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Sleeping hours: a relatively protected period for impending myocardial infarction
International Elsevier
Journal of Cardiology,
161
16 (1987) 161-167
IJC 00562
Sleeping hours: a relatively protected period for impending myocardial infarction Tomaso
Gnecchi
Ruscone
‘, Stefano Guzzetti *, Emanuela Daniel Di Mattia *
Piccaluga
‘,
’ Cardiology Unit, Merate General Hospital, Merate, Italy; ’ Medicina II, Ospedale L. Sacco, Vialha. Milano, Italy (Received
8 December
1986: revision
accepted
4 March
1987)
Gnecchi Ruscone T, Guzzetti S, Piccaluga E, Di Mattia D. Sleeping hours: a relatively protected period for impending myocardial infarction. Int J Cardiol 1987:16:161-167. We have retrospectively investigated the time of the onset of acute myocardial infarction in 2046 patients admitted to six coronary care units in a two-year period. A significantly reduced number of patients (P < 0.01) showed the beginning of acute myocardial infarction during the 0 to 6 a.m. period, while, during the remaining periods, no difference in frequency distribution was observed. Our results suggest that an impending myocardial infarction is more likely to occur at certain times of the day than others, suggesting a period of relative protection from onset.
Key words: Myocardial infarction; Time; Circadian rhythm
Introduction
Knowledge concerning the diagnosis and care of acute myocardial infarction has progressed considerably in recent years. It is, therefore, disappointing that information about the factors involved in the precipitation of the event is scanty [l]. It is common opinion that unusual physical efforts or strong emotional stress are causally linked with the infarctive event, although this relationship has been clearly established only in a low percentage of patients [2,3]. Recently, the time of onset of the acute myocardial infarction has been an object of investigation by several authors. By analyzing the distribution of the events over the 24 hours, high frequency peaks were recognized at different times by different
Correspondence
0167-5273/87/$03.50
to: Tomaso
Gnecchi
0 1987 Elsetier
Ruscone,
M.D., Viale Piave 40, 20129 Milano,
Science Publishers
B.V. (Biomedical
Division)
Italy.
162
authors. Some demonstrated a predominance of acute events during the morning hours [4,5], others in the evening [6] while still further investigations showed peaks in the morning and late evening hours [7]. A decrease in the total number of events during nighttime has also been reported [4,8]. In a recent study, we investigated [9] the relationship between meteorological factors and the beginning of the infarctive event in patients admitted to six coronary care units during a two-year period (1979-1980). In the present investigation we analyzed retrospectively the frequency distribution of the onset of acute myocardial infarction in those patients in whom this event could accurately be confined within a 30minute period.
Methods We analyzed retrospectively the records of all patients (2830) admitted over a two-year period (1979-1980) to six coronary care units in Milan (“De Gasperis” and “Rizzi” from the Niguarda Regional, S. Carlo Provincial and Maggiore-Policlinico Hospitals) and two nearby towns (Monza and Merate). We considered the diagnosis of acute myocardial infarction to be established by the presence of the following criteria: pain typical of myocardial ischemia for at least 30 minutes along with shock or syncope; electrocardiographic changes indicative of acute ischemia or infarction (new Q waves or 0.1 mV ST segment elevation or depression or both) and significative elevation of serum creatinephosphokinase (not the MB fraction). The time of the onset of acute myocardial infarction was determined within an accuracy of 30 minutes or less in 2046 patients. This was done by correlating the estimated time of onset of pain by the patients with the estimated time derived from the ascending curve of serum creatinephosphokinase (samples were collected every 4-6 hours). In the remaining 784 patients, onset could not be determined with such precision because of the occurrence of more than one episode of prolonged chest pain in the twelve hours preceding the principal episode or because it was impossible to determine with sufficient accuracy the time at which the symptoms appeared. Furthermore, no patients with silent myocardial infarction were admitted during the period we studied. The frequency distribution was analysed by dividing the day into intervals of six hour periods, starting from 0 to 6 a.m., in order better to represent the sleep-wakefulness cycle. The intervals were the ones selected by most previous authors dealing with this matter. The distribution of the number of acute myocardial infarctions occurring in these six-hour intervals was then analyzed with the &i-square test [lo]. If this test had significant results, the differing period was tested against the average of the other three periods of the day. The hourly trend was determined in the overall population as well as in subgroup of patients according to sex, age (under and over sixty), smoking habits and the site of myocardial infarction. The pattern of frequency distribution of onset of acute myocardial infarction was also determined by taking the day of the week and the season into account. Using a contingency table with 23 degrees of freedom, we compared the hourly frequency on weekdays with those of Saturday or Sunday. We also tested the first day of the week versus the hourly
163
average of the other significant.
weekdays.
