Basic Res. Cardiol. 68, 3-20 (1973)

From the Departments of Cardiovascular Research and Physiological Data-Systems, Research Laboratoria Janssen Pharmaceutica

Beerse (Belgium)

Myocardial steal produced by coronary vasodilation in chronic coronary artery occlusion

By W. Schaper, P. Lewi, W. Flameng and L. Gijpen

With 5 figures and 7 tables

(Received December 15, 1971)

The deve lopment of electronic flowmeters (f, 2, 3) and of inert gas techni- ques (4, 5, 6) has made it possible to measure coronary ar ter ia l inflow or coronary venous outflow with re la t ive ease.

Myocard ia l bloodflow obtained in this way represents , however , only average values and no deductions can be made about the regional distri- but ion of coronary flow. The work of Kirk and Honig (7), Honig, Kirk and Myers (8) suggested several years ago that in the normal dog hear t the endocardia l layers may receive less blood than epicardia l myocardium. The introduct ion of t racer microspheres (TM) by Domenech, Hoffmann, Nobel et al. (9) has, however, provided evidence for a homogeneous distri- bution of flow in the normal canine left ventricle. The dis tr ibut ion of flow might, however , be different if one of the large epicardia l coronary ar ter ies is chronical ly occluded. W e have shown i n recent years (10, 11) that such a procedure results in a t remendous enlargement of preexis tent col la tera l ves- sels by a growth process. The growth-transformation of col la terals is so effi- cient that in a great number of animals the chronic occlusion of the larges t subbranch of the coronary ar ter ia l tree was to lera ted without myocard ia l infarction. Clinical and pathological studies (12, 13, 14) have also shown that coronary occlusion in man need not necessar i ly lead to infarct ion be- cause col la terals are potent ia l ly able to replace the occluded ar tery. It is therefore to be expected that many pat ients suffering from angina pector is may have vary ing degrees of col la teral enlargement.

Ve ry l i t t le is known about the reac t iv i ty of col la terals and their depen- dent vascu la r beds to physiological and pharmacologica l stimuli. It has, however , been reported, that the inject ion of a vasodi la tor drug to a pre- v ious ly non-symptomat ic anginal pat ient may precip i ta te a typica l attack of angina pector is (15, 16). This finding is suggest ive for a re-dis t r ibut ion of myocard ia l blood flow caused by vasodi la t ion in hear ts with ar ter ia l lesions which are par t ly compensated for by enlarged collaterals . One might speculate about the poss ibi l i ty that myocard ium supplied by normal arte- ries "steals" from the myocard ium supplied by collaterals , a s i tuat ion which one could descr ibe by analogy as a "myocardia l steal syndrom".

4 Basic Research in Cardiology, Vol. 68, No. 1

T h e p o s s i b i l i t y t h a t t h i s m i g h t h a p p e n in t h e c o l l a t e r a l i z e d h e a r t of e x - p e r i m e n t a l a n i m a l s w i t h c h r o n i c c o r o n a r y a r t e r y o c c l u s i o n w a s i n v e s t i g a - t e d u s i n g T M b e f o r e a n d a f t e r c o r o n a r y v a s o d i l a t i o n w i t h t h e c o r o n a r y v a s o d i l a t o r l i d o f l a z i n e (17), a n d a f t e r t h e i n j e c t i o n of g l y c e r y l t r i n i t r a t e (GTNT) .

Materia ls and M e t h o d s

l. The tracer microsphere me thod (TM)

Trace r mic rosphe res (TM) are r ad ioac t i ve ly l abe l led spheru les of p r ecap i l l a ry size which can be purchased commerc ia l ly in va r ious sizes {i. e. 5 to 80 microns) . They are labe l led wi th di f ferent g a m m a - r a y emi t t ing nuc l ides (i. e. 125-I, 141-Ce, 51-Cr, and 85-Sr) and t hey h a v e a specific dens i ty (J,3 g/cm 3) s imilar to tha t of blood. W h e n in jec ted into the b lood s t ream, TM h a v e app rox ima te ly the same flow proper t i e s as the corpuscu la r c o m p o n e n t s of who le blood. This is e spec ia l ly t rue for the small TM, in the r a n g e b e t w e e n 5 and 15 microns.

Studies b y Phibbs, W y l e r , and N e u t z e (18) h a v e s h o w n tha t TM are r andomly d i s t r ibu ted over the c ross-sec t ion of the l a rger ar ter ies . Because of these p roper t i e s the t i ssue concen t r a t i on of t r apped TM is an accura te ref lect ion of the amoun t of b lood which the t i ssue received. In o the r words: TM can be used to s tudy the d i s t r ibu t ion of cardiac ou tpu t as wel l as poss ib le i nhomogene i t i e s of flow wi th in one pa r t i cu la r organ. The m e t h o d is, however , no t t ime d e p e n d e n t and on ly the re la t ive f rac t ion of the cardiac ou tpu t which en te r s the o rgan unde r s tudy can be measured . If, howeve r , the cardiac ou tpu t is m e a s u r e d i n d e p e n d e n t l y and if the amoun t of in jec ted spheres (i. e. the n u m b e r of in j ec ted counts pe r minute) w e r e known, o rgan flow in ml /min X 100 g t i ssue could be ca lcu la ted - because of the re la t ion

f = C O X q Q

where f s t ands for o rgan flow, CO for cardiac output , q for the de tec ted a m o u n t of t issue r ad ioac t iv i ty which is p ropor t iona l to the t i ssue concen t r a t i on of TM, and Q is the to ta l a m o u n t of in j ec ted TM and hence the to ta l n u m b e r of counts per minute . This las t in fo rmat ion is ha rd to ob ta in s ince it is for technical reasons not poss ible to p lace a sy r inge con ta in ing the TM r e a d y for in jec t ion into the wel l - type counter . A l t e r n a t i v e ways to es t imate Q h a v e b e e n p roposed b y Domenech, Hoff- mann et al. (9) bu t the degree of accu racy r ema ins doubtful . A t p r e sen t the me thod is the re fore res t r ic ted, bu t idea l ly suited, for the de tec t ion of n o n - h o m o g e n e o u s o rgan flow.

2. Detec t ion of gamma rays b y mul l ichannel sc int i l la t ion counter

G a m m a rays p roduce ion i sa t ion w h e n t hey in te rac t w i th mat ter . In the case of a solid detector , such as a NaI crystal , the inc iden t gamma rays p roduce ioniz ing par t ic les by th ree f undam en t a l in t e rac t ions (20). In the low e n e r g y r ange (up to O. 5 Mev) the g a m m a r ay is p r e d o m i n a n t l y abso rbed b y an a tom of the c rys ta l lat{ice, fo l lowed by emiss ion of a pho to -e l ec t ron from the K-e lec t ron s h e l l . These pho to- e lec t rons con t r ibu te to the photo-e lec t r ic p e a k of the spect rum. At h ighe r energ ies (up to 10 Mev) sca t t e r ing of gamma rays b y the ou te r e l ec t ron shel ls is p redomi- nant . A recoi l e l ec t ron car r ies some of the e n e r g y of the inc iden t g a m m a q u a n t u m and the w a v e l e n g t h of the sca t t e red gamma r ay is increased. A. H. Compton deri- ved in 1923 a r e l a t i on b e t w e e n the shif t in w a v e l e n g t h A ;~ and the sca t t e r ing angle {9 b e t w e e n the inc iden t and ref lected g a m m a rays (19):

2 h (9

w h e r e h is Planck's cons tant , m the mass of the e l ec t ron and c the ve loc i ty of light.

