Kojiro Awano

Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome.

OBJECTIVES To determine the morphologic features of coronary plaques associated with acute coronary syndrome, we prospectively followed patients with atherosclerotic disease identified by intravascular ultrasound (IVUS). BACKGROUND Although clinical evaluation of the vulnerable atherosclerotic plaque is important, few data exist regarding the morphology of the vulnerable plaque in clinical settings. METHODS We examined 114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patients. All the sites exhibited atherosclerotic lesions by IVUS. These lesions consisted of 22 concentric and 92 eccentric plaques with a percent plaque area averaging 59 +/- 12%. RESULTS During the follow-up period of 21.8 +/- 6.4 months (range 1 to 24), 12 patients had an acute coronary event at a previously examined coronary site at an average of 4.0 +/- 3.4 months after the initial IVUS study. All the preexisting plaques related to the acute events exhibited an eccentric pattern and the mean percent plaque area was 67 +/- 9%, which was greater than plaque area in the other 90 patients without acute events (57 +/- 12%, p < 0.05). There was no statistically significant difference in lumen area between two patient groups (6.7 +/- 3.0 vs. 7.5 +/- 3.7 mm2). Among 12 coronary sites with an acute occlusion, 10 sites contained the echolucent zones, eight of these shallow and two deep, likely representing a lipid-rich core. In 90 sites without acute events, an echolucent zone in the shallow portion was seen at only four sites (p < 0.05). CONCLUSIONS Large eccentric plaque containing an echolucent zone by IVUS can be at increased risk for instability even though the lumen area is preserved at the time of initial study. Compensatory enlargement of vessel wall due to remodeling may contribute to the relatively small degree of stenosis by angiography.

Interaction of Oxidative Stress and Inflammatory Response in Coronary Plaque Instability: Important Role of C-Reactive Protein

Objective—C-reactive protein (CRP), a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells. Reactive oxygen species (ROS) have been implicated in atherogenesis and plaque instability. Methods and Results—Expressional pattern of CRP in directional coronary atherectomy specimens from 39 patients was examined. Characteristics of histological plaque instability and higher levels of serum CRP and fibrinogen were associated with the CRP immunoreactivity. In situ hybridization revealed the presence of CRP mRNA in coronary vasculature. Furthermore, the expression of CRP mRNA and protein was detected in cultured human coronary artery smooth muscle cells (CASMCs) by reverse transcriptase–polymerase chain reaction and Western blotting. In addition, CRP was frequently colocalized with p22phox, an essential component of NADH/NADPH oxidase, which is an important source of ROS in vasculature. Moreover, the incubation of cultured CASMCs with CRP resulted in the enhanced p22phox protein expression and in the generation of intracellular ROS. Conclusions—The expression of CRP in coronary arteries was associated with histological and clinical features of vulnerable plaque, and it had a prooxidative effect on cultured CASMCs, suggesting that it might play a crucial role in plaque instability and in the pathogenesis of acute coronary syndrome via its prooxidative effect.

Superoxide Generation in Directional Coronary Atherectomy Specimens of Patients With Angina Pectoris: Important Role of NAD(P)H Oxidase

Objective—NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22phox, an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22phox, the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. Methods and Results—DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22phox and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22phox and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22phox or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. Conclusions—ROS generated by p22phox-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.

Possible Role of Brain-Derived Neurotrophic Factor in the Pathogenesis of Coronary Artery Disease

Background— The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear. Methods and Results— To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non–coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non–coronary artery disease groups. Immunohistochemical investigations demonstrated BDNF expression in the atheromatous intima and adventitia in atherosclerotic coronary arteries. BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries. Stimulation with recombinant BDNF significantly enhanced NAD(P)H oxidase activity and the generation of reactive oxygen species in cultured human coronary artery smooth muscle cells. Conclusions— BDNF has an important role in atherogenesis and plaque instability via the activation of NAD(P)H oxidase.

“Arteries Within the Artery” After Kawasaki Disease A Lotus Root Appearance by Intravascular Ultrasound

A 26-year-old man underwent cardiac catheterization because of abnormal electrocardiography (QS in leads V1 to V3) and thallium stress scintigraphy (a fixed defect in the anteroseptal wall). The patient had a history of suspected Kawasaki disease with sudden cardiac arrest at the age of 1 year. Coronary angiography showed no significant …

Effect of Culprit-Lesion Remodeling Versus Plaque Rupture on Three-Year Outcome in Patients With Acute Coronary Syndrome

