Abstract
The aim was to investigate the circadian and seasonal variation of acute myocardial infarction (AMI). Clinical data of 3867 AMI patients hospitalized from November 2010 to October 2019 in the Border Yanbian Minority Autonomous Prefecture, China were collected, and 3158 patients with definite AMI onset times were analyzed. The clinical data analyzed included the time of onset, nationality, age, laboratory data. We divided the patients into 4 groups based on the timepoint of their AMI onsets: 00:00–05:59, 06:00–11:59, 12:00–17:59, and 18:00–23:59. We also divided the patients based on nationality: Chinese Korean and Han groups. We observed that there is a circadian rhythm in the incidence of AMI, and the peak of AMI is in the morning (7:00–9:00). Unexpectedly, the incidence of AMI was significantly lower in the cold winter than that of other 3 warm seasons (P < 0.01) and the peak of AMI presented at the months of the large contrast between day and night temperature difference (over 20°C) like May of Spring and October of Fall. Finally, there was no difference in circadian rhythm between Chinese Korean and Han, although these groups differed in age, body mass index, and the inflammatory cell level. These findings have shown a different seasonal and circadian variation in onset of AMI. Further studies are required to determine the pathophysiological mechanism(s) underlying these differences and to guide prevention of AMI for reducing its mortality and disability.
Keywords: acute myocardial infarction, circadian rhythm, ethnicity, season variation
1. Introduction
Coronary Artery Disease (CAD) has become the main cause of human death, and although the CAD mortality rate has decreased year by year in developed countries, it is on the rise in developing countries.[1] AMI is the most serious type of CAD, and in recent years, the incidence rate and mortality rate of AMI in China has increased rapidly, causing an enormous burden to society. The circadian rhythm of AMI was first reported in 1963 by Pell and D’Alonzo,[2] and many subsequent studies also indicated the circadian rhythm of AMI; most of them indicated that the incidence rate of AMI is high in the morning.[3–10] The circadian rhythm of AMI may be caused by an increase of sympathetic tension and platelet aggregation, and by a decrease of plasma fibrinolysis activity.[11] Although the incidence rate of AMI has been described as reaching its peak in the morning (especially in the first few hours after waking up), it has been shown that the circadian rhythm of AMI varies among geographic regions and nationalities.[12–14]
In the past few decades, there are limited studies regarding the seasonal and circadian variation in onset of AMI. Understanding these aspects of AMI is likely to guide prevention of AMI for reducing its mortality and disability. We conducted the present study to determine whether there is ethnic difference in the seasonal and circadian variations in the onset of AMI.
2. Methods
2.1. Data sources and definitions
Yanbian is the largest Chinese Korean settlement in China, with a total population of 2.08 million, of which the Han nationality accounts for 60.01% and Chinese Korean accounts for 35.9%. Yanbian Hospital is both the central hospital of the Yanbian area and the treatment center for critical patients from throughout the Yanbian area. The diagnosis of AMI used at Yanbian Hospital follows a uniform definition: AMI is diagnosed if the patient has a history of prolonged typical symptoms, an Electrocardiograph (ECG) indicative of new ischemia (new left bundle branch block or new ST-T change), and an elevated biomarker (at least 1 positive biomarker: troponin T or creatine kinase-MB).[15] Hypertension and diabetes are diagnosed based on the patient’s medical history (not based on the blood pressure and blood sugar at the time of the attack, considering the stress condition). Smoking history includes current smoking (still smoking within the last 1 year) and nonsmoking (had quit smoking ≥1 year ago or never smoked). A family history of CAD includes any immediate family member (parent, sibling, or child) with angina, myocardial infarction, sudden cardiac death of no apparent cause, or a history of coronary artery bypass grafting or percutaneous coronary intervention.
