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Circadian variation in the efficacy of tissue-type plasminogen activator
1Department of Medicine, Cooper Hospital/University Medical Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden 08103.
Insights
Tissue-type plasminogen activator (TPA) demonstrates enhanced efficacy in opening coronary arteries when administered between noon and midnight. This finding supports the circadian pattern of myocardial infarction and suggests optimized timing for TPA treatment.
Area of Science:
- Cardiology
- Circadian Biology
- Pharmacology
Background:
- Acute myocardial infarction (AMI) onset exhibits a circadian pattern, peaking between 6:00 AM and noon.
- Circadian variations in hemostatic factors suggest a predisposition to morning clotting and evening thrombolysis.
- Previous research indicates potential time-dependent efficacy of treatments for AMI.
Purpose of the Study:
- To investigate the hypothesis that tissue-type plasminogen activator (TPA) is more effective when given in the afternoon/evening (noon to midnight).
- To assess TPA efficacy by measuring coronary artery patency 90 minutes after treatment initiation.
Main Methods:
- Retrospective analysis of 728 patients from two studies using TPA for AMI under a uniform protocol.
- Standardized assessment of 90-minute coronary patency by a core angiographic laboratory for 692 patients with qualifying arteriograms.
- Analysis of TPA efficacy in relation to administration time, correlating with the circadian variation of AMI onset.
Main Results:
- TPA demonstrated a circadian pattern of efficacy, with significantly greater TIMI grade 3 coronary artery patency when administered between noon and midnight (P < .001).
- In patients treated within 2 hours of symptom onset (n=127), overall patency was highest, with a trend towards greater AM/PM patency differences.
- Peak TPA efficacy occurred around 8:00 PM, approximately 10 hours after the peak incidence of myocardial infarction around 10:00 AM.
Conclusions:
- A significant circadian variation exists in TPA's ability to rapidly restore coronary artery patency, with maximal efficacy observed between noon and midnight.
- Findings align with known increased morning thrombosis and a more favorable evening fibrinolytic profile.
- The study has implications for understanding AMI pathophysiology and developing chronotherapy strategies for TPA administration.
Background:
The frequency of onset of acute myocardial infarction follows a circadian pattern, with a peak incidence between 6:00 AM and noon. Circadian variations have been defined for platelet aggregation, plasminogen-activator inhibitor, and a number of hemostatic and physiological factors, all of which might predispose toward clotting in the late morning and thrombolysis in the evening. Thus, the hypothesis for this retrospective analysis was that tissue-type plasminogen activator (TPA) has greater efficacy when administered between noon and midnight, as measured by coronary patency 90 minutes after initiation of treatment.
Methods And Results:
Seven hundred twenty-eight patients were enrolled in either of two studies in which TPA was administered under a uniform protocol for the treatment of acute myocardial infarction. Of these, 692 patients had qualifying arteriograms that allowed standardized assessment by a core angiographic laboratory of the primary end point of 90-minute patency. TPA has a circadian pattern of efficacy, with greater TIMI grade 3 patency when administered between noon and midnight (P < .001). When TPA was given within 2 hours of symptoms (n = 127), the total patency was highest and there was a trend (P = .055) toward the greatest magnitude difference occurring between AM and PM patency. The onset of myocardial infarction was confirmed to have a marked circadian variation with a peak incidence about 10:00 AM. The peak efficacy of TPA was about 8:00 PM, representing a phase difference of about 10 hours after peak infarction incidence.
Conclusions:
There is a circadian variation in the ability of TPA to rapidly open coronary arteries, with highest efficacy between noon and midnight. This complements clinical and in vitro knowledge of increased morning thrombosis and is concordant with knowledge of increased morning thrombosis and is concordant with knowledge of a fibrinolytic profile that is more favorable for evening lysis. This finding has implications for understanding the circadian pathophysiology of myocardial infarction and for its chronotherapy.