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Effect of activity on circadian variation in time of onset of acute myocardial infarction
be reassuredthat their risk of restenosisdoesnot appear to be significantly higher than the risk among patients who did not develop restenosisafter a prior angioplasty. 1. Holmes DR Jr, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, Van Raden MJ, Mock MB. Restenosisafter percutaneoustransluminal coronary angioplasty: a report from the PICA Registry of National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C-81C. 2. Myler RK, Topol EJ, Shaw RE, Stertzer SH, Clark DA, FishmanJ, Murphy MC. Multiple vesselcoronary angioplasty: classification, results, and patter& of restenosisin 494 consecutivepatients. Carhe! Cordiwasc Diagn 1987;13:1-15. 3. Meier B. Chronic total occlusion. In Meier B, ed. Coronary Angioplasty.
Effect of Activity on Circadian Myocardial Infaktion John Zornosa,
MD,
Martha Smith,
MD,
Orlando, FL: Grune & Stratton, 1987:190-199. 4. Ellis SG, Roubin GS, King SB III, Douglas JS Jr, Cox WR. Importance of stenosismorphologyin the estimationof restenosisrisk after electivepercutaneous transluminal coronary angioplasty. Am J Cwdiol 1989;63:30-34. 5. Meier B, Long SB III, Gruentzig AR, DouglasJS Jr, Hollman J, IschingerT, Galan K, Tankersley R. Repeat coronary angioplasty. J Am COILCardiol 1984;4:463-466. 6. Quigley PJ, Hlatky MA, Hinohara T, Rendall DS, PerezJA, Phillips HR III, Califf RM, Stack RS. Repeat percutaneoustransluminal coronary angioplasty and predictors of recurrent restenosis.Am J Cardiol 1989;63:409-413. 7. Williams DO, Gruentzig AR, Kent KM, Detre KM, Kelsey SF. Effxacy of repeat percutaneoustransluminal coronary angioplasty on coronary restenosis. Am J Cardiol 1984;53:32C-35C.
8. Brew SJ, JacobsAJ, Garber GR, Ruocca NA, Mills RM, Berg&on BA, Ryan TJ, Faxon DP. Prior restenosispredicts restenosisafter coronary angie plasty of a new significant narrowing. Am J Cardiol 1991;68:1158-1162.
Variation
and William Little,
in Time of Onset of Acute MD
here is a circadian variation in the onset of acute T myocardial infarction (AMI) with the peak inciand 12:00 Muller denceoccurring between630
mild exertion (3 to 5 METS) and moderate to marked exertion (>5 METS) using a previously described format.6 Patients were then classified into 2 groups: those A.M. A.M. et ali proposedthat this increasedfrequency of AM1 in who were asleep or at rest were classified as “No Exerthe morning is due to the circadian variation of potential tion” and those participating in mild or greater exertion triggers of plaque rupture and developmentof occlusive (>3 METS) as “Exertion.” Time of AMI was tabulated thrombosis. These potential triggers of AM1 include by 2-hour intervals, beginning 1 minute after the hour. The chi-square test was used to compare the distrimorning surgesof cortisol and catecholamines,increases in blood pressureand heart rate, as well as increasesin bution of AMIfor all patients, and then for the exertion platelet aggregability,2 blood viscosity,3 and vasomotor and no exertion groups. All patients were grouped totone in conjunction with diminished fibrinolytic activity.4 gether to analyze the significance of circadian variaThe peak incidence of AM1 occurs somewhatlater in the tion, comparing frequency during four &hour intervals
morning (1O:OOA.M. to 12:00A.M.) than the peak activity of most of the potential triggers that occur between6:00 A.M. and 9530A.M.~ Exertion enhancesthe potential adverseeffectsof all thesepotential triggers of AMI. Thus, we hypothesizedthat baselineresting circadian variation of potential triggers of AM1 would have the greatest effect on AM1 occurring in the absenceof exertion. If this hypothesis is correct, AM1 not associatedwith exertion would have a peak incidencecoinciding more closelywith the peak adverseeffects of the potential triggers in the early morning. Accordingly, this study wasundertaken to evaluate prospectively the influence of activity at the onset of AM1 to the circadian variation in the time of onset of AMI. Consecutive patients admitted to North Carolina Baptist Hospital with AMI were interviewed within 48 hours of admission. AMI was defined as significant elevation of creatine kinase-MB (total creatine kinase >250, MB >5%). Twenty-three patients were excluded because their clinical histories were judged to be unreliable. Two hundred ninety-four patients were evaluated (34% anterior, 28% inferioposterior, 38% non-Q-wave AMZs). The time of onset of AMI was quantitated as the time of onset of chest pain. Patients were questioned regarding their activity within 30 minutes before pain onset. Activity was graded as sleep/rest (<3 METS), From the Section of Cardiology, Bowman Gray School of Medicine, Wake Forest University, 300 South Hawthorne Road, Winston-Salem, North Carolina 27103. Manuscript received August 30, 1991; revised manuscript received and accepted December 11, 1991.
