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Prevention of ventricular fibrillation after ligation of circumflex artery
Prevention of ventricular fibrillation after ligation of circumflex artery N. Hiatt, M.D., B. Rabinowitz, M.D., T. Yamakawa, M.D., A. Miller, B.A., J. A. Sheinkopj, M.D., and N. E. Warner, M.D., Los Angeles, Calif.
Experimentation involving the circumflex artery of dogs is difficult, because occlusion of the vessel near its origin is quickly followed by a variety of ventricular arrhythmias that almost invariably terminate in fatal ventricular fibrillation within 30 minutes.':" During an investigation of postligation changes in blood cyclic adenosine monophosphate (AMP), the circumflex artery was not occluded immediately after opening the chest; thoracotomy induces an elevation of cAMP that lasts from 30 to 90 minutes. We found that if 2 hours elapsed between completion of thoracotomy and ligation of the circumflex artery, ventricular arrhythmias were few, ventricular fibrillation absent, and survival significantly prolonged. Methods Twelve dogs of both sexes, weighing between IS and 21.5 kilograms, were used. Six were used as experimental animals and 6 as control subjects. After anesthesia with sodium pentobarbital (30 mg. per kiloFrom the Departments of Surgery. Cardiology, and Medicine, and the Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif., and the Department of Pathology (Dr. Warner), U.S.C. School of Medicine, Los Angeles, Calif. This work was supported by the following: Grant No.5 SOl RR 05468-06, Surgical Research Project, BlumKovler Foundation, the Harry and Rae Warner Foundation, and the Medical Research Foundation for Heart Disease. Received for publication April 3, 1973. Address for reprints: Dr. Nathan Hiatt, Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif. 90029.
gram), positive pressure respiration, recording of the electrocardiogram, and a slow continuous infusion of 0.15M sodium chloride were begun. The heart was exposed by thoracotomy in the fourth left intercostal space, and the origin of the circumflex artery was dissected free (for later ligation). In control dogs the circumflex artery was doubly ligated within 2 minutes after the completion of thoracotomy and artery dissection. In experimental dogs the incision in the fourth left intercostal space was closed with towel clips. Two hours after completion of thoracotomy and artery dissection, the chest wound was reopened, ligatures were passed, and the circumflex artery was doubly ligated. In all dogs a specimen of blood for determination of immunoreactive insulin (IR!) was obtained before the artery was ligated and thereafter at 30 minute intervals or whenever there were electrocardiographic changes. Thoracotomies in surviving dogs were closed I to 2 hours after ligation of the artery; none of the control animals survived long enough to require closure. Dogs were kept on the respirator until they were sufficiently awake to cough out the tracheal tube. Necropsy was performed and the coronary arteries dissected in every animal. The exact site of ligation and the location of infarcts were determined. Appropriate samples were fixed in formalin for examination by light microscopy. Insulin was determined by the method of Morgan and Lazarow.'
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Fig. 1. Effect of a 2 hour post-thoracotomy interval on survival after circumflex artery ligation: Comparison with effect of insulin. A, Control (time recorded in seconds). B, Treatment with insulin (time recorded in minutes) . C, Ligation 2 hours 'after completion of thoracotomy and artery dissection (time recorded in minutes).
Table I. Survival after ligation of the circumflex artery* No. 0/ dogs Control Survival for I to 10 minutes Experimental Sur vival for 10 or more hours Survi val for 4 or more hours
6
6 6 4 2
Le gend: In the control animals, the artery was ligated 2 minutes aft er the thoracotomy. In the experimental animals, it was do ne 2 hours after the thoracotomy, .p < 0.005 bet ween the control and experimental dogs , as tested by contin gency analysis.
Fig. Z. Electrocardiographic changes following circumflex artery ligation 2 hours after thoracotom y. A , Short bursts of rapid ventricular tachy cardia. B, Profuse premature ventricular contractions that appear approximately 4 hours after ligat ion .
