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Mechanism of myocardial dysfunction in the Presence of chronic coronary stenosis and Normal resting myocardial blood flow: Clinical implications
ORIGINAL ARTICLES
Mechanism of Myocardial Dysfunction in the Presence of Chronic Coronary Stenosis and Normal Resting Myocardial Blood Flow: Clinical Implications Robert A. Pelberg, MD, William D. Spomitz, MD, Jian-Ping Bin, MD, Elizabeth I x , MD, N. Craig Goodman, BS, and Sanjiv Kaul, MD, Charlottesville, Virginia
I n c h r o n i c c o r o n a r y a r t e r y disease, resting m y o c a r d i a l d y s f u n c t i o n c a n e x i s t d e s p i t e n o r m a l r e s t i n g transr e n t a l m y o c a r d i a l b l o o d f l o w (MBF). We h y p o t h e s i z e d t h a t this p h e n o m e n o n o c c u r s b e c a u s e o f d i m i n i s h e d e n d o c a r d i a l MBF r e s e r v e . MBF ( m e a s u r e d w i t h r a d i o l a b e l e d m i c r o s p h e r e s ) a n d wall t h i c k e n i n g (WT) ( m e a s u r e d w i t h e c h o c a r d i o g r a p h y ) w e r e assessed i n 7 dogs after t h e d e v e l o p m e n t o f s e v e r e left v e n t r i c u l a r dysfunction caused by placement of ameroid cons t r i c t o r s o n t h e left a n t e r i o r d e s c e n d i n g (LAD) a n d left c i r c u m f l e x a r t e r i e s a n d 3 w e e k s after selective b y p a s s s u r g e r y to t h e LAD. Before surgery, t h e m e a n t r a n s m u r a l MBF at r e s t a n d at p e a k d o b u t a m i n e d o s e i n t h e LAD b e d w e r e 1.1 _+ 0.5 a n d 3.0 -+ 1.5 m L / m i n per gram, respectively, and were not significantly c h a n g e d after LAD b y p a s s . The r e s t i n g e n d o c a r d i a l t o - e p i c a r d i a l MBF ratio (EER) w a s also n o r m a l b e f o r e
b y p a s s (1.5 _+ 0.6) a n d r e m a i n e d u n c h a n g e d a f t e r s u r g e r y . T h e p r e b y p a s s EER at p e a k d o b u t a m i n e dose, however, was m a r k e d l y d i m i n i s h e d in t h e LAD b e d (0.7 -+ 0.3) a n d i m p r o v e d significantly (1.3 -+ 0.8, P < .01) after surgery. Resting WT i n t h e LAD b e d also i m p r o v e d to n o r m a l levels (36% -+ 4% versus 13% -+ 6%, P = .0001) a n d n o l o n g e r d e m o n s t r a t e d a b i p h a s i c r e s p o n s e to d o b u t a m i n e . I n c o m p a r i s o n , t h e n o n b y p a s s e d left c i r c u m f l e x b e d c o n t i n u e d to s h o w r e d u c e d r e s t i n g WT (12% __.6%), a b i p h a s i c r e s p o n s e to d o b u t a m i n e , a n d a b n o r m a l EER d u r i n g r e s t a n d d o b u t a m i n e (0.7 -+ 0.3). We c o n c l u d e that p e r s i s t e n t myocardial dysfunction in the presence of normal r e s t i n g t r a n s m u r a l MBF c a n o c c u r as a r e s u l t o f d i m i n i s h e d e n d o c a r d i a l MBF resetwe, w i t h t r a n s m u r a l MBF r e s e r v e r e m a i n i n g n o r m a l (J Am Soc Echocardiogr 2001;14:1047-56.)
From the Cardiac Imaging Center of the Cardiovascular DMsion (R.A.P., J.-P.B., E.L., N.C.G., S.K.) and the Division of Thoracic and Cardiovascular Surgery (W.D.S.), University of Virginia School of Medicine, Charlottesville. Supported in part by a grant from the National Institutes of" Health (R01-HL-48890), Bethesda, Md. The radiolabeled microspheres were provided by Dupont Pharmaceuticals, North Billerica, Mass, and the ultrasound equipment was supplied by Advanced Technology Laboratories, Bothell, Wash. Dr Pelberg was supported by a Fellowship Training Grant from the Virginia Affiliate of the American Heart Association, Glen Alien, and Dr Elizabeth Le was supported bv a postdoctoral training grant (HL-07355) from the National Institutes of Health. Presented in part at the Young Investigator Award Competition at the 10th Annual Scientific Session of the American Society of Echocardiography, June 1999, in Washington, DC. Reprint requests: Sanjiv Kaul, MD, Cardiovascular DMsion, Box 158, University of Virginia Medical Center, Charlottesville, VA 22908 (E-mail: sk@virginia.~du). Copyright © 2001 by the American Sociew of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/113232 doi: 10.1067/mje.2001.113232
I t is n o w well r e c o g n i z e d that in c h r o n i c c o r o n a r y a r t e r y disease, r e s t i n g m y o c a r d i a l d y s f u n c t i o n c a n exist d e s p i t e n o r m a l resting t r a n s m u r a l m y o c a r d i a l b l o o d f l o w (MBF). 1~, In m o s t h u m a n studies a n d in l o n g - t e r m a n i m a l s t u d i e s o f single-vessel s t e n o s i s , r e s t i n g MBF r e m a i n s n o r m a l b e c a u s e o f e x t e n s i v e collateral vessel d e v e l o p m e n t . In b o t h situations, it is t h o u g h t that t r a n s m u r a l MBF r e s e r v e is r e d u c e d a n d that r e p e a t e d e p i s o d e s o f d e m a n d i s c h e m i a o c c u r ring d u r i n g daily activities result in p e r s i s t e n t myocardial stunning. 7-12 In t h e clinical setting, d e t e c t i o n o f r e d u c e d transmural MBF r e s e r v e is a c c o m p l i s h e d b y c a r d i a c imagi n g d u r i n g stress. T h u s d y s f u n c t i o n a l m y o c a r d i a l regions demonstrate a reversible perfusion defect d u r i n g e x e r c i s e o r p h a r m a c o l o g i c stress, 13,14 w h e r e as t h e y e x h i b i t a "biphasic" r e s p o n s e d u r i n g d o b u t a m i n e stress. 15 In m a n y instances, h o w e v e r , dysfunctional m y o c a r d i a l s e g m e n t s e x h i b i t n o r m a l o r n e a r
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n o r m a l t r a n s m u r a l p e r f u s i o n at rest, a n d n o reversible p e r f u s i o n d e f e c t is s e e n d u r i n g s t r e s s . W h e n this d y s f u n c ti o n a l r e g i o n is s u b t e n d e d b y a h e m o d y namically significant c o r o n a r y stenosis, it is generally revascularized, despite no objective evidence of i n d u c i b l e ischemia. Most often, r e g i o n a l f u n c t i o n is s e e n to r e c o v e r after revascularization. For this reason, dysfunctional m y o c a r d i u m is c o n s i d e r e d to b e viable and w o r t h revascularizing e v e n w h e n resting p e r f u s i o n is n o r m a l o r n e a r n o r m a l , w i t h o u t t h e n e e d for actually d e m o n s t r a t i n g i n d u c i b l e ischemia. A p a r a d o x s e e m s to e x i s t in this s i t u a t i o n . If m y o c a r d i u m is viable distal t o a stenosis an d is dysf u n c t i o n a l b e c a u s e o f r e p e a t e d e p i s o d e s o f stunning, t h e n it s h o u l d d e m o n s t r a t e a r e d u c t i o n in transmural MBF reserve. In this study, w e h y p o t h e s i z e d that p e r s i s t e n t m y o c a r d i a l d y s f u n c t i o n in t h e p r e s e n c e o f n o r m a l resting t r a n s m u r a l MBF c a n o c c u r as a result o f d i m i n i s h e d e n d o c a r d i a l MBF r e s e r v e w i t h o u t affecting transmural MBF reserve. B e c a u se t h e endoc a r d i u m c o n t r i b u t e s almost t w o thirds to total wall t h i c k e n i n g , 16-18 r e p e a t e d e p i s o d e s o f e n d o c a r d i a l s t u n n i n g c o u l d lead t o r e s t i n g w a l l m o t i o n a b n o r malities. If o u r h y p o t h e s i s is c o r r e c t , t h e n revascularization should reverse the abnormal endocardial MBF r e s e r v e and n o r m a l i z e th e resting wall m o t i o n abnormality.
METHODS Animal Preparation For this study, we used a previously described canine model of multivessel coronary stenosis in which ameroid constrictors are placed on the coronary arteries supplying the left ventricle. 6 When the ameroid constrictor is placed very proximal on the left circumflex coronary artery (LCx), collateral development is inadequate, and in the ensuing weeks MBF may b e c o m e reduced, leading to myocardial hibernation. Because the first septal perforator often arises from the left main coronary artery in dogs, placement of a constrictor on the left anterior descending coronary artery (LAD) spares the first septal perforator and permits collateral vessels to develop from it to the distal LAD. In this situation, transmural MBF can remain normal in the LAD bed, but regional wall motion abnormalities are consistently seen. 6 In this study, w e allowed collateral blood flow to develop in the LCx bed as well by placing the ameroid constrictor more distally on the LCx. This maneuver permitted resting transmural MBF in this region to remain normal. We evaluated percent wall thickening (WT), MBF and endocardial-to-epicardial MBF ratio (EER) at rest and dur-
Journal of the American Society of Echocardiography November 2001
ing dobutamine-induced hyperemia in both the LAD and LCx beds, before and after selective coronary artery bypass to the LAD. In this study, both the LAD and LCx beds demonstrated regional left ventricular (LV) dysfunction before surgery despite normal resting transmural MBF and EER.Thus the LCx bed, which did not tmdergo revascularization, acted as the control bed. The study was approved by the Animal Research Committee at the University of Virginia and conforms to the American Heart Association Guidelines for Animal Research. Animals were pretreated with 75 mg of aspirin daily for 3 days before surgery and were maintained on this dose until euthanasia. An intravenous dose (1 g) of cefazolin sodium was administered before surgery and was continued twice daily for 5 days.A single intravenous dose (80 mg) of gentamicin was also administered immediately before surgery. Surgery was performed under sterile conditions. Anesthesia was induced with 20 ~tg/kg fentanyl, 400 lLg/kg etomidate, and 300 ~tg/kg diazepam, administered intravenously. The animal was intubated and anesthesia was maintained with a mixture of 1% to 1.5% isofluorane, 02, and room air given through a respirator (model 607, Harvard Apparatus, North Bellerica, Mass). Minute volume was set between 5.5 and 6.5 L/min to maintain a physiologic Pco 2. Heart rate and rhythm were monitored throughout the operation. A small incision was made in the right groin, and a 6F indwelling catheter was inserted into the femoral artery and secured in place with silk ties. The catheter was flushed with a dilute solution of heparin and capped off with a rubber injection port. It was then tunneled beneath the skin to allow subsequent transcutaneous access for arterial pressure monitoring as well as withdrawal of samples for blood gas and radiolabeled microsphere-derived MBF analyses.The groin incision was then closed in layers. After skin preparation, 300 ~tg/kg atracurium was administered to induce muscle paralysis.A left lateral thoracotomy was performed in the fourth intercostal space, and the heart was suspended in a pericardial cradle. The mid-portions of the LAD and LCx were dissected free from surrounding tissues. Any large proximal branches of these arteries were similarly dissected. Up to 4 appropriately sized (1 to 3.5 mm) ameroid constrictors were placed around these arteries. Regional LV function was then assessed by direct epicardial 2-dimensional echocardiography (2DE), with the transducer placed in a sterile sleeve to ensure that deterioration in regional systolic function did not occur after placement of the ameroid constrictors. A 6F indwelling catheter was inserted in the left atrium and secured in place with prolene sutures. After flushing with a dilute heparin solution, its end was capped off with a rubber injection port.The catheter was tunneled beneath the dorsal skin to allow subsequent transcutaneous injec-
Journal of the American Society of Echocardiography Volume 14 Number 11
