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The effect of chronic coronary sinus occlusion on the vascularity of the dog's myocardium
THE
EFFECT THE
OF CHRONIC
VASCULARITY
CORONARY OF THE
SINUS
DOG’S
OCCLUSION
ON
MYOCARDIUM
VICTOR, LORBER, M.D., AND AI,BERT J. GREENBERG, M.l). ~~INiYEAl’OLIS, &~Ii’X.
N THE search for effective therapeutic measures against coronary disease, attent,ion has turned in recent years to surgical procedures aimed at providing the heart with an additional blood supply from extracardiac sources. In 1935, Gross and Bluml demonstrated by an injection and roentgenographic technique that occlusion of t,he coronary sinus produced an augmentation of the intrinsic arterial vascular bed. In dogs with previous coronary sinus occlusion, the incidence of infarction after ligation of the left anterior descending ,coronary artery was reduced. Gross, Blum, and Silverman,2 in subsequent experiments, found that the mortality after ligation of t,he left anterior descending coronary artery was reduced by previous partial coronary sinus occlusidn, but not by total sinus occlusion. The size and frequency of infarction was reported to be diminished, and the arterial vascular bed enlarged, in hearts with partial sinus occlusion. Electrocardiographic observations made after sinus occlusion yielded transient abnormalities which were ascribed by Gross and his co-workers3 to myocardial ischemia due to venous congestion. The dilatation and cyanotic appearance of the left ventricle aft,cr obturation of the coronary sinus is in consonance with this view. The experiments to be described were under&ken in order to ascertain whether or not the augmentation in the coronary arterial bed which has been noted within a period of several weeks after coronary sinus occlusion persists over a period of years.
I
METHODS
Adult mongrel dogs were anesthetized by giving nembutal intraperiThb surgical approach to the sinus toneally (25 mg. per kilogram). was essentially that employed by Gross and his co-workers.2’ 4 Procaine solution, applied to the surface of the heart as described by Mautz,5 eliminated cardiac irregularities produced by manipulation. A method of sinus closure was used which, it was hoped, would be gradual and progressive, and circumvent the effects of complete and sudden ligation. Although it was subsequently shown by Beck6 that the high mortality after complete coronary sinus ligation in normal dogs observed by Gross* need not occur, this gives no assurance that a heart already impaired by coronary diseasecould survive the immediate deleterious effects of acute venous stasis. From the Department Minnesota. Received for publication
of Physiology, University Sept. 3, 1943. ::7s
of Minnesota.
Minneapolis,
LORBER
AND
GREENBERG:
ICIWEC’L
Oh-
SIX-S
OCC’I~I’SIOS
379
Accordingly, the coronary sinus was picked up gently in an Allis forceps at a point about 1 cm. from its entrance into the right atrium. A second Allis was then placed as completely around the sinus as possible. A small, e-shaped, metal clip, about l/s inch in width, and large enough in circumference to fit around the sinus and perisinus fat,, was grasped in a Kocher’s forceps and slipped around the vessel just at ttrc side of the Allis forceps near the entrance of the sinus into t,hc right atrium. The ends of the clip were serrated to prevent slipping. Xftcr being placed around the coronary sinus, t.he rlil) was compressed until the sinus beyond the clip just hepan to hulgc. The I)cricardium ;ln
*Rinqor’s mixture
Haart
lnjacti&
mci5s Fig.
Wotur
bath
1.
