Volume 70, Number 6 December 1975 The Journal of THORACIC AND CARDIOVASCULAR SURGERY Ischemic contracture of the left ventricle Production and prevention Ischemic contracture of the left ventricle ("stone heart") is a recognized complication of prolonged periods of interruption of the coronary circulation during open-heart surgery. We have examined the effects of moderate hypothermia (28 0 C.) and preoperative beta-adrenergic blockade (propranolol', 0.5 mg. per kilogram; 1.0 mg. per kilogram) on contracture development during ischemic arrest of the heart. Four groups of 8 dogs each were placed on total cardiopulmonary bypass, and ischemic arrest of the heart was produced by cross-clamping the ascending aorta and venting the left ventricle. Intramyocardial carbon dioxide tension was continuously monitored by mass spectrometry. When anaerobic energy production ceased, as indicated by a final plateau in the intramyocardial carbon dioxide accumulation curve, the ischemic arrest was terminated and the contractile state of the heart observed. These results are given in the text. We conclude that beta-adrenergic blockade delays, but does not prevent, the onset of ischemic contracture of the left ventricle under normothermic conditions. Moderate hypothermia appears to prevent this complication completely. David C. MacGregor, M.D. (by invitation), Gregory J. Wilson, M.Sc. (by invitation), Shigeo Tanaka, M.D. (by invitation), Donald E. Holness, Ph.D. (by invitation), Wolfgang Lixfeld, D.V.M. (by invitation), Malcolm D. Silver, M.D. (by invitation), Lorraine J. Rubis, M.D. (by invitation), William Goldstein, M.D. (by invitation), and John Gunstensen, M.B., Ch.B. (by invitation), Toronto, Ontario, Canada Sponsored by W. G. Bigelow, Toronto, Ontario, Canada From the Cardiovascular Laboratories, Banting Institute, University of Toronto, and the Defence and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada. Supported by the Ontario Heart Foundation Grants 1-29 and T 1-32. Read at the Fifty-fifth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y., April 14, IS, and 16, 1975. Ischemic contracture of the left ventricle ("stone heart"), which may occur following prolonged periods of ischemic arrest of the Address for reprints: Dr. D. C. MacGregor, Director, Cardiovascular Laboratories, Banting Institute, 100 College Street, Toronto, Ontario, Canada. 945
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Ischemic contracture of the left ventricleThe Journal of THORACIC AND
CARDIOVASCULAR SURGERY
Ischemic contracture of the left ventricle Production and prevention
Ischemic contracture of the left ventricle ("stone heart") is a recognized complication of prolonged periods of interruption of the coronary circulation during open-heart surgery. We have examined the effects of moderate hypothermia (28 0 C.) and preoperative beta-adrenergic blockade (propranolol', 0.5 mg. per kilogram; 1.0 mg. per kilogram) on contracture development during ischemic arrest of the heart. Four groups of 8 dogs each were placed on total cardiopulmonary bypass, and ischemic arrest of the heart was produced by cross-clamping the ascending aorta and venting the left ventricle. Intramyocardial carbon dioxide tension was continuously monitored by mass spectrometry. When anaerobic energy production ceased, as indicated by a final plateau in the intramyocardial carbon dioxide accumulation curve, the ischemic arrest was terminated and the contractile state of the heart observed. These results are given in the text. We conclude that beta-adrenergic blockade delays, but does not prevent, the onset of ischemic contracture of the left ventricle under normothermic conditions. Moderate hypothermia appears to prevent this complication completely.
David C. MacGregor, M.D. (by invitation), Gregory J. Wilson, M.Sc. (by invitation), Shigeo Tanaka, M.D. (by invitation), Donald E. Holness, Ph.D. (by invitation), Wolfgang Lixfeld, D.V.M. (by invitation), Malcolm D. Silver, M.D. (by invitation), Lorraine J. Rubis, M.D. (by invitation), William Goldstein, M.D. (by invitation), and John Gunstensen, M.B., Ch.B. (by invitation), Toronto, Ontario, Canada Sponsored by W. G. Bigelow, Toronto, Ontario, Canada
From the Cardiovascular Laboratories, Banting Institute, University of Toronto, and the Defence and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada.
Supported by the Ontario Heart Foundation Grants 1-29 and T 1-32.
Read at the Fifty-fifth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y., April 14, IS, and 16, 1975.
Ischemic contracture of the left ventricle ("stone heart"), which may occur following prolonged periods of ischemic arrest of the Address for reprints: Dr. D. C. MacGregor, Director,
Cardiovascular Laboratories, Banting Institute, 100 College Street, Toronto, Ontario, Canada.
