Impact of Morning Onset on the Incidence of Recurrent Acute Coronary Syndrome and Progression of Coronary Atherosclerosis in Acute Myocardial Infarction

Abstract

Background: The relationship between time of onset of acute myocardial infarction (MI) and long-term clinical outcome has not been completely understood. We hypothesized that morning onset acute MI may be associated with adverse cardiac events.

Methods and Results: This study involved 663 patients who underwent primary percutaneous coronary intervention (PCI). The main outcome measures were cardiac death, recurrent acute coronary syndrome (ACS), and re-hospitalization for heart failure. Major adverse cardiac events (MACE) were defined as a composite of individual adverse outcomes. Morning onset acute MI occurred in 212 patients (32.0%); they had higher rates of recurrent ACS (13% vs. 8%, P=0.03) and MACE (21% vs. 14%, P=0.012) than the patients with other times of onset. The PCI rate for progressive lesions was also higher than for patients with other times of onset (23% vs. 14%, P=0.013). On multivariate Cox regression analysis, morning onset was an independent predictor of recurrent ACS, MACE, and PCI for progressive lesions, with adjusted hazard ratios of 1.34 (95% CI: 1.06–2.92, P=0.030), 1.51 (95% CI: 1.02–2.23, P=0.038), and 1.58 (95% CI: 1.03–2.42, P=0.037), respectively.

Conclusions: Morning onset may be associated with increased risk of recurrent ACS and coronary atherosclerosis progression.

The time of onset of acute myocardial infarction (MI) shows a clear circadian variation, with a peak incidence between 06:00 and 12:00 hours.^1,2 Sympathetic nerve activity, myocardial oxygen consumption, coagulation status and platelet reactivity are increased in the morning, and these physiologic stresses may trigger an unstable plaque rupture and subsequent coronary thrombosis.³ The association between time of onset and short-term clinical outcomes has received much attention for more than a decade, and several studies have reported higher in-hospital or 30-day mortality in patients who presented during off-hours than in those who presented during regular hours (normal working hours on weekdays).^4–6 System delays from symptom onset to reperfusion treatment rather than intrinsic effects of circadian variation had been considered to play a major role in the worse clinical outcomes of off-hours presentation. A few previous studies found that infarct size had a circadian variation, although 2 studies showed that infarct size was increased between 00:00 and 05:59 hours,^7,8 and 1 study showed that infarct size was increased between 06:00 and 11:59 hours.⁹ One study using intravascular ultrasound found that plaque rupture was more likely to occur in the morning.¹⁰ Patients with plaque rupture had larger infarct size and a higher incidence of no-reflow phenomenon compared with those without plaque rupture.¹¹ No previous studies, however, have investigated the relationship between time of onset of acute MI and adverse cardiovascular events during a follow-up period >1 year. We hypothesized that patients with morning onset acute MI may have different long-term clinical outcomes compared with those with other times of onset. On coronary angiography, we examined the association between morning onset and target vessel revascularization (TVR) and percutaneous coronary intervention (PCI) for progressive lesion.

Methods

A total of 753 patients admitted to the present hospital between January 2003 and December 2012, with definite time of onset of acute MI and who underwent primary PCI within 24 h of onset, were initially considered for inclusion in this study. Acute MI was defined as ischemic symptoms lasting ≥30 min with ST-segment elevation or depression (≥1 mm) and elevated cardiac troponin T ≥0.1ng/mL. The inclusion criteria were as follows: (1) discharged alive; (2) initial episode of MI; and (3) ≥1-year follow-up results available. On the basis of these criteria, 90 patients were excluded from the study (Figure 1). The remaining 663 patients were divided into 2 groups according to whether or not they had morning onset acute MI, defined as onset between 06:00 and 11:59 hours. This study complies with the Helsinki Declaration and was approved by all relevant institutional committees. Written informed consent was obtained from all patients.

Figure 1.

Patient selection procedure. MI, myocardial infarction; PCI, percutaneous coronary intervention.

