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Seasonal variation in sudden cardiac death after experimental myocardial infarction
Seasonal Variation in Sudden Cardiac Death After Experimental Myocardial ~f~~ion
Benjamin J. Scherlag, PhD, Eugene Patterson, PhD, and Ralph Lazzara, MD
Abstract: The authors
studied the incidence of sudden death by monitoring the ECG after ligation of the left anterior descending coronary artery in 184 dogs. A significant number of sudden deaths (46 dogs) occurred in the cold weather months, November-February (42%), compared to the summer months, July and August (6%). All deaths resulted from ventricular tachyarrhythmias (2 3OO/min) and occurred between 13 and 22 hours after coronary artery ligation. The survivors ( 138 dogs) were subjected to electrophysiological study, during which a significantly higher number showed induced sustained monomorphic ventricular tachycardia (VT) (heart rate 5: 300Imin) during the winter months than during the summer months. Heart weight and infarct mass were not significantly different throughout the year. Higher sympathetic tone or catecholamine levek may account for the seasonal variation in sudden death during
evolving myocardial infarction. Key words: sustained ventricular tachycardia, ventricular fibrillation, ECG monitoring, electrophysiological studies.
hesive platelet counts* and increased adrenal and thyroid function during winter months.5 In order to determine systematically what factors play a role in this seasonal trend, it would be useful to have an experimental analog in relation to acute myocardial infarction. Karris, in 1950,6 found that a two-stage ligation of the left anterior descending (LAD) coronary artery in the dog prevented early (first 30 minutes) mortality and resulted in acute myocardial infarction within the first 24 hours. Harris noted that the overall mortality in the first 24 hours of myocardial infarction ranged from 25% to 33%. Using a similar experimental preparation of acute myocardial infarction we reviewed 24-hour continuous ECG recordings and noted a definite seasonal trend in mortality related to this experimental procedure. In order to document this seasonal variability we initiated a l-year retrospective study,
Several clinical studies have documented the seasonal variations in mortality in patients with coronary heart disease. ie3 This relationship has been attributed to various factors and possible mechanisms. Dunnigan et al. emphasized the importance of environmental temperature on the seasonal variation of hospital admission for ischemic heart disease and sudden death such that more deaths occur in winter than in summer months.2 Other authors also cited possible underlying factors, such as increased ad-
From the University of Oklahoma Health Sciences Center, Departments of MedicinelCardiology and Pharmacology, and the Veterans Administration Medical Center, Oklahoma City, Oklahoma. Supported in part by Grant HL-32191 from the Veterans Ad-
ministration and National Institutes of Health, Heart, Lung, and Blood Institute. Reprint requests: Benjamin J. Scherlag, PhD, VA Medicat Center ( 15I-F), 92 1 Northeast 13th Street, Oklahoma City, OK 73 104.
223
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Journal of Electrocardiology
Vol. 23 No. 3 July 1990
which was followed by a 2-year prospective study of the electrocardiographic responses during the first 24 hours of acute myocardial infarction.
Materials
and Methods
Adult mongrel dogs weighing 12-25 kg were anesthetized with intravenous Na-pentobarbital, 30 mgkg. A 12-lead ECG was taken with the dog in the supine position. Under positive pressure ventilation the heart was exposed via a left thoracotomy and pericardiotomy. The left anterior descending (LAD) coronary artery was exposed within 1 cm of its origin and two silk ligatures were placed around it. Prior to ligation the apex was elevated to determine whether there were any direct anatomic connections between the LAD and the posterior descending branch, which arises from the circumflex coronary artery. In those showing anastomotic connection (3%), it was ligated at its most distal point from the origin of each vessel. Then the LAD was ligated by the two-stage procedure of Harris6 in order to mitigate malignant arrh~hmias. These occur in the first 30 minutes of severe myocardial ischemia after single-stage ligation. ECG leads II and VZ were monitored continuously before, during, and after two-stage ligation. S-T elevation in lead VZ usually exceeded 2 mm after LAD occlusion. Ten to 15 minutes after complete ligation, and when the ECG was stable, the left thoracotomy was closed to ensure that air was evacuated to prevent pneumothorax. Intramuscular ampicillin, 10 mg/kg, was then administered. The dogs were then allowed to recover in the animal facility, which is maintained at a constant 75°F with 12 hours of light and dark ~roughout the year. Some dogs with labored or shallow breathing were placed in a respirometer chamber into which 100% oxygen was continuously admitted. Continuous electrocardiographic monitoring was obtained from bipolar chest leads attached by adhesive electrodes. The feads were secured under a nylon vest (Alice King-Chatham) and connected to an ECG recorder (Del Mar Avionics) held within a specially designed pocket of the vest. The records were monitored from 2 to 24 hours after LAD ligation. Complete disclosure records were obtained in order for various kinds of determinations to be made, such as frequency of ventricular premature beats, specifically the occurrence of short runs of ventricular tachycardia, or sustained monomorphic or polymorphic ventricular tachycardia and ventricular ~brillation. The distribution of the 184 dogs studied over the
Table 1. Number of Dogs Studied with Acute Myocardial Infarction According to Their Bimonthly Distribution
No.
Deaths
Survivors
January-February
23
March-April May-June July-August September-October November-December
40 33 36 18 34
10 10 6 2 4 14
13 30 27 34 14 20
184
46
138
Total
3-year period is shown in Table 1. All of these dogs survived for the first 3Ominute period after complete LAD ligation due to the two-stage method of Harris for LAD stenosis prior to complete ligation.6 The bimonthly numbers ranged from a low of 18 in September-October to 40 in March-April, with simiiar numbers in May-June (33), July-August (36), and November-December (34).