945
Thorocic and Cardiovascular
Surgery
Fig. 1. A schematic diagram showing the components of the mass spectrometer. G, Entering gas. F, Ionizing filament. P, Plate (2,000 volts). S, Exit slit. M, Magnet. C, Collectors. E, Electrometers.
heart, is characterized by a firm, contracted left ventricle with virtual obliteration of the ventricular cavity and blanching of the deeper layers of the myocardium.': " When a surgeon faces the problem of a stone heart, either during or following cardiopul- monary bypass, he is usually unable to induce the left ventricle to beat despite prolonged bypass support or any pharma- cologic manipulation. Recently, hypothermia and beta-adrenergic receptor blockade have been advocated as possible means of either preventing or reversing this phenomenon.v 4
The development of myocardial rigor un- der conditions of ischemia has been attrib- uted to the anaerobic depletion of myocar- dial energy stores leading to a critical reduc- tion in adenosine triphosphate (ATP) con- centration which, in turn, produces strong linkages between actin and myosin fila- merits." The anaerobic generation of ATP in the nonperfused heart produces an ac- cumulation of carbon dioxide which can be measured by a mass spectrometer. Failure of anaerobic glycolysis at low ATP levels results in a cessation of carbon dioxide production. 6
In this study, we have utilized intramyo- cardial carbon dioxide tension (Pco.) mea- surements to evaluate the effects of moder-
ate hypothermia (28 0 C.) and beta-adrener- gic receptor blockade by propranolol on the development of ischemic contracture of the left ventricle precipitated by the failure of myocardial anaerobic metabolism.
Materials and methods
Measurement system. Intramyocardial Pco, was continuously monitored by means of a mass spectrometer (Medspect MSBR medical mass spectrometer*) adapted for tissue measurements by the use of a special sampling catheter. The catheter consists of a flexible stainless steel tube surrounded by a Teflon diffusion membrane (over-all diam- eter 1.39 mm.) as previously described." The distal end of the catheter is inserted to a depth of 2 to 4 mm. into the left ven- tricular myocardium midway between the base and apex of the heart and parallel to the left anterior descending coronary artery. The proximal end of the catheter enters the mass spectrometer and is connected to an ionization chamber which is maintained at a near vacuum (10-" mm. Hg). Gases dif- fuse through the Teflon membrane and enter the mass spectrometer through the stainless steel tube. The rate of flow for
'Scientific Research Instruments Corp., Baltimore, Md.
Volume 70
Number 6
December, 1975
U 0-
Ischemic contracture of left ventricle 9 4 7
PLATEAU (Aorta Unclamped)
I+--------ISCHEMIC ARREST ------::::::==,.,.,
o 10 20 30 40 50 60 70 80
Minutes Fig. 2. A typical intramyocardial carbon dioxide accumulation curve during ischemic arrest of the heart (dog No.5). Following aortic cross-clamping, there is an early acceleration in the anaerobic production of carbon dioxide followed by a period during which carbon dioxide accumulates at an essentially constant rate. This period is followed by a decline in the rate of rise of intramyocardial Pco, to zero, at which time the plateau of the carbon dioxide accumulation curve is reached. The aorta is then undamped, but only partial recovery of the intramyocardial Pea, takes place.
each gas is directly proportional to its par- tial pressure in the tissue surrounding the catheter tip. It is by means of the mass spectrometer that these flow rates, and therefore the corresponding partial pres- sures, are determined separately for each gas.
Fig. 1 is a schematic diagram which il- lustrates the principles of operation of the mass spectrometer. As the gas molecules ar- rive they are ionized by an intensely hot filament, and the electrical charge they gain allows them to be accelerated in an electro- static field. They leave the ionization cham- ber through a narrow slit at high velocity and their trajectories are altered as they pass through a constant magnetic field, the heavier ions having their trajectories altered less than the lighter ions. Each target elec- trode is appropriately placed to collect gas ions of a particular mass number (e.g., car-
bon dioxide at 44 daltons). The ions' charge is transferred to each target electrode, and the resulting current is proportional to the number of molecules of the particular gas entering the mass spectrometer per second and therefore the partial pressure of the gas in the myocardium.
During ischemic arrest of the heart there is an early acceleration in the anaerobic production of carbon dioxide followed by a period during which carbon dioxide ac- cumulates at an essentially constant rate. This period is followed by a decline in the rate of rise of intramyocardial Pco, to zero, at which time the plateau of the carbon dioxide accumulation curve is reached (Fig. 2).
Experimental protocol. Thirty-eight dogs, weighing between 19 and 35 kilograms, were placed on total cardiopulmonary by- pass for which a Ringer's lactate prime was
948 MacGregor et al.
used. Ischemic arrest of the heart was pro- duced by cross-clamping the ascending aorta and venting the left ventricle as previously described. G As a result of hemodilution, the mean hematocrit of the 38 dogs dropped from a control value of 42.1 ± 1.3 (mean ± S.E.M.) per cent prior to cardiopulmo- nary bypass to a final value of 23.4 ± 0.8 per cent at the end of the experiments. The left femoral artery was cannulated to moni- tor systemic blood pressure and to provide blood samples for the determination of pH, Paz, and Pco.. The electrocardiogram and both the intramyocardial and esophageal temperatures (Electric Universal thermom- eter Type TE-3) were continuously moni- tored. Intramyocardial Pco, was plotted as a continuous curve on a Hewlett-Packard X-Y recorder. The mass spectrometer was calibrated before and after each experiment with the use of a stirred, constant-tempera- ture (38° C.) water bath into which mix- tures of gases of known concentrations were bubbled.
