Linking Triggers And Acute Coronary Events Circadian Changes in Physiologic Variables

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Daily activities and experiences, which act as triggers of acute coronary syndromes, must act through the perturbation of the physiologic milieu in which a vulnerable atherosclerotic plaque exists (Fig. 11). Circadian variation in hemodynamic variables has been studied to explain the circadian variation of acute cardiac events. The morning hours are associated with a rise in arterial blood pressure and an increase in heart rate, both of which are reduced during sleep (109,110). This hemodynamic surge appears to be related to assumption of the upright posture (111). Most studies have shown that episodes of ambulatory ischemia are related to an increase in rate-pressure product (111), and that ambulatory myocardial ischemia is more frequent and more prolonged in the morning (42-47). Angina patients and normal subjects have a significantly greater blood pressure and heart rate response during an exercise test in the morning compared to the response during an afternoon exercise test (112).

In another study, the rate-pressure product at which ischemia was induced was lower in the morning, in parallel with an increase in postischemic forearm vascular resistance (113). A study of forearm blood flow found vasodilatory responses to acetylcholine to be greater in normal subjects in the morning compared to afternoon; however, no such morning increase in endothelium-dependent vasodilation was found in subjects with coronary artery disease (114). One study directly examined circadian variation in coronary artery tone. Segments of artery with dysfunctional endothelium showed exaggerated constrictor responses to acetylcholine and also greater dilator responses to nitroglycerin at 6 AM as compared to 1 pm, whereas segments with normal endothelium showed no diurnal variations (115/These data suggest that, in addition to the morning increase in myocardial oxygen demand, coronary disease patients may have increased coronary vascular resistance plus a morning blunting of compensatory vasodilatory responses.

A number of hemostatic variables follow a circadian rhythm paralleling that of cardiac events (116). The morning hours are associated with an increase in platelet aggre-gability, which occurs with the assumption of the upright posture (117-119). Plasma

Fig. 11. Potential mechanisms linking atherogenic risk factors, plaque evolution and the transformation from stable to vulnerable plaque, and the means by which external triggers produce various acute coronary syndromes.

Fig. 12. Circadian variation in physiologic processes mediating the triggering of acute coronary events. The level of plasminogen activator inhibitor (higher levels favor thrombosis) in 6 healthy volunteers undergoing sampling every 3 h (including during sleep from midnight to 8 am) is shown by the dotted line. The level of tissue-type plasminogen activator (higher levels favor fibrinolysis) is shown by the solid line. Whiskers indicate standard error of the mean. Asterisks indicate significant difference between peak and nadir values. The balance of factors in the morning favors thrombosis, and in the evening, the balance of factors favors fibrinolysis. Reprinted with permission from ref. 126.

viscosity (120), fibrinogen levels (121),white blood cell aggregation (122), and lipoprotein (a) levels (123) increase in the morning. These changes favor thrombosis. The morning hours bring a decrease in resting tissue-type plasminogen activator (tPA) levels (124-127) and an increase in tPA inhibitor, PAI-1 (124-128), which reduces the activity of the intrinsic fibrinolytic system (Fig. 12). Recent studies of other markers of coagulability and fibrinolysis have further strengthened the appreciation of the morning hours as a period of relative hypercoagulability (129,130).

The activity of the autonomic nervous system has been studied to elucidate circadian patterns. Plasma norepinephrine falls to a nadir at night and increases in the morning in association with awakening and resumption of upright activty (131,132). Forearm vascular resistance has been shown to increase in the morning in normal subjects, a change attenuated by phentolamine but not nitroprusside, suggesting that the increase in vasomotor tone in the morning is mediated through a-adrenergic activity (133). A morning withdrawal of vagal tone and an increase in sympathetic tone has been suggested by spectral analysis of heart rate variability (134-139). Autonomic nervous system dysfunction in diabetic patients with coronary artery disease was shown to be associated with a blunted circadian pattern of myocardial ischemia (140).

Circadian variation has been shown for electrophysiologic variables such as the length of the refractory period (141) and the QT interval (142). Increased QT interval p<0.05

Before 7-14 days Before 7-14 days after atter

Fig. 13. In 42 elderly patients who experienced "high stress" but no physical injury during a major earthquake in Japan, levels of coagulation and fibrinolyis-related proteins increased significantly following the quake. Blood samples from within the 60 d preceeding the quake were available for analysis (X-axis, before) and were matched with samples 7-14 d after the quake. In addition to fibrinogen levels, results are reported for plasmin-a2-plasmin inhibitor complex (PIC, a fibrinolytic factor), von Willebrand factor (vWF, an endothelial cell derived factor), and tissue-type plasminogen (tPA antigen, also a fibrinolytic factor). Reprinted with permission from ref. 99.

Before 7-14 days Before 7-14 days after atter

Fig. 13. In 42 elderly patients who experienced "high stress" but no physical injury during a major earthquake in Japan, levels of coagulation and fibrinolyis-related proteins increased significantly following the quake. Blood samples from within the 60 d preceeding the quake were available for analysis (X-axis, before) and were matched with samples 7-14 d after the quake. In addition to fibrinogen levels, results are reported for plasmin-a2-plasmin inhibitor complex (PIC, a fibrinolytic factor), von Willebrand factor (vWF, an endothelial cell derived factor), and tissue-type plasminogen (tPA antigen, also a fibrinolytic factor). Reprinted with permission from ref. 99.

dispersion (difference between the longest and shortest QT interval in a given patient) has been considered to represent inhomogeneous ventricular repolarization and is thought to be a risk factor for malignant ventricular arrhythmias (143,144). Variations in QT interval dispersion throughout the day support the concept of the morning hours as a period of heightened sympathetic tone, and that autonomic imbalance, with increased sympathetic nervous system output or sensitivity, may be a risk factor for malignant ventricular arrhythmias and sudden cardiac death (143,144).

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