Electrophysiological Studies Twenty-four hours after coronary occlusion, 138 dogs that survived were anesthetized with intravenous sodium pentobarbital, 30 mg/kg. After incubation the animals were ventilated with room air using a Harvard respirator. A 12-lead ECG was again performed to determine the location and extent of the induced infarction. Extensive transmural infarction of the anterior wall was indicated by a QS pattern from VZto Vg. Nontransmural infarction showed small R waves in these leads. These different diagnoses were confirmed by histochemical examination (see Infarct Size Dete~ination, below). Blood pressure was monitored via a Statham pressure transducer attached to a femoral artery cannula. ECG leads II and VZ were recorded, as was a His bundle electrogram from an electrode catheter inserted via a common carotid artery and wedged at the aortic root7 The left thoracotomy incision was reopened and the heart exposed through the pericardium. A composite electrode recordingse9 was made from the epicardial surface overlying the infarct on the anterior left ventricle, and a similar composite electrode recording was taken from the posterior left ventricle overlying normal, noninfarcted myocardium. In some cases a third electrode catheter was introduced into the left ventricle and positioned against the subendocardium in the infarct zone.” Vagosympathetic trunk stimulation consisting of square wave stimuli, 0.05 msec in duration at a frequency of 20 Hz and
Seasonality of Sudden Death an intensity of l-20 V caused sufficient slowing of the sinus rate to unmask underlying ventricular ectopic activity commonly seen in these X-hour infarcted hearts6 Ventricular pacing was achieved after the insertion of close bipolar plunge wires into the right ventricular outflow tract. An S-88 Grass stimulator and SIU5 isolation unit delivered square wave pulses with 2 msec duration at 2-20 V. Three to four consecutive ventricular stimuli (burst pacing) were applied to the right ventricle after every sixth to eighth sinus or ectopic beat in an attempt to induce ventricular tachyarrhythrnias. lo The burst ventricular pacing started at a rate of 240/min and was repeated 3-5 times at that rate. The pacing rate was then increased by 30/min, again with 3-5 repetitions at each rate, until sustained ventricular tachycardia was induced or the test completed at a rate of 390/min. This protocol optimized the inducibility of sustained ventricular tachycardia, while minimizing the induction of ventricular fibrillation. The latter tended to occur at rates greater than 3 90/min. lo Recordings were obtained on a multichannel oscilloscopic-photographic recorder (Honeywell, Electronics for Medicine VR- 12) and permanent records made on an interfaced Gould photographic recorder (Gould 2000) at paper speeds of 25-250 mmsec. ECG recordings were made at filter frequencies of DC to 250 Hz and electrograms were filtered within a range of 30-250 Hz. The data obtained in this study represent a compilation from several experimental protocols that used the same 24-hour infarcted dog heart. The prospective aspect of this study was a byproduct of several different protocols in which various antiarrhythmic agents were tested in the 24-hour infarct preparation. Drugs were used after inducibility studies were performed in the survivors. No drugs were used in the 24-hour period prior to electrophysiology study so as not to influence spontaneous arrhythmias and incidence of sudden death. All of these studies were carried out in accordance with the guidelines of American Association of Animal Laboratory Care (AAALAC) and approved by an institutional animal care and use committee.
Infarct Size Determination Hearts were excised from dogs that died suddenly and from survivors of 24-hour infarction after electrophysiological study. After a thorough cold water rinse, the hearts were sectioned in 5-mm-thick slices parallel to the A-V groove. These sections were
l
Scherlag et al.
225
placed in a warm solution of 0.4% triphenyltetrazolium chloride. The histological stain forms a deep red formazan precipitate when intracellular dehydrogenase is present (viable tissue). Infarcted tissue remains pale and unstained. After fixation in 10% formalin for 24 hours the infarct and noninfarct portion were dissected and weighed. Infarct size was expressed as a percent of total left ventricular mass. In this study we used the following definitions. Sustained monomorphic or polymorphic ventricular tachycardia-A ventricular tachycardia of uniform or variable morphology that persisted for at least 100 beats. Nonsustained ventricular tachycardia-Short runs of ventricular tachycardia with multiple QRS morphologies, commonly seen when sinus rhythm was suppressed by vagosympathetic trunk stimulation. The data are expressed as mean 2 the standard error of the mean. Chi-square analysis was used to evaluate the incidence of seasonal differences. A oneway analysis of variance followed by Bonferoni’s test was used to evaluate differences between group means; p 5 0.05 was used as criterion for significance.
Results Of the 184 dogs studied, there were 46 sudden arrhythmic deaths in the first 24 hours after coronary artery occlusion. All 46 died between 13 and 22 hours after LAD ligation. From a seasonal standpoint there was a significant trend in the number of spontaneous sudden deaths (Table 1 and solid line, Figure 1) in that a higher percentage of dogs died in the winter months, January-February (10 of 23, 43%) and November-December (14 of 34, 41%) than at the height of the summer (July-August, 2 of 36,6%), p < 0.0004. Examination of the mode of death from the tape-recorded data showed that in all but two dogs sudden death (ie, ventricular fibrillation) was preceded by sustained monomorphic ventricular tachycardia at rates between 300 and 400/min, or polymorphic ventricular tachycardia at rates between 400 and 600/min. The bars in Figure 2 represent the total incidence of sustained ventricular tachycardia (mono- or polymorphic) occurring spontaneously in those with sudden deaths as well as the induced sustained ventricular tachycardias in the survivors. It should be noted that although the number of dogs in the midsummer group (July-August) and early winter
226
Journal of Electrocardiology
Vol. 23 No. 3 July 1990
no
t
.
(0
x x
p
<
0.004 0
0
JF
MA
.I* MJ MONTH
SO
ND
Fig. 1. Graphic representation of the relation between sudden death during the first 24 hours of myocardial infarction and average bimonthly temperatures throughout the 3 years of this study (1983, 1984, 1985). During the winter months (November-February), 40-45% of dogs studied with induced myocardial infarction died due to spontaneously occurring ventricular tachyarrhythmias. In contrast, during the summer months (July-August) there was only a 6% mortality representing a significant difference between winter and summer, p < 0.0004. The temperature data were obtained from the Oklahoma City office of the National Oceanic and Atmospheric Administration (NOAA). The local climatological data was published as an official record on file at the National Climate Data Center, North Carolina.
100-
$
I
90
‘.
6.0
”
70
.’
60..
50 40
”‘.
30
.’
