Circadian Variation of Plaque Rupture inAcute Myocardial Infarction

Atsushi Tanaka, MD, Takahiko Kawarabayashi, MD, Daiju Fukuda, MD,Yoshiharu Nishibori, MD, Tsunemori Sakamoto, MD, Yukio Nishida, MD,

Kenei Shimada, MD, and Junichi Yoshikawa, MD

Studies have reported a circadian variation in the onsetof acute myocardial infarction (AMI). Pathologic studieshave revealed that plaque rupture is 1 of the majorcauses of AMI, but none of these has looked specificallyat the circadian variation of plaque rupture. The aim ofthis study was to use intravascular ultrasound (IVUS) toinvestigate the circadian variation of plaque rupture inAMI. This study included 174 consecutive patients withAMI who underwent preinterventional IVUS. All patientswere assigned to either a rupture group or a nonrupturegroup according to the preinterventional IVUS. In the 81patients (47%) in the rupture group, the frequency of theonset of AMI increased significantly in the period from 6

A.M. to 12 P.M. compared with all other time periods (p<0.05). The clinical features of AMI in the rupture groupwere characterized as occurring significantly more atrest (67% vs 31%, p <0.01) and after significantly lesspreinfarction angina (22% vs 57%, p <0.01) comparedwith the nonrupture group. A different circadian varia-tion was identified in the nonrupture group, character-ized as a significant nocturnal nadir (12 to 6 A.M. com-pared with all other periods, p <0.05). The circadianvariation of AMI is the result of a morning increase inincidence of plaque rupture. �2003 by Excerpta Med-ica, Inc.

(Am J Cardiol 2004;93:1–5)

A number of studies have reported a circadianvariation in the onset of acute myocardial infarc-

tion (AMI).1–4 One large-scale multicenter study hasdemonstrated that AMI is 1.28 times more likely tobegin between 6:00A.M. and 12:00P.M. than duringthe other three 6-hour intervals of the day.1 Pathologicstudies have revealed that plaque rupture and subse-quent thrombosis is one of the major causes ofAMI. 5–8 Therefore, the hypothesis that increasedphysiologic activities in morning hours may triggerplaque disruption has been proposed.9 There has,however, been no study into the circadian rhythm ofplaque rupture in AMI. We have previously reportedthat preinterventional intravascular ultrasound (IVUS)is able to identify lesion morphology, including thefeatures of plaque rupture, in the acute phase ofAMI. 10–12The aim of this study was to investigate thecircadian rhythm of plaque rupture identified by IVUSin patients with AMI.

METHODSSubjects: Our study population comprised 174 con-

secutive patients with AMI who underwent preinter-ventional IVUS within 12 hours of the onset of symp-toms. The diagnosis of AMI was determined from thepresence of�30 minutes of continuous chest pain,

ST-segment elevation�2.0 mm on�2 contiguouselectrocardiographic leads, and more than a threefoldincrease in serum creatine kinase levels. We excludedpatients with left main coronary artery disease (n�2), an occlusion of a small branch where IVUS wasimpracticable (n� 3), bypass failure (n� 2), sub-acute stent thrombosis (n� 1), restenosis after angio-plasty (n� 2), and subjects who were unsuitable foremergency coronary angiography because of their ad-vanced age (�90 years, n� 3).

The study protocol was approved by the EthicsCommittee of Baba Memorial Hospital. We also ob-tained written informed consent from all the partici-pants before coronary angiography.

Protocol: All patients received an intravenous bolusinjection of heparin 10,000 IU and intracoronaryisosorbide dinitrate (2 mg) before angiography. Aftercompletion of diagnostic coronary angiography, allpatients were further evaluated with IVUS. The IVUScatheter (UltraCross or Atlantis; Boston Scientific,Clearview, California) was carefully advanced distalto the lesion under fluoroscopic guidance. It was thenpulled back automatically from the distal portion at0.5 mm/s, facilitating observation of the lesion. IVUSimages were recorded on S-VHS video for off-lineanalysis. While pulling back the catheter, we manuallyinfused a contrast medium or saline for IVUS imag-ing,11 carefully observing the lesion.

Analysis of clinical history and time of onset of AMI:Physical examinations were carefully conducted byour trained cardiology staff in the emergency room.Degree of congestive heart failure was classified ac-cording to the Killip classification. In the CoronaryCare Unit, our staff, who were blinded to the IVUSfindings, carefully reviewed by interview the patients’detailed clinical history and identified the time of

From the Baba Memorial Hospital, Sakai; and Department of InternalMedicine and Cardiology, Graduate School of Medicine, Osaka CityUniversity, Osaka, Japan. Manuscript received June 9, 2003; revisedmanuscript received and accepted September 2, 2003.

Address for reprints: Atsushi Tanaka, MD, Department of Cardiol-ogy, Baba Memorial Hospital, 4-244, Hamadera-funao-cho Higashi,Sakai, 592-8555 Japan. E-mail: m4497147@msic.med.osaka-cu.ac.jp.

