August

Fears et al.

34.

35.

36.

37.

of anisoylated lys-plasminogen streptokinase activator complex with its glu-plasminogen variant and streptokinase-gluplasminogen: binding to human fibrin and plasma clots. Fibrinolysis 1989;3:93-100. Hogg KJ, Gemmill JD, Burns JMA, Lifson WK, Rae AP, Dunn FG, Hillis WS. Angiographic patency study for anistreplase versus streptokinase in acute myocardial infarction. Lancet 1990;335:254-8. Pacouret G, Charbonnier B, Curien ND, Monassier JP, Cribier A, Materne P, Brochier ML, Letac R, Hanssen M, Sacrez A. Kulbertus H. Invasive reperfusion study II: multicentre European randomised trial of anistreplase vs streptokinase in acute myocardial infarction. Eur Heart J 1991:12:179-85. Dykewicz MS, McGrath KG, Davison R, Kaplan KJ, Patterson R. Identification of patients at risk for anaphylaxis due to streptokinase. Arch Intern Med 1986;146:305-7. Brower RW, Arnold AER, Lubsen J, Verstraete M. Coronary patency after intravenous infusion of recombinant tissue-type

American

:38. 39. 10. Il.

42.

43.

Heart

1992 Jaurnai

plasminogen activator in acute myocardial itiiarct LOII. ,I .+‘\:I, Co11 Cardiol 1988;11:681-8. Sigwart U, Grbic M, Bachmann F. Measurement ot antistrep tokinase antibodies [Abstract]. J Am (loll Cardiol 1985;1:151)~~ Nazari .J, Davison R, Kaplan K, Fintel D. Adverse reactions 10 thrombolytic agents. Med Toxicol 1987;Z:XS+X(i. ,Jalihal S, Morris GK. Antistreptokinase tilt+ ;rRer intra\e nous streptokinase. Lancet 1990:335:184-S. Masse1 D, Turpie AGG, Gill .JB, O’Dell c’. liu>sell .I. Per& tence of neutralizing antibodies at one year following 11 streptokinase for acute myocardial infarction 1Abstract]. (‘irculation 1990;82:II-1007. White HD, Cross DB. Williams BF. Norris Iibl, Safety aud efficacy of readministration of thrombolytic treatment after acute myocardial infarction. Br Heart .J 1990;64:177-81. Dudley NJ, Burns E. Thrombolytic treatment for recurrent myocardial infarction [Abstract]. Br Med .J 1991;302:786.

-

Plasma plasminogen activator inhibitor activity and tissue plasminogen activator levels in patients with unstable angina and those with coronary spastic angina Plasminogen activator inhibitor (PAI) activity and tissue plasminogen activator (TPA) antigen were measured in venous samples in 14 patients with unstable angina consisting of eight patients with organic stenosed coronary arteries and six patients with coronary spastic angina (unstable angina group); in 14 patients with stable exertional angina (stable exertional angina group); and in 14 patients with chest pain syndrome (chest pain syndrome group). The plasma levels of PAI activity were higher (p < 0.01) in the unstable angina group than in the stable exertional angina group and the chest pain syndrome group (12.3 + 1.0 versus 5.1 f 0.7 and 4.8 r 0.6 IUlml). The plasma levels of TPA antigen were also higher (p < 0.05) in the unstable angina group than in the stable exertional angina group and the chest pain syndrome group (10.2 t 1.3 versus 6.5 k 0.8 and 6.0 + 0.7 rig/ml). There were no significant differences in PAI activity and TPA antigen levels between the stable exertional angina group and the chest pain syndrome group. Furthermore, both PAI activity and TPA antigen levels in the unstable angina group decreased to the levels in the stable exertional angina group and the chest pain syndrome group after treatment (p < 0.01). In conclusion, the increased plasma PAI activity in patients with unstable angina and in those with coronary spastic angina indicates that the fibrinolytic system is impaired in these patients. (AM HEART J 1992;124:314.)

Takenobu Masuda, MD, Hirofumi Yasue, MD, Hisao Ogawa, MD, Ikuo Misumi, MD, Tomohiro Sakamoto, MD, Hiroto Okubo, MD, Yuji Miyao, MD, and Hideji Kato, MD Kumamoto City, Japan

From the Division of Cardiology, Kumamoto University School of Medicine. Supported in part by a Grant-in Aid for Scientific Research from the Ministry of Education (B03454257, CO2670402) and by a Research Grant from the Smoking Research Foundation, Tokyo, Japan. Received for publication Nov. 18, 1991; accepted Feb. 10, 1992. Reprint requests: Hirofumi Yasue, MD, Division of Cardiology, Kumamotrl University School of Medicine. 1-l-l. Honjo, Kumamotc City 860, .Japan. 411138104