The data of the AMI inpatients were collected from the AMI data included in the electronic medical records (EMR) system of Yanbian Hospital. Depending on ICD-10, AMI was classified as ST-segment elevation myocardial infarction (STEMI) (ICD-10: 121.0–121.3, 122.0–122.1) and nonST-segment elevation myocardial infarction (NSTEMI) (ICD-10: 121.4). We collected each patient’s information from their medical records, including demographic data, hospital date, examination results, and more. Through a data collation procedure, the cases of 3867 inpatients with an AMI who were admitted during the period from November 1, 2010 to October 31, 2019 were selected. We excluded 323 cases of readmission and 386 cases without a definite time of AMI onset, and thus a final total of 3158 cases with a definite time of AMI onset was analyzed (Fig. 1).
Figure 1.
Case screening flowchart. A total of 3867 patients from the electronic medical record system of Yanbian Hospital were included, excluding 323 readmission cases and 386 cases with no definite onset time.
We divided the 24-hour day into 4 time periods for the analysis of AMI onset: the first period is 00:00–05:59, the second is 06:00–11:59, the third is 12:00–17:59, and the fourth is 18:00–23:59. We divided the patients into 4 groups based on which period their AMI onsets occurred. We also divided the patients based on their nationalities, into the Chinese Korean group and the Han group. A third division of patients was made based on the ages: younger (<55 years old), intermediate (55–75 years old), and older (≥75 years old). Finally, we also divided 4 season groups including the Spring (March, April, and May), Summer (June, July, and August), Fall (September, October, and November), and Winter (December, January, February). This study was reviewed and approved by the ethics committee of Yanbian Hospital.
2.2. Statistical analyses
Categorical variables are expressed in terms of frequency and percentage, and when appropriate, they were compared using the χ2-test or Fisher exact test. The continuous variables are expressed as the mean ± standard deviation, and the normal distribution was evaluated. Probability (P)-values <0.05 were considered significant. All statistical analyses were performed with SPSS 26.0 software (SPSS, Chicago, IL).
3. Results
During the 9-year period of study, 3867 patients were diagnosed with AMI in the Yanbian University Hospital. We excluded 709 patients from our database because of incomplete formation on the time of onset of symptoms (n = 386) or rehospitalization (n = 323), the 3158 patients for analysis. The clinical characteristics of the study patients stratified according to time of AMI onset are summarized in Table 1.
Table 1.
Baseline characteristics.
| 00:00–05:59 | 06:00–11:59 | 12:00–17:59 | 18:00–23:59 | P-value | |
|---|---|---|---|---|---|
| No. of patients | 714 (22.6%) | 967 (30.6%) | 783 (24.8%) | 694 (22.0%) | <0.01 |
