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Division of Cardiology and Medical Research Council Clinical Sciences Centre and National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom W12 0NN
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Nine patients with coronary artery disease and normal left ventricular (LV) function underwent two episodes of dobutamine-induced ischemia to determine whether repeated episodes of ischemia lead to cumulative stunning. Positron emission tomography (PET) and oxygen 15-labeled H2O was used to assess myocardial blood flow (MBF) at baseline, peak stress, and after stress for each ischemic episode. Quantitative echocardiographic assessment of global ejection fraction (EF) and regional systolic function (SF) was performed at rest and regular intervals after dobutamine. SF was assessed for regions subtended by a coronary artery with a >70% diameter stenosis. Both EF and SF were more severely impaired 45 min after the second episode of stress compared with 45 min after the first (both P < 0.01), despite no difference in duration of the two dobutamine infusions or MBF at peak stress (1.72 vs. 1.69). After both episodes of ischemia, when LV function was impaired but subsequently recovered, MBF (1.15 ± 0.39 and 1.20 ± 0.43, respectively) was no different to baseline MBF (1.02 ± 0.35), confirming that repeated episodes of dobutamine-induced ischemia lead to cumulative myocardial stunning.
myocardial stunning; coronary artery disease
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MYOCARDIAL STUNNING is the postischemic left ventricular (LV) dysfunction that persists despite the absence of irreversible damage and despite the return of normal or near-normal myocardial perfusion (8, 11). Myocardial stunning has been reported in animal models after ischemia-reperfusion (17, 26, 33) and after exercise-induced ischemia (20, 36), as well as in patients with coronary artery disease after a single episode of exercise-induced ischemia (1, 6). In animals, repeated episodes of ischemia followed by reperfusion have been shown to lead to more severe and prolonged LV dysfunction that is still reversible and occurs despite normal myocardial blood flow (MBF) (9, 10, 17, 18).
Hibernation is the chronic LV dysfunction due to coronary artery disease that improves after revascularization (22). The pathophysiology of hibernation remains incompletely understood. Initially, this condition was attributed to a matched reduction of MBF and function (27). This hypothesis was supported by experimental data in a canine model where 5 h of reduced MBF led to a matched reduction in myocardial function (short-term hibernation) (23). On restoration of normal MBF, there was prolonged myocardial dysfunction (up to 7 days), which was followed by complete recovery and was interpreted by the authors as myocardial stunning (30).
Recent studies of patients with the use of positron emission tomography (PET) have indicated that resting transmural MBF in hibernating myocardium may often be within normal limits (12), although other PET studies (16) have shown that MBF to hibernating myocardium can also be reduced. Despite this controversy regarding resting MBF, it is generally accepted that the coronary flow reserve to hibernating segments is severely reduced, and it has therefore been hypothesized that repeated episodes of demand ischemia followed by stunning could be a potential pathophysiological mechanism (38).
We (29) have shown that in patients with coronary artery disease, two episodes of exercise-induced ischemia separated by 60 min cause cumulative but reversible LV dysfunction. The present study was undertaken to assess whether this cumulative dysfunction observed after two episodes of ischemia represents myocardial stunning. Absolute MBF was measured with the use of PET. Dobutamine stress was employed to induce ischemia because we (5) have shown that this drug produces a degree of postischemic dysfunction similar to exercise.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patient Selection
We studied nine patients (8 males, mean age 59 ± 8 yr) with chronic stable angina pectoris, normal resting LV function, and coronary artery disease (
70% stenosis in at least one major
epicardial coronary artery, as shown at coronary angiography within 4 mo of recruitment). Patients were excluded if there was a history of an
acute coronary syndrome within 4 mo of recruitment or if it was not
possible to obtain echocardiograms of sufficient quality for
quantitative analysis (Table 1).
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Study Protocol
LV function was assessed by quantitative transthoracic echocardiography before symptom-limited dobutamine stress and at regular intervals after each dobutamine infusion. MBF was measured with PET and oxygen 15-labeled water (H215O) at baseline, at peak stress, and during recovery after each episode of dobutamine-induced ischemia (Fig. 1).
-Blockers and calcium antagonists were withdrawn 72 h before
the study, and other antianginal medication was withdrawn on the day of
the study. Patients were asked to avoid activities that might
precipitate angina for 12 h before the study and were excluded if
they had suffered angina or used glyceryl trinitrate within 4 h
before the study. The study protocol was approved by The Research
Ethics Committee of the Imperial College School of Medicine at
Hammersmith Hospital and radiation exposure was licensed by the United
Kingdom Administration of Radioactive Substances Advisory Committee.
All patients gave fully informed written consent.
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Dobutamine stress.
