Circadian variation in the incidence of sudden cardiac death in the framingham heart study population

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CircadianVariationin the Incidenceo Deathin the FraminghamHea STEFAN N. WILLICH, MD, DANIEL LEVY, MD, MICHAEL GEOFFREY H. TOFLER, MB, PETER H. STONE, MD, and JA

To determine if sudden cardiac death shows circadian variation, the time of day of sudden cardiac deaths in the Framingham Heart Study was analyzed. Analysis was based on mortality data collected in a standardized manner for the past 38 years for each death among the 5,209 persons in the original cohort., The necessary assumptions about the cause and timing of unwitnessed deaths were made in a manner likely to diminish the possibility of detecting an increased incidence of sudden cardiac death during the morning. In the Framingham study, analyses using these assumptions reveal a significant circadian variation (p
peak incidence from 7 to 9 AM and a decreased incidence from 9 AM to 1 PM. Risk of sudden cardiac death was at least 70% higher during the peak period than was the average risk during other times of the day. Further studies are needed to confirm this finding in other populations, to collect data regarding medications and to determine activity immediately before sudden cardiac death. Investigation of physiologic changes occurring during the period of increased incidence of sudden cardiac death may provide increased insight into its causes and suggest possible means of prevention. (Am J Cardiol 1987;60:891-80

A

lthough sudden cardiac death accounts for 10 to 20% of deaths in industrialized societies, afflicting over 400,000 persons each year in the U.S., the pathophysiologic mechanisms of this catastrophic event are poorly understood and potential means of prevention are undeveloped .1-3 A new approach to identification of the mechanisms of sudden cardiac death is suggested by recent reports that nonfatal myocardial infarction and episodes of silent or symptomatic myocardial ischemia occur more frequently in the morning than during other times of the day.4-6 Investigation of the time of sudden cardiac death is complicated by several obstacles. Diagnosis of sudden cardiac death can rarely be confirmed by objective data and determination of the time of its occurrence is complicated because many deaths are unwitnessed. Furthermore, because the probability that a sudden

cardiac death will be unwitnessed is higher during the night than during other periods of the day, many deaths that occur during the night may escape analysis, creating the false appearance of a low frequency of sudden cardiac death during the night. Finally, it is generally believed that approximately one-third of sudden cardiac deaths are associated with acute myocardial infarction.7-z1 Since nonfatal myocardial infarction exhibits circadian ,variation,4 this association complicates assessment of the time of day of “primary” sudden cardiac death, i.e., sudden cardiac death not secondary to acute myocardial infarction. To overcome these difficulties, we analyzed the time of sudden cardiac death in the prospectively defined and closely monitored original cohort of the Framingham Heart Study.

From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, and the Framingham Heart Study, Framingham, Massachusetts. Manuscript received March 30, 1987; revised manuscript received and accepted May 29,1987. Address for reprints: Stefan N. Willich, MD, Harvard Medical School, 164 Longwood Avenue, Boston, Massachusetts

Study population: The present study is based on mortality data that have been collected in a standardized manner by the Framingham Heart Study for 38 years, The original cohort consisted of 5,209 residents of Framingham, Massachusetts, who were between 30 and 62 years old in 1948. 22 The Framingham Heart Study personnel learned of the death of a member of the study from the family, from an obituary notice,

Methods

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from monitoring of hospitalizations in the only hospital in Framingham or during an attenipt to contact the subject for routine biennial examination. All data concerning the deafh, including autopsy reports, if available, are supplied to the Mortality Review Committee of the Framinghtim Heart Study, which determines the unclerlying cause of death. The present analysis does not include deaths of patients who were hospitalized or bedridden; since their endogenous and exogenous circtidian rhythms were likely to have been altered, or deaths occurring within 1 month after a documented myocardial iQfarction, which were likely to be secondary to that event. Deaths of nursing home residents were included in the study unless there was evidence that the deceased was continuously confined to bed.

Identification of definite sudden cardiac deaths: Since its inception, the Framingham Heart Study has classified a death 3~ a sudden cardiac death using the following definitionz3: “If a subject, apparently we!l, was observed to have died within a few minutes (operationally documented as under one hour) from onset of symptoms and if the cause of death could not reasonably be attributed on the basis of the full clinical iriformation and the info:mation concerning death to some potentially lkthal disease other than coronary heart disease, this was called sudden death and was attributed to co?onary heart disease.” For the present study, deaths that met this definition were considered definite sudden cardiac deaths.

