Basic Research in

Cardiology

Basic Res Cardio186:363-377 (1991 )

Variations in myocardial contraction sequence under various hypoxic conditions M. Akaishi, T. Ikegawa, Y. Nishikawa, H. Yokozuka, S. Handa, and Y. Nakamura Cardiopulmonary Division, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan

Summary: Hypokinetic myocardial segment motion is observed in various pathophysiologic conditions. The aim of this study was to clarify the mechanisms involved in differences in segment motion of hypokinesis. Nineteen open-chest dogs were studied with regard to myocardial segment length, left ventricular pressure, and internal minor-axis diameter. Sequential instantaneous myocardial elastance [c~(t) curve] was calculated under 4 different hypoxic conditions: complete coronary occlusion and reperfusion, partial coronary occlusion, coronary microembolization, and anoxic perfusion. The a(t) curve peaked at end-systole in the case of normal contraction; but it was almost totally flat when complete bulging occurred. The hypokinesis which occurred during development of the complete systolic bulge immediately after complete coronary occlusion had an earlier a(t) peak curve than the hypokinesis resulting from partial coronary stenosis (209.5 _+35.6 ms after end-diastole vs. 261.9 ,+ 18.2 ms; p < 0.02), microsphere injection into the coronary artery (243.2 _+24.5 ms vs. 289.3 + 15.4 ms; p < 0.05), or anoxic perfusion (213.4 _+40.2 vs. 275.6 _+28.3 ms; p < 0.05). The early ct(t) peak resulted in a late-systolic bulge in segment length motion. In conclusion, hypokinetic segment motion differed depending on whether the coronary blood flow was present or not. A late-systolic bulge only developed immediately after complete coronary occlusion, and resulted from an abrupt decrease in myocardial stiffness during the cardiac cycle, which is closely related to the abrupt cessation of coronary blood flow. Key words: hypokinesis, myocardial ischemia, wall motion, myocardial stiffness, coronary blood flow

Introduction

The occlusion of a coronary artery results in myocardial bulging in the area perfused by the artery. This bulge formation was first described by Tennant and Wiggers in 1935 (1). Its pathogenetic mechanism involves interaction between the ischemic myocardium and nonischemic myocardium (2). Our previous studies have reported that systolic bulging in a severely ischemic segment is related to the passive elastic properties of the ischemic tissue as it responds to local loading conditions or tension (3, 4). Since bulging in the presence of severe ischemia is a completely passive phenomenon (4), there is a range of variation in myocardial segment motion between normal contraction and complete bulging (5). Thus, partial coronary stenosis with decreased myocardial blood flow and mild ischemia results in various degrees of impaired segment motion or hypokinesis (6-8). Therou× and his colleagues (9) reported the development of systolic bulging after complete coronary occlusion. Immediately after coronary occlusion, but prior to complete bulging, they described temporary hypokinetic segment motion. Hypokinetic segment motion was defined as a modest decrease in systolic shortening of segment length or systolic thickening of myocardial wall (6-8). Hence, hypokinetic segment motion produced under 685

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various conditions was c o n s i d e r e d to b e t h e s a m e (10) until D o y l e et al. (11) r e p o r t e d a difference b e t w e e n h y p o k i n e t i c m o t i o n in c o m p l e t e c o r o n a r y occlusion a n d partial c o r o n a r y occlusion. T h e r e are several e x p l a n a t i o n s for this difference: t h e a b r u p t loss of c o r o n a r y erectile effect m a y modify t h e m y o c a r d i a l stiffness of the v e n t r i c u l a r wall; s u b e n d o c a r d i a l m y o c a r d i a l i s c h e m i a m a y cause a n i n t e r a c t i o n b e t w e e n severely ischemic s u b e n d o c a r d i u m a n d less severely ischemic or n e a r l y n o n - i s c h e m i c s u b e p i c a r d i u m ; or t h e r e m a y b e two t e m p o r a l l y different m y o c a r d i a l c o n t r a c t i o n m e c h a n i s m s influenced by the ischemic insult. This study was d e s i g n e d to clarify t h e m e c h a n i s m s i n v o l v e d in differences in h y p o k i n e t i c s e g m e n t m o t i o n using t h e newly d e v e l o p e d time-varying n o n - l i n e a r elastance m o d e l of c o n t r a c t i o n (5).

