Effect of Ezetimibe on Stabilization and Regression of Intracoronary Plaque　- The ZIPANGU Study.

BACKGROUND: Diminishing yellow color is associated with plaque stabilization. We assessed the hypothesis that a combination of ezetimibe and statin provides more effective plaque stabilization and regression than statin alone as assessed by plaque color.Methods and Results:Stable coronary artery disease patients (n=131) who underwent elective percutaneous coronary intervention and had yellow plaques were randomized to combination therapy (atorvastatin 10-20 mg and ezetimibe 10 mg/day; Group C) or statin monotherapy (atorvastatin 10-20 mg; Group M). Changes in plaque color and plaque volume during 9 months were assessed by angioscopy and intravascular ultrasound. Low-density lipoprotein cholesterol (LDL-C) decreased from 103±28 to 63±18 mg/dL in Group C (P<0.001) and from 100±28 to 75±17 mg/dL in Group M (P<0.001). Yellow color grade decreased significantly in both Group M (2.1±1.1 vs. 1.7±1.0, P=0.005) and Group C (2.2±1.2 vs. 1.8±1.2, P=0.002), but did not differ between the groups. %plaque volume did not change in Group M (48.5±10.2% vs. 48.2±10.4%, P=0.4), but decreased significantly in Group C (50.0±9.8% vs. 49.3±9.8%, P=0.03). CONCLUSIONS: Compared with statin monotherapy, combination therapy with ezetimibe further reduced LDL-C levels. Significant plaque volume reduction was achieved by the combination therapy, but not statin monotherapy; however, plaque stabilization was similarly achieved by both therapies. Furthermore, reduction in plaque volume was dependent on reduction in LDL-C, regardless of whether it was achieved by statin alone or statin plus ezetimibe.

Early detection of vulnerable atherosclerotic plaque for risk reduction of acute aortic rupture and thromboemboli and atheroemboli using non-obstructive angioscopy.

The mortality rate due to rupture of aortic dissection and aortic aneurysm is approximately 90%. Acute aortic rupture can be fatal prior to hospitalization and has proven difficult to diagnose correctly or predict. The in-hospital mortality rate of ruptured aortic aneurysm ranges from 53 to 66%. Emergency surgical and endovascular treatments are the only options for ruptured aortic dissection and aortic aneurysm. No method of systematic early detection or inspection of vessel injury is available at the prevention stage. Regardless of the improvement in many imaging modalities, aortic diameter has remained a major criterion for recommending surgery in diagnosed patients. Previous reports have suggested a relationship between vulnerable plaque and atherosclerotic aortic aneurysm. Non-obstructive angioscopy is a new method for evaluating intimal injury over the whole aorta. It has been used to identify many advanced atherosclerotic plaques that were missed on traditional imaging modalities before aneurysm formation. Non-obstructive angioscopy has shown that atherosclerosis of the aorta begins before that of the coronary artery, which had been noted on autopsy "in vivo". Strong or repetitive aortic injuries might cause sudden aortic disruption. Aortic atheroma is also a risk factor of stroke and perivascular embolism. Detecting aortic vulnerable atherosclerotic plaque on non-obstructive angioscopy may not only clarify the pathogenesis of acute aortic rupture and "aortogenic" thromboemboli and atheroemboli but also play a role in the pre-emptive medicine.

Remodeling pattern is related to the degree of coronary plaque regression induced by pitavastatin: a sub-analysis of the TOGETHAR trial with intravascular ultrasound and coronary angioscopy.