Identification of possible sudden cardiac deaths: To permit inclusion of sudden cardiac deaths tl+ occurred during the night [or at other times] but could not be termed-definite because they were unwitnessed, the following definition was developed: Deaths that may have occurred within 1 hour of onset of symptoms and in which there, was no apparent noncardiac cause of death were considered cases of possible sudden cardiac death. Possible sudden cardiac deaths were identified from a review of deaths originally classified as due to “coronary heart disease death riot known to be sudden” or due to “unknown cause.” Cases for which inclusion in the present study was questionable were preSented for arbitration to a study committee blinded as to the time of day at which the person died. Determination of time of death: If conflicti?g data on time of death were encountered, the time was determined on the basis of the highest ranked of the follqwing sources:’ First, interviews with witnesses of the death, or interviews with persons in close contact with the deceased, who cotild describe the circumstar&s surrounding the death; second, medical reports, including autopsy results; third, newspaper accou@s of the death; and fourth, death certificates. The times of unwitnessed deaths were estimated. on the basis of the mqst precise information available. For purpgses of analysis, the hourly probability of death w&s equally distributed over the interval in which the death was known tq have occurred. In some cases, this period was the interval between the time the person was last seen alive and the time the person was found dead. Ifi cases in which the quarte? of the day in which

the death occurred could be determined but more precise timing was not possible, the probability of death was evenly distributed over the 6 hours of the quarter of the day. When the only information available about the nighttime interval was that the individual was found dead in bed, the probability of: death was evenly distributed between midnight and 6 AM. If no estimate of time of death could be made, the probability of death was evenly distributed over 24 hours. Siatistical analysis: Assessment of the periodicity of sudden cardiac death: The distribution of sudden cardiac death was first tested for differences among the four 6-hour intervals of the day with a chi-square test for goodness of fit. If this test showed significant differences, the period with the highest frequency was tested to evaluate its difference from the average of the other 3 periods. To quantify the periodic structure of the frequency distribution ‘of sudden cardiac death, a Z-harmonic regression model was fitted to the data. It contained 2 sine and cosine functions in which the independent variable was the time of the day. As time of day varied, this model generated a regression curve that was compared with the observed hourly distribution of sudden cardiac death. Model goodness-of-fit was evaluated by t tests (2-tailed) on the estimated coefficients, an F test on the overall model, and R2 and adjusted R2 statistics. 24 A p value
Results Since its inception in 1948, a total of 2,458 (47%] of the 5,209 persons originally enrolled in the Framingham Heart Study have died and their cause of death has been recorded. In the present study 726 certain and 156 possible cardiac deaths were identified. Of these, there were 264 definite sudden cardiac deaths (11% of total deaths) and 165 possible sudden cardiac deaths [7% of total deaths). The mean age of patients in

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the combined group of 4.29 definite or possible sudden cardiac death victims was 69 f lo.7 years. Gender distribution was 65% male and 35% female. The primary source of information about time of death was an interview or a telephone discussion with a witness of the death or a close relative of the deceased in 43% of cases, a medical report in 34%, newspaper account in 11% and the death certificate in 12%. The precise time of death could be identified for 255 of the 429 persons (59%). For 82 persons (19%], the quarter of the day in which death occurred was the most specific information that was identified. The interval between the time a person was last seen alive and the time found dead [unless found dead in bed) was the most precise timing that could be ascertained for 26 (6%). In 42 persons (10%) the only information available on time of death was the report that they were found dead in bed. No estimate of time of death could be made for 24 persons (6%) (1 file was missing, 3

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deaths were unwitnessed an 20 deaths were witnessed but the file did not contain a report of time of death and time of death could not be ascertained retrospectively). The known or estimated time of occurrence of definite sudden cardiac death exhibited a prominent circadian variation [p ~0.05) with a low frequency during the night, as would be expected from the requirement that the deaths be witnessed (Fig. 1A). However, circadian variation remained when the known or estimated time of possible sudden cardiac death was added to that of definite sudden cardiac death (Fi. 1B). The hourly risk of sudden cardiac death was at least 70% greater between 7 and 9 AM than the average risk during the remaining 22 hours of the day. Significantly more sudden cardiac deaths occurred between 6 AM and noon than during the other quarters of the day (p
3