| Men | 518 (72.6%) | 725 (75.0%) | 568 (72.6%) | 508 (73.2%) | 0.61 |
| Age, yr | 62.2 ± 11.9 | 62.2 ± 12.1 | 60.8 ± 12.2 | 60.5 ± 12.3 | <0.01 |
| BMI, kg/m2 | 24.6 ± 3.6 | 24.7 ± 3.5 | 24.8 ± 3.5 | 24.9 ± 3.5 | 0.45 |
| SBP, mm Hg | 131.7 ± 24.5 | 130.6 ± 25.1 | 130.8 ± 25.0 | 131.1 ± 23.8 | 0.81 |
| DBP, mm Hg | 82.8 ± 15.5 | 82.2 ± 16.2 | 82.7 ± 16.2 | 82.9 ± 15.4 | 0.83 |
| HR, bpm | 79.4 ± 17.4 | 78.3 ± 17.5 | 80.4 ± 18.6 | 80.1 ± 18.7 | 0.08 |
| Killip score, III/IV | 105 (14.7%) | 145 (15.0%) | 111 (14.2%) | 113 (16.3%) | 0.71 |
| Nationality: | 0.91 | ||||
| Chinese Korean | 248 (34.7%) | 333 (34.4%) | 271 (34.6%) | 244 (35.2%) | |
| Han | 449 (62.9%) | 603 (62.4%) | 492 (62.8%) | 435 (62.7%) | |
| Others | 17 (2.4%) | 31 (3.2%) | 20 (2.6%) | 15 (2.2%) | |
| Medical history: | |||||
| Ischemic heart disease | 16 (2.2%) | 32 (3.3%) | 18 (2.3%) | 12 (1.7%) | 0.20 |
| Hypertension | 379 (53.1%) | 480 (49.6%) | 382 (48.8%) | 334 (48.1%) | 0.24 |
| Diabetes | 158 (22.1%) | 213 (22.0%) | 166 (21.2%) | 140 (20.2%) | 0.78 |
| Family history | 14 (2.0%) | 35 (3.6%) | 19 (2.4%) | 25 (3.6%) | 0.12 |
| Current smoker | 361 (50.6%) | 487 (50.4%) | 407 (52.0%) | 379 (54.6%) | 0.33 |
| Laboratory findings: | |||||
| Max. CK, U/L | 1220 ± 1275 | 1449 ± 1390 | 1429 ± 1560 | 1162 ± 1243 | <0.01 |
| Max. CK-MB, U/L | 115.9 ± 126.2 | 136.0 ± 136.3 | 142.0 ± 158.5 | 111.2 ± 120.0 | <0.01 |
| Max. cTnI, ng/mL | 10.8 ± 16.8 | 8.5 ± 14.3 | 8.9 ± 14.1 | 10.7 ± 15.1 | <0.01 |
| NT-proBNP, pg/mL | 1329 ± 2857 | 1168 ± 3403 | 1501 ± 3871 | 1570 ± 2840 | 0.19 |
| Glucose, mmol/L | 7.2 ± 3.1 | 7.0 ± 3.4 | 7.4 ± 3.6 | 7.5 ± 3.8 | 0.08 |
| Creatinine, µmol/L | 77.9 ± 44.9 | 80.3 ± 49.1 | 78.8 ± 49.3 | 78.6 ± 43.4 | 0.77 |
| Cholesterol, mmol/L | 4.6 ± 1.2 | 4.6 ± 1.2 | 4.6 ± 1.1 | 4.7 ± 1.2 | 0.90 |
| Triglyceride, mmol/L | 1.9 ± 1.4 | 1.9 ± 1.5 | 1.8 ± 1.5 | 1.8 ± 1.6 | 0.86 |
| HDL-C, mmol/L | 1.2 ± 0.4 | 1.2 ± 0.3 | 1.2 ± 0.4 | 1.2 ± 0.3 | 0.051 |
| LDL-C, mmol/L | 3.0 ± 0.9 | 3.0 ± 0.9 | 3.1 ± 0.9 | 3.0 ± 1.0 | 0.26 |
| PT, sec | 12.7 ± 2.2 | 12.7 ± 2.0 | 12.7 ± 1.9 | 12.6 ± 2.0 | 0.67 |
| APTT, sec | 33.2 ± 12.1 | 33.4 ± 11.5 | 33.0 ± 12.6 | 33.1 ± 12.9 | 0.90 |
| PLT, 109/L | 214.8 ± 61.2 | 213.0 ± 63.3 | 218.6 ± 61.8 | 217.2 ± 62.6 | 0.26 |
| WBC, 109/L | 10.7 ± 3.8 | 11.2 ± 4.1 | 11.57 ± 4.1 | 11.2 ± 3.8 | <0.01 |
| NEUT, 109/L | 8.0 ± 3.8 | 8.8 ± 5.9 | 8.9 ± 5.2 | 8.3 ± 3.7 | <0.01 |
| MONO, 109/L | 0.6 ± 0.3 | 0.6 ± 0.4 | 0.6 ± 0.4 | 0.6 ± 0.3 | <0.05 |
| hs-CRP, mg/L | 25.6 ± 44.6 | 20.2 ± 37.5 | 20.0 ± 40.5 | 22.7 ± 44.3 | 0.19 |
| EF value, % | 56.6 ± 7.5 | 57.3 ± 6.5 | 56.5 ± 8.0 | 56.1 ± 7.9 | 0.06 |
| Target coronary artery: | 0.23 | ||||
| Left anterior descending | 240 (33.6 %) | 321 (33.2%) | 240 (30.7%) | 218 (31.4%) | |
| Left circumflex | 87 (12.2%) | 98 (10.1%) | 78 (10.0%) | 79 (11.4%) | |
| Right coronary | 182 (25.5%) | 289 (29.9%) | 222 (28.4%) | 169 (24.4%) | |