Methods Nineteen mongrel dogs weighing 18-25 kg were anesthetized with pentobarbital (25 mg/kg) and ventilated with a mixture of oxygen and room air, using a Harvard respirator. Blood gases were monitored intermittently. A catheter was placed in the left femoral artery to monitor blood pressure. Thoracotomy was performed in the 5th left intercostal space, and the heart was suspended in a pericardial cradle. The right atrium was paced to maintain the heart rate constant. The left anterior descending artery (LAD) was isolated. A microtransducer (Millar Instruments PC-350) was introduced into the left ventricle via the apex to measure left ventricular (LV) pressure and dP/dt. A pair of ultrasonic crystals was placed on the endocardial surface of the LV anterior and posterior wall to measure the diameter of the LV minor axis (12). Another pair of ultrasonic crystals was implanted perpendicularly to the long axis of the heart in the inner third of the myocardium of the central LADperfused area in the anterior LV wall. The position of the crystals was checked at autopsy. The LAD was ligated proximally, and a 14-gauge blunt-tipped metal cannula was inserted distal to the site of occlusion. Perfnsion was maintained via a polyvinyl catheter bypass system using arterial blood from the left common carotid artery. This procedure interrupts perfusion for about i rain (40-70 s). A 2ram cannulating-type electromagnetic flow probe (Nihon Koden FD-120T, 150T) was included in the LAD cannulation system, and flow was monitored with an electromagnetic flowmeter (Nihon Koden MVF-1200). Perfusion pressure was measured through a side arm in the bypass system, using a Statham P23Db pressure transducer. After complete restoration of LAD flow and segment shortening following LAD cannulation and a 10-min stabilization period, 10 second total coronary occlusion followed by reperfusion was performed to determine the degree of reactive hyperemia. Dogs exhibiting less than 100 % reactive hyperemia were excluded. These experiments were carried out in conformance with standards for humane treatment set forth by our animal experimentation committee. Complete coronary occlusion vs. partial coronary occlusion Nine dogs were included in this protocol. After hemodynamic stabilization, the bypass system was clamped completely for two min. Segment length motion and left ventricular dynamics were monitored continuously. Serial recordings were performed until the systolic bulge was complete. After a 2-rain period of occlusion, the coronary artery was completely reperfused. In 6 of the 9 dogs, restoration of segment length was recorded. After complete hemodynamic recovery, graded partial stenosis was created with a screw clamp on the bypass system, and coronary perfusion pressure was monitored. The coronary perfusion pressure was adjusted to 40, 35, 30, and then 25 mmHg. Each level of hypoperfusion was maintained for 5 min. Finally, the coronary artery was completely occluded. Complete occlusion vs. microsphere injection Five dogs were included in this protocol. After hemodynamic stabilization, the bypass system was clamped completely for two min. Segment length motion and left ventricular dynamics were monitored continuously. Serial recordings were performed until the systolic bulge was complete. After a 2-rain period of occlusion, the coronary artery was completely reperfused. After complete hemodynamic

Akaishi et al., Myocardial contraction sequence during hypoxia

365

restoration, 0.15 mgtkg of 50 gm non-radioactive microspheres were iniected through the bypass system into the left anterior descending coronary artery, and segment length motion and left ventricular dynamics were monitored. After 5 min, another 0.15 mg/kg of microspheres were injected. Microsphere injection was repeated every five min, and segment length motion was observed throughout the iujections period. A total of 0.6 mg/kg of mierospheres were injected.

Complete occlusion vs. perfusion of anoxic solution Five dogs were included in this protocol. After hemodynamic stabilization, the bypass system was clamped completely for two min. Segment length motion and left ventricular dynamics were continuously monitored. Serial recordings were made until the systolic bulge was complete. After a 2-min period of occlusion, the coronary artery was completely reperfused. After complete hemodynamics recovery, Krebs-Henseleit solution (118 mM NaC1, 25 mM NaHCO3, 3.8 mM KCI, 1.2 mM KH2PO4, 1.2 mM MgSO4, 10 mM glucose, 2.5 mM CaCI2, 95 % N2, 5 % CO2, 37 °C) was perfused via the bypass system at the same pressure as aortic pressure using a balloon perfusion technique (13). The KrebsHenseleit solution was adjusted to pH 7.4 with 95 % N2 and 5 % COe.

Data analysis End-diastole was defined as the time of abrupt change in LV dP/dt during diastole; this always occurred after the A wave, if any. End-systole was defined as occurring 20 ms before the negative dP/dt peak. End-diastolic length (EDL) and end-systolic length (ESL) were measured and %AL was computed as (EDL-ESL)/EDL x 100. All segment lengths were normalized by expressing EDL in the control state as 10 mm. Myocardial wall tension can be expressed as follows: T = 1.36 × P × R/2 where P is left ventricular pressure and R is the ventricular radius, c~(t) was calculated from tension and length, expressing inotropic state as a simple time variation in this index. A detailed discussion of ct(t) has been reported previously (5). a(t) relates segmental length to load. T(t) = e ~(t)L(0+[~ solving for ct(t), cfft) = (lnT(t)-13)/L(t) where T(t) and L(t) are the instantaneous tension and length, respectively, t3 is a constant, ct(t) is a timevarying index of the regional myocardial contractile state over the course of the cardiac cycle. In this expression, tension was used to calculate a(t) instead of stress, because the segment length shortens as a whole unit across the full thickness of the left ventricular wall (8), and thus tension provides a better expression of regional load (4, 5). Using ct(t), myocardial contraction can be expressed as a monophasic change in one cardiac cycle independent of changes in regional load. The shape of the a(f) curve describes the time-course of regional elastance while its peak is related to regional contractility (5). To demonstrate the shape of the ct(t) curve for hypokinetic segment motion, the c~(t) curve of hypokinetic segment motion was normalized by expressing its peak as 1.0 and its minimum as 0.

Statistics All data are expressed as means ± standard deviation. Analysis of variance for repeated measures was used to determine the significance of changes in hemodynamic measurements within each group and to compare the shape of ct(t) curve of two types of hypoxia. Student's paired t test was used in comparing c~(t) at individual timing and in comparing the timing of peak c~(t) after end-diastole between the two hypoxic conditions. A p value < 0.05 was considered significant.