20
”
10 ..
o-
x p < o.ooos Fig. 2. The incidence of sustained
(mono- or polymorphic) ventricular tachycardia in the dogs with 24-hour myocardial infarction. Sustained ventricular tachycardia, either spontaneously occurring or induced during electrophysiological study, was found more predominantly in the winter months (80-90%) than during the summer (20-30%) a significant difference (x), p < 0.0005. The number in parentheses above each bar is the total number of dogs studied in each bimonthly period.
group (November-December) are comparable at 36 and 34, respectively, the percentage of sudden deaths and spontaneous and induced sustained ventricular tachycardia are significantly different, p < 0.0005. Figure 3 is an example of a 24-hour ECG recording that captured the minutes before and after the onset of the lethal arrhythmia preceding sudden death. At 21 hours after LAD coronary artery ligation there was a multiform ventricular tachycardia with few, if any, sinus beats observed. At the beginning of the 13th minute (2 1: 13) of this record, a sustained ventricular tachycardia at a rate of 445/min spontaneously commenced and lasted more than 2.5 minutes before degenerating into ventricular fibrillation. Note that the close coupled beats in bursts of three or four, which appeared sporadically prior to the lethal event (circled triplets and quadruplets), show a similar morphology and rate (range, 375-428/min) as the initial beats of the sustained monomorphic ventricular tachycardia. The implications of these findings are discussed below. The 24-hour survivors were subjected to electrophysiological study in the anesthetized, open-chest state. In order to simulate the rapid three- to fourbeat runs that occurred spontaneously, we delivered three- to four-beat bursts of electrical stimuli to the right ventricular outflow tract. Figure 4 is a record of the induction of sustained ventricular tachycardia in a 24-hour infarcted dog heart. During sinus rhythm at a rate of 140/min, four ventricular paced beats at a rate of 330/min were introduced causing fractionation, delay and continuous activation in the composite electrogram from the epicardium overlying the infarct (IZ epi). These changes were associated with the onset of a monomorphic ventricular tachycardia at a rate of 325/min. Note the circumscribed potentials recorded by another composite electrode in the normal zone (NZ epi) and by the catheter electrode adjacent to the infarcted endocardium (IZ endo) during the sustained ventricular tachycardia. The mean arterial blood pressure (MBP) declined to a stable level of 60 mmHg during the tachycardia. Burst pacing was able to terminate the tachycardia with resumption of previous electrocardiographic and electrographic morphologies. In an attempt to determine the basis for the seasonal differences in arrhythmias and mortality (Figs. I and 2), we compared the infarct size of the dogs’ hearts within the bimonthly categorization, as well as their total left ventricular weight in grams. Figure 5 indicates that the average rate of the induced ventricular tachycardias were significantly faster in the winter months (November-February) versus the spring months (March-April) p < 0.0 1, whereas there was a greater number of nontransmural in-
Seasonality of Sudden Death
l
Scherlag et al.
227
Fig. 3. Transcription of the taped ECG records before and after the terminal events leading to death in a dog. The penultimate ECG finding, in almost all the deaths, was SUStained monomorphic or polymorphic ventricular tachycardia whose rate exceeded 300lmin. Such an example is seen starting at 21: 13 of the present record which degenerated into ventricular fibrillation within 2.5 minutes. The beats within the ovals were selected because their (37%428/min) approximate rate and morphology are similar to those at the beginning of the sustained ventricular tachycardia. See text for details and further explanation.
VT +325/min
.
.
.
.
1
.
.
.
.
.
.
.
.
.
M8P ‘XX: mmHg o_ Fig. 4. Response to electrophysiological studies in a 24-hour survivor of acute myocardial infarction. Traces from the top are: ECG lead II (L-2); His bundle electrogram; electrode catheter recording from the endocardial surface in the infarcted zone of the left ventricle (IZ endo); composite electrode recordings from the viable but sick epicardium overlying the infarct (IZ epi) and from noninfarcted or normal epicardium at the posterior of the left ventricle (NZ epi); mean blood pressure registered O-100 mmHg. Ventricular pacing (VP) with four ventricular stimuli (arrowheads, 3rd trace) at 330/min caused marked fractionation of the IZ epi electrogram preceding the onset of sustained ventricular tachycardia (VT). Continuous electrical activity is seen during the VT whose rapid rate, 325/min, is associated with a drop in mean blood pressure toward 60 mmHg. Calibration for time and voltage are seen at the upper and lower right.
228 Journal of Electrocardiology 400
VT
Vol. 23 No. 3 July 1990 RATE
(BPM)
INFARCT
(ZLV)
40
Fig. 5. Bar
graph representation of salient relationships between bimonthly time periods and rate of ventricular tachycardia (VT), percent of dogs showing transmura~ infarction, infarct size in percent of left ventricle (LV) infarcted and LV weight in grams (gms). VT rate was significantly higher, p < 0.01 between winter (November-Febma~~ and spring months (March-April) whereas transmural infarction was more predominant in the winter infarcts than in the summer (p = 0.05). Infarct size and LV weight did not vary significantly throughout the yearly periods. See text for further discussion.
farcts in the summer months (28-30%) versus transmural (70-72%). On the other hand, the incidence in the winter months was 12- 13% nontransmura1 and 87438% transmural. There were no statistical differences in either infarct size nor in left ventricular weights within the same bimonthly periods, even though there was a significant difference between the summer and winter months in regard to the incidence of transmural or nontransmural infarction.
