Physiological Assessment with iFR prior to FFR Measurement in Left Main Disease.

Despite guideline-based recommendation of the interchangeable use of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) to guide revascularization decision-making, iFR/FFR could demonstrate different physiological or clinical outcomes in some specific patient or lesion subsets. Therefore, we sought to investigate the impact of difference between iFR and FFR-guided revascularization decision-making on clinical outcomes in patients with left main disease (LMD). In this international multicenter registry of LMD with physiological interrogation, we identified 275 patients in whom physiological assessment was performed with both iFR/FFR. Major adverse cardiovascular event (MACE) was defined as a composite of death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The receiver-operating characteristic analysis was performed for both iFR/FFR to predict MACE in respective patients in whom revascularization was deferred and performed. In 153 patients of revascularization deferral, MACE occurred in 17.0% patients. The optimal cut-off values of iFR and FFR to predict MACE were 0.88 (specificity:0.74; sensitivity:0.65) and 0.76 (specificity:0.81; sensitivity:0.46), respectively. The area under the curve (AUC) was significantly higher for iFR than FFR (0.74; 95%CI 0.62-0.85 vs. 0.62; 95%CI 0.48-0.75; p = 0.012). In 122 patients of coronary revascularization, MACE occurred in 13.1% patients. The optimal cut-off values of iFR and FFR were 0.92 (specificity:0.93; sensitivity:0.25) and 0.81 (specificity:0.047; sensitivity:1.00), respectively. The AUCs were not significantly different between iFR and FFR (0.57; 95%CI 0.40-0.73 vs. 0.46; 95%CI 0.31-0.61; p = 0.43). While neither baseline iFR nor FFR was predictive of MACE in patients in whom revascularization was performed, iFR-guided deferral seemed to be safer than FFR-guided deferral.

Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder.

An 84-year-old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high-intensity signal lesions on fluid-attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well-defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8-positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti-AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing-remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

Proteomics associated with coronary high-risk plaques by optical coherence tomography.

Biomarkers are widely used for the diagnosis and monitoring of cardiovascular disease. However, markers for coronary high-risk plaques have not been identified. The aim of this study was to identify proteins specific to coronary high-risk plaques. Fifty-one patients (71.2 ± 11.1 years, male: 66.7%) who underwent intracoronary optical coherence tomography imaging and provided blood specimens for proteomic analysis were prospectively enrolled. A total of 1470 plasma proteins were analyzed per patient using the Olink® Explore 1536 Reagent Kit. In patients with thin-cap fibroatheroma, the protein expression of Calretinin (CALB2), Corticoliberin (CRH) and Alkaline phosphatase, placental type (ALPP) were significantly increased, while the expression of Neuroplastin (NPTN), Folate receptor gamma (FOLR3) and Serpin A12 (SERPINA12) were significantly decreased. In patients with macrophage infiltration, the protein expressions of Fatty acid-binding protein, intestinal (FABP2), and Fibroblast growth factor 21 (FGF21) were significantly decreased. In patients with lipid-rich plaques, the protein expression of Interleukin-17 C (IL17C) was significantly increased, while the expression of Fc receptor-like protein 3 (FCRL3) was significantly decreased. These proteins might be useful markers in identifying patients with coronary high-risk plaques. Clinical Trial Registration: https://www.umin.ac.jp/ctr/ , UMIN000041692.

Higher Noncalcified Plaque Volume Is Associated With Increased Plaque Vulnerability and Vascular Inflammation.

