Cardiovascular Research, 1975,9, 468-472.
~
Ventricular fibrillation threshold in acute myocardial infarction and its relation to myocardial infarct size' COLIN M . BLOOR, ALI EHSANI, FRANCIS
c.
WHITE,
and
BURTON E .
SOB EL^
From the Departments of Pathology and Medicine, University of California at San Diego, School of Medicine, La Jolla, California 92037, USA
on ventricular fibrillation threshold (VFT) was evaluated by determining changes in VFT during acute myocardial infarction and relating those changes to infarct size. Infarct size was estimated from gross measurement and from serial changes in serum CPK activity in 25 dogs. VFT reduction correlated well with gross infarct size (r=0.92). This suggests that the severity of electrical instability during AM1 is related to the size of the developing infarct, and that appropriate therapeutic interventions to reduce infarct size during this time may also render the heart more electrically stable.
AUTHORS' SYNOPSIS The effect of myocardial infarct size
This study was supported in part by National Heart and Lung Institute Research Contract Award No. 1-HL81332 and the San Diego County Heart Association. Reprint requests to C.M.B.. Department of Pathology, UCSD School of Medicine. La Jolla, California 92037, USA. a Present address: Cardiovascular Division, Department of Medicine, Barnes and Who1 Hospitals, 660 South Euclid Avenue, St Louis, Missouri 631 10, USA.
1
infarcts occur in individuals with well-developed collaterals, a smaller reduction in VFT and an increase in survival might be expected. The findings of Meesmann et al(l970) support this view. They found that in animals with welldeveloped collaterals mortality after coronary occlusion was lower. While they presumed death was due to ventricular fibrillation, they did not determine fibrillation threshold. If infarct size does influence VFT, this relationship needs definition, since several therapeutic interventions have been shown to alter infarct size (Maroko et al, 1971). Since techniques are available for assessing the vulnerability of the myocardium to fibrillation (Wiggers eta,, 1940; Han et al, 1967; Burgess et al, 1971; Kent et al, 1973), and for determining infarct size (Shell et al, 1971; Alonso et al, 1973), we determined ventricular fibrillation threshold in experimental animals before and at various times after coronary occlusion and correlated these findings with the resulting infarct size. Our results show that large infarcts result in a greater reduction of VFT. Thus, appropriate interventions to reduce infarct
Downloaded from by guest on March 22, 2016
Ventricular fibrillation causes significant mortality in the early stages of acute myocardial infarction. In part this is due to the reduction of ventricular fibrillation threshold (VFT) that follows the onset of myocardial ischaemia (Wiggers et al, 1940; Han et al, 1967; Han, 1969; Burgess et al, 1971). However, other factors can also influence this threshold. These changes in heart rate and vagal stimulation (Kent et al, 1973), metabolic acidosis and alkalosis (Gerst et al, 1966), antiarrhythmic drugs (Vanremoortere and Wauters, 1968; Allen et al, 1971;Spear et al, 1972), adrenergic effects (Han et al, 1964), and the extent of development of the coronary collateral circulation (Garza et al, 1974). The relation between VFT and the extent of development of the coronary collateral circulation is of particular interest, for if smaller
469 Fibrillation threshold and infarct size size may decrease the vulnerability of the myocardium to ventricular fibrillation after coronary occlusion and render the heart electrically more stable.
Methods
VFT determination VFT was determined by the following techniques. A lead I1 EKG signal was monitored on a Tektronix storage oscilloscope and fed into an electronic triggering device. This trigger was a voltage comparator set to trigger off the QRS complex and t o send a 25-V pulse to a Grass S-88 stimulator. The stimulator incorporated a train duration of 350 ms with a 100 ms delay after the rise of the QRS triggering signal. This placed the beginning of the stimulation within the vulnerable period of the cardiac cycle. It may also have extended the stimulation into the vulnerable period of any premature beat which was generated. We may therefore have obtained VFT for premature beats, a situation comparable t o that of acute myocardial infarction and not incompatable with our research aim. We were able to obtain repeatable control values with this technique. Pulse frequency was 100 Hz and pulse duration was 1 ms, biphasic. This output from the stimulator was led into the gate of a Nuclear Chicago stimulator which yielded a final biphasic output with a constant amperage capability of 0 to 11 mA. The biphasic pulse eliminated polarization of the electrodes, assuring us that the discharge was only that intended and not an
Myocardial infarct size determination Myocardial infarct size was determined by two independent methods; gross measurement and serial serum creatine phosphokinase (CPK) assays (Shell et a / , 1971). Gross measurement of myocardial infarct size was accomplished on hearts obtained at necropsy as follows. After weighing the hearts the crux of the heart was identified and a cut made 2 cm below the crux, parallel to the atrio-
Downloaded from by guest on March 22, 2016
Animal preparation Experiments were performed on 25 mongrel dogs of either sex weighing 20 to 27 kg. The animals were anaesthetized with sodium pentobarbital (25 mg/ kg, intravenously) and maintained on a Harvard positive pressure respirator. We performed a left thoracotomy at the fifth intercostal space and suspended the heart in a pericardial cradle to expose its anterior surface. We attached bipolar, copper hook stimulating electrodes 2 mm apart to the left ventricle to a depth of 2 mm and well outside that region of the left ventricle that became ischaemic during the experimental coronary artery occlusions. A pacing electrode was attached to the right ventricle 2 cm below the origin of the pulmonary artery. Other electrodes were attached to the legs to obtain a lead 11 of a n electrocardiogram (ECG) to use for monitoring and triggering the stimulator. We implanted a catheter in the femoral artery to monitor blood pressure and to obtain blood samples for pOz, pCO2, and p H determinations using an IL blood gas analyser.
