Continued from previous page Acute myocardial infarction. Epicardial lesions related to acute myocardial infarctions are less than 50% in diameter in two-thirds of cases and less than 75% in diameter in more than 90% of cases,147,170,244 suggesting plaque rupture with thrombus superposition as the mechanism of vascular occlusion (Type VIc lesions).212 Using intravascular ultrasound, complete occlusion of the artery by thrombus formation usually in the neighborhood of calcified lesions is documented.27 Using angioscopy, white thrombi over ruptured plaques were found superimposed by red thrombi.232 They were still present 4 weeks after the acute event.235 Reopening of the occluded coronary vessel by thromboembolytic therapy is successful in angioplasty, improving ventricular function and/or survival,62,95,118,172,221 but combined therapy failed to demonstrate superior results to thrombolytic therapy alone.208,224 However, after thrombolytic therapy, only 60% of patients have full restoration of coronary blood flow (TIMI 3), whereas 20–30% still have reduced flow (TIMI 2).93,258 Using PTCA to reopen occluded coronary vessels, TIMI 3 flow is achieved in 90% of patients.165,238 In the beginning of the thrombolytic era, vessels with TIMI 2 and 3 flow were regarded as patent vessels and this criterion was used to describe the efficacy of thrombolytic agents.165,238 However, patients with reduced coronary blood flow (TIMI 2) have reduced prognosis compared to patients with TIMI 3 flow.15,240 This prognosis is even as poor as if the vessels had never been opened.15 Using contrast echocardiography, it has been demonstrated that despite reopening of coronary vessels, in acute myocardial infarction full restoration of myocardial perfusion is incomplete in part of the patients.5,117,120,121,239 Areas with incomplete restoration of flow with reduced or no contrast enhancement of the myocardium in echocardiography have less improvement of ventricular function than areas with complete opacification. Full contrast opacification after reopening the infarct-related vessel is an indicator of viable myocardium with functional improvement during follow-up.117,120,199 Intracoronary Doppler flow velocity measurements demonstrate an increase in coronary flow velocity reserve in recanalized infarcted arteries, which is also related to left ventricular recovery.167,231 The incomplete restoration of ventricular function and perfusion may be explained by a so-called “no-reflow” phenomenon.135 Additionally, differences in collateral blood flow may play a role.37 Also, abnormalities of microvascular perfusion secondary to leukocyte plugging and microembolization must be discussed.146,226 An increased expression of neutrophil and monocyte adhesion molecules could be shown.155 They can induce enhanced vasoconstriction and local thrombolytic effects due to tissue factor expression secondary to monocyte adhesion engagement.155 Activated leukocyte may form microaggregates, causing plugging in the microvasculature. New therapeutic options may be based on these findings. After reopening of coronary vessels in acute myocardial infarction, recurrent chest pain and ST-segment elevation can be observed in 10–15% of patients.139,173 Patients with this phenomenon have higher CK elevation, lower ejection fraction and a worse prognosis than patients with rapid decline of the ST segment after reopening the vessel.50 This is also true for those patients who have permanent ST-segment elevation compared to those with a transient ST shift. Permanent ST-segment elevation is associated with extensive infarction and reduced recovery of ventricular function.50,137 Preliminary results demonstrate that coronary blood flow and ventricular function are improved when a glycoprotein IIb/IIIa antagonist is given in order to reduce thrombus formation and fragmentation at the lesion site and the subsequent distal microembolization, resulting in improved myocardial perfusion.166 Sudden death. Sudden death is the most severe form of acute coronary syndrome. Published data are mainly derived from autopsy studies.64,143 Coronary lesions are similar to those in other acute syndromes. Plaque rupture is found in up to 70–80% and fissures are found in 20–30% of cases.64,143 Most importantly, microemboli in the coronary microcirculation are frequently seen.64,143 Microemboli are found in patients with and without unstable angina, but microinfarcts are more frequent in patients with unstable than stable angina prior to sudden death.64 Often, there is evidence for more than one episode of embolism.234 Microembolism during coronary interventions Unstable angina. PTCA was introduced by Andreas Gruentzig94 in order to treat patients with stable angina and was extended to treat patients with unstable angina as well.156 Early on, the results of PTCA revealed a higher complication rate, including acute myocardial infarction and need for coronary bypass surgery and mortality in patients with unstable than with stable angina.65,192 After PTCA, not all patients are free of chest pain. Some