A
P
value
of less
than
0.05
was
considered
Results The hourly frequency of onset of acute myocardial infarction was assessed in 2046 patients. The distribution, in six-hour intervals, of the number of acute myocardial infarctions showed that there was a significant reduction in the occurrence of acute myocardial infarction in the period between 0 to 6 a.m., compared to the remaining parts of the day (Fig. 1). This difference was also found when the same period incidence was compared with the average of the other three periods throughout the day. The proportion of acute myocardial infarction onset in the period between 0 to 6 a.m. was 0.77 times lower than the average proportion during the other periods. The analysis of hourly frequency of onset of acute myocardial infarction (in six-hour periods) was performed according to the day of the week. During a weekday or Saturday or Sunday, or a combination of the two, the single hourly incidence was not significantly different. On all days of the week there was a significant reduction of acute myocardial infarction in the interval between 0 to 6 a.m. The hourly trend in the day was also the same in the different seasons. No difference in this trend was found between males (1595) and females (451) or smokers (1031) and nonsmokers (1015). Moreover, a significant reduction in this hour interval was observed in the groups of patients under (990) and over 60 (1056). A further division in two groups of anterior (1234) versus inferior (812) acute
120
(
Fig. 1. Frequency
I
of onset of myocardial
infarction
in 2046 patients.
myocardial infarction showed a similar significant reduction during the 0 to 6 a.m. period (0.80 and 0.74, respectively).
of the proportion
Discussion Our data show a significant reduction in the frequency of onset of acute myocardial infarction in the period between 0 to 6 a.m. and a distribution without significant peaks during other periods throughout the day. This time interval is presumably the period when most people are asleep. Remarkably, this rhythm is present not only in every season of the year but also when a stratification for age, sex, and smoking habit, is carried out. It is interesting to note that this pattern was also observed in patients over and under 60 (i.e. retirement age for the majority) and independently of the day of the week. These findings, which seem contradictory to what is commonly believed, suggest that working rhythms do not seem to be directly correlated with the time of onset of acute myocardial infarction. They parallel the observations reported in the pioneering works of Master [2] and Pell and D’Alonzo [3]. Our results, in addition, are consistent with those of Yamazaki [8] and Pell and D’Alonzo [3] in demonstrating a significant decrease in the frequency of acute myocardial infarction in the same period of night hours. At variance with other reports, however we did not find a significant frequency peak either in the morning hours [4,5] or in the evening [6], or in the morning or at midnight [7]. There is an increase in the frequency of onset of acute myocardial infarction from 7 a.m. onwards together with an ascending trend from 8 p.m. to midnight. Even if there is no definite explanation of these different results, it must be remembered that differences in sample size as well as in life style may well affect the data. The exact definition of the onset of acute myocardial infarction is a complex matter. In this study, we determined a creatinephosphokinase curve with 4- to 6-hour interval sampling to confirm that myocardial infarction was indeed responsible for the occurrence of symptoms. Accordingly we limited our study to the group of patients in which we could determine the precise onset of the acute events while excluding the remaining 784 patients in which the time of onset could not be confined with precision to a half hour period. Special patterns of timing presentation are frequently seen in patients with coronary heart disease. A circadian variation has been demonstrated in patients with variant angina [ll]. A peak incidence of attacks occurs in the early morning hours along with a reduction in the ergonovine provocative test threshold [12]. Sudden coronary deaths [13] were also found to decrease significantly between 2 and 6 a.m. In addition, in patients with coronary heart disease, a significant reduction in the frequency and the pattern of ventricular ectopic beats is observed during sleeping hours [14]. Mixed angina, by far the most common form of angina [15], presents the maximal frequency of episodes during the period from 6 a.m. to noon and the minimum during the night [16,17].