| Left main | 2 (0.3%) | 5 (0.5%) | 0 (0.0%) | 1 (0.1%) | |
| Age groups, yr: | <0.05 | ||||
| 55 | 181 (25.4%) | 264 (27.3%) | 251 (32.1%) | 223 (32.1%) | |
| 55–75 | 415 (58.1%) | 546 (56.5%) | 420 (53.6%) | 375 (54.0%) | |
| ≥75 | 118 (16.5%) | 157 (16.2%) | 112 (14.3%) | 96 (13.8%) | |
| Discharge medications: | |||||
| Aspirin | 705 (98.7%) | 946 (97.8%) | 759 (96.9%) | 677 (97.6%) | 0.13 |
| Clopidogrel | 701 (98.2%) | 934 (96.6%) | 755 (96.4%) | 668 (96.3%) | 0.13 |
| Statin | 704 (98.2%) | 944 (97.6%) | 760 (97.1%) | 680 (98.0%) | 0.23 |
| β-blocker | 438 (61.3%) | 561 (58.0%) | 455 (58.1%) | 423 (61.0%) | 0.37 |
| CCB | 79 (11.1%) | 111 (11.5%) | 78 (10.0%) | 69 (9.9%) | 0.66 |
| ACEI/ARB | 332 (46.5%) | 442 (45.7%) | 356 (45.5%) | 347 (50.0%) | 0.27 |
| Digitonin | 156 (21.9%) | 188 (19.4%) | 160 (20.4%) | 144 (20.7%) | 0.68 |
| Diuretic | 254 (35.6%) | 304 (31.4%) | 274 (35.0%) | 217 (31.3%) | 0.14 |
Values are mean ± SD or number (%).
ACEI = angiotensin-converting enzyme inhibitors, APTT = activated partial thromboplastin time, ARB = angiotensin receptor blocker, BMI = body mass index, CCB = calcium channel blocker, CK = creatine kinase, CK-MB = creatine kinase-MB, cTnI = cardiac troponin I, DBP = diastolic blood pressure, EF = ejection fraction, HDL-C = high-density lipoprotein cholesterol, HR = heart rate, hs-CRP = high-sensitive C-reactive protein, LDL-C = low-density lipoprotein cholesterol, MONO = monocytes, NEUT = neutrophils, NT-proBNP = N-terminal pro brain natriuretic peptide, PLT = platelets, PT = prothrombin time, SBP = systolic blood pressure, WBC = white blood cells.
In total 3158 patients were divided into 4 groups by 6-hour interval over 24 hours. The onset of AMI was 00:00–05:59 in 714 (22.6%), between 06:00–11:59 in 967 patients (30.6%), between 12:00–17:59 in patients 783 (24.8%), and 18:00–23:59 in 694 patients (22.0%). As shown in Table 1, the average age (62.2 ± 12.1) as well as the levels plasma maximum creatinine kinase (CK; 1449 ± 1390 U/L) and creatinine kinase-MB (CK-MB; 136.0 ± 136.3 U/L) levels of patients with an AMI during the second period was significantly higher than those in the other 3 periods (P < 0.01). However, the levels of cardiac troponin I (cTnI; 8.9 ± 14.1 ng/mL), white blood cells (WBC; 11.6 ± 4.1 × 109/L) and neutrophils (8.9 ± 5.2 × 109/L) during the third time period were significantly higher than those parameters in the other 3 periods (both P < 0.01). We also observed that there were significant differences in the age stratification of patients in the 4 time periods, and the proportion of the older (≥75 years old) in the first time period was the highest. As shown in Fig. 2A, the number of patients whose AMI occurred during the second time period (06:00–11:59) was significantly higher than those of the other 3 periods (P < 0.01), with the peak from 7 to 9 am
Figure 2.
