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Circulation. 1996;94:2072-2076

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(Circulation. 1996;94:2072-2076.)
© 1996 American Heart Association, Inc.

Articles

Serum Lipoprotein(a) Level Is Related to Thrombin Generation and Spontaneous Intermittent Coronary Occlusion in Patients With Acute Myocardial Infarction

Agha W. Haider, MD, PhD; Felicita Andreotti, MD, PhD; Gilbert R. Thompson, FRCP; Cornelis Kluft, PhD; Attilio Maseri, FRCP; Graham J. Davies, FRCP

the Division of Clinical Cardiology and MRC Lipoprotein Team, Royal Postgraduate Medical School, Hammersmith Hospital, London, England (A.W.H., G.R.T., G.J.D.); TNO Gaubius Laboratory, Leiden, Netherlands (C.K.); and Istituto di Cardiologia, Catholic University of the Sacred Heart, Rome, Italy (F.A., A.M.).

Correspondence to Dr Graham J. Davies, FRCP, Division of Cardiology, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W12 ONN, England or Dr A.W. Haider, MD, PhD, Boston University School of Medicine, Framingham Study, 5 Thurber St, Framingham, MA 01701. E-mail AGHA@FRAM.NHLBI.NIH.GOV.


*    Abstract
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Background Thrombotic occlusion of the infarct-related coronary artery is often intermittent in the early, evolving phase of acute myocardial infarction. To assess their relationship to this pattern of coronary occlusion, serum or plasma concentrations of cholesterol, triglyceride, lipoprotein(a), and coagulation and fibrinolytic factors were measured in venous blood before the initiation of thrombolytic therapy.

Methods and Results Thirty-two patients (23 men, 9 women; age, 30 to 70 years) with acute myocardial infarction received intravenous recombinant tissue plasminogen activator (20 to 60 megaunits) within 6 hours of the onset of symptoms. Continuous ECG ST-segment recording demonstrated intermittent occlusion of the infarct-related coronary artery in 12 patients (group 1) before the start of thrombolytic treatment and persistent occlusion in 20 patients (group 2). Groups 1 and 2 were similar in age, sex, race, duration of symptoms, blood sample collection time, location of the infarct-related coronary artery, and extent of coronary artery disease. The serum level (median [interquartile range]) of lipoprotein(a) was 34 (13 to 47) mg/dL versus 11.5 (5 to 27) mg/dL (P=.02), and the plasma level (median [interquartile range]) of thrombin–antithrombin III complex was 10.85 (6.4 to 21.5) versus 6.8 (4.2 to 8.7) µg/L-1 (P<.04) in groups 1 and 2, respectively. The levels of the other factors were similar in both groups.

Conclusions The phenomenon of spontaneous intermittent closure and reopening of coronary arteries early during acute myocardial infarction in humans is associated with a higher level of lipoprotein(a) and of a marker of thrombin generation, suggesting that lipoprotein(a) and thrombin are closely related to coronary patency in these patients.


Key Words: lipoproteins • occlusion • myocardial infarction • coagulation • fibrinolysis • thrombosis


*    Introduction
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Coronary thrombosis is an important pathogenetic mechanism in myocardial infarction.1 2 Thrombotic coronary occlusion is intermittent in its early phase in 30% to 45% of patients, so the infarction develops in a stuttering manner.3 4 The results of experimental studies have indicated that lipoprotein(a) can interfere with hemostasis by influencing fibrinolysis and coagulation.5 6 An association between infarct-related coronary artery patency and serum lipoprotein(a) level has been found in patients with myocardial infarction.7 It is therefore possible that serum lipoprotein(a) can influence the time course and mode of development of coronary thrombosis in patients with myocardial infarction by an effect on coagulation or fibrinolysis or both. In this study we have examined the relationship between early intermittency of coronary occlusion, pretreatment plasma hemostatic factor levels, and serum lipid and lipoprotein(a) levels in patients presenting within 6 hours of the onset of symptoms of their myocardial infarction.


