Circadian Variation in the Onset of Myocardial Infarction: Effect of Duration of Diabetes

The Onset Study was conducted in 64 medical centers in the United States. Between August 1989 and September 1996, 3,882 patients (1,258 women and 2,624 men) were interviewed at a median of 4 days (range 0–30) after having an MI.

Trained research interviewers identified eligible patients by reviewing coronary care unit admission logs and patient charts. For inclusion, patients were required to have a creatine kinase level above the upper limit of normal for each center, positive MB isoenzymes, an identifiable onset of symptoms typical of infarction, and the ability to complete a structured interview. The institutional review board of each center approved this protocol, and interviewers obtained informed consent from each patient.

Interviewers used a structured data abstraction and questionnaire form. Information collected from each interview and chart review included patient age, sex, medical history, and medication use (both prescription and nonprescription). We used the patient-reported time that the discomfort began as the onset time for acute MI, a method previously validated with the use of serial creatine kinase values (1).

We defined diabetes as a history of diabetes obtained during chart review or the current use of any hypoglycemic medication. The type of treatment for diabetes was considered as diabetes controlled by diet, use of oral hypoglycemics (first- and second-generation sulfonylureas, metformin), or insulin therapy. Duration since diagnosis of diabetes was established from the medical records if available; otherwise, interviewers asked the patients to report the duration.

The hourly frequency of the onset of MI symptoms was graphically displayed. We used harmonic regression models to evaluate the circadian variation of onset of MI symptoms in patients with diabetes and patients without diabetes as previously reported (17). For further analysis we divided the day in into four 6-h intervals from 0:00 to 5:59, 6:00 to 11:59, 12:00 to 17:59, and 18:00 to 23:59. The presence of circadian variation was tested using the χ² one degree of freedom goodness-of-fit test for uniform distribution. Difference in the circadian variation in the onset of MI was assessed using a Pearson χ² test.

The characteristics of the study population have been previously reported (16,17,18) and are summarized in Table 1. Figure 1 shows the hourly distribution of MI symptom onset among patients with and without a history of diabetes. A statistically significant circadian pattern of MI symptom onset with a single peak in the morning hours was observed in patients without diabetes (P < 0.001), whereas no such peak was observed among 814 patients with a history of diabetes (P = 0.16).

Table 2 shows the distribution of the time of MI onset in 6-h intervals, according to the type and duration of diabetes. A significant morning peak in MI symptom onset was seen among patients without diabetes and was somewhat blunted in the entire group of patients with diabetes. Further analysis revealed that the expected morning peak in the MI symptom onset was preserved among patients who had type 2 diabetes diagnosed within the past 5 years. However, there was no apparent circadian variation in MI onset among patients with type 1 diabetes or those with type 2 diabetes of 5 years or more duration.

In a sensitivity analysis, we found that the circadian variation in MI onset was absent in all patients with diabetes for 5 or more years, regardless of treatment type. Among patients with diabetes for <5 years, the morning peak was maintained only among those who were treated with diet or oral hypoglycemic agents but was lost among insulin-treated patients. This may reflect a more severe disease or perhaps a longer preclinical phase among patients who are treated with insulin soon after receiving the diagnosis.

Although not a previous hypothesis, we noted that patients with diabetes seemed to have a higher proportion of infarcts in the late evening at approximately 22:00 to 23:00 (Fig. 1). Despite this, the harmonic regression analysis did not demonstrate a statistically significant secondary peak in MI onset among patients with diabetes (P = 0.13).

In this multicenter study of early survivors of acute MI, we observed a circadian pattern of acute MI symptom onset in patients with and without a history of diabetes. However, patients with type 1 diabetes and those with type 2 diabetes for 5 or more years had a marked attenuation of the morning peak in acute MI.

Hjalmarson et al. (4) were the first to show that the characteristic day-night pattern in the onset of MI is altered in patients with diabetes. These findings have been confirmed by several studies (19,20,21,22). In conflicting reports, other studies failed to show such a variation in the circadian pattern in the onset of MI (5,6,23,24) among patients with a history of diabetes.