To investigate intravascular ultrasound predictors of long-term clinical outcome in patients with acute coronary syndrome, 94 patients with a first acute coronary syndrome with both preintervention intravascular ultrasound imaging and long-term follow-up were enrolled in this study. Remodeling index was defined as external elastic membrane cross-sectional area at the target lesion divided by that at the proximal reference. Arterial remodeling was defined as either positive (PR: remodeling index >1.05) or intermediate/negative remodeling (remodeling index < or =1.05). Clinical events were death, myocardial infarction, and target-lesion revascularization. Patients were followed up for a mean of 3 years. PR was observed in 50 (53%), and intermediate/negative remodeling, in 44 (47%). During the 3-year follow-up, there were 20 target-lesion revascularization events and 5 deaths (2 cardiac and 3 noncardiac), but no myocardial infarctions. Patients with PR showed significantly lower major adverse cardiac event (MACE; death, myocardial infarction, and target-lesion revascularization)-free survival (log-rank p = 0.03). However, patients with plaque rupture showed a nonsignificant trend toward lower MACE-free survival (p = 0.13), but there were no significant differences in MACE-free survival between those with single versus multiple plaque ruptures. Using multivariate logistic regression analysis, only culprit lesion PR was an independent predictor of MACEs (p = 0.04). In conclusion, culprit-lesion remodeling rather than the presence or absence of culprit-lesion plaque rupture was a strong predictor of long-term (3-year) clinical outcome in patients with acute coronary syndrome.

Role of Serotonin, Histamine, and Thromboxane A2 in Platelet-Induced Contractions of Coronary Arteries and Aortae from Rabbits

The present study was undertaken to clarify the underlying mechanisms responsible for contractions of isolated coronary arteries and aortae from rabbits in response to thrombin-stimulated autologous platelets. Thrombin-stimulated platelets evoked potent contractions of both arteries in a platelet concentration-related manner. Pretreatment of platelets with aspirin, which almost completely inhibited thromboxane A2 synthesis but not the release reaction of biologic monoamines from platelets, caused only slight suppression of platelet-induced contractions of both arteries. Ketanserin as well as methysergide markedly inhibited aortic contractions to platelets. In contrast, the contractile responses of coronary arteries to platelets were suppressed by methysergide but not by ketanserin. Pretreatment of the arteries with diphenhydramine did not inhibit the aortic responses to platelets, but significantly suppressed coronary arterial contractions induced by higher concentrations of platelets. Phentolamine had no inhibitory effects on the responses of either artery to platelets. Pretreatment of arteries with aspirin did not affect the contractile responses of either artery to platelets. The contractile responses of aortae to exogenously administered serotonin were competitively antagonized by ketanserin, but those of coronary arteries were not. Coronary contractions to serotonin were competitively inhibited by methiothepin and significantly suppressed by methysergide. The contractile responses of both arteries to histamine were antagonized by diphenhydramine but not by cimetidine. On the basis of our results obtained from studies in organ chamber, we conclude that a major role of thromboxane A2 was not demonstrated in platelet-induced contractions of the arteries, and that those of aortae were mainly mediated by platelet-derived serotonin at S2 receptor and those of coronary arteries at S1-like receptor. The contractions of coronary arteries in responses to higher concentrations of platelets were partly mediated by histamine at H1 receptor.

Impact of NAD(P)H Oxidase-Derived Reactive Oxygen Species on Coronary Arterial Remodeling - A Comparative Intravascular Ultrasound and Histochemical Analysis of Atherosclerotic Lesions -

Background—Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. Methods and Results—Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of >1.0. ROS generation and NAD(P)H oxidase p22phox expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22phox expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18±0.12 versus 0.03±0.02, P<0.0001, 0.10±0.08 versus 0.04±0.05, P=0.0039, respectively). Both ROS generation and p22phox expression significantly correlated with the intravascular ultrasound-derived remodeling index (r=0.77, P<0.0001, r=0.53, P<0.0001, respectively). Conclusions—Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

Excessively Enlarged Right Coronary Artery Aneurysm With Intramural Thrombus Causing Recurrent Acute Coronary Syndrome

A 45-year-old man was admitted to our hospital with exertional chest pain. He had been diagnosed with membranoproliferative glomerulonephritis at the age of 20 and had undergone kidney transplantation at the age of 33. After that, he had taken some immunosuppressant drugs and steroids. Two years previously, he had presented with acute chest pain. On that occasion, cardiac enzymes were not elevated, but ECG showed the inversion of the T waves in II, III, aVF, V5, and V6 leads. We diagnosed angina pectoris and performed cardiac catheterization. Cardiac catheterization revealed a 75%-stenosed left anterior descending coronary artery (LAD) and a giant right coronary artery (RCA) aneurysm (50 mm) with intramural thrombus. Because the intravascular lumen of the RCA had been …