1©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matterThe American Journal of Cardiology Vol. 93 January 1, 2004 doi:10.1016/j.amjcard.2003.09.002

onset. In this study, we defined cases in which oc-curred AMI during bed rest or while sitting as “onsetat rest.”

The hourly frequency of onset of AMI as deter-mined by the onset of symptoms was analyzed in3-hour periods of the day. The frequency of onset ofsymptoms in patients with plaque rupture and those inthe nonrupture group were analyzed in 6-hour periodsof the day.

IVUS analysis: The morphologic features identifiedby IVUS were analyzed and interpreted by 2 experi-enced independent observers (DF and KS) who wereblinded to angiographic and clinical data. Evaluationof lesion morphology and other measurements duringIVUS was done according to the American College ofCardiology clinical expert consensus document onstandards for acquisition, measurement, and reportingof intravascular ultrasound studies.13 Fissure was de-fined as an abrupt, focal, superficial break in the linearcontinuity of the plaque and extending in a radialdirection. Dissection was defined as rupture of theplaque creating �1 neolumina. A lipid–pool-like im-age was defined as a pooling of low-echoic material orecholucent material covered with a high-echoiclayer.12

Computer planimetry (TapeMeasure; Indec Sys-tems, Mountain View, California) was used to mea-

sure external elastic membrane(EEM) cross-sectional area (CSA) atthe lesion site and at proximal anddistal reference segments. Incidencesof lesion EEM CSA larger than prox-imal reference EEM CSA were de-fined as positive remodeling.

We defined the IVUS criteria foridentifying plaque rupture in AMI as:(1) lesions with fissure and/or dissec-tion, or (2) lesions with no visualevidence of fissure and/or dissectionbut in which infusion of saline orcontrast medium confirms communi-cation between the vascular lumenand the plaque. Figure 1 shows sometypical images of lesions with plaquerupture and nonrupture in the settingof AMI. Based on these findings, pa-tients were divided into either rup-ture or nonrupture groups.

Angiographic analysis: Coronaryangiograms were reviewed sepa-rately by 2 independent observers(YN and TS) who were unaware ofthe IVUS findings. The degree ofperfusion was evaluated according toThrombolysis In Myocardial Infarc-tion (TIMI) criteria.14 Collateral flowwas graded according to Rentrop’sclassification,15 with good collateralflow defined as grade 2 or 3.

Statistical analysis: Results are ex-pressed as mean � SD for continu-ous variables. Qualitative data are

presented as numbers (percentages). Continuous vari-ables were compared using the t test, and categoricdata were compared with Fisher’s exact test. Steel’stest16 was used for comparing the frequency of onsetof AMI for each 6-hour period for all patients andacross each group. A p value �0.05 was consideredstatistically significant.

RESULTSClinical characteristics: The features of plaque rup-

ture were seen in 81 patients (47%). The remaining 93patients made up the nonrupture group. Patient char-acteristics for both groups are listed in Table 1. In therupture group, only 26% of patients had previousangina, and AMI developed at rest in 67% of patients.

IVUS results: Coronary artery lesions were observedunder IVUS in all patients without any serious proce-dural complications. The preinterventional IVUS find-ings are listed in Table 2. IVUS identified plaquerupture in 81 patients (47%). Fissure and/or dissectionwas observed in 67 of these 81 patients. Injection ofsaline or contrast medium confirmed communicationbetween the lumen and plaque in 14 of these 81patients. The rupture group showed higher plaque plusmedia eccentricity index compared with the nonrup-ture group (0.46 � 0.20 vs 0.28 � 0.2, p �0.01).EEM CSA in the rupture group was larger than in the

FIGURE 1. Typical IVUS images of AMI lesions. (A) Typical image of plaque rupture.An eccentric plaque has ruptured at the shoulder (white arrow). (B) Typical image ofplaque rupture. The thin fibrous cap has broken at the shoulder of the plaque (whitearrow) with some part of the plaque contents being washed out into the lumen; theresidual plaque has a complex morphology. (C) Typical image of nonrupturedplaque. IVUS shows concentric calcified plaque with several highly echoic layers ontop of each other, like the rings of a tree. (D) Typical image of nonruptured plaque.Severely calcified concentric plaque with shrinkage is shown.

2 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 93 JANUARY 1, 2004

nonrupture group. Calcified lesions were observed in99 patients (57%) among all subjects.

Circadian variation: Figure 2 shows the times ofday at which the onset of AMI began in our patientpopulation. The onset of AMI was significantly morecommon in the period from 6:00 A.M. to 12:00 P.M.than during any other period (p �0.03). In the plaquerupture group, a morning increase (from 6:00 A.M. to12:00 P.M.; p �0.05 compared with any other period)was observed, whereas in the nonrupture group therewas a nocturnal nadir (from 12 to 6:00 A.M.; p �0.05compared with any other period) and no significantmorning increase was detected (Figure 3).