Discussion These studies provide experimental corroborative evidence for the findings of seasonal variation in death due to myocardial infarction in the clinical setting.‘-5 Our experimental findings in recently published studies contain lines of evidence implicating an important role for the sympathetic nervous system as an important underlying factor responsible for the lethal arrhythmias in acute myocardial in-
farction. Various epidemiological studies have shown statistically significant differences in seasonal death rates due to myocardial infarction which were directly related to cold temperatures.‘-’ Two hypotheses have been proposed to explain the seasonal variation in mortality observed clinically, and either or both explanations may also be applicabIe to the seasonal difference in mortality found in our experimental study. First, animals exposed to cold for prolonged periods, as in our dog population obtained in winter, tend to show increased thyroid hormone production.’ ’ It has been well established that such thyroid stimulation can cause an increase in the number of membrane-bound B-adrenoceptors and enhanced beta-agonist effects.i2 Second, enhanced thyroid and adrena function may augment adhesive-platelet counts.r3 Indeed, deep vein thrombosis increases sig~~can~y in Australia during the winter months (May-October). I* Severai observations made in our experimental study are consonant with these hypotheses: The heart rate of the spontaneous and induced sustained
Seasonality of Sudden Death ventricular tachycardia was significantly higher in the colder months (November-February) than in the spring months of March and April and tended to be higher than any of the other bimonthly periods covering May-October (Fig. 4). Also, in a previous study from our laboratory done in two groups of 20 “winter” dogs, Patterson et al. l5 found that selective betablockade with nadolol significantly reduced the incidence of sudden death, from 35% to 5%. Furthermore, there was a significant reduction in the rate of spontaneously occurring triplets in the recorded 24-hour tapes in the treated group (241 * Urnin) as compared to the untreated group (328 + Wmin). These triplets, whether spontaneous or induced, occurring at rates >300/min, served as the triggering mechanism for the sustained ventricular tachycardias seen in this study (Fig. 4) as well as in other reports,‘5,16 which comprised portions of the population of dogs used in this study. It should be noted that both the untreated and nadolol-treated dogs that survived 24 hours of infarction (75-80% or greater) could be induced by ventricular pacing to show sustained monomorphic ventricular tachycardia. Thus, even though the substrate for sudden death was present in both groups, the rate and number of triggering beats was markedly reduced in the dogs after beta-blockade.16 The thrombotic hypothesis may play a role in the finding that nontransmural infarction was significantly higher in the summer months. It has been shown that nontransmural infarction provides a poorer substrate for induced ventricular tachycardia.” The fact that infarct size did not vary throughout the year, while the occurrence of nontransmural infarction was higher in the warmer periods, indicates that the transmural rather than lateral extent of the infarct followed a seasonal pattern. Therefore, transmural infarction was more likely to be seen in the colder months and nontransmural more likely in the warmer months. A possible explanation for such a seasonal difference may lie in the greater thrombotic tendencies that have been shown to occur in the winter months.4”4 If the transmural extent of the infarct is related to necrotic destruction of the microvasculature and their obstruction by invading leukocytes and the products of their action, then a greater endocardial-epicardial extent of the infarct could be expected. Several clinical studies of sudden death captured on 24-hour ECG recordings”-*’ show at least two important characteristics in common with our experimental model. First, is the increasing frequency of complex ectopic beats in the hours preceding sudden death, and second is that the great majority of arrhythmic deaths in both settings were preceded by
l
Scherlag
et al.
229
sustained ventricular tachycardia. Both of these factors were salient in the experimental setting, even though longstanding coronary artery disease exhibited clinically was simulated by acute coronary artery ligation.
Acknowledgments The authors thank LaVonna Blair for her technical assistance, Sally Thompson for her help with the 24hour electrocardiographic recordings, and Pamela Tomey for the preparation of the manuscript.
References 1. Rose G: Cold weather and ischemic heart disease. Br J Prev Sot Med 20:97, 1966 2. Dunnigan MG, Harland WA, Fyte T: Seasonal incidence and mortality of ischemic heart disease. Lancet 2:793, 1970 3. Rogot E: Associations between coronary mortality and the weather, Chicago, 1967. Public Health Reports 89:330, 1974. 4. Eastham RD, Avis PRD: Seasonal fluctuation in adhesive platelets during long-term anti-coagulant therapy. Br J Haematol 12:39, 1966 5. Thorp JM: The control of lipid metabolism, Biochemical Society Symposium, London, 24: 161, 1963. 6. Harris AS: Delayed development of ventricular ectopic rhythm following experimental coronary occlusion. Circulation 1:1318, 1950 7. Scherlag BJ, Abelliera JL, Samet P: Electrode catheter recordings from the His bundle and left bundle in the intact dog. p. 223. In: Kao FF, Koizumi K, Vassalle M (eds), Research in physiology. Bologna, 1971 8. Kabell G, Scherlag BJ, Hope RR, Lazzara R: Patterns of interectopic activation recorded during pleomorphic ventricular tachycardia after myocardial infarction in the dog. Am J Cardiol 49:56, 1982 9. Brachmann J, Kabell G, Scherlag BJ et al: Analysis of interectopic activation patterns during sustained ventricular tachycardia. Circulation 67:449, 1983 10. Scherlag BJ, Kabell G, Brachmann J et al: Mechanisms of spontaneous and induced ventricular arrhythmias in the 24-hour infarcted dog heart. Am J Cardiol 51:207, 1983 11. Genuth SM: The thyroid gland. p. 1013. In Beme RM, Levy MN (eds): Physiology. CV Mosby, St. Louis, 1983 12. Limas C, Limas CJ: Influence of thyroid status on intracellular distribution of cardiac adrenoceptors. Circ Res 61:824, 1987 13. Fyfe T, Dunnigan MG, Hamilton E, Rae RJ: Seasonal variation in serum lipids and incidence and mortality of ischemic heart disease. J Atheroscler Res 8:591, 1968
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Vol. 23 No. 3 July 1990
14. Lawrence JC, Xabregas A, Gray L, Ham JM: Seasonal variation in the incidence of deep vein thrombosis. Br J Surg 64:777, 1977 15. Patterson E, Scherlag BJ, Lazzara R: Mechanism of prevention of sudden death by nadolol: differential actions on arrhythmia triggers and substrate after myocardial infarction in the dog. Am Co11 Cardiol 8: 1367, 1986 16. Scherlag BJ, Patterson ES, Berbari EJ, Lazzara R: Experimental simulation of sudden cardiac death in man: electrophysiological mechanisms and role of adrenergic influences. p. 299. In Brachmann J, Kubler W, Schomig A (eds): Adrenergic system and ventricular arrhythmias in myocardial infarction. SpringerVerlag, Berlin, Heidelberg, 1989
17. Scherlag BJ, Brachmamr J, Kabell G et al: Sustained ventricular tachycardia: common functional properties of different anatomic substrates. p. 379. In Zipes DP, Jalife J (eds): Cardiac electrophysiology and arrhythmias. Grune 6 Stratton, Orlando, 1985 18. Bleifer SB, Bleifer DJ, Hansmann DR et al: Diagnosis of occult arrhythmias by Holter electrocardiography. Prog Cardiovasc Dis 16:569, 1974 19. Panidis I, Morgamoth J: Holter monitoring during sudden cardiac death: clues to its etiology and prevention. Circulation 66:11-25, 1982 20. Lewis BH, Antman EM, Graboys TB: Detailed analysis of 24-hour ambulatory electrocardiographic recordings during ventricular fibrillation or Torsade de Pointes. J Am Co11Cardiol 2:426, 1983
Benjamin J. Scherlag, PhD, Eugene Patterson, PhD, and Ralph Lazzara, MD
Abstract: The authors
studied the incidence of sudden death by monitoring the ECG after ligation of the left anterior descending coronary artery in 184 dogs. A significant number of sudden deaths (46 dogs) occurred in the cold weather months, November-February (42%), compared to the summer months, July and August (6%). All deaths resulted from ventricular tachyarrhythmias (2 3OO/min) and occurred between 13 and 22 hours after coronary artery ligation. The survivors ( 138 dogs) were subjected to electrophysiological study, during which a significantly higher number showed induced sustained monomorphic ventricular tachycardia (VT) (heart rate 5: 300Imin) during the winter months than during the summer months. Heart weight and infarct mass were not significantly different throughout the year. Higher sympathetic tone or catecholamine levek may account for the seasonal variation in sudden death during
evolving myocardial infarction. Key words: sustained ventricular tachycardia, ventricular fibrillation, ECG monitoring, electrophysiological studies.
