Healed Plaque Rupture Research Articles

How does atherosclerotic plaque become calcified, and why?

<p>Vascular calcification involves the crystallization of calcium/phosphate in the form of hydroxyapatoite in the extracellular matrix of the arterial wall. Vascular calcification is categorized into 3 main etiologies: (1) inflammatory/atherosclerotic (mostly intimal), (2) metabolic (mostly medial), and (3) genetic background (mostly medial). Several overlapping mechanisms trigger all three types of calcifications. Intimal coronary artery calcification simultaneously develops with the progression of atherosclerosis and has been recognized as a surrogate marker of atherosclerotic inflammatory vascular disease. Pathologically, atherosclerotic calcification initially occurs as microcalcifications (0.5 to 15 µm) and results in larger dense calcification, eventually forming sheet calcifications (>3 mm). Among the plaque types, the degree of calcification is the highest in fibrocalcific plaques, followed by healed plaque ruptures, and is the lowest in pathologic intimal thickening. Recent pathologic and imaging-based studies suggest that massive dense calcifications are usually associated with stable plaques, whereas microcalcifications are indicative of vulnerable plaques which may cause acute thrombotic events. Although the mechanisms of calcification are not fully elucidated, apoptotic inflammatory cells and smooth muscle cells, along with the induction of bone formation, play crucial roles in its initiation and progression. A deeper understanding of vascular calcification will improve the risk stratification and patient outcomes through the development of new therapies.</p>

Subclinical Atherosclerosis: Part 1: What Is it? Can it Be Defined at the Histological Level?

While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location.

P6413Aging increases the plaque vulnerability in non-ischemic non-culprit lesions of diabetic patients, data from COMBINE OCT-FFR study

Abstract Background Little is known about age-related differences in baseline atherosclerotic plaque morphology and composition in patients with diabetes mellites (DM). Purpose For this purpose, we studied DM patients from the Combine trial. Methods COMBINE (OCT-FFR, NCT02989740) is a multi-center, prospective study focusing on the natural history of non-ischemic, non-culprit coronary lesions and evaluate whether certain OCT-assessed variables could predict future adverse events originating from these lesions in a DM population. OCT analysis identifies plaque composition, estimates calcium arc (o), lipid arc (o), and measures thickness of the fibrous cap covering the lipid core. Moreover, OCT records the presence of typical plaque vulnerability traits like thin fibrous cap atheroma (TCFA), plaque erosion (PE), plaque rupture (PR), calcification nodule (CN), heterogeneous tissues (a probably healed plaque rupture), and macrophages accumulation (bright spots). A dedicated software estimated the interpolated percentage area stenosis (AS, %) measuring the minimal lumen area (MLA) and reference vessel area. The present analysis reports the baseline morphology of these lesions respectively in young (<70 years) vs. old (≥70 years) DM patients. Results OCT imaging was performed in 300 patients (361 lesions) from the COMBINE study, of which 203 lesions assessed in young and 158 lesions in old DM patients. There were no significant differences in MLA (mm2) 2.40 (1.85–315 vs. 2.30 (1.80–3.00), p=0.92), lesions length (mm 24.11 (15.10–33.10) vs. 24.20 (15.10–35.10), p=0.78), AS% (%) 63 (1.85–3.15) vs. 64 (56–73), p=0.41; lipid arc (o), 182 (140–250) vs. 175 (128–240), p=0.35), fibrous cap thickness covering the lipid arc (μm), 117 (65–193) vs. 110 (64–168), p=0.45, in the prevalence of TCFA 37 (18%) vs. 33 (21%), p=0.53, PR 17 (18%) vs. 15 (10%), p=0.71, heterogenous tissue 39 (19%) vs. 31 (20%), p=0.92, and bright spots 98 (48%) vs. 69 (44%), p=0.38. The patients ≥70 years had a higher prevalence of calcified plaques 171 (84%) vs. 143 (90%), p=0.08 and wider calcium arc. These lesions included more PE 7 (3%) vs. 13 (8%), p=0.05, CN 73 (36%) vs. 75 (47%), p=0.03, and CN associated with overlying thrombus 11 (5%) vs. 20 (13%), p=0.02. Conclusion Non-ischemic, non-culprit lesions in elderly DM patients present the same prevalence of soft, vulnerable plaques as it is a younger cohort, however, they have a higher prevalence of calcified plaque including complex calcified plaques as eroded plaques and calcification nodules with overlying thrombus. Whether these complex calcified plaques are associated with a higher risk of adverse events remains questionable and could be further elucidated from longer follow-up data of the COMBINE trial.