tions of radiolabeled microspheres. The chest was then c l o s e d in layers, a n d t h e a n i m a l w a s revived a n d transferred to an o b s e r v a t i o n area in the vivarium. T h e animals w e r e e x a m i n e d t w i c e daily a n d treated for h e a r t failure a n d infection if required. A s s e s s m e n t o f R e g i o n a l a n d G l o b a l LV F u n c t i o n Regional f u n c t i o n was assessed w i t h t h e use of quantitative 2DE. Imaging was p e r f o r m e d w i t h t h e use of a phasedarray digital s y s t e m (HDI 3000cv, A d v a n c e d T e c h n o l o g y Laboratories, Bothell, Wash) w i t h a 2.3-MHz probe. Apart from t h e intraoperative 2DE d e s c r i b e d above, all data w e r e a c q u i r e d w i t h t h e dog lying o n its left side w h i l e imaging from t h e right thorax. Two short-axis views (high a n d low papillary muscle levels) w e r e r e c o r d e d o n e a c h examination. Care was t a k e n to acquire t h e same views every time in a n individual dog. Images w e r e r e c o r d e d o n 1.25-cm v i d e o t a p e w i t h an S-VHS r e c o r d e r (Panasonic AG-MD830, Matsushita, Secaucus, NJ). Two-dimensional e c h o c a r d i o g r a p h i c images w e r e analyzed as p r e v i o u s l y d e s c r i b e d . 19 T h e y w e r e t r a n s f e r r e d from v i d e o t a p e to t h e m e m o r y of a c o m p u t e r at 30 Hz in a 320 x 240 x 8 bit m a t r i x . T h e o b s e r v e r t h e n defined several endocardial a n d epicardial targets in e a c h frame from e n d diastole to e n d systole.These points w e r e automatically c o n n e c t e d b y u s i n g cubic-spline i n t e r p o l a t i o n to derive epicardial a n d endocardial contours.To c o r r e c t for systolic cardiac rotation, t h e j u n c t i o n of the p o s t e r i o r LV wall a n d t h e right v e n t r i e u l a r free wall was defined o v e r t h e epic a r d i u m in e a c h frame, a n d 100 e q u i d i s t a n t c h o r d s bet w e e n t h e 2 c o n t o u r s w e r e g e n e r a t e d starting at this point. Each c h o r d r e p r e s e n t e d t h e s h o r t e s t distance b e t w e e n t h e epicardial a n d e n d o c a r d i a l c o n t o u r s . T h e o b s e r v e r t h e n s e l e c t e d t h e m y o c a r d i a l r e g i o n s in w h i c h t h e c h o r d lengths w e r e averaged. Plots of WT over t h e entire systolic c o n t r a c t i o n s e q u e n c e w e r e t h e n automatically generated, w i t h t i m e r e p r e s e n t e d in deciles. 19 Maximal W T at any p o i n t in systole was t a k e n to r e p r e s e n t WT. W i t h t h e use of t h e endocardial contour, end-diastolic a n d end-systolic areas w e r e automatically calculated b y t h e computer. Regional end-systolic wall stress (ESWS) was calculated b y using t h e c o m p u t e r - d e r i v e d c u r v a t u r e calculation for t h e LAD and LCx segments, w h e r e c u r v a t u r e represents t h e inverse of t h e radius. Therefore, ESWS ( d y n e / c m ) = (p • r)/(2t • c), w h e r e p = end-systolic pressure, r = radius, t = wall thickness, a n d c = curvature. 2° Myocardial Blood Flow Measurements Four sets of radiolabeled m i c r o s p h e r e s w e r e u s e d in e a c h animal, el T h o s e w i t h longer half-lives w e r e injected earlier in t h e p r o t o c o l to allow e n o u g h c o u n t s in t h e sample o n p o s t m o r t e m analysis.Approximately 2 x 106 11 ~ m radiol a b e l e d m i c r o s p h e r e s ( D u p o n t Medical Products, N o r t h Bellerica, Mass) w e r e s u s p e n d e d in 4 mL of n o r m a l saline
Pclberg et al 1 0 4 9
a n d 0.01% Tween-80 solution and injected into the left atriu m over a p e r i o d of 20 s e c o n d s . T h i s dose of radiolabeled m i c r o s p h e r e s allows at least 1000 m i c r o s p h e r e s to b e c o u n t e d in e a c h gram of n o r m a l tissue a n d at least 300 m i c r o s p h e r e s in each gram of i s c h e m i c tissue. Reference samples w e r e w i t h d r a w n from t h e femoral artery over a p e r i o d of 130 s e c o n d s w i t h a c o n s t a n t rate w i t h d r a w a l p u m p ( m o d e l 944, Harvard Apparatus). T h e t w o p o s t m o r t e m h e a r t slices c o r r e s p o n d i n g to t h e 2DE short-axis images w e r e c u t i n t o 16 w e d g e - s h a p e d pieces. Each piece was f u r t h e r divided into epicardial, midcardial, a n d e n d o c a r d i a l portions. T h e tissue a n d arterial reference samples w e r e c o u n t e d in a well c o u n t e r w i t h a m u l t i c h a n n e l analyzer ( m o d e l 1282, LKB Wallac, Washington, DC). Corrections w e r e m a d e for activity spillover from o n e w i n d o w to t h e n e x t b y using a set of s i m u l t a n e o u s equations p r o g r a m m e d o n a computer. 2~ MBF to e a c h sample w a s c a l c u l a t e d b y t h e e q u a t i o n Qm = (Cm " Qr)/Cr, w h e r e Qm = flow (mL/min), C m = tissue counts, Qr = rate of arterial blood withdrawal (mL/min), and C r = c o u n t s in the reference sample.Transmural MBF (mL/min p e r gram) to e a c h s e g m e n t was derived by dividing the sum of MBF to i n d i v i d u a l s e g m e n t s b y t h e i r c o m b i n e d w e i g h t . 21 Transmural MBF w a s c a l c u l a t e d b y averaging t h e transmural MBF in t h e s e g m e n t s in w h i c h W T was measured. Average endocardial a n d epicardial MBF w e r e similarly calculated. Experiniental Protocol The first data set was o b t a i n e d 5 days after p l a c e m e n t of a m e r o i d c o n s t r i c t o r s w h e n , a c c o r d i n g to o u r p r e v i o u s e x p e r i e n c e , resting MBF a n d W T are normal. 6 T h e dogs w e r e heavily sedated w i t h fentanyl (20 ~ g / k g ) and etomidate (300 lag/kg).They w e r e placed o n t h e i r left side, paralyzed w i t h 10 m g of atracurium, intubated, a n d ventilated o n r o o m air w i t h a respirator p u m p , as d e s c r i b e d previously. Arterial pressures w e r e obtained, a n d 2DE was perf o r m e d at rest a n d d u r i n g d o b u t a m i n e infusion (5-minute stages e a c h at d o s e s of 5, 10, 20, 30, a n d 40 ~tg/kg p e r minute), t 5 Two-dimensional e c h o c a r d i o g r a p h y was s u b s e q u e n t l y p e r f o r m e d t w i c e weekly. After t h e d e v e l o p m e n t of global LV dysfunction (at a m e a n of 59 -+ 20 days), t h e s e c o n d data set was obtained. Arterial pressures w e r e again o b t a i n e d and 2DE was r e p e a t e d at rest and d u r i n g n c r e m e n t a l dobut a m i n e doses. MBF was also m e a s u r e d by u s i n g radiolab e l e d m i c r o s p h e r e s at rest a n d d u r i n g p e a k d o b u t a m i n e . I m m e d i a t e l y after t h e s e c o n d data set w a s o b t a i n e d , s e l e c t i v e c o r o n a r y b y p a s s to t h e LAD w a s p e r f o r m e d u n d e r sterile conditions. Anesthesia a n d muscle paralysis w e r e i n d u c e d in a m a n n e r similar to w h e n t h e a m e r o i d c o n s t r i c t o r s w e r e placed. A left lateral t h o r a e o t o m y was p e r f o r m e d in the fourth intercostal space followed by an intravenous injection of h e p a r i n (80 1U/kg). After isolation
Journal of the American Society of Echoeardiography November 2001
1050 Pelberg et al
Hemodynamics
Table 1 Hcmodynamic data Resting aortic
Dobutamtne* Dobutamine* (aortic (heart
pressure
Resting heart rate
Stage
(ram rig)
(bpm)
(ram Hg)
rate) (bpm)
Baseline Betbre bypass Before bypass
89 -+ 11 94 -+22 88 ± 11
79 +_12 95 _+l i t 81 _+17
103 _+23 104 -+21 100 _+31
157 _+36 174 ± 26 147 _+27*
pressure)
*At 40 ~tg/kg per minute. tSignificant compared with baseline (P = .02). *Significant compared with prebypass values (P = .03).
of the LAD,the left internal mammary artery was dissected free from surrounding tissues and ligated distally.The midLAD was isolated, and an end-to-side anastomosis was performed between the left internal mammary artery and the LAD, the integrity of which was assessed with a probe. After the administration of 1 mg/kg protamine, the thorax was examined for bleeding. The chest was then closed in layers, and the animal was revived and transferred to the vivarium, where it was examined twice dally and treated for infection if necessary. The third data set was obtained 3 weeks after bypass surgery. This data set was identical to the second data set as described above. The animals were then euthanized with an overdose of pentobarbital and potassium chloride. The hearts were sliced and immersed in a solution of 1.3% 2,3,5-triphenyl tetrazolium chloride (Sigma) and 0.2 mol/L Sorensen buffer (KHzPO 4 and KeHPO 4 in distilled water, pH 7.4) at 37°C for 20 minutes to delineate any gross necrosis. 22 The slices corresponding to the 2DE planes were then prepared for MBF analysis.
Statistics Unless otherwise stated, data are expressed as mean _+ 1 SD. Interstage comparisons were made by analysis of variance or Student t test. Differences between stages were considered significant at a level of P < .05 (2-sided).
~S~TS I n o n e dog, it was n o t possible to o b t a i n images at the l o w papillary m u s c l e level; i n 2 dogs, the high papillary level did n o t d e m o n s t r a t e resting dysfunction before bypass.Therefore, a total of 22 s e g m e n t s w e r e i n c l u d e d in this analysis (11 LAD a n d 11 LCx). P o s t m o r t e m tissue staining revealed i n f a r c t i o n i n a single s e g m e n t (anterior) i n only 1 of 7 animals, a n d this r e g i o n was n o t i n c l u d e d i n t h e analysis. Myocardial infarction i n this dog was caused b y t e c h n i c a l difficulties d u r i n g the initial a m e r o i d p l a c e m e n t o n the LAD. Severe h e a r t failure e n s u e d a n d w a s successfully treated w i t h d i g o x i n a n d furosemide.
The h e m o d y n a m i c data are d e p i c t e d i n T a b l e 1 .There w e r e n o significant differences i n the m e a n resting arterial p r e s s u r e at any stage.The m e a n arterial pressures d u r i n g d o b u t a m i n e stress w e r e also similar a m o n g stages. A difference was f o u n d i n the h e a r t rate b e t w e e n the b a s e l i n e a n d p r e b y p a s s resting as well as d o b u t a m i n e stages.
Myocardial Blood Flow Figure 1 depicts the radiolabeled microsphered e r i v e d MBF data for the LAD b e d before a n d after bypass surgery. Before selective LAD bypass, the m e a n transmural MBF at rest a n d at the peak d o b u t a m i n e dose were 1.1 + 0.5 and 3.0 + 1.5 m L / m i n p e r gram, respectively, a n d w e r e n o t significantly c h a n g e d after LAD bypass. The resting EER was n o r m a l i n the LAD b e d before bypass surgery (1.5 + 0.6) a n d r e m a i n e d u n c h a n g e d after surgery. I n c o m p a r i s o n , the EER at peak d o b u t a m i n e dose was markedly d i m i n i s h e d in the LAD b e d before surgery (0.7 _+ 0.3) a n d i m p r o v e d significantly (1.3 -+ 0.8) 3 w e e k s after surgery. Figure 2 d e p i c t s t h e MBF data for t h e LCx b e d before a n d after LAD bypass. Similar to the LAD bed, resting t r a n s m u r a l MBF (1.3 -+ 0.2 m L / m i n p e r gram) a n d EER (1.2 _+ 0.3) w e r e n o r m a l i n t h e LCx b e d despite the p r e s e n c e of regional d y s f u n c t i o n a n d did n o t change significantly after bypass to the LAD.The m e a n t r a n s m u r a l MBF (3.1 _+ 1 m L / m i n p e r gram) in the LCx b e d d u r i n g p e a k d o b u t a m i n e dose before LAD bypass was also similar to that i n the LAD b e d a n d r e m a i n e d u n c h a n g e d after surgery.Although the t r a n s m u r a l MBF reserve i n t h e LCx b e d w a s slightly less t h a n that of the LAD b e d (2.4 versus 2.7) before LAD bypass surgery, this difference was n o t significant a n d did n o t c h a n g e after surgery. Similar to the LAD bed, the EER d u r i n g the p e a k d o b u t a m i n e dose in the LCx b e d was markedly d i m i n i s h e d (0.7 +_-0.4). I n c o n t r a d i s t i n c t i o n to the LAD bed, however, it did n o t i m p r o v e (0.75 + 0.4) after LAD bypass.
