(Circulation. 1996;93:737-744.)
© 1996 American Heart Association, Inc.
Articles |
Pathophysiology of Chronic Left Ventricular Dysfunction
New Insights From the Measurement of Absolute Myocardial Blood Flow and Glucose Utilization
From the MRC Clinical Sciences Centre and Royal Postgraduate Medical School, Hammersmith Hospital (N.V.S.M., B.E.K., A.A.L., P.G.C.), and the Institute of Nuclear Medicine, UCL Medical School (N.V.S.M., D.C.C., P.J.E.), London, United Kingdom.
Correspondence to Paolo G. Camici, MD, Cyclotron Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Rd, London W12 ONN, UK.
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Abstract |
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Background Chronically dysfunctional myocardium may improve after coronary revascularization. This condition was thought to be due to a chronically reduced myocardial blood flow (MBF). Recently, however, it has been shown that in patients without previous infarction but with chronic left ventricular dysfunction, baseline MBF was normal.
Methods and Results To study the pathophysiology of chronic left ventricular dysfunction in patients with previous infarction, regional MBF (milliliter per minute per gram of water-perfusable tissue) and glucose utilization (MRG; micromoles per minute per gram) during hyperinsulinemic euglycemic clamp were measured with positron emission tomography in 30 patients before bypass. At baseline, 133 myocardial segments were normal, and 107 were dysfunctional. After revascularization, 59 of 107 segments improved, while 48 of 107 were unchanged. MBF was 0.92±0.25 mL · min-1 · g-1 in normal segments, 0.87±0.31 mL · min-1 · g-1 in improved segments (P=NS versus normal), and 0.82±0.40 mL · min-1 · g-1 in unchanged segments (P<.05 versus normal). In 90% of the dysfunctional segments, MBF was >0.42 mL · min-1 · g-1, a cutoff value corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71±0.14 µmol · min-1 · g-1 in 9 age-matched normal subjects, 0.45±0.19 µmol · min-1 · g-1 (P<.01) in normal segments, 0.44±0.14 µmol · min-1 · g-1 in improved segments (P=NS versus normal), and 0.34±0.17 µmol · min-1 · g-1 in unchanged segments (P<.01 versus normal and improved).
Conclusions The results suggest that resting MBF measured with 15O-labeled water in chronically dysfunctional segments is not reduced and that the myocardium of these patients is less sensitive to insulin than that of normal subjects.
Key Words: coronary disease • ischemia • metabolism • insulin
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Introduction |
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It is now well established that myocardial regions with chronic wall motion abnormalities subtended by stenotic arteries may have improved function after coronary revascularization. To describe this condition, the term "hibernating myocardium" was introduced by Rahimtoola.1 On the basis of a retrospective analysis of three studies, which included a large number of patients with coronary artery disease randomized to receive either medical or surgical treatment, he concluded that "there is a prolonged subacute or chronic stage of myocardial ischemia that is frequently not accompanied by pain and in which myocardial contractility and metabolism are reduced to match the reduced blood supply."1
This hypothesis was challenged recently by Vanoverschelde et al,2 who demonstrated that baseline MBF was normal in chronically dysfunctional myocardium subtended by occluded coronary arteries in patients with angina but without previous infarction. These authors suggested that repeated episodes of ischemia rather than chronic hypoperfusion might form the basis of chronic LV dysfunction in these patients.
In most cases, however, chronic myocardial dysfunction is detected in patients with previous infarction. In these patients, wall motion abnormalities may be the result of permanent anatomic damage and/or a state of hibernation. It has been demonstrated that the simultaneous assessment of myocardial blood flow and metabolism with PET allows differentiation between scarred and viable myocardium in patients with chronic LV dysfunction who are potential candidates for coronary revascularization.3 4 5 6 In this context, however, PET has been used primarily to provide qualitative or semiquantitative information rather than to exploit its capability to give absolute measurements. In addition, no effort has been made to standardize the dietary state of patients undergoing the PET studies, thereby precluding a reliable quantification of the metabolic data.7 The latter point is particularly relevant given the high prevalence of insulin resistance among patients with coronary artery disease.
The aim of the present study was to investigate the pathophysiology of chronic LV dysfunction in patients with previous infarction before coronary artery bypass graft. With PET, absolute regional MBF and MRG during hyperinsulinemic euglycemic clamp8 were measured.
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Methods |
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Study Population
Patients
The patient population consisted of 30 patients (2 women, 28 men; mean [±SD] age, 56±11 years; range, 34 to 72 years) with coronary artery disease and at least one chronically dysfunctional LV region subtended by a diseased coronary artery amenable to revascularization (Table 1
). All patients had
suffered a previous myocardial
infarction at least 6 months before the study; 5 patients were
diabetic, and 4 had arterial hypertension.
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Normal Control
Subjects
A group of 25 normal volunteers (9 women, 16 men; mean age,
56±12 years; range, 33 to 77 years; P=NS versus
patients)
served as control subjects for the MBF measurements. A second group of
9 normal volunteers (all men; mean age, 47±7 years; range, 31 to 56
years; P=NS versus patients) served as control subjects for
measurement of the myocardial MRG during
hyperinsulinemic euglycemic clamp. The
normal volunteers were selected on the basis of their clinical
histories and physical examinations, which indicated a low risk of
coronary artery disease. All had normal resting ECGs and
negative exercise tests in response to a high workload.