Optical coherence tomography-verified morphological correlates of high-intensity coronary plaques on non-contrast T1-weighted magnetic resonance imaging in patients with stable coronary artery disease.

AimsCoronary high-intensity plaques (HIPs) with a high plaque-to-myocardial signal intensity ratio (PMR) on non-contrast T1-weighted imaging in patients with stable coronary artery disease (CAD) are associated with future coronary events. To characterize the morphological substrate of HIP, we performed a correlative optical coherence tomography (OCT) study.Methods and resultsWe examined 137 lesions in 105 patients with stable angina pectoris or silent myocardial ischaemia scheduled for percutaneous coronary intervention (PCI) using a 3 T magnetic resonance scanner. Pre-interventional OCT was performed for PCI target lesions. HIP was defined as PMR ≥ 1.4. Of the 137 lesions, 34% were HIP and 66% were non-HIP. The prevalence of lipid-rich plaque (96% vs. 70%, P < 0.001), macrophage accumulation (65% vs. 46%, P = 0.046), cholesterol crystals (46% vs. 22%, P = 0.006), and healed plaque rupture (multiple layers of different optical densities overlaying a large lipid accumulation, 72% vs. 18%, P < 0.001) was significantly higher in the HIP group than the non-HIP group; no significant differences were observed for the presence of thin cap fibroatheroma, intracoronary thrombus, and plaque rupture between the two groups. Multivariable stepwise logistic regression analysis showed that HIP was significantly associated with the presence of healed plaque rupture [odds ratio (OR) 9.32; 95% confidence interval (95% CI) 4.05–22.71; P < 0.001] and lipid-rich plaque (OR 4.38; 95% CI 1.08–29.77; P = 0.038).ConclusionsThe significant association between HIP- and OCT-derived healed plaque rupture and large lipid core provides new insights into the characteristics of high-risk plaques, even in clinically stable CAD.

Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus.

The continuing increase in the prevalence of diabetes mellitus in the general population is predicted to result in a higher incidence of cardiovascular disease. Although the mechanisms of diabetes mellitus-associated progression of atherosclerosis are not fully understood, at clinical and pathological levels, there is an appreciation of increased disease burden and higher levels of arterial calcification in these subjects. Plaques within the coronary arteries of patients with diabetes mellitus generally exhibit larger necrotic cores and significantly greater inflammation consisting mainly of macrophages and T lymphocytes relative to patients without diabetes mellitus. Moreover, there is a higher incidence of healed plaque ruptures and positive remodeling in hearts from subjects with type 1 diabetes mellitus and type 2 diabetes mellitus, suggesting a more active atherogenic process. Lesion calcification in the coronary, carotid, and other arterial beds is also more extensive. Although the role of coronary artery calcification in identifying cardiovascular disease and predicting its outcome is undeniable, our understanding of how key hormonal and physiological alterations associated with diabetes mellitus such as insulin resistance and hyperglycemia influence the process of vascular calcification continues to grow. Important drivers of atherosclerotic calcification in diabetes mellitus include oxidative stress, endothelial dysfunction, alterations in mineral metabolism, increased inflammatory cytokine production, and release of osteoprogenitor cells from the marrow into the circulation. Our review will focus on the pathophysiology of type 1 diabetes mellitus- and type 2 diabetes mellitus-associated vascular disease with particular focus on coronary and carotid atherosclerotic calcification.

TCT-587 Can OCT-Detected Healed Plaque Rupture or Erosion Predict Side Branch Occlusion?

Healed asymptomatic plaque rupture/erosion can be detected by optical coherence tomography (OCT). We hypothesized that healed plaque (HP) is relatively soft and easily shifts into a side branch (SB) during bifurcation stenting. We studied 195 pts with 207 bifurcation lesions (SB diameter >1.5 mm)

Additive Value of Integrated Backscatter IVUS for Detection of Vulnerable Plaque by Optical Frequency Domain Imaging: An Ex Vivo Autopsy Study of Human Coronary Arteries