accumulated charge of unknown intensity. The bipolar electrode preparation allowed us to define the area receiving stimulation, since a pair of electrodes near each other, floating with respect to ground, and in a conducting medium confine current flow to a small area around and between the electrodes. In this way we limited stimulation to the non-ischaemic area of the myocardium. The heart was paced at 160 beats/min. Initial stimulation was 1 mA for each of three beats every 10 to 15 beats. If fibrillation did not occur, the amperage was increased in increments of approximately 0.33 mA, followed by stimulation, until an amperage was reached which induced fibrillation. This amperage was the VFT. The animal was immediately defibrillated with direct current electric shocks of 10 to 20 W-s, and 10 to 15 min were allowed to elapse before the next VFT determination. In this interval blood p02, pCOz, and pH were determined and blood pH was adjusted, when necessary, by administering sodium bicarbonate to maintain a pH of 7.35 to 7.45. VFTs were considered valid if pH was within this range and if mean aortic blood pressure was between 10.6 to 17.3 kPa (80 to 130 mm Hg). When three control VFTs within 0.5 mA of each other were obtained, we dissected the proximal 3 cm of the left anterior descending coronary artery (LAD) free from the epicardial surface, and placed a pneumatic occlusive latex cuff on it (Sham et a/, 1970), and determined VFT after 10 to 15 min of occlusion. No spontaneous fibrillation occurred during these occlusions. The train duration of 350 ms was similar to that used by Burgess et al (1971) and Han (1969). Bipolar, DC, rectangular pulses have been used by a number of investigators (Brooks et al, 1960; Gerst et al, 1966; Han, 1969). Bipolar stimulation provides more reliable data than monopolar or other types (Brooks et a / , 1960). Since the train duration extended into the vulnerable period of premature beats, elicited by stimulation, it is likely that the VFTs are those of these premature-beat situations as noted above. The values of our VFTs were in the range of 2-10 mA, similar to those reported by Han (1969) and Burgess et al(1971) in stimulations of similar train duration.
470 Bloor, Ehsani, White, and Sobel ventricular groove. The remaining ventricular portion was cut at 2-cm intervals into parallel coronal slices. Using tracing tissue overlays the individual coronal slices were outlined and the zones of necrosis outlined. The cross-sectional areas of the coronal slices and the infarcts were measured by planimetry. The percentage of left ventricular mass involved by the infarct was calculated from these values and expressed as g/tissue. We used the method of Shell et a1 (1971) to estimate myocardial infarct size from serial CPK assays. Baseline blood samples were drawn before coronary occlusion. Additional samples were drawn at 60- to 120-min intervals during coronary occlusion for serial CPK determinations. Myocardial infarct size (in g-Eq) was then estimated using appropriate equations (Shell et al, 1971).
b
--
% 4
t > 2
0 Thoracotomy No2
Ventricular fibrillation threshold (VFT) before (open columns) and 15 min afrer (hatched columns) coronary occlusion during each of two thoracotomies performed 10 days apart (group A ) . Bar height = mean values (mA). Vertical lines are standard errors of the mean. FIG. I
Experimental design
The experimental studies were conducted in the following two groups.
-j
Results In the 14 dogs in which ventricular fibrillation threshold (VFT) was determined before and after 15 rnin of coronary occlusion, during each of two thoracotomies performed 10 days apart (group A), the preocclusive VFTs averaged 5.9 f0.4 (SEM)and 6.0 f0.6 mA, respectively (Fig. 1). These were similar to other control VFT
Ventricular fibrillation thresholds (VFT) before, 15 min, and 24 h after coronary occlusion (group B). Bar height = mean value of VFT (mA) Vertical lines are standard errors of the mean. FIO, 2
Downloaded from by guest on March 22, 2016
values obtained in this laboratory (Garza et al, 1974). After 15 rnin of coronary occlusion VFT decreased 29% from control to 4.2f0.6 mA Group A VFTs were determined in 14 dogs before and after (P
~
Ventricular fibrillation threshold in acute myocardial infarction and its relation to myocardial infarct size' COLIN M . BLOOR, ALI EHSANI, FRANCIS
c.