This study aimed to clarify the relationships between arterial remodeling patterns and plaque volume regression or stabilization. The TOGETHAR trial is a prospective open-label trial designed to assess coronary plaque regression and stabilization with multiple plaque imaging modalities following 52 weeks of pitavastatin treatment (2 mg/day). Coronary plaques were observed in 46 patients with both angioscopy and intravascular ultrasound at baseline and after 52 weeks of drug treatment. We divided these patients into three groups according to their remodeling indices (RI). Group P consisted of patients with a baseline RI >1.05, Group M of patients with a baseline RI of 0.95-1.05, and Group N of patients with a baseline RI <0.95 and then evaluated differences in coronary plaque volume changes and yellow grade among the three groups. In the positive remodeling group, whose remodeling index (RI) exceeded 1.05 at baseline, RI and percent atheroma volume (PAV) were significantly reduced (RI 1.14 ± 0.07 to 1.05 ± 0.10, p = 0.010, PAV 47.3 ± 8.3 to 45.3 ± 7.3 mm(3), p = 0.048). There was no relationship between baseline RI and the change in yellow grade of plaque. RI increased without significant change of PAV or a decrease in lumen volume in group N, with RI below 0.95 at baseline. Plaques with positive remodeling were more likely to have plaque volume regression by pitavastatin than those without in patients with coronary artery disease. Moreover, plaques with positive and negative remodeling were changed into those with intermediate remodeling by pitavastatin. Pitavastatin might induce not only plaque regression or stabilization, but also conformational normalization of vessel structure.

Different Characteristics and Interleukin-6 Ratios of Scattering-Type Aortic Plaques.

Background Cholesterol crystals (CCs) are related to innate inflammation in spontaneously ruptured aortic plaques (SRAPs), and variability exists in the CCs and interleukin (IL)-6 ratio in SRAPs. Methods The prevalence of scattering-type ruptures that glittered against the light of angioscopic fibers (puff-chandelier ruptures) and those that did not (puff ruptures) was analyzed in 848 patients with suspected coronary artery disease. Overall, 177 puff-chandelier ruptures and 105 puff ruptures were sampled using nonobstructive general angioscopy (NOGA). The sampled plaques were analyzed by direct detection of CCs with polarized light microscopy. The characteristics of the plaque fragments from puff and puff-chandelier ruptures were compared. The Interleukin-6 (IL-6) ratios were calculated for 100 puff-chandelier ruptures and 100 puff ruptures. Results CCs were detected in 54% of puff-chandelier ruptures and 20% of puff ruptures. The longer and shorter dimensions of the puff ruptures were smaller than those of the puff-chandelier ruptures. CCs were more prevalent in puff chandeliers than in puff ruptures (54% vs. 20%, respectively; p<0.0001). The number of CCs was higher in puff chandeliers than in puff ruptures with CCs (median 12,727 (interquartile range (IQR) 3,636-25,909)/10 mL vs. median 3,182 ( IQR 909-9,318)/10 mL) in CC-positive samples (p=0.0120). The IL-6 ratio of puff-chandelier ruptures was higher than that of puff ruptures (p=0.0014). Conclusions Examination of plaque fragments from puff-chandelier and puff ruptures revealed a higher prevalence of CCs in puff-chandelier ruptures compared to puff ruptures. Puff chandeliers exhibited a significantly greater number of CCs, suggesting a potential correlation with inflammatory levels. The IL-6 ratio was also higher in puff-chandelier ruptures. Direct detection of CCs and hematoxylin and eosin staining for SRAPs demonstrated variations in CC degree and dimensions between puff-chandelier and puff ruptures. Puff-chandelier ruptures exhibited more CCs associated with innate inflammation and larger fragments than puff ruptures. NOGA proved effective in detecting diverse characteristics and inflammation levels, as indicated by IL-6, in scattering-type SRAPs.

Cholesterol Crystal Embolization Exacerbates Critical Limb Ischemia.

