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The relationship of coronary collateral inlet flow and retrograde flow in mongrel dogs
Experimental and laboratory
reports
The relationship of coronary collateral inlet flow and retrograde flow in mongrel dogs Anthony A. Cibulski, M.D., Patrick H. Lehan, M.D. Harfier K. Hellems, M.D. Jackson, Miss.
T
B.E.E.
he flow collected from a coronary artery opened to atmospheric pressure distal to its ligation (i.e., retrograde flow) was introduced by Anrep and Hausler’ as a means to evaluate the intercoronary collateral system in the open-chest animal. Subsequently Gregg and associates2 popularized the retrograde flow technique as a quantitative tool for assessing the magnitude of the intercoronary collateral system and over the last three decades the bulk of information regarding the collateral network has been uncovered with this technique. Prinzmetal and associates3 employed radioactive microsphere and erythrocyte myocardial distribution techniques to estimate the actual collateral flow delivered to the peripheral vascular bed of an occluded coronary vessel (abrupt closure) and concluded that retrograde flow underestimated the actual clollateral flow. Eckstein4 stated that retrograde flow exceeds actual collateral flow Iby 10 per cent in normal dogs. This opinion was later supported by Kattus and Gregg,5 with the reasoning that more blood would be likely to flow through the intercoronary anastomoses and out a low resistance coronary cannula opened to atmospheric pressure than through the
myocardial arterioles, capillaries, and veins of the ischemic myocardium. Levy, Imperial, and Zieske 6 have suggested that retrograde flow is only 30 per cent of actual collateral flow on the basis of regional rubidium-86 myocardial clearance studies. Bloor and Roberts’ proposed that the intravascular content of isotope is responsible for falsely high myocardial rubidium-86 uptake rates (index of flow) and accounts for the disparity between the results of the retrograde flow and rubidium-86 clearance measurements. In theory the krypton-85 or xenon-133 clearance techniques* for measuring myocardial flow are independent of the intravascular isotope content. In normal dogs these techniques estimate collateral flow to be approximately 2.5 per cent of normal (direct) perfusion rates whereas retrograde flow measurements in these animals are equivalent to 10 per cent of normal (direct) perfusion rates.g Thus the relationship of retrograde flow to actual collateral flow in the mongrel dog remains controversial. In this study work was undertaken to investigate the relationship between retrograde and actual collateral flow in normal dogs and dogs subjected to chronic myocardial ischemia.
Fmm the Department of Medicine. University of Mississippi Medical Center. Jackson, Miss. Supported by National Institutes of Health Grant No. HE-11426. Received for publication Sept. 18. 1972. Reprint requests to: Anthony A. Cibulski, M.D., University of Mississippi Medical Center. 2500 N. State Miss. 39216.
Vol. 84, No. 4, t,$. 485-494
October, 1973
American Heart Journal
St., Jackson.
485
486
.‘lrn. Ifcart /. October, 1973
Cibulski, Lehan, and Hellems
Retrograde Flow
Modified Gregg Cannula
Tmnrducer
Fig. 1. Perfusion pressure gradient.
of artery.
25 gauge needle
Ant. Desc. A., Anterior
descending
The approach employed was proposed to measure the total anastomotic flow delivered by the normally perfused (donor) coronary arteries to a recipient coronary artery under conditions in which the recipient vessel was either occluded or opened to atmospheric pressure for the collection of retrograde flow. The information derived with this approach was supplemented by regional flow determinations in the ischemic and nonischemic myocardial territories under conditions in which a coronary vessel was simply occluded or opened to atmospheric pressure for the collection of retrograde flow. In this study the regional myocardial blood flows were obtained with the krypton-85 clearance technique which has been shown in previous reports to provide reasonable estimates of f-low under steady state conditions.8 Methods
The data to be reported were collected in experiments with eight normal mongrel dogs and ten mongrel dogs subjected to chronic myocardial ischemia by placing ameroid constrictors on their proximal circumflex arteries for periods of eight weeks or more prior to study (chronic ischemic preparations). At the time of study, all
artery;
Cx.
Art., circumflex
artery;
PCT, catheter
animals (15 to 35 kilograms in weight) were anesthetized with 30 mg. per kilogram of body weight of intravenously administered pentobarbital, intubated, and ventilated with a Harvard pump respirator. The dogs were secured in the right lateral decubitus position and a left thoracotomy was performed. The pericardium was incised and sutured to the thoracic wall to minimize movement of the heart. The proximal circumflex artery (or the segment of the vessel distal to the ameroid constrictor in the chronic preparation) was dissected, ligated proximally, cannulated just distal to the ligature, and perfused from the left carotid artery through a series-coupled polyethylene tubing, T tube, externally mounted A-C electromagnetic flow probe as illustrated in Fig. 1. The proximal anterior descending artery was dissected free in order to implant an A-C electromagnetic flow probe. A small-caliber (1 mm. internal diameter) modified Gregg cannula was inserted into the left subclavian artery for transient selective catheterization of the left main stem coronary artery. The cannula was employed as a conduit for the delivery of saline solutions of krypton-85 to the left main coronary artery. The femoral artery was catheterized
Volume Number
86 4
with a large-bore cannula for coupling to a constant-pressure reservoir of easily adjustable height. The reservoir was employed to maintain the systemic pressure in experiments in which acute myocardial ischemia was induced. Following major surgical manipulations and prior to the insertion of all catheters, heparin (10 mg. per kilogram of body weight) was given intravenously followed by repetitive doses of 2 mg. per kilogram of body weight every 30 minutes. Retrograde $0~ measurements. The circumflex arterial cannula was opened to atmospheric pressure (Fig. 1, clamp B open, clamp A fastened) and retrograde flow (RF) collected in a volumetric flask for 20 to 30 seconds and concomitantly recorded with the circumflex cannula flow probe. In chronic preparations with large retrograde flows, the pressure gradient across the circumflex cannula was estimated (e.g., predetermined circumflex cannula resistance X retrograde flow [flow probe]) and counte,rbalanced by adjusting the height of the retrograde flow outlet tubing to assure atmospheric to subatmospheric pressures at the arterial end of the cannula. Regional myocardial JEow measurements. Regional myocardial blood flow in the circumflex (CX.) and anterior descending (A.D.) myocardial territories was determined with the use of the krypton-85 clearance technique. A Chicago Nuclear scintilation detector collimator was positioned over the left ventricle. A two-inch sodium iodide crystal was mounted 20 cm. above the 10 cm. diameter orifice of the collimator. Saline solutions (0.2 to 0.5 c.c.) of krypton-85 yielding counts of 20,000 to 50,000 per minute were delivered over periods of 5 to 10 seconds to the A.D. or CX. myocardial regions via the modified Gregg cannula or CX. arterial cannula, respectively. During the period of krypton-85 infusion the CX. arterial cannula system was opened to systemic pressure (Fig. 1, clamp A open, clamp B fastened). Under these conditions the mean intraepicardial coronary pressures of the circumflex and adjacent coronary arteries are equal (phasic differentials are unavoidable) and the collateral flow is assumed equal to zero, as is the delivery of krypton-85 from one arterial cannula (e.g., the Gregg cannula) to the
Coronary
collateral circulation
487
adjacent coronary bed (e.g., the circumflex bed). Direct perfusion of the circumflex bed was maintained for at least 5 seconds following the termination of krypton-85 infusions. K, and K,, are defined as the time constants of the logarithmic clearance curves describing desaturation of the A.D. and CX. myocardial territories, respectively. The time constants were interpreted to represent the flow per unit mass (in cubic centimeters per minute per 100 Cm.) of their respective regions and were determined in the following manner: (1) The half-time (e.g., TX expressed in minutes) of the linear stable phase of the krypton-85 logarithmic clearance curve was determined. TX is the duration of the interval during which the linear stable phase of the logarithmic clearance curve decreases to half of its initial clearance phase intercept value. (2) The time constant (K) was equated to 100 (0.693/T%) C.C. per minute per 100 Gm. To avoid induction of ventricular fibrillation, the krypton-85 clearance phase was limited to 2 to 3 minutes in preparations subjected to severe myocardial ischemia (for example, following circumflex arterial cannula occlusion in the normal dog). The initial fast phases of all clearance curves (5 to 10 seconds’ duration) was graphically eliminated and the stable linear phase was accepted as representative of mean clearance rates determined with infinitely long desaturation curves.lO The following six krypton-85 washout studies were performed: K, and K,, were individually determined with (1) the CX. cannula opened to systemic pressure, (2) the CX. cannula clamped, and (3) the CX. cannula opened to atmospheric pressure for the collection of retrograde flow. Ten-minute recovery periods were allowed between the washout studies. Change of donor coronary inlet $0~. This method is a resurrection of an expedient employed by Wiggers and Green” in 1936 but performed without the limitations imposed by the art of technology existing at that time. The method is illustrated in Fig. 2. The increase in the inlet flow of the anterior descending artery (AFA) following occlusion of the circumflex artery is interpreted as the collateral flow delivered from the anterior descending artery to
488
Cibulski,
Et%? IILI
Ant. Desc. Artery
FA
Cx.