Results

Complete coronary occlusion vs. partial coronary occlusion H e a r t r a t e was 100 ± 3 b e a t s p e r m i n u t e , u n c h a n g e d t h r o u g h o u t t h e e x p e r i m e n t . T h e h e m o d y n a m i c d a t a are p r e s e n t e d in T a b l e s 1 a n d 2. Left v e n t r i c u l a r systolic p r e s s u r e

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Table 1. Hemodynamics after complete coronary occlusion. Complete occlusion

LVSP LVEDP LVdPldt -LVdP/dt EDL %AL

before

10 s

30 s

1 min

1.5 min

119 _+ 18 3.8_+2.6 1705 _+279 -1624 _+349 t0.0 17.7_+6.2

122 _+ 16 120 ± 16 109 _+ 18" 109 _+ 16" 4.2_+2.2 4,5±2.3 7.1_+2.8" 6.4±3.0 1727 + 289 1582 ± 207 1353 _+240* 1370 _+282 -1439 _+276 -1376 -+ 316 -1354 _+362* -1374 _+313 10.3 -+ 0.3 10.9 ± 0.5* 11.0 -+ 0.6* 11.0 _+0.6 11.6_+8.0" 2.0_+5.6* -4.0_+2.2* -6.4_+2.7

2 min 112 _+ 14" 6.4 _+3.7* 1448 ___225* -1410 _+276* 11.1 4- 0.5* .6.6 _+3.4*

EDL, end-diastolic length (mm); LVdP/dt, peak left ventricular dP/dt (mmHg/s); -LVdP/dt, peak negative left ventricular dP/dt (mm Hg); LVSP, left ventricular systolic pressure (ram Hg); LVEDP, left ventricular end-diastolic pressure (mm Hg); % AL, % systolic shortening (%) *: p < 0.05 compared with before complete occlusion.

Table 2. Hemodynamics during partial coronary occlusion. Partial occlusion

LVSP LVEDP LVdP/dt -LVdP/dt CoSP CoDP EDL %AL

before

40 mm Hg

118 + 16 3.4_+3.0 1676 _+205 -1642 -+ 236 118 ± 17 77 ± 13 10.0-+0.3 17.5_+5.0

116 _+ 17 3.3_+2.9 1639 _+ 189 -1566 -+ 303 82 _+ 12' 40 + 8* 9.9-+0.3 14.9_+8.9"

30 mm Hg 112 _+20 2.9_+2.4 1553 ± 250 -1492 _+321 68 _+ 17" 32 -+ 12" 10.0_+0.3 10.3 ± 8 . 9 "

25 lnm Hg 111 + 19 2.9_+2.8 1519 _+266 -1441 _+303 52 ± 15" 25 ± 9* 10.1_+0.3 4.9_+8.5*

20 mm Hg

CO

109 _+ 19" 108 + 20* 2.5_+2.1 4.1_+3.0" 1452 _+288 1472 -+ 313 -1378 ± 323* -1344 _+315" 42 _+ 12' 37 ± 10" 22 _+7* 19 ± 5* 10.4_+0.3' 10.7_+0.4" -2.7 ± 6.9" -6.1_+7.2"

CoDP, coronary arterial diastolic pressure (mmHg); CoSP, coronary arterial systolic pressure (mmHg); EDL, end-diastolic length (mm); LVdP/dt, peak left ventricular dP/dt; -LVdP/dt, peak negative left ventricular dP/dt; LVSP, left ventricular systolic pressure (ram Hg); LVEDP, left ventricntar end-diastolic pressure (mmHg); %AL, % systolic shortening *: p < 0.05 compared with before partial occlusion.

d e c r e a s e d u n d e r b o t h conditions, c o m p l e t e c o r o n a r y occlusion a n d partial c o r o n a r y occlusion. Left v e n t r i c u l a r end-diastolic p r e s s u r e i n c r e a s e d 2 rain after c o r o n a r y occlusion or d u r i n g the steady state of c o m p l e t e c o r o n a r y occlusion. C o r o n a r y arterial b l o o d flow d e c r e a s e d to zero i m m e d i a t e l y after c o m p l e t e c o r o n a r y occlusion, b u t d e c r e a s e d gradually in t h e case of partial c o r o n a r y occlusion. I n c o m p l e t e c o r o n a r y occlusion, % A L d e c r e a s e d with time, a n d it was a l m o s t z e r o 30 s a f t e r c o m p l e t e c o r o n a r y occlusion. In partial c o r o n a r y occlusion, %zkL d e c r e a s e d gradually as t h e c o r o n a r y b l o o d flow d e c r e a s e d , a n d it was a l m o s t zero a f t e r partial c o r o n a r y stenosis with a c o r o n a r y p e r f u s i o n p r e s s u r e of 25 m m H g . F i g u r e 1 shows t h e tracings of s e g m e n t l e n g t h m o t i o n in a typical animal. T i m i n g was s t a r t e d at end-diastole. Six tracings are s h o w n in t h e u p p e r panel. T h e " c o n t r o l " tracing r e p r e s e n t s systolic s h o r t e n i n g b e f o r e c o r o n a r y occlusion. T h e n u m b e r e d tracings indicate s e g m e n t l e n g t h m o t i o n 6, 8, 15, 20 a n d 90 s after c o r o n a r y occlusion. E i g h t seconds after

367

Akaishi et al., Myocardial contraction sequence during hypoxia mm 12.o

Complete Occlusion 90"