Chronic life-threatening ischemia (CLTI), characterized by chronic severe ischemic ulcers or gangrene in the legs with arterial occlusive disease, has a high rate of amputation and mortality. However, how lower extremity artery disease (LEAD) leads to CLTI is not fully understood yet. Here, we report a 79-year-old man with resting pain and gangrene in the left first and fifth toes for a year who had undergone repetitive endovascular treatment (EVT) that temporarily improved the ischemia. Non-obstructive general angioscopy (NOGA) revealed yellow and red floating emboli at the occluded left superficial femoral artery (SFA). Although a second EVT for the reoccluded SFA was successful, amputation of the left lower knee remained necessary because of osteomyelitis of the left heel. Cholesterol crystals (CCs) associated with innate inflammation were detected in spontaneously ruptured aortic plaques (SRAPs) via aortic screening using the NOGA, in occluded SFAs, and on the surface of the muscle cross-section of the amputated legs via a polarizing microscope. Histopathological analysis demonstrated CCs in small vessels in various stages of patchy necrosis and muscle regeneration. In this case, the process of CC embolization, such as the embolic source of CCs, occlusion in arteries, small arteries, and deposition in muscles, was confirmed in CLTI. CCs are the principal trigger of IL-6 production through the innate inflammatory response in spontaneously ruptured aortic plaques. Mechanical ischemia and chronic inflammation due to embolized CCs may cause chronic limb damage. In this case, the CC embolization might exacerbate CLTI.

Demonstrating an Adult Ventricular Septal Defect Using Non-obstructive General Angioscopy.

A ventricular septal defect (VSD) is a common congenital heart disease, and the transcatheter technique for VSD requires practical guidance because it requires a complicated procedure. A non-obstructive angioscopy catheter system via the right ventricle successfully revealed an approximately 3-mm VSD with the shape of a rugby ball at the center of the white membranous septum of Kirklin type II in an older female with suspected coronary artery disease. A white membranous terraced septum was observed to be surrounded by a reddish ventricle. Conservative therapy was performed for her VSD because she did not meet the criteria for surgical treatment.

Angioscopy-Guided Selective Pulmonary Thrombectomy and Angioscopy-Monitored Systemic Thrombosis for a Pulmonary Embolism.

Few modalities have the capacity to demonstrate massive or fragmented thrombi to evaluate the effect of catheter-based or systemic thrombosis for pulmonary embolism (PE). We herein present a patient who underwent a thrombectomy for PE using a non-obstructive general angioscopy (NOGA) system. Small floating mobile thrombi were aspirated using the original method, and massive thrombi were aspirated using the NOGA system. Systemic thrombosis was also monitored via NOGA for 30 minutes. Detachment of thrombi from the wall of the pulmonary artery began two minutes after infusion of a recombinant tissue plasminogen activator (rt-PA). Six minutes after thrombolysis, the thrombi lost their erythematous color, and the white thrombi gradually floated and dissolved. NOGA-guided selective pulmonary thrombectomy and NOGA-monitored systemic thrombosis contributed to improved patient survival. Rapid systemic thrombosis for PE using rt-PA was also demonstrated by NOGA.

Multiple and Multidirectional Fissure Bleedings in a Patient With a Spontaneous Isolated Dissection of the Iliac Artery.

A 63-year-old man with a history of hypertension and dyslipidemia on medication was found to have an enlargement of an asymptomatic iliac artery aneurysm with an ulcer-like projection on computed tomography angiography. The longer and shorter diameter of the right iliac was increased from 24.0 × 18.1 mm to 38.9 × 32.1 mm over four years. Preoperative non-obstructive general angiography revealed multiple, multidirectional fissure bleedings. Fissure bleedings were found where computed tomography angiography appeared normal at the aortic arch. He was diagnosed with spontaneous isolated dissection of the iliac artery and was treated successfully with endovascular treatment.

Atherosclerosis of the aorta before blue toe syndrome: Spontaneously ruptured aortic plaques revealed by non-obstructive general angioscopy.

A 50-year-old man who had undergone endovascular therapy 70 days previously was referred to us for the sudden onset of cyanosis with rest pain in the bilateral lower limbs. The patient was diagnosed with blue toe syndrome. Although computed tomography angiography showed irregular aortic wall thickness, preoperative aortic angioscopy detected a remarkable number of spontaneously ruptured aortic plaques, such as puff-chandelier ruptures, predominantly in the abdominal aorta. Continuous embolization of a large quantity of cholesterol crystals from puff-chandelier ruptures subsequently might be responsible for cholesterol embolization syndrome. Learning objective: A patient presenting with cholesterol embolization syndrome had undergone a non-obstructive general angioscopy. We highlight the numerous spontaneously ruptured aortic plaques demonstrated by non-obstructive general angioscopy.

