Research articles

By Dr. Muralikrishna Gopal , Dr. Nagendra Boopathy , Dr. R Venkatesan , Dr. V Jagannathan
Corresponding Author Dr. Muralikrishna Gopal
Division of Pulmonary-Critical Care, Montefiore Medical Center , - United States of America
Submitting Author Dr. Muralikrishna Gopal
Other Authors Dr. Nagendra Boopathy
Department of Cardiology, All India Institute of Medical Sciences (AJMS), - India

Dr. R Venkatesan
Department of Cardiology, Madras Medical College, - India

Dr. V Jagannathan
Department of Cardiology, Madras Medical College, - India


Acute Coronary Syndromes, Circadian, Variation, Hypertension

Gopal M, Boopathy N, Venkatesan R, Jagannathan V. Circadian Variation In Acute Coronary Syndromes. WebmedCentral CARDIOLOGY 2010;1(9):WMC00533
doi: 10.9754/journal.wmc.2010.00533
Submitted on: 06 Sep 2010 09:54:43 PM GMT
Published on: 06 Sep 2010 10:21:44 PM GMT


Background: Studies have shown that a circadian rhythm may exist in the onset of acute coronary syndromes. More studies are needed in the Indian population to confirm the existence of this circadian variation and add to the existing literature in the Indian population. Methods: Two hundred twenty consecutive patients with acute coronary syndromes, admitted to the coronary care unit were included in the study. The time of onset of symptoms was noted into six categories of four hours each. Results: The statistical analysis of the data obtained showed that acute coronary syndromes was commonest from 4am to 8 am (35%, P valueConclusions The circadian variation in the time of onset of acute coronary syndromes in an Indian population is similar to data published in the western literature, with a peak in the early morning. This variation appears to be exaggerated in the treatment naïve-hypertensive population. Further research is needed to assess the cellular and neuro-hormonal mechanisms of this circadian variation and may have implications in therapeutics.


Circadian rhythms are biological rhythms that occurendogenously in most biological organisms. The effectthat these biological oscillations have on thepathophysiology of various diseases is currently thefocus of numerous research studies. The increasedrisk of occurrence of acute coronary syndromes in theearly morning has been demonstrated in a few studies1,2,3,11,12,17,25,26. A meta-analysis showed a 40% increasein risk of myocardial infarction between 6 am and noon1and another showed an increased occurrence ofischemic stroke in the morning18. The pathogeneticmechanism of this circadian variation is a subject ofongoing research. It is also now known that thepathogenetic mechanisms of cardiovascular disease inthe Indian population may be different from thewestern population.In the scientific literature, only one prior study7 hasbeen published attempting to determine if thiscircadian variation in acute coronary syndromes existsin the Indian population, in addition to one other study,that shows a circadian variation in the onset ofischemic stroke in a geriatric population in India18. Thesub-group analysis of one study involving over onethousand patients done in the United Kingdom did notshow a circadian variation in the south Asianpopulation13. Current research has also focused on thevariation in the circadian rhythm in acute coronarysyndromes in patients with co-morbidities, especiallydiabetes13,15 , which has shown no circadian variationin diabetic patients. So far, studies have not focusedon the circadian variation of acute coronarysyndromes in hypertensives. In normal subjects, bloodpressure appears to fall nocturnally, whereas, it hasbeen shown that a sub-group of patients withhypertension do not exhibit this nocturnal fall in bloodpressure16, so called non-dippers, and this maycontribute to an increased occurrence of acutecoronary syndromes, especially in the early morning inthis population. We wanted to further delineate thisrelationship by performing a sub-group analysis ofhypertensive as compared to non-hypertensivepatients.


Patients presenting to the Coronary Care Unit (CCU)with a diagnosis of acute coronary syndrome- unstableangina, non- ST elevation myocardial infarction(NSTEMI) and ST-segment elevation myocardialinfarction (STEMI) were included in the study.Exclusion criteria included the absence of chest pain,treatment with fibrinolysis/ PCI prior to admission tocoronary care unit, current use of anti-hypertensivemedications, current use of aspirin, inability to providehistory at time of admission, presence of malignanthypertension and secondary causes of hypertension.Patients with a history of hypertension and onanti-hypertensive medications were excluded due toprior studies showing significant effects of thesemedications, especially beta blockers13 andangiotensin converting enzyme inhibitors on thecircadian rhythm of the autonomic nervous system10and acute coronary syndromes13.Ours is a single centre study which enrolled two hundred twenty consecutive patients selected from agroup of 316 patients. 96 patients were excludedbased on the exclusion criteria. The study wasconducted at the Coronary Care Unit (CCU) of theDepartment of Cardiology, Government GeneralHospital, Chennai. The time of onset of symptomswere then divided into six periods of four hours eachex: 12-4am, 4-8am, 8-12 am and so on. Thesepatients were then treated in the CCU according to theexisting management protocols. Also, after the acutephase management, the patients were then enquiredas to whether they had been diagnosed withhypertension in the past, and if so, a detailedmedication history was obtained. The results aresummarized in table 1. The statistical analysisperformed from the data of the above table with thehelp of chi- square plots, Mann Whitney tests,continuity correction gave the results as follows.