Follow-up Data Collection

Patient follow-up was scheduled at 6 months, 1 year and annually thereafter. Clinical outcome was determined from review of medical records. When medical records were unavailable, patients or their families who were aware of the patients’ vital status and history of admission to other hospitals, were contacted via telephone. When clinical events were confirmed via telephone interview, we then contacted the patients’ attending physician by mail.

Main clinical outcome measures were cardiac death, recurrent acute coronary syndrome (ACS), and re-hospitalization for heart failure (HF). ACS was defined as acute MI or unstable angina. Unstable angina was defined as new onset, worsening or resting angina associated with ST-segment elevation or depression without cardiac troponin T elevation. Decompensated HF was defined as exacerbation of dyspnea or edema associated with increased pulmonary congestion or cardiomegaly and elevation of N-terminal pro-brain natriuretic peptide. Major adverse cardiac events (MACE) were defined as a composite of individual clinical outcomes.

Angiography was performed in 523 patients for whom at least 1 coronary arteriogram was obtained during the follow-up period. Scheduled coronary arteriography was performed at 6 months and at 1 year, although the implementation of follow-up coronary arteriography was at the discretion of the attending cardiologist on initial admission. Suspected recurrence of myocardial ischemia was another indication for examination. All PCI during follow-up were based on coronary diameter stenosis ≥50% causing myocardial ischemia, confirmed by changes in the ST segments and T waves during ischemic symptoms, myocardial perfusion imaging or fractional flow reserve. PCI-related adverse outcomes were TVR and ischemia-driven PCI for progressive lesions. TVR was defined as repeat PCI for vessels successfully dilated at first admission.

Definition of Coronary Risk Factors

Hypercholesterolemia, diabetes, and hypertension were defined as use of lipid-lowering agents; oral hypoglycemic agents and/or insulin; and antihypertensive agents prior to acute MI onset, respectively. In patients who had not been treated for these risk factors, hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on 3 separate occasions; hypercholesterolemia was defined as low-density lipoprotein cholesterol ≥140 mg/dL; and diabetes was defined as fasting blood glucose ≥126 mg/dL on 2 separate occasions or glycohemoglobin A1c ≥6.5%.

Statistical Analysis

Continuous variables are expressed as median (IQR) because they were not normally distributed (Shapiro-Wilk test), and were compared between patients with morning onset acute MI and those with other times of acute MI onset, using Wilcoxon rank sum test. Dichotomous variables are expressed as n (%) and were compared using the chi-squared test. The day was divided into four 6-h intervals: 00:00–05:59 hours, 06:00–11:59 hours, 12:00–17:59 hours, and 18:00–23:59 hours. The presence of circadian variation across the four 6-h intervals was tested using chi-squared goodness-of-fit test for uniform distribution. Univariate Cox regression analysis was carried out for individual clinical risk factors that could affect prognosis (morning onset, male sex, age ≥75 years, onset to first balloon time >12 h, Killip class at initial admission, peak creatine kinase >median, ≥2 diseased vessels, hypertension, final Thrombolysis in Myocardial Infarction (TIMI) flow grade, diabetes, dyslipidemia, and current smoking), recurrent ACS, and MACE. Time to event was calculated from the date of discharge of the initial admission to the date that the clinical events first occurred. Multiple Cox regression analysis using backward elimination procedure adjusted for clinical risk factors was performed to identify independent predictors for recurrent ACS and MACE. The cumulative incidence of cardiac death, recurrent ACS, re-hospitalization for HF and MACE were calculated using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was defined as 2-sided P<0.05. Data analysis was performed using SPSS version 19.0 (SPSS, Chicago, IL, USA).

Results

In total, 212 patients (32%) had morning onset acute MI at first admission (Figure 2). Patient characteristics for the 2 groups are listed in Table 1. There were no significant differences between the 2 groups in terms of follow-up duration, age, sex, time to hospital visit from onset of symptoms, and previous angina within 24 h before onset. The frequency of ST-segment elevation MI (STEMI), infarct location and acute HF, defined as Killip class ≥2, were similar between the 2 groups. A trend toward a smaller infarct size, estimated using peak creatine kinase, was found in patients with morning onset acute MI. There were no differences between the groups in terms of coronary angiography, achievement of TIMI flow grade 3, and implantation of coronary stent. Conventional coronary risk factors except for lower rate of current smoking in patients with morning onset acute MI, baseline medications at discharge, and baseline C-reactive protein (CRP) at discharge, were similar between the groups.