After insertion of the sampling catheter of the mass spectrometer into the myocar- dium, total cardiopulmonary bypass was initiated and the intramyocardial Pco, was allowed to stabilize. A mean systemic pres- sure of 80 mm. Hg was maintained by ad- justing the pump flow, and the blood tem- perature was regulated to keep the intra- myocardial temperature absolutely constant at either 38° C. (normothermia) or 28° C. (moderate hypothermia) as required.
The following experiments were per- formed to determine the effects of beta- adrenergic blockade and moderate hypo- thermia on contracture development during ischemic arrest of the heart.
The first group of 8 dogs (Group I) was studied under normothermic conditions (38° C.) without propranolol (lnderal*) pretreatment. The second and third groups of 8 dogs each (Groups II and III) were also studied under normothermic conditions (38° C.), but they were pretreated with propranolol in doses of 0.5 mg. per kilo-
• Ayerst Laboratories, Montreal, Quebec, Canada.
The Journal of
Thoracic and Cardiovascular
Surgery
gram and 1.0 mg. per kilogram, respec- tively. The drug was administered intrave- nously in 250 ml. of normal saline over a 15 minute period beginning 30 minutes prior to the induction of ischemia. The fourth group of 8 dogs (Group IV) was studied under conditions of moderate hypothermia (28° C.) without propranolol pretreat- ment. In an additional group of 6 dogs (Group V), esophageal temperature was kept constant at 38° C., but no attempt was made to prevent the intramyocardial tem- perature from drifting toward the operating room temperature (21.7 ± 0.3 0 C.) during the ischemic period. Both anterior and pos- terior intramyocardial temperatures were monitored in this group.
After allowing the intra myocardial Pco, to reach a steady state, ischemic arrest of the heart was initiated by cross-clamping of the ascending aorta with venting of the left ventricle. In Groups I to IV inclusive, the intramyocardial temperature was main- tained at the desired level during the arrest period by partially closing the chest, cover- ing it was a plastic sheet, and making slight adjustments to the heat exchanger in the pump-oxygenator circuit.
In every experiment, the continuous rise of intramyocardial Pco, was followed on the X-Y recorder (Fig. 2). The ischemic ar- rest period was terminated by unclamping the ascending aorta at the point when there was no further rise in intramyocardial Pe0 2
(i.e., the plateau of the carbon dioxide ac- cumulation curve). The 8 dogs studied at 28° C. were rewarmed to 38° C. Appropri- ate corrections were made for all intramyo- cardial Pe02 values recorded under hypo- thermia, with consideration given to the temperature-dependent diffusion properties of the sampling catheter. Following reper- fusion of the coronary arteries, the contrac- tile state of the heart was observed while the intramyocardial Pco, was allowed to stabilize at a lower level. In the absence of ischemic contracture of the left ventricle, attempts were made to defibrillate the heart and to wean the dog from cardiopulmonary bypass.
Volume 70
Termination of arrest"
Temperature I 38° C. 38° C. 38° C. 28° C.
Propranolol
120.4 ± 5.5
474 ± 29 527 ± 38 455 ± 42 341 ± 26
Ischemic contracture
"Mean ± S.E.M.: Eight dogs in each group.
Following each experiment the heart was removed, sliced transversely midway be- tween base and apex, and examined for evi- dence of contracture development. The heart was then fixed in 10 per cent neutral formalin, and a full-thickness block of the posterior wall of the left ventricle, which included the base of the posterior papillary muscle, was embedded in paraffin. Sections were stained with hematoxylin and eosin, elastic trichrome, and alcian blue plus periodic acid-Schiff and were examined by light microscopy.
Results
The occurrence of ischemic contracture of the left ventricle under the various stated conditions (Groups I through IV) is sum- marized in Table I. Group V, in which the intramyocardial temperature was not con- trolled, will be considered separately.
In every experiment in which the intra- myocardial temperature was kept constant at 38° C. (Groups I, II, and III), severe left ventricular rigor was observed after the carbon dioxide accumulation curve had reached its plateau. With no propranolol pretreatment, the plateau was reached after only 54.4 ± 4.2 (mean ± S.E.M.) minutes of ischemia and corresponded to an intra- myocardial Pco, of 474.4 ± 29 mm. Hg. Propranolol pretreatment in doses of 0.5 and 1.0 mg. per kilogram delayed the onset of rigor to 79.6 ± 5.1 minutes and 76.6 ± 4.9 minutes, respectively, and the plateau corresponded to intramyocardial Pco, val- ues of 527 ± 38 mm. Hg and 455 ± 42 mm. Hg, respectively. Whereas the times re- quired for the onset of ischemic contracture did not differ with the two doses of pro-
pranolol (p > 0.05), both times were sig- nificantly longer than those of the untreated groups (p < 0.01).