== I-- 11,0

io.o "=' E

9.0 CONTROL

¢4J

8.0

7.0 Graded Partial Occlusion

mill

12.0

TOTALOCCLUSION

11.0 ~10.0 F-,-

E

50mmHg

9.0 8.0

7,0 0

1~0

200

a~o

4~0

5~0

B~om~,o

Fig. 1. Myocardial segment length immediately after coronary occlusion (upper panel) and during graded partial occlusion (lower panel). Each panel shows six cardiac cycles superimposed with respect to time: the beginning of the tracing represents end-diastole. Numbers indicate the seconds after coronary occlusion (upper panel) and diastolic coronary perfusion pressures (lower panel). coronary occlusion, segment motion is biphasic, characterized by late-systolic lengthening or bulging. The 6 tracings in the lower panel represent a gradual decrease in coronary blood flow, from control to complete occlusion. There is no late-systolic lengthening here. The numbers indicate coronary diastolic perfusion pressures. Figure 2 shows the sequence of changes in c~(t) corresponding to Figure 1. Before coronary occlusion, c~(t) changed monophasically in both panels. At 6 to 20 s after complete occlusion, ct(t) peaked earlier than in the control pre-occlusion curve (upper panel). Thus, both the time course and the shape of the ct(t) curve differed from the control. This early peaking of ct(t) corresponded to late systolic lengthening at 6 to 20 seconds. Finally, 90 s after complete coronary occlusion, the c~(t) curve was almost completely flat throughout the entire cardiac cycle. In contrast, graded partial occlusion resulted in a gradual decrease in the height of a(t), with little change in the timing of its peak. As ischemia became more severe, the curve became flatter, but otherwise its time" course and shape did not change. To demonstrate differences in the shape of the c~(t) curve in the two types of hypokinesis, hypokinetic segment motions for which % A L ranged from 0.2 to 0.5 to the control value were selected from among the variations in segmental motion immediately after complete coronary occlusion or during partial coronary stenosis. The mean % A L in hypokinesis 20.4 _+9.8 s after complete coronary occlusion was 0.39 _+0.13 of the control value, which was almost identical with that of hypokinesis during partial coronary stenosis with a 32.5 +_ 13.6 m m H g coronary diastolic perfusion pressure (0.37 _+0.15 of the control). Peak ct(t) was 2.05 _+0.30 in the case of hypokinesis after complete coronary occlusion, while the c~(t) peak was 2 . 0 0 _ 0.24 in hypokinesis during partial coronary occlusion. Hypokinesis

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Complete Occlusion

2.5

2.0

1.5

Graded Partial Occlusion 2.5

v

2.0

1.5

,oo

2oo soo

4oo

8oosec

Fig. 2. ct(t) curves of a typical animal. The upper panel shows changes in the ct(t) curve during development of the myocardial systolic bulge. Numbers indicate seconds after coronary occlusion. The lower panel shows the c~(t) curves under conditions of partial coronary stenosis. Numbers indicate diastolic coronary perfusion pressures, Table 3. Comparison between normalized a(t) for hypokinetic segment motion immediately after complete coronary occlusion and during partial coronary occlusion. Time (ms) after end-diastolie

0 ms 50 100 150 200 250 300 350 400 450 500 550 600

Normalized a(t) Complete occlusion

Partial occlusion

0.05 _+0.06 0.37 ± 0.31 0.67 _+0.19 0.87 -+ 0.09 0.98 ± 0.04 0.86 ± 0.09 0.72 ± 0.18 0.39 ± 0.14 0.21 +- 0.09 0.10 -+ 0.06 0.12 ± 0.06 0.08 ± 0.05 0.09 ± 9.05

0.07 0.41 0.63 0.75 0.86 0.95 0.96 0.56 0.26 0.19 0.11 0.08 0.09

_+0.09 ± 0.27 ± 0.18 -+ 0.15" ± 0.13"* _+0.05 ± 0.07* ± 0.09** ± 0.05 + 0.t0 ± 0.08 -+ 0,06 ± 0.06

*: p < 0.01 compared with the same timing of complete occlusion, **: p < 0.05 compared with the same timing of complete occlusion.

369

Akaishi et al., Myocardial contraction sequence during hypoxia Table 4. Hemodynamics during coronary reperfusion. Reperfusion

LVSP LVEDP LVdPldt -LVdP/dt EDL %AL

Occlusion

10 s

30 s

1 rain

114 + 19 8.3 +_9.7 1449 ± 377 -1444 + 301 11.120.6 -6.8±7.6

126 + 21 4.6 + 2.7 1774 +_347 -1674 ± 382 10.7_+0.6 5.4-+8.3*

135 _+22* 2.9 -+ 2.3* 2037 -+ 463* -1860 _+358* 10.0_+0.5 * 19.5-+4.5"

124 + 19 2.6 ± 3.3* 1971 _+441" -1742 ± 348 9.6-+0.3* 22.9 +_5.8"

2 rain 123 ± 21 2.7 _+2.6* 1732 ± 310 -1697 + 368 9.8 ± 0.3' 17.8±4.3"

EDL, end-diastolic length (mm); LVdP/dt, peak left ventricular dP/dt (mmHg/s); -LVdP/dt, peak negative left ventricular dP/dt (mm Hg/s); LVSP, left ventricular systolic pressure (ram Hg); LVEDP, left ventricular end-diastolic pressure (mm Hg); % AL, % systolic shortening *: p < 0.05 compared with complete occlusion.