BACKGROUND: Recently, it was reported that noncalcified plaque (NCP) volume was an independent predictor for cardiac events. Pericoronary adipose tissue (PCAT) attenuation is a marker of vascular inflammation and has been associated with increased cardiac mortality. The aim of this study was to evaluate the relationships between NCP volume, plaque vulnerability, and PCAT attenuation. METHODS: Patients who underwent preintervention coronary computed tomography angiography and optical coherence tomography were enrolled. Plaque volume was measured by computed tomography angiography, plaque vulnerability by optical coherence tomography, and the level of coronary inflammation by PCAT attenuation. The plaques were divided into 2 groups of high or low NCP volume based on the median NCP volume. RESULTS: Among 704 plaques in 454 patients, the group with high NCP volume had a higher prevalence of lipid-rich plaque (87.2% versus 75.9%; P<0.001), thin-cap fibroatheroma (38.1% versus 20.7%; P<0.001), macrophage (77.8% versus 63.4%; P<0.001), microvessel (58.2% versus 42.9%; P<0.001), and cholesterol crystal (42.0% versus 26.7%; P<0.001) than the group with low NCP plaque volume. The group with high NCP volume also had higher PCAT attenuation than the group with low NCP volume (-69.6±10.0 versus -73.5±10.6 Hounsfield unit; P<0.001). In multivariable analysis, NCP volume was significantly associated with thin-cap fibroatheroma and high PCAT attenuation. In the analysis of the combination of PCAT attenuation and NCP volume, the prevalence of thin-cap fibroatheroma was the highest in the high PCAT attenuation and high NCP volume group and the lowest in the low PCAT attenuation and low NCP volume group. CONCLUSIONS: Higher NCP volume was associated with higher plaque vulnerability and vascular inflammation. The combination of PCAT attenuation and NCP volume may help identify plaque vulnerability noninvasively. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Cardiovascular Risk Factors and Culprit Plaque Characteristics in Women With Acute Coronary Syndromes.

Outcomes after myocardial infarction in women remain poor. The number of cardiovascular risk factors in women increase with age, however the relation between risk factors and culprit plaque characteristics in this population is poorly understood. The aim of the study was to investigate the relation between risk factors and culprit plaque characteristics in women with acute coronary syndrome (ACS). A total of 382 women who presented with ACS and underwent pre-intervention optical coherence tomography imaging of the culprit lesion were included in this analysis. The culprit plaques were categorized as plaque rupture, plaque erosion or calcified plaque, and then stratified by age and risk factors. The predominant pathology of ACS was plaque erosion in young patients (<60 years), which decreased with age (p <0.001). Current smokers had a high prevalence of plaque rupture (60%) and lipid plaque (79%). Women with diabetes tended to have more lipid plaque (70%) even at a young age. In women with hyperlipidemia, the prevalence of lipid plaques was modest in younger ages, but rose gradually with age (p <0.001). An increasing age trend for lipid plaque was also observed in women with hypertension (p = 0.03) and current smokers (p = 0.01). In conclusion, early treatment of risk factors such as diabetes in young women might be important before accelerated progression of atherosclerosis begins as age advances. Clinical trial registration: http://www.clinicaltrials.gov, NCT01110538, NCT03479723 and NCT02041650.

Impact of Stent Expansion Index on Stent Failure After Left Main Stenting.

Impact of the stent expansion index (EXPI) in percutaneous coronary intervention (PCI) for unprotected left main distal bifurcation lesions (ULMD) has been not completely understood especially in current-generation drug-eluting stent (cDES) era. We evaluated the impact of EXPI on clinical outcomes after PCI with cDES for ULMD. We identified 342 patients treated with cDES for ULMD and postintervention intravascular ultrasound between January 2010 and December 2019. In this study, the ratio of minimum stent area (MSA) to reference vessel area at the MSA site was adopted to assess the stent expansion. We defined the patients with the first and second tertile as low-intermediate EXPI group and those with the third tertile as high EXPI group and compared the clinical outcomes between both groups. The primary end point was target lesion failure (TLF). TLF was defined as a composite of cardiac death, target lesion revascularization (TLR) ,and myocardial infarction. The MSA was located in the ostium of left anterior descending coronary artery in most cases (318 of 342 patients; 93.0%). There were no significant differences between both groups in the baseline clinical, lesion, and procedural characteristics. The high EXPI group had lower TLF rate than the low-intermediate EXPI group (10.2% vs 19.9%, log-rank p = 0.033). In conclusion, this is the first report that the higher ratio of MSA to reference vessel area at the MSA site, which was defined as stent EXPI, was associated with more favorable clinical outcomes after PCI for ULMD.