W. Schaper et al., Myocardial steal produced by coronary vasodilation 5

This relat ion shows that the energy loss is maximal when the scat ter ing angle equals 180 ~ .

Usual ly the photoelectr ic peak of the spectrum is preceded by a sharp Compton edge and a continuous pla teau produced by backscat ter ing and scat ter ing at smaller angles of the gamma rays.

The third interact ion occurs at still h igher energies when a gamma quantum is complete ly absorbed by a nucleus of the crystal with subsequent emission of an electron and a positron.

The minimum energy for pair product ion is equal to the sum of the rest ing energies of the two part icles (1.03 Mev) and hence of less importance for the pre- sent study.

na I crystal ~ i

lead shield I

TI I activa- photo- tor

r162 electron multiplier

prr amplifier

j ~ print-out

O O O O O

ASR-33 teletype

amplifier J gain select i~ J

t analog to digital J converter 1-- 10 bit j 5MHz l lower level and J upper level ~ J

t data handling module

section J 128 or

timer .~ 12ss channels dead time "?" I correction "~

1 memory section

display transfer

O 0 m " l

tape

- - - = = 1 I I

a a a ~ l B B

I I PDP - 11 computer

Fig. 1. Diagram of the multichannel analyzer and the data handl ing and data processing modules.

6 Basic Research in Cardiology, Vol. 68, No. I

W h e n ionizing par t ic les are t rapped by Thallium iodide impuri t ies in the crystal, l ight is emit ted. This signal h o w e v e r is too small for direct detect ion. The crysta l therefore makes contac t wi th the photoca thode of an e lec t ron mult ipl ier tube which can amplify the original signal several million times. The amplified signal is then sampled at a rate of 5 MHz by the analog to digital conver te r (fig. 1}. Each analog value is conver t ed in a f0 bit b inary number and s tored in one of the 256 memory locat ions of the mult ichannel analyzer. Each posi t ion of the memory or channel cor responds wi th a small in terval of the gamma ene rgy scale. The contents of the memory, after accumulat ion of a spect rum during a prese t time, can be d isplayed on a ca thode ray tube or pr in ted and punched on a te le type (21). The paper tape p roduced by the te le type is p rocessed by a PDP-11 digital computer for mathe- matical and statistical analysis.

Analysis ot gamma spectra obtained from microspheres Fig. 2 shows a typical spect rum obta ined from a mixture of the four radionucl ides

used in this study. The nucleor characterist ics (22} of these isotopes and their daughter nuclides are summarized in table 1. The hor izontal scale represen ts the channel numbers, cal ibrated at 4.5 key/channel . The ver t ical scale represen ts the number of counts accumula ted in each channel (reduced to pe rcen tage values of the h ighes t intensity}.

In order to reso lve the compound spec t rum into its components , th ree effects must be taken into account.

First the spect rum must be cor rec ted for background radiation, which is most in tensive in the lower energy domain. Secondly, the finite reso lv ing power of the crystal de tec tor must be determined. The resolut ion is defined as the wid th of a photoe lec t r ic peak at 50 % of the peak heigth, d ivided by the ene rgy cor responding with the top of the peak. The resolut ion of the 3" X 3" crystal of the Nuclear Data spec t rometer was measured in a series of cal ibrat ions and approaches 8 % around 500 key. The resolut ion de ter iora tes h o w e v e r to a va lue of 16 % at lower energies around 50 key. As can be der ived from table 1, the resolut ion of the sys tem is sufficient to separa t the main photoe lec t r ic peaks in a compound spectrum.

I00

Sr85 t'L

L aCel&l |Kx) ~

0 IJ ~ . . i , l L , ,

0 20

C e 141

~ Sr 85

40 60 80 100 120 CHANNELS

Fig. 2. Typical spect rum obta ined from a mixture of four radioisotopes in a bio- logical tissue. Horizontal scale is cal ibrated at 3.5 key/channel . Ver t ica l scale r epresen t s the act ivi ty accumula ted in each channel, reduced to pe rcen tage values of the h ighes t intensi ty . The channel ranges used in the resolut ion scheme are

indicated by brackets.

W. Schaper et al., Myocardial steal produced by coronary vasodilation 7

Table 1. Nuclear characterist ics of the i sotopes and their daughte r nucl ides used in the microsphere exper iments .

Mode of half life emiss ion Nuclide Decay (days) (Mev) Daughter nucl ide

24 Cr 51 EC 27.8 .320 25 V 51 stable 38 Sr 85 EC 64 .023 (Kx) 37 Rb 85 stable

.514 EC 60 ,0355 IT 58 .110

33 .036 (Kx) ,145

53 1 125 52 Te 125 m 52 Te 125 m 25 Te 125 stable 58 Ce 141 59 Pr 141 s table

EC: orbital e lec t ron capture IT: isomeric t ransi t ion Kx: X-ray emission from K e lec t ron shell

The third and far most important factor is the over lap (or spillover) p roduced by Compton scat ter ing. Especial ly for high energy radiation, the en e rg y loss due to elastic scat ter ing may ex tend over a large number of channels, due to mult iple in teract ions wi th mater ia ls other than the de tec tor crystal such as the glass of the test tube, the aluminium hermet ic seal of the crystal and the lead shield.

A scheme for resolving a compound spect rum has been descr ibed by Rudolph and Heymann (23) which has been used in all subsequent papers deal ing wi th microspheres . This scheme is based on the calculat ion of partial a reas under a set of cal ibrat ion spectra, a background spect rum and a compound spec t rum by sum- ming the contents of a number of adjacent channels. The ranges of the channels are chosen in such a way that they cover in turn each of the main photoe lec t r ic peaks of the isotopes. In addition, the total areas under the spect ra have to be computed. This scheme al lows to es t imate the total gamma-ray emiss ion of each nucl ide in the mixture, using ten correct ion factors in the case of four rad ioac t ive components .

In our s tudy a modified scheme was devised which requires only six correct ion factors and does not call for the total spectral counts. Our scheme differs from the Rudolph-Heymann scheme in the reduct ion to photo-elect r ic act ivi t ies ra ther than total spect ra l intensi t ies . The details of the calculat ions are de fe r red to the appendix,

The express ion of the re la t ive error on the reso lved act ivi t ies was der ived from mathemat ica l analysis and contains fewer terms than in the Rudolph-Heymann scheme. The error formula takes into account the summed act ivi t ies over the selec- ted channel ranges and the s tandard deviat ions which were obta ined exper iment - ally from thir ty cal ibrat ion runs.

Table 2 lists the six correct ion factors and their s tandard deviat ions .