Results
Results are outlined in Table I. The 6 control animals , in which the artery was ligated 2 minutes after thoracotomy, rapidl y developed electrocardiographic changes of myocard ial ischemia and injury, numerous arrhythmias, and a ventricular tachycardia that terminated in ventricular fibrillation within 10 minutes (Fig. 1, A). The 6 ex-
perimental dogs, in which the artery was ligated 2 hours after thoracotomy, also developed the electrocardiographic changes of myocardial ischemia and injury, but ventricular arrhythmias were few-limited to some premature ventricular contractions and infrequent burst of ventricular tachycardia that subsided spontaneously in 2 to 3 seconds (Figs. 1, C, and 2, A). Four of the experimental dogs recovered completely from anesthesia and developed numerous premature ventricular contractions approximately 4 hours after ligation (Fig. 2, B); no treatment was given for the premature ventricular contractions, and, during the
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period of observation, no other ventricular arrhythmias were associated with these premature beats. All 4 animals were in good condition when last observed, approximately I 0 hours after ligation, but none survived until morning. Two of the experimental animals developed sudden ventricular fibrillation about 4 hours after ligation. This was soon after they were extubated, as they were awakening from anesthesia. Fibrillation quickly followed a short run of ventricular tachycardia. None of the dogs (control or experimental) had a significant change of serum IRI. In all of the dogs the circumflex artery was ligated within 5 mm. of its origin, proximal to any of its branches but distal to the septal artery. Hearts of control dogs (survived for I 0 minutes or less) were dilated but otherwise were grossly normal. Hearts of animals that survived longer (4 to I0 hours) had large infarcts on the posterior and lateral walls of the left ventricle that extended to the adjacent interventricular septum and posterior papillary muscle. The pathologic and electrocardiographic changes that follow occlusion of the circumflex artery at its origin are surprisingly uniform. They are to be described in detail in another report that will include an analysis of the differing R wave-premature contraction intervals in control and experimental animals. Discussion
In experimental ligation of a coronary artery it is usual to open the chest and ligate the vessel in one continuous operation. Our investigation shows that a 2 hour interval between completion of thoracotomy and ligation of the circumflex artery results in a marked diminution of postligation ventricular arrhythmias and a striking prolongation of survival-from 10 minutes or less in controls, to over 10 hours in four, and to over 4 hours in two, of the experimental dogs. In dogs ligated immediately after thoracotomy, treatment with insulin accomplishes the same result as the 2 hour interval between thoracotomy and ligation. Large doses of insulin prolong survival by suppressing
the ventricular arrhythmias that precede fatal ventricular fibrillation" (Fig. 1, B). The effect of the 2 hour interval between thoracotomy and ligation, i.e., the virtual elimination of postligation arrhythmias and prolongation of survival, does not involve insulin. Serum insulin is never elevated. We have been able to demonstrate similar suppression of ventricular arrhythmias and prolongation of survival in a few dogs subjected to pancreatectomy. Our results at this time are difficult to interpret. With studies of blood cyclic adenosine monophosphate and catecholamines, we are exploring the possibility that insulin and the post-thoracotomy interval both deactivate a mechanism that sensitizes the myocardium to postligation arrhythmias. For the present, by waiting for 2 hours after ligation, it is easy to prepare dogs for the study of late postligation arrhythmias (Fig. 2, B) and for use as models in studying the improvement of collateral circulation by surgical means. The circumflex is the largest and (to us) the most accessible of the coronary arteries in dogs. G Clinically, an interval after thoracotomy may lessen the incidence of ventricular arrhythmias in operations on the heart and its arteries. Summary In dogs the usually fatal result that follows ligation of the circumflex artery near its origin can be averted for up to I0 hours and more by a change of operative procedure. If the occluding ligatures are passed and tied 2 hours after completion of the thoracotomy and dissection of passage beneath the vessel, postligation ventricular arrhythmias are minimal and survival is prolonged more than twentyfold.
REFERENCES Fineberg, C., Foris, N., and Cam ishion, R. C.: Revascularization of the Dog Myocardium, Arch. Surg. 49: 762, 1962. 2 Goldfarb, D., Conti, C. R., Brown, B. G., and Gott, V. L.: Treatment of Severe Cardiogenic Shock by Diastolic Augmentation After Ligation and Division of Left Circumflex Artery in
286
Hiatt et al.
The Journol of Thorocic ond Cordiovosculor Surgery
Dogs, J. THORAC. CARDIOVASC. SURG. 51: 783, 1966. 3 Lumb, G., Shacklett, R. S., and Dawkins, W. A.: The Cardiac Conduction Tissue and Its Blood Supply in the Dog, Am. J. PathoJ. 35: 467, 1959. 4 Morgan, C. R., and Lazarow, A.: Immunoassay of Insulin: Two Antibody Systems. Plasma
Insulin Levels of Normal, Subdiabetic and Diabetic Rats, Diabetes 12: 115, 1963. 5 Hiatt, N., Sheinkopf, J. A., and Warner, N. E.: Prolongation of Survival After Circumflex Artery Ligation by Treatment With Massive Doses of Insulin, J. Cardiovasc. Res. 5: 48, 1971. 6 Moore, R. A.: The Coronary Arteries of the Dog, Am. Heart J. 5: 743, 1930.