In the dogs subjected to moderate, gen- eralized hypothermia (Group IV), left ven- tricular rigor was never observed following release of the aortic clamp. The time re- quired to reach the plateau of the carbon dioxide accumulation curve was significantly extended to 120.4 ± 5.5 minutes (p < 0.01), and the plateau corresponded to an intramyocardial Pco, of 341 ± 26 mm. Hg. Although all 8 hearts in this group could be defibrillated, none was capable of main- taining a normal blood pressure without the aid of supplementary drugs or bypass assistance. Similarly, in the 6 dogs in which the intramyocardial temperature was allowed to drift toward the operating room tempera- ture, left ventricular rigor was completely prevented and the plateau was delayed to 75.8 ± 10.3 minutes, corresponding to an intramyocardial Pco, of 465 ± 30 mm. Hg. Before the ascending aorta was cross- clamped in this group of dogs (esophageal temperature controlled at 38° G), both the anterior and posterior intramyocardial temperatures were measured at 37.8 ± 0.6 0
C. By the end of 1 hour of ischemic arrest, the anterior and posterior intramyocardial temperatures had drifted to and stabilized at 31.8 ± 0.7 0 C. and 32.5 ± 1.2° G, respec- tively, as illustrated in Fig. 3.
The mean initial intramyocardial Pco, of the normothermic hearts (Groups I, II, III, and V) was 80 ± 3 mm. Hg. The means of the initial intramyocardial Pco, values of these four individual groups of dogs have been compared by an analysis of variance, and no significant difference exists
9 5 0 MacGregor et al. The Journal of
Thoracic and Cardiovascular
~
~
E g E 32
Minutes
Fig. 3. Intramyocardial temperature drift during ischemic arrest of the heart. Values are mean ± S.E.M. for 6 dogs. Esophageal temperature was kept constant at 38 0 C., but no at- tempt was made to prevent intramyocardial temperature from drifting toward the operating room temperature (22 0 C.). Left ventricular rigor was completely prevented by this degree of myocardial cooling.
(p > 0.05). In the experiments in which ischemic contracture of the left ventricle was observed, there was only a partial re- covery in intramyocardial Pco, following restoration of the coronary circulation (Group I, 290 ± 46 mm. Hg; Group II, 266 ± 47 mm. Hg; Group III, 386 ± 67 mm. Hg). In contrast, the extent of recovery of intramyocardial Pco, was much greater in the absence of contracture development (Group IV, 111 ± 23 mm. Hg; Group V, 152 ± 33 mm. Hg).
On gross examination, the hearts which developed ischemic contracture were noted to have a left ventricle which was very firm to palpation and which did not beat or fibrillate after reperfusion of the coronary arteries. In most cases, the free wall of the right ventricle was not contracted. Weak, isolated right ventricular contractions could frequently be achieved by defibrilla- tion. A transverse section of the contracted heart, midway between its base and apex, revealed a markedly thickened left ventricu- lar wall with blanching of the deeper layers and virtual obliteration of the left ventricu- lar cavity (Fig. 4). The gross appearance
of the noncontracted hearts was essentially normal.
Thirty of the 38 hearts were available for histologic examination. Fifteen hearts showed no myocardial damage, 10 showed minimal changes characterized by focal coarsening of cross striations in the myo- cardial fibers and a slight condensation of cytoplasmic material into bands, and 5 showed moderate-to-severe changes charac- terized by additional focal areas of myofi- brillar degeneration of frank necrosis. Al- though not statistically significant, the degree of myocardial degeneration appeared to re- late more to the duration of ischemic arrest than to the development of a stone heart.
Discussion
Myocardial contracture, occurring after prolonged periods of ischemia, has received much attention both clinically and experi- mentally. In a large series of 4,732 patients, Cooley and associates! have reported a 0.3 per cent incidence of stone heart during open-heart surgery. A similar state of con- tracture was observed in normal canine hearts by Gott and associates? over a decade
Volume 70
Number 6
December, 1975
ago and was termed "myocardial rigor mortis." They monitored intramyocardial pressure in isolated canine hearts placed in a constant-temperature chamber at 37 0 C. and observed the onset of rigor after about 50 minutes of ischemia, the process being complete at about 80 minutes. Although intramyocardial pressure was not monitored in this study , marked left ventricular con- tracture was similarly present on gross ex- amination after 54 ± 4.2 minutes (range 37.5 to 70.0 minutes) of normothermic (38 0 C.) ischemia.
The development of myocardial rigor has been attributed to an interaction between the actin and myosin filaments resulting from low concentrations of ATP. I , 5 The inter- action between actin and myosin in all vertebrate muscle is regulated by two mus- cle proteins, troponin and tropomyosin, which are complexed together and bound to the actin filaments. In the absence of cal- cium ions, the troponin-tropomyosin com- plex blocks the interaction between actin and myosin and thus permits muscle relaxa- tion to occur. In contrast, in the presence of an adequate concentration of calcium ions, actin and myosin interact through the repeated forming and breaking of cross- bridges to produce contraction." However, relaxation cannnot occur when the concen- tration of ATP is very low. ATP is normally bound to myosin as a chelate with the diva- lent ion magnesium to form magnesium- ATP complexes. Regardless of the presence or absence of calcium ions, when the con- centration of magnesium-ATP falls below a critical level, tension is developed. " 1 0 The troponin-tropomyosin complex is capable of preventing the interaction between actin and myosin in the special conformational state adopted by myosin-magnesium-ATP. However, when myosin is free of mag- nesium-ATP, interaction with actin can no longer be blocked by troponin-tropornyosin. Bonds known as "rigor complexes" develop , and contracture takes place. The forma- tion of these "rigor complexes" is inde- pendent of calcium ion concentration. Weber
Ischemic contracture of left ventricle 9 5 1
Fig. 4. Ischemic contracture of the left ventricle (stone heart). Note the markedly thickened left ventricular wall with blanching of the deeper lay- ers and virtual obliteration of the left ventricular cavity.
