Toward a New Frontier in Myocardial Reperfusion Therapy

Topol, Eric J.

doi:10.1161/01.cir.97.2.211

Cited by 229 publications

(106 citation statements)

References 78 publications

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“…Conversely, blockade of platelet aggregation with glycoprotein IIb/IIIa inhibitors, tested in several trials, invariably reduced death or nonfatal infarction at 30 days in both groups. 68 These findings are consistent with autopsy studies that point to the formation of platelet thrombi as a central pathogenetic mechanism in both of these unstable syndromes.…”

Section: Coronary Angioscopic Findingssupporting

confidence: 87%

“…Because activated platelets secrete plasminogen activator inhibitor type 1, the most powerful inhibitor of fibrinolysis, a vicious circle ensues. 68 The recanalization rate of 50% achieved with intravenous thrombolytic therapy corresponds approximately to the prevalence of fibrin-rich coagulation thrombi at autopsy. 63 Such thrombi present the most promising targets for fibrinolytic therapy.…”

Section: Discussionmentioning

confidence: 96%

“…68 Fibrinolysis enhances platelet aggregation by exposing thrombin, a very potent platelet activator, which is abundantly bound within the clot. It has been suggested that exposure of thrombin results in growth of the platelet core of the occluding thrombus.…”

Section: Discussionmentioning

confidence: 99%

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Thrombi in Acute Coronary Syndromes

2000

Circulation

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O ver the past 35 years, the view has evolved that the acute coronary syndromes, ie, unstable angina pectoris, myocardial infarction, and sudden death, are caused by plaque rupture and formation of a platelet thrombus. There is at least a transient total or subtotal coronary occlusion in all cases of acute myocardial infarction. Q-wave infarcts are thought to differ from non-Q-wave infarcts by more stable platelet thrombi causing more prolonged and/or severe ischemia, leading to more extensive infarction. The greater platelet stability in transmural infarction is attributed to more severe or extensive plaque rupture. 1-3 Unstable angina and non-Qwave infarction, in the present view, are due to less extensive, less stable platelet thrombi that cause less severe, less extensive ischemia and/or infarction.However, autopsy data and more recent clinical findings require significant refinement of this viewpoint on the basis of the following observations. The occlusive thrombi causing Q-wave myocardial infarction contain more fibrin than the thrombi found in the other acute coronary syndromes that are characterized by more platelets and less fibrin. The higher fibrin content of thrombi causing Q-wave infarction explains their greater stability. Furthermore, this higher fibrin content suggests that the coagulation cascade is activated to a greater degree during Q-wave infarction than during non-Q-wave infarction in which platelets play a more dominant role. This review analyzes our evolving concepts focusing on the growing divergence of the different mechanisms underlying the different acute coronary syndromes and their clinical and therapeutic implications. Morphological Basis for the Current Concept of Acute Coronary SyndromesBy the mid-1930s, acute myocardial infarction was shown to be caused by coronary thrombosis resulting from intimal fissuring, which is often associated with dissecting hemorrhage into the underlying plaque. 4 -7 In the late 1930s, however, intimal fissuring was questioned and subendothelial hemorrhages were ascribed to rupture of capillaries within the plaque. 8,9 The causative role of coronary thrombosis became controversial in 1956 when pathologists first reported a low prevalence of thrombi in fatal infarction. 10 -16 The pendulum began to swing back in the mid-1960s because of improved autopsy techniques. Coronary thrombi were found in Ͼ90% of fatal infarcts, most being occlusive.Plaque hemorrhages, which were usually traceable to an intimal tear within the thrombosed segment, were found in most cases. [17][18][19][20][21] These observations reaffirmed that intimal rupture was the essential mechanism causing both subendothelial hemorrhage and intraluminal thrombosis. 22 Having found that three quarters of occlusive coronary thrombi were composed of layers of different ages, Sinapius 17,21 concluded that these thrombi developed in a protracted, recurring course. The oldest portion of thrombus usually sealed the intimal fissure and was rich in platelets. The finding that mural thrombus forma...