Cholesterol Crystals as the Main Trigger of Interleukin-6 Production through Innate Inflammatory Response in Human Spontaneously Ruptured Aortic Plaques.

AIM: This study aimed to clarify whether cholesterol crystals (CCs) are the main trigger of innate inflammation in human spontaneously ruptured aortic plaques (SRAPs). METHODS: This study included 260 SRAPs collected during nonobstructive general angioscopy (NOGA) from 126 patients with confirmed or suspected coronary artery disease. Interleukin (IL)-6 levels in SRAPs were measured. IL-6 levels in the Valsalva sinus and femoral or brachial arteries were measured. IL-6 ratios (the IL-6 level in SRAPs and arteries divided by the IL-6 level at the Valsalva sinus at the beginning of the aorta) were calculated. Quantitative analysis of CCs was performed from SRAPs. The correlation between the count of CCs and IL-6 levels in SRAPs and that between the counts of CCs and IL-6 ratios in SRAPs were analyzed. RESULTS: The IL-6 levels in SRAPs were 3.4 [2.1, 7.2] pg/mL, and the IL-6 ratio (median [interquartile range]) in SRAPs was 1.10 [1.00, 1.26]. CCs were detected in 94 of 260 SRAPs (36%). The count of CCs was 11,590 (95% confidence interval, 2,386-30,113) per 10 mL in CC-positive samples. There was a moderate correlation between the counts of CCs and IL-6 ratios in SRAPs (r=0.49, r＜0.0001), whereas there was no correlation between the count of CCs and IL-6 levels in SRAPs. The IL-6 ratios of the brachial and femoral arteries were 1.06 (95% CI, 0.99-1.20) and 1.11 (95% CI, 1.04-1.20), respectively. CONCLUSIONS: CC is the main trigger of IL-6 production through innate inflammatory response in human SRAPs in situ.

Influence of achieved low-density lipoprotein cholesterol level with atorvastatin therapy on stabilization of coronary plaques: sub-analysis of the TWINS study.

BACKGROUND: Previously the stabilization of coronary plaque with atorvastatin was demonstrated in the TWINS (evaluaTion With simultaneous angIoscopy and iNtravascular ultraSound) study. The influence of the low-density lipoprotein cholesterol (LDL-C) level on plaque stabilization was analyzed. METHODS AND RESULTS: Patients (n=29) with hypercholesterolemia and coronary artery disease (CAD) were analyzed. They received atorvastatin (10-20mg/day) for 80 weeks and were divided into low (< 91 mg/dl) and high (≥ 91 mg/dl) LDL-C groups based on their 80-week LDL-C level. Angioscopy was performed before and after treatment. Yellow coronary plaques were classified into six grades (grades 0 to 5) and mean grade was determined for each patient. The LDL-C levels at week 28 and 80 were reduced in both low LDL-C groups (n=14, 140.3 to 77.9 and 75.9 mg/dl; P<0.001 both groups) and high LDL-C groups (n=15, 151.7 to 93.0 and 99.1mg/dl; P<0.001 both groups). Significant improvement in the mean grade was shown in the low LDL-C groups (1.44 to 1.00 and 1.05; P=0.003 both groups) at week 28 and 80 vs. no significant change in high LDL-C groups (1.43 to 1.23 and 1.28; P=0.032 and P=0.169 respectively). CONCLUSIONS: Adequate reduction of LDL-C is important for the stabilization of coronary plaques.

Continuous 1-Month Release of Cholesterol Crystals in a Patient With Acute Coronary Syndrome After Stenting.

Coronary stenting was performed for a 76-year-old patient with acute coronary syndrome with severe stenosis of the right coronary artery. Puff rupture including cholesterol crystals was detected on nonobstructive general angioscopy. One month after intervention, continuous release of cholesterol crystals was found despite successful percutaneous coronary intervention. (Level of Difficulty: Intermediate.).

Debris collected in-situ from spontaneously ruptured atherosclerotic plaque invariably contains large cholesterol crystals and evidence of activation of innate inflammation: Insights from non-obstructive general angioscopy.