Regional LV Function Figure 3 s h o w s e x a m p l e s of 2DE end-diastolic a n d end-systolic short-axis images at t h e high papillary m u s c l e level o b t a i n e d at rest from a dog before a n d 3 w e e k s after bypass surgery to the LAD.The prebypass images d e p i c t r e d u c e d W T in b o t h t h e LAD a n d LCx b e d s . T h r e e w e e k s after bypass, W T in the LAD b e d is n o r m a l a n d t h e LV e n d - s y s t o l i c area is reduced. Figure 4 s h o w s e x a m p l e s of end-diastolic a n d end-systolic images d u r i n g p e a k d o b u t a m i n e dose in this same dog. Again, t h e W T r e s p o n s e to d o b u t a m i n e ( i n c l u d i n g end-systolic LV d i m e n s i o n s ) is imp r o v e d after bypass surgery.
Journal of the American Society of Echocardiography Volume 14 Number 11
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Figure 1 Transmural myocardial blood flow (MBF) (A) and MBF endocardial/epicardial ratio (EER) (B) for the left anterior descending coronary artery bed at rest (left panels) and during peak dobutamine dose (right panels) both before (filled bars) and after (hatched bars) selective left anterior descending bypass surgery. P < .O1 compared with measurements performed before surgery; P = .02 compared with MBF at peak dobutaminc dose before surgery. Sce text for details.
Figure 5 d e p i c t s m e a n W T in t h e LAD b e d at rest and during dobutamine before the placement of a m e r o i d c o n s t r i c t o r s , after t h e d e v e l o p m e n t o f LV dysfunction, a n d 3 w e e k s after selective LAD bypass. As e x p e c t e d , resting W T in t h e LAD b e d was n o r m a l before ameroid constrictor placement and increased in a s t e p w i s e fashion at i n c r e m e n t a l d o s e s o f d o b u tamine.After placement of the ameroid constrictors a n d t h e d e v e l o p m e n t o f LV dysfunction, W T in t h e LAD b e d d e c r e a s e d significantly c o m p a r e d w i t h that b e f o r e a m e r o i d c o n s t r i c t o r p l a c e m e n t (13% _+ 6% versus 36% + 4°/% P = . 0 0 0 1 ) . T h e d e v e l o p m e n t o f a critical stenosis w a s e v i d e n c e d b y a b l u n t e d , biphasic r e s p o n s e to d o b u t a m i n e . T h r e e w e e k s after selective LAD b y p a s s , r e s t i n g W T in t h e LAD b e d i m p r o v e d to n o r m a l l e v e l s ( P = .0001) c o m p a r e d
Pre
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DOBUTAMINE Figure 2 Transmural myocardial blood flow (MBF) (A) and MBF endocardial-epicardial ratio (EER) (B) for the left circumfex bed at rest (left panels) and during peak dobutamine dose (right panels), both before (solid bars) and after (hatched bars) sclectivc lcft anterior descending bypass surgcry. P < .01 compared with measurements performed at rcst bcforc surgery. Sce text for details.
w i t h b e f o r e b y p a s s a n d d i d n o t d e m o n s t r a t e a biphasic r e s p o n s e to d o b u t a m i n e , i n d i c a t i n g s u c c e s s f u l b y p a s s o f the critical s t e n o s i s . A l t h o u g h t h e r e s p o n s e to d o b u t a m i n e w a s b e t t e r at e a c h d o s e c o m p a r e d w i t h i m m e d i a t e l y b e f o r e bypass, it d i d n o t r e a c h t h e levels o b t a i n e d b e f o r e a m e r o i d c o n s t r i c t o r p l a c e ment. Similar to t h e LAD bed, W T in t h e LCx b e d w a s normal before ameroid constrictor placement ( F i g u r e 6) a n d d e c r e a s e d s i g n i f i c a n t l y j u s t b e f o r e LAD b y p a s s (12% _+ 6% versus 37% -+ 2 % , P = .0001). T h e r e s p o n s e to d o b u t a m i n e b e f o r e a m e r o i d cons t r i c t o r p l a c e m e n t a n d after t h e d e v e l o p m e n t o f LV d y s f u n c t i o n w a s also similar to that o f t h e LAD b e d . T h e b i p h a s i c r e s p o n s e o f t h e LCx b e d to d o b u t a m i n e i n d i c a t e d t h e d e v e l o p m e n t o f a c r i t i c a l LCx stenosis. Unlike t h e LAD b e d , h o w e v e r , W T in t h e LCx b e d d i d n o t i m p r o v e after selective LAD b y p a s s
1052 Pelberg et al
Journal of the American Society of Echocardiography November 2001
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Figure 3 Two-dimensional echocardiographic end-diastolic (left panel) and end-systolic (right panel) short-axis images at thc high papillary muscle level obtained from one dog at rest before bypass surgery when left vcntricular dysfunction had developed (top panel) and 3 weeks after bypass surgery to the left anterior dcsccnding coronary artery (bottom panel).
e i t h e r at rest o r d u r i n g d o b u t a m i n e a n d w a s a l m o s t i d e n t i c a l to p r e b y p a s s values. ESWS i n c r e a s e d in b o t h b e d s w h e n LV d y s f u n c t i o n d e v e l o p e d (from a m e a n o f 10 to 17.1 d y n e / c m for t h e LAD b e d , P = .002, a n d 9.6 to 13.2 d y n e / c m for t h e LCx b e d , P = .005). T h r e e w e e k s after selective LAD bypass, t h e ESWS d e c r e a s e d in t h e LAD b e d to 10.6 d y n e / c m ( P = .01 c o m p a r e d w i t h b e f o r e bypass), w h e r e a s it r e m a i n e d essentially u n c h a n g e d in t h e LCx bed.
Global LV F u n c t i o n B e c a u s e o f g l o b a l LV s y s t o l i c d y s f u n c t i o n , t h e LV short-axis end-systolic area i n c r e a s e d f r o m 7.4 _+ 3.5 to 10.6 _+ 3.5 c m 2 ( P < .01) after t h e p l a c e m e n t o f t h e a m e r o i d c o n s t r i c t o r s a n d d i d n o t c h a n g e after LAD b y p a s s (9.8 -+ 2.3 c m 2) b e c a u s e o f p e r s i s t e n t dysf u n c t i o n in t h e n o n r e v a s c u l a r i z e d LCx b e d . In comparison, t h e LV short-axis end-diastolic area i n c r e a s e d minimally (from 15.5 -+ 5.0 to 17.0 _+ 3.8 c m 2) after
d e v e l o p m e n t of LV systolic d y s f u n c t i o n a n d continu e d to i n c r e a s e to 18.3 _+ 4.0 c m z 3 w e e k s after LAD b y p a s s surgery. T h e s e i n c r e a s e s in LV e n d - d i a s t o l i c areas, however, d i d n o t r e a c h statistical significance.
DISCUSSION W e h a v e d e m o n s t r a t e d t h a t in a c a n i n e m o d e l o f c h r o n i c i s c h e m i c LV d y s f u n c t i o n in w h i c h r e s t i n g t r a n s m u r a l MBF a n d EER are n o r m a l , d i m i n i s h e d resting m y o c a r d i a l W T is a s s o c i a t e d w i t h an a b n o r m a l EER reserve. R e v a s c u l a r i z a t i o n r e v e r s e s this a b n o r mality as w e l l as t h e a b n o r m a l i t i e s in r e g i o n a l resting W T a n d ESWS. To o u r k n o w l e d g e , t h i s is t h e first c l e a r d e m o n s t r a t i o n o f r e d u c e d e n d o c a r d i a l MBF reserve as a c a u s e o f resting m y o c a r d i a l d y s f u n c t i o n in c h r o n i c i s c h e m i c LV d y s f u n c t i o n in w h i c h r e s t i n g t r a n s m u r a l MBF a n d EER are normal. It is also t h e first illustration of the reversibility of this abnormality
Journal of the American Socie~ of Echocardiography Volume 14 Number 11
Pelberg et al 1053
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Figure 4 Two-dimensional cchocardiographic end-diastolic (left panel) and end-systolic (right panel) short-axis images at the high papillary muscle level during peak dobutamine dose obtained from the same dog whose images are depicted in Figure 3. Toppanel illustrates images obtained before bypass surgery when left ventricular dysfunction had developed; bottompanel illustrates images acquired 3 weeks after bypass surgery to the left anterior descending coronary artery,.
with revascularization. Our results also form the basis of a putative mechanism for the dissociation b e t w e e n stress-induced regional transmural perfusion and regional function. These findings provide valuable insights into the mechanism for ischemic LV dysfunction in the setting of normal resting transmural MBF and EER and provide a better understanding of cardiac stress imaging in this setting. T h e P r o b l e m o f C h r o n i c I s c h e m i c LV Dysfunction There is controversy regarding the pathogenesis of chronic ischemic LV dysfunction. One school maintains that "hibernation" or reduced WT in response to reduced resting MBE causes this phenomenon.23-29 A more recent view is that this p h e n o m e n o n occurs as the result of repetitive demand ischemia caused by a severe stenosis but that the resting MBF is normal ("stunning"). 1-5 These views are based on both human and experimental studies•
We have recently described a canine model of chronic multivessel c o r o n a r y stenosis. 6 In this model, MBF andWT remain normal for the first week after placement of ameroid constrictors on the proximal portions of the LAD and LCx and their major branches. Between the first and s e c o n d weeks, myocardial dysfunction develops despite normal resting MBE The flow-function relation in the ensuing weeks is related to development of collateral vessels. If the myocardial region subtended by the stenosis is small (usually the LAD bed in the dog), MBF continues to remain normal. On the other hand, if this region is large (usually the LCx bed), MBF starts to decline and there is close coupling between the degree of MBF reduction and WT. A downregulation of WT is noted at any level of reduced MBE All hibernating segments demonstrate stunning before reduction in MBE 6 Thus a wide spectrum of pathophysiologic mechanisms appears to be operative in chronic ischemic
Journal of the American Society of Echocardiography November 2001
1054 Pelberg et al
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Figure 5 Wall thickening (WT) (y-axis) in the left anterior descending coronary artery (LAD) bed at rest and during incremental doses of dobutamine (x-axis). Dashed line indicates WT at baseline betbre ameroid constrictor placement. Dash-dotted line represents WT after the development of left ventricular dysfunction and before LAD bypass. Solid line represents WT 3 weeks after LAD bypass surgery. Error bars represent _+ 1 standard error of the mean. See text for details.
Figure 6 Wall thickening (WT) (),-axis) in the left circumflex artery (LCx) bed at rest and during incremental doses of dobutamine (x-axis). Dashed line indicates WT at baseline before ameroid constrictor placement. Dash-dotted line represents WT after the development of left ventricular dysfunction and before left anterior descending coronary artery bypass. Solid line represents WT 3 weeks after left anterior descending coronary artery bypass.