created by complete occlusion showed an earlier c~(t) peak (209.5 _+ 35.6 ms after enddiastole) than hypokinesis created by partial coronary occlusion (261.9 _+ 18.2 ms after enddiastole; p < 0.02). The normalized c~(t)'s of hypokinetic segment motion are presented in Table 3. The time course of the normalized c~(t) was different each other (p < 0.001 by

REPERFUSION

inm

14 -1-

12

8 6 111111

2.0

1.0 100

200

300

400

500

600 fllsec

Fig. 3. Myocardial segment lengths (upper panel) and ct(,t) curves (lower panel) immediately after coronary reperfusion following 2-minute occlusion in a typical animal. Each panel shows six cardiac cycles superimposed and adjusted with respect to time. The beginning of the tracings represents enddiastole. Numbers indicate seconds after coronary reperfusion.

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Basic Research in Cardiology, VoL 86. No. 4 (1991)

ANOVA). The normalized c~(t)'s 150 to 200 ms after end-diastole were higher (p < 0.05) in complete occlusion than in partial coronary occlusion, while those at 300 ms and 350 ms were lower (p < 0.05) in complete occlusion than in partial occlusion. Six dogs were monitored during reperfusion after 2 min of complete coronary occlusion. Table 4 presents their hemodynamics after reperfusion. Reperfusion resulted in rapid recovery of left ventricular pressure and segmental shortening. There was no sustained dysfunction after 2 min of reperfusion. Figure 3 shows segment length in the uppel~anel and c~(t) in the lower panel during reperfusion. As regional function recovered, there was no late-systolic segment lengthening or change in the shape of the ct(t) curve. Complete occlusion vs. microsphere injection

Injection of 0.15 mg/kg of microspheres resulted in no change in left ventricular systolic (from 137 _+ 14 m m H g to 139 -+ 12 mmHg) or end-diastolic pressure (from 5.2 ± 2.7 m m H g to 5.5 ± 2.5 mmHg) while there was a decrease in % A L to 0,84 ± 0.38 of the control preinjection value. Additional injection of 0.15 mg/kg of microspheres resulted in a further decrease in % AL to 0.45 ± 0.38 without any change in hemodynamics. Three injections of 0.15 mg/kg of microspheres caused systolic bulging, indicated as % AL of --0.51 _+0.59 of the control. Since % AL decreased progressively as microspheres were injected, four injections of 0.15 mg/kg of microspheres caused complete bulging ( % A L = - 1 . 0 1 _+0.75) with an increase in E D L (10.9 _+ 1.1 ram). Representative tracings of segment length are presented in Figure 4. The appearance of complete bulging after complete occlusion is shown in the

Complete Occlusion

mm

120"

-,13 I-Z2 z

9

Microsphere Injection

14.0 :z: 13,0 z

12.0

0.60r~g/kg

11.0 10.O

9.0 8,0

i;o

I

2oo

aoO

4o0

i

600msec

Fig. 4. Myocardial segment lengths immediately after coronary occlusion (upper panel) and during graded repeated injections of microspheres (lower panel), Each panel shows five cardiac cycles superimposed and adjusted with respect to time. The beginning of the tracings represents end-diastole, Numbers indicate seconds after coronary occlusion (upper panel) and total amount of microspheres injected into the coronary artery (lower panel).

371

Akaishi et al,, Myocardial contraction sequence during hypoxia Complete Occlusion

1.8 1.5

1.0

Microsphere Injection

1.8 1.5

1.0

0

OXTROL

O,15mg/k9

I00

200

300

400

500

600 msec

Fig. 5. c~(t) curves of a typical animal. The upper panel shows the changes in the e(t) curve during development of the myocardial systolic bulge. Numbers indicate seconds after coronary occlusion. The lower panel shows the c~(t) curves during graded repeated injections of microspheres (lower panel). Numbers indicate total amount of microspheres injected into the coronary artery (lower panel). upper panel and the development of complete bulging during graded injection of microspheres in the lower panel. Microsphere injection did not result in late-systolic elongation in the course of development of complete bulging. Figure 5 shows the sequence of changes in c~(t) corresponding to Figure 4. Before coronary occlusion, c~(t) changed monophasically in both panels. For 5 to 10 s after complete occlusion, the shape of c~(t) curve became different, peaking earlier (upper panel). In contrast, repeated microsphere injections resulted in a gradual decrease in the height of a(t), with little change in the timing of its peak. To demonstrate differences in the shape of the c~(t) curve of the two types of hypokinesis, hypokinetic segment motions whose % A L ranged from 0.2 to 0.5 of the control value were selected from the variations in segmental motion immediately after complete coronary occlusion or during graded microsphere injection. The mean % AL in hypokinesis after complete coronary occlusion was 0.25 + 0.10 of the control value, which was almost identical to the value during hypokinesis induced by graded microsphere injection (0.38 _+0.10 of the control). The c~(t) peak was 1.99 + 0.21 in the case of hypokinesis after complete coronary occlusion, and the ct(t) peak was 1.96 + 0.21 in the case of hypokinesis during partial coronary occlusion. Hypokinesis created by complete occlusion had an earlier peak a(t) (243.2 _+24.5 ms after end-diastole) than hypokinesis created by microsphere injection (289.3 +_ 15.4 ms after end-diastole; p < 0.05). Normalized a(t)'s for hypokinetic segment motion are presented in Table 5. The time course of the c~(t) was different each other (p < 0.05 by ANOVA). The normalized c~(t) 300 ms after end-diastole was lower (p < 0.05) after complete occlusion than microsphere injection, suggesting the same difference as seen in the comparison between complete coronary occlusion and partial coronary occlusion.

