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Articles in PresS. Am J Physiol Heart Circ Physiol (April 1, 2005). doi:10.1152/ajpheart.00150.2005
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Influence of Insulin and Free Fatty Acids on Contractile Function
in Patients with Chronically Stunned and Hibernating Myocardium
Henrik Wiggers1, Helene Nørrelund2, Søren Steen Nielsen3,
Niels H. Andersen2, Jens Erik Nielsen-Kudsk1, Jens S. Christiansen2, Torsten T. Nielsen1,
Niels Møller2, Hans Erik Bøtker1
1
2
Department of Cardiology, Skejby Hospital, Aarhus University Hospital
Department of Endocrinology and Metabolism, Aarhus Hospital, Aarhus University Hospital,
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Department of Nuclear Medicine, Skejby Hospital, Aarhus University Hospital, Aarhus,
Denmark
Address for correspondence: Henrik Wiggers, MD, PhD, Department of Cardiology, Skejby
Hospital, Aarhus University Hospital, DK-8200 Aarhus N, Denmark. Fax: (+45) 89496009;
Phone: (+45) 89496235; Email: [email protected]
Running head: Insulin, Free Fatty Acids and Chronic Ischemia
Copyright © 2005 by the American Physiological Society.
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Abstract
Objectives: To study whether modulation of myocardial substrate metabolism with insulin and
free fatty acids (FFA) affects contractile function of chronically stunned (CST) and hibernating
myocardium (HIB) at rest and after maximal exercise.
Background: It is unknown whether short-term modulation of substrate supply affects cardiac
performance in heart failure patients with chronic ischemic myocardium.
Methods: We studied 8 non-diabetic patients with EF 30%±4% (mean±SEM) and CST / HIB in
49%±6% of the left ventricle on 99mTechnetium-Sestamibi / 18F-flouro-deoxyglucose SPECT
(36%±6% CST and 13%±2% HIB). Each patient received a 3-hour infusion of 1) isotonic saline,
2) euglycemic insulin clamping (high insulin, FFA suppressed), and 3) somatostatin and heparin
(insulin suppressed, high FFA). Echocardiographic endpoints were global EF and regional
contractile function by tissue Doppler (maximum velocity Vmax and strain rate Cmax) at steady
state and after maximal exercise.
Results: EF was similar at baseline and steady state and increased after exercise to 36%±5%
(P<0.05). Baseline regional Vmax and Cmax were highest in control, intermediate in CST and HIB,
and lowest in infarct regions (P<0.05). Steady state EF, Vmax and Cmax were not affected by
metabolic modulation in any type of region. After maximal exercise contractile function
increased in control, CST, and HIB (P<0.05), but not in infarct regions. The exercise induced
contractile increments were unaffected by metabolic modulation.
Conclusions: Metabolic modulation does not influence contractile function in CST and HIB.
Chronic ischemic myocardium has preserved ability to adapt to extreme, short-term changes in
substrate supply at rest and after maximal exercise.
Key words: fatty acids, glucose, hibernation, insulin, myocardial stunning
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Metabolic intervention with insulin and glucose exerts beneficial effects on myocardial function
in acute ischemic states(5;7;9;26). The efficacy is based on the well-known preference of the
ischemic myocardium for glucose as the metabolic substrate for oxidative
phosphorylation(27;31;47). A similar preference characterizes the failing heart even in the
absence of ischemia(8). This feature is accompanied by a down regulation of cardiac metabolic
pathways controlling fatty acid oxidation(38) implicating that the failing heart reverts to fetal
phenotypes at molecular, cellular and metabolic levels(37) as demonstrated in viable,
dysfunctional myocardium(50). At the same time patients with advanced stages of heart failure
due to ischemic cardiomyopathy are characterized by whole-body insulin resistance(44) including
increased levels of circulating free fatty acids (FFAs), which may contribute to a suboptimal
substrate supply to the suffering myocardium. Some data suggest that whole-body insulin
resistance in heart failure is accompanied by myocardial insulin resistance(34) that may further
compromise myocardial glucose uptake. At the same time it has been reported that myocardial
insulin sensitivity is preserved to a degree that allows an ample insulin stimulated enhancement
of glucose uptake in reversibly dysfunctional myocardium in patients with ischemic
cardiomyopathy(31). Reversible myocardial dysfunction in ischemic cardiomyopathy is caused
by stunning and hibernation(35;50) but is unknown whether modulation of fuel substrate supply
in patients affects cardiac performance(23;31;33) and whether increased glucose supply and
decreased FFA supply improve cardiac function such that therapeutic strategies designed to
enhance myocardial glucose uptake could be rational goals. The main purpose of the present
study was to study whether modulation of myocardial substrate metabolism affects contractile
function of chronically stunned and hibernating myocardium at rest and after maximal exercise.