(12.91 A.M.
to 6:m
A.M.,
6:01
A.M.
t0
12:00 A.M., 12.91
to 6:00 P.M., and 6:Ol P.M. to 12:OOP.M.). Each 6hour interval was further subdivided into 2-hour intervals, beginning 1 minute after the hour. Patients were then separated into exertion and no exertion groups and again analyzed for circadian variation in a similar manner. AMI occurring between 12:OOP.M. and 6:00 A.M. were then excluded and the 2 groups were again compared. In 232 patients (79%), AMI occurred in the absence of exertion. In the remaining 62 patients, AMI was temporally associated with mild exertion (n = 53), or marked exertion (n = 9). There were no significant differences in age, sex distribution or clinical characteristics between patients with exertionally or nonexertionally related AMI. Analysis of all 294patients (Figure 1) showed a peak occurrence of AMI in the morning (6:Ol A.M. to 12:00 A.M.) (p <0.005) with the greatest frequency between 10:00 A.M. and 12.a A.M. The patients with AMI associated with exertion had a peak occurrence during the midday (1O:OOA.M. to 12:OOA.M.). Patients with nonexertionally related AMIs had a peak incidence from 6:00 A.M. to 8:00 A.M., earlier in the morning than the entire group. Because of customary sleeping patterns, few patients are active between 12:00 P.M. and 6:00 A.M.; thus, AMIs occurring during this time period were excluded and the groups were compared. There was still a significant difference in the distribution of AMIs between the 2 groups (p = 0.001). P.M.
BRIEF REPORTS
1089
Time of Onset of MI All Patients
0 2 4 6 8 101214161820n
With Exertion
0 2 4 6 8 10121416182022 Time
We found that most AMIs occur in the absenceof exertion (<3 METS). The peak incidenceof thesenonexertionally related AMIs is between690 A.M. and 8:00A.M. This is coincident with the peakactivity of many potential triggers of AM1 which include surgesin heart rate, blood pressure,catecholamines,cortisol, platelet aggregability, coronary vascular tone, plasmaviscosity, and fibrinolytic activity associatedwith awakeningand assumptionof the upright posture. Thesefactors have beentermed triggers becauseof their potential role as precipitants of coronary artery plaque rupture and subsequentthrombosis.’ Exercise accentuatesall of thesepotential triggers. Thus, it is not surprising that exertion has beenassociatedwith the occurrence of AM1 and sudden cardiac death. AMIs associatedwith exertion occurred throughout the day with a peak occurrencenear midday. It is possible that exercise’sprofound effect on the potential triggers of AM1 may overwhelm the circadian variation of their basal levels. Combining patients with exertionally and nonexertionally related AM1 shifted the apparent peak incidenceof AM1 severalhours later in the morning, later than the peak activity of most of the presumedtriggers. Thus, inclusion of exertionally precipitated AM1 appears to partially obscurethe early morning peak in AM1 and the potential effect of the circadian variation of the triggers. Our study dependson the ability of patients to accurately time the onsetof their myocardial infarction. However, this method of timing the onset of AM1 correlates well with enzymatic estimation of the time of onset.5The early morning surgein the basal activity of most potential triggers of AM1 is associatedwith awakening. Thus, the incidence of AM1 may be greater at the time of awakening, which may not always occur early in the morning. However, we did not collect this information, and thus are 1090