ObjectivesThis study sought to evaluate the diagnostic performance of optical frequency domain imaging (OFDI) for recognition of coronary plaque morphologies and to assess additive values of integrated backscatter intravascular ultrasound (IB-IVUS) in detection of vulnerable plaque. BackgroundPrecise diagnosis of coronary lesions susceptible to plaque rupture and thrombosis may serve to stratify the risk of future coronary events and to make decisions for appropriate treatment of choice. MethodsTwenty-seven coronary arteries from 14 human autopsy hearts were interrogated ex vivo by OFDI and IB-IVUS. Imaged segments were sectioned at 3 mm intervals where a total of 360 pairs of cross-sectional images coregistered to histology were investigated. ResultsOverall, OFDI could depict various plaque components and structures such as fibrous tissue, sheet and nodular calcification, lipid, cholesterol crystals, and healed plaque rupture. OFDI could detect 14 of 18 thin-cap fibroatheroma (TCFA), however, the diagnostic accuracy was not high (positive predictive value [PPV] = 60.9%, κ = 0.664; area under the curve [AUC]: 0.88) mainly because of signal interference from macrophages. Further, we defined IB-IVUS–derived TCFA by recursive partitioning analysis as: 1) cross-sectional % lipid area >65.1%; 2) % lipid area >32.3 but <65.1% with plaque area >10.5 mm2, where TCFA detection by IB-IVUS alone was marginal (PPV = 50.0%, κ = 0.545; AUC: 0.82). However, when IB-IVUS was combined with OFDI, all pseudo OFDI-derived TCFA (non-TCFA on histology) were excluded. Accordingly, PPV of TCFAs diagnosed by both OFDI and IB-IVUS was improved to 100.0% (κ = 0.704; AUC: 0.93). ConclusionsOFDI could recognize detailed morphologies of human coronary plaque. However, diagnostic accuracy of both OFDI alone and IB-IVUS alone to identify TCFA is limited. Combination of IB-IVUS with OFDI improved the accuracy for TCFA detection, suggesting hybrid imaging or further development of novel devices will be required to identify coronary lesions responsible for future events.

Has Our Understanding of Calcification in Human Coronary Atherosclerosis Progressed?

Coronary artery calcification is a well-established predictor of future cardiac events; however, it is not a predictor of unstable plaque. The intimal calcification of the atherosclerotic plaques may begin with smooth muscle cell apoptosis and release of matrix vesicles and is almost always seen microscopically in pathological intimal thickening, which appears as microcalcification (≥0.5 μm, typically <15 μm in diameter). Calcification increases with macrophage infiltration into the lipid pool in early fibroatheroma where they undergo apoptosis and release matrix vesicles. The confluence of calcified areas involves extracellular matrix and the necrotic core, which can be identified by radiography as speckled (≤2 mm) or fragmented (>2, <5 mm) calcification. The calcification in thin-cap fibroatheromas and plaque rupture is generally less than what is observed in stable plaques and is usually speckled or fragmented. Fragmented calcification spreads into the surrounding collagen-rich matrix forming calcified sheets, the hallmarks of fibrocalcific plaques. The calcified sheets may break into nodules with fibrin deposition, and when accompanied by luminal protrusion, it is associated with thrombosis. Calcification is highest in fibrocalcific plaques followed by healed plaque rupture and is the least in erosion and pathological intimal thickening. The extent of calcification is greater in men than in women especially in the premenopausal period and is also greater in whites compared with blacks. The mechanisms of intimal calcification remain poorly understood in humans. Calcification often occurs in the presence of apoptosis of smooth muscle cells and macrophages with matrix vesicles accompanied by expression of osteogenic markers within the vessel wall.

053 LONGTERM NATURAL HISTORY OF RADIOFREQUENCY INTRAVASCULAR ULTRASOUND IDENTIFIED CORONARY PLAQUES

IntroductionPrior studies have shown that virtual-histology intravascular ultrasound (VH-IVUS) identified thin-capped fibroatheroma (VHTCFA) (figure 1) and plaque burden (PB) >70% are associated with major adverse cardiovascular events (MACE). This study...

Microvascular Obstruction Is Caused by Atherothrombosis in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

The diagnosis of acute coronary syndrome (ACS) is primarily based on the mode of clinical presentation and is a term used for any conditions suggesting the acute induction of myocardial ischemia. The precise molecular and cellular triggers that lead to ACS remain poorly understood; however, histopathologic studies have illustrated several mechanisms that may explain the sudden onset of symptoms in ACS patients. The most common substrate underlying ACS is thought to be rupture of a vulnerable plaque that contains a necrotic core covered by a fibrous cap. The term, thin-cap fibroatheroma (TCFA) is used to describe vulnerable plaque because histomorphometric analysis of ruptured plaques revealed fibrous cap thickness to be 120 degree of circumferential arc; whereas thick cap fibroatheromas have the smallest necrotic core (1.2±2.2 mm2).2,3 The highest positive remodeling index is seen in plaque ruptures, followed by plaque hemorrhage, TCFA, healed plaque rupture, and fibroatheroma.4 Also, plaque rupture and TCFA are located predominantly in the proximal portions of the coronary tree.5 Following the rupture of plaque, the exposure of necrotic core material to blood flow leads to thrombotic luminal obstruction with or without distal embolization of platelet-rich thrombus, or less commonly, atherosclerotic debris. Article see p 620 The main causes of coronary thrombosis include plaque erosion as well as rupture, with erosion accounting for 25% to 35%, and rupture …

