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.

Layered plaque is associated with high levels of vascular inflammation and vulnerability in patients with stable angina pectoris.

Layered plaque, a signature of previous plaque destabilization and healing, is a known predictor for rapid plaque progression; however, the mechanism of which is unknown. The aim of the current study was to compare the level of vascular inflammation and plaque vulnerability in layered plaques to investigate possible mechanisms of rapid plaque progression. This is a retrospective, observational, single-center cohort study. Patients who underwent both coronary computed tomography angiography (CTA) and optical coherence tomography (OCT) for stable angina pectoris (SAP) were selected. Plaques were defined as any tissue (noncalcified, calcified, or mixed) within or adjacent to the lumen. Perivascular inflammation was measured by pericoronary adipose tissue (PCAT) attenuation at the plaque levels on CTA. Features of plaque vulnerability were assessed by OCT. Layered plaques were defined as plaques presenting one or more layers of different optical densities and a clear demarcation from underlying components on OCT. A total of 475 plaques from 195 patients who presented with SAP were included. Layered plaques (n = 241), compared with non-layered plaques (n = 234), had a higher level of vascular inflammation (-71.47 ± 10.74 HU vs. -73.69 ± 10.91 HU, P = 0.026) as well as a higher prevalence of the OCT features of plaque vulnerability, including lipid-rich plaque (83.8% vs. 66.7%, P < 0.001), thin-cap fibroatheroma (26.1% vs. 17.5%, P = 0.026), microvessels (61.8% vs. 34.6%, P < 0.001), and cholesterol crystals (38.6% vs. 25.6%, P = 0.003). Layered plaque was associated with a higher level of vascular inflammation and a higher prevalence of plaque vulnerability, which might play an important role in rapid plaque progression.Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT04523194 .

Cardiac Optical Coherence Tomography: History, Current Status, and Perspective.

For more than 2 decades since the first imaging procedure was performed in a living patient, intravascular optical coherence tomography (OCT), with its unprecedented image resolution, has made significant contributions to cardiovascular medicine in the realms of vascular biology research and percutaneous coronary intervention. OCT has contributed to a better understanding of vascular biology by providing insights into the pathobiology of atherosclerosis, including plaque phenotypes and the underlying mechanisms of acute coronary syndromes such as plaque erosion, neoatherosclerosis, stent thrombosis, and myocardial infarction with nonobstructive coronary arteries. Moreover, OCT has been used as an adjunctive imaging tool to angiography for the guidance of percutaneous coronary intervention procedures to optimize outcomes. However, broader application of OCT has faced challenges, including subjective interpretation of the images and insufficient clinical outcome data. Future developments including artificial intelligence-assisted interpretation, multimodality catheters, and micro-OCT, as well as large prospective outcome studies could broaden the impact of OCT on cardiovascular medicine.

Protruding Aortic Plaque and Coronary Plaque Vulnerability.

BACKGROUND: Protruding aortic plaque is known to be associated with an increased risk for future cardiac and cerebrovascular events. However, the relationship between protruding aortic plaque and coronary plaque characteristics has not been systematically investigated. METHODS AND RESULTS: A total of 615 patients who underwent computed tomography angiography, and preintervention optical coherence tomography imaging were included. Coronary plaque characteristics were compared to evaluate coronary plaque vulnerability in patients with protruding aortic plaque on computed tomography angiography. 615 patients, the 186 (30.2%) patients with protruding aortic plaque were older and had more comorbidities such as hypertension, chronic kidney disease, and a prior myocardial infarction than those without. They also had a higher prevalence of coronary plaques with vulnerable features such as thin-cap fibroatheroma (85 [45.7%] versus 120 [28.0%], P<0.001), lipid-rich plaque (165 [88.7%] versus 346 [80.7%], P=0.014), macrophages (147 [79.0%] versus 294 [68.5%], P=0.008), layered plaque (117 [62.9%] versus 213 [49.7%], P=0.002), and plaque rupture (96 [51.6%] versus 111 [25.9%], P<0.001). Patients with protruding aortic plaque experienced more major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal acute coronary syndromes, and stroke (27 [14.7%] versus 21 [4.9%], P<0.001; 8 [4.3%] versus 1 [0.2%], P<0.001; 5 [2.7%] versus 3 [0.7%], P=0.030; and 5 [2.7%] versus 2 [0.5%], P=0.013, respectively). CONCLUSIONS: The current study demonstrates that patients with protruding aortic plaque have more features of coronary plaque vulnerability and are at increased risk of future adverse events.