Figure 2.

Circadian variation in the frequency of acute myocardial infarction symptom onset.

Table 1. Patient Characteristics

	Morning onset (n=212)	Onset at other time (n=451)	P-value
Follow-up (years)	3.6 (1.5–5.6)	3.3 (1.4–5.1)	0.191
Age (years)	72 (60–80)	70 (60–79)	0.361
Male sex	153 (72)	338 (75)	0.447
Time to admission (h)	2.4 (1.3–5.0)	2.6 (1.4–7.8)	0.111
Door-to-balloon time (min)	58 (48–75)	64 (52–81)	0.277
Pre-infarct angina ≤24 h	64 (30)	141 (31)	0.780
STEMI	184 (87)	387 (86)	0.733
NSTEMI	23 (13)	64 (14)
Anterior infarct	89 (42)	217 (48)	0.139
Killip class ≥2	51 (24)	131 (29)	0.192
Peak CK (IU/L)	1,462 (718–2,859)	1,879 (768–3,819)	0.071
LMT/LAD/LCX/RCA	4/91/29/91	6/218/69/158	0.221
Multivessel disease	101 (48)	230 (51)	0.420
Good collateral	30 (14)	64 (14)	0.989
Initial TIMI flow grade 0 or 1	129 (61)	295 (65)	0.254
Final TIMI flow grade 3	202 (95)	428 (95)	0.833
Stent use	193 (91)	408 (91)	0.813
BMI (kg/m2)	23.3 (21.0–25.2)	23.4 (21.5–25.6)	0.243
Hypertension	126 (59)	282 (63)	0.445
Diabetes	71 (34)	165 (37)	0.438
Hypercholesterolemia	148 (59)	351 (64)	0.212
Current smoking	67 (32)	194 (43)	0.005
Medications at baseline
Aspirin	212 (100)	451 (100)	>0.999
Clopidogrel or ticlopidine	193 (91)	408 (91)	0.813
β-blocker	54 (26)	104 (23)	0.497
CCB	54 (26)	126 (28)	0.505
ACEI or ARB	154 (73)	323 (72)	0.785
Statin	172 (81)	388 (86)	0.104
Baseline CRP (mg/dL)	0.250 (0.090–0.868)	0.250 (0.100–0.743)	0.999

Data given as median (IQR) or n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMI, body mass index; CCB, calcium-channel blocker; CK, creatine kinase; CRP, C-reactive protein; LAD, left anterior descending artery; LCX, left circumflex artery; LMT, left main trunk; (N)STEMI, (non-)ST-segment elevation myocardial infarction; RCA, right coronary artery; TIMI, Thrombolysis in Myocardial Infarction.

Clinical Outcome According to Acute MI Onset Time

The incidence of individual clinical outcomes across four 6-h intervals is presented in Figure 3. The highest incidence of individual adverse events was observed between 06:00 and 11:59 hours, and the lowest incidence between 12:00 and 17:59 hours. All-cause death and cardiac death rates were similar between morning onset and other times of onset (14% vs. 13%, P=0.895; 5% vs. 3%, P=0.249, respectively). There were 61 episodes of recurrent ACS, and 106 MACE. Recurrent acute MI and unstable angina tended towards a higher incidence in the morning onset group compared with other times of onset (8% vs. 5%, P=0.162; 5% vs. 2%, P=0.050, respectively). As a result, patients with morning onset had a significantly higher incidence of recurrent ACS (13% vs. 8%, P=0.031). Re-hospitalization for HF was similar between the groups (11% vs. 8%, P=0.108). There was a significantly higher incidence of MACE in the morning onset acute MI group (21% vs. 14%, P=0.012). On univariate Cox regression analysis, morning onset acute MI was positively correlated with MACE. And on multivariate Cox regression analysis using backward elimination, morning onset, male sex and Killip class during initial admission were independent risk factors of recurrent ACS (Table 2). In addition, morning onset, age ≥75 years, and Killip class were independent risk factors for MACE (Table 3). Figure 4 shows the cumulative incidence of cardiac death, recurrent ACS, re-hospitalization for HF, and MACE using the Kaplan-Meier method. The incidence of MACE was significantly higher in patients with morning onset than in those with other times of onset.