LV d y s f u n c t i o n e v e n w i t h o u t any p r i o r infarction. The basis for d e t e c t i n g viable m y o c a r d i u m in this clinical setting will, therefore, d e p e n d o n the specific mechanism. For instance, if MBF is reduced, t h e n a quantitative assessment o f its d e g r e e of r e d u c t i o n will aid in the prediction of functional recovery.30,31 If transmural MBF is >30% o f n o r m a l and the endoc a r d i u m has n o t u n d e r g o n e necrosis, f u n c t i o n a l r e c o v e r y is likely after revascnlarization.32-34 If resting transmural MBF is normal at rest and a b n o r m a l during stress, t h e n the m y o c a r d i u m is b o t h viable and p r o n e to ischemia and h e n c e is v e r y likely to recover after revascularization. 11,12 This study s h o w s that dysflmctional m y o c a r d i u m may have n o r m a l resting transmural MBF and MBF reserve. Such m y o c a r d i u m will not s h o w a perfusion a b n o r m a l i t y either at stress or during rest, b u t its function will improve after revascularization. Because regional function is highly influenced b y endocardial MBE 1~18 such m y o c a r d i u m will d e m o n s t r a t e a "biphasic" r e s p o n s e o n d o b u t a m i n e e c h o c a r d i o g r a phy. 35,36 Therefore, in this particular setting, dobuta-
mine echocardiography will better predict functional r e c o v e r y than conventional forms o f stress perfusion imaging, w h i c h can only assess transmural and n o t endocardial MBF reserve. Critique of Methods We used a m o d e l o f chronic LV dysfunction, w h i c h is similar to the clinical situation.We also used a m o d e l o f multivessel stenosis, w h i c h is m o r e likely to be present in m o s t cases o f c h r o n i c LV dysfimction seen clinically. 37 From our previous experience, w e learned that p l a c e m e n t o f a v e r y proximal stenosis o n the LCx, w h i c h is t h e larger c o r o n a r y a r t e r y in m o s t dogs, almost invariably leads to eventual r e d u c t i o n in MBF and W T (hibernation) in the LCx bed.6 Because w e w a n t e d MBF in the LCx b e d to remain normal, w e placed the stenosis m o r e distally o n the LCx so that intra-arterial collateral vessels c o u l d develop. Thus in this study, MBF and resting EER w e r e n o r m a l in b o t h the LAD a n d LCx beds, and the LCx b e d served as an adequate control. T h e p r e s e n c e o f a noncritical stenosis (<85% of
Journal of the American Society of Echocardiography Volume 14 Number 11
luminal d i a m e t e r n a r r o w i n g ) w a s e v i d e n c e d b y t h e p r e s e n c e o f a n o r m a l r e s t i n g t r a n s m u r a l MBF a n d t r a n s m u r a l MBF r e s e r v e in b o t h b e d s . T h e p r e s e n c e o f viable m y o c a r d i u m w a s e v i d e n c e d b y t h e lack o f gross infarction in all s e g m e n t s analyzed as w e l l as a biphasic response to dobutamine. This particular r e s p o n s e also c o r r o b o r a t e d t h e p r e s e n c e o f a nonc r i t i c a l s t e n o s i s as w e l l as i n d u c t i o n o f d e m a n d i s c h e m i a in b o t h b e d s . R e v a s c u l a r i z a t i o n s e r v e d to test o u r h y p o t h e s i s , a n d r e p e a t d o b u t a m i n e 2DE 3 w e e k s later p e r m i t t e d t h e a s s e s s m e n t o f b o t h MBF a n d c o n t r a c t i l e r e s e r v e after b y p a s s surgery. One potential limitation was that we bypassed o n l y t h e LAD.The r e a s o n w a s o u r c o n c e r n relating to using c i r c u l a t o r y b y p a s s a n d its i n d e p e n d e n t effect o n m y o c a r d i a l function. To avoid c i r c u l a t o r y bypass, w e w e r e c o n f i n e d to u s i n g t h e i n t e r n a l m a m m a r y a r t e r y . T h e mid-LCx o r a marginal b r a n c h w a s posterior, a n d t h e s h o r t l e n g t h o f t h e internal m a m m a r y d i d n o t a l l o w a n a s t o m o s i s to t h e s e targets. As s t a t e d before, r e g i o n a l MBE MBF reserve, a n d W T in t h e LCx b e d w e r e i d e n t i c a l to t h e LAD b e d b e f o r e LAD byp a s s surgery. A n o t h e r p o t e n t i a l l i m i t a t i o n is t h e l a c k o f MBF measurements before ameroid constrictor placements. O u r p r e v i o u s e x p e r i e n c e f r o m this m o d e l has s h o w n that resting MBF r e m a i n s n o r m a l for t h e first w e e k after a m e r o i d p l a c e m e n t . 6 In t h e d o g s u s e d in o u r study, m i c r o s p h e r e data 5 days after a m e r o i d cons t r i c t o r p l a c e m e n t also s h o w e d n o r m a l MBF r e s e r v e EER. T h e l a c k o f any r e g i o n a l d y s f u n c t i o n d u r i n g s u r g e r y after p l a c e m e n t o f a m e r o i d c o n s t r i c t o r s also confn-med t h e p r e s e n c e o f n o r m a l resting MBE A l t h o u g h t h e b i p h a s i c r e s p o n s e to d o b u t a m i n e w a s n o l o n g e r p r e s e n t in t h e LAD b e d after bypass, i n d i c a t i n g t h e a b s e n c e o f i n d u c i b l e ischemia, 15 t h e contractile reserve had not returned to normal. T h e r e are several p o s s i b l e e x p l a n a t i o n s for this finding, t h e m o s t likely o f w h i c h is that w e m a y n o t have a l l o w e d s u f f i c i e n t t i m e for c o n t r a c t i l ~ r e s e r v e to fully r e c o v e r . M e t a b o l i c a n d c o n t r a c t i l e a p p a r a t u s a b n o r m a l i t i e s m a y t a k e l o n g e r to r e c o v e r . Micros c o p i c infarctions also c o u l d have b e e n p r e s e n t , thus l i m i t i n g c o n t r a c t i l e r e s e r v e , e s p e c i a l l y if t h e y occ u r r e d in t h e e n d o c a r d i n m . Ultrastructural c h a n g e s also c o u l d have o c c u r r e d , w h i c h c o u l d limit contractile reserve. T h e last t w o e x p l a n a t i o n s w o u l d h a v e required detailed histologic examinations, which w e r e n o t p e r f o r m e d in this study. Clinical Implications This s t u d y has o f f e r e d n e w m e c h a n i s t i c insights into t h e p a t h o g e n e s i s o f c h r o n i c i s c h e m i c LV dysfunction. It is k n o w n that m y o c a r d i a l d y s f u n c t i o n c a n b e p r e s e n t w h e n resting t r a n s m u r a l MBF a n d EER are
Pelberg et al 1055
n o r m a l . O u r s t u d y e x p a n d s t h e s e o b s e r v a t i o n s to i n d i c a t e that e v e n t r a n s m u r a l MBF r e s e r v e c a n b e n o r m a l a n d in this setting m y o c a r d i a l d y s f u n c t i o n is a s s o c i a t e d w i t h a b n o r m a l e n d o c a r d i a l MBF reserve. R e v e r s a l o f this a b n o r m a l i t y b y r e v a s c u l a r i z a t i o n leads to r e c o v e r y in resting function. Cardiac i m a g i n g is a m a j o r m o d a l i t y in t h e clinical a s s e s s m e n t o f m y o c a r d i a l viability in p a t i e n t s w i t h c h r o n i c i s c h e m i c LV d y s f u n c t i o n . C o n v e n t i o n a l t e c h n i q u e s u s e d to m e a s u r e m y o c a r d i a l p e r f u s i o n ( s u c h as s i n g l e - p h o t o n a n d p o s i t r o n e m i s s i o n c o m puted tomography) have poor spatial resolution (0.6 to 1.6 c m ) a n d are u n a b l e to d e t e c t an a b n o r mal EER a n d h e n c e t h e p r e s e n c e o f r e v e r s i b l e e n d o cardial i s c h e m i a . T h u s n o r m a l o r n e a r n o r m a l perfusion b o t h at rest a n d d u r i n g stress m a y b e s e e n in dysfunctional myocardial segments with the use of t h e s e t e c h n i q u e s . W h e n d y s f u n c t i o n is u n e q u i v o c a l ly regional, s u c h m y o c a r d i u m is c o n s i d e r e d v i a b l e d e s p i t e n o e v i d e n c e o f r e v e r s i b l e i s c h e m i a a n d is usually r e v a s c u l a r i z e d . O u r results i n d i c a t e t h a t in this setting, stress e c h o c a r d i o g r a p h y c o u l d b e useful in d e m o n s t r a t i n g r e v e r s i b l e i s c h e m i a b e c a u s e w h e n e n d o c a r d i a l MBF r e s e r v e is r e d u c e d , e n d o c a r d i a l t h i c k e n i n g is also r e d u c e d d u r i n g stress38,39 a n d r e v e r s i b l e W T a b n o r m a l i t i e s are n o t e d . Clinical studies w i l l b e r e q u i r e d t o fully a d d r e s s this i s s u e in humans.
REFERENCES
1. Vanoverschelde JLJ, Wijns W, Depr~ C, Essamri B, Heyndrickx GR, Borgers M, et al. Mechanisms of chronic regional postischemic dysfunction in humans: new insights from the study of noninfarcted collateral dependent myocardium. Circulation 1993;87:1513-23. 2. Gerber BL, Vanoverschelde JLJ, Bol A, Michel C, Labar D, Wijns W, et al. Myocardial blood flow, glucose uptake, and recruitment of inotropic reserve in chronic left ventricular ischemic dysfunction: implications tbr the pathophysiology of chronic myocardial hibernation. Circulation 1996;94: 651-9. 3. Shen YT, Vamer S. Mechanism of impaired myocardial function during progressive coronary stenosis in conscious pigs: hibernation versus stunning? Circ Res 1995;76:479 88. 4. Berman M, Fischman AJ, Southern J, Carter E, Mirecki F, Strauss HW, et al. Myocardial adaptation during and after sustained, demand-induced ischemia: observations in closedchest, domestic swine. Circulation 1996;94:755-62. 5. Marinho NVS, Keogh BE, Costa DC, Lamnlerstma AA, Ell PJ, Camici PG. Pathophysiolog3' of chronic left ventricular dysfunction: new insights from the measurement of absolute myocardial blood flow and glucose utilization. Circulation 1996;93:737-44. 6. Firoozan S, Wei K, Linka A, Skyba D, Goodman NC, Kaul S. A canine model of chronic ischemic cardiomyopathy: characterization of regional flow-function relations. Am J Physiol 1999;276:H446-55.
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7. Homans DC, Sublett E, Dai XZ, Bache R. Persistence of regional left ventricular dysfunction after exercise-induced myocardial ischemia. J Clin Invest 1986;77:66-73. 8. Homans DC, Laxson DD, Sublett E, Lindstrom P, Bache RJ. Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia. Am J Physiol 1989;256:H1462 71. 9. Thaulow E, Guth BD, Heush G, Gilpin E, Schulz R, Kroeger K, et al. Characteristics of regional myocardial stunning after exercise in dogs with chronic coronary stenosis. Am J Physiol 1989;257:H113-9. 10. Homans DC, Laxson DD, Sublett E, Pavek T, Crampton M. EffEct of exercise intensity and duration on regional function during and after exercise-induced ischemia. Circulation 1991; 83:2029-37. 11. Kloner RA, Alien J, Cox TA, Zheng Y, Ruiz CE. Stunned left ventricular myocardium after exercise treadmill testing in coronary artery disease. An1 J Cardiol 1991;68:329-34. 12. Ambrosio G, Betocchi S, Pace L, Losi A, Perrone-Filardi P, Soricelli A, et al. Prolonged impairment of regional contrac tile function after resolution of exercise-induced angina: evidence of myocardial stunning in patients with coronary artery disease. Circulation 1996;94:2455-64. 13. Bonow RO, Dilsizian V, Cuocolo A, Bacharach SL. Identification of viable myocardium in patients with chronic coro nary artery disease and left ventricular dysfunction: comparison of thallittm scintigraphy with reinjection and PET imaging with 18F-fluorodeoxyglucose. Circulation 1991;83:26-37. 14. Marzullo P, Sambuceti G, Parodi O. The role of sestamibi scintigraphy in the radioisotopic assessment of myocardial viability. J Nucl Med 1992;33:1925-30. 15. Senior R, Lahiri A. Enhanced detected of myocardial ische mia by stress echocardiography utilizing the "biphasic" response of wall thickening during low- and high-dose dobutamine infusion. J Am Coil Cardiol 1995;26:26-32. 16. Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross J Jr. Regional myocardial pcrfusion and wall thickening during ischemia in conscious dogs. Am J Physiol 1984;247:H727-38. 17. Myers JH, Stirling MC, Choy M, Buda AJ, Gallagher KP. Direct measurement of inner and outer wall thickening dynamics with epicardial echocardiography. Circulation 1986;74:164-72. 18. Weintraub WS, Hattori S, Aggarwal JB, Bodenheimer MM, Banka VS, Helfant RH. The relationship between myocardial blood flow and contraction by myocardial layer in the canine left ventricle during ischemia. Circ Res 1981;48:430-8. 19. Sklenar ], Jayaweera AR, Kaul S. A computer-aided approach for the quantification of regional left vcntricular function using two-dimensional echocardiography. J Am Soc Echo cardiogr 1992;5:33-40. 20. Hood WP, Rackley C, Rollet EL. Wall stress in the normal mad hypertrophied left ventricle. Am J Cardiol 1968;22:550-8. 21. Heymann MA, Paync BD, Hoffinan JI, Rudolph AM. Blood flow measurements with radionuclide labeled particles. Prog Cardiovasc Dis 1977;20:52-79. 22. Fishbein MC, Meerbaum S, Rit J, Lando U, Kammatsusc K, Mercier JC, et al. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride enzyme staining technique. Am Heart J 1981 ;101 :593 -600. 23. Arai AE, Graner SE, Anselone CG, Pantley GA, Bristow D. Metabolic adaptation to a gradual reduction in myocardial blood flow. Circulation 1995;92:244-52.