hesive platelet counts* and increased adrenal and thyroid function during winter months.5 In order to determine systematically what factors play a role in this seasonal trend, it would be useful to have an experimental analog in relation to acute myocardial infarction. Karris, in 1950,6 found that a two-stage ligation of the left anterior descending (LAD) coronary artery in the dog prevented early (first 30 minutes) mortality and resulted in acute myocardial infarction within the first 24 hours. Harris noted that the overall mortality in the first 24 hours of myocardial infarction ranged from 25% to 33%. Using a similar experimental preparation of acute myocardial infarction we reviewed 24-hour continuous ECG recordings and noted a definite seasonal trend in mortality related to this experimental procedure. In order to document this seasonal variability we initiated a l-year retrospective study,
Several clinical studies have documented the seasonal variations in mortality in patients with coronary heart disease. ie3 This relationship has been attributed to various factors and possible mechanisms. Dunnigan et al. emphasized the importance of environmental temperature on the seasonal variation of hospital admission for ischemic heart disease and sudden death such that more deaths occur in winter than in summer months.2 Other authors also cited possible underlying factors, such as increased ad-
From the University of Oklahoma Health Sciences Center, Departments of MedicinelCardiology and Pharmacology, and the Veterans Administration Medical Center, Oklahoma City, Oklahoma. Supported in part by Grant HL-32191 from the Veterans Ad-
ministration and National Institutes of Health, Heart, Lung, and Blood Institute. Reprint requests: Benjamin J. Scherlag, PhD, VA Medicat Center ( 15I-F), 92 1 Northeast 13th Street, Oklahoma City, OK 73 104.
223
224
Journal of Electrocardiology
Vol. 23 No. 3 July 1990
which was followed by a 2-year prospective study of the electrocardiographic responses during the first 24 hours of acute myocardial infarction.
Materials
and Methods
Adult mongrel dogs weighing 12-25 kg were anesthetized with intravenous Na-pentobarbital, 30 mgkg. A 12-lead ECG was taken with the dog in the supine position. Under positive pressure ventilation the heart was exposed via a left thoracotomy and pericardiotomy. The left anterior descending (LAD) coronary artery was exposed within 1 cm of its origin and two silk ligatures were placed around it. Prior to ligation the apex was elevated to determine whether there were any direct anatomic connections between the LAD and the posterior descending branch, which arises from the circumflex coronary artery. In those showing anastomotic connection (3%), it was ligated at its most distal point from the origin of each vessel. Then the LAD was ligated by the two-stage procedure of Harris6 in order to mitigate malignant arrh~hmias. These occur in the first 30 minutes of severe myocardial ischemia after single-stage ligation. ECG leads II and VZ were monitored continuously before, during, and after two-stage ligation. S-T elevation in lead VZ usually exceeded 2 mm after LAD occlusion. Ten to 15 minutes after complete ligation, and when the ECG was stable, the left thoracotomy was closed to ensure that air was evacuated to prevent pneumothorax. Intramuscular ampicillin, 10 mg/kg, was then administered. The dogs were then allowed to recover in the animal facility, which is maintained at a constant 75°F with 12 hours of light and dark ~roughout the year. Some dogs with labored or shallow breathing were placed in a respirometer chamber into which 100% oxygen was continuously admitted. Continuous electrocardiographic monitoring was obtained from bipolar chest leads attached by adhesive electrodes. The feads were secured under a nylon vest (Alice King-Chatham) and connected to an ECG recorder (Del Mar Avionics) held within a specially designed pocket of the vest. The records were monitored from 2 to 24 hours after LAD ligation. Complete disclosure records were obtained in order for various kinds of determinations to be made, such as frequency of ventricular premature beats, specifically the occurrence of short runs of ventricular tachycardia, or sustained monomorphic or polymorphic ventricular tachycardia and ventricular ~brillation. The distribution of the 184 dogs studied over the
Table 1. Number of Dogs Studied with Acute Myocardial Infarction According to Their Bimonthly Distribution
No.
Deaths
Survivors
January-February
23
March-April May-June July-August September-October November-December
40 33 36 18 34
10 10 6 2 4 14
13 30 27 34 14 20
184
46
138
Total
3-year period is shown in Table 1. All of these dogs survived for the first 3Ominute period after complete LAD ligation due to the two-stage method of Harris for LAD stenosis prior to complete ligation.6 The bimonthly numbers ranged from a low of 18 in September-October to 40 in March-April, with simiiar numbers in May-June (33), July-August (36), and November-December (34).