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FIGURE 1. A, time of day of definite sudden cardiac death (n = 264). The frequency is low at night as a consequence of the dlminished likelihood that a nighttime sudden cardiac death will be witnessed, but the decrease in incidence from 9 AM to 1 PM occurs during a period in which observation is likely to be constant. B, time of day of definite or possible sudden cardiac death (n = 429). The hourly risk of sudden cardiac death is approximately 70% higher from 7 to 9 AM than the average risk during the remaining 22 hours Of the

day.

4

6 A.M.

death known

not known

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FIGURE 2. A, time of day of secondary sudden cardiac death assumed to be due to myocardial infarction (n = 143). On the basis of which indicate that no more than one-third of previous stUdies,7,21 sudden cardiac deaths are due to acute occlusfve coronary thrombosis, 143 deaths (one-third of deaths in panel 6) are distributed in the previously observed circadian pattern of nonfatal myocardiaf infarction.4 B, time of day of primary sudden cardiac death, presumably not attributable to myocardial infarction (n = 286). The distrfbution is achieved by subtracting the hourly number of sudden cardiac deaths presumed to be secondary to myocardial infarction (panel A) from the corresponding hourly number of total deflnite 01 possible sudden cardiac deaths (panel B).

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TABLE

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OF SUDDEN

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DEATH

qf Sudden

Cardiac

Deaths Quarter 6-12

O-6 AM

Quarter

known

per

Quarter

of the Day

of Day

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Def

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36

69

19

65

20

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Pos 85 (337)

Quarter

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3

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3

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3

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12

00 (92)

28

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62

“p
sudden

cardiac

96

44

72

(140)’ 33%

(90) 21%

death;

pos = possible

and the months of the year. A fresh occlusive coronary thrombus was found in 8 of the 24 persons (33%) in whom a postmortem report was available. Statistical anqlysi?: Assessment of the periodicity of sudden cardiac death: The periodic nature of the incidence of definite or possible sudden cardiac death (Fig. iB) is indicated by the following %harmonic regression mode!: sudden cardiac deaths per hour = 17.9 - 2.39 cos (27d24) + 1.49 sin (&d&4) + 9.31 cos (47d 24]- 3:33 sin (4?rt/24), where t = time of day in hours. The fit to the data is statistically significant (F test, p <9.02]. Since the coefficients of the second sine and first cosine functions differ significantly from 0 (p <0.05), the distribution has a significant circadian periodicity. The R2 and adjusted R2 for the model are 46.9 and 35.8, respectively. Estimqtion of time of occurrence of primary sudden cardiac death: In a hypothetical analysis, 143 sud,den cardiac deaths (the one-third of total sudden cardiac deaths assumed to be secondary to myocardial infarction] were distributed in the hourly pattern previously observed for nonfatal myocardial infarction (Fig. 2A]. The hourly frequency of these presumed secondary sudden cardiac deaths was then subtracted from the corresponding hourly frequency of total sudden cardiac deaths (Fig. lB], yielding the estimated hourly ‘frequency of primary sudden cardiac death (Fig. 2B]. This distributisn of primary sudden cardiac death reveals an increased incidence (p
Discussion The present study, which is based on the mortality experience of the prospectively defined, routinely monitored population of the Framingham Heart Study, shows a significant circadian variation,in the mcidence of sudden cardiac death, with a peak period