Journal of the American Society of Echocardiography November 2001
24. Bolukoglu HJ, Liedtke S, Nellis AM, Eggleston M, Subramanian R, Renstrom B. An animal model of chronic coronary stenosis resulting in hibernating myocardium. Am J Physiol 1992;263:H20-9. 25. Chen CL, Fallon JT, Ma L, Li L, Bow L, Knibbs LD, et al. Functional and structural alterations with 24-hour myocardial hibernation and recovery after reperfusion: a pig model of myocardial hibernation. Circulation 1996;94:507-16. 26. Fallavollita JA, Perry BJ, Canty JM. 18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium: evidence for transmural variations in chronic hibernating myocardium. Circulation 1997;95:1900-9. 27. Mills I, Fallon JT, Wrenn D, Sasken H, Gray W, Bier J, et al. Adaptive responses of coronary circulation and myocardium to chronic reduction in perfusion pressure and flow. Am J Physiol 1994;266:H447-57. 28. Rahimtoola SH. Hibernating myocardium has reduced blood flow at rest that increases with low-dose dobutamine. Circulation 1996;94:3055-61. 29. Schulz R, Rose j', Martin C, Brodde OE, Heusch G. Development of short-term myocardial hibernation: its limitation by the severity of ischemia and inotropic stimulation. Circulation 1993;88:684-95. 30. Ragosta M, Belier GA, Watson DD, Kaul S, Gimple LW. Quantitative planar rest-redistribution Z°lTl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation 1993;87:1630-41. 31. Udelson JE, Coleman PS, Metherall J, Pandian NG, Gomez AR, Griffith JL, et al. Predicting recovery of severe regional ventricular dysfunction: comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi. Circulation 1994;89:255261. 32. Ragosta M, Camarano GP, Kaul S, Powers E, Sarembock IJ, Gimple LW. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction: new insights using myocardial contrast echocardiography. Circulation 1994;89:2562-9. 33. Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An association between collateral blood flow and myocardial viability in patients with recent myocardial inthrction. N Engl J Med 1992;372:1825-31. 34. Kaul S. There may be more to myocardial viability than meets the eye! Circulation 1995;92:2790-3. 35. Afridi I, Kleiman NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation: optimal dose and accuracy in predicting recovery of ventricnlar function after coronary angioplasty. Circulation 1995;91:663-70. 36. Kaul S. Response of dysfunctional myocardium to dobutamine: "the eyes see what the mind knows!" J Am Coil Cardiol 1996;27:1608-11. 37. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998;97:282-9. 38. Gallagher KS', Osakada G, Matsuzaki M, Kemper WS, Ross J Jr. Myocardial blood flow and function with critical coronary stenosis in exercising dogs. Am J Physiol 1982;243:H698707. 39. Bache RJ, Shwartz JS. Myocardial blood flow during exercise after gradual coronary occlusion in the dog. Am J Physiol 1983;245:H131-8.
Mechanism of Myocardial Dysfunction in the Presence of Chronic Coronary Stenosis and Normal Resting Myocardial Blood Flow: Clinical Implications Robert A. Pelberg, MD, William D. Spomitz, MD, Jian-Ping Bin, MD, Elizabeth I x , MD, N. Craig Goodman, BS, and Sanjiv Kaul, MD, Charlottesville, Virginia
I n c h r o n i c c o r o n a r y a r t e r y disease, resting m y o c a r d i a l d y s f u n c t i o n c a n e x i s t d e s p i t e n o r m a l r e s t i n g transr e n t a l m y o c a r d i a l b l o o d f l o w (MBF). We h y p o t h e s i z e d t h a t this p h e n o m e n o n o c c u r s b e c a u s e o f d i m i n i s h e d e n d o c a r d i a l MBF r e s e r v e . MBF ( m e a s u r e d w i t h r a d i o l a b e l e d m i c r o s p h e r e s ) a n d wall t h i c k e n i n g (WT) ( m e a s u r e d w i t h e c h o c a r d i o g r a p h y ) w e r e assessed i n 7 dogs after t h e d e v e l o p m e n t o f s e v e r e left v e n t r i c u l a r dysfunction caused by placement of ameroid cons t r i c t o r s o n t h e left a n t e r i o r d e s c e n d i n g (LAD) a n d left c i r c u m f l e x a r t e r i e s a n d 3 w e e k s after selective b y p a s s s u r g e r y to t h e LAD. Before surgery, t h e m e a n t r a n s m u r a l MBF at r e s t a n d at p e a k d o b u t a m i n e d o s e i n t h e LAD b e d w e r e 1.1 _+ 0.5 a n d 3.0 -+ 1.5 m L / m i n per gram, respectively, and were not significantly c h a n g e d after LAD b y p a s s . The r e s t i n g e n d o c a r d i a l t o - e p i c a r d i a l MBF ratio (EER) w a s also n o r m a l b e f o r e
b y p a s s (1.5 _+ 0.6) a n d r e m a i n e d u n c h a n g e d a f t e r s u r g e r y . T h e p r e b y p a s s EER at p e a k d o b u t a m i n e dose, however, was m a r k e d l y d i m i n i s h e d in t h e LAD b e d (0.7 -+ 0.3) a n d i m p r o v e d significantly (1.3 -+ 0.8, P < .01) after surgery. Resting WT i n t h e LAD b e d also i m p r o v e d to n o r m a l levels (36% -+ 4% versus 13% -+ 6%, P = .0001) a n d n o l o n g e r d e m o n s t r a t e d a b i p h a s i c r e s p o n s e to d o b u t a m i n e . I n c o m p a r i s o n , t h e n o n b y p a s s e d left c i r c u m f l e x b e d c o n t i n u e d to s h o w r e d u c e d r e s t i n g WT (12% __.6%), a b i p h a s i c r e s p o n s e to d o b u t a m i n e , a n d a b n o r m a l EER d u r i n g r e s t a n d d o b u t a m i n e (0.7 -+ 0.3). We c o n c l u d e that p e r s i s t e n t myocardial dysfunction in the presence of normal r e s t i n g t r a n s m u r a l MBF c a n o c c u r as a r e s u l t o f d i m i n i s h e d e n d o c a r d i a l MBF resetwe, w i t h t r a n s m u r a l MBF r e s e r v e r e m a i n i n g n o r m a l (J Am Soc Echocardiogr 2001;14:1047-56.)
From the Cardiac Imaging Center of the Cardiovascular DMsion (R.A.P., J.-P.B., E.L., N.C.G., S.K.) and the Division of Thoracic and Cardiovascular Surgery (W.D.S.), University of Virginia School of Medicine, Charlottesville. Supported in part by a grant from the National Institutes of" Health (R01-HL-48890), Bethesda, Md. The radiolabeled microspheres were provided by Dupont Pharmaceuticals, North Billerica, Mass, and the ultrasound equipment was supplied by Advanced Technology Laboratories, Bothell, Wash. Dr Pelberg was supported by a Fellowship Training Grant from the Virginia Affiliate of the American Heart Association, Glen Alien, and Dr Elizabeth Le was supported bv a postdoctoral training grant (HL-07355) from the National Institutes of Health. Presented in part at the Young Investigator Award Competition at the 10th Annual Scientific Session of the American Society of Echocardiography, June 1999, in Washington, DC. Reprint requests: Sanjiv Kaul, MD, Cardiovascular DMsion, Box 158, University of Virginia Medical Center, Charlottesville, VA 22908 (E-mail: sk@virginia.~du). Copyright © 2001 by the American Sociew of Echocardiography. 0894-7317/2001/$35.00 + 0 27/1/113232 doi: 10.1067/mje.2001.113232
I t is n o w well r e c o g n i z e d that in c h r o n i c c o r o n a r y a r t e r y disease, r e s t i n g m y o c a r d i a l d y s f u n c t i o n c a n exist d e s p i t e n o r m a l resting t r a n s m u r a l m y o c a r d i a l b l o o d f l o w (MBF). 1~, In m o s t h u m a n studies a n d in l o n g - t e r m a n i m a l s t u d i e s o f single-vessel s t e n o s i s , r e s t i n g MBF r e m a i n s n o r m a l b e c a u s e o f e x t e n s i v e collateral vessel d e v e l o p m e n t . In b o t h situations, it is t h o u g h t that t r a n s m u r a l MBF r e s e r v e is r e d u c e d a n d that r e p e a t e d e p i s o d e s o f d e m a n d i s c h e m i a o c c u r ring d u r i n g daily activities result in p e r s i s t e n t myocardial stunning. 7-12 In t h e clinical setting, d e t e c t i o n o f r e d u c e d transmural MBF r e s e r v e is a c c o m p l i s h e d b y c a r d i a c imagi n g d u r i n g stress. T h u s d y s f u n c t i o n a l m y o c a r d i a l regions demonstrate a reversible perfusion defect d u r i n g e x e r c i s e o r p h a r m a c o l o g i c stress, 13,14 w h e r e as t h e y e x h i b i t a "biphasic" r e s p o n s e d u r i n g d o b u t a m i n e stress. 15 In m a n y instances, h o w e v e r , dysfunctional m y o c a r d i a l s e g m e n t s e x h i b i t n o r m a l o r n e a r
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n o r m a l t r a n s m u r a l p e r f u s i o n at rest, a n d n o reversible p e r f u s i o n d e f e c t is s e e n d u r i n g s t r e s s . W h e n this d y s f u n c ti o n a l r e g i o n is s u b t e n d e d b y a h e m o d y namically significant c o r o n a r y stenosis, it is generally revascularized, despite no objective evidence of i n d u c i b l e ischemia. Most often, r e g i o n a l f u n c t i o n is s e e n to r e c o v e r after revascularization. For this reason, dysfunctional m y o c a r d i u m is c o n s i d e r e d to b e viable and w o r t h revascularizing e v e n w h e n resting p e r f u s i o n is n o r m a l o r n e a r n o r m a l , w i t h o u t t h e n e e d for actually d e m o n s t r a t i n g i n d u c i b l e ischemia. A p a r a d o x s e e m s to e x i s t in this s i t u a t i o n . If m y o c a r d i u m is viable distal t o a stenosis an d is dysf u n c t i o n a l b e c a u s e o f r e p e a t e d e p i s o d e s o f stunning, t h e n it s h o u l d d e m o n s t r a t e a r e d u c t i o n in transmural MBF reserve. In this study, w e h y p o t h e s i z e d that p e r s i s t e n t m y o c a r d i a l d y s f u n c t i o n in t h e p r e s e n c e o f n o r m a l resting t r a n s m u r a l MBF c a n o c c u r as a result o f d i m i n i s h e d e n d o c a r d i a l MBF r e s e r v e w i t h o u t affecting transmural MBF reserve. B e c a u se t h e endoc a r d i u m c o n t r i b u t e s almost t w o thirds to total wall t h i c k e n i n g , 16-18 r e p e a t e d e p i s o d e s o f e n d o c a r d i a l s t u n n i n g c o u l d lead t o r e s t i n g w a l l m o t i o n a b n o r malities. If o u r h y p o t h e s i s is c o r r e c t , t h e n revascularization should reverse the abnormal endocardial MBF r e s e r v e and n o r m a l i z e th e resting wall m o t i o n abnormality.