WHITE,
and
BURTON E .
SOB EL^
From the Departments of Pathology and Medicine, University of California at San Diego, School of Medicine, La Jolla, California 92037, USA
on ventricular fibrillation threshold (VFT) was evaluated by determining changes in VFT during acute myocardial infarction and relating those changes to infarct size. Infarct size was estimated from gross measurement and from serial changes in serum CPK activity in 25 dogs. VFT reduction correlated well with gross infarct size (r=0.92). This suggests that the severity of electrical instability during AM1 is related to the size of the developing infarct, and that appropriate therapeutic interventions to reduce infarct size during this time may also render the heart more electrically stable.
AUTHORS' SYNOPSIS The effect of myocardial infarct size
This study was supported in part by National Heart and Lung Institute Research Contract Award No. 1-HL81332 and the San Diego County Heart Association. Reprint requests to C.M.B.. Department of Pathology, UCSD School of Medicine. La Jolla, California 92037, USA. a Present address: Cardiovascular Division, Department of Medicine, Barnes and Who1 Hospitals, 660 South Euclid Avenue, St Louis, Missouri 631 10, USA.
1
infarcts occur in individuals with well-developed collaterals, a smaller reduction in VFT and an increase in survival might be expected. The findings of Meesmann et al(l970) support this view. They found that in animals with welldeveloped collaterals mortality after coronary occlusion was lower. While they presumed death was due to ventricular fibrillation, they did not determine fibrillation threshold. If infarct size does influence VFT, this relationship needs definition, since several therapeutic interventions have been shown to alter infarct size (Maroko et al, 1971). Since techniques are available for assessing the vulnerability of the myocardium to fibrillation (Wiggers eta,, 1940; Han et al, 1967; Burgess et al, 1971; Kent et al, 1973), and for determining infarct size (Shell et al, 1971; Alonso et al, 1973), we determined ventricular fibrillation threshold in experimental animals before and at various times after coronary occlusion and correlated these findings with the resulting infarct size. Our results show that large infarcts result in a greater reduction of VFT. Thus, appropriate interventions to reduce infarct
Downloaded from by guest on March 22, 2016
Ventricular fibrillation causes significant mortality in the early stages of acute myocardial infarction. In part this is due to the reduction of ventricular fibrillation threshold (VFT) that follows the onset of myocardial ischaemia (Wiggers et al, 1940; Han et al, 1967; Han, 1969; Burgess et al, 1971). However, other factors can also influence this threshold. These changes in heart rate and vagal stimulation (Kent et al, 1973), metabolic acidosis and alkalosis (Gerst et al, 1966), antiarrhythmic drugs (Vanremoortere and Wauters, 1968; Allen et al, 1971;Spear et al, 1972), adrenergic effects (Han et al, 1964), and the extent of development of the coronary collateral circulation (Garza et al, 1974). The relation between VFT and the extent of development of the coronary collateral circulation is of particular interest, for if smaller
469 Fibrillation threshold and infarct size size may decrease the vulnerability of the myocardium to ventricular fibrillation after coronary occlusion and render the heart electrically more stable.
Methods
VFT determination VFT was determined by the following techniques. A lead I1 EKG signal was monitored on a Tektronix storage oscilloscope and fed into an electronic triggering device. This trigger was a voltage comparator set to trigger off the QRS complex and t o send a 25-V pulse to a Grass S-88 stimulator. The stimulator incorporated a train duration of 350 ms with a 100 ms delay after the rise of the QRS triggering signal. This placed the beginning of the stimulation within the vulnerable period of the cardiac cycle. It may also have extended the stimulation into the vulnerable period of any premature beat which was generated. We may therefore have obtained VFT for premature beats, a situation comparable t o that of acute myocardial infarction and not incompatable with our research aim. We were able to obtain repeatable control values with this technique. Pulse frequency was 100 Hz and pulse duration was 1 ms, biphasic. This output from the stimulator was led into the gate of a Nuclear Chicago stimulator which yielded a final biphasic output with a constant amperage capability of 0 to 11 mA. The biphasic pulse eliminated polarization of the electrodes, assuring us that the discharge was only that intended and not an
Myocardial infarct size determination Myocardial infarct size was determined by two independent methods; gross measurement and serial serum creatine phosphokinase (CPK) assays (Shell et a / , 1971). Gross measurement of myocardial infarct size was accomplished on hearts obtained at necropsy as follows. After weighing the hearts the crux of the heart was identified and a cut made 2 cm below the crux, parallel to the atrio-
Downloaded from by guest on March 22, 2016
Animal preparation Experiments were performed on 25 mongrel dogs of either sex weighing 20 to 27 kg. The animals were anaesthetized with sodium pentobarbital (25 mg/ kg, intravenously) and maintained on a Harvard positive pressure respirator. We performed a left thoracotomy at the fifth intercostal space and suspended the heart in a pericardial cradle to expose its anterior surface. We attached bipolar, copper hook stimulating electrodes 2 mm apart to the left ventricle to a depth of 2 mm and well outside that region of the left ventricle that became ischaemic during the experimental coronary artery occlusions. A pacing electrode was attached to the right ventricle 2 cm below the origin of the pulmonary artery. Other electrodes were attached to the legs to obtain a lead 11 of a n electrocardiogram (ECG) to use for monitoring and triggering the stimulator. We implanted a catheter in the femoral artery to monitor blood pressure and to obtain blood samples for pOz, pCO2, and p H determinations using an IL blood gas analyser.
