MORTALITY STUDIES IN EXPERIMENTAL CORONARY OCCLUSION

MORTALITY STUDIES I N EXPERIMENTAL CORONARY OCCLUSION Robert B. Skelton, M.D.*

Nicholas Gergely,

George W. Manning, M.D., F.R.C.P.*** John C. Coles, M.D., F.A.C.S.,****

M.D.**

and

London,

Ontario

I

T has been recognized since 1936 that the mortality rate due to fatal ventricular ectopic rhythms which follow sudden experimental coronary artery occlusion in the dog is lower if the animal is anesthetized. 1 Investigation of possible mechanisms responsible for this protection resulted in the demonstration that cardiac sympathectomy (stellate ganglia and upper five or more thoracic sympathetic ganglia) significantly lowered the mortality rate of conscious dogs subjected to sudden coronary occlusion.2 Many studies have been carried out with a variety of drugs in an attempt to interrupt sympathetic or parasympathetic nerve transmission, 3 ' 6 or to prevent possible reflex coronary artery spasm, or to encourage coronary artery dilatation. 5 ' 6 ' 7 " 10 The decrease in the mortality rate from these measures has never been so marked as that observed with cardiac sympathetic denervation. The prevention of fatal ectopic rhythms after coronary occlusion in the dog by sympathectomy has been confirmed by some11-12 and denied by others, 13 who point out that cardiac sympathectomy is of dubious value if the sudden occlusion is done soon after completion of the denervation proce­ dure and of no value if the occlusion is done 17 days or more after the denerva­ tion. Our interest in methods of achieving myocardial stability in those clinical and experimental situations in which excess myocardial irritability may lead to fatal ectopic rhythms has prompted us to re-examine the mortality rate from sudden coronary occlusion in conscious dogs and in dogs with recent and chronic surgical cardiac sympathectomy. In addition, since it is now possible to obtain a reversible form for cardiac sympathetic denervation by means of thoracic epidural anesthesia,14 we have carried out a series of experiments to ascertain if this form of cardiac sympathectomy, induced immediately before the sudden coronary occlusion, would alter the mortality rate. Prom the Cardiovascular Unit, Department of Medicine and Physiology, University of Western Ontario, London, Ontario, Canada. Supported by The Ontario Heart Foundation. Received for publication Sept. 25, 1961. ♦Fellow in Cardiology. **Fellow in Cardiac Surgery. ** "Chief Cardiovascular Unit, University of Western Ontario. ****Chief Division Cardiac Surgery, University of Western Ontario. 90

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METHODS AND MATERIAL

In these experiments, a total of 90 healthy mongrel dogs selected at random, without regard to sex or weight, were used. Under anesthesia, a loose ligature was placed about the circumflex branch of the left coronary artery close to its origin, in the manner previously described.1 In the sympathectomized group (25 dogs), the stellate and upper sympathetic ganglia were removed on the right side 7 days prior to a second operation, which included left cardiac sympathectomy and the placing of a loose ligature around the left circumflex coronary artery. In the group subjected to epidural anesthesia (15 dogs), in addition to placing the loose ligature on the left circumflex artery, a polyethylene plastic tube was inserted through a needle into the epidural space at the lumbosacral 'junction and advanced so that its tip came to lie approximately at the level of the second thoracic vertebra. In all experiments, sudden occlusion of the left circumflex artery was carried out within 24 to 36 hours after the placing of the loose ligature, with the animal in the conscious state, by sudden traction of the loose ends of the ligature which had been exteriorized when the chest was closed as previously described. 1 ' 2 The electrocardiogram and blood pressure were recorded before, during, and one hour following the experiment. This study has been limited to the first 24 hours after occlusion, since, in our experience, survival up to 24 hours is consistent with long-term survival if the animal is protected against septic complications. Furthermore, since the majority of animals which do not survive the procedure develop fatal ventricular fibrilla­ tions within one hour, the "one hour mortality r a t e " is considered separately from the '' 24 hour mortality rate.'' In the animals subjected to cardiac sympathectomy (25 dogs), the ligature was placed very close to the origin (within 2 mm.) of the left circumflex coro­ nary artery. Fifteen animals were subjected to coronary occlusion one week following sympathectomy and 10, 4 weeks later. For comparison, a control group of 25 dogs without previous cardiac sympathectomy were subjected to sudden coronary occlusion with a similar ligature position. In the epidural anesthesia group of 15 animals and a separate control group of 25 dogs, the ligature position was approximately 4 mm. from the origin of the left circumflex artery branch. In this group of 15 dogs, sympathetic block was produced 15 minutes prior to coronary occlusion by the injection of 0.5 ml. per kilogram of body weight of a 0.7 per cent Xylocaine solution which was introduced slowly through the polyethylene tubing into the epidural space. Postmortem studies were carried out on all animals; these confirmed that the occlusions of the left circumflex arteries were complete, which also had been demonstrated by the electrocardiogram at the time of the experiment. RESULTS