We selected patients with large regions of hibernating and stunned myocardium. The patients
were studied in the fasting state on three separate days and received saline infusion, insulinglucose infusion (high insulin and suppressed FFA), or somatostatin-heparin infusion (suppressed
insulin and high FFA). This approach means that the myocardium is exposed to variable degrees
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of glucose and FFA supply. Main outcome measures were 3-D global and tissue Doppler regional
left ventricular function at rest and after maximal exercise.
Materials and Methods
Patients. We included 8 patients with angiographically verified ischemic cardiomyopathy and
viable myocardium (chronically stunned and/or hibernating myocardium) in 25% of the left
ventricle on 99mTechnetium-Sestamibi single photon emission computed tomography (SPECT)
and 18F-flouro-deoxyglucose (FDG) positron emission tomography (PET). Patients were required
to have an ejection fraction (EF) 40%, be stable on medical treatment, and to be in New York
Heart Association (NYHA) class II or III. We excluded patients with diabetes, cardiac valve
disease, congenital heart disease, atrial fibrillation, bundle branch block, S-creatinine >200
µmol/l, hyperkalemia, or exercise limitation due to angina pectoris or non-cardiac causes.
Design. Prior to the experiments the patients underwent exercise testing to become familiarized
with the experimental setting. The patients were studied on their usual medication after an
overnight fast at 8 a.m. In a cross-over design with the patient blinded to the type of infusion
given, we studied the patients in random order on three separate days: 1) Infusion of isotonic
saline with an infusion rate of 1/3 of the expected/observed glucose infusion rate. 2) Euglycemic
insulin clamping at an insulin infusion rate of 60 mU/m2/min. Blood glucose levels were kept at
baseline levels by infusion of 20% glucose with 20 mmol KCl/l. 3) Infusion of somatostatin and
heparin. We infused saline at the same rate as expected/observed in the control arm. When
plasma glucose levels decreased below 4.5 mmol/l, we infused 20% glucose with 20 mmol KCl/l.
In this study arm the patients were electrocardiographically monitored. In all study arms, we
made baseline echocardiographic measurements after 1 hour of rest. Infusion was then started and
image acquisition was repeated during steady state 165 minutes later. The patients then
underwent a maximal bicycle exercise load and echocardiography was performed after peak
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exercise with the patient in the left supine position. The infusion was continued throughout this
period. The local ethics committee approved the study. Informed consent was obtained from all
patients.
Echocardiography. All echocardiographic examinations were performed by one observer on a
GE Vivid Five ultrasound scanner (GE Medical System, Horten, Norway) with a 2.5 MHz
transducer and stored on optical disk. Echopac analysis software (GE-Vingmed Ultrasound,
Horten, Norway) was used for analysis. Left ventricular volumes and EF were measured by
tracing the endocardial borders using a triplane method(1) as an average of 3-5 consecutive
heartbeats. Regional wall motion scoring was evaluated semi quantitatively using the 16-segment
model(42). We assessed left ventricular diastolic function from mitral inflow parameters(2).
Tissue Doppler imaging was done from the 3 apical standard views as previously described in our
laboratory(2). We recorded data with an average frame rate of 131±4 frames/second and
performed blinded analysis using Echopac analysis software. A sample region of 11 times 11
pixels was placed in the center of the basal and midventricular segments in the same distance
from the mitral ring on each recording. In apical segments we made measurements in the most
basal part. We measured peak systolic velocities Vmax and peak systolic strain rate Cmax during
ejection time in each of the 16 segments(2). In each segment we measured baseline Vmax1 and
Cmax1, the difference between steady state and baseline Vmax2 - Vmax1 and Cmax2 - Cmax1, and the
difference between maximal exercise and steady state Vmax3 - Vmax2, and Cmax3 - Cmax2.
Exercise. The patients underwent bicycle ergometry exercise in an upright position, using an
individualized ramp protocol according to the preliminary exercise test to ensure a test duration
of 7-10 minutes. The initial workload was increased every minute until exhaustion. Breath-bybreath gas exchange analysis was performed and VO2 max determined as the highest VO2
achieved during exercise (Jaeger Oxycon Delta, Erich Jaeger GmbH, Hoechberg, Germany).