Figure 3.

Adverse clinical outcomes vs. time of day of acute myocardial infarction onset. ACS, acute coronary syndrome; MACE, major adverse cardiac event.

Table 2. Predictors for Recurrence of ACS

	Unadjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Morning onset	1.61 (0.97–2.67)	0.068	1.34 (1.06–2.92)	0.030
Male sex	2.37 (1.12–4.96)	0.023	2.69 (1.27–5.68)	0.009
Age ≥75 years	1.02 (0.60–1.73)	0.947
Onset to first balloon time >12 h	0.76 (0.45–1.27)	0.292
Killip class	1.77 (1.06–2.98)	0.030	1.38 (1.08–1.75)	0.010
Peak CK >1,694 IU/L	0.74 (0.44–1.22)	0.235	0.61 (0.40–1.02)	0.059
Diseased vessels ≥2	1.06 (0.64–1.75)	0.817
Final TIMI flow grade	0.83 (0.44–1.64)	0.591
Hypertension	0.98 (0.58–1.63)	0.925
Diabetes	0.95 (0.56–1.63)	0.854
Dyslipidemia	0.81 (0.49–1.34)	0.409
Current smoking	1.67 (1.01–2.76)	0.047

ACS, acute coronary syndrome; CK, creatine kinase; HR, hazard ratio; TIMI, Thrombolysis in Myocardial Infarction.

Table 3. Predictors of Major Adverse Cardiac Events

	Unadjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Morning onset	1.52 (1.04–2.24)	0.035	1.51 (1.02–2.23)	0.038
Male sex	1.10 (0.70–1.71)	0.683	1.49 (0.94–2.37)	0.088
Age ≥75 years	2.14 (1.45–3.13)	<0.001	2.23 (1.50–3.31)	<0.001
Onset to first balloon time >12 h	0.99 (0.67–1.45)	0.945
Killip class	2.65 (1.81–3.88)	<0.001	1.40 (1.18–1.67)	<0.001
Peak CK >1,694 IU/L	0.85 (0.58–1.24)	0.388
Diseased vessels ≥2	1.30 (0.88–1.90)	0.184
Final TIMI flow grade	0.77 (0.49–1.23)	0.271
Hypertension	1.08 (0.73–1.61)	0.699
Diabetes	0.98 (0.65–1.46)	0.905
Dyslipidemia	0.93 (0.63–1.36)	0.694
Current smoking	0.82 (0.55–1.22)	0.325

Abbreviations as in Table 2.

Figure 4.

Kaplan-Meier cumulative incidence of (A) cardiac death; (B) recurrent acute coronary syndrome (ACS), (C) readmission for heart failure (HF) and (D) major adverse cardiac events (MACE) according to time of onset of acute myocardial infarction (morning vs. other times).

PCI-Related Outcomes vs. Time of Acute MI Onset

Coronary arteriograms were performed during the follow-up period in 169 and in 354 patients with morning onset acute MI and other times of onset, respectively. Two hundred and twenty vessels and 457 vessels were successfully dilated in patients with morning onset and in those with other times of onset, respectively. There was no significant difference in TVR between the 2 groups (10% vs. 13%, P=0.285). We performed 87 ischemia-driven PCI for progressive lesion, and the incidence of this was significantly higher in patients with morning onset acute MI (23% vs. 14%, P=0.013). On multivariate Cox regression analysis, morning onset and multi-vessel disease were the 2 risk factors for PCI for progressive lesions (Table 4).