Six animals were prepared in this fashion. One died of a wound infection on the seventh postoperative day, and one of distemper on the twelfth day after operation. The other four survived, and were in good health when sacrificed three years later. The simplicity of the procedure is indicated by the absence of mortality due to the operation itself in the first six animals so treated. After a period of three years, the animals were anesthetized with ether, and the hearts were excised widely in order to leave t.he atria in-
380
AMERICAN
HEART
JOURNAL
tact, and then injected, dissected, and roentgenographed in a manner essentially similar to that described by Schlesinger,’ except for the injection. In the method used, the injection mass was introduced via the aorta, rather than the coronary arteries, for this was found to be simpler and more dependable ; the right coronary artery frequently arises by multiple ostia, and is difficult to cannulate in the dog. The aorta was cannulated under saline, care being taken to prevent the entrance of air into the system. The coronary arteries were then flushed with warm Ringer’s fluid to remove the blood. After this, the heart was suspended in a saline bath at 45” C., the tube from the Ringer’s fluid reservoir was clamped, and a side arm leading to the flask containing the injection mass was opened. The injection mass was then introduced as indicated in Fig. 1, in which a diagram of the method of injection is presented. A pressure of 150 mm. Hg was maintained during the injection and for a period of several minutes after the mass had ceased to move forward Then the short segment of rubber tubing just above the aortic cannula was clamped and disconnect,ed from the system, and, while pressure was still being maintained in t.he aorta, the heart was placed in the icebox until the injection mass had set. The procedure from this point, forward was carried out as indi. cated.’ Nine control hearts were prepared in addition to the four esperimentals. Besides the roentgenograms, microscopic sections were made from the left ventricles of the control and experimental hearts, and the coronary sinuses in the experimental hearts were carefully dissected. RESULTS
Of the four experimental hearts, only one showed a completely OCeluded sinus. The degree of closure was estimated at 30, 50, and 90 per cent in the other three hearts. In those with 30 and 50 per cent occlusion, the clips bad not bent symmetrically on compression, and therefore did not completely surround the sinus. Although they OCCUpied approximately t,he same position with relation to the vesse1, there was an obvious difference in the degree of occlusion; this was probably accounted for by the difference in the material from which the clips were made. That on the more patent sinus had been made of silver, whereas all the others had been fashioned by cutting stainless skin clips down to size and bending them appropriately. This latter material apparently called forth a more marked connective tissue reaction than did the silver. Thus, fortuitously, a series ranging from slight to complete closure of the coronary sinus was obtained. Examination of the roentgenograms of the injected specimens in no case showed augmentation of the arterial (In making the comparison, the bed when compared with the controls. number of small vessels visualized served as the criterion.) Indeed, the experimental specimens, as a group, appeared definitely less vascular than the controls, as a group, although there were less vascular hearts in the control group with which those which showed only partial
LORBER
AXD
GREENBERG
:
EFFECT
OF
SIXI‘S
O(‘CI,lXIOY
:i,i: 1
This way not true, however, of the> sinns occlusion compared favorably. spccimrn with complrtc sinus occlusion, in whkh the lrnst. vascularit! was demonstrated.
Within the experimental series itself, the vascularity appeared 10 vary inversely with the degree of ohturation of the coronary sinus. Although the method, as a quantitat,ive measure of the coronary heel, leaves much to he desired, and although it cannot he suicl with certaini!, that the diff’erences here noted arc not tl~w to some anrecognized s~stematic discrepancy, there can be no doubt that so considerable an augmentation of the coronary arterial bed as that demonstrated by (:ross.
382
AMERICAN
HEART
JOURNAL
et al.,l’ 2 after recent coronary sinus occlusion could not have been missed by this procedure, a,nd certainly did not exist in these specimens. Reproductions of the roentgenograms of the four experimental hearts and three of the controls are presented in Figs. 2 and 3. Observations on the experiment,al hearts are summarized in Table I. TABLE HEART NUMBER 1
2
3 4 *As compared
DEGREE OF SINUS OCCLUSION
I
ROENTGENOGRAPHIC APPEARANCE OF VASCULAR BED
(76)
RELATIVE OF THE
DENSITY VASCULAR BED*
50
Comparable to less vascular control hearts Comparable to less vascular 90 eontro1 hearts Comparable to moderately 30 vascular control hearts Not as vascular as the least 100 vascular control heart to the other experimental hearts.
Fig.
ttt tt tttt
t
3.
It may be observed that all the hearts shown in the figures (and this is true of all the specimens studied) are of the type with a predominant left coronary artery, previously described by Schlesinger8 as typical in the dog. Finally, it should be stated that careful study of the microscopic sections made from the control and experimental hearts showed no demonstrable differences.