165
Thus, with the exception of the special case of variant angina, the other aspects of coronary heart disease occur less frequently during sleeping hours. It is tempting, therefore, to attribute the decrease in frequency of acute myocardial infarction observed in the 0 to 6 a.m. periods to the tonically diminished load imposed on the heart by the net reduction in the heart rate and in blood pressure [18] and by the decrease in serum catecholamine levels [19] occurring during sleeping hours. In this regard, it has recently been shown by Quyyumi et al. [20] that episodes of nocturnal angina were preceded by an increase in heart rate (and presumably in blood pressure) as a result of arousal, lightening of sleep, body movements, rapid eye movement, and sleep apnoea. The absence of a significant pattern of the sleep-wakefulness suggests the relevance of a tonic more than a dynamic role of the sympathetic nervous system in the precipitation of acute myocardial infarction. Interestingly, Mancia et al. [18] have demonstrated a sleep-wakefulness periodicity of blood pressure and heart rate in normal and in hypertensive subjects, showing no significant peaks or nadirs during the 24-hour period. Sinus node function along with refractoriness of the atrioventricular node and myocardium also follow a circadian rhythm, with an acrophase between midnight and 7 a.m. [21]. Indeed, the main exogenous component of the human circadian rhythm is made by the alternation of sleep and wakefulness [22]. On the other hand, recent results obtained through ambulatory monitoring of the electrocardiogram [23] and of arterial blood pressure [24] in patients with stable angina pectoris show that most episodes of angina are not preceded by increased cardiac activity (i.e. without a marked increase in the double product). Furthermore. they occur at levels of exertion that are usually well tolerated and do not have a precipitating cause. The double product index alone does not consider changes in coronary vasomotor tone or the modifications of the ventricular volumes and the cardiac wall tension caused by the posture changes that occur during the 24-hour period. It can mirror the eventual dynamic pattern of the sympathetic nervous activity on heart rate and arterial pressure. The fact that the frequency of events of acute myocardial infarction does not show a significant and definite increase during the waking hours, despite the marked variations in cardiac loading which occurs during daytime, indicates that more complex factors are involved. An attractive hypothesis is that the cumulative effect of intermittent periods of ischemia during the day can result in a myocardial infarction in the later hours of the same day. This has been supported by experiments in anaesthetized dogs where the summing up of nondecisive brief ischemic periods resulted as necrotic events [25]. In conclusion, our results support the hypothesis that the variation in sympathetic tonic activity may well affect the frequency of acute myocardial infarction in parallel with the physiological sleep-wakefulness of the arterial blood pressure and heart rate pattern. Thus, the avoidance of physical and mental stress which can occur at any hour of the day could represent a crucial factor in reducing the incidence of acute myocardial infarction during the presumed period of sleeping hours.
166
Acknowledgements We should like to thank Dr. Federico valuable help.
Lombardi
and Ms. Y. Stewart for their
References 1 Dalen JE, Ockene IS, Alpert J. Coronary spasm, coronary thrombosis and myocardial infarction: a hypothesis concerning the pathophysiology of acute myocardial infarction. Am Heart J 1982;104:1119-1124. 2 Master AM. The role of effort and occupation (including physician) in coronary occlusion. J Am Med Assoc 1960;174:942-948. 3 Pell S, D’Alonzo CA. Acute myocardial infarction in a large industrial population: report of a 6 year study of 1356 cases. J Am Med Assoc 1963;185:831-838. 4 Myocardial infarction community registers: results of a WHO international collaborative study coordinated by the regional office for Europe. In: Public Health in Europe, No. 5. Copenhagen: Regional office for Europe (World Health Organisation), 1976;99. 5 Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-1322. 6 Dimitrov I, Khadzhikhristev A. Dynamics of the incidence of myocardial infarction in Smoljan District for the period 1965-1979. Vutr Boles 1983;22:40-46. 1 Thompson DR, Blandford RL, Sutton TW, Marchant PR. Tie of onset of chest pain in acute myocardial infarction. Int J Cardiol 1985;7:139-146. 8 Yamazaki N. Effects of hereditary and environmental factors on development of myocardial infarction. Jpn Circ J 1973;37:69-76. 