Study Protocol
Coronary Arteriography
Selective
arteriography of the right and left coronary
arteries in multiple views was performed in all patients by use of the
Judkins technique.9 The percent reduction of the internal
luminal diameter in the projection with maximal severity was
assessed visually by one of the investigators (P.G.C.).
Coronary Bypass Graft
All patients except 1 were
operated on by one of the
investigators (B.E.K.) using St Thomas' crystalloid cardioplegia
supplemented with iced topical for myocardial protection. The median
number of bypass grafts was four per patient; all but 1 received a left
internal mammary artery graft to the left anterior descending
coronary artery.
Radionuclide Ventriculography
All
patients underwent radionuclide
ventriculography10 before and 4 to 6 months after
coronary bypass. Briefly, after red blood cells had been
labeled in vivo with 740 MBq of technetium-99m sodium
pertechnetate, the intracardiac blood pool was imaged with a gamma
camera (GE 400 XCT) equipped with a low-energy all-purpose
collimator and interfaced with a dedicated computer system (S3000).
Data for each cardiac cycle, synchronized to the R wave on the ECG,
were divided into 21 frames. Six million counts per view were acquired.
Planar blood pool imaging was performed in two projections: the
left anterior oblique projection (best septal separation) with a
20° caudal tilt and the left posterior oblique
projection.11 LV ejection fraction was obtained from
the left anterior oblique projection. Regional wall motion was
assessed qualitatively from an endless-loop cine format by two
observers (N.V.S.M. and D.C.C.) who were unaware of the patient's
diagnosis. The wall motion was graded as 0 (normal), 1 (hypokinetic), 2
(akinetic), or 3 (dyskinetic). The regional wall motion score was
calculated by adding the values of all segments.
Hypersinulinemic Euglycemic Clamp
Before PET
scanning, which was carried out in all patients
between 11 AM and 1 PM after a light breakfast
with the patient lying on the scanner bed, a 20-gauge polyethylene
cannula was inserted in a superficial forearm vein for infusion of
glucose and insulin as described by De Fronzo et al.8 A
second cannula was inserted retrogradely into a superficial vein of the
wrist or hand that had been arterialized with a
commercially available heating pad set at 50°C. The degree of
arterialization was checked by measurement of respiratory
gases on a blood sample drawn after a 30-minute heating period. At time
zero, the insulin infusion was started. Insulin was given at four times
the final constant rate (calculated according to De Fronzo et
al8 ) for the first 4 minutes, then at two times the final
constant rate for the following 3 minutes, and then at a constant rate
for the remainder of the study. At 4 minutes, exogenous glucose
infusion was started at an initial rate of 1.5
mg · min-1 · kg-1
body wt. The blood glucose concentration from the
arterialized vein was measured at baseline (>30 minutes
after the insertion of the cannula) and every 5 minutes during the
clamp. The glucose infusion rate was adjusted according to the change
in plasma glucose over the preceding 5 minutes. Samples for insulin
assay were taken from the arterialized line immediately
before insulin infusion was begun and 60 minutes into the clamp.
Positron Emission Tomography
The PET study for the
measurement of MBF and MRG was carried out
within a week of radionuclide ventriculography. All PET scans were
performed with an ECAT 931-08/12 scanner (CTI Inc), which consisted of
eight rings of bismuth germanate crystal detectors. This scanner
enables the acquisition of 15 planes of data over a 10.5-cm axial field
of view, thus allowing the whole heart to be imaged. All emission and
transmission sinograms were reconstructed with a Hanning filter with a
cutoff frequency of 0.5 maximum. This resulted in a spatial resolution
of 8.4-mm FWHM for the emission and 7.7-mm FWHM for the transmission
data at the center of the field of view, with a slice thickness of
6.6-mm FWHM.12 All subjects lay supine on the scanner bed.
The optimal imaging position was determined by use of a 5-minute
rectilinear scan after exposure of the external 68Ge ring
source. A 20-minute transmission scan was then performed. These data
were used to correct subsequent emission scans for tissue attenuation
of the annihilation gamma photons.
After the transmission scan, the blood pool was imaged by inhalation of tracer amounts of C15O, which labels erythrocytes through the formation of carboxyhemoglobin. C15O was administered for 4 minutes at a concentration of 3 MBq/mL and a flow rate of 500 mL/min. A 6-minute single-frame emission scan was initiated 1 minute after the end of C15O inhalation to allow equilibration.13 Venous blood samples were taken every minute during the scan, and the C15O concentration in whole blood was measured with an NaI well counter cross-calibrated with the scanner.
After a 15-minute period for decay of 15O radioactivity to background levels, MBF was measured with inhaled C15O2, which is rapidly converted to H215O by carbonic anhydrase in the lungs.13 C15O2 was inhaled for 3.5 minutes (4 MBq/mL at 500 mL/min). A 25-frame dynamic PET scan (frame durations, 1x30 [background], 6x5, 6x10, 6x20, and 6x30 seconds) covering a period of 7 minutes was started 30 seconds before C15O2 inhalation.