Table 4. Predictors of PCI for Progressive Lesion

	Unadjusted HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Morning onset	1.55 (1.01–2.38)	0.043	1.58 (1.03–2.42)	0.037
Male sex	1.32 (0.78–2.25)	0.756
Age ≥75 years	1.18 (0.75–1.88)	0.827
Onset to first balloon time >12 h	1.10 (0.57–2.12)	0.788
Killip class	1.12 (0.87–1.43)	0.395
Peak CK >1,808 IU/L	0.85 (0.58–1.24)	0.388
Diseased vessels ≥2	1.90 (1.23–2.93)	0.004	1.97 (1.28–3.03)	0.002
Final TIMI flow grade	2.40 (0.70–8.23)	0.163	2.44 (0.74–8.10)	0.145
Hypertension	1.30 (0.83–2.04)	0.245
Diabetes	1.39 (0.91–2.13)	0.126
Dyslipidemia	0.91 (0.59–1.40)	0.670
Current smoking	0.95 (0.62–1.45)	0.798

PCI, percutaneous coronary intervention. Other abbreviations as in Table 2.

Discussion

In the present study the morning peak in the incidence of acute MI was 32%, and this circadian variation is in line with previous studies.^1,2 The main finding is that morning onset was an independent risk factor for MACE and recurrent ACS in patients with acute MI. Recurrent ACS is the main contributor to the significantly higher incidence of MACE, given that individual clinical outcomes other than ACS were similar between the 2 groups. On angiography of 523 patients, morning onset increased the risk of PCI for progressive coronary lesions associated with definite myocardial ischemia. This indicates that patients with morning onset acute MI may have a higher risk of plaque rupture and coronary artery lesion progression compared with those with other times of onset because sex, age, Killip class, extent of coronary atherosclerosis and conventional risk factors including body mass index, hypertension, diabetes, and hypercholesterolemia were similar between the 2 groups.

Time of Onset and Short-Term and 1-Year Clinical Outcomes

Earlier studies have demonstrated that off-hours presentation is associated with significantly higher in-hospital or 30-day mortality compared with regular hour presentation.^4–6 The higher off-hours mortality was considered to be due in part to the low incidence of implementation of timely primary PCI and longer door-to-balloon time. Efforts to overcome the delay in symptom onset to hospital visit and door-to-balloon time could improve prognosis in patients with ACS presenting during off-hours.¹² Recent studies have found that infarct size estimated on peak creatine kinase might vary depending on the time of acute MI onset, although there were inconsistent results in terms of the relationship between time of onset and infarct size. Maximum infarct size was noted in patients with symptom onset between 00:00 and 05:59 hours in 2 studies,^7,8 and between 06:00 and 11:59 hours in 1 study.⁹ Fournier et al assessed 6,233 patients and reported that in-hospital mortality followed the circadian variation, depending on time of acute MI onset, and the risk of death was highest for patients with onset at 00:00 hours.⁷

There was little evidence in terms of relationships between circadian variation in time of symptom onset and long-term clinical outcomes. Only 1 study, reported by Bae et al, showed that 12-month mortality was higher in patients with evening onset than in those with morning onset acute MI, and a significantly higher mortality in the evening onset was found in patients with non-STEMI (NSTEMI), but not in those with STEMI.¹³ Patients with evening onset acute MI had larger infarct size, higher Killip class, and reduced left ventricular ejection fraction (LVEF) compared with those with morning onset acute MI, and the authors suggested that unfavorable baseline clinical characteristics resulted in the higher mortality in patients with evening onset acute MI. In contrast, the present study has shown that morning onset acute MI was associated with increased incidence of MACE and recurrent ACS compared with other times of onset. The higher incidence of STEMI (87%) and longer follow-up duration in the present study may have contributed to the discrepancy in the results between the 2 studies.