Table 2. Correc t ion factors and their s tandard devia t ions obta ined exper imen ta l ly from 30 cal ibrat ion runs.

a ~a ~a

o/o o/o

Cr/Sr 3.15 .08 .025 Ce/Sr 7.75 .14 .018

I/Sr 18.99 .20 .011 Ce/Cr 4.86 .24 .049

I/Cr 12.4 .36 .029 I/Ce 35.0 .38 .011

8 Basic Research in C~rdiology, Vol. 68, No. 1

3. Animal sfudies

All studies were carr ied out in mongrel dogs of e i ther sex wi th an average b o d y w e i g h t of 20 kg. Chronic coronary ar tery occlusion was p roduced wi th the Ameroid- technique (24). The chest was opened under anes thes ia with droperidol- fen tany l -pen tobarb i ta l (25), and artificial respira t ion wi th a Bird Mark 8 respirator. The hear t was suspended in a pericardial cradle and an Amero id const r ic tor was s l ipped over the exposed circumflex branch of the left co ronary ar tery close to its origin. The chest was closed in layers and the animal rece ived antibiot ics once immedia te ly after the operation. The degree of nar rowing and the approximate day of complete arterial occlusion was de te rmined by repea ted coronary ang iography using the Sones technique (26). The microsphere exper iments were done not earl ier than 3 weeks after complete coronary occlusion and not later than 6 weeks post occlusion. In total 24 dogs wi th chronic coronary occlusion were studied.

For the TM-studies, the animals were anes the t ized wi th subcutaneous morphine- sulphate (2,5 mg/kg) fol lowed by in t ravenous sodium-dial lylbarbi ta l (25 mg/kg) and in t ravenous ure thane (400 mg/kg). The chest was opened under artificial respi- rat ion and a PE-50 ca the ter for TM inject ion was in t roduced into the left atr ium and secured by a purse str ing suture. The left anter ior descending coronary ar te ry was punctured wi th a fine 22 gauge needle attached to a PE 50 ca the ter to inject 133-Xenon for the measu remen t of total left vent r icu lar coronary blood flow. A needle -p lus -ca the te r of the same dimensions was inser ted into the circumflex coronary ar te ry distal ly from the point of occlusion for the measuremen t of the collateral myocardia l flow using 133-Xenon clearance.

The t i ssue-radioact iv i ty or iginat ing f rom 133-Xenon was picked up by a 2 inch precordial lead-sh ie lded NaI scint i l lat ion crysta l wi th an angle of acceptance of approximante ly 45 ~

In t ravascular p ressures were obta ined from 3 locations: from the descending aorta, from the left anter ior descending coronary ar te ry and from the circumflex branch distal ly from the point of occlusion. Af ter a per iod of approximate ly 30 minutes during which control values for coronary flow, collateral flow and blood pressures were sampled, the first in ject ion of microspheres , label led wi th e i ther 141-Ce or 85-Sr was made into the left atrium. Thereaf ter g lyceryl - t r in i t ra te {stock solut ion conta ined 10 mg/ml in an e thanol so lvent according to BP IV} was infused in t ravenous ly at a rate of .08 mg/kg/min. The average total dose was .16 mg/kg bodyweight . At the peak of the GTNT-action different ly label led TM were injected. W h e n the blood pressures and the hear t rate had re tu rned to pre- in jec t ion levels, 2,5 mg/kg lidofiazine was in jec ted in t ravenously . Coronary blood flow (CBF) and coronary collateral blood flow (CCBF) were measured wi th the 133-Xenon c learance before during and after the drug inject ions.

After the exper iment , the animal was ki l led with an overdose of the anesthet ic , the hear t was removed, r insed and fixed wi th 4 ~ buffered formaldehyde . There- after the hear t was sl iced perpendicu la r to its apex-base axis, the slices be ing about 1 cm thick. Hear t muscle samples were taken from the region of the anter ior papi l lary muscle (APM), from the region be tween the anter ior and the pos ter ior papi l lary muscle and from the pos ter ior papi l lary muscle (PPM). Samples were also taken from the r ight vent r ic le and from the right atrium.

Each block was fur thermore divided into an epicardial , endomural and endo- cardial sample. The anatomical origin of each sample was no ted and ass igned a codenumber . Each sample was then we ighed and t ransfer red to a plast ic d isposable tes t tube for the de te rmina t ion of radioact ivi ty .

From earl ier anatomical s tudies (10), it was known that the APM-region is ex- c lus ively per fused via subbranches of the anter ior descending ar tery whereas the PPM-region rece ives b lood exclus ive ly via collaterals. The area b e t w e e n these regions is per fused in part by normal subbranches of the anter ior descending ar te ry and par t ly by collaterals.

Ident ical exper iments were pe r fo rmed in 7 normal dogs with intact coronary arteries.

W. Schaper et al., Myocard ia l steal produced b y coronary vasodi la t ion 9

4. S tat is t ical analys is of the TM-data

Because of the n u m b e r of va r i ab l e s i n v o l v e d a s ta t i s t ica l ana lys i s of v a r i a n c e of the TM-da ta was car r ied out. Since card iac ou tpu t and the amoun t of in jec ted counts was not known, the d i s t r ibu t ion of each t r ace r ove r the hea r t musc le was compared us ing normal ized numbers . All va lues f rom the ep icard ia l surface of the an t e r io r pap i l l a ry muscle (APM) were a v e r a g e d and t aken as uni ty . The re spec t ive ac t iv i t i es of the o ther ana tomica l loca t ions were expres sed as f rac t ions of the ep icard ia l APM-values .

The s ta t is t ica l t r e a t m e n t of these data employs a fac tor ia l des ign i nvo lv ing 4 fac- tors i . e . an imals (A), c i rcumferen t ia l d i s t r ibu t ion of TM (C), i .e. the d i f ference bet- ween APM and PPM-dis t r ibut ion, the dep th -d i s t r ibu t ion (D), i .e. the di f ference bet- w e e n ep icard ia l and endocard ia l rad ioac t iv i ty , and t r e a t m e n t {T) wi th 2 compounds . Each e l emen t of the 13 X 2 X 2 X 3 factor ia l des ign is r ep l i ca ted 4 t imes. The sum of squares , d iv ided by the n u m b e r of degrees of f r eedom yie lds the con t r i bu t ion to the to ta l v a r i a n c e of the data. These "mean squa re s " - t e rms (see tab le 4) are t es ted for s ignif icance aga ins t the res idual va r i ance or e r ror t e rm b y the F-test. The tests for s ignif icance were car r ied out for each p r i m a ry fac tor (A, T, C, and D) and all poss ib le in t e rac t ions b e t w e e n the factors 2 by 2, i. e. DC, DA etc, 3 b y 3, i. e. DCA, DCT, etc. and f inal ly b y cons ider ing the in te rac t ion of all 4 fac tors t a k e n t oge the r (DCAT).

Resul ts

T h e e f f e c t s of t r e a t m e n t w i t h e i t h e r G T N T or w i t h l i d o f l a z i n e u p o n c a r - d i a c T M d i s t r i b u t i o n a r e s u m m a r i z e d in t a b l e 3 a n d in fig. 3. Fig. 3 r e p r e - s e n t s a t y p i c a l e x p e r i m e n t in a d o g w i t h c h r o n i c c o r o n a r y a r t e r y o c c l u s i o n w h e r e l i d o f l a z i n e h a d p r o d u c e d a d r a m a t i c r e d i s t r i b u t i o n of TM, T h e r e w a s n o s u c h r e d i s t r i b u t i o n i n t h e l e f t v e n t r i c u l a r m y o c a r d i u m b e f o r e l i d o f l a z i n e ( c o n t r o l ) a n d n o o b v i o u s c h a n g e w a s p r o d u c e d b y G T N T . I t is n o t e w o r t h y t h a t t h e r i g h t v e n t r i c u l a r a n d t h e r i g h t a t r i a l m y o c a r d i u m r e c e i v e d r e l a t i - v e l y m o r e T M u n d e r b o t h l i d o f l a z i n e a n d G T N T . R i g h t v e n t r i c u l a r a n d a l s o r i g h t a t r i a l m y o c a r d i u m r e c e i v e d m o r e T M, a n d h e n c e m o r e b l o o d f low,

Table 3. Dis t r ibu t ion of TM over the left v e n t r i c u l a r wal l before and dur ing drug- t rea tment .

