ⅥAcute

Acute Coronary Syndromes

JMAJ 45(4): 155–160, 2002

Hirofumi YASUE

Director, Kumamoto Aging Research Institute

Abstract: Recently, unstable , acute myocardial infarction, and sudden cardiac death have often been put together under the name “acute coronary syn- dromes”, because almost all of these conditions have been shown to be caused by thrombotic occlusion of a coronary artery following atherosclerotic plaque dis- ruption. Acute coronary syndromes occur more frequently in the with no significant organic stenosis than in those with a high degree of stenosis. A plaque prone to disruption has a thin fibrous cap, a large lipid core, and increased infiltration of macrophages and T lymphocytes. The elimination or control of risk factors for such as dyslipidemia, , smoking, diabetes mellitus, obesity, and lack of exercise is essential for the prevention of acute coro- nary syndromes. Key words: Acute myocardial infarction; Atherosclerotic plaque; Coronary spasm; Coronary ;

Introduction between the two diseases. Angina pectoris is divided into stable (organic) and unstable angina. Ischemic heart diseases, including angina pec- The former is stable because advanced organic toris and myocardial infarction, are the leading stenosis is extensively distributed in the coro- cause of death in Europe and America. They nary artery, but develops only when effort have also been increasing in Japan and are increases oxygen demand. The latter develops currently the second highest cause of death in even at rest and is characterized by the increased this country as the result of the westernization severity and duration of the attack and reduced of Japanese dietary habits, the increased use response to nitroglycerin. The latter has been of automobiles, obesity, lack of exercise, and considered to be at high risk of acute myocar- increased stress induced by our complex society. dial infarction or sudden death. Angina pectoris develops by transient ische- Recent studies have revealed that unstable mia of myocardium, while myocardial infarc- angina, acute myocardial infarction, or ischemic tion is the necrosis of myocardium caused by cardiac sudden death develop mostly as a result prolonged . It has therefore been con- of plaque disruption in the coronary artery fol- sidered that a precise line should be drawn lowed by thrombotic formation, thereby com-

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 125, No. 5, 2001, pages 703–707).

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pletely or incompletely occluding the coronary It has been considered that coronary athero- lumen. Based on a similar onset mechanism, sclerosis develops at an early age and pro- unstable angina, acute myocardial infarction, gresses slowly over several decades to cause and ischemic cardiac sudden death have come the stenosis of the coronary lumen, and that to be referred to collectively as acute coronary advanced stenosis is prone to causing myocar- syndromes.1–3) This concept was generated based dial infarction. However, coronary angiograms on rapid advances in clinical medicine, pathol- conducted prior to the attack of myocardial ogy, and molecular biology. At the same time, infarction revealed that few cases had signifi- these advances force us to make a paradigm cant organic stenoses in the responsible coro- shift in the existing way of thinking about these nary artery. Rather, myocardial infarction fre- ischemic heart diseases and the nature of the quently occurs in the coronary lesions with no corrective actions to be instituted. significant stenosis.1,4) A working group of the Ministry of Health and Welfare reported that Clinical Advances the coronary artery responsible for myocardial infarction had no significant stenosis before the The angina syndrome proposed by Heberden onset of the disease in 86% of the patients includes various diseases. James Herrick (1912) examined. Improved intravascular echography considered acute myocardial infarction to be has disclosed that most coronary arteries that an independent disease and inferred that it appear normal on angiograms have been affected might result from coronary occlusion by thrombi. by atherosclerosis. It has also been shown that Since then, coronary thrombosis has been con- plaque progress eccentrically toward the adven- sidered an important potential cause of myo- titia and do not cause the stenosis of the lumen cardial infarction. In the 1970’s, however, there in the early stages of the disease. This has been were investigators, and pathologists in particu- confirmed by autopsy and is known as compen- lar, who believed that coronary thrombosis was satory growth. not a cause of myocardial infarction. The almost Recent studies have indicated that reducing simultaneous introduction of coronary angio- plasma with hydroxymethyl glutaryl graphy during the early stages of acute coro- CoA (HMG-CoA) reductase inhibitors mark- nary infarction in major medical institutions edly lowers the incidence of cardiovascular acci- throughout the world in the 1980s has allowed dents, such as cardiac death and acute myocar- clinicians to identify the responsible artery. dial infarction, without producing significant The experience of the authors shows that the changes in stenotic lesions on coronary angio- artery responsible for myocardial infarction was grams. This suggests that the quality of plaque spontaneously recanalized in the early stages may be more closely involved in the pathogen- of the disease in 18% of the cases examined, esis of myocardial infarction than the degree of and that it was recanalized by the intracoro- coronary stenosis.1–3) nary injection of nitroglycerin in 16%, and by a Recent advances in coronary endoscopy and thrombolytic agent (urokinase) in 46%.1) These intravascular echography have revealed that results indicate that most acute myocardial coronary thrombi or plaque disruption fre- infarction develop as a result of occlusion by quently appear also in unstable angina.3–5) coronary thrombosis, and that coronary spasm also causes myocardial infarction directly. The Plaque Prone to Disruption thrombotic occlusion rate of the coronary artery is higher in the earlier stages of the disease, and Advanced pathological techniques have re- the spontaneous re-canalization rate increases vealed that the coronary lumen was occluded over time. or narrowed by thrombi in most autopsied cases