and Murray have recently provided de- tailed accounts of this phenomenon.v- 1 2
An alternative mechanism for the devel- opment of the stone heart has been con- sidered by Wukasch and associates." They suggest that calcium may become bound to the regulator proteins (troponin-tropomyo- sin) under conditions of intracellular alka- losis to produce a calcium-activated con- tracture. However, to postulate a calcium- dependent mechanism for rigor development following prolonged ischemia is unnecessary when rigor complexes can form in the ab- sence of calcium. Moreover, during pro- longed ischemia, intracellular hydrogen ion concentration increases and a condition of intracellular acidosis develops .
Intracellular acidosis results from the ac- cumulation…
CARDIOVASCULAR SURGERY
Ischemic contracture of the left ventricle Production and prevention
Ischemic contracture of the left ventricle ("stone heart") is a recognized complication of prolonged periods of interruption of the coronary circulation during open-heart surgery. We have examined the effects of moderate hypothermia (28 0 C.) and preoperative beta-adrenergic blockade (propranolol', 0.5 mg. per kilogram; 1.0 mg. per kilogram) on contracture development during ischemic arrest of the heart. Four groups of 8 dogs each were placed on total cardiopulmonary bypass, and ischemic arrest of the heart was produced by cross-clamping the ascending aorta and venting the left ventricle. Intramyocardial carbon dioxide tension was continuously monitored by mass spectrometry. When anaerobic energy production ceased, as indicated by a final plateau in the intramyocardial carbon dioxide accumulation curve, the ischemic arrest was terminated and the contractile state of the heart observed. These results are given in the text. We conclude that beta-adrenergic blockade delays, but does not prevent, the onset of ischemic contracture of the left ventricle under normothermic conditions. Moderate hypothermia appears to prevent this complication completely.
David C. MacGregor, M.D. (by invitation), Gregory J. Wilson, M.Sc. (by invitation), Shigeo Tanaka, M.D. (by invitation), Donald E. Holness, Ph.D. (by invitation), Wolfgang Lixfeld, D.V.M. (by invitation), Malcolm D. Silver, M.D. (by invitation), Lorraine J. Rubis, M.D. (by invitation), William Goldstein, M.D. (by invitation), and John Gunstensen, M.B., Ch.B. (by invitation), Toronto, Ontario, Canada Sponsored by W. G. Bigelow, Toronto, Ontario, Canada
From the Cardiovascular Laboratories, Banting Institute, University of Toronto, and the Defence and Civil Institute of Environmental Medicine, Toronto, Ontario, Canada.
Supported by the Ontario Heart Foundation Grants 1-29 and T 1-32.
Read at the Fifty-fifth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y., April 14, IS, and 16, 1975.
Ischemic contracture of the left ventricle ("stone heart"), which may occur following prolonged periods of ischemic arrest of the Address for reprints: Dr. D. C. MacGregor, Director,
Cardiovascular Laboratories, Banting Institute, 100 College Street, Toronto, Ontario, Canada.
945
Thorocic and Cardiovascular
Surgery
Fig. 1. A schematic diagram showing the components of the mass spectrometer. G, Entering gas. F, Ionizing filament. P, Plate (2,000 volts). S, Exit slit. M, Magnet. C, Collectors. E, Electrometers.
heart, is characterized by a firm, contracted left ventricle with virtual obliteration of the ventricular cavity and blanching of the deeper layers of the myocardium.': " When a surgeon faces the problem of a stone heart, either during or following cardiopul- monary bypass, he is usually unable to induce the left ventricle to beat despite prolonged bypass support or any pharma- cologic manipulation. Recently, hypothermia and beta-adrenergic receptor blockade have been advocated as possible means of either preventing or reversing this phenomenon.v 4
The development of myocardial rigor un- der conditions of ischemia has been attrib- uted to the anaerobic depletion of myocar- dial energy stores leading to a critical reduc- tion in adenosine triphosphate (ATP) con- centration which, in turn, produces strong linkages between actin and myosin fila- merits." The anaerobic generation of ATP in the nonperfused heart produces an ac- cumulation of carbon dioxide which can be measured by a mass spectrometer. Failure of anaerobic glycolysis at low ATP levels results in a cessation of carbon dioxide production. 6
In this study, we have utilized intramyo- cardial carbon dioxide tension (Pco.) mea- surements to evaluate the effects of moder-
ate hypothermia (28 0 C.) and beta-adrener- gic receptor blockade by propranolol on the development of ischemic contracture of the left ventricle precipitated by the failure of myocardial anaerobic metabolism.