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.

Sex-Specific Association Between Perivascular Inflammation and Plaque Vulnerability.

BACKGROUND: It is not known whether there is a sex difference in the association between perivascular inflammation and plaque vulnerability. The aim of this study was to investigate the sex-specific association between perivascular inflammation and plaque vulnerability. METHODS: Patients who underwent coronary computed tomography angiography and optical coherence tomography were enrolled. All images were analyzed at a core laboratory. The level of perivascular inflammation was assessed by pericoronary adipose tissue attenuation on computed tomography angiography and the level of plaque vulnerability by optical coherence tomography. Patients were classified into 3 groups according to tertile levels of culprit vessel pericoronary adipose tissue attenuation (low inflammation, ≤-73.1 Hounsfield units; moderate inflammation, -73.0 to -67.0 Hounsfield units; or high inflammation, ≥-66.9 Hounsfield units). RESULTS: A total of 968 lesions in 409 patients were included: 184 lesions in 82 women (2.2 plaques per patient) and 784 lesions in 327 men (2.4 plaques per patient). Women were older (median age, 71 versus 65 years; P<0.001) and had less severe coronary artery disease with a lower plaque burden than men. In women, it was found that perivascular inflammation was significantly associated with plaque vulnerability, with a higher prevalence of thin-cap fibroatheroma and greater macrophage grades in the high inflammation group compared with the low inflammation group (low versus moderate versus high inflammation in women: 18.5% versus 31.8% versus 46.9%, P=0.002 for low versus high inflammation; 3 versus 4 versus 12, P<0.001 for low versus high inflammation, respectively). However, no significant differences were observed among the 3 groups in men. CONCLUSIONS: Perivascular inflammation was associated with a higher prevalence of thin-cap fibroatheroma and more significant macrophage accumulation in women but not in men. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Coronary plaque phenotype associated with positive remodeling.

BACKGROUND: Positive remodeling is an integral part of the vascular adaptation process during the development of atherosclerosis, which can be detected by coronary computed tomography angiography (CTA). METHODS: A total of 426 patients who underwent both coronary CTA and optical coherence tomography (OCT) were included. Four machine learning (ML) models, gradient boosting machine (GBM), random forest (RF), deep learning (DL), and support vector machine (SVM), were employed to detect specific plaque features. A total of 15 plaque features assessed by OCT were analyzed. The variable importance ranking was used to identify the features most closely associated with positive remodeling. RESULTS: In the variable importance ranking, lipid index and maximal calcification arc were consistently ranked high across all four ML models. Lipid index and maximal calcification arc were correlated with positive remodeling, showing pronounced influence at the lower range and diminishing influence at the higher range. Patients with more plaques with positive remodeling throughout their entire coronary trees had higher low-density lipoprotein cholesterol levels and were associated with a higher incidence of cardiovascular events during 5-year follow-up (Hazard ratio 2.10 [1.26-3.48], P â€‹= â€‹0.004). CONCLUSION: Greater lipid accumulation and less calcium burden were important features associated with positive remodeling in the coronary arteries. The number of coronary plaques with positive remodeling was associated with a higher incidence of cardiovascular events.

Level of Perivascular Inflammation Is Significantly Lower Around the Left Internal Mammary Artery Than Around Native Coronary Arteries.