1~IscussIos* I
Reports made available since t hc present study was unrlertakt~t~ lend some support to the observat.ions just, described. (:rcpg and his co-worker+ ‘I’, I1 have shown that, t,hc bacl~How from :I 1 igaied corotu~~*~. artery peripheral to the point of ligation is considerably above t hc tror110wcver~. Jvt !‘Oma1 if t,hc coronary sinus is ligated simulianeousI!-. grade tlow is onlv slightly increased if cororraray sinus ligation is car’ritxl out thirty days tnior to arterial occlusion. Sirlris occlusion. howPver. was SoUnd to influence favorably t hc mart alit\- from alt(~riill occl lision. Beck” also found a dctinitc dccreasc in t hc mortalityt*atc aft t’r’ coronary artery occlusion if the coronaq- sinus is also li$ltctl. Il(a reported. however, that the beneficial rffcct of venous ligation is least. when vein and artery are closed at. the same operation that ii is greal(,st when carried out six weeks prior t,o ligation of the art.cry, and ticrrrases again when a longer interval ( fol~r months) elapses betwcc~n the t1v-o ~~OC~LW~S. E&k, unlike (iross, tt al..‘. ’ ;kl\va>Ts foad int’al~c*ts after arterial occlusion, but judgetl thrm to be smaller in size xvhcrl sinus ligation had been done l)reviously. ()bviously, before coronary sinus closure can btb tinallg: evaluated as a prot,ective measure against arterial occlusioli, t,hc mortality, induced 1)~ the latter ~~OC~LIR when it is carried out OI~(’ or more years ai’ttlr the former, must be asccrtaincd. The observations recorded to c1at.e lend slight support. to t,he SII~gestion that coronary sinus occlusion might he of value as a therapeut it procedure in coronary disease by pcrmancntl,v increasing ihe basic r;wnlur hrtl. Ihg hearts, after three years of graded coronary sinns occlusion, rarving from slight to complete closure, (iid Jld exhibit the augniciif ation of t tic coronary arterial bed which has l)ccn demonstrated by others within a period of days to mec~lrs after obturation of t.his vessel. ( )I\ ihc c<)ntrirt*r, mvocardial vascnlarity i\t)t~c;\l~cd rcch~ced, if anyt Iline., :LS il t*cstllt of this I)~OW~LWP.
I. <+ross, I,., and Blum, L.: Effert of Corouary Artery Orclusion on Dog’s Heart With Total Coronary Sinus Ligation, Proc. Hoc. Vesper. Biol. & Med. 32: 15%. 1935. ‘J. Gross. L., Blum, L., and Silverman, G.: Eq~crimental Attempts to Increase 11~ Blood Supply to the Dog’s Heart, 11~ Means of Coronary Sinus Occlusion, J. Exper. Med. 65: 91, 1937. ::. Grow, L., Silverman, G., and Master, A. M. : Electrocardiographic c’hanges Following Coronary Sinus Occlusion in the Dog’s IKeart, Axr. HEAI:T J. 11: i:S, 3!t3ti. 1. Blum, L., ancl Gross, L. : Technic .T. Thoracic Surg. 5: 532, 1936.
5. %IIsute, F. R.: Administration Surg.
5:
612,
of
Experimental
Reduction of Cardiac Irrit:lbilit~ of Drugs as a Protection 1936.
(‘oronary
hp the Epicardial m (‘artlinc* Surgery,
Sinus
bigat
iou.
am1 S,vst~rnic~ J. TIIII~:~v~v
384 6. Beck, C. 8.: y;;rt and
AMERICAN
Natural and Artificial Circulation, Lancaster,
HEART
JOURNAL
Collateral Circulation 1940, Science Press
in the Printing
Heart, Blood, Company, p.
7. Schlesinger, M. J.: An Inject,ion Plus Dissection Study of Coronary Artery Occlusions and Anastomoses, AM. HEART J. 15: 528, 1935. S. Schlesinger, M. J.: Significant Variations in the Anatomic Pattern of the Corenary Vessels, Blood, Heart, and Circulation, Lancaster, 1940, Science Press Printing Company, p. (il. 9. Gregg, D. E., and Dewald, D.: Immediate Effects of Coronary Sinus Ligation on Dynamics of Coronary Circulation, Proc. Sot. Exper. Biol. & Med. 39: 202, 1935. The Immediate Effects of the Occlusion of the 10. Gregg, D. E., and Dewald, D.: Coronary Veins on Collateral Blood Flow in the Coronary Arteries, Am. J. Physiol. 124: 435, 1935. 11. Thornton, J. J., and Gregg, D. E.: Effect of Chronic Cardiac Venous Occlusion on Coronary Arterial and Cardiac Venous Hemodynamics, Am. J. Physiol. 128: 179, 1939.