METHODS Animal Preparation For this study, we used a previously described canine model of multivessel coronary stenosis in which ameroid constrictors are placed on the coronary arteries supplying the left ventricle. 6 When the ameroid constrictor is placed very proximal on the left circumflex coronary artery (LCx), collateral development is inadequate, and in the ensuing weeks MBF may b e c o m e reduced, leading to myocardial hibernation. Because the first septal perforator often arises from the left main coronary artery in dogs, placement of a constrictor on the left anterior descending coronary artery (LAD) spares the first septal perforator and permits collateral vessels to develop from it to the distal LAD. In this situation, transmural MBF can remain normal in the LAD bed, but regional wall motion abnormalities are consistently seen. 6 In this study, w e allowed collateral blood flow to develop in the LCx bed as well by placing the ameroid constrictor more distally on the LCx. This maneuver permitted resting transmural MBF in this region to remain normal. We evaluated percent wall thickening (WT), MBF and endocardial-to-epicardial MBF ratio (EER) at rest and dur-
Journal of the American Society of Echocardiography November 2001
ing dobutamine-induced hyperemia in both the LAD and LCx beds, before and after selective coronary artery bypass to the LAD. In this study, both the LAD and LCx beds demonstrated regional left ventricular (LV) dysfunction before surgery despite normal resting transmural MBF and EER.Thus the LCx bed, which did not tmdergo revascularization, acted as the control bed. The study was approved by the Animal Research Committee at the University of Virginia and conforms to the American Heart Association Guidelines for Animal Research. Animals were pretreated with 75 mg of aspirin daily for 3 days before surgery and were maintained on this dose until euthanasia. An intravenous dose (1 g) of cefazolin sodium was administered before surgery and was continued twice daily for 5 days.A single intravenous dose (80 mg) of gentamicin was also administered immediately before surgery. Surgery was performed under sterile conditions. Anesthesia was induced with 20 ~tg/kg fentanyl, 400 lLg/kg etomidate, and 300 ~tg/kg diazepam, administered intravenously. The animal was intubated and anesthesia was maintained with a mixture of 1% to 1.5% isofluorane, 02, and room air given through a respirator (model 607, Harvard Apparatus, North Bellerica, Mass). Minute volume was set between 5.5 and 6.5 L/min to maintain a physiologic Pco 2. Heart rate and rhythm were monitored throughout the operation. A small incision was made in the right groin, and a 6F indwelling catheter was inserted into the femoral artery and secured in place with silk ties. The catheter was flushed with a dilute solution of heparin and capped off with a rubber injection port. It was then tunneled beneath the skin to allow subsequent transcutaneous access for arterial pressure monitoring as well as withdrawal of samples for blood gas and radiolabeled microsphere-derived MBF analyses.The groin incision was then closed in layers. After skin preparation, 300 ~tg/kg atracurium was administered to induce muscle paralysis.A left lateral thoracotomy was performed in the fourth intercostal space, and the heart was suspended in a pericardial cradle. The mid-portions of the LAD and LCx were dissected free from surrounding tissues. Any large proximal branches of these arteries were similarly dissected. Up to 4 appropriately sized (1 to 3.5 mm) ameroid constrictors were placed around these arteries. Regional LV function was then assessed by direct epicardial 2-dimensional echocardiography (2DE), with the transducer placed in a sterile sleeve to ensure that deterioration in regional systolic function did not occur after placement of the ameroid constrictors. A 6F indwelling catheter was inserted in the left atrium and secured in place with prolene sutures. After flushing with a dilute heparin solution, its end was capped off with a rubber injection port.The catheter was tunneled beneath the dorsal skin to allow subsequent transcutaneous injec-
Journal of the American Society of Echocardiography Volume 14 Number 11
tions of radiolabeled microspheres. The chest was then c l o s e d in layers, a n d t h e a n i m a l w a s revived a n d transferred to an o b s e r v a t i o n area in the vivarium. T h e animals w e r e e x a m i n e d t w i c e daily a n d treated for h e a r t failure a n d infection if required. A s s e s s m e n t o f R e g i o n a l a n d G l o b a l LV F u n c t i o n Regional f u n c t i o n was assessed w i t h t h e use of quantitative 2DE. Imaging was p e r f o r m e d w i t h t h e use of a phasedarray digital s y s t e m (HDI 3000cv, A d v a n c e d T e c h n o l o g y Laboratories, Bothell, Wash) w i t h a 2.3-MHz probe. Apart from t h e intraoperative 2DE d e s c r i b e d above, all data w e r e a c q u i r e d w i t h t h e dog lying o n its left side w h i l e imaging from t h e right thorax. Two short-axis views (high a n d low papillary muscle levels) w e r e r e c o r d e d o n e a c h examination. Care was t a k e n to acquire t h e same views every time in a n individual dog. Images w e r e r e c o r d e d o n 1.25-cm v i d e o t a p e w i t h an S-VHS r e c o r d e r (Panasonic AG-MD830, Matsushita, Secaucus, NJ). Two-dimensional e c h o c a r d i o g r a p h i c images w e r e analyzed as p r e v i o u s l y d e s c r i b e d . 19 T h e y w e r e t r a n s f e r r e d from v i d e o t a p e to t h e m e m o r y of a c o m p u t e r at 30 Hz in a 320 x 240 x 8 bit m a t r i x . T h e o b s e r v e r t h e n defined several endocardial a n d epicardial targets in e a c h frame from e n d diastole to e n d systole.These points w e r e automatically c o n n e c t e d b y u s i n g cubic-spline i n t e r p o l a t i o n to derive epicardial a n d endocardial contours.To c o r r e c t for systolic cardiac rotation, t h e j u n c t i o n of the p o s t e r i o r LV wall a n d t h e right v e n t r i e u l a r free wall was defined o v e r t h e epic a r d i u m in e a c h frame, a n d 100 e q u i d i s t a n t c h o r d s bet w e e n t h e 2 c o n t o u r s w e r e g e n e r a t e d starting at this point. Each c h o r d r e p r e s e n t e d t h e s h o r t e s t distance b e t w e e n t h e epicardial a n d e n d o c a r d i a l c o n t o u r s . T h e o b s e r v e r t h e n s e l e c t e d t h e m y o c a r d i a l r e g i o n s in w h i c h t h e c h o r d lengths w e r e averaged. Plots of WT over t h e entire systolic c o n t r a c t i o n s e q u e n c e w e r e t h e n automatically generated, w i t h t i m e r e p r e s e n t e d in deciles. 19 Maximal W T at any p o i n t in systole was t a k e n to r e p r e s e n t WT. W i t h t h e use of t h e endocardial contour, end-diastolic a n d end-systolic areas w e r e automatically calculated b y t h e computer. Regional end-systolic wall stress (ESWS) was calculated b y using t h e c o m p u t e r - d e r i v e d c u r v a t u r e calculation for t h e LAD and LCx segments, w h e r e c u r v a t u r e represents t h e inverse of t h e radius. Therefore, ESWS ( d y n e / c m ) = (p • r)/(2t • c), w h e r e p = end-systolic pressure, r = radius, t = wall thickness, a n d c = curvature. 2° Myocardial Blood Flow Measurements Four sets of radiolabeled m i c r o s p h e r e s w e r e u s e d in e a c h animal, el T h o s e w i t h longer half-lives w e r e injected earlier in t h e p r o t o c o l to allow e n o u g h c o u n t s in t h e sample o n p o s t m o r t e m analysis.Approximately 2 x 106 11 ~ m radiol a b e l e d m i c r o s p h e r e s ( D u p o n t Medical Products, N o r t h Bellerica, Mass) w e r e s u s p e n d e d in 4 mL of n o r m a l saline
Pclberg et al 1 0 4 9
a n d 0.01% Tween-80 solution and injected into the left atriu m over a p e r i o d of 20 s e c o n d s . T h i s dose of radiolabeled m i c r o s p h e r e s allows at least 1000 m i c r o s p h e r e s to b e c o u n t e d in e a c h gram of n o r m a l tissue a n d at least 300 m i c r o s p h e r e s in each gram of i s c h e m i c tissue. Reference samples w e r e w i t h d r a w n from t h e femoral artery over a p e r i o d of 130 s e c o n d s w i t h a c o n s t a n t rate w i t h d r a w a l p u m p ( m o d e l 944, Harvard Apparatus). T h e t w o p o s t m o r t e m h e a r t slices c o r r e s p o n d i n g to t h e 2DE short-axis images w e r e c u t i n t o 16 w e d g e - s h a p e d pieces. Each piece was f u r t h e r divided into epicardial, midcardial, a n d e n d o c a r d i a l portions. T h e tissue a n d arterial reference samples w e r e c o u n t e d in a well c o u n t e r w i t h a m u l t i c h a n n e l analyzer ( m o d e l 1282, LKB Wallac, Washington, DC). Corrections w e r e m a d e for activity spillover from o n e w i n d o w to t h e n e x t b y using a set of s i m u l t a n e o u s equations p r o g r a m m e d o n a computer. 2~ MBF to e a c h sample w a s c a l c u l a t e d b y t h e e q u a t i o n Qm = (Cm " Qr)/Cr, w h e r e Qm = flow (mL/min), C m = tissue counts, Qr = rate of arterial blood withdrawal (mL/min), and C r = c o u n t s in the reference sample.Transmural MBF (mL/min p e r gram) to e a c h s e g m e n t was derived by dividing the sum of MBF to i n d i v i d u a l s e g m e n t s b y t h e i r c o m b i n e d w e i g h t . 21 Transmural MBF w a s c a l c u l a t e d b y averaging t h e transmural MBF in t h e s e g m e n t s in w h i c h W T was measured. Average endocardial a n d epicardial MBF w e r e similarly calculated. Experiniental Protocol The first data set was o b t a i n e d 5 days after p l a c e m e n t of a m e r o i d c o n s t r i c t o r s w h e n , a c c o r d i n g to o u r p r e v i o u s e x p e r i e n c e , resting MBF a n d W T are normal. 6 T h e dogs w e r e heavily sedated w i t h fentanyl (20 ~ g / k g ) and etomidate (300 lag/kg).They w e r e placed o n t h e i r left side, paralyzed w i t h 10 m g of atracurium, intubated, a n d ventilated o n r o o m air w i t h a respirator p u m p , as d e s c r i b e d previously. Arterial pressures w e r e obtained, a n d 2DE was perf o r m e d at rest a n d d u r i n g d o b u t a m i n e infusion (5-minute stages e a c h at d o s e s of 5, 10, 20, 30, a n d 40 ~tg/kg p e r minute), t 5 Two-dimensional e c h o c a r d i o g r a p h y was s u b s e q u e n t l y p e r f o r m e d t w i c e weekly. After t h e d e v e l o p m e n t of global LV dysfunction (at a m e a n of 59 -+ 20 days), t h e s e c o n d data set was obtained. Arterial pressures w e r e again o b t a i n e d and 2DE was r e p e a t e d at rest and d u r i n g n c r e m e n t a l dobut a m i n e doses. MBF was also m e a s u r e d by u s i n g radiolab e l e d m i c r o s p h e r e s at rest a n d d u r i n g p e a k d o b u t a m i n e . I m m e d i a t e l y after t h e s e c o n d data set w a s o b t a i n e d , s e l e c t i v e c o r o n a r y b y p a s s to t h e LAD w a s p e r f o r m e d u n d e r sterile conditions. Anesthesia a n d muscle paralysis w e r e i n d u c e d in a m a n n e r similar to w h e n t h e a m e r o i d c o n s t r i c t o r s w e r e placed. A left lateral t h o r a e o t o m y was p e r f o r m e d in the fourth intercostal space followed by an intravenous injection of h e p a r i n (80 1U/kg). After isolation
Journal of the American Society of Echoeardiography November 2001
1050 Pelberg et al
Hemodynamics
Table 1 Hcmodynamic data Resting aortic
Dobutamtne* Dobutamine* (aortic (heart
pressure
Resting heart rate
Stage
(ram rig)
(bpm)
(ram Hg)
rate) (bpm)
Baseline Betbre bypass Before bypass
89 -+ 11 94 -+22 88 ± 11
79 +_12 95 _+l i t 81 _+17
103 _+23 104 -+21 100 _+31
157 _+36 174 ± 26 147 _+27*
pressure)
*At 40 ~tg/kg per minute. tSignificant compared with baseline (P = .02). *Significant compared with prebypass values (P = .03).
of the LAD,the left internal mammary artery was dissected free from surrounding tissues and ligated distally.The midLAD was isolated, and an end-to-side anastomosis was performed between the left internal mammary artery and the LAD, the integrity of which was assessed with a probe. After the administration of 1 mg/kg protamine, the thorax was examined for bleeding. The chest was then closed in layers, and the animal was revived and transferred to the vivarium, where it was examined twice dally and treated for infection if necessary. The third data set was obtained 3 weeks after bypass surgery. This data set was identical to the second data set as described above. The animals were then euthanized with an overdose of pentobarbital and potassium chloride. The hearts were sliced and immersed in a solution of 1.3% 2,3,5-triphenyl tetrazolium chloride (Sigma) and 0.2 mol/L Sorensen buffer (KHzPO 4 and KeHPO 4 in distilled water, pH 7.4) at 37°C for 20 minutes to delineate any gross necrosis. 22 The slices corresponding to the 2DE planes were then prepared for MBF analysis.