A PMendo PPMepi PPMendo PPMendo PPMendo APMepi APMepi APMepi A P M e n d o PPMepi

Chron ic c o r o n a r y a r t e r y occ lus ion

Lidoflazine Ni t rog lyce r ine

Norma l c o r o n a r y a r te r ies Cont ro l Lidoflazine

1.07 0.97 1.03 1.00 1.06 1.03 0.75 0.59 0.76 0.78 0.99 1.09 0.99 0.92 0.91

1.15 1.23 0.99 1.07 1.24 0.97 0.93 0.90 0.93 0.97

APM = reg ion of the an t e r io r pap i l l a ry muscle PPM = reg ion of the pos te r io r pap i l l a ry muscle epi = subep ica rd ia l m y o c a r d i u m endo = subendoca rd i a l m y o c a r d i u m All APMep i -va lues pe r ind iv idua l hea r t and per isotope are e x p r e s s e d as un i ty and used as r e fe rence number . The tab le shows c lear ly the r ed i s t r i bu t ion of TM

caused b y l idoflazine.

10 Basic Research in Cardiology, Vol. 68, No. I

CONTROL LIDOFLAZINE GTNT

APM PPM RV RA APM PPM RV RA APM PPM RV RA

t

o,g

O,B

0,7

O,6

0,S

0.4

0,3

O,2

0,1

Fig. 3. TM content in the left and right ventricle and in the right atrium. All values are expressed relative to the TM-content of epicardial region of the anterior

papillary muscle.

Symbols: APM = anterior papillary muscle PPM = posterior papillary muscle RV = right ventricle RA = right atrium GTNT = glyceryltrinitrate

Empty columns ~ epicardial TM-content Black columns ~ endocardial TM-content

than the endocard ia l par t of the pos te r ior pap i l l a ry musc le unde r the influ- ence of l idoflazine. Table 3 summar izes the degree of r ed i s t r ibu t ion unde r l idoflazine and GTNT in 20 dogs wi th chronic co rona ry a r te ry occlusion. On the ave rage (n = 20) the endocard ia l m y o c a r d i u m of the pos te r ior pap i l l a ry musc le r ece ived on ly 59 % of the flow which goes to the epicardia l r eg ion of the an te r io r pap i l l a ry muscle. The epicard ia l por t ion of the pos te r ior pap i l l a ry musc le r ece ived on ly 75 ~ as compared wi th the flow to the epi- cardial reg ion of the an te r io r pap i l l a ry muscle. The changes p roduced b y GTNT are v e r y sl ight in compar i son wi th those p roduced by l idoflazine. From a func t iona l po in t of v i e w these changes are p r o b a b l y negl ig ib le . They are, however , s ta t i s t ica l ly s ign i f ican t at the 1 % p robab i l i t y level in the mul t i fac tor ia l ana lys i s of var iance . Table 3 shows also that l idof lazine pro- duced a small change in the left ven t r i cu l a r TM-d i s t r ibu t ion in dogs wi th no rma l co rona ry arteries. Usua l ly the TM conc e n t r a t i on in no rma l myocar - d ium is s l ight ly h igher in the endocard ia l as compared wi th the epicardia l layers . Under l idoflazine this type of TM d i s t r ibu t ion is reversed. This rever- sal is s l ight and v e r y much less than in dogs wi th co rona ry a r te ry occlusion. It is, however , s ta t i s t ica l ly s igni f icant (see table 5). The resul ts of the mul t i -

W. Schaper et al., Myocardial steal produced by coronary vasodilation 11

f a c t o r i a l a n a l y s i s of v a r i a n c e a r e s u m m a r i z e d in t a b l e s 4 a n d 5. S t a t i s t i c a l a n a y l s i s of t h e d a t a w a s p e r f o r m e d 3 t i m e s : o n c e fo r a l l c o n t r o l d o g s w i t h n o r m a l c o r o n a r y a r t e r i e s (n = 7), o n c e fo r a l l c o n s t r i c t o r - d o g s t h a t h a d r e c e i v e d b o t h l i d o f l a z i n e a n d G T N T (n = 15) a n d o n c e fo r a l l c o n s t r i c t o r - d o g s t h a t h a d r e c e i v e d l i d o f l a z i n e (n = 20). R e s u l t s a r e o n l y g i v e n fo r t h e c o n t r o l d o g s a n d fo r c o n s t r i c t o r d o g s t r e a t e d w i t h l i d o f l a z i n e . T h e s t a t i s t i c a l a n a l y s i s of t h e G T N T - e f f e c t s is n o t s h o w n h e r e b e c a u s e of t h e v e r y s l i g h t a n d p r o b a b l y f u n c t i o n a l l y i n s i g n i f i c a n t e f t e c [ of t h e d r u g . T a b l e 4 s h o w s t h a t t r e a t m e n t of c o n s t r i c t o r d o g s w i t h l i d o f l a z i n e r e s u l t e d in a s t a t i s t i c a l l y h i g h l y s i g n i f i c a n t r e d i s t r i b u t i o n of l e f t v e n t r i c u l a r b l o o d f low. A d i s t i n c t i o n is m a d e b e t w e e n t h e c i r c u m f e r e n t i a l d i s t r i b u t i o n C (i. e. A P M v e r s u s P P M r e g i o n s ) a n d t h e d e p t h - d i s t r i b u t i o n D (i. e. e p i c a r d i a l v e r s u s e n d o c a r d i a l b l o o d f low). R a n k i n g of t h e F - v a l u e s of t a b l e 4 s h o w s t h a t t r e a t m e n t w i t h l i d o f l a z i n e (T) c o n t r i b u t e d m o s t to t h e t o t a l v a r i a n c e of t h e d a t a . N e x t in l i n e is t h e c i r c u m f e r e n t i a l d i s t r i b u t i o n C, i. e. t h e w h o l e p o s t e r i o r p a p i l l a r y m u s c l e - r e g i o n r e c e i v e d l e s s b l o o d t h a n t h e a n t e r i o r r e g i o n w h i c h is s u p - p l i e d v i a n o r m a l a r t e r i e s . T a b l e 4 s h o w s f u r t h e r t h a t c i r c u m f e r e n t i a l d i s t r i - b u t i o n d u e to t r e a t m e n t (CT) c o n t r i b u t e s a l so h e a v i l y to t h e t o t a l v a r i a n c e as d o e s t h e c o m b i n e d e f f e c t of d e p t h a n d c i r c u m f e r e n c e (DC) as w i l l a s t h e c o m b i n e d e f f e c t of d e p t h a n d t r e a t m e n t (DT).

Table 4. TM-dis t r ibu t ion af ter l idoflazine in dogs wi th chronic c o r o n a r y a r t e ry occlusion. Resul ts of the mul t i fac tor ia l ana lys i s of va r i ance .