Sex Differences in Coronary Atherosclerotic Phenotype and Healing Pattern on Optical Coherence Tomography Imaging.

BACKGROUND: Layered plaque, a signature of previous plaque disruption, is a known predictor of rapid plaque progression. Layered plaque can be identified in vivo by optical coherence tomography. Studies have reported differences in plaque burden between women and men, but sex differences in the pattern of layered plaque are unknown. METHODS: Preintervention optical coherence tomography images of 533 patients with chronic coronary syndromes were analyzed. Detailed plaque characteristics of layered and nonlayered plaques of the target lesion were compared between men and women. RESULTS: The prevalence of layered plaque was similar between men (N=418) and women (N=115; 55% versus 54%; P=0.832). In men, more features of plaque vulnerability were identified in layered plaque than in nonlayered plaque: lipid plaque (87% versus 69%; P<0.001), macrophages (69% versus 56%; P=0.007), microvessels (72% versus 39%; P<0.001), and cholesterol crystals (49% versus 30%; P<0.001). No difference in plaque vulnerability between layered and nonlayered plaques was observed in women. Layered plaque in men had more features consistent with previous plaque rupture than in women: interrupted pattern (74% versus 52%; P<0.001) and a greater layer index (1198 [781-1835] versus 943 [624-1477]; P<0.001). CONCLUSIONS: In men, layered plaques exhibit more features of vascular inflammation and vulnerability as well as evidence of previous plaque rupture, compared with nonlayered plaques, whereas in women, no difference was observed between layered and nonlayered plaques. Vascular inflammation (plaque rupture) may be the predominant mechanism of layered plaque in men, whereas a less inflammatory mechanism may play a key role in women. REGISTRATION: URL: http://www. CLINICALTRIALS: gov; Unique Identifier: NCT01110538, NCT04523194.

The estimation of coronary artery calcium thickness by computed tomography angiography based on optical coherence tomography measurements.

Optical coherence tomography (OCT) is recommended to be the most appropriate modality in assessing calcium thickness, however, it has limitations associated with infrared attenuation. Although coronary computed tomography angiography (CCTA) detects calcification, it has low resolution and hence not recommended to measure the calcium size. The aim of this study was to devise a simple algorithm to estimate calcium thickness based on the CCTA image. A total of 68 patients who had CCTA for suspected coronary artery disease and subsequently went on to have OCT were included in the study. 238 lesions of them divided into derivation and validation dataset at 2:1 ratio (47 patients with 159 lesions and 21 with 79, respectively) were analyzed. A new method was developed to estimate calcium thickness from the maximum CT density within the calcification and compared with calcium thickness measured by OCT. Maximum Calcium density and measured calcium-border CT density had a good correlation with a linear equation of y = 0.58x + 201 (r = 0.892, 95% CI 0.855-0.919, p < 0.001). The estimated calcium thickness derived from this equation showed strong agreement with measured calcium thickness in validation and derivation dataset (r2 = 0.481 and 0.527, 95% CI 0.609-0.842 and 0.497-0.782, p < 0.001 in both, respectively), more accurate than the estimation by full width at half maximum and inflection point method. In conclusion, this novel method provided the estimation of calcium thickness more accurately than conventional methods.

Deferred Versus Performed Revascularization for Left Main Coronary Disease With Hemodynamic Significance.