Materials and methods
Measurement system. Intramyocardial Pco, was continuously monitored by means of a mass spectrometer (Medspect MSBR medical mass spectrometer*) adapted for tissue measurements by the use of a special sampling catheter. The catheter consists of a flexible stainless steel tube surrounded by a Teflon diffusion membrane (over-all diam- eter 1.39 mm.) as previously described." The distal end of the catheter is inserted to a depth of 2 to 4 mm. into the left ven- tricular myocardium midway between the base and apex of the heart and parallel to the left anterior descending coronary artery. The proximal end of the catheter enters the mass spectrometer and is connected to an ionization chamber which is maintained at a near vacuum (10-" mm. Hg). Gases dif- fuse through the Teflon membrane and enter the mass spectrometer through the stainless steel tube. The rate of flow for
'Scientific Research Instruments Corp., Baltimore, Md.
Volume 70
Number 6
December, 1975
U 0-
Ischemic contracture of left ventricle 9 4 7
PLATEAU (Aorta Unclamped)
I+--------ISCHEMIC ARREST ------::::::==,.,.,
o 10 20 30 40 50 60 70 80
Minutes Fig. 2. A typical intramyocardial carbon dioxide accumulation curve during ischemic arrest of the heart (dog No.5). Following aortic cross-clamping, there is an early acceleration in the anaerobic production of carbon dioxide followed by a period during which carbon dioxide accumulates at an essentially constant rate. This period is followed by a decline in the rate of rise of intramyocardial Pco, to zero, at which time the plateau of the carbon dioxide accumulation curve is reached. The aorta is then undamped, but only partial recovery of the intramyocardial Pea, takes place.
each gas is directly proportional to its par- tial pressure in the tissue surrounding the catheter tip. It is by means of the mass spectrometer that these flow rates, and therefore the corresponding partial pres- sures, are determined separately for each gas.
Fig. 1 is a schematic diagram which il- lustrates the principles of operation of the mass spectrometer. As the gas molecules ar- rive they are ionized by an intensely hot filament, and the electrical charge they gain allows them to be accelerated in an electro- static field. They leave the ionization cham- ber through a narrow slit at high velocity and their trajectories are altered as they pass through a constant magnetic field, the heavier ions having their trajectories altered less than the lighter ions. Each target elec- trode is appropriately placed to collect gas ions of a particular mass number (e.g., car-
bon dioxide at 44 daltons). The ions' charge is transferred to each target electrode, and the resulting current is proportional to the number of molecules of the particular gas entering the mass spectrometer per second and therefore the partial pressure of the gas in the myocardium.
During ischemic arrest of the heart there is an early acceleration in the anaerobic production of carbon dioxide followed by a period during which carbon dioxide ac- cumulates at an essentially constant rate. This period is followed by a decline in the rate of rise of intramyocardial Pco, to zero, at which time the plateau of the carbon dioxide accumulation curve is reached (Fig. 2).
Experimental protocol. Thirty-eight dogs, weighing between 19 and 35 kilograms, were placed on total cardiopulmonary by- pass for which a Ringer's lactate prime was
948 MacGregor et al.
used. Ischemic arrest of the heart was pro- duced by cross-clamping the ascending aorta and venting the left ventricle as previously described. G As a result of hemodilution, the mean hematocrit of the 38 dogs dropped from a control value of 42.1 ± 1.3 (mean ± S.E.M.) per cent prior to cardiopulmo- nary bypass to a final value of 23.4 ± 0.8 per cent at the end of the experiments. The left femoral artery was cannulated to moni- tor systemic blood pressure and to provide blood samples for the determination of pH, Paz, and Pco.. The electrocardiogram and both the intramyocardial and esophageal temperatures (Electric Universal thermom- eter Type TE-3) were continuously moni- tored. Intramyocardial Pco, was plotted as a continuous curve on a Hewlett-Packard X-Y recorder. The mass spectrometer was calibrated before and after each experiment with the use of a stirred, constant-tempera- ture (38° C.) water bath into which mix- tures of gases of known concentrations were bubbled.
After insertion of the sampling catheter of the mass spectrometer into the myocar- dium, total cardiopulmonary bypass was initiated and the intramyocardial Pco, was allowed to stabilize. A mean systemic pres- sure of 80 mm. Hg was maintained by ad- justing the pump flow, and the blood tem- perature was regulated to keep the intra- myocardial temperature absolutely constant at either 38° C. (normothermia) or 28° C. (moderate hypothermia) as required.
The following experiments were per- formed to determine the effects of beta- adrenergic blockade and moderate hypo- thermia on contracture development during ischemic arrest of the heart.
The first group of 8 dogs (Group I) was studied under normothermic conditions (38° C.) without propranolol (lnderal*) pretreatment. The second and third groups of 8 dogs each (Groups II and III) were also studied under normothermic conditions (38° C.), but they were pretreated with propranolol in doses of 0.5 mg. per kilo-
• Ayerst Laboratories, Montreal, Quebec, Canada.
