Thin Cap Atheroma Research Articles

Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

The endoplasmic reticulum (ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells and macrophages in the fibrous caps of thin-cap atheroma and ruptured plaques, but not in the fibrous caps of thick-cap atheroma and fibrous plaques, showed a marked increase of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP (a transcription factor induced by ER stress)-dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells. Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.

A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps.

In this article, we advance a hypothesis for the rupture of thin fibrous cap atheroma, namely that minute (10-mum-diameter) cellular-level microcalcifications in the cap, which heretofore have gone undetected because they lie below the visibility of current in vivo imaging techniques, cause local stress concentrations that lead to interfacial debonding. New theoretical solutions are presented for the local stress concentration around these minute spherical inclusions that predict a nearly 2-fold increase in interfacial stress that is relatively insensitive to the location of the hypothesized microinclusions in the cap. To experimentally confirm the existence of the hypothesized cellular-level microcalcifications, we examined autopsy specimens of coronary atheromatous lesions using in vitro imaging techniques whose resolution far exceeds conventional magnetic resonance imaging, intravascular ultrasound, and optical coherence tomography approaches. These high-resolution imaging modalities, which include confocal microscopy with calcium-specific staining and micro-computed tomography imaging, provide images of cellular-level calcifications within the cap proper. As anticipated, the minute inclusions in the cap are very rare compared with the numerous calcified macrophages observed in the necrotic core. Our mathematical model predicts that inclusions located in an area of high circumferential stress (>300 kPa) in the cap can intensify this stress to nearly 600 kPa when the cap thickness is <65 microm. The most likely candidates for the inclusions are either calcified macrophages or smooth muscle cells that have undergone apoptosis.

IVUS-VH: a predictor of plaque morphology?The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Imaging modalities that identify plaques vulnerable to rupture offer the possibility of preventing the most common substrate of coronary thrombosis. The incidence of progression of thin-cap atheroma, as identified at PCI, is largely unknown. Glaser et al .1 have demonstrated that at 1-year follow-up of a cohort of patients undergoing PCI, at least 6% develop progression of disease requiring additional PCI for another target lesion. The major predictors of plaque progression were multivessel disease, prior PCI, and age less than 65 years. Goldstein et al .2 demonstrated that 17% of acute MI patients with multiple complex angiographic lesions undergo PCI of non-culprit lesions within 1 year. These data underscore the need for identifying those plaques in high-risk patients who will benefit from prophylactic intervention. The hope is that newer imaging modalities, such as IVUS-virtual histology (VH) will precisely identify those lesions. Rodriguez-Granillo et al .3 describe IVUS-VH in a prospective study of 40 patients referred for cardiac catheterization: there were 13 with stable angina, 12 with unstable angina, and 15 with acute myocardial infarction. The risk factor profiles were fairly typical of patients with coronary artery disease (CAD): 10% of patients had diabetes, 73% were male, 38% were smokers, and 50% had elevated cholesterol. Although three-vessel IVUS was the goal in all patients, only two-vessel characterization was possible in nine of the 40 patients. PR was identified in 26 patients and, as expected, was more frequent in patients with acute myocardial infarction and unstable angina. They concluded that patients with plaque ruptures have larger body mass index (BMI) when compared with those without plaque rupture and were more likely smokers and that patients with ruptures had more diffuse calcification and necrotic core area. VH refers to spectral analysis of ultrasound backscatter radiofrequency signals.4 Refinements of IVUS to improve spatial … *Corresponding author. Tel: +1 301 208 2490; fax: +1 301 208 3745. E-mail address : rvirmani{at}cvpath.org

Pathology of the thin-cap fibroatheroma: a type of vulnerable plaque.

Thin cap atheroma is the precursor of plaque rupture, which accounts for a majority of coronary thrombi. The morphologic features of thin cap atheromas that predict rupture are unknown, but we know from studies of ruptured plaques that large necrotic cores, fibrous cap < 65 microns and numerous macrophages within the cap likely indicate instability. There is some evidence that a speckled pattern of calcification is associated with vulnerability to rupture. There are usually multiple thin cap atheroma in the hearts of patients dying with acute plaque rupture, as well as multiple fibroatheromas with intraplaque hemorrhage. Targeted therapy for the purpose of stabilizing coronary lesions that are prone to rupture is a major future goal of the interventionist.

Increased serum homocysteine and sudden death resulting from coronary atherosclerosis with fibrous plaques.

Modest elevations of total homocysteine have been associated with increased risk for coronary atherosclerosis but correlation between elevated homocysteine and plaque morphology has not been described in humans. We determined serum homocysteine at postmortem from 87 men with coronary thrombus (62 of whom were diagnosed as acute), from 35 men with severe coronary disease without thrombus, and from 46 controls. In coronary deaths, atherosclerotic plaques at the sites of maximal luminal narrowing of the four epicardial coronary arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap atheromas, and healed ruptures, and macrophage infiltration was assessed semiquantitatively. Median serum homocysteine postmortem as a result of acute thrombus was 10.4 micro mol/L (P=0.4 versus controls), 12.1 micro mol/L in men with organized thrombi (P=0.1 versus controls), 15.6 micro mol/L in men without thrombus (P=0.007 versus controls), and 9.8 micro mol/L in controls. The median homocysteine was 12.1 micro mol/L in 65 men with healed infarcts (P=0.03 versus controls). The number of fibrous plaques was associated with log-normalized homocysteine (P=0.004), independent of age, albumin, smoking, hypertension, and serum cholesterol. Homocysteine levels in the upper tertile (>15 micromol/L) were associated with sudden death without acute or organized thrombus (odds ratio 3.8, P=0.03) independent of age and other risk factors; the coexistence of diabetes increased the association (odds ratio 25.1, P=0.009, versus lowest tertile < or =8.5 micromol/L). Increased serum homocysteine is associated with sudden death in the absence of acute coronary thrombosis, especially with concomitant diabetes, and with the presence of lipid-poor, fibrous plaques.