Coronary Microembolization — Its Role in Acute Coronary Syndromes and Interventions (Part I)

Raimund Erbel and *Gerd Heusch
Raimund Erbel and *Gerd Heusch
ABSTRACT: The diagnosis coronary artery disease is classically based on patient’s symptoms and morphology, as analyzed by angiography. The importance of risk factors for the development of coronary atherosclerosis and disturbance of coronary vasomotion is clearly established. However, microembolization of the coronary circulation has also to be taken into account. Microembolization may occur as a single or as multiple, repetitive events, and it may induce inflammatory responses. Spontaneous microembolization may occur, when the fibrous cap of an atheroma or fibroatheroma (Stary IV and Va) ruptures and the lipid pool with or without additional thrombus formation is washed out of the atheroma into the microcirculation. Such events with progressive thrombus formation are known as cyclic flow variations. Plaque rupture occurs more frequently than previously assumed, i.e., in 9% of patients without known heart disease suffering a traffic accident and in 22% of patients with hypertension and diabetes. Also, in patients dying from sudden death, microembolization is frequently found. Patients with stable and unstable angina show not only signs of coronary plaque rupture and thrombus formation, but also microemboli and microinfarcts, the only difference between those with stable and unstable angina being the number of events. Appreciation of microembolization may help to better understand the pathogenesis of ischemic cardiomyopathy, diabetic cardiomyopathy and acute coronary syndromes, in particular in patients with normal coronary angiograms, but plaque rupture detected by intravascular ultrasound. Also, the benefit from glycoprotein IIb/IIIa receptor antagonist is better understood, when not only the prevention of thrombus formation in the epicardial atherosclerotic plaque, but also that of microemboli, is taken into account. Microembolization also occurs during PTCA, inducing elevations of troponin T and I and elevations of the ST segment in the electrocardiogram. Elevated baseline coronary blood flow velocity, as a potential consequence of reactive hyperemia in myocardium surrounding areas of microembolization, is more frequent in patients with high-frequency rotablation than in patients with stenting and in patients with PTCA. The hypothesis of iatrogenic microembolization during coronary interventions is now supported by the use of aspiration and filtration devices, where particles with a size of up to 700 µm have been retrieved. In the experiment, microembolization is characterized by perfusion-contraction mismatch, as the proportionate reduction of flow and function seen with an epicardial stenosis is lost and replaced by contractile dysfunction in the absence of reduced flow. The analysis of the coronary microcirculation, in addition to that of the morphology and function of epicardial coronary arteries, and in particular appreciation of the concept of microembolization will further improve the understanding of the pathophysiology and clinical symptoms of coronary artery disease. Microembolization into the coronary microcirculation as a result of dislodgement of thrombi from injured epicardial arteries has previously been described.113,124,125 In patients with fatal ischemic heart disease, post mortem coronary angiography and autopsy procedures provided evidence of recurrent mural thrombus formation with peripheral embolization.64,143 Until recently, clinical cardiology was unable to verify the source and consequences of microembolization. New methods for the measurement of coronary20,131 and myocardial perfusion48,96,141,233,234,255 as well as for the assessment of coronary morphology59,81,157,163,168,245,254 have largely extended our knowledge. It became evident that spontaneous and induced microembolization plays an important role in the development of ischemic heart disease. This review attempts to describe the evidence from pathology for the role of plaque rupture and microembolization, its pathophysiological consequences and the clinical evidence for spontaneous and interventionally induced microembolization. Atherosclerotic lesions Plaque rupture. Plaque fissuring and plaque rupture are the causes of acute coronary syndromes — unstable angina, acute myocardial infarction, sudden death.41,42,44,75,76,185,212 Lesions with plaque fissuring and plaque ruptures are classified according to the American Heart Association (AHA) and American College of Cardiology (ACC) recommendations as Type VI lesions.212 Apparently, healthy people undergoing autopsy after cardiac death have experienced plaque rupture in 9% even at a young age,63 and in patients with diabetes plaque rupture is found in up to 22%.41 In careful pathologic-anatomic studies, ruptured plaques are usually found in more than one area.42,63 Recently, coronary angiography in acute myocardial infarction confirmed these findings; in 21% of patients, more than 1 lesion with signs of