Distribution of 24-hour AMI occurrence for all cases, ethnic, smoking, age, and seasons. Onset time distribution (column) and the modelized sinus function (curve) was plotted. (A, all cases; B, Chinese Korean; C, Han; D, smoking patients; E, age < 55; F, 55 ≤ age < 75; G, age ≥ 75; H, different seasons).
This study recruited 1096 Chinese Korean patients (34.7%) and 1979 Han patients (62.9%). As shown in Table 2, the proportion of males (P < 0.05), proportion of III/IV Killip score (P < 0.05), that of smokers (P < 0.01), and the Body mass index (BMI) level (P < 0.01) were all significantly higher in the Han group compared to the Chinese Korean group. Compared to the Han group, the Chinese Korean group’s values were all significantly higher: average age, proportion of older patients (≥75 years old), N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), creatinine, platelet level, and the proportion of diuretic use (Table 2). The circadian rhythm of AMI was almost similar between the Chinese Korean and Han groups, and their rhythms are quite similar to that of whole (Fig. 2A–C). Moreover, the circadian rhythm of the smokers showed a single peak, and there was no significant difference between the smokers and the entire cohort (Fig. 2D), indicating that CAD risk factor smoking might have no effect on circadian rhythm in the onset of AMI.
Table 2.
Differences by nationality
| Chinese Korean | Han | P-value | |
|---|---|---|---|
| No. of patients | 1096 | 1979 | |
| Men | 771 (70.4%) | 1477 (74.6%) | <0.05 |
| Age, yr | 64.5 ± 11.6 | 59.9 ± 12.1 | <0.01 |
| BMI, kg/m2 | 24.1 ± 3.4 | 25.0 ± 3.5 | <0.01 |
| SBP, mm Hg | 130.8 ± 25.3 | 131.1 ± 24.3 | 0.75 |
| DBP, mm Hg | 82.4 ± 16.4 | 82.7 ± 15.5 | 0.60 |
| HR, bpm | 80.3 ± 18.8 | 79.1 ± 17.6 | 0.10 |
| Killip score, III/IV | 201 (18.3%) | 264 (13.3%) | < 0.01 |
| Medical history: | |||
| Ischemic heart disease | 36 (3.3%) | 41 (2.1%) | <0.05 |
| Hypertension | 565 (51.6%) | 968 (48.9%) | 0.16 |
| Diabetes | 230 (21.0%) | 433 (21.9%) | 0.58 |
| Family history | 31 (2.8%) | 61 (3.1%) | 0.74 |
| Current smoker | 506 (46.2%) | 1071 (54.1%) | <0.01 |
| Laboratory findings: | |||
| Max. CK, U/L | 1255 ± 1306 | 1371 ± 1414 | <0.05 |
| Max. CK-MB, U/L | 125.7 ± 133.5 | 129.1 ± 140.2 | 0.53 |
| Max. cTnI, ng/mL | 9.4 ± 20.2 | 12.6 ± 115.6 | 0.39 |
| NT-proBNP, pg/mL | 1730 ± 3687 | 1153 ± 2933 | <0.01 |
| Glucose, mmol/L | 7.2 ± 3.7 | 7.3 ± 3.4 | 0.41 |
| Creatinine, µmol/L | 81.1 ± 47.1 | 76.4 ± 38.7 | <0.01 |
| Cholesterol, mmol/L | 4.7 ± 1.2 | 4.6 ± 1.2 | 0.34 |
| Triglyceride, mmol/L | 1.8 ± 1.6 | 1.9 ± 1.4 | 0.68 |