054 Plaque vulnerability is an important feature of chronic stable coronary disease: a comparison of lesion characteristics in stable angina and acute coronary syndrome patients using virtual histology

Introduction Rupture of a vulnerable plaque is the most important mechanism leading to acute coronary syndromes (ACS). Studies have shown that the most common feature of these plaques is the presence of a thin-cap fibroatheroma (TCFA). Previous studies have also shown the presence of TCFA and healed plaque rupture in some stable lesions. We sought to compare directly the frequency of TCFA and volume of necrotic core present in stable angina (SA) patients, referred for PCI, to those from patients presenting with high-risk ACS. Intravascular Ultrasound (IVUS) derived Virtual Histology (VH) was used to determine plaque morphology as it is validated against post-mortem histological findings. Methods This single centre, prospective, observational study received ethical approval locally. 15 SA and 45 ACS patients (CD=30; NCD=15) were recruited. IVUS-VH imaging was undertaken using a phased array catheter (EagleEye catheter, 2.9 F/20 MHz; Volcano Corp) with a continuous motorised pullback of 0.5 mm/s. Plaque composition and analysis was determined by off-line analysis (PC VIAS 3.0.394 software; Volcano Corporation) From post-mortem correlation data, the highest risk VH-Thin Cap Fibroatheroma (TCFA) consists of three or more IVUS-VH frames with a confluent necrotic core greater than 20% and no evidence of a fibrous cap. Each lesion pullback was examined frame by frame for VH-TCFA and the overall mean percentage of necrotic core present in each lesion type was calculated. An unpaired t-test was used to compare normally distributed data. Results Sixty lesions and 3543 IVUS-VH frames were analysed in total (15 SA/30 CD/15 NCD) We found no statistical differences between SA and NCD plaque volume constituents (mm 3 ): Fibrous=51.4±33.6 vs 66.7±48.7 p=0.32; Fibrofatty=8.7±6.3 vs 12.5±11.9 p=0.3; Necrotic Core=22.5±15.8 vs 29.3±40.1 p=0.5 and Dense Calcium=13.8±11.8 vs 11.2±14.4 p=0.6) SA lesions had on average 1.86 TCFA per lesion which was very similar to 1.88 TCFA per lesion in unstable CD (p=ns). NCD had a trend towards more TCFA per patient (2.33 vs 1.86, p=0.2). SA lesions typically had a reduced mean total plaque volume (mm 3 ) compared to ACS culprit lesions (SA=162±93 3 ) of all plaque constituents except dense calcium. However, the mean percentage of unstable necrotic core, per lesion type, was not different: SA 22.7% vs CD 21.9% vs NCD 21.3% p=0.75. Conclusions Stable coronary artery lesions differ from culprit ACS lesions in terms of the quantity of plaque present. However, they do not differ from culprit or non-culprit lesions in the percentage contribution of unstable plaque. Importantly, high risk VH-TCFA appears to occur with similar prevalence across the groups. There are structural similarities between SA and NCD lesions suggesting that some SA lesions that contain increased numbers of TCFA are not benign.

Defining and Defending Murine Models of Plaque Rupture

There is general agreement that atherosclerotic plaque rupture is a major clinical problem and that finding ways to prevent it would be greatly facilitated by an animal model of plaque rupture. The article by Schwartz et al1 seeks to clarify and define the terms used in descriptions of disrupted atherosclerotic plaques, and then to apply these to murine models in order to assess their similarities to and differences from human ruptured lesions. On the face of it this seems a reasonable thing to do, but it has some serious conceptual problems. The first is the issue of whether it is useful at all to provide definitions of disrupted plaques, especially when these are based on histopathology. The second concerns the transferability of such definitions from human to mouse. I would like also to deal with issues relating to reevaluation of existing mouse models of plaque rupture. What do we gain from framing scientific definitions of real-world phenomena? In the context of the ruptured plaque, Schwartz et al1 argue that this would provide an agreed upon and consistent framework that would make it easier for different labs to compare and contrast their data. There is obviously virtue in this as a general principle in science, but we have to consider the possibility that in the developing field of plaque rupture it may be premature. We do not know why plaques rupture, we do not know whether “plaque erosions” are simply the adjacent manifestations of ruptures that are out of the plane of the section, and we do not know whether “plaque fissures” arise through a different set of processes to plaque ruptures. In other words, this means that we do not know whether ruptures, erosions and fissures are ontogenically similar or different. We are therefore moving beyond the boundaries …