EFFECT THE
OF CHRONIC
VASCULARITY
CORONARY OF THE
SINUS
DOG’S
OCCLUSION
ON
MYOCARDIUM
VICTOR, LORBER, M.D., AND AI,BERT J. GREENBERG, M.l). ~~INiYEAl’OLIS, &~Ii’X.
N THE search for effective therapeutic measures against coronary disease, attent,ion has turned in recent years to surgical procedures aimed at providing the heart with an additional blood supply from extracardiac sources. In 1935, Gross and Bluml demonstrated by an injection and roentgenographic technique that occlusion of t,he coronary sinus produced an augmentation of the intrinsic arterial vascular bed. In dogs with previous coronary sinus occlusion, the incidence of infarction after ligation of the left anterior descending ,coronary artery was reduced. Gross, Blum, and Silverman,2 in subsequent experiments, found that the mortality after ligation of t,he left anterior descending coronary artery was reduced by previous partial coronary sinus occlusidn, but not by total sinus occlusion. The size and frequency of infarction was reported to be diminished, and the arterial vascular bed enlarged, in hearts with partial sinus occlusion. Electrocardiographic observations made after sinus occlusion yielded transient abnormalities which were ascribed by Gross and his co-workers3 to myocardial ischemia due to venous congestion. The dilatation and cyanotic appearance of the left ventricle aft,cr obturation of the coronary sinus is in consonance with this view. The experiments to be described were under&ken in order to ascertain whether or not the augmentation in the coronary arterial bed which has been noted within a period of several weeks after coronary sinus occlusion persists over a period of years.
I
METHODS
Adult mongrel dogs were anesthetized by giving nembutal intraperiThb surgical approach to the sinus toneally (25 mg. per kilogram). was essentially that employed by Gross and his co-workers.2’ 4 Procaine solution, applied to the surface of the heart as described by Mautz,5 eliminated cardiac irregularities produced by manipulation. A method of sinus closure was used which, it was hoped, would be gradual and progressive, and circumvent the effects of complete and sudden ligation. Although it was subsequently shown by Beck6 that the high mortality after complete coronary sinus ligation in normal dogs observed by Gross* need not occur, this gives no assurance that a heart already impaired by coronary diseasecould survive the immediate deleterious effects of acute venous stasis. From the Department Minnesota. Received for publication
of Physiology, University Sept. 3, 1943. ::7s
of Minnesota.
Minneapolis,
LORBER
AND
GREENBERG:
ICIWEC’L
Oh-
SIX-S
OCC’I~I’SIOS
379
Accordingly, the coronary sinus was picked up gently in an Allis forceps at a point about 1 cm. from its entrance into the right atrium. A second Allis was then placed as completely around the sinus as possible. A small, e-shaped, metal clip, about l/s inch in width, and large enough in circumference to fit around the sinus and perisinus fat,, was grasped in a Kocher’s forceps and slipped around the vessel just at ttrc side of the Allis forceps near the entrance of the sinus into t,hc right atrium. The ends of the clip were serrated to prevent slipping. Xftcr being placed around the coronary sinus, t.he rlil) was compressed until the sinus beyond the clip just hepan to hulgc. The I)cricardium ;ln
*Rinqor’s mixture
Haart
lnjacti&
mci5s Fig.
Wotur
bath
1.