MRG during hyperinsulinemic euglycemic clamp was measured with the glucose analogue 18FDG. 18FDG (185 MBq) was infused intravenously over 2 minutes with a pump beginning 30 seconds after the beginning of the scan. A 36-frame dynamic PET scan with progressive increases in frame duration (1x30 [background], 12x10, 3x20, 4x30, 5x60, 4x150, 5x300, and 2x600 seconds) was performed over a total period of 65 minutes. Arterialized whole blood was withdrawn continuously at 5 mL/min for the first 10 minutes and 2.5 mL/min thereafter, and an on-line detection system, cross-calibrated against the PET scanner, was used to measure radioactivity in blood as described previously.14 At set times (5, 10, 20, 45, and 60 minutes after the start of the 18FDG infusion), continuous blood withdrawal was interrupted briefly for the collection of blood samples, which were used to estimate plasma-to-whole-blood ratios of radioactivity. After each sample, the line was flushed with heparinized saline.
The study protocol was approved by the Research Ethics Committee of Hammersmith Hospital, and radiation exposure was licensed by the UK Administration of Radioactive Substances Advisory Committee. All patients gave written informed consent before the study.
Data Analysis
PET Data Analysis
All sinograms
were corrected for tissue attenuation and
reconstructed on a MicroVax II computer (Digital Equipment Corp) with
dedicated array processors and standard reconstruction algorithms.
Images were transferred to SPARC 2 workstations (Sun Mycrosystems) for
further analysis. Image manipulation and data handling were
performed with the ANALYZE (version 3.0, Biodynamics Research Unit,
Mayo Foundation)15 and MATLAB (The MathWorks Inc) software
packages. All images were resliced in the short-axis view.
Initially, a myocardial blood volume image was generated by dividing the C15O image by the average concentration of the blood samples on a voxel-by-voxel basis and the density of whole blood (1.06 g/mL). Appropriate corrections for decay were applied to both the C15O image and the blood samples. These images were used to position two to four regions of interest, each with an average size of 1.5 mL, in the left atrial chamber so that myocardial blood volume and thus the recovery of counts were >90%. These regions of interest were then projected onto the dynamic H215O images to generate arterial time-activity curves. The average of these atrial curves was used as the arterial input function for the subsequent kinetic MBF analysis.13 The above-mentioned atrial regions of interest were not used to generate the input function for the kinetic 18FDG analysis. Because of the high tissue-to-blood ratio at late times, even a limited amount of spillover would significantly affect the tail of the blood curve. Instead, the continuously monitored arterialized venous whole-blood curve was used. This curve was multiplied by the average plasma-to-whole-blood ratio obtained from the discrete samples to generate the plasma input function. A correction for the delay of this curve (arm and tubing) was made by shifting it so that the initial rise coincided with that from the atrial regions of interest.
Four equally spaced sectors corresponding to the anterior, septal, lateral, and inferior myocardium were defined separately on each plane of the last 18FDG frame. Within each sector, three to four elliptical regions of interest (1 mL each) were drawn. These regions of interest also were projected onto the entire dynamic 18FDG and H215O data sets, and tissue time-activity curves were generated for each region of interest.
The tissue H215O time-activity curves were fitted for MBF and TF (the fraction of tissue within a region of interest that exchanges water rapidly) with standard nonlinear regression techniques and a tracer kinetic model described previously.13 Unlike other implementations, this model provides MBF values per 1 mL perfusable tissue (not per 1 mL of region of interest), based on the assumption that the uptake of H215O in scar tissue is negligible compared with that in normal myocardium. Therefore, in a myocardial region consisting of an admixture of normal and necrotic tissue, this model predominantly measures flow to the residual normal myocardium.16 At variance, the flow measured with other methods, eg, 13N-labeled ammonia, represents an average flow per unit mass of tissue as with the microsphere technique.17 Therefore, to allow comparison with published data, flow per unit mass of tissue was also computed as MBF times TF.
Because basal MBF is closely related to the RPP,18 basal flow data also were corrected for the RPP, an index of myocardial oxygen consumption, by the following equation: RPP-Corrected Basal Flow=Basal Flowx(Mean Patient RPP÷Individual RPP). The mean patient RPP also was used for correction to compute the corrected basal flow in the 25 normal subjects to normalize the entire study population to the same workload.
Tissue 18FDG time-activity curves were analyzed by use of the linearized approach proposed by Patlak et al19 for irreversible processes. The ratio of tissue concentration to plasma concentration was plotted against the ratio of the integral of the plasma concentration to the plasma concentration, and a linear regression was performed for all data points corresponding to times >10 minutes after injection. The slope of this line provides the net influx rate of 18FDG. The myocardial MRG was then obtained by multiplying these regional influx rates by the plasma concentration of stable glucose, assuming a lumped constant of one, and by dividing the product by the corresponding TF. This last step was performed to correct for partial volume effects, thereby allowing comparison with corresponding MBF values. A conversion from milliliters to grams of perfusable tissue was made by dividing the flow and metabolic data by tissue density (1.04 g/mL). Thus, the MBF values are expressed as milliliter per minute per gram and the MRG values as micromole per minute per gram of perfusable tissue.