Subjects underwent two episodes of dobutamine-induced ischemia
separated by 75 min. Dobutamine was infused at incremental doses
(starting at 5 µg · kg
1 · min1 and
increased at 3-min intervals to 10, 20, 30, and 40 µg · kg1 · min1) until
patients experienced chest pain or reached their target heart rate
(calculated as 220/age in years). Dobutamine was discontinued if there
was a drop in systolic blood pressure >20 mmHg or significant arrhythmias were induced. The second infusion of dobutamine was of the
same duration as the first. The electrocardiogram (ECG) was monitored
continuously, and blood pressure and a 12-lead ECG were recorded every
3 min during stress and every 5 min during recovery. The rate-pressure
product (RPP) was calculated as systolic blood pressure × heart rate.
Echocardiography. Two-dimensional echocardiography was performed by one operator (E. Barnes) with the patient in the left lateral position with the use of commercially available equipment (model HDI 3000, ATL; Bothell, WA) with a P3-2 broadband-phased array transducer. Images were recorded at baseline and 30, 45, and 60 min after the end of the first dobutamine infusion and then 30, 45, 60, 120, and 180 min after the end of the second infusion. To minimize beat-to-beat variability, all recordings were made in gently held midexpiration (3) and recorded onto super-VHS videotape for subsequent off-line analysis. LV contractile function was assessed in the apical 2-chamber and apical 4-chamber views according to the guidelines from the American Society of Echocardiography (31).
Echocardiographic analysis. Videotaped images were analyzed using a personal computer-based digitizing program as previously described (3). Three consecutive beats (excluding extrasystolic and postextrasystolic beats) were analyzed for each time point. Endocardial borders (excluding papillary muscles) were traced at end diastole, timed as the closure of the mitral valve leaflets, and at end systole, defined as the point of maximal inward excursion of the endocardial contour. The centreline method was used to assess regional LV function calculated as the difference between the end-diastolic and end-systolic endocardial tracings. The deviation from the centerline of 100 chords around the LV circumference is calculated after correction for the end-diastolic circumference and expressed as a percentage of shortening fraction (SF). Each apical view of the LV is divided into six segments and the SF of the chords in each segment is averaged so that a total of 12 values are obtained (6 apical 4-chamber and 6 apical 2-chamber). SF was assessed for regions subtended by a coronary artery with a >70% diameter stenosis (SFdysfunction). LV volumes at end diastole and end systole were calculated using the biplane disk method and global ejection fraction (EF) derived as previously described (28). The coefficient of repeatability for this method is 2.6% as assessed by the method of Bland and Altman (7).
PET scanning procedure. The PET scans were performed with an ECAT 931-08/12 15-slice tomograph (CTI/Siemens; Knoxville, TN), and the heart was imaged in 15 planes over a 10.5-cm axial field of view. The emission and transmission data were reconstructed with a Hanning filter with a cut-off frequency of 0.5 units of the reciprocal of the sampling interval of the projection data, achieving an image resolution of 8.4 × 8.3 × 6.6-mm full-width half maximum at the center of the field of view (35). Subjects were positioned in the scanner using a 2-min rectilinear transmission scan obtained after exposure of a retractable 68Ge-ring source and a mark placed on the chest using two laser beams in orthogonal planes to assist repositioning after the first episode of dobutamine stress and subsequent echocardiography. A 5-min transmission scan was then performed for attenuation correction of all subsequent emission scans. An infusion of H215O (10 MBq/kg) was injected intravenously to determine baseline MBF as previously described (21). MBF scans were repeated at the peak of each dobutamine infusion and 22 min after termination of each infusion.
PET image processing.
Acquired sinograms were corrected for attenuation and reconstructed as
previously described (21). Myocardial images were generated directly from the dynamic H215O
study. Briefly, regions of interest were placed over the lungs for the
variate and covariate factors (myocardial and blood time-activity curves) for modeling the factor sinograms by means of the recently reported linear dimension reduction (15). Factor images
were generated by iterative reconstruction (15). The
images were then resliced along the short axis of the LV and regions of
interest drawn in the left atrium to generate blood time-activity
curves (arterial input function). Similarly, the LV was divided into 12 regions of interest [anterior, septal, lateral, and inferior (basal,
mid, and apical)] (21) comparable to those used for echocardiographic analysis and projected onto the dynamic
H215O images to obtain myocardial time-activity
curves. A single tissue compartment tracer kinetic model was used to
calculate regional and global MBF
(ml · min1 · g1) as
previously described (2, 15). The reproducibility of this
method is excellent (21).