Experimentation involving the circumflex artery of dogs is difficult, because occlusion of the vessel near its origin is quickly followed by a variety of ventricular arrhythmias that almost invariably terminate in fatal ventricular fibrillation within 30 minutes.':" During an investigation of postligation changes in blood cyclic adenosine monophosphate (AMP), the circumflex artery was not occluded immediately after opening the chest; thoracotomy induces an elevation of cAMP that lasts from 30 to 90 minutes. We found that if 2 hours elapsed between completion of thoracotomy and ligation of the circumflex artery, ventricular arrhythmias were few, ventricular fibrillation absent, and survival significantly prolonged. Methods Twelve dogs of both sexes, weighing between IS and 21.5 kilograms, were used. Six were used as experimental animals and 6 as control subjects. After anesthesia with sodium pentobarbital (30 mg. per kiloFrom the Departments of Surgery. Cardiology, and Medicine, and the Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif., and the Department of Pathology (Dr. Warner), U.S.C. School of Medicine, Los Angeles, Calif. This work was supported by the following: Grant No.5 SOl RR 05468-06, Surgical Research Project, BlumKovler Foundation, the Harry and Rae Warner Foundation, and the Medical Research Foundation for Heart Disease. Received for publication April 3, 1973. Address for reprints: Dr. Nathan Hiatt, Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif. 90029.
gram), positive pressure respiration, recording of the electrocardiogram, and a slow continuous infusion of 0.15M sodium chloride were begun. The heart was exposed by thoracotomy in the fourth left intercostal space, and the origin of the circumflex artery was dissected free (for later ligation). In control dogs the circumflex artery was doubly ligated within 2 minutes after the completion of thoracotomy and artery dissection. In experimental dogs the incision in the fourth left intercostal space was closed with towel clips. Two hours after completion of thoracotomy and artery dissection, the chest wound was reopened, ligatures were passed, and the circumflex artery was doubly ligated. In all dogs a specimen of blood for determination of immunoreactive insulin (IR!) was obtained before the artery was ligated and thereafter at 30 minute intervals or whenever there were electrocardiographic changes. Thoracotomies in surviving dogs were closed I to 2 hours after ligation of the artery; none of the control animals survived long enough to require closure. Dogs were kept on the respirator until they were sufficiently awake to cough out the tracheal tube. Necropsy was performed and the coronary arteries dissected in every animal. The exact site of ligation and the location of infarcts were determined. Appropriate samples were fixed in formalin for examination by light microscopy. Insulin was determined by the method of Morgan and Lazarow.'
283
The Journal of
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Hiatt et al.
Thoracic and Card iovascular Surgery
Fig. 1. Effect of a 2 hour post-thoracotomy interval on survival after circumflex artery ligation: Comparison with effect of insulin. A, Control (time recorded in seconds). B, Treatment with insulin (time recorded in minutes) . C, Ligation 2 hours 'after completion of thoracotomy and artery dissection (time recorded in minutes).
Table I. Survival after ligation of the circumflex artery* No. 0/ dogs Control Survival for I to 10 minutes Experimental Sur vival for 10 or more hours Survi val for 4 or more hours
6
6 6 4 2
Le gend: In the control animals, the artery was ligated 2 minutes aft er the thoracotomy. In the experimental animals, it was do ne 2 hours after the thoracotomy, .p < 0.005 bet ween the control and experimental dogs , as tested by contin gency analysis.
Fig. Z. Electrocardiographic changes following circumflex artery ligation 2 hours after thoracotom y. A , Short bursts of rapid ventricular tachy cardia. B, Profuse premature ventricular contractions that appear approximately 4 hours after ligat ion .