occlusion, ulceration, fissuring or filling defects could be detected, so that the authors suggested that plaque instability is not a vascular accident but a generalized coronary process.205 Complex lesions are subdivided: Type VIa: plaque ulceration; Type VIb: intramural hematoma; and Type VIc: incomplete or complete thrombus formation.212 Plaque ulceration. Type VIa is often misinterpreted by coronary angiography as coronary aneurysm,84,176,256 but represents a typical phenomenon, which has been described by Ambrose et al.12,13 Overhanging edges and scalloped borders are classified as Ambrose Type II eccentric lesions and are found in two-thirds of patients with unstable angina.12,13 Pathologic-anatomic studies confirmed that these lesions are mainly eccentric and have irregular borders,41,42,63 whereas angiography cannot visualize the intimal structure or biological features characteristic of the unstable lesion.144 Using intracoronary ultrasound, plaque rupture (Figure 1) can now be imaged.80,84,256 These studies demonstrated plaque ulcerations (Type VIa) with tears in the fibrous cap located in the center in 26% or the outer edges in 55% of patients.80 Richardson et al.185 described in their pathologic-anatomic studies centrally and eccentrically located tears in 29% and 49%, respectively. The incidence was only underestimated in superficially distributed lesions (9% versus 22%), possible due to the limited resolution of intravascular ultrasound.185 The ulcerated plaques may contain free-floating structures indicating thrombus formation.122 The exposed tissue of the plaque ulcer is a strong promoter of coronary thrombosis and contains high levels of tissue factors.16,66,229,249 Shed membrane microparticles with procoagulant potential are found, and apoptosis was suggested as a critical determinant of plaque thrombogenicity after plaque rupture.151 Of utmost importance is the finding that such plaque ruptures occur in the absence of a flow-limiting stenosis, and can even be present when coronary angiography is negative or suggestive of a normal anatomy.21 The calculated volume of plaque ulcera is in the range of 30–60 mm2, but may be as much as 1 ml in single patients.80 After washout, the plaque material is microembolized into the distal coronary circulation. Since plaque rupture appears to be truly a continuously ongoing process, multiple episodes of microembolization at different sites may occur. In pathology, multiple layering of atherosclerotic plaques is frequent, suggesting an ongoing process of rupturing and healing64 as one mechanism of progression of coronary atherosclerosis. Follow-up studies using intravascular ultrasound demonstrated healing with attachment of the fibrous cap to the vessel wall, resulting in wall thickening even within 10 days after onset of symptoms.21,83 Intermittently, the plaque ulcer may be filled up with thrombi, as illustrated recently.122 Intramural hematomas. Such hematomas are classified as Type VIb lesions.212 Hemorrhage into the plaque may be extensive and disruptive and may induce significant luminal narrowing.33,34,64 Intramural hematoma is regarded as the missing link (Figure 2) between morphology, atherosclerosis and function (spasm).11,64 Using coronary angiography, such lesions can only be detected indirectly. They may induce coronary luminal narrowing, which cannot be distinguished from coronary atherosclerotic lesions. Using intravascular ultrasound, few cases of intramural hematoma have been described.80 The sensitivity and accuracy are dependent on the resolution of intravascular ultrasound and may not be high enough to demonstrate all Type VIb lesions. According to pathologic-anatomic studies, Type VIb lesions are very common, and they may be another form of progression of coronary lesions.33,34 Occlusive or non-occlusive thrombus formation. Fissuring or rupturing of atherosclerotic plaques with thrombus formation is classified as a Type VIc lesion. This phenomenon was first described by Sinapius210 in a pathologic-anatomic study. He demonstrated ruptured plaques containing thrombus within the plaque but also protruding into the vascular lumen. Since atherosclerotic plaques are highly thrombogenic, the exposure of subintimal tissue after plaque fissure and rupture induces thrombus formation.151 Thrombi are found within the lumen of the plaque when plaque material has been washed out, and they may fill it completely. Protruding thrombi are visualized by coronary angiography as filling defects.12,13 In patients with episodes of chest pain within 24 hours of coronary angiography, an incidence of thrombosis of up to 100% has been found. In two-thirds of patients, thrombi are also present distal to the lesions, possibly as a result of turbulent blood flow, as suggested by Ambrose et al.11 Using intracoronary ultrasound, single and multiple layering of the lesion has been described and interpreted as mural thrombus formation.129 A fine granular speckled appearance and/or difference in reflectivity from surrounding tissues is typical.246 Such lesion types