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with , and that plaque occlusion is incomplete, non-ST-elevated myo- had been disrupted with fissures in approxi- cardial infarction or unstable angina develops. mately two-thirds of such cases, and had been (2) Coronary spasm disrupted with erosion in the remaining third.4,6) Various factors other than plaque condition The disrupted plaque showed inflammation may induce acute coronary syndromes. The with the infiltration of macrophages and T onset of acute coronary syndromes tends to lymphocytes. develop in the early morning. This is related to Plaque that is prone to disruption is charac- the circadian variation of terized by (1) large lipid nuclei generated by and fibrinolysis systems and blood platelet fused lipids, such as cholesterol, accumulated aggregation. Blood is prone to coagulate, fibri- outside the cells in plaque, (2) thin fibrous cap nolytic activity is reduced, and platelet aggre- that separates lipid nuclei and vascular lumen, gation is accelerated in the early morning. (3) increased infiltration of macrophages and Coronary spasm tends to develop at night and T lymphocytes, and (4) a decreased number in the early morning. When it develops, it of smooth muscle.3,4,6) The plaque is prone to increases the and fibrinopeptide undergo mechanical stress and disrupt at the in blood and reduces the fibrinolytic activity, border between plaque and normal tissue, thereby making it easier for thrombi to develop known as the shoulder, where a particularly and stimulating platelet aggregation. It is there- large infiltration of macrophages occurs. The fore considered that coronary spasm triggers mechanical stress becomes stronger as the acute coronary syndromes through thrombotic diameter of the lumen increases. formation. Moreover, coronary spasm itself Since macrophages produce interstitial metal- causes unstable angina and acute myocardial loprotease that decomposes interstitial col- infarction.1,8) lagen and elastin, which are constituents of (3) Stress fibrous caps, they make the caps thin and prone Stress triggers acute coronary syndromes to breaking. Similarly, T lymphocytes secrete by increasing blood pressure to increase the interferon-␥ to inhibit the production of col- mechanical stress on plaque, by accelerating lagen from smooth muscle cells, thereby mak- blood coagulation and platelet aggregation, ing the fibrous caps even more prone to break- and by causing coronary spasm. It is well age.3) Furthermore, the tissue factor, which known that the incidence of acute myocardial triggers blood coagulation, is expressed in infarction increased in Israel after the Gulf macrophages and lipid nuclei. Therefore, once War and in Hanshin after the Great Hanshin plaque is disrupted to expose the tissue factor Earthquake. to blood, it activates blood coagulation cas- cades, which produces fibrin and thrombotic Pathogenesis and Treatments of 7) formation. Acute Coronary Syndromes

Factors Precipitating Acute Coronary 1. Pathogenesis of acute coronary syndromes Syndromes Figure 1 summarizes the pathogenesis of acute coronary syndromes.1) Thrombi are (1) Plaque disruption formed after plaque disruption or coronary It has been shown that plaque disruption fol- spasm. Acute coronary syndromes develops lowed by thrombotic formation is the origin of when the thrombi become sufficiently large to acute coronary syndromes. ST-elevated myo- occlude the coronary artery. In some cases, cardial infarction develops when thrombi com- coronary spasm may induce plaque disruption pletely occlude the coronary lumen. When the or directly cause coronary occlusion. It is also

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Coronary thrombosis

Coronary spasm Plaque disruption

Coronary occlusion

Acute coronary syndromes

Unstable angina Acute myocardial infarction Ischemic cardiac sudden death

Fig. 1 Pathogenesis of acute coronary syndromes Acute coronary syndromes (unstable angina, acute myocardial infarc- tion, and ischemic cardiac sudden death) mostly result from coronary occlusion by thrombi. However, in some cases they may develop due to coronary spasm or mechanical occlusion by plaque disruption (quoted from Reference 1)