BACKGROUND AND AIMS: Development and expansion of cholesterol crystals (CCs) within a lipid rich atherosclerotic core are believed to predispose to plaque rupture. We have used non-obstructive general angioscopy to described a range of appearances of spontaneously ruptured atherosclerotic plaques (SRAPs) in the aorta in-situ, and have confirmed that debris extruding from some SRAPs (puff-chandelier lesions) are rich in cholesterol crystals and leukocytes. The purpose of this study was to characterized the nature of the inflammatory infiltrate of this debris. METHODS: Debris was collected from puff-chandelier lesions at the time of angioscopy in patients with known coronary disease. Prepared specimens were examined by light microscopy, and immunostaining was used to detect markers of activation of the innate inflammatory pathway including CD68, NLRP3, caspase-1, IL-1ß, IL-18, and IL-6. RESULTS: We analysed debris sampled from 20 puff-chandelier lesions. Microscopy confirmed the presence of large CCs, macrophages, fibrin, calcified gruel, lymphocytes, and neutrophils in 100%, 100%, 95%, 25%, 20%, and 15% of the specimens respectively. Immunostaining confirmed the presence of CD68, NLRP3, IL-1ß, and IL-6 within the debris in 100%, 90%, 80%, and 80%, of the specimens respectively. CCs, NLRP3, caspase-1, IL-1ß, IL-18, were also identified in the cytoplasm of macrophages. CONCLUSIONS: Debris from SRAPs with a puff-chandelier appearance invariably contained large CCs associated with a range of activated leukocytes involved in innate inflammation. This observation supports the thesis that the development and enlargement of CCs in the core of lipid rich plaques may precipitate traumatic and inflammatory injury that may lead to plaque rupture.

Novel Methods for Detecting Human Cholesterol Crystals from Sampled Blood.

OBJECTIVE: Nonobstructive general angiography (NOGA) is a novel modality to detect and sample spontaneous ruptured aortic plaques (SRAPs). We aimed to establish novel methods to detect cholesterol crystals (CCs) in sampled SRAPs. METHODS: Blood specimens containing SRAPs were obtained from patients using NOGA. Blood was instantly frozen on a glass slide and subsequently thawed for quantitative analysis and spread onto a filter paper that was rinsed using distilled water. Qualitative analysis was performed for the rinsed water using polarized light microscopy, and the filter paper was embedded in paraffin for histologic analysis. RESULTS: The CCs were clearly observed after hemolysis using the instant freeze-thaw method. The filter paper rinse method indicated free CCs of varying shapes under polarized light microscopy without erythrocytes. On the filter paper, sampled SRAPs showed Lamé-like small particles. Histopathology revealed various atheromatous components. CONCLUSION: A set of novel methods for detecting CCs from sampled blood was established.

Significant Contribution of Aortogenic Mechanism in Ischemic Stroke: Observation of Aortic Plaque Rupture by Angioscopy.

Background: Although embolic stroke accounts for most cerebral infarction, examinations to identify the embolic source have been insufficient. Nonobstructive general angioscopy (NOGA) has developed to allow the detailed observation of atheromatous changes of the aorta. Objectives: The purpose of this study was to clarify the importance of the aortogenic mechanism in the development of ischemic stroke. Methods: We examined 114 consecutive patients whose aorta was observed by NOGA and who subsequently underwent brain magnetic resonance imaging to detect ischemic stroke lesions. In the evaluation of the aorta, the presence and location of spontaneously ruptured aortic plaque (SRAP) were determined. The aorta was observed from the origin to the arch (proximal aorta [PAo]) and the proximal descending aorta. Results: Forty-nine of 114 patients had SRAP observed by NOGA. Among these, 24 had SRAP in the PAo, and 43 had SRAP in the descending aorta. Thirty-three patients had ischemic stroke lesions, including 6 with a clinical neurologic deficit. The frequency at which SRAP was detected in these patients was significantly higher in comparison to 81 patients without ischemic stroke (69% vs 33%; P < 0.01). The sensitivity and specificity of the presence of SRAP for ischemic stroke were 0.70 and 0.68, respectively. The presence of SRAP in PAo was significantly correlated with ischemic stroke (odds ratio: 14.3; P < 0.001). Conclusions: In the treatment of ischemic stroke, attention should be paid to SRAP, especially that in the PAo. (STROKE-NOGA [SponTaneously Ruptured aOrtic plaques as a potential cause of embolic stroKEs visualized by Non-Obstructive General Angioscopy] Study; UMIN000034588).