BACKGROUND: The left internal mammary artery (LIMA) is protected from developing atherosclerosis. Perivascular inflammation, which is closely associated with atherosclerosis, can be measured by perivascular adipose tissue attenuation on computed tomography angiography. Whether the absence of atherosclerosis in LIMA is related to the lower level of perivascular inflammation is unknown. This study was performed to compare the level of perivascular inflammation between LIMA in situ and native coronary arteries in patients with coronary artery disease. METHODS AND RESULTS: A total of 573 patients who underwent both computed tomography angiography and optical coherence tomography imaging were included. The level of perivascular adipose tissue attenuation between LIMA in situ and coronary arteries was compared. Perivascular adipose tissue attenuation around LIMA in situ was significantly lower around the 3 coronary arteries (-82.9 [-87.3 to -78.0] versus -70.8 [-75.9 to -65.9]; P<0.001), irrespective of the level of pericoronary inflammation or the number of vulnerable features on optical coherence tomography. When patients were divided into high and low pericoronary inflammation groups, those in the high inflammation group had more target vessel failure (hazard ratio, 2.97 [95% CI, 1.16-7.59]; P=0.017). CONCLUSIONS: The current study demonstrated that perivascular adipose tissue attenuation was significantly lower around LIMA in situ than around native coronary arteries. The lower level of perivascular inflammation may be related to the low prevalence of atherosclerosis in LIMA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04523194.

Computed Tomography Angiography Characteristics of Thin-Cap Fibroatheroma in Patients With Diabetes.

BACKGROUND: It was recently reported that thin-cap fibroatheroma (TCFA) detected by optical coherence tomography was an independent predictor of future cardiac events in patients with diabetes. However, the clinical usefulness of this finding is limited by the invasive nature of optical coherence tomography. Computed tomography angiography (CTA) characteristics of TCFA have not been systematically studied. The aim of this study was to investigate CTA characteristics of TCFA in patients with diabetes. METHODS AND RESULTS: Patients with diabetes who underwent preintervention CTA and optical coherence tomography were included. Qualitative and quantitative analyses were performed for plaques on CTA. TCFA was assessed by optical coherence tomography. Among 366 plaques in 145 patients with diabetes, 111 plaques had TCFA. The prevalence of positive remodeling (74.8% versus 50.6%, P<0.001), low attenuation plaque (63.1% versus 33.7%, P<0.001), napkin-ring sign (32.4% versus 11.0%, P<0.001), and spotty calcification (55.0% versus 34.9%, P<0.001) was significantly higher in TCFA than in non-TCFA. Low-density noncalcified plaque volume (25.4 versus 15.7 mm3, P<0.001) and remodeling index (1.30 versus 1.20, P=0.002) were higher in TCFA than in non-TCFA. The presence of napkin-ring sign, spotty calcification, high low-density noncalcified plaque volume, and high remodeling index were independent predictors of TCFA. When all 4 predictors were present, the probability of TCFA increased to 82.4%. CONCLUSIONS: The combined qualitative and quantitative plaque analysis of CTA may be helpful in identifying TCFA in patients with diabetes. REGISTRATION INFORMATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Role of Lipid-Lowering and Anti-Inflammatory Therapies on Plaque Stabilization.

Atherosclerosis is the predominant underlying etiopathology of coronary artery disease. Changes in plaque phenotype from stable to high risk may spur future major adverse cardiac events (MACE). Different pharmacological therapies have been implemented to mitigate this risk. Over the last two decades, intravascular imaging modalities have emerged in clinical studies to clarify how these therapies may affect the composition and burden of coronary plaques. Lipid-lowering agents, such as statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, were shown not only to reduce low-density lipoprotein levels and MACE but also to directly affect features of coronary plaque vulnerability. Studies have demonstrated that lipid-lowering therapy reduces the percentage of atheroma volume and number of macrophages and increases fibrous cap thickness. Future studies should answer the question of whether pharmacological plaque stabilization may be sufficient to mitigate the risk of MACE for selected groups of patients with atherosclerotic coronary disease.

A novel deep learning model for a computed tomography diagnosis of coronary plaque erosion.