Circumflex Artery
Fcx
r-l
Artery
Open
Am. Hart I. Ortohcr, 1973
Lehan, and Hellevas
Cx. Artery
Clamped
Fig. 2. Donor coronary inlet flow method. Following occlusion of the circumflex (CL) artery the increase in anterior descending (Ant. Desc.) inflow (AFA) is intermeted as collateral flow delivered from the anterior descending artery to the circumflex myocardial region. FA, Antegrade flow to the anterior descending myocardial region; Fcx, antegrade flow to the circumflex myocardial region delivered by direct perfusion of the circumflex artery under systemic pressure.
the circumflex myocardial region providing the antegrade capillary flow to the anterior descending myocardial region remains unchanged. A similar interpretation is applied to an increase in the right coronary inflow (AFRc) following occlusion of the circumflex coronary artery. Thus, the total collateral flow (CF) (referred to as collateral inlet flow in subsequent discussions) to the circumflex myocardial region is : Collateral flow (CF) = AFA + AFrrc In this study the right coronary artery was ligated and the total collateral flow was approximated by the collateral flow delivered by the anterior descending artery. In circumstances in which the circumflex artery is opened to atmospheric pressure for the collection of retrograde flow, the increase in flow to the donor coronary vessels is interpreted as total anastomotic flow (AF) delivered by the donor vessels to the collateral system supplying the circumflex artery. The change in donor coronary inflow was measured 15 to 30 seconds following occlusion of the circumflex arterial cannula to allow these determinations to be made under predominantly steady state conditions. Compensatory changes in the peripheral bed of the ischemic region are essentially complete within a period of 15
seconds following occlusion of a coronary vesseI in normal dogs.‘* The donor coronary inlet flow method assumes that the flow delivered by the donor vessel (e.g., anterior descending artery) to its peripheral capillary bed remains unchanged following occlusion of the circumflex arterial cannula or opening the cannula to atmospheric pressure for the collection of retrograde flow. The constancy of the anterior descending capillary flow was evaluated by comparing the krypton-85 clearance rates (K,) of this region prior to and following (1) circumflex cannula occlusion and (2) the collection of circumflex arterial retrograde flow. Care was taken to employ low resistive circumflex arterial cannulas (e.g., 0.05 to 0.1 mm. Hg per cubic centimeter per minute resistance) to assure accuracy of the donor coronary inlet flow method. For example, antegrade flow delivered from the left carotid artery through a high resistive circumflex cannula reduces the effective pressure head in the peripheral circumflex artery to subsystemic levels. Thus anastomotic flow delivered from donor coronary vessels may exist at a time when collateral flow is assumed to be zero (e.g., when the inlet end of the circumflex cannula is opened to systemic pressure). The ECG and systemic pressure were monitored continuously throughout the experiment. All pressures and flows were obtained with the use of Statham strain gauge transducers and statham alternating current electromagnetic flow probes, respectively, and recorded with the Electronics for Medicine recorder. Results
Reported in Table I are the results of the regional anterior descending (K,) and circumflex (K,,) myocardial flow determinations obtained with the krypton-85 clearance technique under the following three conditions: (1) the circumflex arterial cannula opened to systemic pressure, (2) the circumflex cannula clamped, and (3) the circumflex cannula opened to atmospheric pressure for the colIection of retrograde flow. In normal dogs there was no significant difference in the results of the three krypton-85 washout studies of the anterior de-
Volume Number
86 4
Table I. Krypton-85
Coronary
myocardial
Opened to systemic pressure
KS Normal dogs, mean * S.D.t (c.c./min./lOO Gm.) Chronic preparations, mean * SD. (c.c./min./lOO Gm.) *KS. Time constant
cannula
KC%
KC,
KC7
107 *
24
110 * 20
104 *
22
24 *
10
117 *
19
10.5 *
112 *
20
97 *
of the krypton-85 (c.c./min./lOO
20
logarithmic clearance Gm.) of the krypton-as
scending region. Following closure of the circumflex cannula the regional circumflex myocardial flow was 22 per cent (P < 0.05) of perfusion rates achieved with direct perfus’ion of the circumflex cannula under systemic pressure (i.e., normal perfusion rates). Concomitant with the collection of circumflex arterial retrograde flow the antegrade circumflex myocardial flow was determined to be 12 per cent (P < 0.05) of normal perfusion rates. In chronic preparations the anterior descending myocardial flow determinations were not significantly different whether the circumflex arterial cannula was opened to systemic pressure or clamped (K, = 117 C.C. per minute per 100 Gm. vs. K, = 112 C.C. per minute per 100 Gm.; P > 0.05). Following the establishment of retrograde circumflex arterial flow the anterior descending myocardial flow was determined to be 71 per cent of perfusion rates measured when the circumflex arterial cannula was opened to systemic pressure (P < 0.05). Following occlusion of the circumflex arterial cannula the collateral flow delivered to the circumflex myocardial region represented 92 per cent of flows achieved through direct perfusion of the circumflex arterial cannula (P >> 0.05). During the collection of retrograde circumflex arterial flow the antegrade circumflex myocardial flow persisted in magnitudes equivalent to 20 per cent of direct perfusion rates (P < 0.05).
Opened to atmospheric pressure
Clamped -~-
8
(c.c./min./lOO Gm.) ing myocardium; KC,, time constant of the circumflex myocardium. tS.D.. Standard deviation.
489
clearance determinations CX.”
No. o.f determinations
collateral circulation
fL 4.5
16
curve describing desaturation logarithmic clearance curve
Kc,
110~
24
13 A= 2.3
83*
22
21 *
5.8
of the anterior descenddescribing desaturation
During the collection of retrograde circumflex arterial flow alternative routes of krypton-85 circumflex myocardial clearance, other than that resulting from effective antegrade flow in the circumflex capillary bed, were determined to be insignificant. Examples follow: (1) The total blood collected retrogradely from the circumflex arterial cannula under anaerobic conditions was placed under the Chicago Nuclear collimator at a level approximated to be that of the central circumflex myocardial mass. The radioactivity in all cases (23 determinations) was less than 3 per cent of the detected decrease in radioactivity from the circumflex myocardial region during the collection of retrograde flow. The radioactivity of the retrograde Aow volumes was determined to be 96 per cent (10 determinations) of an equal volume of systemic blood collected anaerobically during the period in which retrograde flow was collected. The krypton-85 content in the retrograde flow blood volumes was thus interpreted to represent krypton-85 delivered transanastomotically from the systemic circulation rather than retrograde circumflex capillary clearance. (2) At the termination of the experiment ventricular fibrillation was induced with concomitant occlusion of the anterior descending and circumflex arteries. Subsequent to the onset of ventricular fibrillation the systemic pressure was allowed to decrease spon-
K 1;! Esp.