Source of Sums of Degrees of M e a n F-value Probab i l i t iy v a r i a t i o n squares f reedom squares

D 0.146 1 0.146 4.424 ~ 0 . 0 5 C 4.865 1 4.865 147.424 ~ 0 . 0 1 A 11.215 19 0.590 17.879 ~ 0 . 0 1 T 5.719 1 5.719 173.303 ( 0 . 0 1

DC 0,643 1 0.643 19.485 <:0.01 DA 4.434 19 0.233 7.061 "(0.01 CA 4.905 19 0.258 7.818 <:0.01 DT 0.596 1 0.596 18.061 ~ 0 . 0 1 CT 4.737 1 4.737 143.545 ~ 0 . 0 1 AT 13.469 19 0.709 21.485 ~ 0 . 0 1

DCA 2.418 19 0.127 3.848 ( 0 . 0 1 DCT 0.293 1 0.293 8.879 <:0.01 DAT 2.583 19 0.136 4.121 ( 0 . 0 1 CAT 5.030 19 0.265 8.030 ~ 0 . 0 1

DCAT 2.092 19 0.110 3.333 ~ 0 . 0 1

Error 15.967 480 0.033

Total 79.115 639

D = dep th d i s t r ibu t ion of TM, i.e. ep i -versus endocard ia l d i s t r ibu t ion C = c i r cumferen t i a l d i s t r ibu t ion of TM, i.e. APM versus PPM-reg ion A = in t e r - an ima l v a r i a t i o n T = v a r i a t i o n due to d r ug - t r ea t m en t Combina t i on of symbols (i.e. DT0 CT, etc.) r ep resen t s the combined we igh t of, i.e., deph t -p lu s - t r ea tmen t v a r i a t i o n on tbe to ta l var ia t ion . Table 4 shows tha t the combina t ion of c i rcumferen t ia l TM dis t r ibu t ion due to t r e a t m e n t {i.e. CT) and the combina t ion : dep t h - c i r cum f e r ence - t r e a t m en t show the h ighes t degree of signi-

f icance (F-values).

12 Basic Research in Cardiology, Vol. 68, No. 1

Table 5. TM d is t r ibu t ion af ter l idoflazine in dogs wi th normal co rona ry ar ter ies . Resul ts of the mul t i fac tor ia l ana lys i s of va r iance . For symbols see l egend of t ab le 3.

Note tha t the DCT-combina t ion is not s ignif icant .

Source of Sums of Degrees of M e a n F-va lue P robab i l i ty v a r i a t i o n squares f reedom squares

D 0.411 1 0.411 21.631 ~ 0.01 C 0.012 1 0.012 0.631 n . s . A 0.418 6 0.070 3.684 ~ 0.01 T 1.183 1 1.183 62.263 < 0.01

DC 0.025 1 0.025 1.316 n . s . DA 0.364 6 0.061 3.210 < 0.01 CA 0.112 6 0.019 1.000 n . s . DT 0.711 1 0.711 37.421 ~ 0.01 CT 0.158 1 0.158 8.316 < 0.01 AT 0.601 6 0.101 5.316 ,~ 0.01

DCA 0.160 6 0.027 1.421 n . s . DCT 0.021 I 0.021 1.105 n . s . DAT 0.552 6 0.092 4.842 "~ 0.01 CAT 0.158 6 0.026 1.368 n . s .

DCAT 0.136 6 0.023 1.210 n . s .

Error 3.234 168 0.019

Total 8.267 223

T a b l e 5 r e p r e s e n t s t h e r e s u l t s of t h e m u l t i f a c t o r i a l a n a l y s i s of v a r i a n c e w h i c h w a s c a r r i e d o u t w i t h t h e d a t a o b t a i n e d f r o m t h e a n i m a l s w i t h n o r m a l c o r o n a r y a r t e r i e s .

R a n k i n g of t h e F - v a l u e s s h o w s t h a t t r e a t m e n t T c o n t r i b u t e d m o s t to t h e t o t a l v a r i a n c e of t h e d a t a . T h i s is f o l l o w e d b y t h e c o n t r i b u t i o n of D (epi - c a r d i a l v e r s u s e n d o c a r d i a l ) a n d b y t h e c o m b i n a t i o n of D T ( d e p t h d i s t r i b u - t i o n d u e to t r e a t m e n t ) . T h e r e is n o c i r c u m f e r e n t i a l d i s t r i b u t i o n as i t is t h e c a s e in c o n s t r i c t o r d o g s a n d t h e D C T - c o m b i n a t i o n is a l so n o t s i g n i f i c a n t .

1 3 3 - X e n o n c l e a r a n c e

T a b l e 6 s h o w s t h a t l i d o f l a z i n e i n c r e a s e d t o t a l m y o c a r d i a l b l o o d f l ow s u b - s t a n t i a l l y in c o l l a t e r a l i z e d h e a r t s w i t h c h r o n i c c o r o n a r y o c c l u s i o n as w e l l as in n o r m a l h e a r t s . T h e t o t a l d i l a t o r y r e s e r v e w a s h o w e v e r s l i g h t l y r e d u - c e d i n t h e c o l l a t e r a l i z e d h e a r t s w i t h c o r o n a r y a r t e r y o c c l u s i o n , i . e . 2,7 t i m e s c o n t r o l f l ow in n o r m a l h e a r t s v e r s u s 2,2 t i m e s c o n t r o l f l ow i n c o l l a - t e r a l i z e d h e a r t s . I t is i n t e r e s t i n g to n o t e t h a t t h e a r e a s of t h e l e f t v e n t r i c l e s u p p l i e d b y c o l l a t e r a l s h a v e a m a r k e d l y r e d u c e d d i l a t o r y r e s e r v e (i. e. 1,70 t i m e s c o n t r o l f low) as c o m p a r e d w i t h a r e a s s u p p l i e d b y n o r m a l a r t e r i e s (2,5 t i m e s n o r m a l f low) . A n o t h e r i n t e r e s t i n g f i n d i n g w a s t h a t l i d o f l a z i n e p r o - d u c e d i n a l l h e a r t s a n i n c r e a s e i n c o l l a t e r a l f l ow t h o u g h to a l e s s e r e x t e n t . G l y c e r y l t r i n i t r a t e ( G T N T ) p r o d u c e d n o m e a s u r a b l e c h a n g e , n e i t h e r of col - l a t e r a l f l ow n o r of c o r o n a r y b l o o d f low a n d t h e r e w a s n o d i f f e r e n c e b e t w e e n n o r m a l h e a r t s a n d h e a r t s w i t h c o r o n a r y o c c l u s i o n .

W. Schaper et al., Myocardial steal produced by coronary vasodilation 13

Table 6. C o r o n a r y and c o r o n a r y co l la te ra l b lood f low before and af ter t r e a t m e n t as m e a s u r e d wi th Radio-Xenon. The first n u m b e r in each ind iv idua l squa re is the m e a n value , the n u m b e r be low is the m e d i a n value . No med ian va lue is g iven for

the control dogs before and af ter n i t r og lyce r ine (GTNT).

