(Circulation. 1995;91:1604-1606.)
© 1995 American Heart Association, Inc.
Articles |
Morning Resistance to Thrombolytic Therapy
From the Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
Correspondence to Eugene Braunwald, MD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
Key Words: Editorials • thrombolytic therapy
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Introduction |
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The Multi-center Investigation on the Limitation of Infarct Size (MILIS), begun just before the thrombolytic era of the treatment of acute myocardial infarction (MI), focused in part on the timing of therapies designed to limit infarct size.1 Careful recording of the time of both the onset of symptoms and of the rise of creatine kinase-MB enzyme activity permitted accurate timing of infarction, revealing a circadian pattern with a distinct morning peak. The database of the larger Thrombolysis in Myocardial Infarction (TIMI) II trial allowed prospective testing of our earlier observation in MILIS. The increased incidence of onset in the morning (6 AM to noon, 34%), compared with night (midnight to 6 AM, 15%), was even more prominent than in MILIS.2 Indeed, in almost one half of a subgroup of patients in TIMI, infarction began between 6 AM and noon. Rather than relegating these curious findings to the files, Muller, Tofler, and a growing number of other investigators sensed correctly that research into the mechanisms responsible for the morning peak in the onset of infarction might lead to a better understanding of the pathogenesis of this condition3 and thereby aid in the development of preventive strategies. Their efforts have taken several interesting directions. First, in addition to acute MI, a morning increase in sudden death was described4 and found to be secondary to ventricular fibrillation, rather than to other arrhythmias.5 In the Cardiac Arrhythmia Suppression Trial (CAST), the higher mortality in patients receiving type 1c antiarrhythmic drugs could be explained in part by an excess of morning deaths in patients receiving these agents.6 A circadian variation in the frequency of sudden death appears to be especially prominent in patients with heart failure; Moser et al7 reported a 2.5-fold increase in the risk of sudden death between 6 AM and noon in such patients. In addition to ventricular fibrillation, a variety of other arrhythmias, including supraventricular tachycardia, ventricular ectopic beats, and nonsustained ventricular tachycardia, show a predilection for the morning. In an interesting study published recently in this journal, Lampert et al8 extended these findings to sustained ventricular tachycardia. In an analysis of 2558 episodes of this arrhythmia occurring in patients with coronary artery disease and implantable cardioverter-defibrillators, the same temporal pattern was found. There are many implications of these findings on circadian variations in sudden death and arrhythmias, including the identification of triggers of sudden death3 and the timing and tailoring of antiarrhythmic therapy.
A second line of research into circadian variations of the clinical manifestations of coronary artery disease relates to the now well-established morning peak of myocardial ischemia—as reflected in the frequency of stable angina, of both symptomatic and asymptomatic ST-segment depression on the ambulatory ECG,9 of the onset of the pain of unstable angina,10 and of variant angina.11 These morning increases in ischemia are related, at least in part, to the augmentation of myocardial oxygen demand secondary to the adrenergically mediated increases in heart rate, arterial pressure, and myocardial contractility occurring upon arising, accompanied by a reduction in myocardial oxygen supply secondary to increases in coronary vascular resistance.12 An exception to this pattern has been observed in diabetic patients with autonomic nervous system dysfunction who do not exhibit a morning increase in the frequency of ischemic episodes.13 This exception suggests that alterations in the sympathovagal balance, which characterizes diabetic autonomic dysfunction, may influence the circadian pattern of ischemia. In support of this idea, Marchant et al14 have reported that the morning peak in the frequency of ischemic episodes in patients with chronic stable angina is associated with an increase in the ratio of the low- to the high-frequency components of heart rate variability, reflecting an augmentation of the sympathetic/vagal balance at this time of day. It is not surprising, then, that patients receiving ß-blockers fail to exhibit morning increases in the incidence of angina, silent ischemia, acute MI,1 15 and sudden death.16
In addition to causing an imbalance between myocardial oxygen supply and demand in patients with ischemic heart disease, the morning elevations in arterial pressure and heart rate may also increase shear forces in the coronary arterial bed and thereby precipitate plaque fissuring, causing unstable angina, MI, and sudden death. The reduction in the incidence of reinfarction caused by ß-blockers16 and angiotensin-converting enzyme inhibitors17 may be explained, in part, by the reduction in surges of shear stress induced by these agents.