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Section: Coronary Angioscopic Findingssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 96%

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Thrombi in Acute Coronary Syndromes

2000

Circulation

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“…73 With pharmacological strategies, there are intrinsic obstacles that need to be surmounted. The paradoxical prothrombotic effects of plasminogen activators set up the potential for more accumulation of thrombus, 74 particularly in the lowerflow watershed zone of the infarct. The current approaches do not include any acute platelet-directed strategy except for the modest effects of chewable or orally administered aspirin.…”

Section: Acute MImentioning

confidence: 99%

Recognition of the Importance of Embolization in Atherosclerotic Vascular Disease

2000

Self Cite

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“…Type 2 diabetes per se qualifies for the same risk as having experienced a first myocardial infarction [2,3]. The clinical ischaemia cascade of acute coronary syndromes is clearly a platelet-driven phenomenon [4]. Consequently, increased numbers of platelets circulate in an activated state in diabetic patients [5,6].…”

mentioning

confidence: 99%

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

et al. 2003

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Aims/hypothesis. The gene encoding the β 3 -subunit (GPIIIa) of the platelet α 2 β 3 -integrin (fibrinogen receptor) shows a polymorphism PlA1/A2 with the A2 allele putatively associated with an increased risk of acute ischaemic events. This study investigated whether Type 2 diabetes as a particular macrovascular risk factor associates with the thrombogenic PIA2 genotype. Methods. The PlA genotype was determined in 112 consecutive Type 2 diabetic patients additionally classified according to the presence of macrovascular disease. Forty-four non-diabetic patients with angiografically documented cardiovascular disease (CAD/ AMI) and a further 59 non-diabetic subjects with no angiografical signs of CAD were investigated as genomic background control (n=103). PIA-genotyping was carried out by standard restriction fragment length analysis (RFLA) of PCR amplified lymphocyte template DNA. Results. The overall allelic PlA2-prevalence accounted to 34.8% (39/112) in diabetic patients as compared to 14.6% (15/103) in non-diabetic patients [OR 3.1 (1.6-6.1), p<0.01].This odds ratio increased to 7.0 (2.5-19.7), (p<0.01) in subjects free of criteria of macrovascular disease. In non-diabetic control subjects without CAD there was an allelic PIA2 frequency of 10.2% (6/59) as compared to 20.5% (9/44) in patients with CAD and a history of AMI being less than either diabetes subgroup. The PIA2 prevalence in the subgroup of diabetes patients with macrovascular complications did not differ from the respective value in patients without macrovascular disease. [29.0% (20/69) vs. 44.2% (19/43)]. Conclusion/interpretation. This study confirms a trendwise association of PlA2 with severe coronary artery disease, but rather suggests an even stronger, highly significant association with the metabolic condition of Type 2 diabetes mellitus. This justifies the speculation that pathways dependent on the platelet α 2 β 3 integrin physiology could be implicated in the pathogenesis of Type 2 diabetes which lends further support to the "common soil" hypothesis of diabetes and vascular disease. [Diabetologia (2003) Abbreviations: AMI, acute myocardial infarction; CAD, coronary artery disease; GPIIIa, β 3 subunit of the platelet surface α 2 β 3 -integrin (GPIIb-IIIa, fibrinogen-receptor); PIA, platelet antigen; RGD, aminoacidsequence Arg-Gly-Asp; SNP, single nucleotide polymorphism. Diabetologia (2003) 46:984-989

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Toward a New Frontier in Myocardial Reperfusion Therapy

Cited by 229 publications

References 78 publications

Thrombi in Acute Coronary Syndromes

Thrombi in Acute Coronary Syndromes

Recognition of the Importance of Embolization in Atherosclerotic Vascular Disease

Genetic variation of the platelet- surface integrin GPIIb-IIIa ( PIA1/A2- SNP) shows a high association with Type 2 diabetes mellitus

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