133-Xenon M e a n M e a n Peak Peak C h a n g e of C h a n g e of C lea rance cont ro l cont ro l AD-Flow LC-Flow AD-Flow LC-Flow

m l / m i n x l 0 0 g AD-Flow LC-Flow ( t rea tment) ( t rea tment) (factor) (factor)

Cont ro l dogs 51.6 47.5 139.6 119.4 3.1 2,63 Lidoflazine 52.0 50.0 130.0 125 2.5 2.4

Cont ro l dogs 41.0 51.6 44.6 45,3 1.08 0.89 GTNT

Cons t r i c to r 57.8 60.1 147.0 102.3 2.54 1.70

dogs 55.5 54.5 133.0 99.0 2.45 1.70 Lidoflazine

Cons t r i c to r 57.3 57.6 63.1 66.2 1. i 0 1.11

dogs 53.0 50.0 53.0 66.0 1.00 1.05 GTNT

Pressure data

B o t h d r u g s u n d e r s t u d y d e c r e a s e d in a m o r e o r l e s s t r a n s i e n t w a y t h e a r t e r i a l b l o o d p r e s s u r e as w e l l a s t h e p e r i p h e r a l c o r o n a r y p r e s s u r e (PCP) in c o l l a t e r a l i z e d h e a r t s . S i n c e i t is k n o w n t h a t t h e r a t i o of e n d d i a s t o l i c P C P o v e r e n d d i a s t o l i c A B P is i n f l u e n c e d b y t h e c o l l a t e r a l r e s i s t a n c e as w e l l as b y t h e p e r i p h e r a l r u n - o f f i t w a s of i n t e r e s t to s t u d y t h e b e h a v i o r of t h e PCP/ABP-rat io u n d e r t h e i n f l u e n c e of b o t h d r u g s . T a b l e 7 s u m m a r i z e s t h e p r e s s u r e - d a t a of a n i m a l s f r o m w h i c h a c c u r a t e p r e s s u r e m e a s u r e m e n t s c o u l d b e o b t a i n e d . T h e d a t a s u g g e s t a d i f f e r e n t m o d e of a c t i o n of t h e d r u g s s t u d i e d . L i d o f l a z i n e d e c r e a s e d t h e P C P / A B P - r a t i o in a b o u t h a l f of t h e a n i - m a l s . T h e r e w a s n o c h a n g e in t h e r e m a i n i n g a n i m a l s . N i t r o g l y c e r i n e p r o - d u c e d a n i n c r e a s e in t h e q u o t i e n t P C P / A B P in a b o u t h a l f t h e a n i m a l s , p r o - d u c e d n o c h a n g e in 2 a n d d e c r e a s e d t h e r a t i o in 5. S i n c e G T N T d i d n o t c a u s e v a s o d i l a t i o n in t h e s e h e a r t s , t h e i n c r e a s e of P C P / A B P i n s o m e of t h e s e h e a r t s m i g h t s u g g e s t a d e c r e a s e in c o l l a t e r a l r e s i s t a n c e n o t a c c o m - p a n i e d b y a d e c r e a s e in a r t e r i o l a r r e s i s t a n c e . T h i s r e m a i n s , h o w e v e r , s p e - c u l a t i v e b e c a u s e t h e p r e s s u r e - f l o w r e l a t i o n s of c o l l a t e r a l s w i t h a n d w i t h - o u t n i t r o g l y c e r i n e a r e i n s u f f i c i e n t l y k n o w n .

Table 7. In f luence of d rug - t r ea tmen t on the pe r iphe ra l co rona ry p re s su re in dogs wi th chronic co rona ry a r t e ry occlusion.

PCP Lidoflazine Ni t rog lyce r ine ABP n = 15 n = 15

Inc rease 0/15 8/15 Decrease 8/15 2/15 No change 7/15 5/15

PCP ~- Pe r iphe ra l c o r o n a r y p ressu re measu red dis ta l ly from the po in t of occ lus ion ABP = aor t ic b lood p re s su re The dec rease of the p re s su re ra t io u n d e r l idoflazine ve r sus the inc rease unde r n i t rog lyce r ine is s ta t i s t i ca l ly s igni f icant {p 40.01) accord ing to the chi-square test.

14 Basic Research in Cardiology, Vol. 68, No. 1

Discussion

It was found tha t hear t s wi th chronic c o r o n a r y occ lus ion which show a wel l d e v e l o p e d co l l a t e ra l c i rcu la t ion and no infarcts r eac t d i f fe ren t ly to d rug - induced c o r o n a r y vasod i la t ion , w h e n c o m p a r e d to hear t s wi th no rma l c o r o n a r y ar ter ies . The area suppl ied by co l l a t e ra l s has a r educed c o r o n a r y r e s e r v e and m y o c a r d i a l b lood flow shows a n o n - h o m o g e n e o u s d i s t r ibu t ion w h e n v a s o d i l a t i o n is induced. The total "co l la te ra l " a rea r e c e i v e s less b lood in compa r i son wi th the a rea which r e c e i v e s b lood f rom no rma l a r te r ia l channels and wi th in the co l la te ra l a rea p rope r the endoca rd i a l myo- ca rd ium r e c e i v e s less b lood than the ep ica rd ia l areas.

This appears at first s ight to be the logical c o n s e q u e n c e of the r educed c o r o n a r y d i l a to ry r e s e r v e of the co l l a t e ra l i zed m y o c a r d i u m . The d e g r e e of f low-red i s t r ibu t ion is, h o w e v e r , l a rge r than e x p e c t e d on the basis of the m e a s u r e d (133-Xenon c learance) d i f fe rences in d i l a to ry rese rve . Lidoflazine induced an ove ra l l i nc rease in the co l l a t e ra l i zed area of about 1,70 t imes the cont ro l f low but the compar i son of m i c r o s p h e r e con ten t of the endo- cardia l PPM a rea ( = co l la te ra l dependent ) wi th the endoca rd i a l A P M - a r e a (not co l la te ra l dependent} s h o w e d a much l a rge r d i f ference , i. e. some t imes by a fac tor of 3 to 4. The susp ic ion that f low migh t not i nc rease in the co l l a t e r a l -dependen t endoca rd i a l a rea (it m a y ac tua l ly decrease) is s t rengh- t ened by the o b s e r v a t i o n tha t the r ight a t r ium r e c e i v e s of ten more b lood than the PPM-reg ion of the left ven t r i c l e . The inc rease in to ta l co l l a te ra l f low goes mos t p r o b a b l y on ly to the ep ica rd ia l and e n d o m u r a l areas at the expense of the endoca rd i a l layers . Ear l ie r e x p e r i m e n t s f rom this labora- t o ry (10, 27} h a v e shown that the dec rea se of the co l la te ra l res is tance , as happens in s lowly p rog re s s ing c o r o n a r y a r t e ry s tenosis , needs t ime. This is re f lec ted in the g radua l i nc rease in the PCP as a func t ion of t ime after

Symbols:

Fig. 4.

R1 R~

R~ and R 4 R 5 and R 6

R~ P Pl P~

d

R 5 ~ R6

Model of the coronary and collateral circulation.