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Myocardial SPECT. 99mTc-Sestamibi (700 MBq±10%) was injected after the patient had been
resting for 30 minutes and image acquisition was started 60 min after radioisotope injection.
SPECT acquisition was performed using a dual-headed rotating gamma camera (FORTE, ADAC,
Milpitas, CT, USA) with a high-resolution, parallel-holed collimator. Sixty-four projections of 25
seconds each were obtained over a non-circular 180° arc, extending from the 45° right anterior
oblique to the 45° left posterior oblique position. Attenuation correction was performed using two
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Ga line sources (Vantage ADAC, Milpitas, CT, USA)
FDG gamma camera PET. Patients were examined on a separate day and after 12 hours of
fasting. Injection of 125 MBq 18FFDG was given 2 hours after intake of 500 mg acipimox
(Olbetam®)(25)and 100 ml 50% glucose beverage. Image acquisition was performed on a dual
headed gamma camera with a 5/8" (15.9 mm) crystal and molecular coincidence registration
(FORTE, ADAC, Milpitas, CT, USA). Attenuation correction was performed with a 137Cs point
source.
Image analysis. We aligned the images with the 16 echocardiographic regions and scored the
regional myocardial tracer uptake of Sestamibi and FDG semi quantitatively: 0 normal, 1 mildly
reduced, 2 moderately reduced, 3 severely reduced, and 4 absent uptake(39;41). Regions with
normal wall motion score were classified as control. Dysfunctional segments were defined as
chronically stunned (Sestamibi 1, FDG 1), hibernating (Sestamibi=2 and FDG=0 or
Sestamibi=3 and FDG=1) or infarcted (Sestamibi 2, FDG 2)(41).
P-glucose, S-insulin, S-FFA, P- triglycerides, P-metabolites, P-catecholamines. Plasma glucose
was measured in duplicate immediately after sampling on a glucose analyzer (Beckman Coulter,
Inc., Palo Alto, CA). We determined the other substances as previously described(12;20;32).
Statistical methods. We used the statistical software program SPSS 10.0 (SPSS, Cary, NC) for
statistical analyses. The Kolmogorov-Smirnov test was used to test whether variables were
normally distributed, if not we transformed data logarithmically. We used three-way ANOVA
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and Tukey’s Honestly Significant Difference test for post hoc analysis. Data are expressed as
mean±SEM and P-values <0.05 considered significant.
Results
Patient characteristics are shown in Table 1. All patients were males with a mean age of 65±3
years. Mean EF was 30%±4% and 7/8 patients had a previous myocardial infarct. Three-vessel
disease was found in 7 patients, 1 had 1-vessel disease. Five patients were in NYHA class II, 3 in
NYHA class III. One patient was in CCS class II, the remaining 7 were in CCS class I. ACEinhibitors, diuretics, and statins were taken by all patients, 6/8 received beta-blockers, 4/8
spironolactones, 1/8 digoxin. Mean HgbA1c was 5.9%±0.1% and LDL-cholesterol was 2.3±0.2
mmol/l (=90±8 mg/dL).
Viable and scar regions. The mean number of SPECT viable regions per patient was 7.8±1.0
(5.8±1.0 chronically stunned and 2.0±0.3 hibernating regions per patient). The number of infarct
regions was 5.5±1.7 per patient. Wall motion score was similar in chronically stunned and
hibernating regions (2.1±0.1 vs. 2.2±0.1; P=0.71) and higher in infarct regions 2.6±0.1 (P<0.01
vs. other regions). Six segments could not be visualized echocardiographically, and in the final
analysis 122 segments were included: 22 control, 44 chronically stunned, 14 hibernating, and 42
infarct regions.
P-insulin, S-FFA, and P-glucose in the three study arms are shown in Figure 1A-1C. S-insulin
and S-FFA levels differed between the three study arms (P<0.001). Levels remained stable during
steady state and after exercise apart from S-FFA in the somatostatin-heparin arm where levels
decreased after exercise (P<0.02). P-glucose levels were higher in the somatostatin-heparin arm
than during saline-infusion (P<0.01), but did not differ from insulin clamp (P=0.25). None of the
patients had any episodes of hypoglycemia. In all groups, levels remained stable during steady
state. During somatostatin-heparin infusion, P-glucose levels were 0.6 mmol/l and 0.4 mmol/l
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higher at steady state than in the saline and insulin arm, respectively (P<0.05). At post-exercise,
P-glucose levels were higher in the somatostatin-heparin arm than in the insulin arm (P<0.05).