*    Methods
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Patients
The 32 patients entered into the study were consecutive admissions to the emergency room of the Hammersmith Hospital over a period of 1 year who satisfied the inclusion criteria. These criteria were chest pain lasting between 30 minutes and 6 hours and ECG changes of early evolving acute myocardial infarction (ST-segment elevation >=0.2 mV in at least 2 contiguous leads of the 12-lead ECG) refractory to a 2 mg intravenous bolus of isosorbide dinitrate. Patients with cardiogenic shock, contraindications to thrombolytic therapy, and those >75 years old were excluded. The study was approved by the Hammersmith Hospital Research Ethics Committee, and all patients gave written informed consent.

Protocol
A continuous 24-hour ECG recording (Marquette 8000 AM recorder) of the two leads showing the greatest ST-segment elevation was begun. An intravenous infusion of 1 to 10 mg/h of isosorbide dinitrate, titrated against blood pressure, was commenced and continued for 24 hours. A venous blood sample was taken with minimal venostasis for the determination of serum total cholesterol, triglyceride, LDL, HDL, and lipoprotein(a), levels and of plasma von Willebrand factor, plasmin-antiplasmin complex, thrombin–antithrombin III complex (TAT), D-Dimer, and fibrinogen levels. An intravenous bolus of heparin (5000 IU) was administered. Double-chain recombinant tissue plasminogen activator (rTPA) (Wellcome Foundation) was then administered intravenously within 6 hours of the onset of pain. The start of thrombolysis was indicated by a marker on the 24-hour ECG recording.

As part of a study on different rTPA regimens, the drug was administered according to one of three schedules: as a continuous infusion of 40 clot-lysis megaunits (MU) of active protein over 90 minutes, followed by 4 MU/h over the next 5 hours (n=12); as 4 rapid boluses of 10 MU each, given every 20 minutes over 1 hour, with no subsequent infusion (n=14); or as a single rapid bolus of 0.3 to 0.6 MU/kg body wt (n=6). Coronary angiography was performed 90 minutes after the start of rTPA administration. Heparin infusion was then commenced, to achieve an activated partial thromboplastin time between two and three times control value, and continued for 24 hours. Aspirin 300 mg daily and diltiazem 60 mg q 8 hours orally were started immediately after angiography. A venous blood sample was taken every 6 hours during the first 24 hours for measurement of creatine kinase (CK) level.

Data Analysis
ST-Segment Monitoring
The 24-hour continuous ECG recordings were analyzed with the use of a Marquette 8000 laser system. A mean (±SEM) of 24 (±2) hours per patient of continuous ST monitoring was available for analysis. Spontaneous intermittent recanalization of coronary arteries was defined as >=2 episodes of transient resolution of ST-segment elevation to within 0.05 mV of baseline, lasting >=1 minute and occurring before the start of rTPA treatment. The duration of Holter monitoring before the start of lytic therapy was 112±36 minutes in patients with intermittent occlusion and 105±27 minutes in patients with persistent occlusion (P<.2). The time of resolution of maximum sustained ST elevation to 50%, measured from the onset of rTPA treatment, was taken as an indirect assessment of recanalization time.8

Blood Samples and Laboratory Assays
The first 5 mL of blood was transferred into tubes containing no anticoagulant, and the following 9 mL was transferred into cooled plastic tubes containing 1 mL of 0.109 mol/L trisodium citrate. Serum or platelet-poor plasma was obtained by cold (4°C) centrifugation at 1300g for 20 minutes. Aliquots were frozen within 1 hour of blood collection and stored at -70°C. Total cholesterol, triglyceride, LDL, and HDL were measured by standard enzymatic methods (Boehringer Mannheim Biochemicals and Sigma Chemical Co). The serum concentration of lipoprotein(a) was determined by a sandwich enzyme-linked immunosorbent assay (TintElize, Biopool).9 The plasma concentrations of thrombin–antithrombin III complex (µg/L-1) and plasmin-antiplasmin complex (µg/L-1) were measured by the enzyme-linked immunosorbent assays "Enzygnost-TAT" and "EIA App micro" (Behring, Behringwerke). D-Dimer concentration was measured with the use of the functional assay "Coalize D-Dimer" (Kabi Diagnostica), fibrinogen by clot rate assay,10 and CK kinetically after immunoinhibition; von Willebrand factor concentrations were measured according to Ingerslev.11

Coronary Angiography
The patency of the infarct-related artery was assessed by two independent observers according to the Thrombolysis in Myocardial Infarction (TIMI) perfusion criteria.12 Coronary occlusion was defined as TIMI grade 0, 1, or 2, and patency as TIMI grade 3. Subtotal occlusion was defined as the presence of arteriographic filling defects suggestive of intraluminal thrombus despite TIMI grades 2 or 3.