.vo.
irx.,‘nrirr.
:I F (l-.c.j’wrin.)
C’F (~-.i.,~nli?~. )
) /
Mean
59 10.1 4.1
6.5 11.6
1
3 7
2 3
5 0 1 .6
4
2 .o
7 0
5 ;
4 0 4.7 45
8.7 9.3 9.6
7.8 9.7 11.1 10.7
8
.z 1
8.1
9.8
*
S.I>.
3.7
*
0.9
7.9*
5.1
1.7
*Mean antegrade coronary flows: A.D., 35.2 C.C. per minute; CS. art., 34.4 C.C. per minute. tRF. Retrograde flow; CF. increase in anterior descending inflow following circumflex cannula descending inflow following the establishment of circumflex arterial retrograde flow.
Table
III.
Flow*
Exp.
in chronic
1 2 3 4 5 6 7 8 9 10 Mean
*Mean
antegrade
coronary
CF (c.c./min.)
65.0 63 0 48.0 91 .o 73.5 70.0
20.5 15.9 19.2 26.6 18.1 13.2 17.9 21.5 22.0 27.0
90.0
120.0 160.0 86 0
+ S.D.’
86.2
flows:
occlusion;
AF.
f
2.2
increase
in anterior
preparations RF (c.c./min.)
No.
9.0
*
29 7
-\ D. = 30.5 CL. per minute;
taneously and krypton-85 clearance from the myocardium was measured to be less than the equivalent of 1 c.c. per minute per 100 Gm. (10 determinations). The clearance jvas assumed to be a result of evaporation. Collimator ventilation was maintained during these determinations. The results of the donor cokonary inlet flow and retrograde flow methods are reported for the individual experiments with normal dogs in Table II and the experiments \vith chronic preparations in Table III. The results of the individual experiments represents the mean of three or more determinations. In normal dogs the retrograde flow determinations were 47 per cent (P < 0.05) of collateral flows (CF) estimated \vith the
20.2
+ 3.6
AF (C.C./WZiTZ.)
62.7 59.5 45.9 83.3 69.4 65.0 84.0 99.6 128.3 80.4 77.8
f
2 3
CS. art. = 23.0 cc. per minute.
inflow method during closure of the circumflex cannula. Retrograde flow measurements were 41 per cent (I’ < 0.05) of anastomotic flows (AF) estimated with the inflow method during the collection of retrograde circumflex arterial flow. In chronic preparations retrograde flow were 420 per cent (P measurements < 0.05) of collateral flows (CF) and 111 per cent (P > 0.05) of anastomotic flows (AF) determined with the inflow method. In chronic preparations the difference L)etween the retrograde flow measurements and the anastomotic flows (AF) determined with the donor coronary inflow method during the collection of retrograde flow may be accounted for on the basis of the following mechanisms: (1) The flow to the
Coronary
peripheral bed of the donor vessel decreased. This was demonstrated with the krypton-85 washout technique, e.g., the anterior descending capillary flow decreased to 71 per cent of normal perfusion rates during the collection of retrograde flo\v (Table I). (2) RIeasurement of flow to the proximal anterior descending vessel does not monitor the potential contrihutions to anastomotic flow of the more proximal donor vessels. In the dog the primary seplral artery is the major potential source of annstomotic flow proximal to the anterior descending artery. The primary septal vessel supplies approximately 10 per cent of ‘the total left ventricular flow in the normal dog.‘* The contrit)iition of the primary septal artery to retrograde flow \vas estimated in five chronic preparations. In these animals the septal vessel was dissected free and acute closure of this coronary artery branch produced small discrete reductions in retrograde flow as monitored .with the circumflex cannula A-C electromagnetic flow prolje. The mean reduction in retrograde flow in these experiments was 4 per cent (range, 1 to 7 per cent). Discussion In this study the hemodynamics of the coronary peripheral and collateral vascular networks \vere examined under conditions in lvhich a coronary artery was simply occluded or opened to atmospheric pressure for the collection of retrograde flow. Two methods were employed to investigate the peripheral and collateral circulatory dynamics. Thdonor coronary inlet flow method was proposed to measure the total anastomotic flow delivered 1)~ donor coronary Vessel:5 to the coronary collateral system and the krypton-85 clearance technique ~vas utilized to measure the regional anterior descending and circumflex myocardial I Jood flow. The validity of the krypton-85 clearance technique depends upon stable flow conditions during the period of measurement. In studies in \\~hich the krypton-85 washout method was employed during a two- to three-minute interval follocving aljrupt interception of antegrade circumflex arterial flow, compensatory changes in the distal circumflex I)ed (e.g., mainly ischemia-
collateral circulntion
491
induced vasodilatation and decreased myocardial contractility) occur most intensely in normal dogs and primarily w:ithin the initial 10 to 1.5 second interval follotving occlusion of the circ~umflex cannula. Evidence for this is provided I)y a typical peak reactive hyperemic lIo\v vs. the duration of circumflex cannula occlusion curve.‘” In chronic preparations I\-itll n,ell-developed collaterals reactive hyperemic responses of the peripheral circumflex vascular Iled were not observed following the release of temporary occlusions ( > 1 minute) of the circumflex cannula. Slow changes in local coronary vasoregulation or myocardial COUP tractility over prolonged periods (e.g., hours) were not ruled out. The purpose of this study was to measure the degree of collateral flow delivered to the circumflex bed during the initial two to three minutes following closure of the circumflex arter] or the estal~lishment of retrograde flow. In all studies the krypton-85 myocardial washout period was monitored for a minimum of t\vo minutes, thus minimizing errors resulting from early compensatory changes occuring in the distal circumflex bed. During periods of slo~v changes in flow, the krypton-85 clearance technique provides reasonable estimates of mean flow during the interval of measurement.* The krypton-85 clearance technique \vas employed in this study primarily to supplement, rather than to compare, the information derived with the donor coronary inflow method. For example, the validity of the inflon method is entirely dependent upon stable floes within the peripheral donor coronary beds during periods in k\-hich the adjacent recipient myocardial region is subjected to ischemia. It was sho\vn nith the krypton-85 washout studies that the capillary flow of the anterior descending (donor) artery does not change significantly under conditions in \vhich the circumflex cannula is clamped or opened to atmospheric pressure lvitli the exception of the chronic preparation following the estal)lishment of retrograde flo\v. In the chronic preparation the antegrade anterior descending flow decreased to 7 1 per cent of normal perfusion rates during the collection of retrograde circumflex 8rterial flop\- (to IK discussed in a folloning section).
Donor Art
Cx. Art.
Donor Art
Cx. Art
Donor Art.
Cn Art
Donor Artery Inlet Flow
TIME
I
TIME Retrogmde Flow
Ic Cx. cannula to systemic pressure
open*Cx.
cannula
ciased+
Retrograde Cx arterial
flow Via cannula
Fig. 3. Circulatory dynamics. Upper drawing: Schematic representing the distribution of the donor coronary (e.g., anterior descending) inlet flow of normal dogs under conditions in which the circumflex arterial cannula is (1) open to systemic pressure, (2) clamped, and (3) opened to atmospheric pressure for the collection of retrograde Row. The numerals depicted in the upper drawing represent the mean flows (cubic centimeters per minute) reported for normal dogs in Table I I. The middle and lower drawings represent the donor coronary and circumflex arterial flows (cubic centimeters per minute), respectively, under the three conditions described above.