Statistical Analysis
Data are presented as means ± SD. The primary end points were based on the effects of pharmacological stress on the echocardiographic parameters of LV function (EF and SFdysfunction) and MBF at baseline, at the peak of each dobutamine infusion and during each recovery phase. All echocardiographic data met the assumption of homogeneity of variances required for ANOVA. Echocardiographic parameters, MBF, and hemodynamic parameters were compared using one-way ANOVA with a design for repeated measures, with Bonferroni's test to correct for multiple comparisons. The MBF to regions subtended by an artery with a >70% stenosis was compared with other regions with the use of an unpaired t-test. A value of P < 0.05 was considered significant.| |
RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The mean duration of the first dobutamine infusion was 708 s
(range 420-1,068). This was no different from the second infusion, 700 s (range 420-1,050) [P = not significant
(NS)]. The dobutamine infusion was stopped due to chest pain in all
patients. The mean ST segment depression was 1.1 ± 0.6 mm at the
peak of the first infusion of dobutamine and 1.0 ± 0.5 mm at the
peak of the second (P = NS). There was no
difference in the RPP before each episode of dobutamine stress. The
RPP rose significantly at the peak of the dobutamine infusion
compared with baseline, but had returned to baseline after 20 min when
recovery MBF was assessed. There was no difference between the peak RPP
after the first and second infusion of dobutamine (Fig.
2).
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Echocardiographic Data
Global EF.
The mean resting EF was 58.1 ± 6.5% and was reduced in all but
one subject (subject 2) 30 min after the first dobutamine
infusion (53.5 ± 5.8%, P < 0.01 vs. baseline),
but had recovered at 45 and 60 min (55.5 ± 7.1 and 56.8 ± 6.0, respectively; P = NS vs. baseline). After the
second dobutamine infusion, EF was again reduced in all but one subject
(subject 2) at 30 and 45 min (51.8 ± 6.5 and 52.3 ± 6.6, respectively, both P < 0.001 vs. baseline). Moreover, the EF 45 min after the second dobutamine was reduced (P < 0.01) compared with 45 min after the first (Fig.
3A).
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Regional function. In regions subtended by an artery with a >70% stenosis, the baseline SFdysfunction was 3.26 ± 1.0. Thirty minutes after the first dobutamine infusion, the SFdysfunction was reduced to 2.69 ± 1.1 (P < 0.001 vs. baseline), but had recovered 45 and 60 min after peak stress (2.98 ± 1.1 and 3.05 ± 0.9, respectively, both P = NS vs. baseline). The SFdysfunction was reduced both 30 and 45 min after the second episode of dobutamine stress (2.63 ± 1.1 and 2.65 ± 1.0, respectively; both P < 0.001 vs. baseline). As with global function, 45 min after the second dobutamine infusion, SFdysfunction was reduced compared with 45 min after the first (P < 0.01). At all subsequent time points (60, 120, and 180 min), SFdysfunction had recovered, demonstrating fully reversible postischemic LV dysfunction (3.06 ± 1.1, 3.10 ± 1.0, and 3.18 ± 0.9, respectively; all P = NS vs. baseline) (Fig. 3B).
Myocardial blood flow.
Baseline MBF was 1.02 ± 0.4 ml · min1 · g1 in regions
subtended by an artery with a >70% stenosis and 0.97 ± 0.4 ml · min1 · g1 to other
regions (P = NS). At peak stress, during the first
episode of ischemia, MBF increased to 1.65 ± 0.6 (P < 0.001 vs. baseline). During the second ischemic
episode, flow was also increased compared with baseline (1.69 ± 0.8; P < 0.001) and was no different to flow during
the first episode confirming an equivalent ischemic burden
(P = NS vs. peak MBF of first dobutamine infusion).
During recovery from both the first and second episodes of
dobutamine-induced ischemia when LV function was still impaired, MBF
was no different from baseline (1.15 ± 0.4 and 1.20 ± 0.4;
both P = NS vs. baseline) (Fig.
4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have shown that in patients with coronary artery disease and stable angina pectoris, a repeated episode of demand ischemia leads to cumulative stunning that may be a substrate in the development of ischemic LV dysfunction. The LV dysfunction was more prolonged after the second episode of ischemia despite the same MBF at peak stress. There was also a trend for the dysfunction to be more severe, although this did not reach statistical significance. Moreover, after each episode, when LV function was impaired, MBF was not different from baseline confirming this to be cumulative myocardial stunning.
Since Heyndrickx et al. (17) first described myocardial stunning in 1975, it has been known that the severity of the LV dysfunction associated with stunning is related to the intensity of the preceding bout of ischemia. It is now recognized that the degree of stunning is related to both the intensity and duration of the preceding episode of ischemia (19, 26), although the former is the more important (9). In animal studies (9, 17), repeated episodes of ischemia, followed by reperfusion, lead to a cumulative reduction in LV function due to cumulative myocardial stunning.