In the group subjected to surgical cardiac sympathectomy and the cor­ responding control series ligated at approximately 2 mm. from the origin of the left circumflex, the following results were obtained (Table I ) . In the control group prepared for this series, 20 out of 25 dogs (80 per cent) died in the first hour after sudden occlusion of the coronary artery. One

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more dog died in the succeeding 24 hours bringing the total 24 hour mortality rate to 21 dogs (84 per cent) of the control group. In all dogs whose death was observed in the first hour after occlusion, the mechanism was ventricular tachy­ cardia followed by ventricular fibrillation. Only 2 of the 15 dogs who underwent coronary occlusion one week after cardiac sympathetic denervation died in the first hour after the occlusion (15 per cent). There were no additional deaths in the next 24 hours (Fig. 1). Analysis of the mortality rate by the chi square method, with Yates correction for small numbers, showed this decrease to be highly significant. In the dogs with cardiac sympatheetomy done 4 weeks before sudden coronary occlusion, there were no deaths in the first 24 hours. The deMORTALITY OF LEFT SURGICAL

RATE

AFTER

CIRCUMFLEX CARDIAC

SUDDEN

OCCLUSION

CORONARY

SYMPATHETIC

ARTERY

DENERVATION

I H c o n t r o l (25dogs) 100 recent e.s.d (lwk.l5doqs)

80

£

i chronic c.s.d (4wks.lOdoqs)

60

2 20

0

I I HOUR TIME

24 AFTER Fig. X.

HOURS OCCLUSION

TABLE I. MORTALITY RESULTS FROM SUDDEN OCCLUSION OP THE L E F T CIRCUMFLEX CORONARY ARTERY IN CONSCIOUS DOGS W I T H SURGICAL CARDIO-SYMPATHETIC DENERVATION

GROUP

NO. OF DOGS

NO. OF DOGS T H A T DIED IN THE F I R S T HOUR AFTER OCCLUSION

PER CENT

NO. OF DOGS T H A T DIED IN 2 4 HOURS AFTER OCCLUSION

Control 25 20 80 21 Kecent C-S-D (1 week) 15 2 14* 2 Chronic C-S-D (4 weeks) 10 0 0* 0 C-S-D = cartlio-sympathetic denervation. •Significant decrease in mortality rate (p < 0.05).

LIGATURE POSITION ON CORO­ NARY ARTERY FROM ORIGIN (MM.)

INCIDENCE OF VEN­ TRICULAR FIBRILLA­ TION IN DOGS T H A T DIED ( % )

84

2

100

14*

2

100

0*

2

0

PER CENT

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crease in the mortality rate is apparent. Autopsy studies showed that the mean ligature position on the left circumflex coronary artery was 2.0 mm. from the origin of the coronary artery in this series. A large posterolateral infarct of the left ventricle was found in all dogs that survived a sufficient length of time for necrosis to occur. In the group studied under epidural sympathetic blockade, the following results were obtained (Table I I ) . In the control group of 25 dogs studied for this series, there were 12 deaths in the first hour after sudden coronary occlusion M O R T A L I T Y R A T E A F T E R SUDDEN OF LEFT CIRCUMFLEX CORONARY THORACIC

EPIDURAL

OCCLUSION ARTERY

ANESTHESIA icontrol ( 2 5 doqs)

100

I (epidural l5doq«)

2 4 HOURS

I HOUR TIME

AFTER

OCCLUSION

Fig. 2. TABLE I I . MORTALITY RESULTS FROM SUDDEN OCCLUSION or THE L E F T CIRMCUMFLEX CORONARY ARTERY IN CONSCIOUS DOGS W I T H THORACIC EPIDURAL SPINAL ANESTHESIA (TEMPORARY CARDIO-SYMPATHETIC DENERVATION)

GROUP

Control Epidural (Reversible C-S-D)

NO. OF DOGS

25 15

NO. OF DOGS THAT DIED • IN T H E FIRST HOUR AFTER PER CENT OCCLUSION

12 1

48 6.6*

NO. OF DOGS THAT DIED IN 2 4 HR. AETER OCCLUSION

13 3

C-S-D = cardio-sympathetic denervation. •Significant decrease in the mortality rate (p < 0.05).

LIGATURE POSITION ON LEFT CIRCUMFLEX CORONARY ARTERY FROM PER ORIGIN CENT (MM.)