are predominantly seen in unstable lesions, can be explained by a closely apposed layer of thrombus, and are also found in experimental studies.129 In addition, a rough inner surface with small floating structures can be seen. Similarly, thrombus formation has been demonstrated in acute myocardial infarction, resulting in a typical speckled character when using intravascular ultrasound.27 Intravascular ultrasound has a low sensitivity but high specificity of up to 100% for the detection of mural thrombus formation.71 Mural thrombus formation may be overlooked, particularly when the ruptured plaques are completely filled with thrombi and no thrombus is protruding. Mural thrombus formation and plaque disruption can also be visualized using coronary angioscopy. In patients with recent onset angina an incidence of 100% is found, whereas in patients with a lower class of unstable angina, mural thrombus formation is less frequent.7,46,145,164,217,248 However, mural thrombus formation is even present when coronary angiography is negative.248 Coronary angioscopy appears to be more sensitive than intracoronary ultrasound and angiography for visualizing intracoronary thrombus formation.71 Peripheral coronary microembolization Previous experimental studies have demonstrated that coronary lesions in epicardial arteries can induce microembolization, resulting in severe myocardial ischemia and lethal arrhythmias.113,124,125 Microembolization has been found at autopsy in patients with acute coronary syndromes who died of sudden death.64,143 Even multiple episodes of microinfarcts secondary to atherosclerotic thromboemboli were found. Atherosclerotic material containing cholesterol crystals formed the source for thrombus formation in the microcirculation.64 Such microemboli were also detected in patients with stable angina pectoris.64 The major difference between these clinical situations was only the number of episodes. More than one episode was present in unstable angina in 87% and in stable angina in 71%, with microemboli in 53% and 43% and microinfarcts in 47% and 29% of cases, respectively,64 possibly resulting from intermittent thrombus fragmentation (Figure 2), which may be as frequent as recurrent thrombus formation.64 Recurrent embolization due to remodeling of the platelet thrombus has also been found,113,124,125 and platelet-rich thromboemboli have been demonstrated in up to 79% of patients with unstable angina and sudden death.43,73,145 In a recent study,143 thromboemboli were found at autopsy in 20% of patients with out-of-hospital death due to ischemic heart disease, and all patients in this study had an acute thrombus in the coronary artery supplying the area of myocardium containing the thromboemboli.143 Pathophysiology of microembolization With acute coronary arterial inflow reduction by an epicardial coronary artery stenosis, contractile function in the dependent myocardium is rapidly reduced.225 Within a few minutes, a new steady state of perfusion-contraction matching191 develops where regional myocardial function (demand) is reduced in proportion to regional myocardial blood flow (supply),78 and such perfusion-contraction matching can be maintained over several hours154 and may be the pathophysiologic substrate of hibernating myocardium.107 Experimental microvascular obstruction by intracoronary injection of inert particles with a diameter of 15 or 100 µm also induces regional contractile dysfunction, and the amount of dysfunction is proportionate to the number of injected particles.115,116 In contrast to an epicardial coronary arterial inflow reduction, baseline blood flow into the microembolized area is not reduced, but may actually even be enhanced secondary to an adenosine-related hyperemia of the myocardium surrounding the embolized microregions.116 Comparing an epicardial stenosis to microembolization with microspheres of 45 µm diameter at identical degrees of contractile dysfunction, we have recently demonstrated perfusion-contraction mismatch secondary to microvascular obstruction, with severe contractile dysfunction and no decrease in regional blood flow.53,188 The profound contractile dysfunction could not be related to the amount of infarcted myocardium. Therefore, the mechanical disadvantage from multiple microinfarcts (Figures 3–5) with multiple border zones to nonischemic myocardium appears to be greater than that of a single infarct of the same volume. Importantly, the inflammatory response to microembolization is also greater than the response to inflow reduction, and inflammatory mediators may contribute to the observed contractile dysfunction. Clinical scenarios with microembolization in acute coronary syndromes Unstable angina pectoris. Unstable angina is classified by Braunwald29 according to its time course and extracardiac factors. He also provided an etiological approach to management. In unstable angina, analysis of wall motion by angiography, echocardiography and nuclear medicine techniques revealed significant, transient wall motion abnormalities as signs of myocardial