The incidence of thrombotic conditions other than MI and unstable angina, including ischemic stroke18 and pulmonary thromboembolism,19 also exhibits morning peaks. The third and perhaps the most intriguing line of research emanating from the observed morning peak incidence in the onset of all of these conditions relates to the relative increase in procoagulant activity that occurs at this time. A reduction in blood fibrinolytic activity20 and increase in blood viscosity21 in the morning were first reported more than 2 decades ago. More recently, it has been found that platelet aggregability increases in the morning with assumption of the upright posture.22 The potential importance of this variation in platelet function is underscored by findings in the Physicians Health Study, in which the morning peak in infarction was attenuated in subjects randomized to aspirin,23 presumably by preventing the morning surge in platelet activity.
In addition to platelets, the aggregability of white cells also peaks in the morning.24 In addition, circadian variations in blood coagulability are reflected in temporal fluctuations in heparin resistance. When heparin is infused at a constant rate throughout the day, both the activated partial thromboplastin time and the thrombin time are substantially shortened in the morning.25
Although, as noted, a circadian variation of fibrinolytic activity was described in healthy subjects by Rosing et al20 in 1973, the recognition of a morning increase of MI and of other thrombotic events, as well as the widespread use of thrombolytic therapy in the management of acute MI, sparked renewed interest in this phenomenon. Plasminogen activator inhibitor-1 (PAI-1) activity was shown to be a risk factor for MI26 and for reinfarction.27 Andreotti et al28 then described major circadian fluctuations in fibrinolytic factors in healthy subjects resulting from a marked increase in PAI-1 activity in the early morning. Grimaudo et al29 confirmed these findings, showing reduced plasma fibrinolytic activity at this time, as reflected in a doubling of the euglobulin lysis time. The latter was related to morning elevations of both PAI-1 antigen level and PAI-1 activity but not to morning depressions of the TPA antigen level. Actually, both PAI-1 activity and TPA antigen levels appear to be higher in the morning, while TPA activity is lower at this time, reflecting the important role of PAI-1 levels in regulating TPA activity.30 The circadian variation of PAI-1 activity first observed in healthy subjects was then extended to patients with ischemic heart disease, in whom the baseline levels were elevated and who exhibited a similar morning peak.11 31 32
These temporal variations in PAI-1 activity set the stage for the findings in the interesting paper by Kurnik in this issue of Circulation.33 This author describes a circadian fluctuation in the efficacy of intravenous TPA in reestablishing coronary arterial patency in patients with acute MI, with thromboresistance during the morning hours. This report confirms an earlier study by Becker et al34 on a small number of patients, and it is relevant to two other observations: (1) Patients with acute MI treated with intravenous TPA who have persistently occluded infarct arteries had higher levels of baseline PAI-1 activity than those in whom patency was achieved. This finding points to a causal connection between resistance of thrombi to lysis and elevated levels of PAI-1 and suggests that the morning resistance to lysis is, in fact, related to elevations of PAI-1 at this time.35 (2) A morning increase in resistance of coronary thrombi to lysis by intracoronary urokinase has also been demonstrated,36 showing that the circadian variation in the resistance to lysis is not limited to TPA or to the intravenous administration of a thrombolytic agent.
Thus, it now seems clear that not only does MI occur with disproportionate frequency in the morning, but also that thrombi are more resistant to lysis at this time of day. The clinical importance of this observation is supported by the finding in the TIMI II trial in which the 42-day mortality of patients with acute MI treated with TPA was higher in those in whom the onset of MI was between 6 AM and noon than during any other 6-hour period.2
In addition to adding to the totality of evidence supporting a hypercoagulable state in the morning, Kurnik's33 observations have several practical implications for the treatment of acute MI. It might be appropriate to consider tailoring the dose of thrombolytic agent both to the risk of cerebral hemorrhage and to the time of day when patients with acute MI present. One could argue that patients at higher risk of cerebral hemorrhage (ie, those with borderline hypertension, advanced age, and low body weight37 ) and who present in the afternoon or evening, when thrombi are more responsive to thrombolytic therapy, should receive a lower than usual dose of thrombolytic agent, while patients without any of these risk factors who present in the morning, when clot lysis is less effective, might be treated with a higher than usual dose. Patients at higher risk of cerebral hemorrhage who present in the morning might be most appropriate for primary angioplasty, if it is available. In the light of Kurnik's report, the recent development of a novel plasminogen activator (TNK) that is not inhibited by PAI-138 is of special interest. The TIMI Study Group has just begun clinical evaluation of this agent and will attempt to ascertain whether this unique property of the drug abolishes morning thromboresistance.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
Received January 10, 1995; accepted January 10, 1995.