Statistical Analysis
Clinical data are expressed as mean±SEM unless stated otherwise. The Mann-Whitney U test was used to compare unpaired data as appropriate. Discrete data were analyzed by the {chi}2 test. Significance was defined as P<.05.


*    Results
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Patient Characteristics
Twelve patients (37.5%) showed intermittent resolution and elevation of the ST segment before sustained continuous ST elevation (group 1), before initiation of thrombolytic treatment, indicating spontaneous intermittent reperfusion with reocclusion. Twenty patients (62.5%) exhibited continuous ST elevation with no such preceding intermittent ST elevation (group 2), indicating persistent coronary occlusion. Table 1Down shows the clinical characteristics of the two groups.


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  		Table 1. Clinical Characteristics of the Two Study Groups

Hemostatic Factors and Plasma Lipids
Groups 1 and 2 had similar serum concentrations of total cholesterol, LDL and HDL cholesterol, and triglyceride and similar plasma concentrations of fibrinogen, D-Dimer, von Willebrand factor, and plasmin-antiplasmin complex. The serum concentration of lipoprotein(a) and plasma concentration of thrombin–antithrombin III complex were higher in group 1 than in group 2 (P<.04) (Table 2Down). Lipoprotein(a) values >30 mg/dL were found in 60% of patients in group 1 and 13% of those in group 2 (P<.001).


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  		Table 2. Lipid and Hemostatic Factor Levels Before Thrombolytic and Anticoagulant Treatment


*    Discussion
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 *Discussion
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This study shows that the pretreatment serum lipoprotein(a) level is higher in patients with evolving myocardial infarction in whom the thrombotic coronary occlusion is intermittent from the time of arrival in the hospital to the start of thrombolytic treatment than in patients with persistent occlusion. It also reveals a higher plasma level of thrombin generation in patients with intermittent occlusion compared with those with persistent occlusion. These differences are not necessarily the cause of the different patterns of evolution of the coronary occlusion but may just be a marker. However, they emphasize the possibility that in vivo interference in the hemostatic mechanism by lipoprotein(a) may affect the evolution of spontaneous coronary thrombosis.

Coronary Thrombosis and Intermittent Coronary Occlusion in Myocardial Infarction
In most subjects with myocardial infarction, the initiating pathophysiological event is an occlusive coronary arterial thrombus.1 2 However, in {approx}40% of these individuals, the coronary artery occlusion is intermittent at its onset, so that myocardial infarction develops in a stuttering manner.3 4 Continuous Holter monitoring with subsequent analysis of ST-segment changes has been used in previous studies to monitor the patency of the infarct-related coronary artery in the early phase of infarct evolution. In these studies it has been shown that ST-segment elevation correlates with angiographically documented occlusion and that the resolution of ST-segment elevation to near the baseline correlates with angiographically documented coronary artery patency.4 8 The existence of this phenomenon of early intermittent occlusion and reopening may have important implications for treatment and also for prognosis, as it has been shown in clinical studies that antegrade perfusion of the infarct artery favorably influences long-term morbidity and mortality. Compared with those patients whose infarct artery is occluded, patients with antegrade flow have less left ventricular dilation,13 better regional left ventricular contraction,14 a curtailment of the procoagulant acute-phase response,15 and improved survival.16 17

Lipids, Hemostasis, and Coronary Thrombosis
Previous studies have shown that an imbalance of intrinsic fibrinolytic and prothrombotic activity may exist in patients with unstable angina,18 previous myocardial infarction,19 vein graft occlusion after bypass surgery,20 and fatal cardiovascular events.21 However, no previous study to our knowledge has examined plasma lipids as well as fibrinolytic and prothrombotic factors in patients with acute myocardial infarction in whom the state of patency of the infarct-related artery was known soon after admission to the hospital. Our results show that patients with spontaneous intermittent occlusion of the infarct-related coronary artery (group 1) have a greater plasma level of thrombin–anti thrombin III complex than those with a persistently occluded artery (group 2). This finding is supported by our previously reported results,22 which show elevated plasma levels of prothrombin fragment F1+2 and of soluble fibrin in patients with spontaneous, intermittent coronary occlusion. The differences between the two groups could be due to more rapid washout of thrombin from the infarct zone because of intermittent reperfusion, to more extensive washout from a greater infarct area, to reduced plasma clearance, or to increased generation of thrombin indicative of a prothrombotic state. It probably is not due to increased washout from a larger infarct zone or to reduced plasma clearance, because peak CK values were similar (Table 1Up) in the two groups of patients, as was their hemodynamic status. Therefore, it probably is due to greater thrombogenic activity in the group with spontaneous, intermittent, coronary occlusion and reperfusion.