Statistical Analysis
All data are presented as
mean±SD. Student's
t test was used to compare any pair of mean group values.
Simultaneous comparison of more than two mean values was
performed with one-way ANOVA for repeated measures; Fisher's least
significant difference method was subsequently applied to localize the
source of the difference.20 Regression analysis
was performed according to standard techniques. A value of
P<.05 was considered significant.
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Results |
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Ventricular Function and Metabolic Profile
Before surgery, global LV ejection fraction was 35±11% (range, 12% to 55%). A total of 247 LV segments were analyzed in the 30 patients. Of these, 114 (46%) were dysfunctional and 133 (54%) had a normal function. Regional wall motion score was 5.3±3.1 (range, 1 to 11). Blood glucose concentration, measured before the beginning of the clamp, was 7.1±3.4 mmol/L (range, 4 to 22 mmol/L). Five patients were known diabetics (3 had insulin-dependent and 2 had non–insulin-dependent diabetes). Baseline plasma insulin concentration was 16±12 mU/L (range, 2 to 40 mU/L). During clamp, euglycemia was achieved in all but 1 patient, and blood glucose concentration decreased to 5.8±1.3 mmol/L (range, 4 to 11 mmol/L; P<.01 versus baseline). Plasma insulin during clamp was 88±17 mU/L (range, 68 to 133 mU/L; P<.0001 versus baseline). In the 9 normal subjects, baseline blood glucose was 5.3±0.9 mmol/L (range, 4.1 to 6.7 mmol/L; P=NS versus patients), and plasma insulin was 19±1 mU/L (range, 17 to 21 mU/L; P=NS versus patients). During clamp, blood glucose was 6.1±0.9 (range, 4.8 to 7.6 mmol/L; P=NS versus patients), and plasma insulin was 78±6 mU/L (range, 68 to 87 mU/L; P=NS versus patients).
Global LV ejection fraction after coronary bypass was 36±12% (range, 12% to 60%; P=NS versus baseline). In contrast, regional wall motion score improved significantly to 3.4±3.0 (range, 0 to 11; P<.001 versus corresponding baseline value), suggesting a change in the regional contribution to the global LV ejection fraction.
Ten segments (3 normal and 7 dysfunctional) worsened after surgery and were excluded from the PET data analysis, leaving a total of 107 dysfunctional and 130 normal segments. Of the 107 dysfunctional segments, 59 (55%) had a functional improvement after surgery, and 48 (45%) were unchanged.
Myocardial Blood Flow
In the 25 normal volunteers, MBF was
homogeneously
distributed in the different ventricular regions, and mean
LV MBF was 1.02±0.25
mL · min-1 · g-1
(range, 0.69 to 1.52
mL · min-1 · g-1).
After correction for the resting RPP, mean LV MBF was 1.02±0.40
mL · min-1 · g-1
(range, 0.56 to 1.79
mL · min-1 · g-1).
In the patients, MBF in the 130 segments with normal function was
0.92±0.25
mL · min-1 · g-1
(range, 0.43 to 1.56
mL · min-1 · g-1;
P=.001 versus normal subjects) and 1.00±0.33
mL · min-1 · g-1
(range, 0.37 to 2.45
mL · min-1 · g-1)
after correction for RPP (P=NS versus normal subjects). MBF
was 0.87±0.31
mL · min-1 · g-1
(range, 0.15 to 1.64
mL · min-1 · g-1)
in the 59 segments that improved after bypass (P=NS versus
normal segments) and 0.82±0.40
mL · min-1 · g-1
(range, 0.15 to 2.74
mL · min-1 · g-1)
in the 48 segments that were unchanged after surgery (P<.05
versus normal segments). To identify dysfunctional segments with
abnormally low MBF, a cutoff value of 0.42
mL · min-1 · g-1,
which corresponds to the mean MBF (corrected for RPP) minus 2 SD in
normal segments, was used. In 11 of 107 dysfunctional segments (10%),
MBF was <0.42
mL · min-1 · g-1.
After surgery, regional wall motion improved in 6 of 11, whereas it was
unchanged in 5. In 96 of 107 dysfunctional segments (90%), MBF was
>0.42
mL · min-1 · g-1.
After surgery, regional wall motion improved in 53 of 96 (55%) and was
unchanged in 43 despite comparable MBF values (0.93±0.26 versus
0.88±0.38
mL · min-1 · g-1;
Fig 1).
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Metabolic Rate of Glucose
In the 9 normal volunteers, MRG was
0.71±0.14
µmol · min-1 · g-1
(range, 0.46 to 1.02
µmol · min-1 · g-1).
In the patients, the MRG in the 130 segments with normal function was
0.45±0.19
µmol · min-1 · g-1
(range, 0.10 to 1.02
µmol · min-1 · g-1;
P<.01 versus normal subjects; Fig 2). The
difference between normal subjects and patients wasstill significant
after exclusion of the 5 patients with diabetes and the 4 with
arterial hypertension (0.46±0.18
µmol · min-1 · g-1,
P<.01).