Electrophysiological Studies Twenty-four hours after coronary occlusion, 138 dogs that survived were anesthetized with intravenous sodium pentobarbital, 30 mg/kg. After incubation the animals were ventilated with room air using a Harvard respirator. A 12-lead ECG was again performed to determine the location and extent of the induced infarction. Extensive transmural infarction of the anterior wall was indicated by a QS pattern from VZto Vg. Nontransmural infarction showed small R waves in these leads. These different diagnoses were confirmed by histochemical examination (see Infarct Size Dete~ination, below). Blood pressure was monitored via a Statham pressure transducer attached to a femoral artery cannula. ECG leads II and VZ were recorded, as was a His bundle electrogram from an electrode catheter inserted via a common carotid artery and wedged at the aortic root7 The left thoracotomy incision was reopened and the heart exposed through the pericardium. A composite electrode recordingse9 was made from the epicardial surface overlying the infarct on the anterior left ventricle, and a similar composite electrode recording was taken from the posterior left ventricle overlying normal, noninfarcted myocardium. In some cases a third electrode catheter was introduced into the left ventricle and positioned against the subendocardium in the infarct zone.” Vagosympathetic trunk stimulation consisting of square wave stimuli, 0.05 msec in duration at a frequency of 20 Hz and
Seasonality of Sudden Death an intensity of l-20 V caused sufficient slowing of the sinus rate to unmask underlying ventricular ectopic activity commonly seen in these X-hour infarcted hearts6 Ventricular pacing was achieved after the insertion of close bipolar plunge wires into the right ventricular outflow tract. An S-88 Grass stimulator and SIU5 isolation unit delivered square wave pulses with 2 msec duration at 2-20 V. Three to four consecutive ventricular stimuli (burst pacing) were applied to the right ventricle after every sixth to eighth sinus or ectopic beat in an attempt to induce ventricular tachyarrhythrnias. lo The burst ventricular pacing started at a rate of 240/min and was repeated 3-5 times at that rate. The pacing rate was then increased by 30/min, again with 3-5 repetitions at each rate, until sustained ventricular tachycardia was induced or the test completed at a rate of 390/min. This protocol optimized the inducibility of sustained ventricular tachycardia, while minimizing the induction of ventricular fibrillation. The latter tended to occur at rates greater than 3 90/min. lo Recordings were obtained on a multichannel oscilloscopic-photographic recorder (Honeywell, Electronics for Medicine VR- 12) and permanent records made on an interfaced Gould photographic recorder (Gould 2000) at paper speeds of 25-250 mmsec. ECG recordings were made at filter frequencies of DC to 250 Hz and electrograms were filtered within a range of 30-250 Hz. The data obtained in this study represent a compilation from several experimental protocols that used the same 24-hour infarcted dog heart. The prospective aspect of this study was a byproduct of several different protocols in which various antiarrhythmic agents were tested in the 24-hour infarct preparation. Drugs were used after inducibility studies were performed in the survivors. No drugs were used in the 24-hour period prior to electrophysiology study so as not to influence spontaneous arrhythmias and incidence of sudden death. All of these studies were carried out in accordance with the guidelines of American Association of Animal Laboratory Care (AAALAC) and approved by an institutional animal care and use committee.
Infarct Size Determination Hearts were excised from dogs that died suddenly and from survivors of 24-hour infarction after electrophysiological study. After a thorough cold water rinse, the hearts were sectioned in 5-mm-thick slices parallel to the A-V groove. These sections were
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placed in a warm solution of 0.4% triphenyltetrazolium chloride. The histological stain forms a deep red formazan precipitate when intracellular dehydrogenase is present (viable tissue). Infarcted tissue remains pale and unstained. After fixation in 10% formalin for 24 hours the infarct and noninfarct portion were dissected and weighed. Infarct size was expressed as a percent of total left ventricular mass. In this study we used the following definitions. Sustained monomorphic or polymorphic ventricular tachycardia-A ventricular tachycardia of uniform or variable morphology that persisted for at least 100 beats. Nonsustained ventricular tachycardia-Short runs of ventricular tachycardia with multiple QRS morphologies, commonly seen when sinus rhythm was suppressed by vagosympathetic trunk stimulation. The data are expressed as mean 2 the standard error of the mean. Chi-square analysis was used to evaluate the incidence of seasonal differences. A oneway analysis of variance followed by Bonferoni’s test was used to evaluate differences between group means; p 5 0.05 was used as criterion for significance.
Results Of the 184 dogs studied, there were 46 sudden arrhythmic deaths in the first 24 hours after coronary artery occlusion. All 46 died between 13 and 22 hours after LAD ligation. From a seasonal standpoint there was a significant trend in the number of spontaneous sudden deaths (Table 1 and solid line, Figure 1) in that a higher percentage of dogs died in the winter months, January-February (10 of 23, 43%) and November-December (14 of 34, 41%) than at the height of the summer (July-August, 2 of 36,6%), p < 0.0004. Examination of the mode of death from the tape-recorded data showed that in all but two dogs sudden death (ie, ventricular fibrillation) was preceded by sustained monomorphic ventricular tachycardia at rates between 300 and 400/min, or polymorphic ventricular tachycardia at rates between 400 and 600/min. The bars in Figure 2 represent the total incidence of sustained ventricular tachycardia (mono- or polymorphic) occurring spontaneously in those with sudden deaths as well as the induced sustained ventricular tachycardias in the survivors. It should be noted that although the number of dogs in the midsummer group (July-August) and early winter
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Fig. 1. Graphic representation of the relation between sudden death during the first 24 hours of myocardial infarction and average bimonthly temperatures throughout the 3 years of this study (1983, 1984, 1985). During the winter months (November-February), 40-45% of dogs studied with induced myocardial infarction died due to spontaneously occurring ventricular tachyarrhythmias. In contrast, during the summer months (July-August) there was only a 6% mortality representing a significant difference between winter and summer, p < 0.0004. The temperature data were obtained from the Oklahoma City office of the National Oceanic and Atmospheric Administration (NOAA). The local climatological data was published as an official record on file at the National Climate Data Center, North Carolina.