314

There is now increasing evidence that coronary thrombosis plays an important role in the production of unstable angina132 or acut,e myocardial infarction.3-5 With respect to pathophysiologic mechanisms, the fibrinolytic system is one of the important determinants of thrombus turnover. The key components of the fibrinolytic system are tissue plasmi-

volume

124

Number

2

PAI in unstable angina

nogen activator (TPA) and plasminogen activator inhibitor (PAI). TPA released from endothelial cells upon stimulation promotes fibrinolysis,6, 7 whereas its specific inhibitor PAI continuously reacts with TPA and inhibits TPA activity by forming a complex with the latter.8* g PA1 determines the amount of free TPA that is available for actual plasminogen activation

and fibrinolysis,

and thus

the concentration

of

PA1 is important for the fibrinolytic potential. PAI can be classified into at least four immunologically different groups: the endothelial cell-type PA1 (PAI1): the placental-type PA1 (PAI-2), the urinary inhibitor of urokinase (PAI-3), and protease nexin.lO It has been demonstrated that most of the PA1 activity

in plasma

(80%

to 95%)

originates

from

PAI-1.” In fact, it has been documented that the amount of free PAI-1, or PA1 activity, is a major factor in determining overall fibrinolytic activity by euglobulin clot lysis time and can represent the potential activity of the fibrinolytic system.12 Recent studies1”-15have shown that plasma levels of PA1 are elevated in patients with myocardial infarction. In the present study, we examined whether the fibrin-

olytic system is impaired in patients with unstable angina and in those with coronary spastic angina by measuring plasma TPA antigen and PA1 activity. METHODS Patient population. We studied 42 patients

who underwent diagnostic catheterization (34 men and 8 women patients, mean age 61.5 i: 1.3 years, range 45 to 76 years). They were divided into three groups: an unstable angina group, a stable exertional angina group, and a chest pain syndrome group. The unstable angina group consisted of 14 consecutive patients with unstable angina. Eleven patients had a crescendo pattern of chest pain (including nine patients with angina at rest) and three patients had prolonged chest pain poorly relieved by nitroglycerin. The stable exertional angina group consisted of 14 patients who had typical exertional angina presenting with typical chest pain associated with horizontal or downsloping ST segment depression of greater than 1.0 mm on an exercise test. The chest pain syndrome group consisted of 14 patients who had atypical chest. pain not accompanied with electrocardiographic (ECG) changes and who were all negative for ischemia on a treadmill exercise test and a hyperventilation test. The clinical characteristics of the three groups are described m Table I. The study protocol was in agreement with the guidelines established by the Ethics Committee at our institution. Informed consent was obtained from each patient. Blood sampling. Blood samples were obtained from each patient at 7:OO AM after admission by venipuncture performed by specially trained physicians (TM, IM, and HO). The mean period of time that elapsed between the last episode of chest pain and blood sampling in patients wit.h unstable angina was 18 hours. After the first 3 ml of blood were discarded, 4.5 ml of blood were drawn in a se-

and coronary

315

spasm

Table I. Characteristicsof the study groups(mean -t SEM) Stable exertional angina

Unstable angina No. of patients

14

14

Chest pain syndrome

14

Age (yr)

Mean f SEM Range Male/female ratio Previous myocardial infarction (n) Blood pressure ?150/90 mm Hg (ni Smokers (rz) Diabetes mellitus (n) Obesity (n) Serum cholesterol

61.3 k 2.5 45-76 12/Z 2

63.9 k 1.6 52-72 11/3 2

59.3 2 2.3 48-73 11/3 0

7 10

10 3

3 2 199 f 7

10 2

n

206 :S

203 t 11

161 + 19

157 + 19

bddl)

Serum triglyceride 144 + 13 (mg/dl) Extent of coronary vessel (275 % stenosis) O-vessel (fl) 6* l-vessel

(n)

2-vessel (n) 3-vessel (n) EF ~50% (n) Medication used In) &Blockers Long-acting nitrates Calcium antagonists Aspirin Diuretics Antidiabetic drug (glyburide) Angiotensinconverting enzyme inhibitors

0

2 3 3

6 5

1

14 0 0 0 0

2 8 6 6

6 5

0 1

1 1

1

0

1

0

EF, Ejection fraction. *p c 0.05 compared with stable exertional

3

angina.

quential manner directly into a glasstube containing 0.5 ml of 3.8 % buffered citrate solution and was processed immediately. Samples were centrifuged immediately (4’ C at 3000rpm for 15 minutes) to obtain platelet poor plasma; plasma was stored at -80” C until used. Determination of TPA antigen and PAI activity. TPA

antigen was measuredby an enzyme-linked immunosorbent assay with an ASSERACHROM (Diagnostica Stago, Inc., Franconville,

TPA reagent kit France).16 Results

were expressedin nanogramsper milliliter. Intra-assay and interassay coefficients of variation were 2.4 % and 4.7 9,) respectively. The normal value for TPA antigen in our lab-

oratory (n = 33) was 5.6 * 0.3 rig/ml (mean % SEM). PA1 activity was determined by a chromogenic substrate assay with the Spectrolyse/PL reagent kit (Biopool, Umea, Sweden).” The result was expressed in international units per milliliter. Intra-assay and interassay coefficients of variation were 9.4 ‘% and 11.4 %, respectively. The normal

316

Masuda

et al.

American

August 1992 Heart Journal

P