ischemia.10,74,91,127,182,198 Nuclear medicine studies in patients with unstable angina also demonstrated perfusion defects as well as areas with redistribution, indicating maintained viability.74,91,127,198 New markers for the detection of myocardial necrosis were recently introduced.17,98,128,175,182,187 An increase of troponin T and troponin I was found in a higher percentage than the elevation of CK and CK-MB in unstable angina, and these marker elevations are now regarded as indicators of micronecrosis.187 Positive troponin T and troponin I levels in unstable angina indicate a reduced prognosis.175,187,236 Angiographic signs of unstable angina include occlusive filling defects, irregular coronary artery contours and aneurysms. The prevalence of these signs depends on the time between start of symptoms and angiography.11,12 The degree of coronary luminal narrowing is below 50% in the majority of patients, so that a flow reduction due to coronary luminal narrowing cannot explain the onset of ischemic symptoms. In up to 15% of patients, no coronary luminal narrowing is detected.51 However, the prognosis of those with minor or no luminal narrowing has been as poor as the prognosis of those with significant luminal narrowing.51 Since significant coronary luminal narrowing cannot explain the symptoms and signs of myocardial ischemia, different pathophysiologic mechanisms must be discussed: 1. Intermittent coronary spasm enhanced by plaque rupture with activation of platelets and leukocytes and release of vasoactive mediators, such as serotonin and endothelin.9,30,70,90,162,171,213 2. Imbalance of vasoconstriction and vasodilation due to endothelial damage and dysfunction,19,88,161,171,213 which may be enhanced by plaque hemorrhage (Type VIb lesion).33,34 3. Cyclic flow variations with recurrent platelet aggregation and thrombus formation and washout.19,213 4. Thrombus formation after plaque fissuring or rupture (Type VIc lesion) which is not totally blocking the coronary artery, but may or may not embolize, as demonstrated by angioscopy and intravascular ultrasound.7,46,88,129,163,164,248 5. Plaque rupture and ulceration with microembolization of plaque debris (Type VIa lesions).21,80 All these factors are certainly involved, but according to pathologic-anatomic studies and the evidence of plaque ulceration obtained by intracoronary ultrasound, microembolization plays an important role. The development of thromboemboli after microembolization of plaque debris helps to explain why patients with acute coronary syndromes respond to treatment with glycoprotein IIb/IIIa receptor antagonists and experience a reduction of adverse cardiac events.218,222,223 The efficacy of this treatment can be explained by the reduction of thrombus formation induced by atherosclerotic material from ruptured plaques both at the site of the epicardial artery but also of the embolizing plaque particles in the microcirculation. In patients with unstable angina, elevated levels of C-reactive protein were found at discharge.22,24,148,153,159,186,230 C-reactive protein is a non-specific but sensitive marker of inflammation (Figure 3) and was observed for up to 3 months in patients admitted with severe unstable angina.148 Whereas a chlamydia pneumoniae or helicobacter infection as the source of inflammation has been proposed,24 inflammatory reactions such as an increase of eosinophiles have also been reported after microvascular embolization.40,178 Continued on next page
1. Abdelmeguid AE, Topol EJ, Whitlow PL, et al. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528–1536. 2. Abdelmeguid AE, Topol EJ. The myth of the myocardial “infarctlet” during percutaneous coronary revascularization procedures. Circulation 1996;94:3369–3375. 3. Adelman AG, Cohen EA, Kimball BP, et al. A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending coronary artery. N Engl J Med 1993;329:228–233. 4. Aengevaeren WRM, Uijen GJH, van der Werf T. Comparison of coronary flow velocity and regional myocardial perfusion for functional evaluation of coronary artery disease in the setting of angioplasty. Cathet Cardiovasc Diagn 1998;45:16–24. 5. Agati L, Voci P, Bilotta F, et al. Influence of residual perfusion within the infarct zone on the natural history of left ventricular dysfunction after acute myocardial infarction: A myocardial contrast echocardiographic study. J Am Coll Cardiol 1994;24:336–342. 6. Ahn SS, Auth D, Marcus DR, et al. Removal of focal atheromatous lesions by angioscopically guided high-speed rotary atherectomy: Preliminary experimental observations. J Vasc Surg 1988;7:292–300. 7. Alfonso F, Goicolea J, Hernandez R, et al. Findings of coronary angioscopy in angiographically normal coronary segments of patients with coronary artery disease. Am Heart J 1995;130:987–993. 8. Alfonso F, Macaya C, Goicolea J, et al. Angiographic changes induced by intracoronary ultrasound imaging before and after coronary angioplasty. Am Heart J 1993;125:877–880. 9. Alpert JS. Coronary vasomotion, coronary thrombosis, myocardial infarction and the camel’s back. J Am Coll Cardiol 1985;5:617–619. 