Statistics Unless otherwise stated, data are expressed as mean _+ 1 SD. Interstage comparisons were made by analysis of variance or Student t test. Differences between stages were considered significant at a level of P < .05 (2-sided).
~S~TS I n o n e dog, it was n o t possible to o b t a i n images at the l o w papillary m u s c l e level; i n 2 dogs, the high papillary level did n o t d e m o n s t r a t e resting dysfunction before bypass.Therefore, a total of 22 s e g m e n t s w e r e i n c l u d e d in this analysis (11 LAD a n d 11 LCx). P o s t m o r t e m tissue staining revealed i n f a r c t i o n i n a single s e g m e n t (anterior) i n only 1 of 7 animals, a n d this r e g i o n was n o t i n c l u d e d i n t h e analysis. Myocardial infarction i n this dog was caused b y t e c h n i c a l difficulties d u r i n g the initial a m e r o i d p l a c e m e n t o n the LAD. Severe h e a r t failure e n s u e d a n d w a s successfully treated w i t h d i g o x i n a n d furosemide.
The h e m o d y n a m i c data are d e p i c t e d i n T a b l e 1 .There w e r e n o significant differences i n the m e a n resting arterial p r e s s u r e at any stage.The m e a n arterial pressures d u r i n g d o b u t a m i n e stress w e r e also similar a m o n g stages. A difference was f o u n d i n the h e a r t rate b e t w e e n the b a s e l i n e a n d p r e b y p a s s resting as well as d o b u t a m i n e stages.
Myocardial Blood Flow Figure 1 depicts the radiolabeled microsphered e r i v e d MBF data for the LAD b e d before a n d after bypass surgery. Before selective LAD bypass, the m e a n transmural MBF at rest a n d at the peak d o b u t a m i n e dose were 1.1 + 0.5 and 3.0 + 1.5 m L / m i n p e r gram, respectively, a n d w e r e n o t significantly c h a n g e d after LAD bypass. The resting EER was n o r m a l i n the LAD b e d before bypass surgery (1.5 + 0.6) a n d r e m a i n e d u n c h a n g e d after surgery. I n c o m p a r i s o n , the EER at peak d o b u t a m i n e dose was markedly d i m i n i s h e d in the LAD b e d before surgery (0.7 _+ 0.3) a n d i m p r o v e d significantly (1.3 -+ 0.8) 3 w e e k s after surgery. Figure 2 d e p i c t s t h e MBF data for t h e LCx b e d before a n d after LAD bypass. Similar to the LAD bed, resting t r a n s m u r a l MBF (1.3 -+ 0.2 m L / m i n p e r gram) a n d EER (1.2 _+ 0.3) w e r e n o r m a l i n t h e LCx b e d despite the p r e s e n c e of regional d y s f u n c t i o n a n d did n o t change significantly after bypass to the LAD.The m e a n t r a n s m u r a l MBF (3.1 _+ 1 m L / m i n p e r gram) in the LCx b e d d u r i n g p e a k d o b u t a m i n e dose before LAD bypass was also similar to that i n the LAD b e d a n d r e m a i n e d u n c h a n g e d after surgery.Although the t r a n s m u r a l MBF reserve i n t h e LCx b e d w a s slightly less t h a n that of the LAD b e d (2.4 versus 2.7) before LAD bypass surgery, this difference was n o t significant a n d did n o t c h a n g e after surgery. Similar to the LAD bed, the EER d u r i n g the p e a k d o b u t a m i n e dose in the LCx b e d was markedly d i m i n i s h e d (0.7 +_-0.4). I n c o n t r a d i s t i n c t i o n to the LAD bed, however, it did n o t i m p r o v e (0.75 + 0.4) after LAD bypass.
Regional LV Function Figure 3 s h o w s e x a m p l e s of 2DE end-diastolic a n d end-systolic short-axis images at t h e high papillary m u s c l e level o b t a i n e d at rest from a dog before a n d 3 w e e k s after bypass surgery to the LAD.The prebypass images d e p i c t r e d u c e d W T in b o t h t h e LAD a n d LCx b e d s . T h r e e w e e k s after bypass, W T in the LAD b e d is n o r m a l a n d t h e LV e n d - s y s t o l i c area is reduced. Figure 4 s h o w s e x a m p l e s of end-diastolic a n d end-systolic images d u r i n g p e a k d o b u t a m i n e dose in this same dog. Again, t h e W T r e s p o n s e to d o b u t a m i n e ( i n c l u d i n g end-systolic LV d i m e n s i o n s ) is imp r o v e d after bypass surgery.
Journal of the American Society of Echocardiography Volume 14 Number 11
A
p = 0.02
6
Pelberg et al 1051
A
p = 0.02
6
p = 0.0001
5
p = 0.0001
5
*IN
4
ocm
4
3
m
2
3 2
m
1 0
Pre
Post
REST
Pre
DOBUTAMINE
Pre
REST
Post
DOBUTAMINE p = 0.26
3
p = 0.01
2
p = 0.35
1
1 0
Post
p -- 0 . 0 1
p = 0.003
3 2
Pre
B
p = 0.1
B
0
Post
Pre
Post
REST
Pre
Post
DOBUTAMINE
Figure 1 Transmural myocardial blood flow (MBF) (A) and MBF endocardial/epicardial ratio (EER) (B) for the left anterior descending coronary artery bed at rest (left panels) and during peak dobutamine dose (right panels) both before (filled bars) and after (hatched bars) selective left anterior descending bypass surgery. P < .O1 compared with measurements performed before surgery; P = .02 compared with MBF at peak dobutaminc dose before surgery. Sce text for details.
Figure 5 d e p i c t s m e a n W T in t h e LAD b e d at rest and during dobutamine before the placement of a m e r o i d c o n s t r i c t o r s , after t h e d e v e l o p m e n t o f LV dysfunction, a n d 3 w e e k s after selective LAD bypass. As e x p e c t e d , resting W T in t h e LAD b e d was n o r m a l before ameroid constrictor placement and increased in a s t e p w i s e fashion at i n c r e m e n t a l d o s e s o f d o b u tamine.After placement of the ameroid constrictors a n d t h e d e v e l o p m e n t o f LV dysfunction, W T in t h e LAD b e d d e c r e a s e d significantly c o m p a r e d w i t h that b e f o r e a m e r o i d c o n s t r i c t o r p l a c e m e n t (13% _+ 6% versus 36% + 4°/% P = . 0 0 0 1 ) . T h e d e v e l o p m e n t o f a critical stenosis w a s e v i d e n c e d b y a b l u n t e d , biphasic r e s p o n s e to d o b u t a m i n e . T h r e e w e e k s after selective LAD b y p a s s , r e s t i n g W T in t h e LAD b e d i m p r o v e d to n o r m a l l e v e l s ( P = .0001) c o m p a r e d
Pre
Post
Pre
Post
REST
DOBUTAMINE Figure 2 Transmural myocardial blood flow (MBF) (A) and MBF endocardial-epicardial ratio (EER) (B) for the left circumfex bed at rest (left panels) and during peak dobutamine dose (right panels), both before (solid bars) and after (hatched bars) sclectivc lcft anterior descending bypass surgcry. P < .01 compared with measurements performed at rcst bcforc surgery. Sce text for details.
w i t h b e f o r e b y p a s s a n d d i d n o t d e m o n s t r a t e a biphasic r e s p o n s e to d o b u t a m i n e , i n d i c a t i n g s u c c e s s f u l b y p a s s o f the critical s t e n o s i s . A l t h o u g h t h e r e s p o n s e to d o b u t a m i n e w a s b e t t e r at e a c h d o s e c o m p a r e d w i t h i m m e d i a t e l y b e f o r e bypass, it d i d n o t r e a c h t h e levels o b t a i n e d b e f o r e a m e r o i d c o n s t r i c t o r p l a c e ment. Similar to t h e LAD bed, W T in t h e LCx b e d w a s normal before ameroid constrictor placement ( F i g u r e 6) a n d d e c r e a s e d s i g n i f i c a n t l y j u s t b e f o r e LAD b y p a s s (12% _+ 6% versus 37% -+ 2 % , P = .0001). T h e r e s p o n s e to d o b u t a m i n e b e f o r e a m e r o i d cons t r i c t o r p l a c e m e n t a n d after t h e d e v e l o p m e n t o f LV d y s f u n c t i o n w a s also similar to that o f t h e LAD b e d . T h e b i p h a s i c r e s p o n s e o f t h e LCx b e d to d o b u t a m i n e i n d i c a t e d t h e d e v e l o p m e n t o f a c r i t i c a l LCx stenosis. Unlike t h e LAD b e d , h o w e v e r , W T in t h e LCx b e d d i d n o t i m p r o v e after selective LAD b y p a s s
1052 Pelberg et al
Journal of the American Society of Echocardiography November 2001
:,)
" •
t
Figure 3 Two-dimensional echocardiographic end-diastolic (left panel) and end-systolic (right panel) short-axis images at thc high papillary muscle level obtained from one dog at rest before bypass surgery when left vcntricular dysfunction had developed (top panel) and 3 weeks after bypass surgery to the left anterior dcsccnding coronary artery (bottom panel).
e i t h e r at rest o r d u r i n g d o b u t a m i n e a n d w a s a l m o s t i d e n t i c a l to p r e b y p a s s values. ESWS i n c r e a s e d in b o t h b e d s w h e n LV d y s f u n c t i o n d e v e l o p e d (from a m e a n o f 10 to 17.1 d y n e / c m for t h e LAD b e d , P = .002, a n d 9.6 to 13.2 d y n e / c m for t h e LCx b e d , P = .005). T h r e e w e e k s after selective LAD bypass, t h e ESWS d e c r e a s e d in t h e LAD b e d to 10.6 d y n e / c m ( P = .01 c o m p a r e d w i t h b e f o r e bypass), w h e r e a s it r e m a i n e d essentially u n c h a n g e d in t h e LCx bed.
Global LV F u n c t i o n B e c a u s e o f g l o b a l LV s y s t o l i c d y s f u n c t i o n , t h e LV short-axis end-systolic area i n c r e a s e d f r o m 7.4 _+ 3.5 to 10.6 _+ 3.5 c m 2 ( P < .01) after t h e p l a c e m e n t o f t h e a m e r o i d c o n s t r i c t o r s a n d d i d n o t c h a n g e after LAD b y p a s s (9.8 -+ 2.3 c m 2) b e c a u s e o f p e r s i s t e n t dysf u n c t i o n in t h e n o n r e v a s c u l a r i z e d LCx b e d . In comparison, t h e LV short-axis end-diastolic area i n c r e a s e d minimally (from 15.5 -+ 5.0 to 17.0 _+ 3.8 c m 2) after
d e v e l o p m e n t of LV systolic d y s f u n c t i o n a n d continu e d to i n c r e a s e to 18.3 _+ 4.0 c m z 3 w e e k s after LAD b y p a s s surgery. T h e s e i n c r e a s e s in LV e n d - d i a s t o l i c areas, however, d i d n o t r e a c h statistical significance.