even develop new chest pain during the procedure itself which is not related to prolonged balloon inflation times.56 Transient or permanent ST-segment changes are observed.252 Signs of ischemia in electrocardiography, echocardiography or scintigraphy may persist or disappear incompletely.18,67,85,142,252 With close follow-up of cardiac enzymes after interventions, CK and CK-MB were elevated in 15–40% of patients.2,35,99,104,105,215 After PTCA, CK was elevated in 6%, CK-MB in 16%, and troponin T (> 0.4 ng/ml) in 11–19% of cases.104,105 When in-stent restenosis is treated by PTCA, the frequency of CK elevation was much lower.104 After PTCA, the ECG changes include T-wave attenuation, T-wave inversion and ST-segment depression.104 Q-wave infarcts after intervention were, however, rare and found in only 1.3% of patients.104 The release of cardiac enzymes and myocardial markers as well as the ECG changes after PTCA may indicate myocardial necrosis since its temporal occurrence is clearly related to the intervention.104,105 Whereas many studies suggest ischemia and prolonged inflation of the balloon as the major pathogenic factors,1 others did not confirm this hypothesis.138 We used only single and short inflation times in the order of 15–30 seconds, and therefore these explanations do not hold to explain the elevation of CK after PTCA in all patients. In some patients, a sidebranch occlusion was found.35,105 Thrombus formation at the lesion site and intermittent occlusion due to spasm, dissection and intramural hematoma were reported.99,215 Pathologic-anatomic studies have demonstrated severe damage of the coronary arterial wall with signs of dissection, intramural hematoma and thrombus formation after PTCA.54,242 The degree of injury is related to the amount of thrombus formation, platelet aggregation and neointimal proliferation at the site of the lesion.202 Multiple studies have shown that coronary flow reserve after PTCA is improved, but in most patients not normalized.140,180,181,251 Multiple explanations have been put forward in order to explain this surprising finding which has to be interpreted in view of angiographically optimal results on the one hand and the frequent CK elevation on the other hand. Mechanical factors such as dissection, elastic recoil, intramural hematoma and microcirculatory vasoconstriction are being discussed.4,14,82,102,108,130,131,158 Coronary stenting after angioplasty is able to increase coronary blood flow beyond the level of PTCA alone, and normalizes it in up to 80% of the patients with single vessel disease.82,102 However, stenting cannot normalize flow in all patients due to persistent abnormalities of the microvascular circulation.102 A pre-existing reduction of coronary flow reserve in patients with diabetes mellitus, hypertension and previous myocardial infarction may limit the restoration of flow.109,134 In addition, vasoconstriction may occur induced by serotonin149 and endothelin after PTCA.14 Since PTCA destroys the endothelium at the lesion site, acetylcholine can induce coronary constriction rather than coronary vasodilatation.76,77,257 Such vasoconstriction seems to occur routinely after PTCA.55,68,216,237 Also, an increased a-adrenergic tone both in the epicardial artery and at the microvascular level may play a significant role.132 Such a-adrenergic coronary constriction can be attenuated by anti-adrenergic agents.92,106 Visible embolization is rarely documented after PTCA, but may be more often found in unstable than stable angina and explain the reduced event-free survival in these patients. The vascular injury is underestimated by coronary angiography, as shown by intravascular ultrasound. Subintimal and submedial dissections are observed in 70–80% of patients with stable angina secondary to vessel wall stretching.86,97,114,119,206,227,247 In patients with unstable angina, however, dissections are rare but plaque size reduction has been found,129 possibly due to plaque compression, plaque redistribution, or dislodgement of plaque material leading to microembolization. This aspect of microembolization after PTCA became even more obvious when studies demonstrated the use of platelet aggregation inhibitors or anti-thrombin therapy leading to a reduction in the incidence of adverse cardiac events.58,218,219,222,223 Patients who do not normalize coronary flow reserve demonstrate an elevated baseline coronary flow velocitiy after PTCA which subsequently decreases during follow-up.237 As outlined above, this phenomenon may result from microembolization-induced hyperemia of adjacent myocardium.116 Visible embolization is, however, a common event when saphenous vein grafts undergo PTCA.45,111,126,194,195 In order to achieve better results, directional atherectomy,52,112 excimer laser angioplasty,25 stenting179,253 and ultrasound therapy190 were initiated as well as adjunctive medication with urokinase100,101 and a platelet glycoprotein IIb/IIIa receptor inhibitor (abciximab).150 However, distal embolization could not be eliminated.150,200 These observations are now confirmed