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Basic Research in Cardiology, Vol. 86, No. 4 (1991)

Table 5. Comparison between normalized a ( 0 for hypokinetic segment motion immediately after complete coronary occlusion and during microsphere injection. Time (ms) after end-diastolie

0 50 100 150 200 250 300 350 400 450 500 550 600

Normalized ct(t) Complete occlusion

Microsphere injection

0.07 ± 0.12 0.2t ± 0.16 0.47 ± 0.13 0.80 _ 0.12 0.91 ± 0,81 0.97 ± 0.06 0.77 ± 0.11 0,47 ± 0,10 0.18 ± 0,09 0.06 ± 0,04 0,04 ± 0,07 0.03 ± 0,01 0.03 -+ 0,04

0.10 ± 0.13 0.19 ± 0.18 0.48 ± 0.13 0.71 ± 0.10 0.85 ± 0.07 0.91 ± 0.07 1.00 _+0.00" 0.48 _+0.12 0.19 _+0.07 0.06 + 0.03 0.02 ± 0.02 0.04 + 0.03 0.05 + 0.04

*: p < 0.02 compared with the same timing of complete occlusion.

Table 6. Comparison between normalized a(t) for hypokinetic segment motion immediately after complete coronary occlusion and immediately after anoxic perfusion. Time (ms) after end-diastolie

0 50 t00 150 200 250 300 350 400 450 500 550 600

Normalized ct(t)

Complete occlusion

Anoxic perfusion

0.07 ± 0.07 0,57 +__0,28 0,79 ± 0,17 0.95 ± 0,06 0,99 4- 0.01 0,83 _+0.07 0,59 ± 0.20 0.31 ± 0.17 0.18 ± 0.11 0.09 ± 0.05 0.10 ± 0,06 0,07 ± 0,03 0,05 ± 0,05

0.15 4-_0,10 0.58 + 0.25 0.73 + 0,13 0,82 + 0.11" 0.93 + 0.06 0.97 _+_0,04 0.95 + 0.04* 0.57 _+0.09 0.24 -4--0.05 0.09 -+ 0.07 0.06 + 0.04 0.08 ± 0.05 0.05 ± 0.03

*: p < 0.05 compared with the same timing of complete occlusion.

Complete occlusion vs. perfusion o f anoxic solution Five dogs u n d e r w e n t anoxic p e r f u s i o n i n s t e a d of c o m p l e t e c o r o n a r y occlusion, at t h e s a m e p r e s s u r e as in the aorta. Figure 6 shows changes in s e g m e n t l e n g t h d u r i n g d e v e l o p m e n t of t h e m y o c a r d i a l b u l g e in o n e dog with c o m p l e t e c o r o n a r y occlusion a n d anoxic perfusion.

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Akaishi et al., Myocardial contraction sequence dut4ng hypoxia

COMPLETEOCCLUSION

mm

12.0

11.0

~= lO.O Q"

9.0

ANOXICPERFUSION

gllfl

12.0

11.0

E

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Fig. 6. Myocardial segment length immediately after coronary occlusion (upper panel) and after coronary perfusion with anoxic Krebs-Henseleit solution (lower panel) in a typical animal. Each panel shows several cardiac cycles superimposed and adjusted with respect to time. The beginning of the tracings represents end-diastole. Numbers indicate seconds (") after the beginning of interventions.

The numbers indicate the time (s) after complete occlusion or anoxic perfusion. Before the interventions, myocardial segmental motion was the same under both conditions, as indicated by "0"". Complete coronary occlusion resulted in immediate appearance of a latesystolic bulge, while anoxic perfusion resulted in a gradual decrease in segmental shortening. Figure 7 shows the sequence of changes in ct(t) corresponding to Figure 6. A n early drop in c~(t) 10 s after complete coronary occlusion was noted. Anoxic perfusion, on the other hand, resulted in a gradual decrease in peak c~(t) without any change in the shape of c~(t). The peak c~(t) occurred earlier in complete coronary occlusion (213.4 _+40.2 ms after end-diastole) than in anoxic perfusion (275.6 _+28.3 ms after end-diastole; p < 0.05). The normalized c~(t)'s of hypokinetic segment motion where % AL ranged between 0.2 and 0.5 of the control value are presented in Table 6. The time course of the normalized a(t) was different each other ( p < 0 . 0 2 by A N O V A ) . Normalized a(t) 150 ms after end-diastole was higher (p < 0.05) in complete occlusion than in anoxic perfusion, whereas 300 ms after end-diastole it was lowr (p < 0.05) in complete occlusion than in anoxic peffusion, suggesting the same difference as seen when complete coronary occlusion and partial coronary occlusion were compared. Discussion

This study demonstrated that the salient feature of segment length motion immediately after abrupt coronary occlusion was a late-systolic bulge, whereas the salient feature of segment length motion during partial coronary occlusion or under other hypoxic settings was