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
No Exertion
0 2 4 8 8 10121416142022
unable to perform this correction. If we had, we assume that the morning peakincidenceof AM1 in the absenceof exertion would be even more marked. Sinceexertion is rare between12:OOA.M. and 6:00A.M., this might accountfor the differencein distribution of the time of onset of AMIs with and without exertion. In contrast, analysis of the data after exclusion of events occurring from 12:00A.M. to 6:00 A.M. demonstratesthat this is not correct. In conclusion, our study suggeststhat the circadian variation in the basal level of potential triggers of AM1 has its most marked effect on AM1 occurring in the absenceof exertion. The peak incidence of AM1 in the absenceof exertion is early in the morning, coincident with the peak level of the potential triggers. Exertionally related AMIs occur throughout the day, with a peak incidence in the midday. It is possiblethat exertionally related changesin the potential triggers of AM1 overcomethe basal variation in thesetriggers, supporting the speculation that exertion may trigger AMI. 1. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onsetof acute cardiovascular disease.Circulation 1989;79:733-743. 2. Tofler JH, Brezinski DA, 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 SCD. N Engl J .&fed 1987;316:1514-1518. 3. Ehrly AM, Jung J. Circadian rhythm of human blood viscosity. Biorheobgy 1973;10:577-583. 4. Andreotti F, Davies GJ, Hackett DR, Khan MI, De Bart ACW, Aber VR,
Maseri A, Kluft C. Major circadian fluctuations in tibrinolytic factors and possible relevanceto time of onsetof myocardial infarction, suddencardiac death and stroke. Am J Cardiol 1988;62:635-639. 1. Muller JE, StonePH. Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK. PassamaniE, Roberts R, RobertsonT, Sobel BE, WilIerson JT, Braunwald E, and the Milis Study Group. Circadian variation in the frequency of onsetof acute myocardial infarction. N Engl J Med 1985;313:1315-1322. 6. Greenland P, Chu JS. Efficacy of cardiac rehabilitation services.Am Infern Med 1988;109:650-663. APRIL 15, 1992
Effect of Activity on Circadian Myocardial Infaktion John Zornosa,
MD,
Martha Smith,
MD,
Orlando, FL: Grune & Stratton, 1987:190-199. 4. Ellis SG, Roubin GS, King SB III, Douglas JS Jr, Cox WR. Importance of stenosismorphologyin the estimationof restenosisrisk after electivepercutaneous transluminal coronary angioplasty. Am J Cwdiol 1989;63:30-34. 5. Meier B, Long SB III, Gruentzig AR, DouglasJS Jr, Hollman J, IschingerT, Galan K, Tankersley R. Repeat coronary angioplasty. J Am COILCardiol 1984;4:463-466. 6. Quigley PJ, Hlatky MA, Hinohara T, Rendall DS, PerezJA, Phillips HR III, Califf RM, Stack RS. Repeat percutaneoustransluminal coronary angioplasty and predictors of recurrent restenosis.Am J Cardiol 1989;63:409-413. 7. Williams DO, Gruentzig AR, Kent KM, Detre KM, Kelsey SF. Effxacy of repeat percutaneoustransluminal coronary angioplasty on coronary restenosis. Am J Cardiol 1984;53:32C-35C.
8. Brew SJ, JacobsAJ, Garber GR, Ruocca NA, Mills RM, Berg&on BA, Ryan TJ, Faxon DP. Prior restenosispredicts restenosisafter coronary angie plasty of a new significant narrowing. Am J Cardiol 1991;68:1158-1162.