= resistance of the left anterior descending coronary artery = resistance of the left circumflex coronary artery

resistances of the arteriolar resistance vessels capillary resistances

= collateral resistance = pressure aortic perfusion = pressure head at origin of collateral

pressure at point of reentry of collateral into vascular tree of recipient system

= flows over correspondent resistances

W. Schaper et al., Myocardial steal produced by coronary vasodilation 15

co rona ry a r te ry occlusion. This suggests that the r ed i s t r ibu t ion of myo- cardial f low is p robab ly most ou t spoken du r ing the ear ly s tages of colla- teral adap ta t ion and less so du r ing the la ter s tages w h e n the col la tera ls and anas tomoses have g rown to their full size. Since the p rev ious s tudies and ear l ier exper imen t s wi th different techniques (10) lend suppor t to this v iew we des igned a computer -model which s imula tes the even t s which take place dur ing s lowly progress ing co rona ry a r te ry s tenosis (see fig. 4). The model consists bas ica l ly of a whea t s tone br idge and the res i s tance of the left c i rcumflex co rona ry a r te ry (R.~) increases over a per iod of about 20 days to va lues approaching infinity. This somehow induces g rowth in the colla- teral res i s tance (RT) as was p rev ious ly descr ibed by Schaper et al. (11) on the bas is of DNA rep l ica t ion studies. Once e v e r y w e e k du r ing t2 weeks total va sod i l a t i on was induced by a decrease of the res i s tance R~ and R4 to their lowest possible values . These va lues were chosen as to a l low a flow increase (in the absence of occlusion) of 3 t imes cont ro l flow, i. e. the nor- real co rona ry reserve at m a i n t a i n e d ar ter ia l b lood pressure . The respec t ive increases in i 3 and i4 (CBF and CCBF) were then ca lcu la ted u n d e r the con- di t ions of total vasod i l a t ion and co rona ry occ lus ion and the degree of non- homogeneous flow changes is shown in fig. 5 as a func t ion of t ime and as a func t ion of col la tera l res is tance respect ive ly .

The model was p rog rammed in For t ran IV and tes ted on an IBM-1800 computer . The resul ts show that induced vasod i l a t ion produces non -homo- geneous d i s t r ibu t ion of flow at all se lected t ime in te rva l s after the onset of stenosis. Redis t r ibu t ion due to vasod i l a t ion is most p r o n o u n c e d dur ing severe s tenosis (i. e. pr ior to complete occlusion) and ear ly after co rona ry ar te ry occlusion. Redis t r ibu t ion did, however , pers is t though to a lesser degree over the ent i re range of selected t ime intervals . The la t ter f inding is in comple te ag reemen t wi th the exper imen ta l f indings p re sen t ed in this paper. A l though we tested an imals be tween 3 and 6 weeks after the coro- n a r y occlusion, n o n - h o m o g e n e o u s flow was a common f inding dur ing vaso- di lat ion. There was no s ignif icant difference b e t w e e n an imals tes ted at 3 and those tes ted at 6 weeks post occlusion. This was to be expec ted s ince the PCP/ABP rat ios did no t v a r y be tween groups.

The ana lys i s of factors con t r ibu t ing to red i s t r ibu t ion poin ts to the fact that the col la tera l res i s tance does no t drop wi th in the t ime l imits of the expe r imen t s repor ted here to va lues as low as those of a no rma l c o r o n a r y ar tery. Long term obse rva t ions from our l abo ra to ry (i. e. 2 yea r s after oc- clusion) (10) sugges t that the col la tera l res i s tance c losely approaches bu t n e v e r qui te reaches the res i s tance of the a r te ry before s tenosis was pro- duced. It should be kept in mind, however , that the obse rved r ed i s t r i bu t ion of myoca rd i a l flow is no t a u n i q u e p roper ty of l idoflazine bu t also of o ther co rona ry vasod i l a to r s such as d ipyr idamole (10). It is also i n t e r e s t i ng to no te that l idoflazine di la tes the coronar ies in dogs on ly bu t ne i the r in pigs nor in m a n (10, 28, 29). It should fur thermore be m e n t i o n e d that vaso- d i l a t ion - induced red i s t r ibu t ion of flow occurs m a i n l y at m a x i m a l vasod i la - t ion or at v e r y high flow rates. At lower than max imal bu t still e l eva t ed flows, h o m o g e n e o u s flow d i s t r ibu t ion is possible.

16 Basic Research in Cardiology, Vol. 68, No. I

J3/J4 = CORONARY

2.

FLOW/COLLATERALFLOW

VASODILATION

Q

§

1 WEEKS AFTER ONSET OF CORONARY STENOS|S

Fig. 5. Degree of imba lance b e t w e e n c o r o n a r y and co rona ry co l la te ra l f low as a func t ion of t ime. The flow va lues were ob ta ined from the compute r model of f igure 4. The res i s t ance R 7 ( = co l la te ra l res is tance) drops as func t ion of t ime due to va scu l a r growth. Once e v e r y w e e k af ter onse t of co rona ry s tenos is the re- s i s tance vesse ls were desc reased to the i r lowes t poss ib le values . Open circles: degree of imba lance which resul t s w h e n the col la tera ls do not d i la te bu t r a t h e r

b e h a v e as r igid b lood conductors . Solid dots: degree of imba lance which resu l t s w h e n the col la tera l vesse l s di la te

to the same ex ten t as do the r e s i s t ance vessels . Solid squares: degree of imba lance in the absence of a d i la t ing st imulus.

Cross: ac tua l ly m e a s u r e d degree of imba lance of the en t i re co l la te ra l d e p e n d e n t a rea (PPM) as m e a s u r e d wih t Radio-Xenon.

X = ac tua l ly m e a s u r e d a v e r a g e imbalance , as m e a s u r e d wi th the TM-dis t r ibu t ion technique.

T h e r e s u l t s o b t a i n e d w i t h n i t r o g l y c e r i n e (GTNT) a r e d i f f i c u l t to e x p l a i n . S i n c e G T N T d i d n o t p r o d u c e a m e a s u r a b l e c h a n g e i n f low, t h e i n a b i l i t y of G T N T to p r o d u c e n o n - h o m o g e n e o u s f l ow is q u i t e u n d e r s t a n d a b l e . T h e p o s s i b i l i t y t h a t G T N T m i g h t c a u s e a d e c r e a s e i n c o l l a t e r a l r e s i s t a n c e w i t h - o u t a f f e c t i n g t h e r e s i s t a n c e v e s s e l s as p r o p a g a t e d b y Faro a n d M c G r e g o r (30), s e e m s p o s s i b l e b u t is r a t h e r s p e c u l a t i v e a n d c a n n e i t h e r b e s u b s t a n t i a - t e d n o r r e f u t e d o n t h e b a s i s of o u r p r e s e n t f i n d i n g s .

W. Schaper et al., Myocardial steal produced by coronary vasodilation 17

T h e c l i n i c a l i m p l i c a t i o n s of o u r r e s u l t s a r e o b v i o u s . T h e l a c k of i m p r o v e - m e n t a n d t h e r e p o r t e d d e l e t e r i o u s e f f e c t s of c o r o n a r y v a s o d i l a t o r s in p a t i e n t s w i t h i s c h e m i c h e a r t d i s e a s e (15, 16, 31) is s u b s t a n t i a t e d a n d is n o w f o u n d e d o n a s o u n d e x p e r i m e n t a l b a s i s , i . e . c o r o n a r y v a s o d i l a t o r s c a u s e a n o n - h o m o g e n e o u s d i s t r i b u t i o n of m y o c a r d i a l b l o o d f l o w a t t h e e x p e n s e of t h o s e a r e a s of t h e h e a r t b a d l y i n n e e d of b l o o d a n d o x y g e n . I t s h o u l d b e n o t e d t h a t r e d i s t r i b u t i o n of f low w a s o b s e r v e d in a n i m a l s w i t h o n l y o n e c o r o n a r y o c c l u s i o n a n d a w e l l d e v e l o p e d c o l l a t e r a l c i r c u l a t i o n . H u m a n i s c h e m i c h e a r t d i s e a s e m o r e o f t e n t h a n n o t i n v o l v e s m o r e t h a n o n e v e s s e l a n d c o l l a t e r a l c o m p e n s a t i o n m a y n o t b e as e f f i c i e n t as o b s e r v e d in d o g s . I n d u c t i o n of c o r o n a r y v a s o d i l a t i o n m i g h t i n t h e s e c a s e s i n d u c e a m u c h m o r e p r o n o u n c e d d e g r e e of n o n - h o m o g e n e o u s m y o c a r d i a l f low.