27

68

(99) 23%

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32 WO) 23%

264

165

(4291 100%

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from 7 to 9 AM. The 2 greatest obstacles to the present study were the well-known difficulty of identifying all cases of sudden cardiac death in a population, and the problem, specific to this study, of determining the time of occurrence of an event that is often unwitnessed and whose victim, by definition, dies, eliminating the possibility of obtaining first-hand historical data. The ideal database on which to determine the time of day of sudden cardiac death consists of a large population followed for decades, in which a postmortem examination was performed for each death (to eliminate the need for assumptions about the cause of death), and in which some form of continuous surveillance would permit determination of the exact time of death (to eliminate the need for assumptions about the time of unwitnessed deaths]. Since such a database does not exist and is unlikely to exist soon, we turned to the Framingham Heart Study as a close approximation to the ideal database for the present study. Commonly used estimates ‘of the prevalence of sudden cardiac death are already based on data from the Framingham Heart Study.2J The necessary assumptions about identification of cases of possible sudden cardiac death and their time of occurrence were than made in a manner most likely to diminish the possibility of detecting an increased frequency of sudden cardiac death in the period from 6 AM to noon. For instance, persons found dead in bed who might Nell have died at 7 or 8 AM, thereby augmenting an increased morning frequency, were considered to have died between midnight and 6 AM [Fig. lB), raising the estimated occurrence of sudden cardiac death during the hours of sleep, the period initially hypothesized to be a trough of a circadian variation. Several features of the data presented in Figure 1 deserve comment. First, in addition to the demonstration of a circadian variation in the incidence of sudden cardiac death, the figures provide upper and lower limits for its amplitude. The distribution of definite sudden cardiac death with time of death known is an overestimation of the amplitude of the circadian periodicity [unwitnessed deaths during the night and deaths for which the time of death is estimated are

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excluded),whereasthe distribution of definite or sible sudden cardiac deathswith known or estimated time of death[Fig. 1Bj is an underestimationbecauseit is partially basedon worst-caseassumptions.Furthermore, both figures would be likely to show a more prominent peak if the data were adjusted to account for the variable wake-times of the victims. Second, there is a decrease in incidence of sudden cardiac death from 9 AM to 1 PM, a period in which observation is likely to be constant.Third, the incidence of sudden cardiac death during the normal hours of sleep (11 PM to 8AM) is lower than during the normal hoursof activity. This finding is supported by previous results of epidemiologic studies of activity preceding sudden cardiac death.7,8v25 Severalstudiesof time of deathsupport the conclusionof the presentstudy. In a summary report of 432,892deathsfrom 49separatestudies,Smolensky et aP reported a circadian variation for total mortality, with a peak at 8 AM. In a subgroupof 7,644 personsin whom death was reported to be due to a cardiovascularcause,there was significant circadian variation, with a peak at 10 AM. Mitler et alz7reporteda circadian variation for total mortality in a study of 4,619 deathsin New York state.The variation for total mortality was generated by a circadian variation of ischemic heart diseasemortality, which peaked at 8 AM. A study from the German Democratic Republic revealed a similar rhythm for out-of-hospital cardiac death.z8A study based solely on death certificates, which have certain limitations, shows an increased incidence of sudden cardiac death in the morningaz5 One may arguethat the circadian variation of sudden cardiac death reported in the present study is merely an expected result of the previously reported circadian variation of nonfatal myocardial infarction4 and the known relation between myocardial infarction and sudden cardiac death. In our opinion, such a viewpoint is an overinterpretation of the previously available studiesaboutthe myocardial infarction/sudden cardiac death relation and an underestimation of the difficulties inherent in such studies.There arebiologic barriers to confirmation of the diagnosisof myocardial infarction in personswho die lessthan 1 hour after the onsetof the event, since there is no time for myocardial enzymes to appear in plasma, and even direct observationof the myocardium provided by autopsy examination cannot reliably detect myocardial necrosisat such an early stage.29Of necessity,therefore, autopsystudiesfocuson the incidence of an acute occlusivecorQnarythrombus,which was found in 29f 8% of sudden cardiac death victims7-I8(33% in the presentstudy). The other important source of information about the role of myocardial infarction in causing sudden cardiac death are findings in victims of cardiac arrest who are resuscitated.l*-21However, in these studies enzymatic or electrocardiographicevidence of myocardial infarction doesnot indicate whether infarction was the causeor the result of the cardiac arrest.Thus, the reported 26 f 12% and 39 f 2% incidence of myocardial infarction (as determined by electrocar-