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References |
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TopIntroductionReferences |
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1. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel BE, Willerson JT, Braunwald E, MILIS Study Group. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313:1315-1322. [Abstract]
2. Tofler GH, Muller JE, Stone PH, Forman S, Solomon RE, Knatterud GL, Braunwald E. Modifiers of timing and possible triggers of acute myocardial infarction in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Study Group. J Am Coll Cardiol. 1992;20:1049-1055. [Abstract]
3. Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994;23:809-813. [Abstract]
4.
Muller JE, Ludmer PL, Willich SN, Tofler GH, Ayler G, Klangos
I, Stone PH. Circadian variation in the frequency of sudden cardiac
death. Circulation. 1987;75:131-138.
5. Arntz HR, Willich SN, Oeff M, Bruggeman T, Stern R, Heinzmann A, Matenaer B, Schroder R. Circadian variation of sudden cardiac death reflects age-related variability in ventricular fibrillation. Circulation. 1993;88(pt 1):2284-2289.
6. Peters RW, Mitchell B, Brooks MM, Echt DS, Barker AH, Capone R, Liebson PR, Greene HL, for the CAST Investigators. Circadian pattern of arrhythmic death in patients receiving encainide, flecainide or moricizine in the Cardiac Arrhythmia Suppression Trial (CAST). J Am Coll Cardiol. 1994;23:283-289. [Abstract]
7. Moser DK, Stevenson WG, Woo MA, Stevenson LW. Timing of sudden death in patients with heart failure. J Am Coll Cardiol. 1994;24:963-967. [Abstract]
8.
Lampert R, Rosenfeld L, Batsford W, Lee F, McPherson C.
Circadian variation of sustained ventricular tachycardia in patients
with coronary artery disease and implantable
cardioverter-defibrillators. Circulation. 1994;90:241-247.
9.
Parker JD, Testa MA, Jimenez AH, Tofler GH, Muller JE, Parker
JO, Stone PH. Morning increase in ambulatory ischemia in patients with
stable coronary artery disease: importance of physical activity and
increased cardiac demand. Circulation. 1994;89:604-614.
10. Behar S, Reicher-Reiss H, Goldbourt U, Kaplinsky E, and the Principal Investigators of SPRINT, Israel. Circadian variation in pain onset in unstable angina pectoris. Am J Cardiol. 1991;67:91-93. [Medline] [Order article via Infotrieve]
11.
Masuda T, Ogawa H, Miyao Y, Yu Q, Misimi I, Sakamoto T, Okubo
H, Yasue H. Circadian variation in fibrinolytic activity in patients
with variant angina. Br Heart J. 1994;71:156-161.
12.
Fujita M, Franklin D. Diurnal changes in coronary blood flow
in conscious dogs. Circulation. 1987;76:488-491.
13. Zarich S, Waxman S, Freeman RT, Mittleman M, Hegarty P, Nesto RW. Effect of autonomic nervous system dysfunction on the circadian pattern of myocardial ischemia in diabetes mellitus. J Am Coll Cardiol. 1994;24:956-962. [Abstract]
14.
Marchant B, Stevenson R, Vaishnav S, Wilkinson P, Ranjadayalan
K, Timmis AD. Influence of the autonomic nervous system on circadian
patterns of myocardial ischaemia: comparison of stable angina with the
early postinfarction period. Br Heart J. 1994;71:329-333.
15.
Willich SN, Linderer T, Wegscheider K, Leizorovicz A,
Alamercery I, Schroder R, ISAM Study Group. Increased morning incidence
of myocardial infarction in the ISAM study: absence with prior
ß-adrenergic blockade. Circulation. 1989;80:853-858.
16. Peters RW, Muller JE, Goldstein S, Byington R, Friedman LM. Propranolol and the morning increase in the frequency of sudden cardiac death (BHAT Study). Am J Cardiol. 1989;63:1518-1520. [Medline] [Order article via Infotrieve]
17.
Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker GC, Kowey
PR, Lamas GA, Miller HS, Packer M, Rouleau JL, Braunwald E, on behalf
of the SAVE Investigators. Effects of captopril on ischemic events
after myocardial infarction: results of the Survival and Ventricular
Enlargement trial. Circulation. 1994;90:1731-1738.
18. Tsementzis SA, Gill GS, Hitchcock ER, Gill SK, Beevers DG. Diurnal variation of and activity during the onset of stroke. Neurosurgery. 1985;17:901-904. [Medline] [Order article via Infotrieve]
19. Colantonio D, Casale R, Abruzzo BP, Lorenzetti G, Pasqualetti P. Circadian distribution in fatal pulmonary thromboembolism. Am J Cardiol. 1989;64:403-404. [Medline] [Order article via Infotrieve]
20.