52 19.8

4.1 1 0.42 3.410.17

INCIDENCE OF VEN­ TRICULAR FIBRILLA­ TION IN DOGS DYING IN FIRST HOUR AFTER OCCLUSION

100% Died in com­ plete heart block

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(48 per cent). One more dog died overnight which brought the total number of deaths to 13 dogs (52 per cent). In the group of 15 dogs with thoracic epidural anesthesia before the occlusion, only one died in the first hour after coronary occlusion (7 per cent) (Fig. 2). Statistical analysis showed this in­ crease to be highly significant. There were two more deaths in the next 24 hours, so that a total of 3 dogs died in the 24 hours. Statistical analysis showed that this decrease was not significant. Autopsy studies again showed gross myocardial infarction which involved the posterolateral wall of the left ventricle in dogs surviving more than a few hours. The mean ligature position was found to be 4.1 ± 0.42 mm. in the control group and 3.4 ± 0.17 mm. from the origin of the coronary artery in the treated group. DISCUSSION

I t has been shown that experimental coronary occlusion in the conscious dog is followed by increased ectopic activity which is characterized by showers of extrasystoles and culminates in rapid ventricular tachycardia that progresses to fatal ventricular fibrillation in a high percentage of the animals. 1 ' 2 ' 3 ' 1 0 The mortality rate from this sequence is influenced by a number of factors. One of the most important is the distance at which the coronary artery is ligated from its origin.15 It is apparent that the marked difference in the mortality rate of the two control groups in our experiments can be related to their respective mean ligature position. Thus, our surgical sympathectomy control group, with a mean ligature position of 2.0 mm. and a 24 hour mortality rate of 84 per cent, and the epidural control group, with a mean ligature position of slightly greater than 4 mm. and a 24 hour mortality rate of 57 per cent, demonstrate the validity of these previous observations15 and emphasizes the critical importance of liga­ ture placement in this type of experimental study. In our experience, none of the many types of drugs tested will produce as great and consistent a decrease in the mortality rate from sudden experimental coronary occlusion as that seen in dogs protected by removal of the cardiac sympathetic innervation. Originally, this beneficial result was thought to be due to interruption of a reflex arc whose afferent limb travelled centrally in the cardiac sympathetic nerves and caused stimulation of vagal efferents that resulted in spasm of the nonoccluded vessels.1 Subsequent investigations have not generally supported this view and, indeed, suggest that coronary flow in­ creases in the nonoccluded coronary vessels after coronary occlusion. 16 ' 17 Never­ theless, it is apparent that some fibrillatory mechanism is interrupted by cardiac sympathetic denervation. It has been reported that cardiac sympathectomy will not lower the mortality rate if occlusion is carried out more than 17 days after sympathectomy. 13 Also, other denervation studies 18 suggest that cardiac sympa­ thectomy might sensitize the heart to stimuli of various sorts, particularly Adrenalin. Our results, however, indicate again that surgical cardiac sympa­ thectomy will significantly lower the mortality rate due to sudden coronary oc­ clusion in the dog and that the protection is effective both one week and 4 weeks after completion of the sympathectomy.

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It has been shown that 0.5 ml. per kilogram of body weight of a 0.5 to 0.7 per cent Xylocaine solution will produce effective sympathetic blockade without causing respiratory paralysis. 14 During the occlusion procedure and, particu­ larly, at the time of traction on the ligature, the dogs in this group showed little subjective pain response; they lay passively indifferent to the entire procedure. Furthermore, unlike the control animal, there was generally little ventricular ectopic activity during the period of mechanical traction on the ligature and in the hour following. The mortality results showed that thoracic epidural anesthesia will produce a significant decrease in the one hour mortality rate. It was interesting that the one death in the first hour after occlusion in this group was caused by complete heart block and cardiovascular collapse and not ventricular fibrillation. The protective effect of the epidural anesthesia decreased with time so that the 24 hour mortality rate was not significantly less than the rate of the control group, although it was less than half that of the 24 hour control group. Studies with continuous epidural spinal anesthesia would be of considerable interest in this regard. It is not known exactly how cardiac sympathectomy prevents the fatal ectopic rhythms that develop after experimental coronary occlusion in the dog. Some investigators implicate the local production of metabolites and potassium from the injured myocardium. 1 ' 2 ' 4>19 Others emphasize the importance of the catecholamines. 20 ' 21 The current availability of drugs capable of producing selective interference in adrenergically mediated responses will be of consider­ able interest in the study of this problem. CONCLUSIONS

