uptake rate
constants (Ki) and myocardial uptake rates (MUR) for [18F]FTHA before and after carvedilol treatment are shown in
Figure 3. All patients demonstrated a decrease in Ki and MUR
for [18F]-FTHA after carvedilol treatment. The estimated
myocardial oxygen consumption related to FFA use decreased by 57% after carvedilol treatment (from 871⫾122 to
376⫾30 ␮moL O2 consumed · 100 g–1 · min–1; P⬍0.05).
[18F]-FDG
As expected for fasting patients, dynamic [18F]-FDG images
demonstrated low levels of myocardial [18F]-FDG uptake. An
2444
Circulation
May 22, 2001
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Figure 2. Representative parametric slope
images of [18F]-FTHA and [18F]-FDG
images before and after carvedilol treatment, with pixel values expressed in mL ·
100 g–1 · min–1). Transaxial images of 4
midventricular slices are shown for one
patient. Images are oriented with the right
ventricle in the upper left hand corner of
each image frame. The top 2 image sets
demonstrate myocardial [18F]-FTHA uptake
before and 3 months after carvedilol treatment, respectively. A decrease in myocardial [18F]-FTHA uptake is seen on the
images taken after carvedilol treatment.
The bottom 2 image sets demonstrate
myocardial [18F]-FDG uptake before and 3
months after carvedilol treatment, respectively. An increase in myocardial [18F]-FDG
uptake is seen on the images taken after
carvedilol treatment.
example of parametric slope images before and after carvedilol for [18F]-FDG from one patient are shown in Figure 2
(bottom). The change in individual and mean uptake rate
constants (Ki) and myocardial uptake rates (MUR) for [18F]FDG are shown in Figure 4. The mean Ki for [18F]-FDG was
unchanged (from 1.4⫾0.4 to 2.4⫾0.8 mL · 100 g–1 · min–1;
P⫽0.12), and the mean glucose use was unchanged (from
11.1⫾3.1 to 18.7⫾6.0 mmoL · 100 g–1 · min–1; P⫽0.12).
Eight of the 9 patients demonstrated an increase in Ki uptake
rates and MUR for [18F]-FDG, whereas one patient demonstrated a decrease in Ki uptake rates and MUR for [18F]-FDG.
Discussion
18
[ F]-FTHA Imaging
In this study, carvedilol therapy administered over a 3-month
period to patients with stable NYHA functional class III heart
failure resulted in a 57% decrease in myocardial [18F]-FTHA
uptake rates and [18F]-FTHA uptake rate constants (Ki).
Because the rate of radioactivity accumulation of [18F]-FTHA
is believed to reflect the ␤-oxidation rate of long chain fatty
acids,18 our results are consistent with a marked decrease in
myocardial FFA oxidation after carvedilol therapy. The
decrease in myocardial [18F]-FTHA uptake does not seem to
be the result of altered substrate availability given the lack of
a significant change in serum FFA or glucose concentration.
Instead, a consistent lowering of [18F]-FTHA uptake rate
constants (Ki) suggests carvedilol affects FFA uptake at the
level of the myocyte. Maki et al25 recently demonstrated a
similar reduction in myocardial [18F]-FTHA uptake in patients with preserved left ventricular function who were
treated with insulin infusion. In contrast to our findings,
however, no effect of insulin on myocardial [18F]-FTHA
uptake rate constants (Ki) was observed, and effects were
associated with a significant lowering of serum FFA concentration. Thus, the change in myocardial [18F]-FTHA uptake in
the study by Maki et al25 was related to changes in substrate
availability rather than the cellular handling of the substrate.
A potential explanation for our observed decrease in
[18F]-FTHA uptake rate constants (Ki) after carvedilol therapy
is a decrease in the activity of myocardial carnitine palmitoyl
transferase I (CPT I), a key enzyme involved in mitochondrial
FFA uptake.26 Recent work by Panchal et al,27 who used a
canine model of heart failure, demonstrated a 28% decrease
in the activity of CPT I after metoprolol treatment. Decreased
Figure 3. Ki (left) and MUR (right) rates for
[18F]-FTHA before and after carvedilol treatment in individual patients. The overall
decrease in Ki and MUR is shown by ⫺. A
decrease in both Ki and MUR for [18F]-FTHA
is demonstrated after 3 months of carvedilol
treatment.
Wallhaus et al
Fatty Acid and Glucose Metabolism in Heart Failure
2445
Figure 4. Ki (left) and MUR (right) rates for
[18F]-FDG before and after carvedilol treatment in individual patients. The overall
decrease in Ki and MUR is shown by ⫺. An
overall increase in Ki and MUR for [18F]-FDG
is demonstrated after carvedilol.
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
CPT I activity by carvedilol could account for a significant
lowering of myocardial FFA oxidation, and it provides a
potential mechanism for the improved energy efficiency seen
in patients with heart failure who are treated with ␤-adrenoreceptor blockade.12 Although CPT I activity was not directly
measured in our patients, DeGrado et al18 previously demonstrated an 87% decrease in myocardial [18F]-FTHA uptake
in mice treated with the CPT I inhibitor 2[5(4chlorophenyl)pentyl] oxirane-2-carboxylate.