Blood pressure and heart rate remained stable during the resting study period and did not differ
between the study arms (Table 2).
P-potassium, P-triglycerides, P-lactate, and P-catecholamines are shown in Table 2. Lactate
levels increased 4-fold in all groups after maximal exercise. After maximal exercise
norepinephrine levels increased 2-fold in all groups whereas epinephrine levels remained
constant.
Exercise data. There were no differences between the control, insulin clamp, and somatostatinheparin arm with regard to exercise time (7.8±0.4, 7.7±0.5, and 7.6 minutes±0.3 minutes,
P=0.21), maximal work load (108±11, 107±11, and 107 W±14 W, P=0.42), peak heart rate
(119±6, 115±9, and 120 beats/min±9 beats/min, P=0.23), peak systolic blood pressure (140±10,
138±9, and 131 mmHg±11 mmHg, P=0.10), or VO2 max (16.6±1.2, 16.4±1.0, and 16.6
ml/kg/min±1.4 ml/kg/min, P=0.47).
Global left ventricular function (Figure 2) did not differ between the control, insulin clamp, and
somatostatin-heparin arm at baseline (P=0.83). EF did not differ between baseline and steady
state (P=0.41), but increased significantly at post-stress (P=0.04 vs. baseline and steady state).
Metabolic modulation did not induce any significant differences in EF at steady state or poststress (P=0.67).
Regional myocardial contractile function. (Figure 3A-3D and Figure 4A-4D). Vmax1 and Cmax1
(i.e. at baseline) was similar the three study arms in all categories of regions. Vmax1 and Cmax1 were
highest in control regions (P<0.05 vs. other categories), lowest in infarct regions (P<0.05 vs.
other categories), and intermediate and at the same level in chronically stunned and hibernating
regions. In regions classified as chronically stunned and hibernating there was a correlation
between semi quantitative Sestamibi uptake and Vmax (r=0.18, P<0.01) and Cmax (r=0.16, P<0.01).
Metabolic modulation did not induce any significant changes at steady state (Vmax2 - Vmax1 and
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Cmax2 - Cmax1) in any of the different categories of regions. Vmax increased significantly after
maximal exercise in control, chronically stunned, and hibernating regions (P<0.001), whereas this
was not observed in infarct regions (P=0.10). Cmax increased after exercise in control and
chronically stunned regions (P<0.05), but was unaltered in hibernating (P=0.11) and infarct
regions (P=0.31). The response to maximal exercise (Vmax3 - Vmax2 and Cmax3 - Cmax2) was
unaffected by metabolic modulation in all types of regions. The echocardiographic methods had a
power to detect a significant difference between Vmax2 and Vmax1 of 0.41 cm/s in control regions,
0.20 cm/s in chronically stunned regions, 0.40 cm/s in hibernating regions, and 0.19 cm/s in
infarct regions. For Vmax3 and Vmax2 the figures were 0.41, 0.31, 0.59, and 0.22 cm/s, respectively.
For Cmax2 and Cmax1 as well as Cmax3 and Cmax2 tissue Doppler echocardiography had a power to
detect a significant difference of 0.20 and 0.21 s-1 in control regions, 0.11 and 0.14 s-1 in
chronically stunned regions, 0.14 and 0.24 s-1 in hibernating regions, and 0.11 and 0.11 s-1 in
infarct regions.
Diastolic left ventricular function (Table 2). Metabolic intervention did not affect peak E-wave
(P=0.19), peak A-wave (P=0.17), E/A ratio (P=0.24), E-deceleration time (P=0.37), or Vp/dt
(P=0.51). There were no changes in any of these indices over time.
Discussion
The main finding of the present study is that acute modulation of circulating insulin and FFA
levels does not influence myocardial contractile function in patients with chronic heart failure and
large regions of dysfunctional, viable myocardium. These findings were unexpected because
interventions that switch energy substrate preference and improve coupling between glycolysis
and glucose oxidation are generally considered beneficial in the failing heart irrespective of
whether ischemia is the underlying mechanism. However, our findings indicate that chronically
stunned and hibernating myocardium have preserved ability to adapt to extreme, short-term
changes in myocardial substrate supply at rest and after maximal exercise.