1. Surgical cardiac sympathectomy significantly lowers the mortality rate after sudden occlusion of the left circumflex coronary artery in conscious dogs. 2. This protection against fatal ventricular fibrillation is effective whether sudden occlusion is done one week or 4 weeks after completion of surgical cardiac sympathetic denervation. 3. High thoracic epidural anesthesia provides an equally effective and re­ versible form of cardiac sympathetic denervation, the duration of protection being limited by the duration of action of the anesthetic. 4. The proximity of the occluding ligature to the origin of the left circum­ flex coronary artery is of critical importance in mortality in experimental coronary occlusion studies. 5. The precise mechanism by which sympathetic denervation lowers the mortality rate due to ventricular fibrillation requires investigation. REFERENCES

1. Manning, G. W., McEachern, C. G., and Hall, G. E . : Reflex Coronary Artery Spasm Fol­ lowing Sudden Occlusion of Other Coronary Branches, Arch. Int. Med. 64: 661, 1939. 2. McEachern, C. G., Manning, G. W., and Hall, G. E . : Sudden Occlusion of Coronary Ar­ teries Following Removal of the Cardio-Sensory Pathways, Arch. Int. Med. 65: 661, 1940. 3. Manning, G. W., and Caudwell, G. C.: The Effect of Demerol, Ergotamine and Dihydroergotamine on Mortality Rate After Coronary Occlusion in Dogs, Brit. Heart J . 9: 85, 1947.

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4. Harris, A. S., and Bisteni, A.: Effects of Sympathetic Blockade Drugs on Ventricular Tachycardia, Am. J . Physiol. 181: 599, 1955. 5. Manning, G. W.: Thesis, University of Toronto, 1948. 6. Eegelson, W., Hoffmeister, F . S., and Wilkins, H . : The Effect of Iproniazid on Survival Following Acute Coronary Occlusion, Ann. New York Acad. Sc. 80: 981, 1959. 7. McEachern, C. G., Smith, F . M., and Manning, G. W.: The Effect of Intravenous Injection of Papaverine Hydrochloride Upon the Mortality Bate Resulting From Sudden Oc­ clusion of Coronary Arteries in Hogs, Am. Heart J . 2 1 : 25, 1941. 8. Allen, E. V., and MacLean, A. E.: Treatment of Sudden Arterial Occlusion With Papav­ erine Hydrochloride, Proc. Staff Meet. Mayo Clin. 10: 216, 1935. 9. Smith, F . M., McEachern, C. G., and Hall, G. E . : The Effect of the Intravenous Adminis­ tration of Quinidine Sulf ate on the Development of Ventricular Fibrillation Following Sudden Occlusion of Circumflex Branch of the Left Coronary Artery, Am. Heart J . 20: 620, 1940. 10. LeBoy, G. V., Fenn, G. K., and Gilbert, N. C.: The Influence of Xanthines and Atropine on the Mortality Rate After Experimental Coronary Occlusion, Am. Heart J . 23: 637, 1942. 11. Milch, E., Zimdahl, W. T., Egan, R. W., Hsia, T. W., Anderson, A. A., and David, J . : Experimental Prevention of Sudden Death From Acute Coronary Occlusion in the Dog, Am. Heart J. 50: 483, 1955. 12. Opdyke, D. F., and Selkurt, E. E . : A Study of Alleged Intercoronary Eeflexes Following Coronary Occlusion, Am. Heart J . 36: 73, 1948. 13. Yodice, A.: Sympathectomy and Experimental Occlusion of a Coronary Artery, Am. Heart J . 22: 545, 1941. 14. Spoeral, W. E. G. A.: A personal communication, Ontario Heart Foundation Progress Eeport, June, 1959. 15. Allen, J . B., and Laadt, J . E.: The Effect of the Level of the Ligature on Mortality Following Ligation of the Circumflex Coronary Artery in the Dog, Am. Heart J . 39: 273, 1950. 16. Exkenhoff, J . E., Hafkenschiel, J . H., and Landmesser, C. M.: The Coronary Circulation in the Dog, Am. J . Physiol. 148: 582, 1947. 17. Wang, H. H., Frank, C. W., Kanter, D. M., and Wegria, R.: An Experimental Study of Intercoronary Reflexes, Circulation Res. 5: 91, 1957. 18. Cannon, W. B., and Rosenblueth, A.: The Supersensitivity of Denervated Structures, a Low of Denervation, New York, 1949, The Macmillan Company, 245 pp. 19. Harris, A. S., Bisteni, A., Russell, R. A., Brigham, J . C , and Firestone, J . E.: Excitatory Factors in Ventricular Tachycardia Resulting From Myocardial Ischemia, Potassium a Major Excitant, Science 119: 200, 1954. 20. Eaab, W., and Lepeschkin, E.: Heart " S y m p a t h i n , " Circulation 1: 741, 1950. 21. Richardson, J . A., Woods, E. F., and Bagwell, E. E.: Circulating Catecholamines in Coronary Occlusion, Am. J . Cardiol. 5: 613, 1960.