by newly designed protection catheter systems.174 After intervention, plaque material could be removed from the saphenous vein graft in 7 of 15 patients (47%) and with a length of up to 700 µm capable of occluding the distal coronary circulation.36,152 As soon as this interventional modification is performed in native vessels, it will become obvious whether microembolization also occurs during conventional PTCA and stenting. In peripheral arteries, high-frequency ultrasound already visualized embolization of distal plaque material after angioplasty of the peripheral arteries.61 Rotational coronary angioplasty. New interventional devices have been developed. Rotational coronary atherectomy is particularly useful in calcified lesions and as an adjunct to coronary stenting (rota-stenting).6,31,32,49,183,184 The potential danger of embolization became obvious when experimental studies analyzed the particle size produced by the device. In 90% the particles were less than 10 µm in diameter, but larger particles were also present.6 Microinfarcts were demonstrated at autopsy.72 Rarely, visible coronary embolization is demonstrated by coronary angiography.61 In addition, high-speed rotational angioplasty produces microcavitations in a size of 60–90 µm in diameter which are able to block the microcirculation. This blockade, however, is transient, as the cavitations disappear within 20–30 seconds.211 Microcavitations are explained by the Bernoulli effect and are suppressed in experimental studies with high pressure in the surrounding fluid.259 Since the speed of the cavitations is in the range of 60–90 cm/s, the rapid blockade of the microcirculation can induce bradycardia or AV blocks when rotational atherectomy is used in the right or circumflex coronary artery.211 A greater production of microcavitations and/or microparticles may be one reason for the more pronounced “no-reflow” phenomenon after rotational angioplasty.31,57,136 Early on, with improper use of the rotational device, an increased complication rate was observed, which can now be avoided by using short runs, intermittent pause and stepwise increase of the burr size.28,49,183,197 All these maneuvers decrease the particle size and the production of cavitations. Nevertheless, 10–15% of patients treated with rotational angioplasty develop CK elevation.31,57 Again, treatment with platelet aggregation inhibitors leads to a more favorable outcome and improves coronary blood flow. Despite adjunctive PTCA, coronary flow reserve remains abnormally low;28 microembolization and/or microvascular spasm were proposed as explanations.28 These authors also observed an increase in baseline flow velocity (> 150%) which contributed to the minimal change of the coronary flow reserve (1.2 ± 0.1 at baseline, 1.3 ± 0.1 after rotablation, and 1.5 ± 0.1 after adjunctive PTCA).28 Baseline flow increased from 17.8 ± 1.9 m/s to 28.8 ± 3.8 m/s after rotablation and 39.5 ± 3.7 m/s after adjunctive PTCA.28 In comparison to the results of van Liebergen et al.237 after PTCA, this increase of baseline flow velocity is much more pronounced at 27 ± 20 cm/s. This may suggest that a much more pronounced microembolization-induced hyperemia occurs after rotational angioplasty. Directional coronary atherectomy. Direction coronary atherectomy (DCA) was developed by John Simpson for ablating plaque material in order to improve coronary luminal size and replace angioplasty, which stretches and dissects the arterial wall.209 DCA can also remove plaque material for histological analyses.111,196 Intima with or without thrombus formation and lipid core elements, parts of the media and even parts of the adventitia are cut off.110,112,196 Studies comparing this method to PTCA demonstrated that CK and CK-MB elevations were more frequent, i.e., in 37–38% of the patients.99,241 CK elevation was more prominent in those with Type C and complex lesions,228 possibly related to plaque dislodgement and microembolization. These results may explain why DCA produces more peri-interventional infarctlets and is related to a higher mortality rate despite better improvement of luminal dimensions.3,228 Coronary stenting. Stenting has become a regular adjunct to PTCA not only in order to induce wall wrapping after dissection,103,201 but also to treat unfavorable PTCA results,69 reduce the restenosis rate60,89,204 and improve myocardial perfusion.109 The coronary lumen after stenting is much smoother and larger than after angioplasty due to greater stretching and expansion of the coronary artery wall.38 When oversized balloons and high-pressure balloon inflations are used, the subacute thrombosis rate after stenting is reduced.39,160,214 Stenting improves not only coronary luminal dimensions, but also coronary flow reserve beyond that reached by PTCA; however, coronary reserve is not normalized in all patients and remains reduced in 20% of patients with single vessel disease and 60% of patients with multiple vessel disease.82,108,123,130 Stent placement may also lead to enhanced expression or squeezing of plaque material