possible that a small artery running through the The GPIIb/IIIa (platelet glycoprotein IIb/ plaque is ruptured to cause a hemorrhage, IIIa) receptor antagonists, which block the com- which suddenly increases the size of the plaque mon final pathways of platelet aggregation, to mechanically occlude the coronary lumen. have recently attracted a great deal of atten- It is also known that thrombi cause coronary tion. Its efficacy and safety have been estab- spasm by serotonin or thromboxane A2 secreted lished via the many clinical trials conducted from blood platelets. in Europe and America.1,9) It has been demon- strated to be particularly useful when intra- 2. Treatment of acute coronary syndromes venously administered in percutaneous coro- Since the pathogenesis of acute coronary syn- nary interventions, such as percutaneous trans- dromes is now well understood, it has become luminal coronary angioplasty (PTCA). How- possible to apply appropriate treatment for the ever, the effectiveness of these anti-clotting syndromes. That is, acute coronary syndromes agents when orally administered over long should be treated by combining the treatments periods have yet to be demonstrated. Its effi- for coronary thrombosis, spasm, and plaque dis- cacy for acute coronary syndromes by an intra- ruption. Among such treatments, the treatment venous route also remains controversial when for coronary thrombosis is most important. used without PCI. (1) Treatment for coronary thrombosis is effective only when it combines Anti-platelet drugs, such as aspirin and ticlo- with antithrombin III, and is not effective for pidine, and anti-coagulants, such as heparin, thrombin combining with fibrin. Heparin is are now most frequently used to treat coronary inactivated by platelet factor 4. Therefore, thrombosis. The effect of aspirin is relatively hirudine and hirulog, which acts directly on weak and inhibits only one platelet coagulation thrombin, and low-molecule heparin with more pathway by thromboxane A2. Ticlopidine inhib- stable activity have been studied in clinical set- its the pathway through ADP (adenosine 5Ј- tings. Clinical studies on activated protein C, diphosphate), but may have adverse effects. which inhibits thrombotic formation, and the

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tissue factor pathway inhibitor (TFPI), which tase inhibitors markedly reduced cardiovascu- inhibits the tissue factor itself, are also under lar events, such as acute myocardial infarction going trials. and cardiac death. It has been established that thrombolytic Moreover, recent studies have shown that therapy using tissue plasminogen activator (t- the following therapies are effective for pre- PA) or urokinase is effective for transmural venting acute myocardial infarction and sud- myocardial infarction with elevated ST on ECG. den death: anti-platelet drugs, such as a small PTCA or insertion without thrombolytic amount of aspirin, anti-coagulants, such as war- therapy is also performed for quick re-. farin, angiotensin converting enzyme (ACE) However, it should be noted that thrombolytic inhibitors, anti-oxidants, such as vitamin E, therapy is ineffective for, or rather aggravates and estrogen replacement therapy for post- unstable angina.1,9) menopausal women. (2) Treatment for coronary spasm Nitrates, calcium antagonists, and nicorandil Conclusion are effective for coronary spasm.1) Most cases with unstable angina can be successfully con- Recent studies have revealed that most cases trolled by these medications. However, some with unstable angina, acute myocardial infarc- cases require percutaneous coronary interven- tion, or ischemic cardiac sudden death result tion or coronary bypass. In such cases, PTCA from coronary plaque disruption followed by itself can cause plaque disruption, thereby formation of thrombi, which occlude or narrow worsening acute coronary syndromes. There- the coronary lumen. These diseases have there- fore, plaque in unstable angina that is prone to fore come to be referred to collectively as acute thrombi formation, should be stabilized by coronary syndromes. The syndromes are char- medical therapy as far as possible before acterized by its frequent onset from mildly nar- PTCA. The recent introduction of stent inser- rowed coronary arteries and easily disrupted tion techniques has contributed to the preven- plaque with large lipid nuclei, thin fibrous caps, tion of acute coronary occlusion due to PTCA together with marked infiltration of macroph- in a considerable number of cases. ages and T lymphocytes. Coronary spasm not only triggers acute coronary syndromes, but 3. Prevention of acute coronary syndromes also occludes the coronary arteries to directly Although various treatments for acute coro- cause acute coronary syndromes. nary syndromes have been developed as Eliminating or controlling coronary risk fac- described above, it is still often difficult to treat tors including hypertension, diabetes mellitus, these syndromes once they develop. Therefore, smoking, hyperlipemia, and lack of exercise is preventing the syndromes is quite important. crucial for preventing acute coronary syndromes. It is necessary to suppress atherosclerosis in Anti-platelet drugs, such as aspirin, and anti- order to prevent acute coronary syndromes coagulants, such as warfarin, are also useful. because atherosclerosis is the base of the syn- Calcium antagonists are effective for coronary dromes. It is also important to eliminate or con- spasm. trol risk factors, such as hypertension, smoking, diabetes mellitus, hyperlipemia, obesity, and lack of exercise.10) The importance of eliminat- REFERENCES ing or controlling such factors was fully estab- 1) Yasue, H.: Pathogenesis and treatment of acute lished by several multi-center prospective ran- coronary syndromes. Journal of Japanese Soci- domized studies which demonstrated that cor- ety of Internal Medicine 1998; 87: 296–301. (in recting hyperlipemia with HMG-CoA reduc- Japanese)

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