10. Amanullah AM, Lindvall K, Bevegard S. Exercise echocardiography after stabilization of unstable angina: Correlation with exercise thallium-201 single photon emission computed tomography. Clin Cardiol 1992;15:585–589. 11. Ambrose JA, Hjemdahl-Monsen CE. Arteriographic anatomy and mechanism of myocardial ischemia in unstable angina. J Am Coll Cardiol 1987;9:1397–1402. 12. Ambrose JA, Winters SL, Arora RR, et al. Evolution of coronary morphology in unstable angina pectoris. J Am Coll Cardiol 1986;7:472. 13. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609. 14. Ameli S, Kaul S, Castro L, et al. Effect of percutaneous transluminal coronary angioplasty on circulating endothelin levels. Am J Cardiol 1993;72:1352–1356. 15. Anderson JL, Karagounis LA, Becker LC. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction. Circulation 1993;87:1829–1839. 16. Annex BH, Denning SM, Channon KM, et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 1995;91:619–622. 17. Antman EM, Grudzien C, Mitchell RN, et al. Detection of unsuspected myocardial necrosis by rapid bedside assay for cardiac troponin T. Am Heart J 1997;133:596–598. 18. Aoki T, Konishi T, Futagami Y, et al. Clinical significance of exercise induced ST segment depression after successful percutaneous transluminal coronary angioplasty. Assessment by thallium-201 SPECT. Jpn J Nucl Med 1989;26:733–741. 19. Ashton JH, Golino P, McNatt JM, et al. Serotonin S-2 and thromboxane A-2-prostaglandin H-2 receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries. J Am Coll Cardiol 1989;13:755–763. 20. Baumgart D, Haude M, Goerke G, et al. Improved assessment of coronary stenosis severity using the relative flow velocity reserve. Circulation 1998;98:40–46. 21. Baumgart D, Liu F, Haude M, et al. Acute plaque rupture and myocardial stunning in patients with normal coronary arteriography. Lancet 1995;346:193–194. 22. Benamer H, Steg PG, Benessiano J, et al. Comparison of the prognostic value of C-reactive protein and troponin I in patients with unstable angina pectoris. Am J Cardiol 1998;82:845–850. 23. Betrand ME, Lablanch JM, Leroy F, et al. Percutaneous transluminal coronary rotary ablation with rotablator (European experience). Am J Cardiol 1992;69:470–474. 24. Biasucci LM, Liuzzo G, Grillo RL, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99:855–860. 25. Bittle JA, Sanborn TA, Yardley DE, et al. Predictors of outcome of percutaneous excimer laser coronary angioplasty of saphenous vein bypass graft lesions. Am J Cardiol 1994;74:144–148. 26. Bocksch W, Schartl M, Beckmann S, et al. Intravascular ultrasound assessment of direct percutaneous transluminal coronary angioplasty in patients with acute myocardial infarction. Coron Art Dis 1997;8:265–273. 27. Bocksch WG, Schartl M, Beckmann S, et al. Intravascular ultrasound imaging in patients with acute myocardial infarction: Comparison with chronic stable angina pectoris. Coron Art Dis 1994;5:727–735. 28. Bowers TR, Stewart RE, O’Neill WW, et al. Effect of rotablator atherectomy and adjunctive balloon angioplasty of coronary blood flow. Circulation 1997;95:1157–1164. 29. Braunwald E. Unstable angina: A classification. Circulation 1989;80:410–414. 30. Bresnahan DR, Davies JL, Holmes DR, et al. Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: Role of unstable angina. J Am Coll Cardiol 1985;6:285–289. 31. Brogan WC III, Popma JJ, Pichard AD, et al. Rotational coronary atherectomy after unsuccessful coronary balloon angioplasty. Am J Cardiol 1993;71:794–798. 32. Brown DL, George CJ, Steenkiste AR, et al. High-speed rotational atherectomy of human coronary stenoses: Acute and one-year outcomes from the New Approaches to Coronary Intervention (NACI) registry. Am J Cardiol 1997;80:60K–67K. 33. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in patients with coronary disease dying suddenly. N Engl J Med 1997;336:1276–1282. 34. Burke AP, Farb A, Malcom GT, et al. Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 1999;281:921–926. 35. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998;31:241–251. 36. Carlino M, De Gregorio J, Di Mario C, et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999;99:3221–3223. 37. Cheirif JB, Narkiewicz-Jodko JB, Hawkins HK, et al. Myocardial contrast echocardiography: Relation of collateral perfusion to extent of injury and severity of contractile dysfunction in a canine model of coronary thrombosis and reperfusion. J Am Coll Cardiol 1995;26:537–546. 38. Colombo A, Goldberg SL, Almagor Y, et al. A novel strategy for stent deployment in the treatment of acute or threatened closure complicating balloon coronary angioplasty. Use of short or standard (or both) single or multiple Palmaz-Schatz stents. J Am Coll Cardiol 1993;22:1887–1891. 39. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995;91:1676–1688. 40. Colt HG, Begg RJ, Saporito JJ, et al. Cholesterol emboli after cardiac catheterization. Eight cases and a review of literature. Medicine (Baltimore) 1988;67:389–400. 