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Patients, design, and methods. Although it has previously been demonstrated that wall motion
may not improve with insulin-infusion in patients with ischemic heart disease without heart
failure(31), the effects of metabolic modulation on resting contractile function in patients with
left ventricular dysfunction are not consistent(23;31;33). A plausible explanation is heterogeneity
of the patient populations studied, i.e. inclusion of patients with relatively preserved EF(23;31),
diabetes mellitus(23), and dilated cardiomyopathy(33). Furthermore, omission of viability
testing(33), episodes of hypoglycemia(23), lack of a control study arm(23) and insensitive
measures of contractile function(31;33) may contribute to the variable results. In the present
study, we included non-diabetic patients with severe ischemic cardiomyopathy who were
carefully characterized with respect to myocardial viability. We selected patients with large
regions of viable, dysfunctional myocardium and with NYHA class II or III heart failure. We
avoided hypoglycemia and included a control arm in our study design to avoid any bias by
changes in preload and of the resting state on our outcome measures. Finally, we used sensitive
echocardiographic techniques to detect changes in myocardial contractile function.
Modulation of myocardial substrate supply by glucose-insulin infusion and contractile
function in chronically stunned and hibernating myocardium. Insulin decreases circulating
levels of FFAs through inhibition of lipolysis and increases myocardial glucose uptake and
oxidation because of translocation of insulin sensitive glucose transporter proteins (GLUT4) to
the plasma membrane and because the low levels of FFAs yield a minor contribution to oxidation
as compared with glucose(24;36;57). Although insulin may improve contractile function during
acute ischemia independently of its effect on substrate supply(22), improvement of myocardial
contractile function or outcome observed in experimental(9;27) and clinical settings of acute
ischemia(7) is associated with decreased FFA oxidation and increased glucose uptake. These
beneficial effects of increased glucose uptake in acute ischemic states demonstrate a coupling
between glucose uptake and myocardial contractile function. This is mediated by increased
glycolytic ATP production(3;9) which improves sarcoplasmatic reticulum Ca2+ transport(56) and
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protects ion pumps(10) and by mitochondrial ATP-production from glucose oxidation which
preserves a favorable myocytic energetic profile(5). We found that in chronically stunned and
hibernating myocardium contractile function was unaffected by infusion of insulin at a rate
known to increase myocardial glucose uptake(4;17;30;31;54). This is consistent with our
previous findings that dysfunction is not associated with reduced ATP levels and lactate content
is negligible(55) and that oxidative metabolism is preserved or only slightly reduced(18;21). Our
results therefore support that ongoing biochemical signs of myocardial ischemia is an infrequent
phenomenon in chronically stunned and hibernating myocardium. The present study shows that
in contrast to acute ischemic states, but similar to what is observed in the normal heart(40)
contractile function of chronically stunned and hibernating is not improved by an acute increase
in glucose uptake.
Myocardial lipotoxicity in patients with ischemic cardiomyopathy? High FFA levels exert
negative inotropic effects in experimental models of acute myocardial ischemia(9;27) and insulin
resistance(58) and reduces the ischemic threshold in patients with angina pectoris(16). FFA may
compromise contractile function because loss of coupling between FFA uptake and oxidation
leads to intracellular accumulation of nonoxidized fatty acid derivatives(58). The effects of
elevated circulating FFA levels on contractile function in patients with stable chronic heart failure
and viable, dysfunctional myocardium are unknown. We hypothesized that acute lipotoxicity
could be induced or chronic lipotoxicity unmasked during massive FFA exposure. Pancreatic
insulin release was completely suppressed by somatostatin and heparin was infused to mobilize
lipoprotein lipase and achieve very high FFA levels. Myocardial glucose uptake measured by
quantitative PET decreases from 25 µmol/100 g/min in the fasting state to below 2 µmol/100
g/min during somatostatin-heparin infusion(4) indicating a major reliance on FFA uptake and
oxidation for energy generation during such pronounced FFA exposure. We observed no
deterioration of cardiac contractile function in chronically stunned, hibernating, or control
regions. Our results show that chronically stunned and hibernating regions of non-diabetic
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patients with ischemic cardiomyopathy can resist the potential lipotoxic effects induced by a 3hour period of very high FFA exposure.