The krypton-85 washout technique yields estimates of the flo\\- per unit mass of the myocardiat region under stud),. Thus the donor coronary inflo\\- and krypton-85 \\-asliout techniques are not comparat)te on a flo\v-to-flo\Jr tjasis unless the mass of the region under study is knonn. F-or this report it \\:a~ chosen to compare these methods by normalizing collateral flon measurements to the normal perfusion rates (all flows are reported in Tables 1 to III). For example, in the normal dog the circumflex myocardiat collateral flo\~ during closure of the circumflex artery \vas estimated to be 23 per cent of normal perfusion rates with the inflohv method and 22 per cent of normal perfusion rates \vith the washout techniqu-. The difference \\-as not significant. In chronic preparations the cotlateral flow UYLSestimated to t)e 8X and 92 per cent of normal perfusion rates with the inflo\\, and washout techniques, respectively. Again the difference between the t\~o methods \~as not significant.
Fig. 3 is presented to provide a schematic of the peripheral and collateral circulator> dynamics which summarize the comt)ined results of the donor coronary inlet flo\~ and krypton-85 clearance studies in normal dogs. Illustrated in the upper portion of Fig. 3 is the distribution of the donor coronary inlet flow of normal dogs (mean values are presented) under conditions in I\-hich the circumflex arterial cannuta is (lj open (2j clamped, and to systemic pressure, (3) open to atmospheric pressure for the collection of retrograde floes. Fotto\\-ing occlusion of the circumflex arterial cannuta the mean donor coronary inlet flo\\- increased from 35 to 43 C.C. per minute. The results of the krypton-S.5 clearance studies (Table I) indicate that the antegrade flow to the peripheral bed of the anterior descending artery \\;a~ not significantly changed following occlusion of the circumflex arterial cannuta. Therefore, the increase in the donor coronary inlet flon (e.g., 8 C.C. per minute) is interpreted as
Coronary
collateral flow delivered to the peripheral vascular bed of the occluded circumflex artery. Following the establishment of retrograde circumflex arterial flow the donor coronary inlet flow increased to 44 c.c. per minute. Again, utilizing the krypton-85 clearance technique, the peripheral flow of the ianterior descending artery was determined to be virtually unchanged folloiving the establishment of retrograde flolv (Table I). Therefore, the increase in the donor coronary inlet flow (9 C.C. per minute) is interpreted as the total anastomotic flow delivered to the collateral system during the collection of retrograde flow. Of the total transanastomotic flow (9 C.C. per minute) delivered to the recipient circumflex vascular bed, 3.7 C.C. per minute are diverted retrogradely via the circumflex arterial cannula. The difference between the total anastomotic flow (9 c.c. per minute) and retrograde flow (3.7 C.C. per minute) equals 5.3 c.c. per minute and is interpreted as anastomotic flow delivered antegradely to the peripheral bed of the circumflex artery. The presence of an effective antegrade capillary perfusion of the circumflex myocardial region concomitant with the collectimon of retrograde circumflex arterial flow was demonstrated with krypton-85 washout studies (Table I). In chronic preparations the flow to the peripheral bed of the anterior descending vessel, determined nith the krypton-85 w\:ashout method, was not significantly changed following closure of the circumflex arterial cannula. Thus, the increase in total donor coronary inlet flow following occlusion of the circumflex arterial cannula would reasonably be interpreted as collateral flow delivered to the recipient circumflex myocardial region. Following the estal)lishmen t of retrograde circumflex arterial flow, the flo\v to the peripheral l)ed of the anterior descending artery was reduced to 71 per cent of levels achieved during direct pIerfusion of the circumflex arterial cannula. This decreased peripheral anterior descending flow is presumably a reflection of the decreased effective perfusion pressure throughout the anterior descending epicardial network resulting from the large increase in anastomotic flo~l: established in this bed during the collection of circumflex arterial retrograde flow. Upon
collaternl circulation
493
re-establishment of antegrade circumflex arterial flow a marked reactive hyperemic response was noted in the circumflex arterial system and a mild reactive hyperemic response was observed in the anterior descending inlet flow. The mild reactive hyperemic response of the anterior descending inflow may be the result of one or two mechanisms. For example: (1) hypoxia induced within the anterior descending bed as a result of the reduced capillary flow (i.e., 71 per cent of normal) during the collection of retrograde flow and (2) a reflection of the reactive hyperemic response in the circumflex bed. The latter mechanism is explained on the basis of the marked reactive hyperemic circumflex arterial inflows and the resultant pressure gradients generated across the circumflex cannula, arterial, and arteriolar systems. The reduced intra-arterial pressures of the circumflex bed could thus establish transient transanastomotic pressure gradients and collateral flows temarterial porally related to the circumflex hyperemic response. The continued perfusion of the circumflex myocardial region following the establishment of circumflex arterial retrograde flow is not unexpected since a spatial intravascular pressure gradient must exist throughout the circumflex myocardial region falling from near systemic pressures at the collateral inlets to atmospheric pressures in the central epicardial portions of the circumflex arterial network. Thus, an effective perfusion pressure is maintained for the subepicardial collateral complexes in both normal and chronic ischemic dogs during the collection of retrograde flow. In nchroic preparations, retrograde flow collected in the conventional manner by maintaining the circumflex arterial cannula at atmospheric pressure does not reduce in the entire circumflex the pressures epicardial bed to atmospheric levels. During the collection of retrograde flow in systems with large epicardial anastomoses, an intra-arterial epicardial pressure gradient must necassarily be established from the normally perfused coronary arteries to the circumflex arterial cannula. Thus, the tributaries arising from at least the peripheral portions of the circumflex artery continue to receive some degree of perfusion
iJ,’ ,r< ,r, :. I I, ?.,I,,., I ‘IT.<
during tile collection of I-ctrogr;id(~ Ilo\\ Fillton’” has demonstrated, \vi tlr Ilk stereoradiographic technique, large sulm~locat-dial collateral coulplexes \vllic-11 could provide a source of an tegrade capillary flw not easily diverted II~ opening the tircumflex arterial cannuln to atmospheric pressure. The combined results of the donor coronary inflow and krypton-X.5 clearance studies are summarized ;I5 folio\\-5: (1) retrograde HOI\- IVES 47 per cent of actual collateral flow in normal dogs; (1) retrograde flo\~ 1~2~s 420 per cent of actual collatmll HOK in chronic preparntions, reflecting the results of opening the circumflex artc.rial ~ysten~ supplied 11~. large-calilw anastonioses to atmospllcric pressure; and (3) concwiitant I\-ith the collection of rcl rograde circumflex arterial flo\v an tegrade flow to the ischemic circumflex myocnrdium persists in l)oth normal dogs (13 per cent of normal perfusion rates) and chronic prcparations (20 per cent of normal perfusion I-ates) .
1. Anrep, G. V., and Hausler, II.: circulation I. The effect of chatqes pressure and of the output of Physiol. 65:357, 1928. 2. Gregg, D. I,., Thornton. J. J., and The mnpnitude, adecluacy, and colinteml blood llow and pressure
The ccmm~r); of the blood the heart, J. Mautz, I-. Ii.: source of the ill chronically
4.
6.
J, .75:689, I
1948. I<. \I‘.:
The
ineffectiveness
of corti-
I,\vy. kl. N.,“imperial. E. S., rind Zieske, tl.: Collateral blood tlow tn the m> owl-dium as determined by the c-lear.~llcc of rubidiun~86 chloride, Circ-. Kes. 9:10X, 1961. 7. I3loor, C. Xl., and Knberts, I.. E.: ERects of intr.lvascular isotope content on the isotopic determination of coronary collateral blood flow, Cirr. Res. 16:j37, 1965. 8. l.indcr, E.: ~leasurements of normal and colI;lter.~l coronary t)lood llow by close-arterial .~nd irltmln)rocnrdi~~l injection of kryptona and xenon’38, Acta I’hysiol. Scnnd. 272:5. 1966. 9. Hood, Jr., I\‘. 13.: I’;lthr)l’hysioloR4. of ischemic heart disease. I’rocr. it, Cardiovnsc. Ibis.
reports
The relationship of coronary collateral inlet flow and retrograde flow in mongrel dogs Anthony A. Cibulski, M.D., Patrick H. Lehan, M.D. Harfier K. Hellems, M.D. Jackson, Miss.