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(mono- or polymorphic) ventricular tachycardia in the dogs with 24-hour myocardial infarction. Sustained ventricular tachycardia, either spontaneously occurring or induced during electrophysiological study, was found more predominantly in the winter months (80-90%) than during the summer (20-30%) a significant difference (x), p < 0.0005. The number in parentheses above each bar is the total number of dogs studied in each bimonthly period.
group (November-December) are comparable at 36 and 34, respectively, the percentage of sudden deaths and spontaneous and induced sustained ventricular tachycardia are significantly different, p < 0.0005. Figure 3 is an example of a 24-hour ECG recording that captured the minutes before and after the onset of the lethal arrhythmia preceding sudden death. At 21 hours after LAD coronary artery ligation there was a multiform ventricular tachycardia with few, if any, sinus beats observed. At the beginning of the 13th minute (2 1: 13) of this record, a sustained ventricular tachycardia at a rate of 445/min spontaneously commenced and lasted more than 2.5 minutes before degenerating into ventricular fibrillation. Note that the close coupled beats in bursts of three or four, which appeared sporadically prior to the lethal event (circled triplets and quadruplets), show a similar morphology and rate (range, 375-428/min) as the initial beats of the sustained monomorphic ventricular tachycardia. The implications of these findings are discussed below. The 24-hour survivors were subjected to electrophysiological study in the anesthetized, open-chest state. In order to simulate the rapid three- to fourbeat runs that occurred spontaneously, we delivered three- to four-beat bursts of electrical stimuli to the right ventricular outflow tract. Figure 4 is a record of the induction of sustained ventricular tachycardia in a 24-hour infarcted dog heart. During sinus rhythm at a rate of 140/min, four ventricular paced beats at a rate of 330/min were introduced causing fractionation, delay and continuous activation in the composite electrogram from the epicardium overlying the infarct (IZ epi). These changes were associated with the onset of a monomorphic ventricular tachycardia at a rate of 325/min. Note the circumscribed potentials recorded by another composite electrode in the normal zone (NZ epi) and by the catheter electrode adjacent to the infarcted endocardium (IZ endo) during the sustained ventricular tachycardia. The mean arterial blood pressure (MBP) declined to a stable level of 60 mmHg during the tachycardia. Burst pacing was able to terminate the tachycardia with resumption of previous electrocardiographic and electrographic morphologies. In an attempt to determine the basis for the seasonal differences in arrhythmias and mortality (Figs. I and 2), we compared the infarct size of the dogs’ hearts within the bimonthly categorization, as well as their total left ventricular weight in grams. Figure 5 indicates that the average rate of the induced ventricular tachycardias were significantly faster in the winter months (November-February) versus the spring months (March-April) p < 0.0 1, whereas there was a greater number of nontransmural in-
Seasonality of Sudden Death
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Fig. 3. Transcription of the taped ECG records before and after the terminal events leading to death in a dog. The penultimate ECG finding, in almost all the deaths, was SUStained monomorphic or polymorphic ventricular tachycardia whose rate exceeded 300lmin. Such an example is seen starting at 21: 13 of the present record which degenerated into ventricular fibrillation within 2.5 minutes. The beats within the ovals were selected because their (37%428/min) approximate rate and morphology are similar to those at the beginning of the sustained ventricular tachycardia. See text for details and further explanation.
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M8P ‘XX: mmHg o_ Fig. 4. Response to electrophysiological studies in a 24-hour survivor of acute myocardial infarction. Traces from the top are: ECG lead II (L-2); His bundle electrogram; electrode catheter recording from the endocardial surface in the infarcted zone of the left ventricle (IZ endo); composite electrode recordings from the viable but sick epicardium overlying the infarct (IZ epi) and from noninfarcted or normal epicardium at the posterior of the left ventricle (NZ epi); mean blood pressure registered O-100 mmHg. Ventricular pacing (VP) with four ventricular stimuli (arrowheads, 3rd trace) at 330/min caused marked fractionation of the IZ epi electrogram preceding the onset of sustained ventricular tachycardia (VT). Continuous electrical activity is seen during the VT whose rapid rate, 325/min, is associated with a drop in mean blood pressure toward 60 mmHg. Calibration for time and voltage are seen at the upper and lower right.
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Fig. 5. Bar
graph representation of salient relationships between bimonthly time periods and rate of ventricular tachycardia (VT), percent of dogs showing transmura~ infarction, infarct size in percent of left ventricle (LV) infarcted and LV weight in grams (gms). VT rate was significantly higher, p < 0.01 between winter (November-Febma~~ and spring months (March-April) whereas transmural infarction was more predominant in the winter infarcts than in the summer (p = 0.05). Infarct size and LV weight did not vary significantly throughout the yearly periods. See text for further discussion.
farcts in the summer months (28-30%) versus transmural (70-72%). On the other hand, the incidence in the winter months was 12- 13% nontransmura1 and 87438% transmural. There were no statistical differences in either infarct size nor in left ventricular weights within the same bimonthly periods, even though there was a significant difference between the summer and winter months in regard to the incidence of transmural or nontransmural infarction.