9 Gnecchi Ruscone T, Crosignani P, Micheletti T, Sala L, Santomauro D. Meteorological influences on myocardial infarction in the metropolitan area of Milan. Int J Cardiol 1985;9:75-80. 10 Armitage P. Statistical methods in medical research. Oxford: Blackwell Scientific Publications, 1971. 11 Araki H, Nakamura M. Diurnal variation of variant angina. Int J Cardiol 1984;5:402-405. 12 Waters DD, Millar DD, Bouchard A, Bosch X, Theroux P. Circadian variations in variant angina. Am J Cardiol 1984;54:61-64. 13 Myers A, Dewar HH. Circumstances attendiug 100 sudden deaths from coronary heart disease with coroner’s necropsies. Br Heart J 1975;37:1133-1143. 14 Lawn B, Calvert AF, Armington R, Ryan M. Monitoring for sudden serious arrhythmias and high risk for sudden death. Circulation 1975;51/52(suppl 111):189-198. 15 Maseri A, Chierchia S, Kaski JC. Mixed angina pectoris. Am J Cardiol 1985;56:30E-33E. 16 Deanfield JE, Maseri A, Selwin AP, et al. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;October 1:753-758. 17 Quyyumi AA, Mockus L, Wright C, F ox KM. Morphology of ambulatory ST segment changes in patients with varying severity of coronary artery disease. Investigation of the frequency of nocturnal ischaemia and coronary spasm. Br Heart J 1985;53:186-193. in normotensive 18 Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart rate variabilities and hypertensive human beings. Circ Res 1983;53;96-104. 19 Turton MB, Deegan T. Circadian variations in plasma catecholamines, cortisol and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta 1974;55:389-397. AA, Efthimiou J, Quyyumi A, Mockus LJ, Spiro SG, Fox KM. Nocturnal angina: 20 Quyyumi precipitating factors in patients with coronary artery disease and those with variant angina. Br Heart J 1986;56:346-352. 21 Cinca J, Moya A, Figueras J, Roma F, Rius J. Circadian variations in the electrical properties of the human heart assessed by sequential bedside electrophysiological testing. Am Heart J 1986;112:315-321. JM. Circadian rhythms and their mechanism. Experientia 1986;42:1-13. 22 Minor DS, Waterhouse
167 23 Chierchia S, Gallino A, Smith G, et al. Role of heart rate in pathophysiology of chronic stable angina. Lancet 1984;Dec 15:1353-1357. 24 Chierchia S, Balasubramanian V, Muiesan L, et al. Transient impairment of coronary flow: a frequent cause of ischemia in chronic stable angina during normal daily life (abstract). J Am Co11 Cardiol 1984;3:579. 25 Geft IL, Fishbein MC, Ninomiya K, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982:66:1150-1153.
Journal of Cardiology,
161
16 (1987) 161-167
IJC 00562
Sleeping hours: a relatively protected period for impending myocardial infarction Tomaso
Gnecchi
Ruscone
‘, Stefano Guzzetti *, Emanuela Daniel Di Mattia *
Piccaluga
‘,
’ Cardiology Unit, Merate General Hospital, Merate, Italy; ’ Medicina II, Ospedale L. Sacco, Vialha. Milano, Italy (Received
8 December
1986: revision
accepted
4 March
1987)
Gnecchi Ruscone T, Guzzetti S, Piccaluga E, Di Mattia D. Sleeping hours: a relatively protected period for impending myocardial infarction. Int J Cardiol 1987:16:161-167. We have retrospectively investigated the time of the onset of acute myocardial infarction in 2046 patients admitted to six coronary care units in a two-year period. A significantly reduced number of patients (P < 0.01) showed the beginning of acute myocardial infarction during the 0 to 6 a.m. period, while, during the remaining periods, no difference in frequency distribution was observed. Our results suggest that an impending myocardial infarction is more likely to occur at certain times of the day than others, suggesting a period of relative protection from onset.
Key words: Myocardial infarction; Time; Circadian rhythm
Introduction
Knowledge concerning the diagnosis and care of acute myocardial infarction has progressed considerably in recent years. It is, therefore, disappointing that information about the factors involved in the precipitation of the event is scanty [l]. It is common opinion that unusual physical efforts or strong emotional stress are causally linked with the infarctive event, although this relationship has been clearly established only in a low percentage of patients [2,3]. Recently, the time of onset of the acute myocardial infarction has been an object of investigation by several authors. By analyzing the distribution of the events over the 24 hours, high frequency peaks were recognized at different times by different
Correspondence
0167-5273/87/$03.50
to: Tomaso
Gnecchi
0 1987 Elsetier
Ruscone,
M.D., Viale Piave 40, 20129 Milano,
Science Publishers
B.V. (Biomedical
Division)
Italy.