T
B.E.E.
he flow collected from a coronary artery opened to atmospheric pressure distal to its ligation (i.e., retrograde flow) was introduced by Anrep and Hausler’ as a means to evaluate the intercoronary collateral system in the open-chest animal. Subsequently Gregg and associates2 popularized the retrograde flow technique as a quantitative tool for assessing the magnitude of the intercoronary collateral system and over the last three decades the bulk of information regarding the collateral network has been uncovered with this technique. Prinzmetal and associates3 employed radioactive microsphere and erythrocyte myocardial distribution techniques to estimate the actual collateral flow delivered to the peripheral vascular bed of an occluded coronary vessel (abrupt closure) and concluded that retrograde flow underestimated the actual clollateral flow. Eckstein4 stated that retrograde flow exceeds actual collateral flow Iby 10 per cent in normal dogs. This opinion was later supported by Kattus and Gregg,5 with the reasoning that more blood would be likely to flow through the intercoronary anastomoses and out a low resistance coronary cannula opened to atmospheric pressure than through the
myocardial arterioles, capillaries, and veins of the ischemic myocardium. Levy, Imperial, and Zieske 6 have suggested that retrograde flow is only 30 per cent of actual collateral flow on the basis of regional rubidium-86 myocardial clearance studies. Bloor and Roberts’ proposed that the intravascular content of isotope is responsible for falsely high myocardial rubidium-86 uptake rates (index of flow) and accounts for the disparity between the results of the retrograde flow and rubidium-86 clearance measurements. In theory the krypton-85 or xenon-133 clearance techniques* for measuring myocardial flow are independent of the intravascular isotope content. In normal dogs these techniques estimate collateral flow to be approximately 2.5 per cent of normal (direct) perfusion rates whereas retrograde flow measurements in these animals are equivalent to 10 per cent of normal (direct) perfusion rates.g Thus the relationship of retrograde flow to actual collateral flow in the mongrel dog remains controversial. In this study work was undertaken to investigate the relationship between retrograde and actual collateral flow in normal dogs and dogs subjected to chronic myocardial ischemia.
Fmm the Department of Medicine. University of Mississippi Medical Center. Jackson, Miss. Supported by National Institutes of Health Grant No. HE-11426. Received for publication Sept. 18. 1972. Reprint requests to: Anthony A. Cibulski, M.D., University of Mississippi Medical Center. 2500 N. State Miss. 39216.
Vol. 84, No. 4, t,$. 485-494
October, 1973
American Heart Journal
St., Jackson.
485
486
.‘lrn. Ifcart /. October, 1973
Cibulski, Lehan, and Hellems
Retrograde Flow
Modified Gregg Cannula
Tmnrducer
Fig. 1. Perfusion pressure gradient.
of artery.
25 gauge needle
Ant. Desc. A., Anterior
descending
The approach employed was proposed to measure the total anastomotic flow delivered by the normally perfused (donor) coronary arteries to a recipient coronary artery under conditions in which the recipient vessel was either occluded or opened to atmospheric pressure for the collection of retrograde flow. The information derived with this approach was supplemented by regional flow determinations in the ischemic and nonischemic myocardial territories under conditions in which a coronary vessel was simply occluded or opened to atmospheric pressure for the collection of retrograde flow. In this study the regional myocardial blood flows were obtained with the krypton-85 clearance technique which has been shown in previous reports to provide reasonable estimates of f-low under steady state conditions.8 Methods
The data to be reported were collected in experiments with eight normal mongrel dogs and ten mongrel dogs subjected to chronic myocardial ischemia by placing ameroid constrictors on their proximal circumflex arteries for periods of eight weeks or more prior to study (chronic ischemic preparations). At the time of study, all
artery;
Cx.
Art., circumflex
artery;
PCT, catheter
animals (15 to 35 kilograms in weight) were anesthetized with 30 mg. per kilogram of body weight of intravenously administered pentobarbital, intubated, and ventilated with a Harvard pump respirator. The dogs were secured in the right lateral decubitus position and a left thoracotomy was performed. The pericardium was incised and sutured to the thoracic wall to minimize movement of the heart. The proximal circumflex artery (or the segment of the vessel distal to the ameroid constrictor in the chronic preparation) was dissected, ligated proximally, cannulated just distal to the ligature, and perfused from the left carotid artery through a series-coupled polyethylene tubing, T tube, externally mounted A-C electromagnetic flow probe as illustrated in Fig. 1. The proximal anterior descending artery was dissected free in order to implant an A-C electromagnetic flow probe. A small-caliber (1 mm. internal diameter) modified Gregg cannula was inserted into the left subclavian artery for transient selective catheterization of the left main stem coronary artery. The cannula was employed as a conduit for the delivery of saline solutions of krypton-85 to the left main coronary artery. The femoral artery was catheterized
Volume Number
86 4
with a large-bore cannula for coupling to a constant-pressure reservoir of easily adjustable height. The reservoir was employed to maintain the systemic pressure in experiments in which acute myocardial ischemia was induced. Following major surgical manipulations and prior to the insertion of all catheters, heparin (10 mg. per kilogram of body weight) was given intravenously followed by repetitive doses of 2 mg. per kilogram of body weight every 30 minutes. Retrograde $0~ measurements. The circumflex arterial cannula was opened to atmospheric pressure (Fig. 1, clamp B open, clamp A fastened) and retrograde flow (RF) collected in a volumetric flask for 20 to 30 seconds and concomitantly recorded with the circumflex cannula flow probe. In chronic preparations with large retrograde flows, the pressure gradient across the circumflex cannula was estimated (e.g., predetermined circumflex cannula resistance X retrograde flow [flow probe]) and counte,rbalanced by adjusting the height of the retrograde flow outlet tubing to assure atmospheric to subatmospheric pressures at the arterial end of the cannula. Regional myocardial JEow measurements. Regional myocardial blood flow in the circumflex (CX.) and anterior descending (A.D.) myocardial territories was determined with the use of the krypton-85 clearance technique. A Chicago Nuclear scintilation detector collimator was positioned over the left ventricle. A two-inch sodium iodide crystal was mounted 20 cm. above the 10 cm. diameter orifice of the collimator. Saline solutions (0.2 to 0.5 c.c.) of krypton-85 yielding counts of 20,000 to 50,000 per minute were delivered over periods of 5 to 10 seconds to the A.D. or CX. myocardial regions via the modified Gregg cannula or CX. arterial cannula, respectively. During the period of krypton-85 infusion the CX. arterial cannula system was opened to systemic pressure (Fig. 1, clamp A open, clamp B fastened). Under these conditions the mean intraepicardial coronary pressures of the circumflex and adjacent coronary arteries are equal (phasic differentials are unavoidable) and the collateral flow is assumed equal to zero, as is the delivery of krypton-85 from one arterial cannula (e.g., the Gregg cannula) to the
Coronary
collateral circulation
487
adjacent coronary bed (e.g., the circumflex bed). Direct perfusion of the circumflex bed was maintained for at least 5 seconds following the termination of krypton-85 infusions. K, and K,, are defined as the time constants of the logarithmic clearance curves describing desaturation of the A.D. and CX. myocardial territories, respectively. The time constants were interpreted to represent the flow per unit mass (in cubic centimeters per minute per 100 Cm.) of their respective regions and were determined in the following manner: (1) The half-time (e.g., TX expressed in minutes) of the linear stable phase of the krypton-85 logarithmic clearance curve was determined. TX is the duration of the interval during which the linear stable phase of the logarithmic clearance curve decreases to half of its initial clearance phase intercept value. (2) The time constant (K) was equated to 100 (0.693/T%) C.C. per minute per 100 Gm. To avoid induction of ventricular fibrillation, the krypton-85 clearance phase was limited to 2 to 3 minutes in preparations subjected to severe myocardial ischemia (for example, following circumflex arterial cannula occlusion in the normal dog). The initial fast phases of all clearance curves (5 to 10 seconds’ duration) was graphically eliminated and the stable linear phase was accepted as representative of mean clearance rates determined with infinitely long desaturation curves.lO The following six krypton-85 washout studies were performed: K, and K,, were individually determined with (1) the CX. cannula opened to systemic pressure, (2) the CX. cannula clamped, and (3) the CX. cannula opened to atmospheric pressure for the collection of retrograde flow. Ten-minute recovery periods were allowed between the washout studies. Change of donor coronary inlet $0~. This method is a resurrection of an expedient employed by Wiggers and Green” in 1936 but performed without the limitations imposed by the art of technology existing at that time. The method is illustrated in Fig. 2. The increase in the inlet flow of the anterior descending artery (AFA) following occlusion of the circumflex artery is interpreted as the collateral flow delivered from the anterior descending artery to
488
Cibulski,
Et%? IILI
Ant. Desc. Artery
FA
Cx.