41. Davies MJ, Bland MJ, Hangartner WR, et al. Factors influencing the presence or absence of acute coronary thrombi in sudden ischemic death. Eur Heart J 1989;10:203–208. 42. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137–1140. 43. Davies MJ, Thomas AC, Knapman PA, et al. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418–427. 44. Davies MJ, Thomas AC. Plaque fissuring — The cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363–373. 45. De Feyter P, Serruys P, van den Brand M, et al. Percutaneous transluminal angioplasty of a totally occluded bypass graft: A challenge that should be resisted. Am J Cardiol 1989;64:88–90. 46. Den Heijer P, Foley DP, Escaned J, et al. Angioscopic versus angiographic detection of intimal dissection and intracoronary thrombus. J Am Coll Cardiol 1994;24:649–654. 47. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897–902. 48. Di Carli M, Czernin J, Hoh CK, et al. Relation among stenosis severity, myocardial blood flow and flow reserve in patients with coronary artery disease. Circulation 1995;91:1944–1951. 49. Dietz U, Erbel R, Rupprecht H, et al. High frequency rotational ablation: An alternative in treating coronary artery stenoses and occlusions. Br Heart J 1993;70:327–336. 50. Dissmann R, Linderer T, Goerke M, et al. Sudden increase of the ST segment elevation at time of reperfusion predicts extensive infarcts in patients with intravenous thrombolysis. Am Heart J 1993;126:832–839. 51. Diver DJ, Bier JD, Ferreira PE, et al. Clinical and arteriographic characterization of patients with unstable angina without critical coronary arterial narrowing (from the TIMI-IIIa Trial). Am J Cardiol 1994;74:531–537. 52. Dooris M, Hoffmann M, Glazier S, et al. Comparative results of transluminal extraction coronary atherectomy in saphenous vein graft lesions with and without thrombus. J Am Coll Cardiol 1995;25:1700–1705. 53. Dörge H, Behrends M, Neumann T, et al. Perfusion-contraction mismatch with coronary microvascular obstruction. J Mol Cell Cardiol 1999;31:A58. 54. Düber C, Jungbluth A, Rumpelt HJ, et al. Morphology of the coronary arteries after combined thrombolysis and percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol 1986;58:698–703. 55. El Tamimi H, Davies GJ, Hackett D, et al. Abnormal vasomotor changes early after coronary angioplasty: A quantitative arteriographic study of their time course. Circulation 1991;84:1198–1202. 56. El Tamimi H, Hackett D. Holter monitoring after PTCA. Eur Heart J 1989;10:33–35. 57. Ellis SG, Popma JJ, Buchbinder M, et al. Relation of clinical presentation, stenosis morphology, and operator technique to the procedural results of rotational atherectomy and rotational atherectomy-facilitated angioplasty. Circulation 1994;89:882–892. 58. EPILOG Investigators. Effect of the platelet glycoprotein IIb/IIIa receptor inhibitor abciximab with lower heparin dosages on ischemic complications of percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696. 59. Erbel R, Ge J, Görge G, et al. Neue Aspekte zur Pathogenese der koronaren Hererkrankung auf dem Boden intravaskulärer Ultraschalluntersuchungen. Dtsch Med Wochenschr 1995;120:847–854. 60. Erbel R, Haude M, Höpp HW, et al., for the Restenosis Stent Study Group. Coronary-artery stenting compared with balloon angioplasty. N Engl J Med 1998;339:1672–1678. 61. Erbel R, O’Neil W, Auth D, et al. Hochfrequenz-Rotationsatherektomie bei koronarer Herzkrankheit. Dtsch Med Wochenschr 1989;114:487–495. 62. Erbel R, Pop T, Henriche KJ, et al. Percutaneous transluminal coronary angioplasty after thrombolytic therapy: A prospective controlled randomized trial. J Am Coll Cardiol 1986;8:485–495. 63. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127–134. 64. Falk E. Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation 1985;71:699–708. 65. Faxon DP, Detre KM, McGabe CH, et al. Role of percutaneous transluminal coronary angioplasty in the treatment of unstable angina: Report from the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty and Coronary Artery Surgery Study Registries. Am J Cardiol 1983;53:131C–135C. 66. Fernandez-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture. J Am Coll Cardiol 1994;23:1562–1569. 67. Fioretti PM, Pozzoli MMA, Ilmer B, et al. Exercise echocardiography versus thallium-201 SPECT for assessing patients before and after PTCA. Eur Heart J 1992;13:213–219. 68. Fischell TA, Derby G, Tse TM, et al. Coronary artery vasoconstriction routinely occurs after percutaneous transluminal coronary angioplasty: A quantitative arteriographic analysis. Circulation 1988;78:1323–1334. 69. Fishman DL, Leon MB, Baim DS. For the stent restenosis study investigators. N Engl J Med 1994;331:496–501. 70. Folts JD, Gallagher K, Rowe GG. Blood flow reductions in stenosed canine coronary arteries: Vasospasm of platelet aggregation? Circulation 1982;65:248. 71. Franzen D, Sechtem U, Höpp HW. Comparison of angioscopic, intravascular ultrasonic, and angiographic detection of thrombus in coronary stenosis. Am J Cardiol 1998;82:1273–1275. 