Preserved capacity of viable, dysfunctional myocardium to adapt to changes in myocardial
substrate supply at rest and during exercise. A global preference of glucose as the substrate for
energy generation accompanied by a downregulation of FFA uptake and metabolism is observed
in patients with ischemic heart disease(47;48) and heart failure(8;37;38). Myocardial ischemia is
observed in human chronically stunned and hibernating myocardium during episodes of
stress(50;53) but it is uncertain whether substrate metabolism is different from control regions at
rest and during submaximal workloads(17;18;21;28;30;31;54). Whereas the normal human heart
is able to adapt to differences in substrate supply(45), chronically stunned and hibernating
myocardium have been proposed to be dependent on high rates of anaerobic glycolysis as an
adaptive metabolic mechanism to preserve function and to avoid cellular degeneration during
superimposed stress(11;51). We found that viable, dysfunctional myocardium could increase
contractile function after maximal exercise similar to control regions despite profound changes in
substrate levels. In a chronic animal model, hibernating myocardium retained the ability to
increase function during stress without any metabolic evidence of ischemia suggesting that
adaptive mechanisms prevent the development of ischemia during submaximal workloads(14).
The present study shows that chronically stunned and hibernating myocardium possess a
preserved ability to adapt to differences in the metabolic environment and to withstand extreme
short-term changes in substrate supply even at increased workloads without any critical reliance
on high glucose uptake rates. Whether this ability represents preserved normal metabolism or is
part of a protective and adaptive metabolic response remains unknown.
Clinical implications. Our results indicate that short-term interventions specifically targeting
intermediary metabolism is without any clinically important improvement of contractile function
in patients with chronically stunned and hibernating myocardium. The efficacy of glucose-insulin
infusion observed in some(7;26;29) but not all(49) studies of acute ischemic and postoperative
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states may in part be related to an anti-inflammatory rather than a metabolic effect(6). It remains
to be studied whether long-term metabolic intervention is beneficial and whether patients with
diabetes or acute decompensated heart failure can benefit from such treatment.
The subdivision of viable heart muscle into chronically stunned and hibernating
myocardium may be of minor importance when deciding whether to revascularize heart failure
patients or not and these two classifications share a number of pathophysiological and clinical
aspects(35;50). However, there are data to suggest differences between myocardium classified as
chronically stunned and hibernating myocardium by perfusion/metabolic imaging. Haas et al.
studied the time course of improvement of dysfunctional myocardium after revascularization
(19). Dysfunctional regions with normal perfusion and metabolism (i.e. “stunning”) differed from
regions with reduced perfusion and preserved metabolism (“mismatch regions”) with respect to
the degree and time course of functional recovery after coronary artery bypass surgery. Schwartz
et al. studied biopsies from dysfunctional myocardium in patients with variable duration of
chronic ischemia (43). Morphologic tissue analysis identified different histological changes
between dysfunctional segments with preserved perfusion and FDG uptake (“stunning”) and
mismatch (“hibernation”) on FDG PET/ Sestamibi SPECT. A number of experimental studies by
Fallavollita and Canty and co-workers(13;15;46) have supported that chronically stunned
myocardium over time progresses into a state of hibernation. Together these observations suggest
that some differences exist between myocardium classified as chronically stunned and
hibernating myocardium. This led us to sub classify the viable, dysfunctional regions although
this distinction from a clinical point of view may be of minor importance.
Study limitations. We did not study the relationship between oxygen consumption and left
ventricular performance i.e. myocardial efficiency that theoretically could improve although
function was unchanged. Myocardial substrate uptake was not quantified during the different
metabolic interventions of the present study. Previous studies using PET and invasive techniques
have documented that modulation of myocardial FFA and glucose uptake can be achieved by the
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interventions used in our design(4;17;30;31;54). Anticongestive medication affects myocardial
substrate metabolism(52) and could bias metabolic interventions. We found it unethical to
withdraw well-documented medical therapy in these patients and secured that interventions were
performed on top of optimized medication that remained constant throughout the study period.
We cannot exclude that higher insulin infusion rates could have additional beneficial effects.
However, the insulin infusion rate chosen in the present study secured an insulin infusion rate
exceeding 6 U per hour, which is comparable or even higher than most previous clinical studies
documenting a beneficial effect in postoperative or in acute ischemic states (7;26;29;31;33). We
documented that circulating FFAs were totally suppressed and that we achieved plasma insulin
levels in the supraphysiological range.
Recovery of function after revascularization in chronically stunned and hibernating
myocardium was not confirmed, and it can be argued that the absence of contractile response to
metabolic modulation was due to degeneration of the sarcomere(11;50;51) making the myocyte
unable to respond to an improvement in the metabolic status of the cell. However, function
improved during stress in these regions demonstrating a contractile reserve.