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diographic changes13-21 or enzymatic changes,zOJi respectively)representupper limits of the percentageof casesin which myocardial infarction causedthe cardiac arrest. A statistical analysisbased on the assumptionthat one-third of suddencardiac deathsare causedby myocardial infarction indicates that there is a significant circadian variation of primary sudden cardiac death. This is an important, conceptually new finding of the presentstudy, sincethere have been few cluesasto its cause,and, for resuscitatedpersons,primary sudden cardiac death has been considered to have a worse prognosisthan secondarysudden cardiac death.20~21 The observationthat suddencardiac death is more likely to occurfrom 8 AM to noon is compatible with the z leading theoriesof causationof this disorder.First, it has been proposedthat most casesof sudden cardiac death are a consequenceof myocardial ischemia.3°-32 On the basisof the finding that coronarythrombi could be identified in 95 to 100 cases of sudden cardiac death, the hypothesishas been advancedthat sudden cardiac death results from ischemia secondary to platelet aggregatesforming on an atheroscleroticcoronary lesion.gThis processmay well be more likely to occur in the morning becauseit is a time of increasing arterial pressure33 (which may increasethe likelihood of rupture of an atheroscleroticplaque,therebyexposing thrombogenic collagen34],increasing coronary artery tones5and increasing platelet aggregability.36 Second, it has been proposed that sudden cardiac death is frequently the result of a primary arrhythmic event.lJ7s3* A fatal arrhythmia might be more likely in the morning becauseincreasedactivity of the sympathetic nervoussystem,which is known to occur in the morning,3gmay predisposeto an arrhythmia.40 Acknowle ent: We are grateful to MeavenAnderson, PhD, programming assistance,to Emery Brown, PhD, for statistical analysis of the circadian waveform, and to Kathleen Barney for assistancein the preparation of the manuscript. 1. Lawn B. Sudden cardiac death: the maior challenne confrontina contemporary cardiology. Am f Cardiol 1979;&?:3’~%%28. y ’ t 2. Schatzkin A, Cupples LA, Heeren T, Morelock S, Kannel WB. Sudden death in the Framingham Heart Study. Am 1 Epidemiol 2984;220:888-899. 3. Kannel WE, Doyle JT, McNamara PM, Quickenton P, Gordon T. Precursors of sudden coronary death. Factors related to the incidence of sudden death. Circulation 1975;51:606-613. 4. Muller IE, Stone PH, Turi ZG, Rutherford JD, Czeisler C, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel BE, Willerson JT, Braunwald E, and the MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl f Med 1985;313:1325-1322. 5. Campbell S, Barry J, Rebecca GS, Rocco MB, Nabel EG, Wayne RR, Selwyn AP. Active transient myocardial ischemia during daily life in asymptomatic patients with positive exercise test and coronary artery disease. Am l Cardiol 1986;57:1010-1016.

6. Mattiolo G, Cioni G, Andre& C. Time sequence of anginal pain. CJin Cardiol 1986;9:165-169. 7. Hinkle LE, Tbaler IIT. Clinical classification of cardiac deaths. CircuJation 1982;65:457-464. 8. Myers A, Dewar HA. Circumstances attending 100 sudden deaths from coronary artery disease with coroner’s necropsies. Br Heart !1975;37:11331143. 9. Davies Mj, Thomas AC. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N EngJ r Med 1984;310:1137-1140. 10. Kuller LH, Cooper M, Perper J, Fisher R. Myocardial infarctjon and

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sudden death in an urban community. Bull NY Acad Med 1973;49:532-543. 11. Baba N, Bashe W] (r, Keller MD, Geer ]C, Anthony JR. PathoJogy of atherosclerotic heart disease in sudden death. I. Organizing thrombus and acute coronary vessel lesions. Circulation 1975;52:suppJ JJJ:III-53-III-59. 12. Rissanen V, Romo M, Siltanen P. Prehospital sudden death from ischemic heart disease-a postmortem study. Br Heart J 1978;40:1025-1033. 13. Scott RG, Briggs RS. Pathological findings in pre-hospital deaths due to coronary atherosclerosis. Am J CarioI 1972;29:782-787. 14. Crawford T, Dexter D, Teare RD. Coronary artery pathology in sudden death from myocardial ischemia. Lancet 1961;1:181-185. 15. Lovegrove T, Thompson P. The role of acute myocardial infarction in sudden cardiac death. A statistician’s nightmare (editorial). Am Heart J 1978:96:711-713.