BACKGROUND: The majority of randomized controlled trials of revascularization decision-making excludes left main coronary artery disease (LMD). Therefore, contemporary clinical outcomes of patients with stable coronary artery disease and LMD with proven ischemia remain poorly understood. The aim of this study was to assess the long-term clinical outcomes of physiologically significant LMD according to the treatment strategies of revascularization versus revascularization deferral. METHODS: In this international multicenter registry of stable LMD interrogated with the instantaneous wave-free ratio, patients with physiologically significant ischemia (instantaneous wave-free ratio ≤0.89) were analyzed according to the coronary revascularization (n=151) versus revascularization deferral (n=74). Propensity score matching was performed to adjust for baseline clinical characteristics. The primary end point was a composite of death, nonfatal myocardial infarction, and ischemia-driven target lesion revascularization of left main stem. The secondary end points were as follows: cardiac death or spontaneous LMD-related myocardial infarction; and ischemia-driven target lesion revascularization of left main stem. RESULTS: At a median follow-up period of 2.8 years, the primary end point occurred in 11 patients (14.9%) in the revascularized group and 21 patients (28.4%) in the deferred group (hazard ratio, 0.42 [95% CI, 0.20-0.89]; P=0.023). For the secondary end points, cardiac death or LMD-related myocardial infarction occurred significantly less frequently in the revascularized group (0.0% versus 8.1%; P=0.004). The rate of ischemia-driven target lesion revascularization of left main stem was also significantly lower in the revascularized group (5.4% versus 17.6%; hazard ratio, 0.20 [95% CI, 0.056-0.70]; P=0.012). CONCLUSIONS: In patients who underwent revascularization for stable coronary artery disease and physiologically significant LMD determined by instantaneous wave-free ratio, the long-term clinical outcomes were significantly improved as compared with those in whom revascularization was deferred.

Multimorbidity, Polypharmacy, Severe Hypoglycemia, and Glycemic Control in Patients Using Glucose-Lowering Drugs for Type 2 Diabetes: A Retrospective Cohort Study Using Health Insurance Claims in Japan.

INTRODUCTION: This study aimed to understand the actual status of multimorbidity and polypharmacy among patients with type 2 diabetes using glucose-lowering drugs, and to assess the effects of patient characteristics on severe hypoglycemia and glycemic control. METHODS: We designed a retrospective cohort study using health insurance claims and medical checkup data in Japan from April 2016 to February 2021 and identified patients with type 2 diabetes who were prescribed glucose-lowering drugs. We analyzed data on patient characteristics, including multimorbidity and polypharmacy, calculated the incidence rate for severe hypoglycemic events, applied a negative binomial regression model to explore factors that affected severe hypoglycemia, and analyzed the status of glycemic control in the subcohort for which HbA1c data were available. RESULTS: Within the analysis population (n = 93,801), multimorbidity was present in 85.5% and mean ± standard deviation for oral drug prescriptions was 5.6 ± 3.5 per patient, while for those aged 75 years or older these numbers increased to 96.3% and 7.1 ± 3.5, respectively. The crude incidence rate for severe hypoglycemia was 5.85 (95% confidence interval 5.37, 6.37) per 1000 person-years. Risk factors for severe hypoglycemia included younger and older age, prior severe hypoglycemia, use of insulin, sulfonylurea, two-drug therapy including sulfonylurea or glinides, three-or-more-drug therapy, excessive polypharmacy, and comorbidities including end-stage renal disease (ESRD) requiring dialysis. Subcohort analysis (n = 26,746) showed that glycemic control is not always maintained according to guidelines. CONCLUSION: Patients with type 2 diabetes, particularly older patients, experienced high multimorbidity and polypharmacy. Several risk factors for severe hypoglycemia were identified, most notably younger age, ESRD, history of severe hypoglycemia, and insulin therapy. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry (UMIN000046736).

Physiology-guided PCI versus CABG for left main coronary artery disease: insights from the DEFINE-LM registry.