which is sometimes observed by intravascular ultrasound.38 Patients after stenting are complaining more often about chest discomfort than patients after PTCA. The chest discomfort persists for several hours and disappears within the next 24–48 hours. It has been suggested that this chest discomfort is due to an enhanced vessel wall stretching by stenting compared to PTCA since similar symptoms can be observed in some patients at the moment when the balloon is inflated.123 However, since CK and CK-MB elevations are more often found after stenting than after PTCA, the chest pain may also be due to infarctlets secondary to microemboli.2 This would also explain why this form of chest pain after stenting is not responding to nitroglycerin. Microembolization after stenting therefore appears to be enhanced as compared to plain old balloon angioplasty. Interventions in acute myocardial infarction. Interventions in acute myocardial infarction are an alternative to thrombolytic therapy.87 Direct balloon angioplasty has been introduced in addition to thrombolytic therapy,62 but also as a stand-alone procedure.172 However, the expected superior effect of angioplasty compared to thrombolysis could initially not be proven.208,224 Meanwhile, multiple studies using newer PTCA equipment have shown that the technique seems to be as good as thrombolytic therapy or may even be better.26,93 The most important difference between both techniques has been related to the higher percentage of full restoration of normal (TIMI 3) coronary blood flow, which is achieved in 85–95% after PTCA and in only 65–75% after thrombolysis, and to reduced bleeding complications.93 Intravascular ultrasound in the acute phase after PTCA has shown that it almost never induces dissections but mainly reduces plaque size secondary to plaque redistribution or embolization.8 Already passing a catheter through the coronary lesion in acute myocardial infarction improves the coronary diameter.169 Footprints are indicating the way of the catheter.26,27 After PTCA, a significant plaque size reduction in the range of 60–70% has been observed.8 With mechanical reopening of the vessel, coronary emboli are observed in up to 11% of patients.62 Even PTCA in the subacute setting can induce significant peripheral coronary embolization leading to myocardial reinfarction despite an open vessel, with a distal occlusion due to dislodgement of plaque or thrombotic material.169 Stenting was introduced for the treatment of acute myocardial infarction243 once the subacute thrombosis problem could be handled by using high-pressure balloon stenting and new treatment regimens including inhibition of platelet aggregation.220 Therefore, a trial was introduced comparing PTCA with the glycoprotein IIb/IIIa inhibitor abciximab to stenting with and without the drug.220 The results demonstrated that PTCA combined with the new platelet aggregation inhibitor was significantly better than stenting without and only slightly worse than the combination of stenting with the drug, indicating that enhanced platelet aggregation plays an important role in myocardial infarction. The pretreatment with abciximab may avoid microembolization and plugging of the microcirculation. Improved coronary flow after administration of abciximab in myocardial infarction was described, along with improved ventricular function,166 possibly related to reduced microembolization. The use of filter or aspiration systems will again test the hypothesis of microembolism development and degree in acute myocardial infarction. Clinical implications The pathogenesis of coronary artery disease seems to include not only the development of luminal narrowing of epicardial coronary arteries and disturbed vasomotion related to hypercholesterolemia and other risk factors, but also single or even multiple episodes of microembolization. During life, these events can be ongoing, repetitive, periodical and enhanced by inflammation which may induce a weakening of the fibrous cap and intima of a vulnerable plaque. Well known clinical entities such as ischemic cardiomyopathy, diabetic cardiomyopathy, acute coronary events and other syndromes are better understood when the potential mechanisms of microembolization are taken into account. In addition, therapeutic strategies to stabilize a vulnerable plaque and prevent plaque rupture with microembolization of plaque material become more important. The therapeutic benefit of glycoprotein IIb/IIIa receptor inhibitors such as abciximab can now be related to the prevention or resolution of thrombo-emboli in the microcirculation. For interventional cardiology, the development of filters or absorption devices in order to reduce the induced microembolization by plaque disruption or squeezing is reinforced. Even the use of graft stents for sequestration of thrombi or vulnerable plaques, once they have been visualized by intravascular ultrasound or in the future magnetic resonance imaging or optical coherence tomography, represent therapeutic options.
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