DISCUSSIONOur findings in this study population are similar to

previous reports on circadian rhythm,1 and they sug-

gest that the circadian rhythm of on-set of plaque rupture in vivo is char-acterized by a morning increase. Thiscircadian pattern was not detectablein our nonrupture group. This morn-ing increase in the incidence ofplaque rupture accounts for the char-acteristic circadian rhythm of AMI.

Various physiologic studies havehighlighted the fact that systemicphysiologic processes increase in in-tensity in the morning, such as anarterial pressure surge accompaniedby an increase in heart rate17 andincreased vascular tone.18 Serumcortisol levels also decrease duringthe period of increased plaque dis-ruption.19 Because the Japanese pop-ulation of patients with AMI com-pared with whites shows a higherincidence of spasm and greater vaso-constriction of nonspastic segmentsafter acetylcholine,20 this decrease inserum cortisol levels could enhancethe sensitivity of the coronary arter-ies to the vasoconstrictive effects ofcatecholamines.21 Such physiologicalterations may, alone or in combi-nation, account for the morning in-crease in plaque rupture. Whenplaque rupture occurs, the contentsof the lipid core that form the mostthrombogenic components of theplaque22 may be released into thelumen and precipitate a cascade thatproduces thrombosis. Increasedplatelet activity,23 increased bloodviscosity,24 and the minimal level offibrinolytic activity25 may furthercontribute to thrombosis in this set-ting during the morning hours. Theefficacy of � blockers26 and aspirinin preventing AMI27 indirectly lendssupport to the idea that these physi-ological variations may play an etio-

logic role in plaque disruption and resultant thrombo-sis.

Several studies have shown that in many instances,MI may occur without any obvious precipitatingevents and may occur at rest.4,28 Grines et al29 re-ported that one independent predictor of a higherfrequency of onset during the morning hours was theabsence of a history of angina. Our data clearly dem-onstrate that patients with AMI caused by plaquerupture fit this pattern of less preinfarction angina,with onset increasing during the morning hours andoccurring at rest.

Controversially, we have also encountered somepatients with AMI developing from stable angina oroccurring as a result of physical exertion. Willich etal30 have reported that physical exertion is one of thetriggers of AMI. In our study, 53% of the patients in

TABLE 1 Clinical Characteristics

VariablesRupture Group

(n � 81)Non-rupture Group

(n � 93)

Age (yrs) 62 � 11.5 65 � 9.6Men 66 (81%) 68 (73%)Systemic hypertension 47 (58%) 52 (56%)Diabetes mellitus 22 (27%) 23 (25%)Current smoker 60 (74%) 61 (66%)Total cholesterol �220 mg/dl 41 (51%) 41 (44%)Killip class

1 66 (81%) 73 (78%)2 9 (11%) 16 (17%)3 3 (4%) 2 (2%)4 3 (4%) 2 (2%)

Preinfarction angina 21 (26%)* 49 (53%)Onset at rest 54 (67%)* 29 (31%)No. of patients with Q-wave MI 62 (77%) 69 (74%)Infarct-related coronary artery

Left anterior decending 32 (40%) 57 (61%)Left circumflex 5 (6%) 6 (6%)Right 44 (54%) 30 (32%)

TIMI flow grade 0 at initial angiogram 45 (56%) 47 (51%)Good collateral flow 17 (21%) 22 (24%)Single-vessel disease 61 (75%) 64 (69%)

*p �0.01 for comparison with the nonrupture group.Values expressed as mean � SD or number (%).

TABLE 2 Intravascular Ultrasound (IVUS) Findings

Rupture Group(n � 81)

Nonrupture Group(n � 93)

IVUS morphologyFissure/dissection 67 (83%) 0Lipid–pool-like image 52 (64%) 0Superficial calcium 24 (30%) 40 (43%)Deep wall calcium 39 (48%) 32 (34%)Positive remodeling 21 (26%) 27 (29%)

IVUS measurementsPlaque plus media eccentricity index 0.46 � 0.2* 0.28 � 0.2Distal reference EEM CSA (mm2) 13.8 � 4.8* 12.1 � 4.2Distal reference luminal area (mm2) 7.4 � 3.4 6.6 � 3.0Lesion EEM CSA (mm2) 15.7 � 4.7* 13.0 � 4.8Proximal reference EEM CSA (mm2) 17.2 � 4.4* 15.0 � 4.5Proximal reference luminal area (mm2) 9.5 � 3.0* 7.5 � 3.1

*p �0.01 for comparison with the nonrupture group.Values expressed as mean � SD or number (%).

CORONARY ARTERY DISEASE/CIRCADIAN VARIATION OF PLAQUE RUPTURE 3

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FIGURE 2. The frequency of onset of MI in 3-hour (top panel)and 6-hour periods (bottom panel). There is a statistically signifi-cant morning increase in the frequency of the onset of MI com-pared with the other time periods. *p <0.05 for comparison withthe other time periods.

FIGURE 3. The frequency of onset of MI in 6-hour periods. There is a significantmorning increase in the rupture group and a nocturnal nadir in the nonrupturegroup. *p <0.05 for comparison with the other time periods.

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