Rosing DR, Brakman P, Redwood DR, Goldstein RE, Beiser GD,
Astrup T, Epstein SE. Diurnal variation and the response to varying
intensities of exercise. Circ Res. 1970;27:171-184.
21. Ehrly AM, Jung G. Circadian rhythm of human blood viscosity. Biorheology. 1973;10:577-583. [Medline] [Order article via Infotrieve]
22. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. [Abstract]
23.
Ridker PM, Manson JAE, Buring JE, Muller JE, Hennekens CH.
Circadian variation of acute myocardial infarction and the effect of
low-dose aspirin in a randomized trial of physicians.
Circulation. 1990;82:897-902.
24.
Bridges AB, Scott NA, McNeill GP, Pringle TH, Belch JJF.
Circadian variation of white blood cell aggregation and free radical
indices in men with ischaemic heart disease. Eur Heart J. 1992;13:1632-1636.
25. Decousus HA, Croze M, Levi FA, Jaubert JG, Perpoint BM, de Bonadona JF, Reinberg A, Queneau PM. Circadian changes in anticoagulant effect of heparin infused at a constant rate. Br Med J. 1985;290:341-344.
26. Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985;313:1557-1563. [Abstract]
27. Hamsten A, Walldius G, Szamosi A, Blomback M, de Faire U, Dahlen G, Landou C, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987;2:3-9. [Medline] [Order article via Infotrieve]
28. Andreotti F, Davies GJ, Hackett DR, Khan MI, de Bart ACW, Aber VR, Maseri A, Kluft C. Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol. 1988;62:635-637. [Medline] [Order article via Infotrieve]
29. Grimaudo V, Hauert J, Bachmann F, Kruithof EKO. Diurnal variation of the fibrinolytic system. Thromb Haemost. 1988;59:495-499. [Medline] [Order article via Infotrieve]
30.
Angleton P, Chandler WL, Schmer G. Diurnal variation of
tissue-type plasminogen activator and its rapid inhibitor (PAI-1).
Circulation. 1989;79:101-106.
31. Huber K, Rosc D, Resch I, Schuster E, Glogar DH, Kaindl F, Binder BR. Circadian fluctuations of plasminogen activator inhibitor and tissue plasminogen activator levels in plasma of patients with unstable coronary artery disease and acute myocardial infarction. Thromb Haemost. 1988;60:372-376. [Medline] [Order article via Infotrieve]
32.
Bridges AB, McLaren M, Scott NA, Pringle TH, McNeill GP, Belch
JJF. Circadian variation of tissue plasminogen activator and its
inhibitor, von Willebrand factor antigen, and prostacyclin stimulating
factor in men with ischaemic heart disease. Br Heart J. 1993;69:121-124.
33.
Kurnik PB. Circadian variation in the efficacy of tissue-type
plasminogen activator. Circulation. 1995;91:1341-1346.
34. Becker RC, Corrao JM, Baker SP, Gore JM, Alpert JS. Circadian variation in thrombolytic response to recombinant tissue-type plasminogen activator in acute myocardial infarction. J Appl Cardiol. 1988;3:213-221.
35. Barbash GI, Hod H, Roth A, Miller HI, Rath S, Zahav YH, Modan M, Zivelin A, Laniado S, Seligsohn U. Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction. Am J Cardiol. 1989;64:1231-1235. [Medline] [Order article via Infotrieve]
36. Fujita M, Araie E, Yamanishi K, Miwa K, Kida M, Nakajima H. Circadian variation in the success rate of intracoronary thrombolysis for acute myocardial infarction. Am J Cardiol. 1993;71:1369-1371. [Medline] [Order article via Infotrieve]
37. Simoons ML, Magglioni AP, Knatterud G, Leimberger JD, de Jaegere P, van Domburg R, Boermusa E, Franzosi MG, Califf R, Schroeder R, Braunwald E. Individual risk assessment for intracranial hemorrhage during thrombolytic therapy. Lancet. 1993;342:1523-1528. [Medline] [Order article via Infotrieve]
38.
Keyt BA, Paoni NF, Refino CJ, Berleau L, Nguyen H, Chow A, Lai
J, Pena L, Pater C, Ogez J, et al. A faster-acting and more potent form
of tissue plasminogen activator. Proc Natl Acad Sci U S A. 1994;91:3670-3674.
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