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Fig. 7. cfft) curves for the corresponding segment lengths in Figure 6. The beginning of the tracings represents end-diastole. Numbers indicate seconds (") after the start of interventions. early diastolic shortening. This late systolic bulging corresponded to the early fall in ct(t) in mid-systole after complete coronary occlusion. To rule out any effect of repeated exposure to hypoxia on segment motion, additional 4 dogs were subjected to repeated 2-rain complete coronary occlusions at 15-min intervals. These additional experiments confirmed that the late-systolic bulging of segment motion during the development of systolic bulging after complete coronary occlusion was completely reproducible. Segment length motion is so sensitive that a small change in myocardial tension may cause a large change in the pattern of motion (4). The motion of a partially ischemic segment may be characterized by tension to which the segment must react as an elastic material with nonHookian characteristics, and its own reduced but still present inotropic state, which actively and instantaneously changes. This time-varying elastance can be expressed by cfft). A previous report demonstrated that the motion of hypocontractile segment throughout the cardiac cycle can be both characterized and explained by this time-varying index of contractility, ct(t) (5). Although ideally ct(t) should be derived from the stress-strain relationship, an empirical relation between tension and length was used to obtain cfft), since it is difficult to measure length at zero stress in vivo and our interest lay in segment length motion, not changes in strain. Thus, a(t) should be synonymous with the myocardial stiffness constant. The early fall in ct(t) implied early attenuation of regional myocardial stiffness in one cardiac cycle. There were methodological limitations in obtaining a(t). Local tension was calculated in this study using left ventricular radius instead of the local curvature. Since regional myocardial ischemia affected left ventricular shape (14), left ventricular minor axis diameter may not have represented the local curvature of the ischemic region. Furthermore, left ventricular diameter data at frequencies above the heart rate may vary depending on the site

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of measurement (15). On the other hand, a previous study (12) showed that the two ventricular minor axis diameters (anterior-posterior and septal-lateral minor axis internal diameter) changes in a similar manner, even in acute regional myocardial ischemia. Tsujioka et al. reported that the local curvature of ischemic segments decreased during systole (16), despite the appearance of regional systolic bulging. Since changes in regional tension are mainly determined by changes in left ventricular internal pressure, a small variation in left ventricular diameter changes should not affect changes in calculated tension. Despite these limitations in computing regional tension, the tensions calculated and presented in this study are a reasonable good, but not perfect, index of local load during the cardiac cycle, even in the presence of regional ischemia. In the past, myocardial segment motion has been explained mostly on the basis of the interaction between ischemic and non-ischemic myocardium, since reciprocal changes in the segment length of ischemic and non-ischemic myocardium were observed during acute myocardial ischemia (2, 17, 18). In this study, since the length of non ischemic segments was not measured, the role of interaction in the difference between the results immediately after complete coronary occlusion and partial coronary occlusion cannot be ruled out completely. The most prominent difference in segment motion was present during late systole not after end-systole. Although post-systolic shortening in hypokinetic segment motion was exaggerated by late-systolic bulging, similar post-systolic segment motion could be observed in various hypokinetic motions. The asynchrony which was related to post-systolic shortening (19) under both conditions may play a small role in the early attenuation of myocardial stiffness during complete coronary occlusion. There may be several explanations for the difference. Based on an analysis of myocardial contraction under "rested-state" and "steady-state" stimulation (20, 21), myocardial contraction was considered to have two components, early and late. If myocardial ischemia affects the two contractile mechanisms regulating myocardial contraction differently, an early fall in c~(t) should occur immediately after complete coronary occlusion. The data in this study did not show this early attenuation during anoxic perfusion, suggesting that this hypothesis is less likely. Another explanation of the difference in segment motion under these two conditions is transmural coronary distribution. During partial coronary occlusion, subendocardial myocardium is more severely impaired. The less severely impaired subepicardium may contract to maintain myocardial stiffness in late systole in the setting of partial coronary occlusion (22). Although myocardial blood flow distribution was not determined in this study, the previous study (23) demonstrated that microspheres injected into the coronary artery were distributed transmurally in the perfused area, resulting in transmurally uniform underperfusion. In this study, microsphere injection produced the same length motion as partial coronary occlusion. Thus, transmural myocardial blood flow distribution could not explain late systolic lengthening immediately after coronary occlusion. A final explanation for the difference in response to ischemia is the mechanical effect of abrupt cessation of coronary blood flow. The sudden disappearance of the erectile effect of coronary blood flow may cause the late-systolic bulge. Although Doyle et al. (9) proposed this mechanism, their description did not explain it. We therefore subjected a group of dogs to anoxic perfusion instead of complete coronary occlusion, with the same pressure as in the aorta. This type of intervention did not create the late-systolic bulge that occurred immediately after complete coronary occlusion, indicating that the difference in the time course of c~(t) is mainly due to a difference in the mechanical properties of the myocardium. The erectile effect on the myocardium may be most severely compromised in late-systole, as the intramyocardial capacitor discharges. While normally there may be blood in the myocardium throughout the cardiac cycle (24), after coronary occlusion this may no longer be true.

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It is concluded that the occurrence of the late-systolic bulge is due to an abrupt decrease in myocardial stiffness during the cm'diac cycle, which is closely related to the abrupt loss of coronary erectile effect caused by the cessation of coronary Mood flow.

Acknowledgement

We acknowledge William S. Weintraub, M.D., Emory University, for his thoughtful comments.