In the present study, we scored Sestamibi and FDG images semi quantitatively. We
have previously validated Sestamibi SPECT without attenuation correction against 13N-ammonia
PET and obtained different results in only 8% of segments(39). An even better correlation would
be expected in the present study between perfusion measured by Sestamibi SPECT and the “gold
standard” 13N-ammonia PET becaused we performed attenuation correction of Sestamibi uptake.
We therefore believe, that the estimates of perfusion and viability status used in the present study
are valid. It is not likely that differences in wall thickening contributed to the differences in tracer
uptake between chronically stunned and hibernating myocardium since wall motion score was
similar in the two types of regions.
The possibility of a Type 2 statistical error must be considered. We used a crossover design and sensitive, reproducible(2) echocardiograhic techniques with paired measurements
15
of regional contractile function. This approach eliminated interpatient and minimized intrapatient
variation and resulted in a low variability of Vmax2 - Vmax1, Cmax2 - Cmax1, Vmax3 - Vmax2, and Cmax3 Cmax2 (Figure 3 and 4). It is possible that the echocardiographic techniques used to assess regional
function were insensitive to detect subtle changes in contractile function. However, our data
consistently demonstrated that global and measures of regional contractility as well as
hemodynamics were unaffected by modulation of substrate supply supporting that short-term
metabolic modulation is without any clinically important effect.
Conclusions. Contractile dysfunction of chronically stunned and hibernating myocardium in nondiabetic patients with chronic heart failure remains unchanged during extreme acute changes in
FFA and insulin levels at rest and during exercise. These regions have preserved ability to adapt
to short-term changes in substrate supply.
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Acknowledgements
We thank Lone Svendsen and Elsebeth Hornemann for skillful technical assistance.
Grants
The Danish Heart Foundation (grant no. 03-1-3-70-22075), The Danish Health Science Research
Council (Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration),
and Desirée and Niels Yde’s Foundation, Copenhangen, Denmark.
Disclosures
None of the authors have any conflicts of interest.
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FIGURE 1
28
FIGURE 2
29
FIGURE 3
30
FIGURE 4
31
Figure legends
Figure 1
Levels of S-insulin, S-FFA, and P-glucose in the three study arms (saline, euglycemic insulin
clamp, somatostatin-heparin). * P<0.001 vs. other study arms; † P<0.02 vs. time 0 – 180 minutes;
‡ P<0.01 (somatostatin-heparin vs. saline). § P<0.05 vs. 0 – 180 minutes.
Figure 2A – 2C
Ejection fraction in the three study arms (saline, euglycemic insulin clamp, somatostatin-heparin)
at baseline, steady state, and after maximal exercise. * P<0.05 vs. other time points. There were
no differences between the 3 study arms (P=0.67).
Figure 3A – 3D
* P<0.001 vs. steady-state. Regional peak systolic velocity during ejection time at baseline Vmax1,
the change in Vmax between baseline and steady state (Vmax2 - Vmax1), and between steady state
and maximal exercise (Vmax3 - Vmax2) during infusion of saline (open circles), euglycemic insulin
clamp (filled circles), and somatostatin-heparin (squares). Data are shown for control, chronically
stunned, hibernating, and infarct regions. Vmax was highest in control regions (P<0.05 vs. other
categories), lowest in infarct regions (P<0.05 vs. other categories), and intermediate and at the
same level in chronically stunned and hibernating regions. After maximal exercise Vmax increased
significantly in control, chronically stunned, and hibernating regions (P<0.001), whereas no
change was observed in infarct regions. Metabolic modulation did not affect Vmax2 - Vmax1 and
Vmax3 - Vmax2 in any type of region.
32
Figure 4A – 4D
* P<0.05 vs. steady state. Regional peak systolic strain rate during ejection time, Cmax. Please,
refer to legends in Figure 3A-3D. Cmax1 was highest in control regions (P<0.05 vs. other
categories), lowest in infarct regions (P<0.05 vs. other regions), and intermediate and at the same
level in chronically stunned and hibernating regions. After maximal exercise Cmax increased
significantly in control and chronically stunned regions (P<0.05), whereas no change was
observed in hibernating and infarct regions. Metabolic modulation did not affect Cmax 2 - Cmax 1 and
Cmax 3 - Cmax 2 in any type of region.
33
Table 1. Patient characteristics.