Variation
and William Little,
in Time of Onset of Acute MD
here is a circadian variation in the onset of acute T myocardial infarction (AMI) with the peak inciand 12:00 Muller denceoccurring between630
mild exertion (3 to 5 METS) and moderate to marked exertion (>5 METS) using a previously described format.6 Patients were then classified into 2 groups: those A.M. A.M. et ali proposedthat this increasedfrequency of AM1 in who were asleep or at rest were classified as “No Exerthe morning is due to the circadian variation of potential tion” and those participating in mild or greater exertion triggers of plaque rupture and developmentof occlusive (>3 METS) as “Exertion.” Time of AMI was tabulated thrombosis. These potential triggers of AM1 include by 2-hour intervals, beginning 1 minute after the hour. The chi-square test was used to compare the distrimorning surgesof cortisol and catecholamines,increases in blood pressureand heart rate, as well as increasesin bution of AMIfor all patients, and then for the exertion platelet aggregability,2 blood viscosity,3 and vasomotor and no exertion groups. All patients were grouped totone in conjunction with diminished fibrinolytic activity.4 gether to analyze the significance of circadian variaThe peak incidence of AM1 occurs somewhatlater in the tion, comparing frequency during four &hour intervals
morning (1O:OOA.M. to 12:00A.M.) than the peak activity of most of the potential triggers that occur between6:00 A.M. and 9530A.M.~ Exertion enhancesthe potential adverseeffectsof all thesepotential triggers of AMI. Thus, we hypothesizedthat baselineresting circadian variation of potential triggers of AM1 would have the greatest effect on AM1 occurring in the absenceof exertion. If this hypothesis is correct, AM1 not associatedwith exertion would have a peak incidencecoinciding more closelywith the peak adverseeffects of the potential triggers in the early morning. Accordingly, this study wasundertaken to evaluate prospectively the influence of activity at the onset of AM1 to the circadian variation in the time of onset of AMI. Consecutive patients admitted to North Carolina Baptist Hospital with AMI were interviewed within 48 hours of admission. AMI was defined as significant elevation of creatine kinase-MB (total creatine kinase >250, MB >5%). Twenty-three patients were excluded because their clinical histories were judged to be unreliable. Two hundred ninety-four patients were evaluated (34% anterior, 28% inferioposterior, 38% non-Q-wave AMZs). The time of onset of AMI was quantitated as the time of onset of chest pain. Patients were questioned regarding their activity within 30 minutes before pain onset. Activity was graded as sleep/rest (<3 METS), From the Section of Cardiology, Bowman Gray School of Medicine, Wake Forest University, 300 South Hawthorne Road, Winston-Salem, North Carolina 27103. Manuscript received August 30, 1991; revised manuscript received and accepted December 11, 1991.
(12.91 A.M.
to 6:m
A.M.,
6:01
A.M.
t0
12:00 A.M., 12.91
to 6:00 P.M., and 6:Ol P.M. to 12:OOP.M.). Each 6hour interval was further subdivided into 2-hour intervals, beginning 1 minute after the hour. Patients were then separated into exertion and no exertion groups and again analyzed for circadian variation in a similar manner. AMI occurring between 12:OOP.M. and 6:00 A.M. were then excluded and the 2 groups were again compared. In 232 patients (79%), AMI occurred in the absence of exertion. In the remaining 62 patients, AMI was temporally associated with mild exertion (n = 53), or marked exertion (n = 9). There were no significant differences in age, sex distribution or clinical characteristics between patients with exertionally or nonexertionally related AMI. Analysis of all 294patients (Figure 1) showed a peak occurrence of AMI in the morning (6:Ol A.M. to 12:00 A.M.) (p <0.005) with the greatest frequency between 10:00 A.M. and 12.a A.M. The patients with AMI associated with exertion had a peak occurrence during the midday (1O:OOA.M. to 12:OOA.M.). Patients with nonexertionally related AMIs had a peak incidence from 6:00 A.M. to 8:00 A.M., earlier in the morning than the entire group. Because of customary sleeping patterns, few patients are active between 12:00 P.M. and 6:00 A.M.; thus, AMIs occurring during this time period were excluded and the groups were compared. There was still a significant difference in the distribution of AMIs between the 2 groups (p = 0.001). P.M.