accumulated charge of unknown intensity. The bipolar electrode preparation allowed us to define the area receiving stimulation, since a pair of electrodes near each other, floating with respect to ground, and in a conducting medium confine current flow to a small area around and between the electrodes. In this way we limited stimulation to the non-ischaemic area of the myocardium. The heart was paced at 160 beats/min. Initial stimulation was 1 mA for each of three beats every 10 to 15 beats. If fibrillation did not occur, the amperage was increased in increments of approximately 0.33 mA, followed by stimulation, until an amperage was reached which induced fibrillation. This amperage was the VFT. The animal was immediately defibrillated with direct current electric shocks of 10 to 20 W-s, and 10 to 15 min were allowed to elapse before the next VFT determination. In this interval blood p02, pCOz, and pH were determined and blood pH was adjusted, when necessary, by administering sodium bicarbonate to maintain a pH of 7.35 to 7.45. VFTs were considered valid if pH was within this range and if mean aortic blood pressure was between 10.6 to 17.3 kPa (80 to 130 mm Hg). When three control VFTs within 0.5 mA of each other were obtained, we dissected the proximal 3 cm of the left anterior descending coronary artery (LAD) free from the epicardial surface, and placed a pneumatic occlusive latex cuff on it (Sham et a/, 1970), and determined VFT after 10 to 15 min of occlusion. No spontaneous fibrillation occurred during these occlusions. The train duration of 350 ms was similar to that used by Burgess et al (1971) and Han (1969). Bipolar, DC, rectangular pulses have been used by a number of investigators (Brooks et al, 1960; Gerst et al, 1966; Han, 1969). Bipolar stimulation provides more reliable data than monopolar or other types (Brooks et a / , 1960). Since the train duration extended into the vulnerable period of premature beats, elicited by stimulation, it is likely that the VFTs are those of these premature-beat situations as noted above. The values of our VFTs were in the range of 2-10 mA, similar to those reported by Han (1969) and Burgess et al(1971) in stimulations of similar train duration.
470 Bloor, Ehsani, White, and Sobel ventricular groove. The remaining ventricular portion was cut at 2-cm intervals into parallel coronal slices. Using tracing tissue overlays the individual coronal slices were outlined and the zones of necrosis outlined. The cross-sectional areas of the coronal slices and the infarcts were measured by planimetry. The percentage of left ventricular mass involved by the infarct was calculated from these values and expressed as g/tissue. We used the method of Shell et a1 (1971) to estimate myocardial infarct size from serial CPK assays. Baseline blood samples were drawn before coronary occlusion. Additional samples were drawn at 60- to 120-min intervals during coronary occlusion for serial CPK determinations. Myocardial infarct size (in g-Eq) was then estimated using appropriate equations (Shell et al, 1971).
b
--
% 4
t > 2
0 Thoracotomy No2
Ventricular fibrillation threshold (VFT) before (open columns) and 15 min afrer (hatched columns) coronary occlusion during each of two thoracotomies performed 10 days apart (group A ) . Bar height = mean values (mA). Vertical lines are standard errors of the mean. FIG. I
Experimental design
The experimental studies were conducted in the following two groups.
-j
Results In the 14 dogs in which ventricular fibrillation threshold (VFT) was determined before and after 15 rnin of coronary occlusion, during each of two thoracotomies performed 10 days apart (group A), the preocclusive VFTs averaged 5.9 f0.4 (SEM)and 6.0 f0.6 mA, respectively (Fig. 1). These were similar to other control VFT
Ventricular fibrillation thresholds (VFT) before, 15 min, and 24 h after coronary occlusion (group B). Bar height = mean value of VFT (mA) Vertical lines are standard errors of the mean. FIO, 2
Downloaded from by guest on March 22, 2016
values obtained in this laboratory (Garza et al, 1974). After 15 rnin of coronary occlusion VFT decreased 29% from control to 4.2f0.6 mA Group A VFTs were determined in 14 dogs before and after (P