The results of this study also show a higher plasma concentration of lipoprotein(a) in those with intermittent coronary occlusion than in those with persistent occlusion. The plasma concentration of lipoprotein(a) varies over a wide range between individuals but is relatively constant throughout an individual's life.23 Plasma concentrations of lipoprotein(a) are remarkably uninfluenced by age or sex, with the exception of a small rise in women at the menopause.24 The level of plasma lipoprotein(a) concentrations varies greatly among different ethnic groups: Asian Indians, Orientals, and Caucasians have distributions that are markedly slanted toward lower levels, whereas Africans have a nearly symmetrical distribution.25 26 27

Lipoprotein(a) is composed of an LDL particle linked to a unique glycoprotein, apolipoprotein(a) [apo(a)]. Apo(a) shows marked structural similarities to the plasma zymogen plasminogen.28 29 Experimental evidence exists that suggests that increased levels of lipoprotein(a) might impair fibrinolysis by binding to plasminogen receptors on fibrin, endothelial cells, mononuclear cells, and platelets5 6 30 and, reversibly, by binding TPA.31 The results of this study would appear to contradict this evidence. However, the role of lipoprotein(a) during acute myocardial infarction is controversial, and there is also some evidence, in vitro and in vivo, that increased lipoprotein(a) levels promote fibrinolysis.32 33 34 Several epidemiological studies have been inconclusive in demonstrating a link between lipoprotein(a) and future risk of myocardial infarction, some studies showing no relationship35 36 and others a clear link.37 38 There have been no other studies investigating lipoprotein(a) with respect to the pattern of evolution of acute myocardial infarction. A recent study has suggested that elevated LDL levels are essential for lipoprotein(a) to exert a pathogenic influence in vivo in humans.39 Moreover, there might be differences between plasma and tissue lipoprotein(a) with respect to fibrinolysis, since it has been shown that tissue concentrations are not as critical as plasma concentrations in thrombosis risk.40

The different lipoprotein(a) levels between the two groups of patients in our study could be an incidental manifestation or a marker of an underlying mechanism determining the rate and pattern of evolution of coronary thrombosis. However, it is also possible that lipoprotein(a) concentration itself determines the rate at which thrombotic coronary occlusion and myocardial infarction evolves.

In our group of patients with spontaneous intermittent coronary occlusion and reperfusion, reopening may have occurred due to resolution of vasomotor tone but, once open, plasma lipoprotein(a) coming into contact with the ruptured plaque and thrombus interfered with fibrinolysis, resulting in reocclusion. It is also possible that patients with high lipoprotein(a) levels, by reason of higher endogenous thrombin generation, are more able to form occlusive clots in a mildly diseased vessel than can patients with lower lipoprotein(a) levels. Subsequent fragmentation of the thrombus may have been related to hydrodynamic stress on a clot that is unstable because of its greater lipoprotein(a) content.

Conclusions
Our study provides the first in vivo data during acute myocardial infarction in patients of a possible interaction between lipoprotein(a) and hemostasis that appears to influence the patency of the infarct-related coronary artery and the time course and mode of development of coronary thrombosis.


*    Acknowledgments
 
Dr Haider was supported by an Overseas Training Award from the Ministry of Science and Technology, Government of Pakistan, Islamabad, Pakistan. Dr Andreotti was supported by a grant from the British Heart Foundation (90/151). We are indebted to Dr Maria Carla Roncaglioni for von Willebrand factor measurements.

Received September 11, 1995; revision received May 10, 1996; accepted May 21, 1996.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
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 *References
 

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