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The MRG in the 59 segments that improved after
bypass was 0.44±0.14
µmol · min-1 · g-1
(range, 0.04 to 0.71
µmol · min-1 · g-1;
P=NS versus normal segments). In the 48 segments that were
unchanged after surgery, MRG was 0.34±0.17
µmol · min-1 · g-1
(range, 0.09 to 0.78
µmol · min-1 · g-1;
P<.01 versus both normal and improved segments; Fig
3). MRG in the 11 of 107 dysfunctional segments
with MBF <0.42
mL · min-1 · g-1
was 0.26±0.17
µmol · min-1 · g-1
(range, 0.04 to 0.57
µmol · min-1 · g-1).
In the 96 of 107 dysfunctional segments with MBF >0.42
mL · min-1 · g-1,
MRG was 0.40±0.15
µmol · min-1 · g-1
(range, 0.09 to 0.75
µmol · min-1 · g-1;
P<.01 versus segments with MBF <0.42
mL · min-1 · g-1).
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Discussion |
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Blood Flow in Chronically Dysfunctional Myocardium
The present study demonstrates that most chronically dysfunctional segments in a series of patients with previous infarction have MBF values measured with H215O and PET within the normal range (Fig 1
). Because the definition of low
MBF (ie,
mean MBF minus 2 SD in normally contracting
myocardium) is somewhat arbitrary, a less conservative
cutoff value of 0.67
mL · min-1 · g-1
(mean MBF minus 1 SD in normally contracting myocardium)
also was considered. Even in the latter case, >80% of the
dysfunctional segments had MBF values >0.67
mL · min-1 · g-1.
The latter cutoff value is identical to that proposed by Bergmann et
al21 and very similar to that (0.70
mL · min-1 · g-1)
proposed by Perrone-Filardi et al,22 both obtained in
normal subjects by use of H215O and PET.
The
present finding indicates that chronic ventricular
dysfunction is not accompanied by a chronically reduced MBF. It is
worth noting, however, that the kinetic model used in the present
study to quantify MBF with H215O provides
values of flow per 1 g perfusable tissue (not per 1 g region of
interest).13 Because the uptake of
H215O in scar tissue is negligible compared
with normal myocardium, in a myocardial region consisting
of an admixture of viable and necrotic tissue, this model predominantly
measures flow to the residual normal
myocardium.16 At variance, the flow measured
with other tracers, eg, 13N-labeled ammonia
(13NH3), represents an average flow per
unit mass of tissue as with the microsphere
technique.17 In other words, dysfunctional regions in
which perfusion is measured as milliliter per minute per gram of
tissue, including fibrotic and viable myocardium (eg,
13NH3), would have low perfusion and therefore
would be defined as hibernating. However, the same dysfunctional
segments in the same heart in which myocardial perfusion is measured as
milliliter per minute per gram of viable tissue (water-diffusible
space), excluding fibrotic tissue, might have normal flow and therefore
would be defined as stunned.2 To be able to compare our
data with those obtained with 13NH3, our
MBF values, expressed as flow per 1 g perfusable tissue, were
multiplied by TF to yield values of 1 mL per unit mass of total tissue
(Table 2). It should be noted that even in control
subjects MBF expressed as milliliter per minute per gram of total
tissue is lower than that expressed as milliliter per minute per gram
of water-perfusable tissue. The reason is that the latter
measurement includes an intrinsic correction for partial volume
effect.13 23
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In several other studies, MBF has been assessed by use of PET with 13NH3 in patients with chronic myocardial infarction. In 15 patients with reperfused anterior infarction who were studied 42±25 days after the acute event, transmural flow averaged 0.8±0.1, 0.7±0.2, and 0.5±0.1 mL · min-1 · g-1 in remote segments, adjacent segments, and segments at the center of the infarcted area.24 Similar findings were reported recently in 26 patients with chronic healed infarction studied 44±65 months after the event.25 In some of these studies, MBF measured with 13NH3 in the core of the infarcted segments was lower than the flow values obtained by multiplying MBF measured with H215O by TF. This could be explained, at least in part, by the size and location of the regions of interest used in the different studies. In the present study, rather large fixed regions of interest were used, which may have led to overestimation of MBF in the infarcted areas.
Potential Mechanisms of Chronic LV Dysfunction
In our series
of patients with previous myocardial infarction,
both fibrotic and hibernating tissue may contribute in different
proportions to the maintenance of chronic LV dysfunction. Using
H215O, we have selectively measured MBF in
water-perfusable tissue, excluding scar. Data showed that MBF was
within the normal range in 90% of dysfunctional segments. This is
consistent with the finding of Vanoverschelde et
al,2 who found a preserved baseline MBF measured with PET
and 13NH3 in a highly selected group of
patients with coronary artery disease and chronic LV
dysfunction but without previous infarction. This indicates that
chronic LV dysfunction is not a consequence of a chronic reduction of
baseline flow.