Circumflex Artery
Fcx
r-l
Artery
Open
Am. Hart I. Ortohcr, 1973
Lehan, and Hellevas
Cx. Artery
Clamped
Fig. 2. Donor coronary inlet flow method. Following occlusion of the circumflex (CL) artery the increase in anterior descending (Ant. Desc.) inflow (AFA) is intermeted as collateral flow delivered from the anterior descending artery to the circumflex myocardial region. FA, Antegrade flow to the anterior descending myocardial region; Fcx, antegrade flow to the circumflex myocardial region delivered by direct perfusion of the circumflex artery under systemic pressure.
the circumflex myocardial region providing the antegrade capillary flow to the anterior descending myocardial region remains unchanged. A similar interpretation is applied to an increase in the right coronary inflow (AFRc) following occlusion of the circumflex coronary artery. Thus, the total collateral flow (CF) (referred to as collateral inlet flow in subsequent discussions) to the circumflex myocardial region is : Collateral flow (CF) = AFA + AFrrc In this study the right coronary artery was ligated and the total collateral flow was approximated by the collateral flow delivered by the anterior descending artery. In circumstances in which the circumflex artery is opened to atmospheric pressure for the collection of retrograde flow, the increase in flow to the donor coronary vessels is interpreted as total anastomotic flow (AF) delivered by the donor vessels to the collateral system supplying the circumflex artery. The change in donor coronary inflow was measured 15 to 30 seconds following occlusion of the circumflex arterial cannula to allow these determinations to be made under predominantly steady state conditions. Compensatory changes in the peripheral bed of the ischemic region are essentially complete within a period of 15
seconds following occlusion of a coronary vesseI in normal dogs.‘* The donor coronary inlet flow method assumes that the flow delivered by the donor vessel (e.g., anterior descending artery) to its peripheral capillary bed remains unchanged following occlusion of the circumflex arterial cannula or opening the cannula to atmospheric pressure for the collection of retrograde flow. The constancy of the anterior descending capillary flow was evaluated by comparing the krypton-85 clearance rates (K,) of this region prior to and following (1) circumflex cannula occlusion and (2) the collection of circumflex arterial retrograde flow. Care was taken to employ low resistive circumflex arterial cannulas (e.g., 0.05 to 0.1 mm. Hg per cubic centimeter per minute resistance) to assure accuracy of the donor coronary inlet flow method. For example, antegrade flow delivered from the left carotid artery through a high resistive circumflex cannula reduces the effective pressure head in the peripheral circumflex artery to subsystemic levels. Thus anastomotic flow delivered from donor coronary vessels may exist at a time when collateral flow is assumed to be zero (e.g., when the inlet end of the circumflex cannula is opened to systemic pressure). The ECG and systemic pressure were monitored continuously throughout the experiment. All pressures and flows were obtained with the use of Statham strain gauge transducers and statham alternating current electromagnetic flow probes, respectively, and recorded with the Electronics for Medicine recorder. Results
Reported in Table I are the results of the regional anterior descending (K,) and circumflex (K,,) myocardial flow determinations obtained with the krypton-85 clearance technique under the following three conditions: (1) the circumflex arterial cannula opened to systemic pressure, (2) the circumflex cannula clamped, and (3) the circumflex cannula opened to atmospheric pressure for the colIection of retrograde flow. In normal dogs there was no significant difference in the results of the three krypton-85 washout studies of the anterior de-
Volume Number
86 4
Table I. Krypton-85
Coronary
myocardial
Opened to systemic pressure
KS Normal dogs, mean * S.D.t (c.c./min./lOO Gm.) Chronic preparations, mean * SD. (c.c./min./lOO Gm.) *KS. Time constant
cannula
KC%
KC,
KC7
107 *
24
110 * 20
104 *
22
24 *
10
117 *
19
10.5 *
112 *
20
97 *
of the krypton-85 (c.c./min./lOO
20
logarithmic clearance Gm.) of the krypton-as
scending region. Following closure of the circumflex cannula the regional circumflex myocardial flow was 22 per cent (P < 0.05) of perfusion rates achieved with direct perfus’ion of the circumflex cannula under systemic pressure (i.e., normal perfusion rates). Concomitant with the collection of circumflex arterial retrograde flow the antegrade circumflex myocardial flow was determined to be 12 per cent (P < 0.05) of normal perfusion rates. In chronic preparations the anterior descending myocardial flow determinations were not significantly different whether the circumflex arterial cannula was opened to systemic pressure or clamped (K, = 117 C.C. per minute per 100 Gm. vs. K, = 112 C.C. per minute per 100 Gm.; P > 0.05). Following the establishment of retrograde circumflex arterial flow the anterior descending myocardial flow was determined to be 71 per cent of perfusion rates measured when the circumflex arterial cannula was opened to systemic pressure (P < 0.05). Following occlusion of the circumflex arterial cannula the collateral flow delivered to the circumflex myocardial region represented 92 per cent of flows achieved through direct perfusion of the circumflex arterial cannula (P >> 0.05). During the collection of retrograde circumflex arterial flow the antegrade circumflex myocardial flow persisted in magnitudes equivalent to 20 per cent of direct perfusion rates (P < 0.05).
Opened to atmospheric pressure
Clamped -~-
8
(c.c./min./lOO Gm.) ing myocardium; KC,, time constant of the circumflex myocardium. tS.D.. Standard deviation.
489
clearance determinations CX.”
No. o.f determinations
collateral circulation
fL 4.5
16
curve describing desaturation logarithmic clearance curve
Kc,
110~
24
13 A= 2.3
83*
22
21 *
5.8
of the anterior descenddescribing desaturation
During the collection of retrograde circumflex arterial flow alternative routes of krypton-85 circumflex myocardial clearance, other than that resulting from effective antegrade flow in the circumflex capillary bed, were determined to be insignificant. Examples follow: (1) The total blood collected retrogradely from the circumflex arterial cannula under anaerobic conditions was placed under the Chicago Nuclear collimator at a level approximated to be that of the central circumflex myocardial mass. The radioactivity in all cases (23 determinations) was less than 3 per cent of the detected decrease in radioactivity from the circumflex myocardial region during the collection of retrograde flow. The radioactivity of the retrograde Aow volumes was determined to be 96 per cent (10 determinations) of an equal volume of systemic blood collected anaerobically during the period in which retrograde flow was collected. The krypton-85 content in the retrograde flow blood volumes was thus interpreted to represent krypton-85 delivered transanastomotically from the systemic circulation rather than retrograde circumflex capillary clearance. (2) At the termination of the experiment ventricular fibrillation was induced with concomitant occlusion of the anterior descending and circumflex arteries. Subsequent to the onset of ventricular fibrillation the systemic pressure was allowed to decrease spon-
K 1;! Esp.