162
authors. Some demonstrated a predominance of acute events during the morning hours [4,5], others in the evening [6] while still further investigations showed peaks in the morning and late evening hours [7]. A decrease in the total number of events during nighttime has also been reported [4,8]. In a recent study, we investigated [9] the relationship between meteorological factors and the beginning of the infarctive event in patients admitted to six coronary care units during a two-year period (1979-1980). In the present investigation we analyzed retrospectively the frequency distribution of the onset of acute myocardial infarction in those patients in whom this event could accurately be confined within a 30minute period.
Methods We analyzed retrospectively the records of all patients (2830) admitted over a two-year period (1979-1980) to six coronary care units in Milan (“De Gasperis” and “Rizzi” from the Niguarda Regional, S. Carlo Provincial and Maggiore-Policlinico Hospitals) and two nearby towns (Monza and Merate). We considered the diagnosis of acute myocardial infarction to be established by the presence of the following criteria: pain typical of myocardial ischemia for at least 30 minutes along with shock or syncope; electrocardiographic changes indicative of acute ischemia or infarction (new Q waves or 0.1 mV ST segment elevation or depression or both) and significative elevation of serum creatinephosphokinase (not the MB fraction). The time of the onset of acute myocardial infarction was determined within an accuracy of 30 minutes or less in 2046 patients. This was done by correlating the estimated time of onset of pain by the patients with the estimated time derived from the ascending curve of serum creatinephosphokinase (samples were collected every 4-6 hours). In the remaining 784 patients, onset could not be determined with such precision because of the occurrence of more than one episode of prolonged chest pain in the twelve hours preceding the principal episode or because it was impossible to determine with sufficient accuracy the time at which the symptoms appeared. Furthermore, no patients with silent myocardial infarction were admitted during the period we studied. The frequency distribution was analysed by dividing the day into intervals of six hour periods, starting from 0 to 6 a.m., in order better to represent the sleep-wakefulness cycle. The intervals were the ones selected by most previous authors dealing with this matter. The distribution of the number of acute myocardial infarctions occurring in these six-hour intervals was then analyzed with the &i-square test [lo]. If this test had significant results, the differing period was tested against the average of the other three periods of the day. The hourly trend was determined in the overall population as well as in subgroup of patients according to sex, age (under and over sixty), smoking habits and the site of myocardial infarction. The pattern of frequency distribution of onset of acute myocardial infarction was also determined by taking the day of the week and the season into account. Using a contingency table with 23 degrees of freedom, we compared the hourly frequency on weekdays with those of Saturday or Sunday. We also tested the first day of the week versus the hourly
163
average of the other significant.
weekdays.
A
P
value
of less
than
0.05
was
considered
Results The hourly frequency of onset of acute myocardial infarction was assessed in 2046 patients. The distribution, in six-hour intervals, of the number of acute myocardial infarctions showed that there was a significant reduction in the occurrence of acute myocardial infarction in the period between 0 to 6 a.m., compared to the remaining parts of the day (Fig. 1). This difference was also found when the same period incidence was compared with the average of the other three periods throughout the day. The proportion of acute myocardial infarction onset in the period between 0 to 6 a.m. was 0.77 times lower than the average proportion during the other periods. The analysis of hourly frequency of onset of acute myocardial infarction (in six-hour periods) was performed according to the day of the week. During a weekday or Saturday or Sunday, or a combination of the two, the single hourly incidence was not significantly different. On all days of the week there was a significant reduction of acute myocardial infarction in the interval between 0 to 6 a.m. The hourly trend in the day was also the same in the different seasons. No difference in this trend was found between males (1595) and females (451) or smokers (1031) and nonsmokers (1015). Moreover, a significant reduction in this hour interval was observed in the groups of patients under (990) and over 60 (1056). A further division in two groups of anterior (1234) versus inferior (812) acute
120
(
Fig. 1. Frequency
I
of onset of myocardial
infarction
in 2046 patients.
myocardial infarction showed a similar significant reduction during the 0 to 6 a.m. period (0.80 and 0.74, respectively).