Our study does not provide any clues to the mechanisms responsible for chronic dysfunction. It has been suggested that dysfunction may be secondary to repeated episodes of ischemia and stunning.2 This hypothesis is in line with recent experimental work in conscious animals26 that demonstrated that "the reduced function during ameroid-induced coronary stenosis reflected cumulative myocardial stunning rather than a primary deficit in coronary blood flow... ." In patients with coronary artery disease, resting MBF remains normal despite increasing stenosis severity, whereas coronary vasodilator reserve is progressively reduced27 and myocardial ischemia may develop as a consequence of small increases in oxygen demand.28 On the other hand, it is also possible that recurrent myocardial injury can occur secondary to transient primary reductions in blood flow. In this case, plaque fissuring with the associated platelet-induced vasoconstriction and thrombosis could be the triggering events.29 In all cases, MBF measured outside the episodes would be normal. In light of this, coronary revascularization, by restoring coronary vasodilator reserve, would be of value in patients in whom stunning is secondary to ischemia owing to increased demand. Conversely, revascularization would be of limited value in those patients with recurrent plaque instability in whom alternative therapeutic approaches aiming at plaque stabilization should be evaluated. This could explain, at least in part, the variable functional response to revascularization observed in these patients.
MRG and Insulin Resistance
Traditionally, the assessment of
myocardial viability with PET has
involved the simultaneous semiquantitative evaluation of
regional myocardial perfusion with 13NH3 and
exogenous glucose uptake with 18FDG. Maintained
18FDG uptake in an area of reduced perfusion should
identify viable tissue, whereas simultaneously reduced
13NH3 and 18FDG uptake should
define irreversibly scarred tissue.3 Patients are
generally given an oral glucose load before the PET study to promote
the secretion of endogenous insulin, which in turn will
stimulate glucose uptake by insulin-sensitive
tissues.3 However, many patients undergoing viability
studies may have other conditions known to be associated with insulin
resistance.30 31 32 To circumvent this
problem,
18FDG myocardial uptake can be measured during
hyperinsulinemic euglycemic
clamp.33 34 35 36 This
involves the simultaneous
infusion of insulin and glucose, acting as a metabolic
stressor by promoting glucose uptake in insulin-sensitive
tissues.8
With this approach, the second major finding of
the present study
was that MRG in the normally contracting segments in patients was 35%
lower than that measured in the myocardium of normal
subjects (Fig 2). This was observed despite comparable values
of
circulating glucose and insulin achieved in patients and control
subjects during clamp. This seems to be true even in the absence of
other conditions known to be associated with insulin resistance. In
fact, the difference between normal control subjects and patients was
still highly significant after removal of the data from those patients
who had diabetes or arterial hypertension, conditions known
to be associated with insulin resistance. Insulin resistance has been
demonstrated in the principal insulin-sensitive tissues (skeletal
muscle and adipose tissue) in patients with different diseases,
including diabetes,30 arterial
hypertension,31 and coronary artery
disease,32 but it is not clear whether myocardial tissue
is equally resistant to the action of this hormone. In two
different studies performed during hyperinsulinemic
euglycemic clamp, myocardial MRG measured with PET in
patients with type 1 diabetes was found to be similar to that in
nondiabetic control subjects.33 34 In contrast, both
MRG
in skeletal muscle and whole body glucose uptake were significantly
reduced in diabetic patients compared with normal control
subjects.33 A similar study performed in patients with
type 2 diabetes demonstrated that during clamp myocardial MRG was
reduced by 39% compared with values in normal control
subjects.35 Some differences in the absolute values of
myocardial MRG exist between the above reports and the present
study. It should be mentioned that in the present study a
"lumped constant" value of one was used compared with a value of
0.67 in the above-mentioned reports. The value of 0.67 was obtained
from studies in control animals,37 and it is not known
whether this value is applicable to human myocardium. In
addition, it is unknown whether the same lumped constant value can be
used for normal and ischemic myocardium. Although
the observation of a reduced MRG in normal myocardium of
patients with coronary artery disease is original, a similar
conclusion could be inferred from two separate articles from the same
Finnish group.35 36 The MRG measured in a group of
normal
volunteers during euglycemic
hyperinsulinemic clamp35 was 0.97
µmol · min-1 · g-1
using a lumped constant of 0.67, which translates to 0.65
µmol · min-1 · g-1
if the lumped constant is set to one as in the present study. This
value is comparable to that measured in normal volunteers in the
present study (0.71
µmol · min-1 · g-1).
In the second article from the same group,36 MRG during
euglycemic hyperinsulinemic clamp was
measured in the normal myocardial segments of a group of patients with
coronary artery disease. After conversion to a lumped constant
of one, MRG was on average 0.49
µmol · min-1 · g-1,
which compares well with the present value of 0.45
µmol · min-1 · g-1
measured in normal myocardial regions remote from dysfunctional
segments.
Differences in the dietary state of the study population could account for differences in insulin sensitivities even during hyperinsulinemic euglycemic clamp.38 However, as stated in the "Methods" section, all patients and normal volunteers were scanned between 11 AM and 1 PM after a light breakfast, providing a reasonable standardization of the dietary state.
The results of the
present study indicate that on average the MRG
measured during hyperinsulinemic euglycemic
clamp is significantly higher in the segments that will improve after
surgery compared with those that will not (Fig 3). It should be
noted
that these differences in MRG could be explained, at least in part, by
changes in the lumped constant caused by myocardial ischemia.