| HDL-C, mmol/L | 1.2 ± 0.4 | 1.2 ± 0.3 | 0.14 |
| LDL-C, mmol/L | 3.0 ± 1.0 | 3.0 ± 0.9 | 0.35 |
| PT, Sec | 12.7 ± 1.6 | 12.7 ± 2.1 | 0.28 |
| APTT, Sec | 33.4 ± 13.0 | 33.1 ± 11.9 | 0.46 |
| PLT, 109/L | 219.3 ± 63.5 | 213.9 ± 63.2 | <0.05 |
| WBC, 109/L | 11.4 ± 4.1 | 11.1 ± 3.9 | 0.08 |
| NEUT, 109/L | 8.6 ± 4.0 | 8.4 ± 3.8 | 0.15 |
| MONO, 109/L | 0.6 ± 0.4 | 0.6 ± 0.3 | 0.40 |
| hs-CRP, mg/L | 24.3 ± 46.0 | 20.6 ± 20.6 | 0.08 |
| EF value, % | 56.4 ± 8.0 | 56.9 ± 7.2 | 0.17 |
| Target coronary artery: | 0.77 | ||
| Left anterior descending | 339 (31.0%) | 659 (33.3%) | |
| Left circumflex | 119 (10.9%) | 215 (10.9%) | |
| Right coronary | 305 (27.8%) | 536 (27.1%) | |
| Left main | 2 (0.2%) | 4 (0.2%) | |
| Age groups, yr | <0.05 | ||
| <55 | 211 (19.3%) | 674 (34.1%) | |
| 55–75 | 657 (60.0%) | 1059 (53.5%) | |
| ≥75 | 228 (20.8%) | 246 (12.4%) | |
| Discharge medications, n (%): | |||
| Aspirin | 1070 (97.6%) | 1937 (97.9%) | 0.70 |
| Clopidogrel | 1056 (96.4%) | 1923 (97.2%) | 0.21 |
| Statin | 1070 (97.6%) | 1939 (98.0%) | 0.52 |
| β-blocker | 640 (58.4%) | 1187 (60.0%) | 0.39 |
| CCB | 123 (11.2%) | 206 (10.4%) | 0.50 |
| ACEI/ARB | 507 (46.3%) | 936 (47.3%) | 0.60 |
| Digitonin | 243 (22.2%) | 388 (19.6%) | 0.09 |
| Diuretic | 402 (36.7%) | 624 (31.5%) | <0.01 |
Values are mean±SD or number (%). Abbreviations are as shown in Table 1.
Next, all patients were divided into 3 groups based on the ages: younger (<55 years old), intermediate (55–75 years old), and older (≥75 years old). The circadian rhythm of the 3 age groups was similar to that of the whole patient cohort, showing that AMI occurred during the second time period was still higher than those of the other 3 periods (P<0.05; Fig. 2E–G). On closer observation, there were differences between groups: in younger and older patients, there was a narrow peak at 7 or 8 am (Figures 2E and G); The intermediate age patients show a widening peak from 7 to 10 am (Fig. 2F).
Finally, a 4 division of patients was made based on the seasons: Spring (month: 3–5), Summer (month: 6–8), Fall (month: 9–11), and Winter (month: 12–2). In the 4 seasons, the number of patients in fall (827, 26.2%) was the most, followed by spring (816, 25.8%), and the number of patients in winter was the least (710, 22.5%). Unexpectly, the incidence of AMI was significantly lower in the winter than that of other 3 seasons (P < 0.01) and the peak of AMI presented at the months of the large contrast between day and night temperature difference (over 20°C) like May of Spring and October of Fall (Fig. 2H).