R eferen ces

1. Tennant R, Wiggers CJ (1935) The effect of coronary occlusion on myocardial contraction. Am J Physiol 112:351-361 2. Lew WYW, Chen Z, Guth B, Covell J (1985) Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle. Circ Res 56:351-358 3. Akaishi M, Schneider RM, Mercier RJ, Agarwat JB, Helfant RH, Weintraub WS (1986) Analysis of phases of contraction during graded acute myocardial ischemia. Am J Physiol 250:H778--785 4. Akaishi M, Weintraub WS, Schneider RM, Klein LW, Agarwal JB, Helfant RH (1986) Analysis of systolic bulging. Mechanical characteristics of acutely ischemic myocardium in the conscious dog. Circ Res 58:209.-217 5. Akaishi M, Schneider RM, Seelaus PA, Klein LW, Agarwal JB, Helfant Rtt, Weintraub WS (1988) A non-linear elastic model of contraction of ischemic segments. Cardiovasc Res 22:889-899 6. Vatner SF (1980) Correlation between acute reductions in myocardial blood flow and function in conscious dogs. Circ Res 47:201--207 7. Gallarger KP, Kumada T, Koziol JA, McKown MD, Kemper S, Ross Jr J (1980) Significance of regional wall thickening abnormalities relative to transmural myocardial perfusion in anesthetized dogs. Circulation 62:1266-1274 8. Weintraub WS, Hattori S, Agarwal JB, Bodenheimer MM, Banka VS, Helfant RH (1981) The relationship between blood flow and contraction by myocardial layer in the canine left ventricle during ischernia. Circ Res 48:430-438 9. Theroux P, Franklin D, Ross J Jr, Kemper WS (1974) Regional myocardial function during acute coronary occlusion and its modification by pharmacologic agents in the dog. Circ Res 35:896-908 10. Nakamura Y, Hayashi J, Mori H, Ogawa S, Ohsuzu F, Takahashi M, Hattori S, Horikawa M (1980) The changes in pattern of myocardial shortening by reduction of regional coronary blood flow. Jpn Heart J 21:225-234 11. Doyle RL, Foex P, Ryder WA, Jones LA (1987) Differences in ischemic dysfunction after gradual and abrupt coronary occlusion: effects on isovolumic relaxation. Cardiovasc Res 21:507-514 12. Akaishi M, Schneider RM, Mercier RJ, Naccarella FF, Agarwal JB, Helfant RH, Weintraub WS (1985) Relation between left ventricutar global and regional function and extent of myocardial ischemia in the canine heart. J Am Coll Cardiol 6:104-112 13. Hirzel HO, Sonnenblick EH, Kirk ES (1977) Absence of a lateral border zone of intermediate creatine phosphokinase depletion surrounding a central infarct 24 hours after acute coronary occlusion in the dog. Circ Res 41:673-693 14. Marino P, Kass D, Lima J, Maughan L, Graves W, Weiss JL (1988) Influence of site of regional ischemia on LV cavity shape change in dogs. Am J Physiol 254:H547-H557 15. Slinker BK, Glantz SA (1985) The accuracy of inferring left ventricular volume fi'om dimension depends on the frequency of information needed to answer a given question. Circ iRes 56:161-174 16. Tsujioka K, Ogasawara Y, Mito K, Hiramatsu O, Wada Y, Goto M, Matsuoka S, Kagiyama M, Kajiya F (1988) Piezoelectric polymer curvature sensor for measurement of regional curvature radius of LV wall. Am J Physiol 254:H1010-1016 17. Gaash WH, Blaustein AS, Bing OHL (1985) Asynchronous (segmental early) relaxation of the left ventricle. J Am Coll Cardiol 5:891-897 18. Smalling RW, Ekas RD, Felli PR, Binion L, Desmond J (1986) Reciprocal functional interaction of adjacent myocardial segments during regional ischemia: An intraventricular loading phenomenon affecting apparent regional contractile function in the intact heart. J Am Coll Cardiol 6:1335-1346

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19. Ehring T, Heusch G (1990) Left ventricular asynchrony: An indicator of regional myocardial dysfunction. Am Heart J 120:1047-1057 20. Beresewicz A, Reuter H (1977) The effect of adrenaline and theophylline on action potential and contraction of mammalian ventricular muscle under "rested-state" and "steady-state" stimulation. Naunyn-Sehmiedeberg's Arch Pharmacol 301:99-107 21. Seibel K, Karema E, Takeya K, Reiter M (1978) Effect of noradrenaline on an early and a late component of the myocardial contraction. Naunyn Schmiedeberg's Arch Pharmacol 305:65-74 22. GaUagher KP, Osakada G, Hess OM, Kozioil JA, Kemper WS, Ross J Jr (1982) Subepicardial segment function during coronary stenosis and the role of myocardial fiber orientation. Circ Res 50:352-359 23. Pelosi G, L'Abbate A, Giovanna T, Vacche MD, Levantesi D, Taddei L, Marzilli M (1988) Persistence of subendocardial perfusion after subtotal coronary embolisation. Cardiovasc Res 22:113-121 24. Spaan JAE, Breuls NPW, Laird JD (1981) Diastolic-systolic coronary flow differences are caused by intramyocardial pump action in the anesthetized dog. Circ Res 49:584-593 Received March 22, 1991 Authors' address: Dr. M. Akaishi, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi Shkinjuku-ku, Tokyo 160, Japan