The Journal of
Thoracic and Cardiovascular
Surgery
gram and 1.0 mg. per kilogram, respec- tively. The drug was administered intrave- nously in 250 ml. of normal saline over a 15 minute period beginning 30 minutes prior to the induction of ischemia. The fourth group of 8 dogs (Group IV) was studied under conditions of moderate hypothermia (28° C.) without propranolol pretreat- ment. In an additional group of 6 dogs (Group V), esophageal temperature was kept constant at 38° C., but no attempt was made to prevent the intramyocardial tem- perature from drifting toward the operating room temperature (21.7 ± 0.3 0 C.) during the ischemic period. Both anterior and pos- terior intramyocardial temperatures were monitored in this group.
After allowing the intra myocardial Pco, to reach a steady state, ischemic arrest of the heart was initiated by cross-clamping of the ascending aorta with venting of the left ventricle. In Groups I to IV inclusive, the intramyocardial temperature was main- tained at the desired level during the arrest period by partially closing the chest, cover- ing it was a plastic sheet, and making slight adjustments to the heat exchanger in the pump-oxygenator circuit.
In every experiment, the continuous rise of intramyocardial Pco, was followed on the X-Y recorder (Fig. 2). The ischemic ar- rest period was terminated by unclamping the ascending aorta at the point when there was no further rise in intramyocardial Pe0 2
(i.e., the plateau of the carbon dioxide ac- cumulation curve). The 8 dogs studied at 28° C. were rewarmed to 38° C. Appropri- ate corrections were made for all intramyo- cardial Pe02 values recorded under hypo- thermia, with consideration given to the temperature-dependent diffusion properties of the sampling catheter. Following reper- fusion of the coronary arteries, the contrac- tile state of the heart was observed while the intramyocardial Pco, was allowed to stabilize at a lower level. In the absence of ischemic contracture of the left ventricle, attempts were made to defibrillate the heart and to wean the dog from cardiopulmonary bypass.
Volume 70
Termination of arrest"
Temperature I 38° C. 38° C. 38° C. 28° C.
Propranolol
120.4 ± 5.5
474 ± 29 527 ± 38 455 ± 42 341 ± 26
Ischemic contracture
"Mean ± S.E.M.: Eight dogs in each group.
Following each experiment the heart was removed, sliced transversely midway be- tween base and apex, and examined for evi- dence of contracture development. The heart was then fixed in 10 per cent neutral formalin, and a full-thickness block of the posterior wall of the left ventricle, which included the base of the posterior papillary muscle, was embedded in paraffin. Sections were stained with hematoxylin and eosin, elastic trichrome, and alcian blue plus periodic acid-Schiff and were examined by light microscopy.
Results
The occurrence of ischemic contracture of the left ventricle under the various stated conditions (Groups I through IV) is sum- marized in Table I. Group V, in which the intramyocardial temperature was not con- trolled, will be considered separately.
In every experiment in which the intra- myocardial temperature was kept constant at 38° C. (Groups I, II, and III), severe left ventricular rigor was observed after the carbon dioxide accumulation curve had reached its plateau. With no propranolol pretreatment, the plateau was reached after only 54.4 ± 4.2 (mean ± S.E.M.) minutes of ischemia and corresponded to an intra- myocardial Pco, of 474.4 ± 29 mm. Hg. Propranolol pretreatment in doses of 0.5 and 1.0 mg. per kilogram delayed the onset of rigor to 79.6 ± 5.1 minutes and 76.6 ± 4.9 minutes, respectively, and the plateau corresponded to intramyocardial Pco, val- ues of 527 ± 38 mm. Hg and 455 ± 42 mm. Hg, respectively. Whereas the times re- quired for the onset of ischemic contracture did not differ with the two doses of pro-
pranolol (p > 0.05), both times were sig- nificantly longer than those of the untreated groups (p < 0.01).
In the dogs subjected to moderate, gen- eralized hypothermia (Group IV), left ven- tricular rigor was never observed following release of the aortic clamp. The time re- quired to reach the plateau of the carbon dioxide accumulation curve was significantly extended to 120.4 ± 5.5 minutes (p < 0.01), and the plateau corresponded to an intramyocardial Pco, of 341 ± 26 mm. Hg. Although all 8 hearts in this group could be defibrillated, none was capable of main- taining a normal blood pressure without the aid of supplementary drugs or bypass assistance. Similarly, in the 6 dogs in which the intramyocardial temperature was allowed to drift toward the operating room tempera- ture, left ventricular rigor was completely prevented and the plateau was delayed to 75.8 ± 10.3 minutes, corresponding to an intramyocardial Pco, of 465 ± 30 mm. Hg. Before the ascending aorta was cross- clamped in this group of dogs (esophageal temperature controlled at 38° G), both the anterior and posterior intramyocardial temperatures were measured at 37.8 ± 0.6 0
C. By the end of 1 hour of ischemic arrest, the anterior and posterior intramyocardial temperatures had drifted to and stabilized at 31.8 ± 0.7 0 C. and 32.5 ± 1.2° G, respec- tively, as illustrated in Fig. 3.