A p p e n d i x

Resolv ing p rocedure for a mix tu re of four nucl ides : r educ t ion to pho to-e lec t r i c intensi t ies .

The fo l lowing symbols are in t roduced for the de r iva t ion of the r e so lu t ion for- mulas and the error express ions :

Ti total n u m b e r of counts b y summat ion ove r the channel r ange se lec ted for the i- th isotope

Bi background re la t ive to channel r ange for i-th i so tope Ai ac t iv i ty cor rec ted for background Ci net ac t iv i ty of i-th isotope cor rec ted for spi l l -over.

It is a s sumed here tha t the isotopes are labe l led by dec reas ing e n e r g y of the main pho to-e lec t r i c peaks .

The cor rec t ion for spi l l -over is only appl ied from r ight to left s ince there is no con t r ibu t ion to the channels above a photo-e lec t r ic peak.

If aji deno tes the con t r ibu t ions of the j - th isotope to the ac t iv i ty of the i-th nucleide, we can r ep re sen t the six nucl ides in ma t r ix no ta t ion :

Sr 85

Cr 51

Ce 141

I 125

Sr 85 Cr 51 Ce 141 I t25

1 ~1~. ~tt3 Ctt4

0 1 a2s a24

0 0 1 a34

0 0 0 1

It is w o r t h w h i l e to not ice here tha t in the Rudolph-Heymann scheme the d iagona l e l ement s are less t han uni ty .

The fo l lowing steps are requ i red in order to a r r ive at the ne t ac t iv i t ies :

Step 1, co r rec t ion for background

Ai ~ Ti - Bi, i = from 1 to 4

Step 2. co r rec t ion for spi l l -over

C1 = A1 C~ = A2 - a12C1 C a = A s - al~C 1 - a~3C 2

C4 = A4 - a14C1 - a.24C2 - a3,C3

18 Basic Research in Cardiology, Vol. 68, No. 1

or in a more compact notat ion:

C1 ~ A1 i--1

C i ~ A i - - . ~ a j i C ~ , i from 2 to n j ~ t

whe re n is the number of different nucl ides In the Rudolph-Heymann scheme, these formulas have the form:

1 C1 -- A1

all 1 i--1

Ci ~ ( A i - - ~ aji Cj), i from 2 to n aii j -- 1

The genera l error formulas can be der ived easi ly from the above equations.

For our modif ied scheme we obtain:

dC~ ~ /1A1

ACi ~ AAi d- .~ (Cj daj i -~ aji ACj) i--1

i from 2 to n

where daj i are the s tandard devia t ions of the correct ion factors, which can be obta ined exper imen ta l ly from repet i t ive cal ibrat ions and dAi = (Ai -~ 2Bi) 1/2 where Bi is the background in the channels of the i-th isotope.

For the comple te Rudolph-Heymann scheme we obtain:

dC1 -- 1 (danC1 �9 ~A1) all

i--1 Ci -- 1 (4 aiiCi -~ A Ai -~- .~ (Cj d aji ~ aji d Cj)

aii j ~ 1 i from 2 to n

It can be readi ly seen that the lat ter formulas contain one more extra term due to the diagonal e lements of the matr ix being different from unity.

Acknowledgements

The authors are indeb ted to Agnes Quets and Waiter Braet for help wi th the computer p rocess ing of data, to Luc Snoecks for skilled technical ass is tance and to Hugo Geivers for the genera l supervis ion and care of the e lec t ronic instruments .

Summary

Chronic occlusion of the circumflex branch of the left co ronary ar te ry was produced in dogs. All animals deve loped a col lateral c irculat ion fast and efficient enough to p reven t myocardia l infarction. Tracer microsphere exper iments toge ther wi th 133-Xenon studies showed a homogeneous dis t r ibut ion of f low over the ent i re left ventr icle . Drug-induced coronary vasodi la t ion caused a gross ly non-homo- genous distr ibution of coronary blood flow. The collateral dependen t areas of the hear t rece ived much less b lood than the areas which are supplied by normal arterial channels. Wi th in the co l la te ra l -dependent area the endocardia l myocar- dium rece ived less b lood than the epicardial layers. Previous ly well per fused areas can become underpe r fused during overper fus ion of normal myocardium. Similar changes were not obse rved in hear t s wi th normal coronary arteries.

Ni t roc lycer ine did not produce changes in blood flow in hear ts wi th coronary ar te ry occlusion. Consequen t ly changes in the dis t r ibut ion of myocardia l flow were not obse rved wi th this drug. A computer model is p re sen ted for the explana- t ion of the exper imenta l f indings which faci l i tated the analysis of contr ibut ing factors.

W. Schaper et al., Myocardial steal produced by coronary vasodilalion 19

Zusammenfassung

Bei Hunden wurde ein chronischer VerschluB des ramus c i rcumflexes der l inken Koronarar ter ie erzeugt. Eel alien Tieren entwickel te sich ein Kollateralkreislauf, der das Auf t re ten yon Infarkten verh inder te . Die Durchblutung des l inken Ven- tr ikels bei chronischem KoronarverschluB war normal und die Durchblutungsver- tei lung war homogen, wie aus der 133-Xenon c learance zusammen m i t d e r Ge- webekonzen t ra t ion yon Tracer Mic rospheren hervorging . Pharmakologisch indu- zierte Koronardi la t ion verursachte eine ungleichmal~ige Durchblutungsver te i lung. Das yon Kol la tera len abh~ngige Per fus ionsgebie t e rh ie l t bedeu t end weniger Blut als der Tell des Myokards , der fiber normale Koronara r t e r i en versorg t wird. Inner- halb des kol la te ra labh~ngigen Myokards erhiel t das subendokard ia le Gebiet be- deutend weniger Blut pro Zei te inhei t als das subepikard ia le Gebiet. Zonen, die vor der Dilation normal und homogen durchblutet waren, e rh ie l ten w}ihrend der Dila- tat ion wen ige r Blut. Derart ige Ver te i lungs~nderungen wurden nicht beobachte t bei Herzen mit normalen Koronarar ter ien .

Ni t roglycer in verursachte keine Umver te i lung der Durchblutung bei Herzen mit chronischem KoronarverschluB. Ni t roglycer in verursachte a l lerdings auch keine n e n n e n s w e r t e Koronardi latat ion. Ein Komputermodel l wird beschr ieben zum besse- ren Verst/~ndnis der haemodynamischen Zusammenh~nge bei Koronardi la ta t ion.

References

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A u t h o r s a d d r e s s :

Dr. W. Schaper et al., A b t e i l u n g f/.ir E x p e r i m e n t e l l e K a r d i o l o g i e a m W. G. K e r c k h o f f - l n s t J t u t de r M a x - P l a n c k - G e s e l l s c h a f t , 635 B a d N a u h e i m ,

S p r u d e l h o f 11