Morphological characteristics of coronary atherosclerosis in diabetes mellitus

The incidence of diabetes is increasing in the general population because of increasing obesity, and is likely to result in a higher incidence of coronary artery disease. It was recently reported that diabetics (types I and II) dying suddenly from coronary artery disease have greater macrophage and T lymphocyte infiltration in atherosclerotic plaques, as well as larger necrotic cores compared with nondiabetics. The inflammatory cell infiltrates showed human leukocyte antigen-DR expression, which was greater in diabetics. The receptors for advanced glycosylation end-products expression, demonstrated by immunohistochemistry, was greater in diabetics than in nondiabetics in macrophages, smooth muscle cells and endothelial cells, and was associated with apoptosis of macrophages and smooth muscle cells, but not of endothelial cells. There is also a higher incidence of healed plaque ruptures and healed myocardial infarct in type II diabetics. Plaque burden is higher in diabetics than in nondiabetics; however, distal plaque burden was only significantly different in type II diabetics compared with nondiabetics. There was greater positive remodelling in diabetic coronary arteries than in nondiabetic ones, which correlated with the per cent necrotic core. Further studies are needed to better understand the mechanisms that govern greater inflammation and plaque burden in diabetics.

Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression.

Subclinical episodes of plaque disruption followed by healing are considered a mechanism of increased plaque burden. Detailed pathological studies of healed ruptures, however, are lacking. We identified acute and healed ruptures from 142 men who died of sudden coronary death and performed morphometric measurements of plaque burden, luminal stenosis, and smooth muscle cell phenotype. Healed ruptures were found in 61% of hearts and were associated with healed myocardial infarction, increased heart weight, dyslipidemia, and diabetes. Multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture; the percent area luminal narrowing increased with increased numbers of healed sites of previous rupture. The underlying percent luminal narrowing for acute ruptures (mean 79+/-15%) exceeded that for healed ruptures (mean 66+/-14%, P:=0.0001), and the area within the internal elastic lamina was significantly less in healed ruptures than in acute ruptures, when segments were grouped by distance from the ostium. Healed ruptures favored the accumulation of immature smooth muscle cells at repair sites, with a cellular proliferation index of 0.40+/-0.09%, significantly higher than the index at the sites of rupture (P:=0.008). These data provide evidence that silent plaque rupture is a form of wound healing that results in increased percent stenosis. Healed ruptures occur in arteries with less cross-sectional area luminal narrowing than acute ruptures and are a frequent finding in men who die suddenly with severe coronary atherosclerosis.

Effect of menopause on plaque morphologic characteristics in coronary atherosclerosis

Background Coronary artery disease in women appears 10 to 15 years later than in men. To test the hypothesis that the effects of estrogen may manifest themselves as histologic differences in coronary plaques, we examined the hearts of premenopausal and postmenopausal women who died suddenly from coronary artery disease. Methods We studied 51 cases of sudden coronary death and 47 deaths in women who died from noncoronary causes. Coronary deaths were classified on the basis of histologic features. The number of acute plaque ruptures, healed plaque ruptures, vulnerable plaques, and acute plaque erosions were compared between groups. Postmortem values of serum total cholesterol, HDL cholesterol, and thiocyanate were measured, and menopausal status was confirmed by calculating body mass index. Results Women older than 50 years of age were much more likely to have a ruptured plaque than were younger, premenopausal women. Plaque rupture was significantly associated with elevated total cholesterol level. In the 51 women who died of coronary disease, the mean number of vulnerable plaques increased significantly as women advanced into the postmenopausal years. Conclusions Our data suggest that estrogen has an anti-inflammatory effect on atherosclerotic plaques, resulting in plaque stabilization. Plaque erosion, the major substrate for thrombosis in premenopausal women, does not appear to be inhibited by estrogen. Because plaque progression may result both from repeated rupture and repeated erosion, a better understanding of the effect of estrogen on atherosclerosis may yield insights into the nature of coronary artery disease. (Am Heart J 2001;141:S58-62.)

Coronary calcification: insights from sudden coronary death victims.

We studied 108 cases of sudden coronary death at autopsy. Any calcification was present in 55% of men and women under 40 years; all hearts showed some calcification by age 50 in men, and by age 60 in women. The only risk factor independently associated with increased calcification was diabetes mellitus, in women only. The degree of calcification was greatest for acute and healed plaque ruptures, and the least for plaque erosion. Calcification in coronary atherosclerosis appears to be delayed in women, is greatest in women diabetics, and is associated with one type of plaque instability, namely plaque rupture.