4. Discussion
Biological rhythms can affect the behavior of diseases. The study of circadian rhythms contributes to our knowledge of the predictability and management of diseases. Our present analyses revealed that the peak of AMI in China’s Yanbian area is in the morning, as has also been shown by studies in other parts of the world. The mechanism underlying the increased incidence of AMI in the morning is still unclear. It may be related to the increased levels of catecholamine, epinephrine, norepinephrine, and other substance, leading to changes in vascular tension, changes in coagulation factors and the fibrinolysis system, and the enhancement of sympathetic nerve activity.[16–21] These factors may lead to coronary atherosclerotic plaque rupture and coronary artery spasm, resulting in an AMI in the morning time. However, some of the findings among past studies are different from ours. In 1998, Chinese scholars reported that the peak of AMI incidence in the city of Jinan was from 01:00 to 07:00,[22] unlike our observation of a peak from 7:00 to 9:00 am This difference may be due to the changes of Chinese lifestyle and eating habits with the development of the nation’s economy and society. The Han nationality is the majority of Jinan’s population, which is quite different from the Yanbian area, and the population composition may also have contributed to the difference in the peak. However, the circadian rhythm of AMI in the present Han and Chinese Korean patients in Yanbian is the same as the general trend, and there was difference in the rhythm between these 2 nationalities. This may be due to the assimilation of Chinese Korean and Han residents over their long-term coexistence.
In 2018, Kim et al reported the same circadian rhythm of AMIs among Korean individuals as that observed in our present study, but the Japanese who are as the same as the East Asians are different from us.[23] In 2012, Itaya et al reported observing 2 peaks for AMIs (07:00–10:00 and 19:00–21:00) among Japanese patients with an STEMI.[12] They speculated that the second peak may be due to age and gender, especially in elderly women. Compared with the “super-aging society” of Japan, the aging of the residents in the Yanbian area is not as serious. However, as the ages of the residents of the Yanbian area continue to rise, 2 peaks of AMI onset may eventually occur, necessitating further study.
Age is a significant factor in the occurrence and development of cardiovascular diseases. In the present cohort, the average age of the Chinese Korean patients was significantly higher and the proportion of patients aged ≥75 years was significantly higher compared to the Han group, but there was no difference in the groups’ circadian rhythm of the disease. A study conducted in Taiwan revealed that the circadian rhythm of young AMI patients showed clear changes, and the peak appeared at 00:01–06:00.[24] That study’s authors contended that coronary artery spasms usually occur at night or early in the morning, especially in young patients. This difference in timing between that study and our present investigation may be due to the different age spectrum of the patients.
A phenotypic change in the circadian rhythm has been shown to be linked to the mutation of the circadian clock gene,[25] and such a mutation in animal models was suggested to potentially lead to cardiovascular disease.[26] An important underlying reason for a change in circadian rhythm lies in young people’s habit of staying up late and being under high social, psychological, and work pressure, leading to irregular periods of work and rest.
Smoking is linked to acute heart events,[27] perhaps because smoking tobacco can increase the release of catecholamine, active the sympathetic nervous system, and enhance platelet aggregation and thrombosis.[28–30] A comparison of the circadian rhythms of AMI patients in British and Spanish cities revealed a peak in the morning for British Caucasians and Indo-Asians and a peak in the afternoon for Mediterranean Caucasians.[31] The study’s authors proposed several possible reasons for this difference, including the difference in the amount of sunshine, dietary factors, cardiovascular risk prevalence, and even napping habit, among which smoking habit was the main risk factor for AMI. It was recently reported that the smokers among a group of patients with STEMI in the Mediterranean showed a bimodal circadian rhythm change: 1 in the morning (06:01–12:00) and 1 at night (18:01–24:00).[13] The rate of current smokers in the present Han group (54.1%) was significantly higher than that of the Chinese Koreans (46.2%), but there was no significant difference in the circadian rhythm between the 2 nationalities. The results of our analysis of the subgroup of smokers were the same as the general trend, and there was no second peak. This may be due to the differences in inherited characteristics, lifestyles and cultural background among different regions and nationalities.
Our patients’ levels of WBC and neutrophils were considerably higher during the third time period (12:00–17:59) compared to the other 3 periods. The reason for this is not known. The difference may lead to differences in patients’ recovery. Together our present findings demonstrate that there is a circadian rhythm in AMIs in the Border Yanbian Minority Autonomous Prefecture, and the peak of AMI is in the morning. There was no significant difference in this circadian rhythm between the Chinese Korean and Han AMI patients, but there were between ethnic differences in the age at onset, smoking rate, and BMI. Further in-depth study of the circadian rhythms (including the relationships among circadian rhythm genes, the fibrinolysis system, and social and psychological pressure) will have a positive effect on the prevention and reduction of mortality of AMI in the Yanbian area.