.vo.
irx.,‘nrirr.
:I F (l-.c.j’wrin.)
C’F (~-.i.,~nli?~. )
) /
Mean
59 10.1 4.1
6.5 11.6
1
3 7
2 3
5 0 1 .6
4
2 .o
7 0
5 ;
4 0 4.7 45
8.7 9.3 9.6
7.8 9.7 11.1 10.7
8
.z 1
8.1
9.8
*
S.I>.
3.7
*
0.9
7.9*
5.1
1.7
*Mean antegrade coronary flows: A.D., 35.2 C.C. per minute; CS. art., 34.4 C.C. per minute. tRF. Retrograde flow; CF. increase in anterior descending inflow following circumflex cannula descending inflow following the establishment of circumflex arterial retrograde flow.
Table
III.
Flow*
Exp.
in chronic
1 2 3 4 5 6 7 8 9 10 Mean
*Mean
antegrade
coronary
CF (c.c./min.)
65.0 63 0 48.0 91 .o 73.5 70.0
20.5 15.9 19.2 26.6 18.1 13.2 17.9 21.5 22.0 27.0
90.0
120.0 160.0 86 0
+ S.D.’
86.2
flows:
occlusion;
AF.
f
2.2
increase
in anterior
preparations RF (c.c./min.)
No.
9.0
*
29 7
-\ D. = 30.5 CL. per minute;
taneously and krypton-85 clearance from the myocardium was measured to be less than the equivalent of 1 c.c. per minute per 100 Gm. (10 determinations). The clearance jvas assumed to be a result of evaporation. Collimator ventilation was maintained during these determinations. The results of the donor cokonary inlet flow and retrograde flow methods are reported for the individual experiments with normal dogs in Table II and the experiments \vith chronic preparations in Table III. The results of the individual experiments represents the mean of three or more determinations. In normal dogs the retrograde flow determinations were 47 per cent (P < 0.05) of collateral flows (CF) estimated \vith the
20.2
+ 3.6
AF (C.C./WZiTZ.)
62.7 59.5 45.9 83.3 69.4 65.0 84.0 99.6 128.3 80.4 77.8
f
2 3
CS. art. = 23.0 cc. per minute.
inflow method during closure of the circumflex cannula. Retrograde flow measurements were 41 per cent (I’ < 0.05) of anastomotic flows (AF) estimated with the inflow method during the collection of retrograde circumflex arterial flow. In chronic preparations retrograde flow were 420 per cent (P measurements < 0.05) of collateral flows (CF) and 111 per cent (P > 0.05) of anastomotic flows (AF) determined with the inflow method. In chronic preparations the difference L)etween the retrograde flow measurements and the anastomotic flows (AF) determined with the donor coronary inflow method during the collection of retrograde flow may be accounted for on the basis of the following mechanisms: (1) The flow to the
Coronary
peripheral bed of the donor vessel decreased. This was demonstrated with the krypton-85 washout technique, e.g., the anterior descending capillary flow decreased to 71 per cent of normal perfusion rates during the collection of retrograde flo\v (Table I). (2) RIeasurement of flow to the proximal anterior descending vessel does not monitor the potential contrihutions to anastomotic flow of the more proximal donor vessels. In the dog the primary seplral artery is the major potential source of annstomotic flow proximal to the anterior descending artery. The primary septal vessel supplies approximately 10 per cent of ‘the total left ventricular flow in the normal dog.‘* The contrit)iition of the primary septal artery to retrograde flow \vas estimated in five chronic preparations. In these animals the septal vessel was dissected free and acute closure of this coronary artery branch produced small discrete reductions in retrograde flow as monitored .with the circumflex cannula A-C electromagnetic flow prolje. The mean reduction in retrograde flow in these experiments was 4 per cent (range, 1 to 7 per cent). Discussion In this study the hemodynamics of the coronary peripheral and collateral vascular networks \vere examined under conditions in lvhich a coronary artery was simply occluded or opened to atmospheric pressure for the collection of retrograde flow. Two methods were employed to investigate the peripheral and collateral circulatory dynamics. Thdonor coronary inlet flow method was proposed to measure the total anastomotic flow delivered 1)~ donor coronary Vessel:5 to the coronary collateral system and the krypton-85 clearance technique ~vas utilized to measure the regional anterior descending and circumflex myocardial I Jood flow. The validity of the krypton-85 clearance technique depends upon stable flow conditions during the period of measurement. In studies in \\~hich the krypton-85 washout method was employed during a two- to three-minute interval follocving aljrupt interception of antegrade circumflex arterial flow, compensatory changes in the distal circumflex I)ed (e.g., mainly ischemia-
collateral circulntion
491
induced vasodilatation and decreased myocardial contractility) occur most intensely in normal dogs and primarily w:ithin the initial 10 to 1.5 second interval follotving occlusion of the circ~umflex cannula. Evidence for this is provided I)y a typical peak reactive hyperemic lIo\v vs. the duration of circumflex cannula occlusion curve.‘” In chronic preparations I\-itll n,ell-developed collaterals reactive hyperemic responses of the peripheral circumflex vascular Iled were not observed following the release of temporary occlusions ( > 1 minute) of the circumflex cannula. Slow changes in local coronary vasoregulation or myocardial COUP tractility over prolonged periods (e.g., hours) were not ruled out. The purpose of this study was to measure the degree of collateral flow delivered to the circumflex bed during the initial two to three minutes following closure of the circumflex arter] or the estal~lishment of retrograde flow. In all studies the krypton-85 myocardial washout period was monitored for a minimum of t\vo minutes, thus minimizing errors resulting from early compensatory changes occuring in the distal circumflex bed. During periods of slo~v changes in flow, the krypton-85 clearance technique provides reasonable estimates of mean flow during the interval of measurement.* The krypton-85 clearance technique \vas employed in this study primarily to supplement, rather than to compare, the information derived with the donor coronary inflow method. For example, the validity of the inflon method is entirely dependent upon stable floes within the peripheral donor coronary beds during periods in k\-hich the adjacent recipient myocardial region is subjected to ischemia. It was sho\vn nith the krypton-85 washout studies that the capillary flow of the anterior descending (donor) artery does not change significantly under conditions in \vhich the circumflex cannula is clamped or opened to atmospheric pressure lvitli the exception of the chronic preparation following the estal)lishment of retrograde flo\v. In the chronic preparation the antegrade anterior descending flow decreased to 7 1 per cent of normal perfusion rates during the collection of retrograde circumflex 8rterial flop\- (to IK discussed in a folloning section).
Donor Art
Cx. Art.
Donor Art
Cx. Art
Donor Art.
Cn Art
Donor Artery Inlet Flow
TIME
I
TIME Retrogmde Flow
Ic Cx. cannula to systemic pressure
open*Cx.
cannula
ciased+
Retrograde Cx arterial
flow Via cannula
Fig. 3. Circulatory dynamics. Upper drawing: Schematic representing the distribution of the donor coronary (e.g., anterior descending) inlet flow of normal dogs under conditions in which the circumflex arterial cannula is (1) open to systemic pressure, (2) clamped, and (3) opened to atmospheric pressure for the collection of retrograde Row. The numerals depicted in the upper drawing represent the mean flows (cubic centimeters per minute) reported for normal dogs in Table I I. The middle and lower drawings represent the donor coronary and circumflex arterial flows (cubic centimeters per minute), respectively, under the three conditions described above.