However, this explanation probably is not applicable to the lower MRG
found in the normal myocardial regions remote from dysfunctional
segments.
It must be emphasized that the large range of MRG values measured in the dysfunctional territories makes it difficult to discriminate between individual segments that will or will not improve after revascularization. Part of this scatter might be due to the heterogeneity (eg, transmural differences of MBF and MRG) within the regions of interest. In this small series of patients, the quantitative analysis of MBF and MRG scans does not seem to provide additional diagnostic information relative to more qualitative assessments. However, it should be noted that the quantitative approach was essential in acquiring the new pathophysiological information.
Coronary Revascularization and LV
Function
The data of the present study indicate that coronary
revascularization improved regional wall motion in
50% of all dysfunctional segments, whereas baseline MBF measured
with H215O was within normal limits in 90%.
This may lead one to think that recovery of function has little to do
with myocardial perfusion and even question the rationale for
mechanical revascularization procedures. As
previously outlined, the MBF measurements in the present study
reflect flow in the viable tissue only. In a dysfunctional segment,
recovery after revascularization will depend on the
ratio between fibrotic and hypocontractile but viable tissue as
demonstrated by De Silva et al.39 This was confirmed
recently by Depré et al,40 who compared tissue
morphology (intraoperative biopsies) with PET measurements of perfusion
and metabolism using 13NH3 and
18FDG. They found that the amount of tissue fibrosis was
the strongest determinant of recovery after
revascularization and was inversely related to the
uptake of 13NH3 and 18FDG. Indeed,
the values of perfusion and metabolism obtained with these
two tracers are expressed per unit mass of tissue and are sensitive to
the amount of fibrosis within the region of interest. Accordingly, in
the present study, the measurement of 18FDG was
significantly lower in the dysfunctional regions that did not recover
after revascularization.
Conclusions
The results of the present investigation have
provided
evidence that chronic LV dysfunction in patients with previous
infarction is not associated with a reduced baseline MBF in most cases
and that the myocardium of patients with coronary
artery disease is less sensitive to insulin than the myocardial tissue
of normal subjects. In agreement with previous studies,35
the use of the hyperinsulinemic euglycemic
clamp allowed for high-quality 18FDG images in all
subjects; this is particularly important in view of the high prevalence
of insulin resistance demonstrated in the myocardium of
these patients.
|
Selected Abbreviations and Acronyms |
|---|
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Acknowledgments |
|---|
This work was carried out in the framework of the European Economic Community Concerted Action on PET Investigation of Cellular Regeneration and Degeneration. We would like to express our gratitude to the radiochemists of the Medical Research Council Cyclotron Unit for the preparation of radiotracers and to Andrew Blythe and Andreanna Williams for their help in the acquisition of the positron emission tomography data. Special thanks go to Heather Boyd for her help and expertise in the data analysis and to Dr William Wijns and Prof Terry Jones for their support and critical review of the manuscript.
Received August 7, 1995; revision received September 26, 1995; accepted October 4, 1995.
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References |
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F Fath-Ordoubadi, K J Beatt, N Spyrou, and P G Camici Efficacy of coronary angioplasty for the treatment of hibernating myocardium Heart, August 1, 1999; 82(2): 210 - 216. [Abstract] [Full Text] [PDF]
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J. M. Canty Jr. and J. A. Fallavollita Resting myocardial flow in hibernating myocardium: validating animal models of human pathophysiology Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H417 - H422. [Full Text] [PDF]
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J. A. Fallavollita and J. M. Canty Jr Differential 18F-2-Deoxyglucose Uptake in Viable Dysfunctional Myocardium With Normal Resting Perfusion : Evidence for Chronic Stunning in Pigs Circulation, June 1, 1999; 99(21): 2798 - 2805. [Abstract] [Full Text] [PDF]
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H. Schoder, R. Campisi, T. Ohtake, C. K. Hoh, D. H. Moon, J. Czernin, and H. R. Schelbert Blood flow-metabolism imaging with positron emission tomography in patients with diabetes mellitus for the assessment of reversible left ventricular contractile dysfunction J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1328 - 1337. [Abstract] [Full Text] [PDF]
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C A Rinaldi, N D Masani, A Z Linka, and R J Hall Effect of repetitive episodes of exercise induced myocardial ischaemia on left ventricular function in patients with chronic stable angina: evidence for cumulative stunning or ischaemic preconditioning? Heart, April 1, 1999; 81(4): 404 - 411. [Abstract] [Full Text]