72. Friedman HZ, Elliott MA, Gottlieb GJ, et al. Rotational coronary atherectomy: The effects of micro-particle embolization on myocardial blood flow. J Intervent Cardiol 1989;2:77–83. 73. Frink RJ, Rooney PA, Trowbridge JO, et al. Coronary thrombus and platelet/fibrin microemboli in death associated with acute myocardial infarction. Br Heart J 1988;59:196–200. 74. Fukuzawa S, Inagaki M, Morooka S, et al. An effective tool to detect lesions causing unstable angina with multivessel disease: Iodine-123-betamethyl-p-iodopheyl-pentadeanoic acid single photon emission computed tomography. J Cardiol 1996;28:191–198. 75. Fuster V, Badimon JJ, Chesebro JH, et al. Plaque rupture, thrombosis, and therapeutic implications. Haemostasis 1996;4:269–284. 76. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (part I). N Engl J Med 1992;326:242–250. 77. Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (part II). N Engl J Med 1992;326:310–318. 78. Gallagher KP, Matsuzaki M, Osakada G, et al. Effect of exercise on the relationship between myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis. Circ Res 1983;52:716–729. 79. Garratt KN, Edwards WD, Kaufmann UP, et al. Differential histopathology of primary atherosclerotic and restenotic lesions in coronary arteries and saphenous vein bypass grafts: Analysis of tissue obtained from 73 patients by directional atherectomy. J Am Coll Cardiol 1991;17:442–448. 80. Ge J, Chirillo F, Schwedtmann J, et al. Screening of ruptured plaques in patients with coronary artery disease by intravascular ultrasound. Br Heart J 1999;81:621–627. 81. Ge J, Erbel R, Zamorano J, et al. Coronary artery remodeling in atherosclerotic disease: An intravascular ultrasonic study in vivo. Coron Art Dis 1993;4:981–986. 82. Ge J, Erbel R, Zamorano J, et al. Improvement of coronary morphology and blood flow after stenting: Assessment by intravascular ultrasound and intracoronary Doppler. Int J Card Imag 1995;11:81–87. 83. Ge J, Haude M, Görge G, et al. Silent healing of spontaneous plaque disruption demonstrated by intracoronary ultrasound. Eur Heart J 1995;16:1149–1151. 84. Ge J, Liu F, Kearney P, et al. Intravascular ultrasound approach to the diagnosis of coronary artery aneurysms. Am Heart J 1995;130:765–771. 85. Georgoulias P, Demakopoulos N, Kontos A, et al. Tc-99m tetro-fosmin myocardial perfusion imaging before and six months after percutaneous transluminal coronary angioplasty. Clin Nucl Med 1998;23:678–682. 86. Gerber TC, Erbel R, Görge G, et al. Classification of morphologic effects of percutaneous transluminal coronary angioplasty assessed by intravascular ultrasound. Am J Cardiol 1992;70:1546–1554. 87. Gibbons RJ, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction: The Mayo Coronary Care Unit and Catheterization Laboratory Groups. N Engl J Med 1993;328:685–691. 88. Golino P, Buja LM, Sheng-Kun Y, et al. Failure of nitroglycerin and diltiazem to reduce platelet-mediated vasoconstriction in dogs with coronary artery stenosis and endothelial injury: Further evidence for thromboxane A-2 and serotonin as mediators of coronary artery vasoconstriction in vivo. J Am Coll Cardiol 1990;15:718–726. 89. Görge G, Haude M, Ge J, et al. Intravascular ultrasound after low and high inflation pressure coronary artery stent implantation. J Am Coll Cardiol 1995;26:725–730. 90. Gorlin R, Fuster V, Ambrose JA. Anatomic-physiologic links between acute coronary syndromes. Circulation 1986;74:6–9. 91. Gregoire J, Theroux P. Detection and assessment of unstable angina using myocardial perfusion imaging: Comparison between technetium-99m sestamibi SPECT and 12-lead electrocardiogram. Am J Cardiol 1990;66:42E–46E. 92. Gregorini L, Fajadet J, Robert G, et al. Coronary vasoconstriction after percutaneous transluminal coronary angioplasty is attenuated by antiadrenergic agents. Circulation 1994;90:895–907. 93. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction: The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1993;328:673–679. 94. Grüntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: Percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61–67. 95. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI): Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397–401. 96. Guethlin M, Kasel AM, Coppenrath K, et al. Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. Circulation 1999;99:475–481. 97. Gussenhoven EJ, The SHK, Gerritsen P, et al. Real-time intravascular ultrasonic imaging before and after balloon angioplasty. J Clin Ultrasound 1991;19:294–297. 98. Hamm CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327:146–150. 99. Harrington RA, Lincoff AM, Califf RM, et al. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: Insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol 1995;25:1693–1699. 100. Hartmann JR, McKeaver LS, O’Neill W, et al. Recanalization of chronically occluded aortocoronary saphenous vein bypass grafts with long-term, low dose direct infusion of urokinase (ROBUST): A serial trial. J Am Coll Cardiol 1996;27:60–66. 