The krypton-85 washout technique yields estimates of the flo\\- per unit mass of the myocardiat region under stud),. Thus the donor coronary inflo\\- and krypton-85 \\-asliout techniques are not comparat)te on a flo\v-to-flo\Jr tjasis unless the mass of the region under study is knonn. F-or this report it \\:a~ chosen to compare these methods by normalizing collateral flon measurements to the normal perfusion rates (all flows are reported in Tables 1 to III). For example, in the normal dog the circumflex myocardiat collateral flo\~ during closure of the circumflex artery \vas estimated to be 23 per cent of normal perfusion rates with the inflohv method and 22 per cent of normal perfusion rates \vith the washout techniqu-. The difference \\-as not significant. In chronic preparations the cotlateral flow UYLSestimated to t)e 8X and 92 per cent of normal perfusion rates with the inflo\\, and washout techniques, respectively. Again the difference between the t\~o methods \~as not significant.
Fig. 3 is presented to provide a schematic of the peripheral and collateral circulator> dynamics which summarize the comt)ined results of the donor coronary inlet flo\~ and krypton-85 clearance studies in normal dogs. Illustrated in the upper portion of Fig. 3 is the distribution of the donor coronary inlet flow of normal dogs (mean values are presented) under conditions in I\-hich the circumflex arterial cannuta is (lj open (2j clamped, and to systemic pressure, (3) open to atmospheric pressure for the collection of retrograde floes. Fotto\\-ing occlusion of the circumflex arterial cannuta the mean donor coronary inlet flo\\- increased from 35 to 43 C.C. per minute. The results of the krypton-S.5 clearance studies (Table I) indicate that the antegrade flow to the peripheral bed of the anterior descending artery \\;a~ not significantly changed following occlusion of the circumflex arterial cannuta. Therefore, the increase in the donor coronary inlet flon (e.g., 8 C.C. per minute) is interpreted as
Coronary
collateral flow delivered to the peripheral vascular bed of the occluded circumflex artery. Following the establishment of retrograde circumflex arterial flow the donor coronary inlet flow increased to 44 c.c. per minute. Again, utilizing the krypton-85 clearance technique, the peripheral flow of the ianterior descending artery was determined to be virtually unchanged folloiving the establishment of retrograde flolv (Table I). Therefore, the increase in the donor coronary inlet flow (9 C.C. per minute) is interpreted as the total anastomotic flow delivered to the collateral system during the collection of retrograde flow. Of the total transanastomotic flow (9 C.C. per minute) delivered to the recipient circumflex vascular bed, 3.7 C.C. per minute are diverted retrogradely via the circumflex arterial cannula. The difference between the total anastomotic flow (9 c.c. per minute) and retrograde flow (3.7 C.C. per minute) equals 5.3 c.c. per minute and is interpreted as anastomotic flow delivered antegradely to the peripheral bed of the circumflex artery. The presence of an effective antegrade capillary perfusion of the circumflex myocardial region concomitant with the collectimon of retrograde circumflex arterial flow was demonstrated with krypton-85 washout studies (Table I). In chronic preparations the flow to the peripheral bed of the anterior descending vessel, determined nith the krypton-85 w\:ashout method, was not significantly changed following closure of the circumflex arterial cannula. Thus, the increase in total donor coronary inlet flow following occlusion of the circumflex arterial cannula would reasonably be interpreted as collateral flow delivered to the recipient circumflex myocardial region. Following the estal)lishmen t of retrograde circumflex arterial flow, the flo\v to the peripheral l)ed of the anterior descending artery was reduced to 71 per cent of levels achieved during direct pIerfusion of the circumflex arterial cannula. This decreased peripheral anterior descending flow is presumably a reflection of the decreased effective perfusion pressure throughout the anterior descending epicardial network resulting from the large increase in anastomotic flo~l: established in this bed during the collection of circumflex arterial retrograde flow. Upon
collaternl circulation
493
re-establishment of antegrade circumflex arterial flow a marked reactive hyperemic response was noted in the circumflex arterial system and a mild reactive hyperemic response was observed in the anterior descending inlet flow. The mild reactive hyperemic response of the anterior descending inflow may be the result of one or two mechanisms. For example: (1) hypoxia induced within the anterior descending bed as a result of the reduced capillary flow (i.e., 71 per cent of normal) during the collection of retrograde flow and (2) a reflection of the reactive hyperemic response in the circumflex bed. The latter mechanism is explained on the basis of the marked reactive hyperemic circumflex arterial inflows and the resultant pressure gradients generated across the circumflex cannula, arterial, and arteriolar systems. The reduced intra-arterial pressures of the circumflex bed could thus establish transient transanastomotic pressure gradients and collateral flows temarterial porally related to the circumflex hyperemic response. The continued perfusion of the circumflex myocardial region following the establishment of circumflex arterial retrograde flow is not unexpected since a spatial intravascular pressure gradient must exist throughout the circumflex myocardial region falling from near systemic pressures at the collateral inlets to atmospheric pressures in the central epicardial portions of the circumflex arterial network. Thus, an effective perfusion pressure is maintained for the subepicardial collateral complexes in both normal and chronic ischemic dogs during the collection of retrograde flow. In nchroic preparations, retrograde flow collected in the conventional manner by maintaining the circumflex arterial cannula at atmospheric pressure does not reduce in the entire circumflex the pressures epicardial bed to atmospheric levels. During the collection of retrograde flow in systems with large epicardial anastomoses, an intra-arterial epicardial pressure gradient must necassarily be established from the normally perfused coronary arteries to the circumflex arterial cannula. Thus, the tributaries arising from at least the peripheral portions of the circumflex artery continue to receive some degree of perfusion
iJ,’ ,r< ,r, :. I I, ?.,I,,., I ‘IT.<
during tile collection of I-ctrogr;id(~ Ilo\\ Fillton’” has demonstrated, \vi tlr Ilk stereoradiographic technique, large sulm~locat-dial collateral coulplexes \vllic-11 could provide a source of an tegrade capillary flw not easily diverted II~ opening the tircumflex arterial cannuln to atmospheric pressure. The combined results of the donor coronary inflow and krypton-X.5 clearance studies are summarized ;I5 folio\\-5: (1) retrograde HOI\- IVES 47 per cent of actual collateral flow in normal dogs; (1) retrograde flo\~ 1~2~s 420 per cent of actual collatmll HOK in chronic preparntions, reflecting the results of opening the circumflex artc.rial ~ysten~ supplied 11~. large-calilw anastonioses to atmospllcric pressure; and (3) concwiitant I\-ith the collection of rcl rograde circumflex arterial flo\v an tegrade flow to the ischemic circumflex myocnrdium persists in l)oth normal dogs (13 per cent of normal perfusion rates) and chronic prcparations (20 per cent of normal perfusion I-ates) .
1. Anrep, G. V., and Hausler, II.: circulation I. The effect of chatqes pressure and of the output of Physiol. 65:357, 1928. 2. Gregg, D. I,., Thornton. J. J., and The mnpnitude, adecluacy, and colinteml blood llow and pressure
The ccmm~r); of the blood the heart, J. Mautz, I-. Ii.: source of the ill chronically
4.
6.
J, .75:689, I
1948. I<. \I‘.:
The
ineffectiveness
of corti-
I,\vy. kl. N.,“imperial. E. S., rind Zieske, tl.: Collateral blood tlow tn the m> owl-dium as determined by the c-lear.~llcc of rubidiun~86 chloride, Circ-. Kes. 9:10X, 1961. 7. I3loor, C. Xl., and Knberts, I.. E.: ERects of intr.lvascular isotope content on the isotopic determination of coronary collateral blood flow, Cirr. Res. 16:j37, 1965. 8. l.indcr, E.: ~leasurements of normal and colI;lter.~l coronary t)lood llow by close-arterial .~nd irltmln)rocnrdi~~l injection of kryptona and xenon’38, Acta I’hysiol. Scnnd. 272:5. 1966. 9. Hood, Jr., I\‘. 13.: I’;lthr)l’hysioloR4. of ischemic heart disease. I’rocr. it, Cardiovnsc. Ibis.