There have been no studies comparing clinical outcomes of physiology-guided revascularization in patients with unprotected left main coronary disease (ULMD) between percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG). The aim of this study was to assess the long-term clinical outcomes between PCI and CABG of patients with physiologically significant ULMD. From an international multicenter registry of ULMD patients interrogated with instantaneous wave-free ratio (iFR), we analyzed data from 151 patients (85 PCI vs. 66 CABG) who underwent revascularization according to the cutoff value of iFR ≤ 0.89. Propensity score matching was employed to adjust for baseline clinical characteristics. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The secondary endpoints were the individual components of the primary endpoint. Mean age was 66.6 (± 9.2) years, 79.2% male. Mean SYNTAX score was 22.6 (± 8.4) and median iFR was 0.83 (IQR 0.74-0.87). After performing propensity score matching analysis, 48 patients treated with CABG were matched to those who underwent PCI. At a median follow-up period of 2.8 years, the primary endpoint occurred in 8.3% in PCI group and 20.8% in CABG group, respectively (HR 3.80; 95% CI 1.04-13.9; p = 0.043). There was no difference in each component of the primary event (p > 0.05 for all). Within the present study, iFR-guided PCI was associated with lower cardiovascular events rate in patients with ULMD and intermediate SYNTAX score, as compared to CABG. State-of-the-art PCI vs. CABG for ULMD. Study design and primary endpoint in patients with physiologically significant ULMD. MACE was defined as the composite of all-cause death, non-fatal myocardial infarction, and target lesion revascularization. The blue line denotes the PCI arm, and the red line denotes the CABG arm. PCI was associated with significantly lower risk of MACE than CABG. CABG: coronary artery bypass grafting; iFR: instantaneous wave-free ratio; MACE: major adverse cardiovascular events; PCI: percutaneous coronary intervention; ULMD: unprotected left main coronary artery disease.

Layered plaque and plaque volume in patients with acute coronary syndromes.

BACKGROUND: Layered plaque is a signature of previous subclinical plaque destabilization and healing. Following plaque disruption, thrombus becomes organized, resulting in creation of a new layer, which might contribute to rapid step-wise progression of the plaque. However, the relationship between layered plaque and plaque volume has not been fully elucidated. METHODS: Patients who presented with acute coronary syndromes (ACS) and underwent pre-intervention optical coherence tomography (OCT) and intravascular ultrasound (IVUS) imaging of the culprit lesion were included. Layered plaque was identified by OCT, and plaque volume around the culprit lesion was measured by IVUS. RESULTS: Among 150 patients (52 with layered plaque; 98 non-layered plaque), total atheroma volume (183.3 mm3[114.2 mm3 to 275.0 mm3] vs. 119.3 mm3[68.9 mm3 to 185.5 mm3], p = 0.004), percent atheroma volume (PAV) (60.1%[54.7-60.1%] vs. 53.7%[46.8-60.6%], p = 0.001), and plaque burden (86.5%[81.7-85.7%] vs. 82.6%[77.9-85.4%], p = 0.001) were significantly greater in patients with layered plaques than in those with non-layered plaques. When layered plaques were divided into multi-layered or single-layered plaques, PAV was significantly greater in patients with multi-layered plaques than in those with single-layered plaques (62.1%[56.8-67.8%] vs. 57.5%[48.9-60.1%], p = 0.017). Layered plaques, compared to those with non-layered pattern, had larger lipid index (1958.0[420.9 to 2502.9] vs. 597.2[169.1 to 1624.7], p = 0.014). CONCLUSION: Layered plaques, compared to non-layered plaques, had significantly greater plaque volume and lipid index. These results indicate that plaque disruption and the subsequent healing process significantly contribute to plaque progression at the culprit lesion in patients with ACS. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01110538, NCT03479723, UMIN000041692.

Coronary Inflammation and Plaque Vulnerability: A Coronary Computed Tomography and Optical Coherence Tomography Study.