In the presence of a coronary artery stenosis that limits flow reserve (37), exercise leads to ischemia when the oxygen demand is not met by an adequate increase in MBF (demand ischemia). In a canine model with a coronary stenosis, exercise-induced ischemia leads to myocardial stunning (20). Moreover, repeated episodes of exercise-induced ischemia lead to cumulative stunning (18). In a chronically instrumented porcine model with a progressive coronary occlusion, Shen and Vatner (32) observed repeated episodes of demand-ischemia, which were followed by a prolonged reduction in ventricular function despite normal MBF. The animals were conscious and the ischemic episodes occurred spontaneously in response to increases in activity and agitation.
In patients with stable coronary artery disease, as the degree of a coronary stenosis increases, the coronary flow reserve progressively decreases and is exhausted when the stenosis exceeds 80% of the luminal diameter (37). In this situation, any increase in cardiac work above baseline conditions cannot be met by an adequate increase in flow and leads to myocardial ischemia. After such episodes of demand ischemia, stunning has been shown to occur in patients with coronary artery disease (1, 6). We (29) have shown that repetitive episodes of exercise-induced ischemia can lead to cumulative and prolonged LV dysfunction thought to be due to myocardial stunning. In that study, MBF was not assessed, although each episode of ischemia was comparable when assessed noninvasively. In the present study, we confirm these findings and demonstrate an equal rise in MBF at the peak of both episodes of dobutamine-stress, indicating an equivalent ischemic burden. We have also shown that MBF is the same as baseline after each episode of ischemia when LV function is impaired, but subsequently recovers, confirming this to be stunning. The main difference over and above MBF measurement was the type of stress used to induce ischemia. We were unable to use exercise because this leads to movement artefacts when using PET for the assessment of absolute MBF. However, we (5) have shown that in patients with stable coronary artery disease, dobutamine-induced ischemia leads to reversible postischemic LV dysfunction that is equivalent to that seen after exercise.
Heart failure is a common medical problem estimated to affect up to 20% of people over the age of 70 years and the mortality from heart failure is increasing (25). In the developed world, coronary artery disease accounts for approximately two-thirds of cases (14). In patients with coronary artery disease, LV failure occurs due to several factors including, permanent myocyte loss due to infarction, chronic dysfunction in myocardium that recovers after revascularization (hibernating myocardium), and changes in the remote myocardium (adverse remodeling). There is growing evidence that up to 55% of patients with ischemic LV dysfunction have evidence of hibernating myocardium (4).
It was hypothesized initially that hibernating myocardium was due to a matched reduction of MBF and function (27). This hypothesis has been supported by experimental studies showing that a matched reduction in flow and function can be achieved and that this phenomenon of short-term hibernation (23) might be clinically comparable to the events following an acute coronary syndrome (30). However, more recent studies (12) have indicated that resting MBF in patients with hibernating myocardium may be within normal limits, although other PET studies (16) have demonstrated that a slight reduction (on average ~20%) in resting flow can be present. In addition, because in all of these PET studies only total transmural MBF was measured, we cannot completely rule out ongoing subendocardial ischemia in these patients. Several recent studies (13, 24, 34) of animals have demonstrated that flow falls in chronically dysfunction myocardium after a period of chronic stunning with normal resting flow. It is therefore possible that a severe episode of ischemia, such as an acute coronary syndrome, followed by reperfusion could act as the "trigger" for a reduction in myocardial function as in animals with short-term hibernation. In addition, in the presence of a severe coronary stenosis, resting MBF may be normal, but the coronary flow reserve will be reduced so that repeated episodes of demand ischemia may occur in daily life that are followed by stunning that is cumulative. The latter could be an additional pathophysiological mechanism underlying chronic hibernation (38), which could also take place after the resolution of an acute coronary syndrome (e.g., after the lysis of a thrombus in the presence of severe stenosis). All of this therefore illustrates that the timing of the assessment of MBF in patients with hibernation is potentially crucial and that all scenarios may be possible and may occur together.
If repetitive stunning contributes to chronic LV dysfunction in patients with coronary artery disease, heart failure might be prevented by intervening on stunning directly (28) and/or reducing the episodes of ischemia that are the cause of stunning. Once established, chronic LV dysfunction caused by hibernation is improved by revascularization, which restores the coronary flow reserve, thus preventing further episodes of demand ischemia and hence stunning.
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ACKNOWLEDGEMENTS |
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E. Barnes was supported by a Wellcome Research Training Fellowship.
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. Barnes, Dept. of Cardiology, Bristol Royal Infirmary, Marlborough St., Bristol BS2 8HW, United Kingdom (E-mail: ebarnes{at}doctors.org.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00786.2001
Received 4 September 2001; accepted in final form 2 November 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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P < 0.001 vs.
baseline before first infusion.