Finally, meteorological changes including intense external temperature changes can cause the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system activation, neurohormone release, vasoconstriction, and platelet activation, leading to increasing incidence of AMI and its mortality. We also analyzed the impact of season on onset of AMI. We found that the incidence of AMI in winter was significantly lower than that in the other 3 seasons, and the peak of AMI occurred in May of spring and October of Fall. As known, both months are season exchange with the large contrast between day and night temperature differences (over 20°C) in the border Yanbian Minority Autonomous Prefecture area. Although there is no direct evidence, we speculated that intense external temperature changes might contribute to this phenomenon via the sympathetic nervous system activation-related vasoconstriction and platelet activation. Further study will be also required to investigate this issue.
Several limitations of present study should be noted. This was a single retrospective study. In addition, 10% of the original population of AMI patients who did not have specific AMI onset times were excluded from the study, and this might have affected the results and conclusions.
In conclusions, there is a circadian rhythm in the incidence of AMI, and the peak of AMI is in the morning. Moreover, the incidence of AMI was significantly lower in the winter than that of other 3 seasons and the peak of AMI presented at May of Spring and October of Fall. Further studies are required to determine the pathophysiological mechanism (s) underlying these differences and to guide prevention of AMI for reducing its mortality and disability.
Acknowledgements
We thank K. Shimizu for the technical assistance.
Author contributions
X. Yue researched the biological and histological data and wrote the first draft of the manuscript. L. Piao, Z. Huang, Y. Wan, S. Takeshi, and K. Nakamura researched the morphological data and assisted with the 5/6Nx injury mouse models. X. Meng, A. Inoue, and S. Xu researched the real-time PCR data and mouse genotyping. G.P. Shi reviewed the manuscript, contributed to the discussion, and provided the transgenic mice. T. Murohara and M. Kuzuya edited the manuscript and planned the study. X.W. Cheng designed the study and handled the funding and supervision.
Abbreviations:
- ACEI =
- angiotensin-converting enzyme inhibitors
- AMI =
- acute myocardial infarction
- ARB =
- angiotensin receptor blocker
- BMI =
- body mass index
- CCB =
- calcium channel blocker
- CAD =
- coronary artery disease
- CK =
- creatinine kinase
- CK-MB =
- creatinine kinase-MB
- cTnI =
- cardiac troponin I
- DBP =
- diastolic blood pressure
- ECG =
- Electrocardiograph
- EF =
- ejection fraction
- EMR =
- electronic medical records
- HDL-C =
- high-density lipoprotein cholesterol
- HR =
- heart rate
- hs-CRP =
- high-sensitive C-reactive protein
- LDL-C =
- low-density lipoprotein cholesterol
- MONO =
- monocytes
- NEUT =
- neutrophils
- NSTEMI =
- nonST-segment elevation myocardial infarction
- NT-proBNP =
- N-terminal of the prohormone brain natriuretic peptide
- PLT =
- platelets
- SBP =
- systolic blood pressure
- STEMI - ST =
- segment elevation myocardial infarction
- WBC =
- white blood cells.
Funding: This work was supported in part by the Scientific Research Fund of the Chinese Ministry of Education (nos. 81560240, 81660240, and 81770485).
The authors declare that they have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article.
IRB information: The present study was approved by Yanbian University Hospital (Reference number: YUB19-78).
How to cite this article: Xin M, Zhang S, Zhao L, Jin X, Kim W, Cheng XW. Circadian and seasonal variation in onset of acute myocardial infarction. Medicine 2022;101:28(e29839).
Contributor Information
Minglong Xin, Email: xml.vvv@163.com.
Shengming Zhang, Email: 807043452@qq.com.
Longguo Zhao, Email: 2621141500@qq.com.
Xiongjie Jin, Email: 15526782806@163.com.
Weon Kim, Email: mylovekw@hanmail.net.
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