Pasterkamp G, Schoneveld AH, van der Wal AC, et al. Reference
J Am Coll Cardiol 1998; 32: 655-662 Abstract
OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS: Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohisto-logic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.
This study describes an association between outward "positive" remodelling and lesion characteristics associated with unstable clinical presentation. It suggests that outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques).
Citation Count 75
1. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000; 101: 598-603.
2. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000; 35: 106-111.
3. Kotani J, Mintz GS, Castagna MT, et al. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction. Circulation 2003; 107: 2889-2893.
Both plaque and vessel area were geometrical determinants of the presence of markers related to plaque vulnerability. The type of arterial remodelling may have a dual impact on luminal narrowing. Compensatory enlargement will retard chronic luminal narrowing, but it might enhance the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Conversely, paradoxical shrinkage will accelerate chronic luminal narrowing, but it might reduce the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Future studies using intra-vascular ultrasound (IVUS) are needed to verify the inferred predictive value for unstable angina and acute myocardial infarction or compensatory enlarged lesions.
Why it's important
Glagov's observations demonstrate that plaque progression is initially accommodated by an expansion of vessel diameter rather than luminal stenosis (arterial remodelling). Based on the studies correlating remodelling with clinical presentation, it has become obvious that these outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques). It is an attractive hypothesis that changes of regression are also reflected in plaque size rather than luminal dimension.
The careful comparison of lesion geometry with histological lesion characteristics allowed hypothesis about potential interactions between remodelling and plaque vulnerability/stability, which were later confirmed in clinical imaging studies.
These results from femoral vessels may not apply to coronary vessels in particular in the setting of acute coronary syndromes. Therefore clinical confirmation was needed.
This paper and subsequent post-mortem and IVUS studies of coronary arteries have modified the prevailing paradigm about high-risk lesions and focused attention to mildly stenotic but vulnerable plaques and overall plaque burden.
Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized placebo controlled pilot study
Nissen SE, Tsunoda T, Tuzcu EM, et al. Reference
JAMA 2003; 290: 2292-2300 Abstract
CONTEXT: Although low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano/phospholipid complexes produces rapid regression of atherosclerosis in animal models. OBJECTIVE: We assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS). DESIGN: The study was a double blind, randomized, placebo-controlled multicenter pilot study comparing the effects of ETC-216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS). SETTING: Ten community and tertiary care hospitals in the United States. PATIENTS: Between November 2001 and March 2003, 123 patients consented, 57 were randomly assigned, and 47 completed the protocol. INTERVENTIONS: In a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments. MAIN OUTCOME MEASURE: The primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness. RESULTS: The mean (SD) percent atheroma volume decreased by -1.06% (3.17%) in the combined ETC-216 group (median, -0.81%; 95% confidence interval [CI], -0.34% to -1.53%; p = 0.02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%) (median, 0.03%; p = 0.97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was -14.1 mm3 or a 4.2% decrease from baseline (p < 0.001). CONCLUSION: A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.
This study describes the rapid regression of atherosclerotic plaque burden during treatment with an high-density lipoprotein (HDL) mimetic in patients with acute coronary syndromes.
Citation Count 119
1. Takagi T, Yoshida K, Akasaka T, Hozumi T, Morioka S, Yoshikawa J. Intravascular ultrasound analysis of reduction in progression of coronary narrowing by treatment with pravastatin. Am J Cardiol 1997; 79: 1673-1676.
2. Matsuzaki M, Hiramori K, Imaizumi T, et al. Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol 2002; 40: 220-227.
3. Schartle M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001; 104: 387-392.
4. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002; 287: 3215-3222.
5. Schoenhagen P Tuzcu EM, Stillman AE, et al. Non-invasive assessment of plaque morphology and remodeling in mildly stenotic coronary segments: comparison of 16-slice computed tomography and intravascular ultrasound. Coron Artery Dis 2003; 14: 459-462.
This initial trial of an exogenously produced HDL mimetic demonstrated significant evidence of rapid regression of atherosclerosis. The potential utility of the new approach must be fully explored in a larger patient population with longer follow-up, assessing a variety of clinical end points, including morbidity and mortality.
Why it's important
These results demonstrate for the first time that disease regression in patients presenting with acute coronary syndromes can be induced by aggressive modification of HDL levels.
First study showing regression of plaque burden after pharmacological treatment in acute coronary syndromes. The significant change in only 5 weeks is evidence of the highly dynamic nature of coronary artery disease (CAD).
Eventually, these new imaging endpoints will need to the compared to clinical endpoints of morbidity and mortality.
Serial imaging studies will eventually allow to compare plaque burden, plaque characteristics, systemic markers of inflammation, and clinical outcome. These results will be important for disease prevention in primary setting but also for secondary prevention following the interventional treatment of symptomatic patients.
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