Results
Results are outlined in Table I. The 6 control animals , in which the artery was ligated 2 minutes after thoracotomy, rapidl y developed electrocardiographic changes of myocard ial ischemia and injury, numerous arrhythmias, and a ventricular tachycardia that terminated in ventricular fibrillation within 10 minutes (Fig. 1, A). The 6 ex-
perimental dogs, in which the artery was ligated 2 hours after thoracotomy, also developed the electrocardiographic changes of myocardial ischemia and injury, but ventricular arrhythmias were few-limited to some premature ventricular contractions and infrequent burst of ventricular tachycardia that subsided spontaneously in 2 to 3 seconds (Figs. 1, C, and 2, A). Four of the experimental dogs recovered completely from anesthesia and developed numerous premature ventricular contractions approximately 4 hours after ligation (Fig. 2, B); no treatment was given for the premature ventricular contractions, and, during the
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period of observation, no other ventricular arrhythmias were associated with these premature beats. All 4 animals were in good condition when last observed, approximately I 0 hours after ligation, but none survived until morning. Two of the experimental animals developed sudden ventricular fibrillation about 4 hours after ligation. This was soon after they were extubated, as they were awakening from anesthesia. Fibrillation quickly followed a short run of ventricular tachycardia. None of the dogs (control or experimental) had a significant change of serum IRI. In all of the dogs the circumflex artery was ligated within 5 mm. of its origin, proximal to any of its branches but distal to the septal artery. Hearts of control dogs (survived for I 0 minutes or less) were dilated but otherwise were grossly normal. Hearts of animals that survived longer (4 to I0 hours) had large infarcts on the posterior and lateral walls of the left ventricle that extended to the adjacent interventricular septum and posterior papillary muscle. The pathologic and electrocardiographic changes that follow occlusion of the circumflex artery at its origin are surprisingly uniform. They are to be described in detail in another report that will include an analysis of the differing R wave-premature contraction intervals in control and experimental animals. Discussion
In experimental ligation of a coronary artery it is usual to open the chest and ligate the vessel in one continuous operation. Our investigation shows that a 2 hour interval between completion of thoracotomy and ligation of the circumflex artery results in a marked diminution of postligation ventricular arrhythmias and a striking prolongation of survival-from 10 minutes or less in controls, to over 10 hours in four, and to over 4 hours in two, of the experimental dogs. In dogs ligated immediately after thoracotomy, treatment with insulin accomplishes the same result as the 2 hour interval between thoracotomy and ligation. Large doses of insulin prolong survival by suppressing
the ventricular arrhythmias that precede fatal ventricular fibrillation" (Fig. 1, B). The effect of the 2 hour interval between thoracotomy and ligation, i.e., the virtual elimination of postligation arrhythmias and prolongation of survival, does not involve insulin. Serum insulin is never elevated. We have been able to demonstrate similar suppression of ventricular arrhythmias and prolongation of survival in a few dogs subjected to pancreatectomy. Our results at this time are difficult to interpret. With studies of blood cyclic adenosine monophosphate and catecholamines, we are exploring the possibility that insulin and the post-thoracotomy interval both deactivate a mechanism that sensitizes the myocardium to postligation arrhythmias. For the present, by waiting for 2 hours after ligation, it is easy to prepare dogs for the study of late postligation arrhythmias (Fig. 2, B) and for use as models in studying the improvement of collateral circulation by surgical means. The circumflex is the largest and (to us) the most accessible of the coronary arteries in dogs. G Clinically, an interval after thoracotomy may lessen the incidence of ventricular arrhythmias in operations on the heart and its arteries. Summary In dogs the usually fatal result that follows ligation of the circumflex artery near its origin can be averted for up to I0 hours and more by a change of operative procedure. If the occluding ligatures are passed and tied 2 hours after completion of the thoracotomy and dissection of passage beneath the vessel, postligation ventricular arrhythmias are minimal and survival is prolonged more than twentyfold.
REFERENCES Fineberg, C., Foris, N., and Cam ishion, R. C.: Revascularization of the Dog Myocardium, Arch. Surg. 49: 762, 1962. 2 Goldfarb, D., Conti, C. R., Brown, B. G., and Gott, V. L.: Treatment of Severe Cardiogenic Shock by Diastolic Augmentation After Ligation and Division of Left Circumflex Artery in
286
Hiatt et al.
The Journol of Thorocic ond Cordiovosculor Surgery
Dogs, J. THORAC. CARDIOVASC. SURG. 51: 783, 1966. 3 Lumb, G., Shacklett, R. S., and Dawkins, W. A.: The Cardiac Conduction Tissue and Its Blood Supply in the Dog, Am. J. PathoJ. 35: 467, 1959. 4 Morgan, C. R., and Lazarow, A.: Immunoassay of Insulin: Two Antibody Systems. Plasma
Insulin Levels of Normal, Subdiabetic and Diabetic Rats, Diabetes 12: 115, 1963. 5 Hiatt, N., Sheinkopf, J. A., and Warner, N. E.: Prolongation of Survival After Circumflex Artery Ligation by Treatment With Massive Doses of Insulin, J. Cardiovasc. Res. 5: 48, 1971. 6 Moore, R. A.: The Coronary Arteries of the Dog, Am. Heart J. 5: 743, 1930.