Among the 220 patients enrolled in the study, 76% were male. 26% of the patients self-reported a prior history of diabetes. 81 patients self-reported a prior diagnosis of hypertension and not being on anti-hypertensive medications (36%). 46% of patients self-reported a history of smoking.

The time of onset for each patient in the study, and sub-tabulation of the time of onset in two groups of hypertensives and non-hypertensives was noted and the results are summarized in table 1. Table 1 shows that 79 patients had a time of onset between 4 am and 8 am. This amounts to 35 % of the study population compared to significantly lower percentages at other times of the day. This difference was statistically significant, P value < 0.005. A sub-group analysis was conducted based on the presence of pre-existing hypertension that was treatment-naive. The circadian variation in the time of onset of acute coronary syndromes in the non- hypertensive subgroup showed a marked bimodal rhythm. i.e., patients in the non-hypertensive population showed an early morning peak in the onset of acute coronary syndromes accompanied by a late evening rise (4am to 8am-32.3%, 4pm-8 pm -22.3%).This result was statistically significant since P value was


The results of the study are consistent with prior studies in the literature both in the western and Indian literature with a peak occurrence of acute coronary syndromes between 4 am and 8 am. Several mechanisms have been proposed for the pathogenesis of this relationship. Plateletaggregation in response to epinephrine, adenosine diphosphate,and thrombin is heightened during the early morning hours, particularlyafter arising from sleep19,20 Anti-thrombin levels decline and fibrinogen levels increase during this time period as well19 plasminogen activator inhibitor activity shows a marked increase in the early morning hours21 One study also showed a relative resistance to thrombolysis in the early morning hours22 and another showed poorer outcomes with PCI done in the early morning23 and this was attributed to “time of PCI” rather than “time to PCI”, when comparing off-duty and off-hour PCI to regular times.
The results appear to indicate that the circadian variation in the time of onset of acute coronary syndromes is different in hypertensives when compared to non-hypertensives. Thus hypertensives exhibit a circadian rhythm that is exaggerated in the early morning and blunted in the late evening. The circadian variation of acute coronary syndromes in hypertensive patients maybe clinically significant because understanding of the basis of the circadian variation is essential for instituting pharmacological therapy aimed at modifying the circadian rhythm of various physiological variables14. Numerous 24 hour blood pressure recordings have shown that the blood pressure fluctuates widely from time to time but exhibits a significant nocturnal fall of 30-50 mm Hg6 and an early morning rise4. Of greater significance are studies showing the lack of a nocturnal decrease in blood pressure in a sub-population of hypertensives which may contribute to an increased occurrence of acute coronary syndromes in this population. It has been shown in clinical studies that the circadian rhythm of acute coronary syndromes correlates very well with the changes in blood pressure. Since it is clear that early morning peak of acute coronary syndromes is due to the elevation of blood pressure, pharmacologic therapy aimed at blunting the early morning rise with the aid of nocturnal dosing of anti hypertensive therapy could reduce the occurrence of acute coronary syndrome in this population5. This is currently the subject of research, which has been labeled chronotherapeutics8,9. One study showed the lack of a circadian variation of acute coronary syndromes in patients taking beta-blockers24
Our study has several limitations. Our study population of 220 is smaller than the prior study in an Indian population, which included 605 patients7, but larger than one other study in a geriatric population in India, which included cardiovascular and cerebrovascular disease, and included 158 patients18. Our sample size was also severely limited by the exclusion of patients on aspirin and anti-hypertensives, which form a significant proportion of patients presenting with acute coronary syndromes, because of prior studies suggesting a blunting of the circadian rhythm in patients on these medications. Due to the lack of established medical records for most patients admitted to the coronary care unit, we had to rely on a self-reported history of diabetes and hypertension. It is possible that a small population of the “non-hypertensive” population could have had previously undiagnosed hypertension. Because of the use of onset of chest pain, although used by prior studies as well, patients with silent myocardial ischemia are likely to be missed in the study population.


There are two major conclusions we can infer from the study. Firstly, a circadian rhythm exists in the time of onset of acute coronary syndromes in the Indian population as well. Understanding of the mechanism of this circadian rhythm may lead to therapeutic strategies that can reduce the incidence of acute coronary syndromes by blunting this peak. The exaggeration of the early morning peak seen in hypertensive patients could be related to non-dipping, as suggested by one prior study. If this is confirmed by continuous blood pressure recordings in larger studies, this could identify a sub-group of patients with hypertension who maybe at higher risk of acute coronary syndromes than those who experience a nocturnal fall in their blood pressure. As a corollary, institution of pharmacologic therapy aimed at decreasing blood pressure during this period of the day may reduce the peak in the time of onset of acute coronary syndromes in this population. Further prospective, controlled trials are needed to confirm the translation of this pathophysiologic benefit to clinical practice.


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