16. Reichenbach DD. Moss NS, Meyer E. Pathology of the heart in sudden cardiac death. Am I CardioJ 19773393865-872. 17. Goldstein S, Friedman L, Hutchinson R, Canner P, Romhilt D, Schlant R, Sobrino R, Verter 1, Wasserman A, and the Aspirin Myocardial Infarction Study Research Group. Timing, mechanism and clinical setting of witnessed deaths in postmyocardial infarction patients. JACC 1984;3:1111-1117. 18. Libertbson RR, Nagel EL, Hirscbman )C, Nussenfeld SR, Blackbourne BD, Davis )H. Pathophysiologic observations in prehospital ventricular fibrillation and sudden cardiac death. Circulation 1974;49:790-799. 19. Goldstein S. Landis IR. Leiehton R. Ritter G, Vasu CM, Lantis A, Serokman R. Characteristics of the &uscitated out-of-hospital cardiac arrest victim with coronary heart disease. Circulation 1981;64:977-984. 20. Baum RS, Alvarez H III, Cobb LA. Survival after resuscitation from oufof-hosnital ventricular fibrillation. Circulation 1974;50:1231-1235. %%‘haffer WA, Cobb’LA. Recurrent ventricular fibrillation and modes of death in survivors of out-of-hospital ventricular fibrillation. N EngJ J Med 1975;293:259-262.

22. Dawber TR, Meadors GF, Moore FE )r. Epidemiological approaches to heart disease: the Framingham Study. Am J Pub Health 1951;41:279-288. 23. Shurtleff D. Some characteristics related to the incidence of cardiovascuJar disease and death: Framingham Study 18-year follow-up. In: Kannel WG, Gordon T, eds. The Framingham Study. Section 30. Washington, DC: US Govt Print Off, 1974 (DHEW PubJ NO. [NIH] 74-599). 24. Rosner BA. Fundamentals of Biostatistics. 2nd Ed. Boston: Duxbury Press, 1986. 25. Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangos I, Stone P. Circadian variation in the frequency of sudden cardiac death. Circulation 19a7;75:131-138.

28. Smolensky M, Halberg F, Sargent F. Chronobiology of the life sequence. In: Itoh S, Ogata K, Yoshimura, eds. Advances in climatic physiology. New York: Springer-VerJag, 1972;281-318. 27. Mitler MM, Hajdukovic RM, Shafor R, Hahn PM, Kripke DF. When people die: cause of death versus time of death. Am J Med 1987;82:266-274. 28. Otto W, Hempel WE, Wagner CU, Best A. Some periodical and aperiodicaJ variations of mortality from myocardial infarction in the German Democratic Republic. Z Gesamte Inn Med 1982;37:756-763. [Eng. Abstract) 29. Davies MJ. Pathological view of sudden cardiac death. Br Heart J 1981;45:88-96. 30. Kowey PR, Verrier

RL, Lawn B, Handin RI. Influence of coronary platelet aggregation on ventricular electrical properties during partial coronary arferv stenosis. Am T Cardiol 1983:51:596-602. 31:Kubler W, Schbmig A, Senges J. The conduction and cardiac sympathetic systems: metabolic aspects. JACC 1985;5:suppJ:157B-161B. 32. Fuster V, Steele PM, Chesebro JH. Role of platelets and thrombosis in coronary atherosclerotic disease and sudden death. JACC 1985;5:suppJ:175B1848. 33. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood pressure. Lancet 1978;1:795-797. 34. Davies MJ, Thomas AC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363-373. 35. Willerson JT, Campbell

WB, Winniford MD, Schmitz J, Apprill P, Firth BG, Ashton J, Smithennan T, Bush L, Buja IM. Conversion from chronic to acute coronary artery disease: speculation regarding mechanisms (editorial). Am J CardioJ 1984;54:1349-1354. 36. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987;316:1514-1518. 37. Skinner JE. Regulation of cardiac vulnerability by the cerebral defense svstem. lACC 1985:5:sunnk88B-94B. $8. Elioi RS, Buell JC. EoJe of emotions and stress in the genesis of sudden death. JACC 1985;5:suppJ:95B-98B. 39. Turton MB, Deegan T. Circadian variations of plasma catecholamine. cortisol, and immunoreactive insulin concentrations in supine subjects. CJin Chim Acta 1974:55:389-397. 40. Corbalan RI Verrier-R, Lown B. PsychoJogicaI stress and ventricular arrhythmias during myocardial infarction in the conscious dog. Am J Cardiol 1974;34:692-696.