DISCUSSION W e h a v e d e m o n s t r a t e d t h a t in a c a n i n e m o d e l o f c h r o n i c i s c h e m i c LV d y s f u n c t i o n in w h i c h r e s t i n g t r a n s m u r a l MBF a n d EER are n o r m a l , d i m i n i s h e d resting m y o c a r d i a l W T is a s s o c i a t e d w i t h an a b n o r m a l EER reserve. R e v a s c u l a r i z a t i o n r e v e r s e s this a b n o r mality as w e l l as t h e a b n o r m a l i t i e s in r e g i o n a l resting W T a n d ESWS. To o u r k n o w l e d g e , t h i s is t h e first c l e a r d e m o n s t r a t i o n o f r e d u c e d e n d o c a r d i a l MBF reserve as a c a u s e o f resting m y o c a r d i a l d y s f u n c t i o n in c h r o n i c i s c h e m i c LV d y s f u n c t i o n in w h i c h r e s t i n g t r a n s m u r a l MBF a n d EER are normal. It is also t h e first illustration of the reversibility of this abnormality
Journal of the American Socie~ of Echocardiography Volume 14 Number 11
Pelberg et al 1053
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Figure 4 Two-dimensional cchocardiographic end-diastolic (left panel) and end-systolic (right panel) short-axis images at the high papillary muscle level during peak dobutamine dose obtained from the same dog whose images are depicted in Figure 3. Toppanel illustrates images obtained before bypass surgery when left ventricular dysfunction had developed; bottompanel illustrates images acquired 3 weeks after bypass surgery to the left anterior descending coronary artery,.
with revascularization. Our results also form the basis of a putative mechanism for the dissociation b e t w e e n stress-induced regional transmural perfusion and regional function. These findings provide valuable insights into the mechanism for ischemic LV dysfunction in the setting of normal resting transmural MBF and EER and provide a better understanding of cardiac stress imaging in this setting. T h e P r o b l e m o f C h r o n i c I s c h e m i c LV Dysfunction There is controversy regarding the pathogenesis of chronic ischemic LV dysfunction. One school maintains that "hibernation" or reduced WT in response to reduced resting MBE causes this phenomenon.23-29 A more recent view is that this p h e n o m e n o n occurs as the result of repetitive demand ischemia caused by a severe stenosis but that the resting MBF is normal ("stunning"). 1-5 These views are based on both human and experimental studies•
We have recently described a canine model of chronic multivessel c o r o n a r y stenosis. 6 In this model, MBF andWT remain normal for the first week after placement of ameroid constrictors on the proximal portions of the LAD and LCx and their major branches. Between the first and s e c o n d weeks, myocardial dysfunction develops despite normal resting MBE The flow-function relation in the ensuing weeks is related to development of collateral vessels. If the myocardial region subtended by the stenosis is small (usually the LAD bed in the dog), MBF continues to remain normal. On the other hand, if this region is large (usually the LCx bed), MBF starts to decline and there is close coupling between the degree of MBF reduction and WT. A downregulation of WT is noted at any level of reduced MBE All hibernating segments demonstrate stunning before reduction in MBE 6 Thus a wide spectrum of pathophysiologic mechanisms appears to be operative in chronic ischemic
Journal of the American Society of Echocardiography November 2001
1054 Pelberg et al
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Figure 5 Wall thickening (WT) (y-axis) in the left anterior descending coronary artery (LAD) bed at rest and during incremental doses of dobutamine (x-axis). Dashed line indicates WT at baseline betbre ameroid constrictor placement. Dash-dotted line represents WT after the development of left ventricular dysfunction and before LAD bypass. Solid line represents WT 3 weeks after LAD bypass surgery. Error bars represent _+ 1 standard error of the mean. See text for details.
Figure 6 Wall thickening (WT) (),-axis) in the left circumflex artery (LCx) bed at rest and during incremental doses of dobutamine (x-axis). Dashed line indicates WT at baseline before ameroid constrictor placement. Dash-dotted line represents WT after the development of left ventricular dysfunction and before left anterior descending coronary artery bypass. Solid line represents WT 3 weeks after left anterior descending coronary artery bypass.
LV d y s f u n c t i o n e v e n w i t h o u t any p r i o r infarction. The basis for d e t e c t i n g viable m y o c a r d i u m in this clinical setting will, therefore, d e p e n d o n the specific mechanism. For instance, if MBF is reduced, t h e n a quantitative assessment o f its d e g r e e of r e d u c t i o n will aid in the prediction of functional recovery.30,31 If transmural MBF is >30% o f n o r m a l and the endoc a r d i u m has n o t u n d e r g o n e necrosis, f u n c t i o n a l r e c o v e r y is likely after revascnlarization.32-34 If resting transmural MBF is normal at rest and a b n o r m a l during stress, t h e n the m y o c a r d i u m is b o t h viable and p r o n e to ischemia and h e n c e is v e r y likely to recover after revascularization. 11,12 This study s h o w s that dysflmctional m y o c a r d i u m may have n o r m a l resting transmural MBF and MBF reserve. Such m y o c a r d i u m will not s h o w a perfusion a b n o r m a l i t y either at stress or during rest, b u t its function will improve after revascularization. Because regional function is highly influenced b y endocardial MBE 1~18 such m y o c a r d i u m will d e m o n s t r a t e a "biphasic" r e s p o n s e o n d o b u t a m i n e e c h o c a r d i o g r a phy. 35,36 Therefore, in this particular setting, dobuta-
mine echocardiography will better predict functional r e c o v e r y than conventional forms o f stress perfusion imaging, w h i c h can only assess transmural and n o t endocardial MBF reserve. Critique of Methods We used a m o d e l o f chronic LV dysfunction, w h i c h is similar to the clinical situation.We also used a m o d e l o f multivessel stenosis, w h i c h is m o r e likely to be present in m o s t cases o f c h r o n i c LV dysfimction seen clinically. 37 From our previous experience, w e learned that p l a c e m e n t o f a v e r y proximal stenosis o n the LCx, w h i c h is t h e larger c o r o n a r y a r t e r y in m o s t dogs, almost invariably leads to eventual r e d u c t i o n in MBF and W T (hibernation) in the LCx bed.6 Because w e w a n t e d MBF in the LCx b e d to remain normal, w e placed the stenosis m o r e distally o n the LCx so that intra-arterial collateral vessels c o u l d develop. Thus in this study, MBF and resting EER w e r e n o r m a l in b o t h the LAD a n d LCx beds, and the LCx b e d served as an adequate control. T h e p r e s e n c e o f a noncritical stenosis (<85% of
Journal of the American Society of Echocardiography Volume 14 Number 11
luminal d i a m e t e r n a r r o w i n g ) w a s e v i d e n c e d b y t h e p r e s e n c e o f a n o r m a l r e s t i n g t r a n s m u r a l MBF a n d t r a n s m u r a l MBF r e s e r v e in b o t h b e d s . T h e p r e s e n c e o f viable m y o c a r d i u m w a s e v i d e n c e d b y t h e lack o f gross infarction in all s e g m e n t s analyzed as w e l l as a biphasic response to dobutamine. This particular r e s p o n s e also c o r r o b o r a t e d t h e p r e s e n c e o f a nonc r i t i c a l s t e n o s i s as w e l l as i n d u c t i o n o f d e m a n d i s c h e m i a in b o t h b e d s . R e v a s c u l a r i z a t i o n s e r v e d to test o u r h y p o t h e s i s , a n d r e p e a t d o b u t a m i n e 2DE 3 w e e k s later p e r m i t t e d t h e a s s e s s m e n t o f b o t h MBF a n d c o n t r a c t i l e r e s e r v e after b y p a s s surgery. One potential limitation was that we bypassed o n l y t h e LAD.The r e a s o n w a s o u r c o n c e r n relating to using c i r c u l a t o r y b y p a s s a n d its i n d e p e n d e n t effect o n m y o c a r d i a l function. To avoid c i r c u l a t o r y bypass, w e w e r e c o n f i n e d to u s i n g t h e i n t e r n a l m a m m a r y a r t e r y . T h e mid-LCx o r a marginal b r a n c h w a s posterior, a n d t h e s h o r t l e n g t h o f t h e internal m a m m a r y d i d n o t a l l o w a n a s t o m o s i s to t h e s e targets. As s t a t e d before, r e g i o n a l MBE MBF reserve, a n d W T in t h e LCx b e d w e r e i d e n t i c a l to t h e LAD b e d b e f o r e LAD byp a s s surgery. A n o t h e r p o t e n t i a l l i m i t a t i o n is t h e l a c k o f MBF measurements before ameroid constrictor placements. O u r p r e v i o u s e x p e r i e n c e f r o m this m o d e l has s h o w n that resting MBF r e m a i n s n o r m a l for t h e first w e e k after a m e r o i d p l a c e m e n t . 6 In t h e d o g s u s e d in o u r study, m i c r o s p h e r e data 5 days after a m e r o i d cons t r i c t o r p l a c e m e n t also s h o w e d n o r m a l MBF r e s e r v e EER. T h e l a c k o f any r e g i o n a l d y s f u n c t i o n d u r i n g s u r g e r y after p l a c e m e n t o f a m e r o i d c o n s t r i c t o r s also confn-med t h e p r e s e n c e o f n o r m a l resting MBE A l t h o u g h t h e b i p h a s i c r e s p o n s e to d o b u t a m i n e w a s n o l o n g e r p r e s e n t in t h e LAD b e d after bypass, i n d i c a t i n g t h e a b s e n c e o f i n d u c i b l e ischemia, 15 t h e contractile reserve had not returned to normal. T h e r e are several p o s s i b l e e x p l a n a t i o n s for this finding, t h e m o s t likely o f w h i c h is that w e m a y n o t have a l l o w e d s u f f i c i e n t t i m e for c o n t r a c t i l ~ r e s e r v e to fully r e c o v e r . M e t a b o l i c a n d c o n t r a c t i l e a p p a r a t u s a b n o r m a l i t i e s m a y t a k e l o n g e r to r e c o v e r . Micros c o p i c infarctions also c o u l d have b e e n p r e s e n t , thus l i m i t i n g c o n t r a c t i l e r e s e r v e , e s p e c i a l l y if t h e y occ u r r e d in t h e e n d o c a r d i n m . Ultrastructural c h a n g e s also c o u l d have o c c u r r e d , w h i c h c o u l d limit contractile reserve. T h e last t w o e x p l a n a t i o n s w o u l d h a v e required detailed histologic examinations, which w e r e n o t p e r f o r m e d in this study. Clinical Implications This s t u d y has o f f e r e d n e w m e c h a n i s t i c insights into t h e p a t h o g e n e s i s o f c h r o n i c i s c h e m i c LV dysfunction. It is k n o w n that m y o c a r d i a l d y s f u n c t i o n c a n b e p r e s e n t w h e n resting t r a n s m u r a l MBF a n d EER are
Pelberg et al 1055
n o r m a l . O u r s t u d y e x p a n d s t h e s e o b s e r v a t i o n s to i n d i c a t e that e v e n t r a n s m u r a l MBF r e s e r v e c a n b e n o r m a l a n d in this setting m y o c a r d i a l d y s f u n c t i o n is a s s o c i a t e d w i t h a b n o r m a l e n d o c a r d i a l MBF reserve. R e v e r s a l o f this a b n o r m a l i t y b y r e v a s c u l a r i z a t i o n leads to r e c o v e r y in resting function. Cardiac i m a g i n g is a m a j o r m o d a l i t y in t h e clinical a s s e s s m e n t o f m y o c a r d i a l viability in p a t i e n t s w i t h c h r o n i c i s c h e m i c LV d y s f u n c t i o n . C o n v e n t i o n a l t e c h n i q u e s u s e d to m e a s u r e m y o c a r d i a l p e r f u s i o n ( s u c h as s i n g l e - p h o t o n a n d p o s i t r o n e m i s s i o n c o m puted tomography) have poor spatial resolution (0.6 to 1.6 c m ) a n d are u n a b l e to d e t e c t an a b n o r mal EER a n d h e n c e t h e p r e s e n c e o f r e v e r s i b l e e n d o cardial i s c h e m i a . T h u s n o r m a l o r n e a r n o r m a l perfusion b o t h at rest a n d d u r i n g stress m a y b e s e e n in dysfunctional myocardial segments with the use of t h e s e t e c h n i q u e s . W h e n d y s f u n c t i o n is u n e q u i v o c a l ly regional, s u c h m y o c a r d i u m is c o n s i d e r e d v i a b l e d e s p i t e n o e v i d e n c e o f r e v e r s i b l e i s c h e m i a a n d is usually r e v a s c u l a r i z e d . O u r results i n d i c a t e t h a t in this setting, stress e c h o c a r d i o g r a p h y c o u l d b e useful in d e m o n s t r a t i n g r e v e r s i b l e i s c h e m i a b e c a u s e w h e n e n d o c a r d i a l MBF r e s e r v e is r e d u c e d , e n d o c a r d i a l t h i c k e n i n g is also r e d u c e d d u r i n g stress38,39 a n d r e v e r s i b l e W T a b n o r m a l i t i e s are n o t e d . Clinical studies w i l l b e r e q u i r e d t o fully a d d r e s s this i s s u e in humans.
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