A surge in sympathetic activity and vagal withdrawal in the morning hours alters homodynamic forces and may cause atherosclerotic plaques to rupture in the morning (25). Morning elevation in plasma catecholamines and renin levels, heart rate and blood pressure, and coronary blood flow (26,27,28,29) may increase shear forces in the coronary arterial bed, thus promoting plaque disruption and causing unstable angina and acute MI (30). Also, a morning increase in platelet reactivity may make a thrombus more likely to grow and cause symptoms (27). It has been demonstrated that patients who receive β-blockers fail to exhibit the morning increase in the incidence of MI (31,32).

This concept that the autonomic nervous system plays an important role in determining the circadian pattern of cardiovascular events suggests that in patients with diabetes, abnormalities in the circadian rhythm of autonomic tone may be responsible for the altered temporal onset of cardiovascular events (33,34).

Autonomic neuropathy is common in diabetes, affecting 8% of patients with recently diagnosed type 1 diabetes (35). In patients with type 2 diabetes, Toyry et al. (36) observed that the risk of developing parasympathetic neuropathy increased sharply after 5 years, and prevalence for combined autonomic neuropathy reached 65% after 10 years of follow-up. In a recent study in patients with type 2 diabetes, cardiac sympathetic dysinnervation was observed even before electrocardiogram-based cardiac autonomic neuropathy was diagnosed (37).

As previously mentioned, in the general population, the circadian rhythm of sympathovagal balance consists of a daytime prevalence sympathetic activity with a prominent increase in parasympathetic activity during the night (24). Bernardi et al. (38) demonstrated that diabetic autonomic neuropathy is associated with a marked diminution of parasympathetic activation during sleep. Sayer et al. (39) found that the rhythm of sympathovagal balance was significantly attenuated in patients with diabetes compared with those without diabetes. Similarly, patients with diabetes and symptomatic autonomic neuropathy have been shown to have markedly impaired heart rate variability (40,41). Lower heart rate variability in turn has been shown to be associated with an increased risk of development of coronary heart disease in individuals with diabetes (42). Another indicator of autonomic dysfunction in patients with diabetes is increased QT dispersion (43), which is associated with an increased risk of cardiovascular events in this patient population (44,45). Furthermore, increased QT dispersion has been associated with blunted circadian variation in blood pressure and altered sympathovagal balance in patients with type 1 diabetes (46).

Other important physiological correlates of cardiac autonomic dysfunction associated with more prolonged diabetes include loss of normal nocturnal dip in blood pressure during the night (47), blunted circadian variation of fibrinolytic activity and plasminogen activator inhibitor-1 antigen levels (48), persistent elevation of factor VII antigen and von Willebrand factor antigen (48), and increased platelet activation (49). All of these factors predispose patients with long-standing diabetes to trigger cardiovascular events throughout the day with the absence of a morning peak, accounting for attenuation of circadian variation of MI in these patients.

A possible limitation of our study is inaccuracy in the identification of diabetes. We relied on the clinical diagnosis of diabetes made by the treating clinicians in the medical record and by patient self-report. This approach may have misclassified patients with unrecognized diabetes. Such misclassification would tend to minimize the effect of diabetes, so the relative risks reported here might be overly conservative.

Our study demonstrates that the circadian morning peak of MI symptom onset is attenuated in patients with type 1 diabetes or type 2 diabetes for 5 or more years, suggesting a role of autonomic dysfunction. Inconsistency in observation of such an effect in patients with diabetes in the past may well have been due to differences in the duration of diabetes and thus the variable extent of underlying autonomic dysfunction. Variation in the mechanism producing MI may have implications for prevention in patients with diabetes.

This study was supported by Grant HL41016 for the Determinants of Myocardial Infarction Onset Study from the National Heart, Lung, and Blood Institute, Bethesda, MD; Grant T32-HL07374-22 from the National Institutes of Health, Bethesda, MD; and Grant 9630115N from the American Heart Association, Dallas, TX.