Six animals were prepared in this fashion. One died of a wound infection on the seventh postoperative day, and one of distemper on the twelfth day after operation. The other four survived, and were in good health when sacrificed three years later. The simplicity of the procedure is indicated by the absence of mortality due to the operation itself in the first six animals so treated. After a period of three years, the animals were anesthetized with ether, and the hearts were excised widely in order to leave t.he atria in-
380
AMERICAN
HEART
JOURNAL
tact, and then injected, dissected, and roentgenographed in a manner essentially similar to that described by Schlesinger,’ except for the injection. In the method used, the injection mass was introduced via the aorta, rather than the coronary arteries, for this was found to be simpler and more dependable ; the right coronary artery frequently arises by multiple ostia, and is difficult to cannulate in the dog. The aorta was cannulated under saline, care being taken to prevent the entrance of air into the system. The coronary arteries were then flushed with warm Ringer’s fluid to remove the blood. After this, the heart was suspended in a saline bath at 45” C., the tube from the Ringer’s fluid reservoir was clamped, and a side arm leading to the flask containing the injection mass was opened. The injection mass was then introduced as indicated in Fig. 1, in which a diagram of the method of injection is presented. A pressure of 150 mm. Hg was maintained during the injection and for a period of several minutes after the mass had ceased to move forward Then the short segment of rubber tubing just above the aortic cannula was clamped and disconnect,ed from the system, and, while pressure was still being maintained in t.he aorta, the heart was placed in the icebox until the injection mass had set. The procedure from this point, forward was carried out as indi. cated.’ Nine control hearts were prepared in addition to the four esperimentals. Besides the roentgenograms, microscopic sections were made from the left ventricles of the control and experimental hearts, and the coronary sinuses in the experimental hearts were carefully dissected. RESULTS
Of the four experimental hearts, only one showed a completely OCeluded sinus. The degree of closure was estimated at 30, 50, and 90 per cent in the other three hearts. In those with 30 and 50 per cent occlusion, the clips bad not bent symmetrically on compression, and therefore did not completely surround the sinus. Although they OCCUpied approximately t,he same position with relation to the vesse1, there was an obvious difference in the degree of occlusion; this was probably accounted for by the difference in the material from which the clips were made. That on the more patent sinus had been made of silver, whereas all the others had been fashioned by cutting stainless skin clips down to size and bending them appropriately. This latter material apparently called forth a more marked connective tissue reaction than did the silver. Thus, fortuitously, a series ranging from slight to complete closure of the coronary sinus was obtained. Examination of the roentgenograms of the injected specimens in no case showed augmentation of the arterial (In making the comparison, the bed when compared with the controls. number of small vessels visualized served as the criterion.) Indeed, the experimental specimens, as a group, appeared definitely less vascular than the controls, as a group, although there were less vascular hearts in the control group with which those which showed only partial
LORBER
AXD
GREENBERG
:
EFFECT
OF
SIXI‘S
O(‘CI,lXIOY
:i,i: 1
This way not true, however, of the> sinns occlusion compared favorably. spccimrn with complrtc sinus occlusion, in whkh the lrnst. vascularit! was demonstrated.
Within the experimental series itself, the vascularity appeared 10 vary inversely with the degree of ohturation of the coronary sinus. Although the method, as a quantitat,ive measure of the coronary heel, leaves much to he desired, and although it cannot he suicl with certaini!, that the diff’erences here noted arc not tl~w to some anrecognized s~stematic discrepancy, there can be no doubt that so considerable an augmentation of the coronary arterial bed as that demonstrated by (:ross.
382
AMERICAN
HEART
JOURNAL
et al.,l’ 2 after recent coronary sinus occlusion could not have been missed by this procedure, a,nd certainly did not exist in these specimens. Reproductions of the roentgenograms of the four experimental hearts and three of the controls are presented in Figs. 2 and 3. Observations on the experiment,al hearts are summarized in Table I. TABLE HEART NUMBER 1
2
3 4 *As compared
DEGREE OF SINUS OCCLUSION
I
ROENTGENOGRAPHIC APPEARANCE OF VASCULAR BED
(76)
RELATIVE OF THE
DENSITY VASCULAR BED*
50
Comparable to less vascular control hearts Comparable to less vascular 90 eontro1 hearts Comparable to moderately 30 vascular control hearts Not as vascular as the least 100 vascular control heart to the other experimental hearts.
Fig.
ttt tt tttt
t
3.
It may be observed that all the hearts shown in the figures (and this is true of all the specimens studied) are of the type with a predominant left coronary artery, previously described by Schlesinger8 as typical in the dog. Finally, it should be stated that careful study of the microscopic sections made from the control and experimental hearts showed no demonstrable differences.