Detection of macrophages engulfing cholesterol crystals and docosahexaenoic acid from spontaneous ruptured aortic plaque.

We visualized macrophages engulfing cholesterol crystals from spontaneously ruptured aortic plaques sampled by angioscopy. Docosahexaenoic acid cholesterol ester (DHA-CE) was demonstrated by imaging mass spectrometry. DHA-CE is reported to be produced by macrophages against inflammation. Activities of macrophages against atherosclerosis inside plaques was shown from spontaneously ruptured aortic plaques in situ. Learning objectives: Activities of macrophages such as engulfing cholesterol crystals and producing docosahexaenoic acid cholesterol ester were shown from spontaneously ruptured aortic plaques in situ.

Aortic plaque burden predicts vascular events in patients with cardiovascular disease: The EAST-NOGA study.

BACKGROUND: Non-obstructive general angioscopy (NOGA) can be used to diagnose aortic atherosclerotic plaques. We examine the association between the number of aortic plaques detected by NOGA and the risk of subsequent cardiovascular events. METHODS: The Evaluation of AtheroScleroTic and rupture events by Non-Obstructive General Angioscopy (EAST-NOGA) was a prospective cohort study of patients with suspected coronary artery disease who underwent NOGA. RESULTS: Of the 577 patients who underwent NOGA, 532 (92%) completed the follow-up (median follow-up: 13 months, interquartile range: 12-16). The median number of plaques per person was 6 (interquartile range: 3-12), and 567 (98%) had at least one aortic plaque. During the 13-month follow-up, 38 (7.1%) patients had a primary composite endpoint [including cardiovascular death, myocardial infarction, stroke, peripheral artery disease (PAD), or worsening renal function], which was significantly associated with chronic kidney disease, a history of PAD, a lower hemoglobin level, and large numbers of aortic plaques [11 (5-17) vs. 6 (2-11), p = 0.003]. A receiver operating characteristic curve analysis for the number of aortic plaques predicting composite endpoints revealed that the cut-off value of aortic plaques was 12. After multivariate adjustment, the presence of ≥12 aortic plaques remained a significant predictor for composite endpoint events (hazard ratio 2.53, 95% confidence interval 1.26-5.04, p = 0.010). CONCLUSIONS: The number of aortic plaques detected by NOGA may predict subsequent clinical events.

Multidetector row computed tomography may accurately estimate plaque vulnerability: does MDCT accurately estimate plaque vulnerability? (Pro).

Over the past decade, multidetector row computed tomography (MDCT) has become the most reliable and established of the noninvasive examination techniques for detecting coronary heart disease. Now MDCT is chasing intravascular ultrasound (IVUS) in terms of spatial resolution. Among the components of vulnerable plaque, MDCT may detect lipid-rich plaque, the lipid pool, and calcified spots using computed tomography number. Plaque components are detected by MDCT with high accuracy compared with IVUS and angioscopy when assessing vulnerable plaque. The TWINS study and TOGETHAR trial demonstrated that angioscopic loss of yellow color occurred independently of volumetric plaque change by statin therapy. These 2 studies showed that plaque stabilization and regression reflect independent processes mediated by different mechanisms and time course. Noncalcified plaque and/or low-density plaque was found to be the strongest predictor of cardiac events, regardless of lesion severity, and act as a potential marker of plaque vulnerability. MDCT may be an effective tool for early triage of patients with chest pain who have a normal ECG and cardiac enzymes in the emergency department. MDCT has the potential ability to analyze coronary plaque quantitatively and qualitatively if some problems are resolved. MDCT may become an essential tool for detecting and preventing coronary artery disease in the future.