By Sean Henahan, Access Excellence

DALLAS- While heart attacks are known to occur more frequently in the morning hours, the clot-buster agent TPA (tissue plasminogen activator) appears to be at its most effective in the evening hours, according to a new study.

Clinicians have known for sometime that myocardial infarctions, heart attacks associated with clotting and closure of coronary vessels, follow a pronounced circadian rhythm and are more likely to occur in the morning, between six a.m. and noon.

These circadian variations have been attributed to an increased tendency to form blood clots during those hours, as well as to the increase in epinephrine and other "stress hormones" that accompany waking. In addition, a number of physiological activities associated with increased clot dissolving, such as an increase in levels of natural TPA, have been observed in the evening hours.

"These observations made me wonder if the clot-dissolving medications we give to heart attack patients are less effective in the morning and more effective in the evening," said researcher Peter Kurnik, M.D., of the Robert Wood Johnson Medical School.

Dr. Kurnik and colleagues evaluated 692 patients who had received TPA within six hours of the onset of chest pain and other symptoms of heart attack. The six hour period following initial onset of symptoms is considered the optimal time to administer thrombolytic agents. (Thrombolytic is medicalese for clot-buster, coming from the Greek meaning clot dissolver). The research team performed angiograms within 90 minutes of treatment in order to determine the efficacy of thrombolytic therapy.

The highest incidence of heart attack occurred at 10:00 a.m., four times higher than the lowest incidence at 2:00 a.m. An analysis of heart attack incidence by six hour intervals showed that 34% of events occurred between six a.m. and noon; 29% between noon and six p.m.; 21% between six p.m. and midnight and 16% between midnight and six a.m.

An analysis of the data revealed that heart attack patients treated between midnight and noon had a much greater likelihood of successful treatment with TPA than those treated between noon and midnight. This observation was particularly strong in patients who were treated within two hours of symptom onset. This indicates a circadian variation in the ability of TPA to open coronary arteries, noted Dr. Kurnik.

"My study implies that higher does of TPA may be needed during midnight and noon than noon to midnight, but additional research is needed to test this possibility," he said. "However, no matter what time the heart attack occurs, it is essential that TPA or some other therapy be given as soon as possible," he emphasized.

So, what is the mechanism of the circadian pattern of TPA efficacy? Four possible mechanisms have been proposed based on the current understanding of clot formation and clot lysis (dissolving) and circadian patterns of hemostatic and fibrinolytic factors.

The researchers believe the circadian activity of a compound known as plasminogen activator inhibitor (PAI-1) may be an important mechanism of the observed difference in TPA efficacy. The levels of PAI-1, a protein which inhibits the action of TPA, are two to fourfold higher in the morning than in the evening.

The function of platelets also follows a circadian rhythm. Platelets are more likely to aggregate, or clump together, in the morning than in the evening. Increased platelet activation has also recently been linked with the release of products that stimulate the synthesis of PAI-1.

Other mechanism might include diurnal variations in clot composition and diurnal variations in the body's natural tendency to keep arteries open. This could translate into an increased chance of blood clot formation in the morning and/or an increased natural clot dissolving action in the evening, notes Kurnik.

Dr. Kurnik's research appeared in the journal Circulation, 3/1/95.

Transmitted: 95-03-03 20:41:28 EST

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