1~IscussIos* I
Reports made available since t hc present study was unrlertakt~t~ lend some support to the observat.ions just, described. (:rcpg and his co-worker+ ‘I’, I1 have shown that, t,hc bacl~How from :I 1 igaied corotu~~*~. artery peripheral to the point of ligation is considerably above t hc tror110wcver~. Jvt !‘Oma1 if t,hc coronary sinus is ligated simulianeousI!-. grade tlow is onlv slightly increased if cororraray sinus ligation is car’ritxl out thirty days tnior to arterial occlusion. Sirlris occlusion. howPver. was SoUnd to influence favorably t hc mart alit\- from alt(~riill occl lision. Beck” also found a dctinitc dccreasc in t hc mortalityt*atc aft t’r’ coronary artery occlusion if the coronaq- sinus is also li$ltctl. Il(a reported. however, that the beneficial rffcct of venous ligation is least. when vein and artery are closed at. the same operation that ii is greal(,st when carried out six weeks prior t,o ligation of the art.cry, and ticrrrases again when a longer interval ( fol~r months) elapses betwcc~n the t1v-o ~~OC~LW~S. E&k, unlike (iross, tt al..‘. ’ ;kl\va>Ts foad int’al~c*ts after arterial occlusion, but judgetl thrm to be smaller in size xvhcrl sinus ligation had been done l)reviously. ()bviously, before coronary sinus closure can btb tinallg: evaluated as a prot,ective measure against arterial occlusioli, t,hc mortality, induced 1)~ the latter ~~OC~LIR when it is carried out OI~(’ or more years ai’ttlr the former, must be asccrtaincd. The observations recorded to c1at.e lend slight support. to t,he SII~gestion that coronary sinus occlusion might he of value as a therapeut it procedure in coronary disease by pcrmancntl,v increasing ihe basic r;wnlur hrtl. Ihg hearts, after three years of graded coronary sinns occlusion, rarving from slight to complete closure, (iid Jld exhibit the augniciif ation of t tic coronary arterial bed which has l)ccn demonstrated by others within a period of days to mec~lrs after obturation of t.his vessel. ( )I\ ihc c<)ntrirt*r, mvocardial vascnlarity i\t)t~c;\l~cd rcch~ced, if anyt Iline., :LS il t*cstllt of this I)~OW~LWP.
I. <+ross, I,., and Blum, L.: Effert of Corouary Artery Orclusion on Dog’s Heart With Total Coronary Sinus Ligation, Proc. Hoc. Vesper. Biol. & Med. 32: 15%. 1935. ‘J. Gross. L., Blum, L., and Silverman, G.: Eq~crimental Attempts to Increase 11~ Blood Supply to the Dog’s Heart, 11~ Means of Coronary Sinus Occlusion, J. Exper. Med. 65: 91, 1937. ::. Grow, L., Silverman, G., and Master, A. M. : Electrocardiographic c’hanges Following Coronary Sinus Occlusion in the Dog’s IKeart, Axr. HEAI:T J. 11: i:S, 3!t3ti. 1. Blum, L., ancl Gross, L. : Technic .T. Thoracic Surg. 5: 532, 1936.
5. %IIsute, F. R.: Administration Surg.
5:
612,
of
Experimental
Reduction of Cardiac Irrit:lbilit~ of Drugs as a Protection 1936.
(‘oronary
hp the Epicardial m (‘artlinc* Surgery,
Sinus
bigat
iou.
am1 S,vst~rnic~ J. TIIII~:~v~v
384 6. Beck, C. 8.: y;;rt and
AMERICAN
Natural and Artificial Circulation, Lancaster,
HEART
JOURNAL
Collateral Circulation 1940, Science Press
in the Printing
Heart, Blood, Company, p.
7. Schlesinger, M. J.: An Inject,ion Plus Dissection Study of Coronary Artery Occlusions and Anastomoses, AM. HEART J. 15: 528, 1935. S. Schlesinger, M. J.: Significant Variations in the Anatomic Pattern of the Corenary Vessels, Blood, Heart, and Circulation, Lancaster, 1940, Science Press Printing Company, p. (il. 9. Gregg, D. E., and Dewald, D.: Immediate Effects of Coronary Sinus Ligation on Dynamics of Coronary Circulation, Proc. Sot. Exper. Biol. & Med. 39: 202, 1935. The Immediate Effects of the Occlusion of the 10. Gregg, D. E., and Dewald, D.: Coronary Veins on Collateral Blood Flow in the Coronary Arteries, Am. J. Physiol. 124: 435, 1935. 11. Thornton, J. J., and Gregg, D. E.: Effect of Chronic Cardiac Venous Occlusion on Coronary Arterial and Cardiac Venous Hemodynamics, Am. J. Physiol. 128: 179, 1939.