of the proportion
Discussion Our data show a significant reduction in the frequency of onset of acute myocardial infarction in the period between 0 to 6 a.m. and a distribution without significant peaks during other periods throughout the day. This time interval is presumably the period when most people are asleep. Remarkably, this rhythm is present not only in every season of the year but also when a stratification for age, sex, and smoking habit, is carried out. It is interesting to note that this pattern was also observed in patients over and under 60 (i.e. retirement age for the majority) and independently of the day of the week. These findings, which seem contradictory to what is commonly believed, suggest that working rhythms do not seem to be directly correlated with the time of onset of acute myocardial infarction. They parallel the observations reported in the pioneering works of Master [2] and Pell and D’Alonzo [3]. Our results, in addition, are consistent with those of Yamazaki [8] and Pell and D’Alonzo [3] in demonstrating a significant decrease in the frequency of acute myocardial infarction in the same period of night hours. At variance with other reports, however we did not find a significant frequency peak either in the morning hours [4,5] or in the evening [6], or in the morning or at midnight [7]. There is an increase in the frequency of onset of acute myocardial infarction from 7 a.m. onwards together with an ascending trend from 8 p.m. to midnight. Even if there is no definite explanation of these different results, it must be remembered that differences in sample size as well as in life style may well affect the data. The exact definition of the onset of acute myocardial infarction is a complex matter. In this study, we determined a creatinephosphokinase curve with 4- to 6-hour interval sampling to confirm that myocardial infarction was indeed responsible for the occurrence of symptoms. Accordingly we limited our study to the group of patients in which we could determine the precise onset of the acute events while excluding the remaining 784 patients in which the time of onset could not be confined with precision to a half hour period. Special patterns of timing presentation are frequently seen in patients with coronary heart disease. A circadian variation has been demonstrated in patients with variant angina [ll]. A peak incidence of attacks occurs in the early morning hours along with a reduction in the ergonovine provocative test threshold [12]. Sudden coronary deaths [13] were also found to decrease significantly between 2 and 6 a.m. In addition, in patients with coronary heart disease, a significant reduction in the frequency and the pattern of ventricular ectopic beats is observed during sleeping hours [14]. Mixed angina, by far the most common form of angina [15], presents the maximal frequency of episodes during the period from 6 a.m. to noon and the minimum during the night [16,17].
165
Thus, with the exception of the special case of variant angina, the other aspects of coronary heart disease occur less frequently during sleeping hours. It is tempting, therefore, to attribute the decrease in frequency of acute myocardial infarction observed in the 0 to 6 a.m. periods to the tonically diminished load imposed on the heart by the net reduction in the heart rate and in blood pressure [18] and by the decrease in serum catecholamine levels [19] occurring during sleeping hours. In this regard, it has recently been shown by Quyyumi et al. [20] that episodes of nocturnal angina were preceded by an increase in heart rate (and presumably in blood pressure) as a result of arousal, lightening of sleep, body movements, rapid eye movement, and sleep apnoea. The absence of a significant pattern of the sleep-wakefulness suggests the relevance of a tonic more than a dynamic role of the sympathetic nervous system in the precipitation of acute myocardial infarction. Interestingly, Mancia et al. [18] have demonstrated a sleep-wakefulness periodicity of blood pressure and heart rate in normal and in hypertensive subjects, showing no significant peaks or nadirs during the 24-hour period. Sinus node function along with refractoriness of the atrioventricular node and myocardium also follow a circadian rhythm, with an acrophase between midnight and 7 a.m. [21]. Indeed, the main exogenous component of the human circadian rhythm is made by the alternation of sleep and wakefulness [22]. On the other hand, recent results obtained through ambulatory monitoring of the electrocardiogram [23] and of arterial blood pressure [24] in patients with stable angina pectoris show that most episodes of angina are not preceded by increased cardiac activity (i.e. without a marked increase in the double product). Furthermore. they occur at levels of exertion that are usually well tolerated and do not have a precipitating cause. The double product index alone does not consider changes in coronary vasomotor tone or the modifications of the ventricular volumes and the cardiac wall tension caused by the posture changes that occur during the 24-hour period. It can mirror the eventual dynamic pattern of the sympathetic nervous activity on heart rate and arterial pressure. The fact that the frequency of events of acute myocardial infarction does not show a significant and definite increase during the waking hours, despite the marked variations in cardiac loading which occurs during daytime, indicates that more complex factors are involved. An attractive hypothesis is that the cumulative effect of intermittent periods of ischemia during the day can result in a myocardial infarction in the later hours of the same day. This has been supported by experiments in anaesthetized dogs where the summing up of nondecisive brief ischemic periods resulted as necrotic events [25]. In conclusion, our results support the hypothesis that the variation in sympathetic tonic activity may well affect the frequency of acute myocardial infarction in parallel with the physiological sleep-wakefulness of the arterial blood pressure and heart rate pattern. Thus, the avoidance of physical and mental stress which can occur at any hour of the day could represent a crucial factor in reducing the incidence of acute myocardial infarction during the presumed period of sleeping hours.