101. Hartmann JR, McKeaver LS, Stamato NJ, et al. Recanalization of chronically occluded aortocoronary saphenous vein bypass grafts by extended infusion of urokinase: Initial results and short-term clinical follow-up. J Am Coll Cardiol 1991;18:1517–1523. 102. Haude M, Caspari G, Baumgart D, et al. Additional improvement of stenosis dimensions and coronary flow after intracoronary implantation of Palmaz-Schatz stents. Circulation 1996;94:286–297. 103. Haude M, Erbel R, Straub U, et al. Results on intracoronary stents for management of coronary dissection after balloon angioplasty. Am J Cardiol 1991;67:691–696. 104. Herrmann J, Sack S, von Birgelen C, et al. Peri-interventionelle Myokardnekrotisierungen — Abhängigkeit von der Interventionstechnik. Z Kardiol 1999;88(Suppl 1):188. 105. Herrmann J, von Birgelen C, Sack S, et al. Klinische Marker myokardialer Mikroinfarkte nach koronaren Interventionen. Z Kardiol 1998;87(Suppl 5):59. 106. Heusch G, Baumgart D, Camici P, et al. a-adrenergic coronary vasoconstriction and myocardial ischemia in man. Circulation (in press). 107. Heusch G. Hibernating myocardium. Physiol Rev 1998;78:1055–1085. 108. Hodgson JM, Riley RS, Most AS, et al. Assessment of coronary flow reserve using digital angiography before and after successful percutaneous transluminal coronary angioplasty. Am J Cardiol 1987;60:61–65. 109. Hoffmann JIE. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153–159. 110. Höfling B, Pölnitz A, Backa D, et al. Percutaneous removal of atheromatous plaques in peripheral arteries. Lancet 1988;1:384–386. 111. Holmes DR, Berger PB. Percutaneous revascularization of occluded vein grafts: Is it still a temptation to be resisted? Circulation 1999;99:8–11. 112. Holmes DR, Topol EJ, Califf RM, et al. A multicenter, randomized trial of coronary angioplasty versus directional atherectomy for patients with saphenous vein bypass graft lesions. Circulation 1995;91:1966–1974. 113. Honour AJ, Ross RW. Experimental platelet embolism. Br J Exp Pathol 1962;43:350–362. 114. Honye J, Mahon DJ, Jain A, et al. Morphological effects of coronary balloon angioplasty in vivo assessed by intravascular ultrasound imaging. Circulation 1992;85:1012–1025. 115. Hori M, Gotoh K, Kitakaze M, et al. Role of oxygen-derived free radicals in myocardial edema and ischemia in coronary microvascular embolization. Circulation 1991;84:828–840. 116. Hori M, Inoue M, Kitakaze M, et al. Role of adenosine in hyperemic response of coronary blood flow in microcirculation. Am J Physiol 1986;250:H509–H518. 117. Iliceto S, Galiuto L, Marchese A, et al. Analysis of microvascular integrity, contractile reserve and myocardial viability after acute myocardial infarction by dobutamine echocardiography and myocardial contrast echocardiography. Am J Cardiol 1996;77:441–445. 118. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group: Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349–360. 119. Isner JM, Rosenfield K, Losordo DW, et al. Combination balloon-ultrasound imaging catheter for percutaneous transluminal angioplasty: Validation of imaging, analysis of recoil, and identification of plaque fracture. Circulation 1991;84:739–754. 120. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon: A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996;93:223–238. 121. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis: A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699–1705. 122. Jeremias A, Ge J, Erbel R. New insight into plaque healing after plaque rupture with subsequent thrombus formation detected by intravascular ultrasound. Heart 1997;3:293. 123. Jeremias A, Kutscher S, Haude M, et al. Nonischemic chest pain induced by coronary interventions. A prospective study comparing coronary angioplasty and stent implantation. Circulation 1998;98:2656–2658. 124. Jorgensen L, Roswell HC, Hovig T, et al. Adenosine diphosphate-induced platelet aggregation and myocardial infarction in swine. Lab Invest 1967;17:616–644. 125. Jorgensen L. Experimental platelet and coagulation thrombi. Acta Pathol Microbiol Scand 1964;62:189–223. 126. Kahn KJ, Rutherford BD, McConahay DR, et al. Initial and long-term outcome of 83 patients after balloon angioplasty of totally occluded bypass grafts. J Am Coll Cardiol 1994;23:1038–1042. 127. Karlsson JE, Bjorkholm A, Nylander E, et al. Additional value of thallium-201 SPECT to a conventional exercise test for the identification of severe coronary lesions after an episode of unstable coronary artery disease. Int J Card Imag 1995;11:127–137. 128. Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficacy of troponin T measurements in acute myocardial infarction. Circulation 1991;83:902–912. 129. Kearney P, Erbel R, Rupprecht HJ, et al. Difference in the morphology of unstable and stable coronary lesions and their impact on the mechanisms of angioplasty. An in vivo study with intravascular ultrasound. Eur Heart J 1996;17:721–730. 130. Kern MJ, Dupouy P, Drury JH, et al. Role of coronary artery lumen enlargement in improving coronary blood flow after balloon angioplasty and stenting: A combined intravascular ultrasound Doppler flow and imaging study. J Am Coll Cardiol 1997;29:1520–1527.