Discussion These studies provide experimental corroborative evidence for the findings of seasonal variation in death due to myocardial infarction in the clinical setting.‘-5 Our experimental findings in recently published studies contain lines of evidence implicating an important role for the sympathetic nervous system as an important underlying factor responsible for the lethal arrhythmias in acute myocardial in-
farction. Various epidemiological studies have shown statistically significant differences in seasonal death rates due to myocardial infarction which were directly related to cold temperatures.‘-’ Two hypotheses have been proposed to explain the seasonal variation in mortality observed clinically, and either or both explanations may also be applicabIe to the seasonal difference in mortality found in our experimental study. First, animals exposed to cold for prolonged periods, as in our dog population obtained in winter, tend to show increased thyroid hormone production.’ ’ It has been well established that such thyroid stimulation can cause an increase in the number of membrane-bound B-adrenoceptors and enhanced beta-agonist effects.i2 Second, enhanced thyroid and adrena function may augment adhesive-platelet counts.r3 Indeed, deep vein thrombosis increases sig~~can~y in Australia during the winter months (May-October). I* Severai observations made in our experimental study are consonant with these hypotheses: The heart rate of the spontaneous and induced sustained
Seasonality of Sudden Death ventricular tachycardia was significantly higher in the colder months (November-February) than in the spring months of March and April and tended to be higher than any of the other bimonthly periods covering May-October (Fig. 4). Also, in a previous study from our laboratory done in two groups of 20 “winter” dogs, Patterson et al. l5 found that selective betablockade with nadolol significantly reduced the incidence of sudden death, from 35% to 5%. Furthermore, there was a significant reduction in the rate of spontaneously occurring triplets in the recorded 24-hour tapes in the treated group (241 * Urnin) as compared to the untreated group (328 + Wmin). These triplets, whether spontaneous or induced, occurring at rates >300/min, served as the triggering mechanism for the sustained ventricular tachycardias seen in this study (Fig. 4) as well as in other reports,‘5,16 which comprised portions of the population of dogs used in this study. It should be noted that both the untreated and nadolol-treated dogs that survived 24 hours of infarction (75-80% or greater) could be induced by ventricular pacing to show sustained monomorphic ventricular tachycardia. Thus, even though the substrate for sudden death was present in both groups, the rate and number of triggering beats was markedly reduced in the dogs after beta-blockade.16 The thrombotic hypothesis may play a role in the finding that nontransmural infarction was significantly higher in the summer months. It has been shown that nontransmural infarction provides a poorer substrate for induced ventricular tachycardia.” The fact that infarct size did not vary throughout the year, while the occurrence of nontransmural infarction was higher in the warmer periods, indicates that the transmural rather than lateral extent of the infarct followed a seasonal pattern. Therefore, transmural infarction was more likely to be seen in the colder months and nontransmural more likely in the warmer months. A possible explanation for such a seasonal difference may lie in the greater thrombotic tendencies that have been shown to occur in the winter months.4”4 If the transmural extent of the infarct is related to necrotic destruction of the microvasculature and their obstruction by invading leukocytes and the products of their action, then a greater endocardial-epicardial extent of the infarct could be expected. Several clinical studies of sudden death captured on 24-hour ECG recordings”-*’ show at least two important characteristics in common with our experimental model. First, is the increasing frequency of complex ectopic beats in the hours preceding sudden death, and second is that the great majority of arrhythmic deaths in both settings were preceded by
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sustained ventricular tachycardia. Both of these factors were salient in the experimental setting, even though longstanding coronary artery disease exhibited clinically was simulated by acute coronary artery ligation.
Acknowledgments The authors thank LaVonna Blair for her technical assistance, Sally Thompson for her help with the 24hour electrocardiographic recordings, and Pamela Tomey for the preparation of the manuscript.
References 1. Rose G: Cold weather and ischemic heart disease. Br J Prev Sot Med 20:97, 1966 2. Dunnigan MG, Harland WA, Fyte T: Seasonal incidence and mortality of ischemic heart disease. Lancet 2:793, 1970 3. Rogot E: Associations between coronary mortality and the weather, Chicago, 1967. Public Health Reports 89:330, 1974. 4. Eastham RD, Avis PRD: Seasonal fluctuation in adhesive platelets during long-term anti-coagulant therapy. Br J Haematol 12:39, 1966 5. Thorp JM: The control of lipid metabolism, Biochemical Society Symposium, London, 24: 161, 1963. 6. Harris AS: Delayed development of ventricular ectopic rhythm following experimental coronary occlusion. Circulation 1:1318, 1950 7. Scherlag BJ, Abelliera JL, Samet P: Electrode catheter recordings from the His bundle and left bundle in the intact dog. p. 223. In: Kao FF, Koizumi K, Vassalle M (eds), Research in physiology. Bologna, 1971 8. Kabell G, Scherlag BJ, Hope RR, Lazzara R: Patterns of interectopic activation recorded during pleomorphic ventricular tachycardia after myocardial infarction in the dog. Am J Cardiol 49:56, 1982 9. Brachmann J, Kabell G, Scherlag BJ et al: Analysis of interectopic activation patterns during sustained ventricular tachycardia. Circulation 67:449, 1983 10. Scherlag BJ, Kabell G, Brachmann J et al: Mechanisms of spontaneous and induced ventricular arrhythmias in the 24-hour infarcted dog heart. Am J Cardiol 51:207, 1983 11. Genuth SM: The thyroid gland. p. 1013. In Beme RM, Levy MN (eds): Physiology. CV Mosby, St. Louis, 1983 12. Limas C, Limas CJ: Influence of thyroid status on intracellular distribution of cardiac adrenoceptors. Circ Res 61:824, 1987 13. Fyfe T, Dunnigan MG, Hamilton E, Rae RJ: Seasonal variation in serum lipids and incidence and mortality of ischemic heart disease. J Atheroscler Res 8:591, 1968
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14. Lawrence JC, Xabregas A, Gray L, Ham JM: Seasonal variation in the incidence of deep vein thrombosis. Br J Surg 64:777, 1977 15. Patterson E, Scherlag BJ, Lazzara R: Mechanism of prevention of sudden death by nadolol: differential actions on arrhythmia triggers and substrate after myocardial infarction in the dog. Am Co11 Cardiol 8: 1367, 1986 16. Scherlag BJ, Patterson ES, Berbari EJ, Lazzara R: Experimental simulation of sudden cardiac death in man: electrophysiological mechanisms and role of adrenergic influences. p. 299. In Brachmann J, Kubler W, Schomig A (eds): Adrenergic system and ventricular arrhythmias in myocardial infarction. SpringerVerlag, Berlin, Heidelberg, 1989
17. Scherlag BJ, Brachmamr J, Kabell G et al: Sustained ventricular tachycardia: common functional properties of different anatomic substrates. p. 379. In Zipes DP, Jalife J (eds): Cardiac electrophysiology and arrhythmias. Grune 6 Stratton, Orlando, 1985 18. Bleifer SB, Bleifer DJ, Hansmann DR et al: Diagnosis of occult arrhythmias by Holter electrocardiography. Prog Cardiovasc Dis 16:569, 1974 19. Panidis I, Morgamoth J: Holter monitoring during sudden cardiac death: clues to its etiology and prevention. Circulation 66:11-25, 1982 20. Lewis BH, Antman EM, Graboys TB: Detailed analysis of 24-hour ambulatory electrocardiographic recordings during ventricular fibrillation or Torsade de Pointes. J Am Co11Cardiol 2:426, 1983