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Deceived incidence of acute coronary syndrome by measurement of FFR: Diagnostic gap of vulnerable plaque between physiology and morphology
Abstract
A 67-year-old male was admitted because of acute myocardial infarction (AMI). An emergent coronary angiography showed a total occlusion in the left anterior descending artery, and a stent was deployed. Moderate lesion stenosis was found in the right coronary artery (RCA). Fractional flow reserve indicated 0.96, and percutaneous coronary intervention was not performed. Six months later, the patient visited an emergency room due to AMI. Angiograms showed a patency of the previous stent and progressed stenosis with filling delay of the RCA. Protruding red thrombi and plaque disruption of thin-cap fibroatheroma (TCFA) were identified by optical coherence tomography. Mild to moderate lesions are physiologically benign but morphologically malignant in cases of TCFA. Learning objective: Severe stenosis is a malignant index of plaque vulnerability on the basis of physiological and morphological evaluation. However, mild to moderate lesions are physiologically benign but morphologically malignant in cases of thin-cap fibroatheroma. Although fractional flow reserve can estimate the extent of severe stenosis, one of the elements of vulnerable plaques, it cannot always predict future events related to morphologically vulnerable plaques.
... The present case demonstrated moderate lesions in the right coronary artery, which had no evidence of ischemia, as indicated by the FFR value (0.96), and rapidly progressed to protruding red thrombi and plaque disruption of thin-cap TCFA, which was identified by OCT six months later. The authors addressed the view that FFR is an insufficient index for predicting future events related to the morphologically vulnerable plaques in mild to moderate lesions, but not severe stenosis, while OCT-derived TCFA is likely to discriminate morphologically malignant lesions from mild to moderate lesions [10]. That is, the report suggests that OCT-derived TCFA bridges the gap from physiologically benign but morphologically malignant in mild to moderate lesions. ...
Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood.
In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years.
The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001).
In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.).
Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.
The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD).
In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up.
At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was <or=0.80.
The number of indicated lesions was 2.7+/-0.9 in the angiography-guided group and 2.8+/-1.0 in the FFR-guided group (p=0.34). The number of stents used was 2.7+/-1.2 and 1.9+/-1.3, respectively (p<0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p=0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p=0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p=0.08). For lesions deferred on the basis of FFR>0.80, the rate of myocardial infarction was 0.2% and the rate of revascularization was 3.2 % after 2 years.
Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774).
IN the 19th century there were two major hypotheses to explain the pathogenesis of atherosclerosis: the "incrustation" hypothesis and the "lipid" hypothesis. The incrustation hypothesis of von Rokitansky,1 proposed in 1852 and modified by Duguid,2 suggested that intimal thickening resulted from fibrin deposition, with subsequent organization by fibroblasts and secondary lipid accumulation. The lipid hypothesis, proposed by Virchow3 in 1856, suggested that lipid in the arterial wall represented a transduction of blood lipid, which subsequently formed complexes with acid mucopolysaccharides; lipid accumulated in arterial walls because mechanisms of lipid deposition predominated over those of removal. The two hypotheses are now . . .
Atherosclerotic diseases and their thrombotic complications remain the leading causes of mortality and morbidity in Western society. In the United States, cardiovascular disease is responsible for one in every 2.4 (41.4%) deaths and is the leading single cause of mortality. Furthermore, the presence of atherosclerotic disease (defined as thickening of the arterial wall through the accumulation of lipids, macrophages, T-lymphocytes, smooth muscle cells, extracellular matrix, calcium and necrotic debris) is more prevalent, but by itself rarely fatal. The crucial, final common process for the conversion of a nonocclusive, often clinically silent atherosclerotic lesion to a potentially fatal condition is often plaque disruption. The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death. Substantial clinical, experimental and postmortem evidence demonstrates the central role that a superimposed acute thrombosis on a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes. Therefore, therapeutic approaches to date have focused on reducing such thrombotic complications of atherosclerotic plaques (i.e., antiplatelet, anticoagulant and thrombolytic therapies) to reduce the resulting morbidity and mortality. In this review, we will focus on the current theories of atherogenesis and how they impact on our understanding of acute coronary syndromes.
Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.6 This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.7 8
Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to the cytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than a dystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23 Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis.
### Mature Plaques: Atherosis and Sclerosis
As the name atherosclerosis implies, mature …
Little is known regarding intravascular ultrasound (IVUS) criteria to determine the functional severity of coronary stenosis. Recently, fractional flow reserve (FFR) has emerged as a lesion-specific index of the functional severity of a coronary stenosis that is independent of systemic hemodynamic variability. The present study was undertaken to determine the IVUS parameters for the physiological severity of coronary stenosis.
Fifty-one lesions in 42 patients were evaluated by means of quantitative coronary angiogram, IVUS, and intracoronary pressure measurements. The FFR was calculated as the ratio of the distal coronary pressure divided by the proximal coronary pressure under hyperemia. We considered a value of the FFR <0.75 as significant in determining inducible ischemia, according to the previous studies. The minimal luminal area (MLA) and the area stenosis were measured by IVUS. By regression analysis, the MLA showed a positive correlation with the FFR value (r(2)=0.62, P<0.0001). The area stenosis had a significant inverse correlation with the value of FFR (r(2)=0.60, P<0.0001). The IVUS thresholds that maximized the sensitivity and specificity were MLA <3.0 mm(2) (sensitivity, 83.0%; specificity, 92.3%) and area stenosis >0.6 (sensitivity, 92.0%; specificity, 88.5%). The combination of both criteria (MLA <3.0 mm(2) and area stenosis <0.6) without exception met a value of the FFR <0.75.
Anatomic parameters obtained by IVUS showed a significant correlation to the FFR values. The present study demonstrated that the combination of the MLA and area stenosis measured by IVUS can be an anatomic predictor for the physiological impact of coronary epicardial stenosis.
Atherosclerotic yellow plaques identified by coronary angioscopy are considered as vulnerable plaques. However, characteristics of yellow plaques are not well understood. Optical coherence tomography (OCT) provides accurate tissue characterization in vivo and has the capability to measure fibrous cap thickness covering a lipid plaque. Characteristics of yellow plaques identified by angioscopy were evaluated by OCT. We examined 205 plaques of 41 coronary arteries in 26 patients. In OCT analysis, plaques were classified as fibrous or lipid. Minimal lumen area of the plaque, arch of the lipid, and fibrous cap thickness on the lipid plaque were measured. Yellow grade of the plaque was defined as 0 (white), 1 (light yellow), 2 (medium yellow), or 3 (dark yellow) based on the angioscopy. A total of 149 plaques were diagnosed as lipid plaques. Neither the minimal lumen area nor the arch of the lipid was related to the yellow grade. There was an inverse relationship between color grade and the fibrous cap thickness (grade 0 [n = 45] 218 +/- 89 microm, grade 1 [n = 40] 101 +/- 8 microm, grade 2 [n = 46] 72 +/- 10 microm, and grade 3 [n = 18] 40 +/- 14 microm; p <0.05). Sensitivity and specificity of the angioscopy-identified yellow plaque for having a thin fibrous cap (thickness <or=110 microm) were 98% and 96%, respectively. In conclusion, angioscopy-identified yellow plaques frequently were lipid tissue with an overlying thin fibrous cap. Fibrous caps of the intense yellow plaques were very thin, and these plaques might be structurally vulnerable.
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part 1.
- Naghavi M.
- Libby P.
- Falk E.
- Casscells S.W.
- Litovsky S.
- Rumberger J.
- Badimon J.J.
- Stefanadis C.
- Moreno P.
- Pasterkamp G.
- Fayad Z.
- Stone P.H.
- Waxman S.
- Raggi P.
- Madjid M.
Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid
M. From vulnerable plaque to vulnerable patient: a call for new definitions and
risk assessment strategies: Part 1. Circulation 2003;108:1664–72.
From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part 1
- Naghavi