BACKGROUND: Vascular inflammation plays a key role in atherogenesis and in the development of acute coronary syndromes. Coronary inflammation can be measured by peri-coronary adipose tissue (PCAT) attenuation on computed tomography angiography. We examined the relationships between the level of coronary artery inflammation assessed by PCAT attenuation and coronary plaque characteristics by optical coherence tomography. METHODS: A total of 474 patients (198 acute coronary syndromes and 276 stable angina pectoris) who underwent preintervention coronary computed tomography angiography and optical coherence tomography were included. To compare the relationships between the level of coronary artery inflammation and detailed plaque characteristics, we divided the subjects into high (n=244) and low (n=230) PCAT attenuation groups using a threshold value of -70.1 Hounsfield units. RESULTS: The high PCAT attenuation group, compared with the low PCAT attenuation group, had more males (90.6% versus 69.6%; P<0.001), more non-ST-segment elevation myocardial infarction (38.5% versus 25.7%; P=0.003), and less stable angina pectoris (51.6% versus 65.2%; P=0.003). Aspirin, dual antiplatelet, and statins were less frequently used in the high PCAT attenuation group compared to the low PCAT attenuation group. Patients with high PCAT attenuation, compared with those with low PCAT attenuation, had lower ejection fraction (median 64% versus 65%; P=0.014) and lower levels of high-density lipoprotein cholesterol (median 45 versus 48 mg/dL; P=0.027). Optical coherence tomography features of plaque vulnerability were significantly more common in patients with high PCAT attenuation, compared to those with low PCAT attenuation, including lipid-rich plaque (87.3% versus 77.8%; P=0.006), macrophage (76.2% versus 67.8%; P=0.041), microchannels (61.9% versus 48.3%; P=0.003), plaque rupture (38.1% versus 23.9%; P<0.001), and layered plaque (60.2% versus 50.0%; P=0.025). CONCLUSIONS: Optical coherence tomography features of plaque vulnerability were significantly more common in patients with high PCAT attenuation, compared with those with low PCAT attenuation. Vascular inflammation and plaque vulnerability are intimately related in patients with coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04523194.

Diagnosis of coronary layered plaque by deep learning.

Healed coronary plaques, morphologically characterized by a layered phenotype, are signs of previous plaque destabilization and healing. Recent optical coherence tomography (OCT) studies demonstrated that layered plaque is associated with higher levels of local and systemic inflammation and rapid plaque progression. However, the diagnosis of layered plaque needs expertise in OCT image analysis and is susceptible to inter-observer variability. We developed a deep learning (DL) model for an accurate diagnosis of layered plaque. A Visual Transformer (ViT)-based DL model that integrates information from adjacent frames emulating the cardiologists who review consecutive OCT frames to make a diagnosis was developed and compared with the standard convolutional neural network (CNN) model. A total of 237,021 cross-sectional OCT images from 581 patients collected from 8 sites were used for training and internal validation, and 65,394 images from 292 patients collected from another site were used for external validation. In the five-fold cross-validation, the ViT-based model provided better performance (area under the curve [AUC]: 0.860; 95% confidence interval [CI]: 0.855-0.866) than the standard CNN-based model (AUC: 0.799; 95% CI: 0.792-0.805). The ViT-based model (AUC: 0.845; 95% CI: 0.837-0.853) also surpassed the standard CNN-based model (AUC: 0.791; 95% CI: 0.782-0.800) in the external validation. The ViT-based DL model can accurately diagnose a layered plaque, which could help risk stratification for cardiac events.

Level of Vascular Inflammation Is Higher in Acute Coronary Syndromes Compared with Chronic Coronary Disease.

BACKGROUND: Vascular inflammation has been recognized as one of the key factors in the pathogenesis of acute coronary syndromes (ACS). Pericoronary adipose tissue (PCAT) attenuation by computed tomography angiography has emerged as a marker specific for coronary artery inflammation. We examined the relationship between clinical presentation and coronary artery inflammation assessed by PCAT attenuation and coronary plaque characteristics. METHODS: Patients with ACS or stable angina pectoris (SAP) who underwent preintervention coronary computed tomography angiography and optical coherence tomography were enrolled. PCAT attenuation was measured around the culprit lesion and in the proximal 40 mm of all coronary arteries. PCAT attenuation and optical coherence tomography findings were compared between patients with ACS versus SAP. RESULTS: Among 471 patients (ACS: 198, SAP: 273), PCAT attenuation was higher in ACS patients than in SAP patients both at the culprit plaque level (-67.5±9.6 Hounsfield unit [HU] versus -71.5±11.0 HU, P<0.001) and at the culprit vessel level (-68.3±7.7 HU versus -71.1±7.9 HU, P<0.001). The mean PCAT attenuation of all 3 coronary arteries was also significantly higher in ACS patients than in SAP patients (-68.8±6.3 HU versus -70.5±7.1 HU, P=0.007). After adjusting patient characteristics, not only thin-cap fibroatheroma (OR: 3.41; 95% CI: 1.89-6.17) and macrophages (OR: 3.32; 95% CI: 1.76-6.26) but also PCAT attenuation around the culprit plaque (OR: 1.03; 95% CI: 1.00-1.05) was associated with the clinical presentation of ACS. CONCLUSIONS: PCAT attenuation at culprit plaque, culprit vessel, and pan-coronary levels was higher in ACS patients than in SAP patients. Vascular inflammation appears to play a crucial role in the development of ACS. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04523194.