BRIEF REPORTS
1089
Time of Onset of MI All Patients
0 2 4 6 8 101214161820n
With Exertion
0 2 4 6 8 10121416182022 Time
We found that most AMIs occur in the absenceof exertion (<3 METS). The peak incidenceof thesenonexertionally related AMIs is between690 A.M. and 8:00A.M. This is coincident with the peakactivity of many potential triggers of AM1 which include surgesin heart rate, blood pressure,catecholamines,cortisol, platelet aggregability, coronary vascular tone, plasmaviscosity, and fibrinolytic activity associatedwith awakeningand assumptionof the upright posture. Thesefactors have beentermed triggers becauseof their potential role as precipitants of coronary artery plaque rupture and subsequentthrombosis.’ Exercise accentuatesall of thesepotential triggers. Thus, it is not surprising that exertion has beenassociatedwith the occurrence of AM1 and sudden cardiac death. AMIs associatedwith exertion occurred throughout the day with a peak occurrencenear midday. It is possible that exercise’sprofound effect on the potential triggers of AM1 may overwhelm the circadian variation of their basal levels. Combining patients with exertionally and nonexertionally related AM1 shifted the apparent peak incidenceof AM1 severalhours later in the morning, later than the peak activity of most of the presumedtriggers. Thus, inclusion of exertionally precipitated AM1 appears to partially obscurethe early morning peak in AM1 and the potential effect of the circadian variation of the triggers. Our study dependson the ability of patients to accurately time the onsetof their myocardial infarction. However, this method of timing the onset of AM1 correlates well with enzymatic estimation of the time of onset.5The early morning surgein the basal activity of most potential triggers of AM1 is associatedwith awakening. Thus, the incidence of AM1 may be greater at the time of awakening, which may not always occur early in the morning. However, we did not collect this information, and thus are 1090
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
No Exertion
0 2 4 8 8 10121416142022
unable to perform this correction. If we had, we assume that the morning peakincidenceof AM1 in the absenceof exertion would be even more marked. Sinceexertion is rare between12:OOA.M. and 6:00A.M., this might accountfor the differencein distribution of the time of onset of AMIs with and without exertion. In contrast, analysis of the data after exclusion of events occurring from 12:00A.M. to 6:00 A.M. demonstratesthat this is not correct. In conclusion, our study suggeststhat the circadian variation in the basal level of potential triggers of AM1 has its most marked effect on AM1 occurring in the absenceof exertion. The peak incidence of AM1 in the absenceof exertion is early in the morning, coincident with the peak level of the potential triggers. Exertionally related AMIs occur throughout the day, with a peak incidence in the midday. It is possiblethat exertionally related changesin the potential triggers of AM1 overcomethe basal variation in thesetriggers, supporting the speculation that exertion may trigger AMI. 1. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onsetof acute cardiovascular disease.Circulation 1989;79:733-743. 2. Tofler JH, Brezinski DA, 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 SCD. N Engl J .&fed 1987;316:1514-1518. 3. Ehrly AM, Jung J. Circadian rhythm of human blood viscosity. Biorheobgy 1973;10:577-583. 4. Andreotti F, Davies GJ, Hackett DR, Khan MI, De Bart ACW, Aber VR,
Maseri A, Kluft C. Major circadian fluctuations in tibrinolytic factors and possible relevanceto time of onsetof myocardial infarction, suddencardiac death and stroke. Am J Cardiol 1988;62:635-639. 1. Muller JE, StonePH. Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK. PassamaniE, Roberts R, RobertsonT, Sobel BE, WilIerson JT, Braunwald E, and the Milis Study Group. Circadian variation in the frequency of onsetof acute myocardial infarction. N Engl J Med 1985;313:1315-1322. 6. Greenland P, Chu JS. Efficacy of cardiac rehabilitation services.Am Infern Med 1988;109:650-663. APRIL 15, 1992