The mean initial intramyocardial Pco, of the normothermic hearts (Groups I, II, III, and V) was 80 ± 3 mm. Hg. The means of the initial intramyocardial Pco, values of these four individual groups of dogs have been compared by an analysis of variance, and no significant difference exists
9 5 0 MacGregor et al. The Journal of
Thoracic and Cardiovascular
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Minutes
Fig. 3. Intramyocardial temperature drift during ischemic arrest of the heart. Values are mean ± S.E.M. for 6 dogs. Esophageal temperature was kept constant at 38 0 C., but no at- tempt was made to prevent intramyocardial temperature from drifting toward the operating room temperature (22 0 C.). Left ventricular rigor was completely prevented by this degree of myocardial cooling.
(p > 0.05). In the experiments in which ischemic contracture of the left ventricle was observed, there was only a partial re- covery in intramyocardial Pco, following restoration of the coronary circulation (Group I, 290 ± 46 mm. Hg; Group II, 266 ± 47 mm. Hg; Group III, 386 ± 67 mm. Hg). In contrast, the extent of recovery of intramyocardial Pco, was much greater in the absence of contracture development (Group IV, 111 ± 23 mm. Hg; Group V, 152 ± 33 mm. Hg).
On gross examination, the hearts which developed ischemic contracture were noted to have a left ventricle which was very firm to palpation and which did not beat or fibrillate after reperfusion of the coronary arteries. In most cases, the free wall of the right ventricle was not contracted. Weak, isolated right ventricular contractions could frequently be achieved by defibrilla- tion. A transverse section of the contracted heart, midway between its base and apex, revealed a markedly thickened left ventricu- lar wall with blanching of the deeper layers and virtual obliteration of the left ventricu- lar cavity (Fig. 4). The gross appearance
of the noncontracted hearts was essentially normal.
Thirty of the 38 hearts were available for histologic examination. Fifteen hearts showed no myocardial damage, 10 showed minimal changes characterized by focal coarsening of cross striations in the myo- cardial fibers and a slight condensation of cytoplasmic material into bands, and 5 showed moderate-to-severe changes charac- terized by additional focal areas of myofi- brillar degeneration of frank necrosis. Al- though not statistically significant, the degree of myocardial degeneration appeared to re- late more to the duration of ischemic arrest than to the development of a stone heart.
Discussion
Myocardial contracture, occurring after prolonged periods of ischemia, has received much attention both clinically and experi- mentally. In a large series of 4,732 patients, Cooley and associates! have reported a 0.3 per cent incidence of stone heart during open-heart surgery. A similar state of con- tracture was observed in normal canine hearts by Gott and associates? over a decade
Volume 70
Number 6
December, 1975
ago and was termed "myocardial rigor mortis." They monitored intramyocardial pressure in isolated canine hearts placed in a constant-temperature chamber at 37 0 C. and observed the onset of rigor after about 50 minutes of ischemia, the process being complete at about 80 minutes. Although intramyocardial pressure was not monitored in this study , marked left ventricular con- tracture was similarly present on gross ex- amination after 54 ± 4.2 minutes (range 37.5 to 70.0 minutes) of normothermic (38 0 C.) ischemia.
The development of myocardial rigor has been attributed to an interaction between the actin and myosin filaments resulting from low concentrations of ATP. I , 5 The inter- action between actin and myosin in all vertebrate muscle is regulated by two mus- cle proteins, troponin and tropomyosin, which are complexed together and bound to the actin filaments. In the absence of cal- cium ions, the troponin-tropomyosin com- plex blocks the interaction between actin and myosin and thus permits muscle relaxa- tion to occur. In contrast, in the presence of an adequate concentration of calcium ions, actin and myosin interact through the repeated forming and breaking of cross- bridges to produce contraction." However, relaxation cannnot occur when the concen- tration of ATP is very low. ATP is normally bound to myosin as a chelate with the diva- lent ion magnesium to form magnesium- ATP complexes. Regardless of the presence or absence of calcium ions, when the con- centration of magnesium-ATP falls below a critical level, tension is developed. " 1 0 The troponin-tropomyosin complex is capable of preventing the interaction between actin and myosin in the special conformational state adopted by myosin-magnesium-ATP. However, when myosin is free of mag- nesium-ATP, interaction with actin can no longer be blocked by troponin-tropornyosin. Bonds known as "rigor complexes" develop , and contracture takes place. The forma- tion of these "rigor complexes" is inde- pendent of calcium ion concentration. Weber
Ischemic contracture of left ventricle 9 5 1
Fig. 4. Ischemic contracture of the left ventricle (stone heart). Note the markedly thickened left ventricular wall with blanching of the deeper lay- ers and virtual obliteration of the left ventricular cavity.
and Murray have recently provided de- tailed accounts of this phenomenon.v- 1 2
An alternative mechanism for the devel- opment of the stone heart has been con- sidered by Wukasch and associates." They suggest that calcium may become bound to the regulator proteins (troponin-tropomyo- sin) under conditions of intracellular alka- losis to produce a calcium-activated con- tracture. However, to postulate a calcium- dependent mechanism for rigor development following prolonged ischemia is unnecessary when rigor complexes can form in the ab- sence of calcium. Moreover, during pro- longed ischemia, intracellular hydrogen ion concentration increases and a condition of intracellular acidosis develops .
Intracellular acidosis results from the ac- cumulation…
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