Enhanced Diagnosis of Plaque Erosion by Deep Learning in Patients With Acute Coronary Syndromes.

BACKGROUND: Acute coronary syndromes caused by plaque erosion might be potentially managed conservatively without stenting. Currently, the diagnosis of plaque erosion requires expertise in optical coherence tomographic (OCT) image interpretation. In addition, the current deep learning (DL) approaches for OCT image interpretation are based on a single frame, without integrating the information from adjacent frames. OBJECTIVES: The aim of this study was to develop a novel DL model to facilitate an accurate diagnosis of plaque erosion. METHODS: A novel "Transformer"-based DL model was developed that integrates information from adjacent frames emulating the cardiologists who review consecutive OCT frames to make a diagnosis and compared with the standard convolutional neural network (CNN) DL model. A total of 237,021 cross-sectional OCT images from 581 patients were used for training and internal validation, and 65,394 images from 292 patients from another dataset were used for external validation. Model performances were evaluated using the area under the receiver-operating characteristic curve (AUC). RESULTS: For the frame-level diagnosis of plaque erosion, the Transformer model showed superior performance than the CNN model, with an AUC of 0.94 compared with 0.85 in the external validation. For the lesion-level diagnosis, the Transformer model showed improved diagnostic performance compared with the CNN model, with an AUC of 0.91 compared with 0.84 in the external validation. CONCLUSIONS: This newly developed Transformer model will help cardiologists diagnose plaque erosion with high accuracy in patients with acute coronary syndromes.

Biomarkers associated with coronary high-risk plaques.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

Gut Microbiota and Coronary Plaque Characteristics.

Background The relationship between gut microbiota and in vivo coronary plaque characteristics has not been reported. This study was conducted to investigate the relationship between gut microbiota and coronary plaque characteristics in patients with coronary artery disease. Methods and Results Patients who underwent both optical coherence tomography and intravascular ultrasound imaging and provided stool and blood specimens were included. The composition of gut microbiota was evaluated using 16S rRNA sequencing. A total of 55 patients were included. At the genus level, 2 bacteria were associated with the presence of thin-cap fibroatheroma, and 9 bacteria were associated with smaller fibrous cap thickness. Among them, some bacteria had significant associations with inflammatory/prothrombotic biomarkers. Dysgonomonas had a positive correlation with interleukin-6, Paraprevotella had a positive correlation with fibrinogen and negative correlation with high-density lipoprotein cholesterol, Succinatimonas had positive correlations with fibrinogen and homocysteine, and Bacillus had positive correlations with fibrinogen and high-sensitivity C-reactive protein. In addition, Paraprevotella, Succinatimonas, and Bacillus were also associated with greater plaque volume. Ten bacteria were associated with larger fibrous cap thickness. Some were associated with protective biomarker changes; Anaerostipes had negative correlations with trimethylamine N-oxide, tumor necrosis factor α, and interleukin-6, and Dielma had negative correlations with trimethylamine N-oxide, white blood cells, plasminogen activator inhibitor-1, and homocysteine, and a positive correlation with high-density lipoprotein cholesterol. Conclusions Bacteria that were associated with vulnerable coronary plaque phenotype and greater plaque burden were identified. These bacteria were also associated with elevated inflammatory or prothrombotic biomarkers. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000041692.