Possible Mechanisms of Unfavorable Clinical Outcome

Previous studies indicate that more extensive coronary and/or systemic atherosclerosis,¹⁴ coronary risk factors,^15,16 HF during first admission,¹⁷ neurohormonal activation,¹⁸ and high CRP¹⁹ are associated with recurrent ACS. In the present study, however, baseline clinical characteristics were not different between the 2 groups, except for the lower rate of current smoking in the morning onset acute MI group (Table 1). Thus, other pathological mechanisms may be involved in this increase in recurrent ACS. Long-standing diabetes and prior use of β-blockers attenuated the morning peak in incidence of MI onset,^20,21 strongly suggesting that increased sympathetic activity after waking plays a pivotal role in the occurrence of acute MI. The first possible mechanism is the higher sympathetic nerve activity or higher susceptibility of the cardiovascular system to sympathetic nerve activity in patients with morning onset acute MI compared with other times of onset. Blood pressure surge, heart rate elevation, and vasoconstriction resulting from sympathetic nerve activation may increase cardiac oxygen consumption and trigger plaque rupture by the increased shear stress of coronary blood flow against unstable plaque. An intravascular ultrasound study reported that plaque characteristics varied according to the time of acute MI onset.¹⁰ Plaque rupture occurred more frequently in the morning compared with any other period, whereas non-ruptured plaque did not show a morning peak in incidence, with the lowest frequency occurring at midnight (00:00–05:59 hours).

Patients with morning onset acute MI may be more likely to have unstable plaque characterized by a thin fibrous cap overlying a large lipid pool. Conventional risk factors and medications were similar between the 2 groups in this study. Thus, something other than conventional risk factors may contribute to increased recurrent ACS in patients with morning onset acute MI. One possible candidate related to plaque instability is sleep-disordered breathing (SDB), because SDB is likely to be underdiagnosed²² and obstructive sleep apnea is regarded as a significant risk factor of recurrent ACS.^23,24 In the present study, overnight polysomnography was carried out in 535 out of 663 study patients, and the incidence of SDB, defined as apnea-hypopnea index ≥15events/h, was significantly higher in patients with morning onset than in those with other times of acute MI onset (56% vs. 44%, P=0.007). A second possible mechanism is that the higher incidence of SDB observed in patients with morning onset acute MI may contribute, at least in part, to plaque instability and progression of coronary atherosclerosis.

The third possible mechanism is that coronary spasm may be related to disease progression and plaque instability. Wakabayashi et al found that 140 of 240 patients (73%) with acute MI had coronary spasm in the infarct-related arteries or non-infarct-related arteries on acetylcholine provocation at 10–20 days after MI onset, and provoked spasm is 1 of the independent risk factors of MACE including ACS.²⁵ Another study reported that provoked coronary spasm using ergonovine was closely related to new MI onset and/or progression of coronary atherosclerosis.²⁶ Among 61 patients with recurrent ACS in the present study, unstable angina caused by coronary spasm was noted in 1 patient with morning onset acute MI and in 1 patient with acute MI onset between 00:00 and 05:59 hours. Although we did not perform provocative testing for coronary spasm, patients with morning onset acute MI may have increased spasticity in the coronary arteries because coronary spasm is more likely to occur in the morning,²⁷ and coronary vasoconstrictor response to acetylcholine also increases in the morning.^28,29

Study Limitations

This study focused on the association between circadian variation of MI onset and long-term prognosis after discharge. Thus, we excluded 43 patients with in-hospital death. In-hospital mortality rates were similar between the morning onset acute MI group and the other times of onset group (4.5% vs. 6.8%, P=0.233), and across the 4 patient groups according to the four 6-h intervals (7.5% vs. 4.5% vs. 7.5% vs. 5.5%, P=0.533), hence the circadian effect on prognosis would apply only to the patients who survived acute illness.

We excluded patients with previous MI because the prognostic implication of the time of onset of the second attack may be different from that of time of onset of the first attack. In addition, patients with previous MI were associated with worse LV function and were more likely to have adverse clinical events during the follow-up period. When Cox regression analysis was re-done including 38 patients with previous MI, morning onset acute MI remained an independent predictor of recurrent ACS and MACE (hazard ratio [HR], 1.72; 95% CI: 1.07–2.75, P=0.024 and HR, 1.51; 95% CI: 1.05–2.17, P=0.027, respectively).

Conclusions

Patients with morning onset acute MI had a higher incidence of MACE and recurrent ACS during a median follow-up duration of 3.5 years. Morning onset was also associated with increased new PCI for progressive lesions, and morning onset acute MI was found to be an independent predictor of clinically suspected plaque vulnerability and progression of coronary atherosclerosis. The mechanisms underlying the increased frequency of subsequent cardiovascular events observed in morning onset acute MI, need to be identified in future studies.

Disclosures

The authors declare no conflict of interest.

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