166
Acknowledgements We should like to thank Dr. Federico valuable help.
Lombardi
and Ms. Y. Stewart for their
References 1 Dalen JE, Ockene IS, Alpert J. Coronary spasm, coronary thrombosis and myocardial infarction: a hypothesis concerning the pathophysiology of acute myocardial infarction. Am Heart J 1982;104:1119-1124. 2 Master AM. The role of effort and occupation (including physician) in coronary occlusion. J Am Med Assoc 1960;174:942-948. 3 Pell S, D’Alonzo CA. Acute myocardial infarction in a large industrial population: report of a 6 year study of 1356 cases. J Am Med Assoc 1963;185:831-838. 4 Myocardial infarction community registers: results of a WHO international collaborative study coordinated by the regional office for Europe. In: Public Health in Europe, No. 5. Copenhagen: Regional office for Europe (World Health Organisation), 1976;99. 5 Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315-1322. 6 Dimitrov I, Khadzhikhristev A. Dynamics of the incidence of myocardial infarction in Smoljan District for the period 1965-1979. Vutr Boles 1983;22:40-46. 1 Thompson DR, Blandford RL, Sutton TW, Marchant PR. Tie of onset of chest pain in acute myocardial infarction. Int J Cardiol 1985;7:139-146. 8 Yamazaki N. Effects of hereditary and environmental factors on development of myocardial infarction. Jpn Circ J 1973;37:69-76. 9 Gnecchi Ruscone T, Crosignani P, Micheletti T, Sala L, Santomauro D. Meteorological influences on myocardial infarction in the metropolitan area of Milan. Int J Cardiol 1985;9:75-80. 10 Armitage P. Statistical methods in medical research. Oxford: Blackwell Scientific Publications, 1971. 11 Araki H, Nakamura M. Diurnal variation of variant angina. Int J Cardiol 1984;5:402-405. 12 Waters DD, Millar DD, Bouchard A, Bosch X, Theroux P. Circadian variations in variant angina. Am J Cardiol 1984;54:61-64. 13 Myers A, Dewar HH. Circumstances attendiug 100 sudden deaths from coronary heart disease with coroner’s necropsies. Br Heart J 1975;37:1133-1143. 14 Lawn B, Calvert AF, Armington R, Ryan M. Monitoring for sudden serious arrhythmias and high risk for sudden death. Circulation 1975;51/52(suppl 111):189-198. 15 Maseri A, Chierchia S, Kaski JC. Mixed angina pectoris. Am J Cardiol 1985;56:30E-33E. 16 Deanfield JE, Maseri A, Selwin AP, et al. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;October 1:753-758. 17 Quyyumi AA, Mockus L, Wright C, F ox KM. Morphology of ambulatory ST segment changes in patients with varying severity of coronary artery disease. Investigation of the frequency of nocturnal ischaemia and coronary spasm. Br Heart J 1985;53:186-193. in normotensive 18 Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart rate variabilities and hypertensive human beings. Circ Res 1983;53;96-104. 19 Turton MB, Deegan T. Circadian variations in plasma catecholamines, cortisol and immunoreactive insulin concentrations in supine subjects. Clin Chim Acta 1974;55:389-397. AA, Efthimiou J, Quyyumi A, Mockus LJ, Spiro SG, Fox KM. Nocturnal angina: 20 Quyyumi precipitating factors in patients with coronary artery disease and those with variant angina. Br Heart J 1986;56:346-352. 21 Cinca J, Moya A, Figueras J, Roma F, Rius J. Circadian variations in the electrical properties of the human heart assessed by sequential bedside electrophysiological testing. Am Heart J 1986;112:315-321. JM. Circadian rhythms and their mechanism. Experientia 1986;42:1-13. 22 Minor DS, Waterhouse
167 23 Chierchia S, Gallino A, Smith G, et al. Role of heart rate in pathophysiology of chronic stable angina. Lancet 1984;Dec 15:1353-1357. 24 Chierchia S, Balasubramanian V, Muiesan L, et al. Transient impairment of coronary flow: a frequent cause of ischemia in chronic stable angina during normal daily life (abstract). J Am Co11 Cardiol 1984;3:579. 25 Geft IL, Fishbein MC, Ninomiya K, et al. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 1982:66:1150-1153.