[18F]-FDG Imaging
No significant change in myocardial glucose use was seen in
our patients. This finding is consistent with a relative switch
in myocardial substrate use from FFA to glucose given the
results of previous investigations demonstrating a reduction
in myocardial oxygen consumption after ␤-blockade.11,12
Changes in lactate oxidation by the heart could contribute
to the variability seen in myocardial glucose uptake in our
study. The inhibition of CPT I activity is known to increase
the activity of pyruvate dehydrogenase,26,28 which catalyzes
the decarboxylation of pyruvate,29 and the increased activity
of this enzyme is expected to cause not only an increase in
glucose oxidation, but an increase in lactate oxidation as
well.30 Because [18F]-FDG provides information only about
glucose uptake, a significant increase in myocardial lactate
uptake may occur in some patients, with only minor or no
changes in myocardial [18F]-FDG uptake. In addition, fasted
studies with [18F]-FDG result in poor myocardial count
statistics and affect the ability to measure a significant change
in myocardial [18F]-FDG uptake. We used the fasted state to
standardize the metabolic state of patients during [18F]-FTHA
and [18F]-FDG PET scans because Patlak graphical analysis
requires a stable serum level of substrate during the dynamic
image acquisition. We evaluated serum FFA and glucose
concentrations under the conditions of fasting, Intralipid (an
intravenous fatty acid solution) infusion, and after a standardized
fatty meal and found the fasted state provided the most stable
concentration of serum FFAs and glucose (unpublished data).
Myocardial Energy Metabolism and Heart Failure
Alterations in myocardial energy metabolism that may occur
in heart failure are somewhat controversial. We recently
reported evidence of increased myocardial FFA and decreased myocardial glucose use in patients with heart failure
using [18F]-FTHA and [18F]-FDG.31 These results are in
agreement with the findings of previous human studies
demonstrating an increase in myocardial FFA metabolism
and a decrease in myocardial glucose metabolism in heart
failure patients compared with controls using direct, invasive
measurements of FFA and glucose metabolism.7,32
Conversely, animal studies have suggested a switch to a
more fetal form of energy metabolism in heart failure, with
increased glycolysis and suppression of FFA metabolism.33,34
Sack et al35 showed a down-regulation of several genes
involved in fatty acid metabolism in heart failure. Doenst et
al36 demonstrated an increase in glucose uptake with
␤-adrenergic stimulation, but other reports have not shown
this increase.37,38 One explanation for the findings of Doenst
et al36 is that an increased lactate production and release of
FFA on adrenergic stimulation results in increased availability of these substrates in the heart. The preference of the heart
for the oxidation of lactate and FFA may then overwhelm the
stimulatory effects of epinephrine on glucose metabolism,
resulting in a net decrease of glucose uptake.36
Although FFA oxidation is the major substrate for the heart
and provides the highest yield of ATP (130 ATP per mole
FFA versus 38 ATP per mole glucose), the metabolism of
FFA requires more oxygen than glucose. The ATP yield
for FFA per oxygen atom taken up is 2.83 compared with
glucose at 3.17.22 Therefore, myocardial FFA oxidation is
less energy-efficient than glucose oxidation given the need
for increased oxygen consumption for the same amount of
ATP produced. Using the calculated myocardial FFA and
glucose use rates in our patients, the amount of ATP produced
decreased by 40% after carvedilol treatment. This decrease
occurred despite the lack of a change in minute work,
suggesting less energy is needed to perform the same amount
of myocardial work after carvedilol treatment.
Estimated myocardial oxygen consumption related to FFA
use fell by 57% after carvedilol treatment. This finding is
consistent with previous studies demonstrating a significant
decrease in myocardial oxygen consumption and improvement in myocardial energy efficiency with ␤-adrenoreceptor
blockade.11,12 Although the mechanism for the improved
energy efficiency is proposed to be the result of a switch from
myocardial FFA oxidation to glucose oxidation,12 this was
not confirmed directly in our study.
The potential of ischemia and hibernation to alter myocardial metabolism was considered given the presence of underlying coronary artery disease in our patients. In the presence
of ischemia, myocardial FFA oxidation is known to be
suppressed and myocardial glucose oxidation is increased.30
It is unlikely that significant myocardial ischemia affected
our results given the high baseline myocardial FFA use and
significant decrease in FFA use after carvedilol treatment
seen in our patients. The effect of myocardial hibernation on
myocardial FFA oxidation has also been previously evaluated
with 18F-FTHA by Maki et al.39 They found no significant
difference in 18F-FTHA uptake in viable versus normal
2446
Circulation
May 22, 2001
myocardial segments, suggesting that the presence of myocardial hibernation is unlikely to have affected our results.
Study Limitations
A control group was not included in this study because of
overwhelming evidence supporting the use of ␤-blocker
therapy in patients with heart failure, thus making it unethical
to withhold this therapy from patients with heart failure.
Establishing a direct link between the changes in substrate
use and a change in myocardial energy efficiency is difficult.
Although factors other than a switch in myocardial substrate
use may affect energy efficiency in patients with heart failure,
the 57% reduction in myocardial FFA use seen in our study
almost certainly led to a significant reduction in energy
consumption by the heart.
Conclusions
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Our results demonstrate carvedilol can significantly lower
myocardial FFA use by 57% in patients with stable NYHA
functional class III heart failure. This change in myocardial
energetics could provide a potential mechanism for the
decreased myocardial oxygen consumption and improved
energy efficiency seen with ␤-adrenoreceptor blockade in the
treatment of heart failure.
Acknowledgments
Financial support for this research was provided by a Merit Review
Grant from the Medical Research Service of the Department of
Veterans Affairs and NIH grant M01 RR03186. We would like to
acknowledge Thankful Sanftleben for her assistance with manuscript
preparation. We would also like to thank Joni Hansen for her
valuable assistance with PET scan acquisition.
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Myocardial Free Fatty Acid and Glucose Use After Carvedilol Treatment in Patients With
Congestive Heart Failure
Thomas R. Wallhaus, Michael Taylor, Timothy R. DeGrado, Douglas C. Russell, Peter Stanko, Robert J.
Nickles and Charles K. Stone
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Circulation. 2001;103:2441-2446
doi: 10.1161/01.CIR.103.20.2441
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