Extent of coronary artery
disease (% diameter
stenosis)
LAD1 100%, Cx diffuse,
severe CAD, RCA2 100%
EF (%)
End diastolic
volume (ml)
Viable regions
23
355
3 CST/ 2 HIB
3/1
Diffuse, severe CAD. LAD
90% x 3, Cx2 100%, OM2
100%, RCA2 100%
24
174
4 CST/ 0 HIB
Q-waves: V3-V5
ST : -
3/1
LAD2 100%, Cx2 80%,
RCA1 100%
16
225
3 CST/ 3 HIB
Yes
Q-waves: ST : -
2/1
LAD1 100%, CX1 95%,
OM1 100%, RCA2 100%
25
202
10 CST/ 2 HIB
65 / Male
Yes
Q-waves: ST : -
3/1
LAD and Cx: multiple
severe stenoses, RCA 100%
and with diffuse CAD
38
94
4 CST/ 2 HIB
6
52 / Male
No
Q-waves: ST : -
2/1
RCA1 100%
40
113
7 CST/ 3 HIB
7
58 / Male
Yes
Q-waves: AVL,V4
ST : I, II, AVF
2/2
LAD2 100%, IM 100%, CX
diffuse CAD, RCA2 90%
31
170
9 CST/ 2 HIB
Patient
Number
Age/sex
Previous
AMI
ECG
NYHA-class/
CCS-class/
1
66 / Male
Yes
Q-waves: V1-V4
ST : II, II, AVF
2/2
2
67 / Male
Yes
Q-waves: V1-V6,
III, AVF
ST : -
3
73 / Male
Yes
4
77 / Male
5
LAD multiple severe
39
203
6 CST/ 2 HIB
stenoses, OM1 100%, RCA2
100%
LAD1: Segment 1 of the left anterior descending coronary artery. CAD: coronary artery disease. CST: Chronically stunned. HIB: Hibernating.
8
65 / Male
Yes
Q-waves: ST : I, V5-V6
2/1
34
Table 2: Hemodynamics, diastolic function, potassium, triglycerides, lactate, catecholamines.
Saline
Baseline
Steady state
Insulin clamp
Exercise
Baseline
Steady state
Somatostatin-heparin
Exercise
Baseline
Steady
Exercise
state
Systolic BP (mmHg)
111±4
108±5
140±10
111±3
108±4
138±9
110±4
107±7
131±11
Diastolic BP (mmHg)
65±3
66±4
-
67±4
64±3
-
70±4
68±4
-
Heart rate (min-1)
59±4
59±4
119±6
58±4
57±4
115±9
59±4
57±4
120±9
E-wave (m/s)
0.63±0.05
0.63±0.04
-
0.60±0.05
0.57±0.04
-
0.60±0.04
0.62±0.04
-
A-wave (m/s)
0.57±0.09
0.60±0.08
-
0.57±0.07
0.57±0.07
-
0.57±0.10
0.61±0.10
-
E/A ratio
1.57±0.47
1.37±0.39
-
1.28±0.31
1.29 ±0.38
-
1.44±0.41
1.33±0.37
-
E-deceleration (ms)
228±22
215±27
-
215±16
238±20
-
202±17
219±20
-
Vp/dt (cm/s)
27.7±3.3
28.2±3.1
-
28.1±5.2
32.6±3.5
-
29.7±7.4
35.0±7.3
-
P-K+ (mmol/l)
3.9±0.2†
3.8±0.2†
-
3.7±0.2†
3.5±0.2*†
-
3.9±0.2†
4.3±0.2*†
-
1.00±0.06†
1.10±0.08†
1.20±0.1†# 0.88±0.03
0.65±0.06‡
0.74±0.07§
0.91±0.05
0.72±0.02‡
0.79±0.04§
P-Lactate (pg/ml)
595±37
555±32
3000±480# 568±27†
829±65*†
3015±338†#
686±36
599±20*
2421±253#
P-Norepinephrine (pg/ml)
457±70
350±48
803±111#
438±101
449±35
771±198#
528±147
385±49
867±193#
P-Epinephrine (pg/ml)
74±10
83±12
87±14
81±10
74±15
82±14
77±15
63±13
87±19
Diastolic function
P-Triglycerides (mmol/l)
Mean±SEM. BP: blood pressure.
ANOVA: * P<0.05 vs. baseline. † P<0.01 vs. other study arms. ‡ P<0.001 vs. baseline. #P<0.001 vs. other time points. § P<0.01 vs. baseline.