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S. Firoozan, K. Wei, A. Linka, D. Skyba, N. C. Goodman, and S. Kaul A canine model of chronic ischemic cardiomyopathy: characterization of regional flow-function relations Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H446 - H455. [Abstract] [Full Text] [PDF]
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I. Matsunari, G. Boning, S. I. Ziegler, S. G. Nekolla, J. C. Stollfuss, I. Kosa, E. P. Ficaro, and M. Schwaiger Attenuation-corrected 99mTc-tetrofosmin single-photon emission computed tomography in the detection of viable myocardium: comparison with positron emission tomography using 18F-fluorodeoxyglucose J. Am. Coll. Cardiol., October 1, 1998; 32(4): 927 - 935. [Abstract] [Full Text] [PDF]
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 G. HEUSCH Hibernating Myocardium Physiol Rev, October 1, 1998; 78(4): 1055 - 1085. [Abstract] [Full Text] [PDF]
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S R Redwood, R Ferrari, and M S Marber Myocardial hibernation and stunning: from physiological principles to clinical practice Heart, September 1, 1998; 80(3): 218 - 222. [Full Text]
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C. A. Rinaldi, A. Z. Linka, N. D. Masani, P. G. Avery, E. Jones, H. Saunders, and R. J. C. Hall Randomized, Double-Blind Crossover Study to Investigate the Effects of Amlodipine and Isosorbide Mononitrate on the Time Course and Severity of Exercise-Induced Myocardial Stunning Circulation, August 25, 1998; 98(8): 749 - 756. [Abstract] [Full Text] [PDF]
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 W. Wijns, S. F. Vatner, and P. G. Camici Hibernating Myocardium N. Engl. J. Med., July 16, 1998; 339(3): 173 - 181. [Full Text] [PDF]
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P. D Verdouw, M. A van den Doel, S. de Zeeuw, and D. J Duncker Animal models in the study of myocardial ischaemia and ischaemic syndromes Cardiovasc Res, July 1, 1998; 39(1): 121 - 135. [Full Text] [PDF]
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R. K. Kudej, B. Ghaleh, N. Sato, Y.-T. Shen, S. P. Bishop, and S. F. Vatner Ineffective Perfusion-Contraction Matching in Conscious, Chronically Instrumented Pigs With an Extended Period of Coronary Stenosis Circ. Res., June 15, 1998; 82(11): 1199 - 1205. [Abstract] [Full Text] [PDF]
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D. J Duncker, R. Schulz, R. Ferrari, D. Garcia-Dorado, C. Guarnieri, G. Heusch, and P. D Verdouw "Myocardial stunning": remaining questions Cardiovasc Res, June 1, 1998; 38(3): 549 - 558. [Full Text] [PDF]
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 D. Pagano, J. N. Townend, W. A. Littler, R. Horton, P. G. Camici, and R. S. Bonser Coronary artery bypass surgery as treatment for ischemic heart failure: the predictive value of viability assessment with quantitative positron emission tomography for symptomatic and functional outcome J. Thorac. Cardiovasc. Surg., April 1, 1998; 115(4): 791 - 799. [Abstract] [Full Text] [PDF]
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D Pagano, R S Bonser, J N Townend, F Ordoubadi, R Lorenzoni, and P G Camici Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure Heart, March 1, 1998; 79(3): 281 - 288. [Abstract] [Full Text]
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G. Heusch, R. Ferrari, D. J Hearse, T. J.C Ruigrok, and R. Schulz 'Myocardial hibernation'--questions and controversies Cardiovasc Res, December 1, 1997; 36(3): 301 - 309. [Full Text] [PDF]
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P. G. Camici, W. Wijns, M. Borgers, R. De Silva, R. Ferrari, J. Knuuti, A. A. Lammertsma, A. J. Liedtke, G. Paternostro, and S. F. Vatner Pathophysiological Mechanisms of Chronic Reversible Left Ventricular Dysfunction due to Coronary Artery Disease (Hibernating Myocardium) Circulation, November 4, 1997; 96(9): 3205 - 3214. [Full Text]
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M. T. Maki, M. T. Haaparanta, M. S. Luotolahti, P. Nuutila, L.-M. Voipio-Pulkki, J. R. Bergman, O. H. Solin, and J. M. Knuuti Fatty acid uptake is preserved in chronically dysfunctional but viable myocardium Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2473 - H2480. [Abstract] [Full Text] [PDF]
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J.-L. J. Vanoverschelde, W. Wijns, M. Borgers, G. Heyndrickx, C. Depre, W. Flameng, and J. A. Melin Chronic Myocardial Hibernation in Humans: From Bedside to Bench Circulation, April 1, 1997; 95(7): 1961 - 1971. [Full Text]
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H. G. Wolpers, W. Burchert, J. van den Hoff, R. Weinhardt, G.-J. Meyer, and P. R. Lichtlen Assessment of Myocardial Viability by Use of 11C-Acetate and Positron Emission Tomography : Threshold Criteria of Reversible Dysfunction Circulation, March 18, 1997; 95(6): 1417 - 1424. [Abstract] [Full Text]
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B. Ghaleh, Y.-T. Shen, and S. F. Vatner Spatial Heterogeneity of Myocardial Blood Flow Presages Salvage Versus Necrosis With Coronary Artery Reperfusion in Conscious Baboons Circulation, November 1, 1996; 94(9): 2210 - 2215. [Abstract] [Full Text]
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 P. Iozzo, P. Chareonthaitawee, M. Di Terlizzi, D. J. Betteridge, E. Ferrannini, and P. G. Camici Regional myocardial blood flow and glucose utilization during fasting and physiological hyperinsulinemia in humans Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1163 - E1171. [Abstract] [Full Text] [PDF]
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