Patients with acute coronary syndromes caused by plaque erosion might be managed conservatively without stenting. Currently, the diagnosis of plaque erosion requires an invasive imaging procedure. We sought to develop a deep learning (DL) model that enables an accurate diagnosis of plaque erosion using coronary computed tomography angiography (CTA). A total of 532 CTA scans from 395 patients were used to develop a DL model: 426 CTA scans from 316 patients for training and internal validation, and 106 separate scans from 79 patients for validation. Momentum Distillation-enhanced Composite Transformer Attention (MD-CTA), a novel DL model that can effectively process the entire set of CTA scans to diagnose plaque erosion, was developed. The novel DL model, compared to the convolution neural network, showed significantly improved AUC (0.899 [0.841-0.957] vs. 0.724 [0.622-0.826]), sensitivity (87.1 [70.2-96.4] vs. 71.0 [52.0-85.8]), and specificity (85.3 [75.3-92.4] vs. 68.0 [56.2-78.3]), respectively, for the patient-level prediction. Similar results were obtained at the slice-level prediction AUC (0.897 [0.890-0.904] vs. 0.757 [0.744-0.770]), sensitivity (82.2 [79.8-84.3] vs. 68.9 [66.2-71.6]), and specificity (80.1 [79.1-81.0] vs. 67.3 [66.3-68.4]), respectively. This newly developed DL model enables an accurate CT diagnosis of plaque erosion, which might enable cardiologists to provide tailored therapy without invasive procedures.Clinical Trial Registration: http://www.clinicaltrials.gov , NCT04523194.

Tomografía de coherencia óptica: situación actual en el diagnóstico intravascular / Optical coherence tomography: its value in intravascular diagnosis today

La tomografía de coherencia óptica es una técnica de diagnóstico intravascular de alta resolución de reciente desarrollo. Inicialmente se centró en la caracterización de la placa arteriosclerótica, ya que permite desde la identificación de placas con alto contenido lipídico hasta la acumulación de macrófagos, ambos hechos relacionados con la inestabilidad de la placa. Actualmente ha cobrado un creciente interés su utilidad en el campo del intervencionismo coronario; presenta grandes ventajas sobre otras técnicas de diagnóstico endovascular más extendidas como la ecografía intravascular: el diámetro de la luz del vaso puede medirse de forma más exacta gracias a su mayor resolución, permite detectar complicaciones del procedimiento como la microdisección de la arteria, puede poner de manifiesto la correcta aposición del stent a la pared del vaso, permite detectar la hiperplasia neointimal tras el implante del stent y la medición del espesor de la neoíntima. Por lo tanto, parece ser una herramienta de gran utilidad para el cardiólogo intervencionista. En esta revisión se analizan los aspectos técnicos y las aplicaciones de esta técnica y se la compara con otras técnicas de diagnóstico intravascular (AU)

Optical coherence tomography is a recently developed high-resolution intravascular diagnostic technique. Initially, it was mainly used for characterizing atherosclerotic plaque because it served a number of functions, from identifying plaque with high lipid content to detecting macrophage accumulation, both of which are associated with plaque instability. Currently, there is growing interest in the value of optical coherence tomography in the area of coronary intervention, where the technique offers significant advantages over more widespread intravascular diagnostic techniques such as intravascular ultrasound: its higher resolution means that the vessel lumen diameter can be measured more precisely, periprocedural complications such microdissection of the coronary artery can be detected, stent apposition relative to the vessel wall can be optimized, neointimal hyperplasia can be detected after stent implantation, and neointimal thickness can be measured. It would therefore appear to be a very useful technique for interventional cardiologists. This review article considers the technical details of the technique and its applications, and compares it with other intravascular diagnostic techniques (AU)

Trombocitopenia inducida por heparina / Heparin-induced thrombocytopenia

La complicación más común y reconocida del tratamiento con heparina es la hemorragia, pero una complicación potencialmente más peligrosa es el desarrollo de la trombocitopenia inducida por heparina (TIH). Todos los pacientes expuestos a heparina de cualquier tipo y a cualquier dosis están en riesgo de TIH. Se debe a la formación de anticuerpos contra el complejo heparina-factor plaquetario 4, que secundariamente activa las plaquetas y la coagulación y finalmente produce un aumento en la formación de trombina. El síntoma principal es una trombocitopenia brusca, con una caída del 50% en el recuento plaquetario con respecto a los valores basales, y/o complicaciones trombóticas que aparecen 5 a 14 días tras el comienzo del tratamiento con heparina. La monitorización del recuento plaquetario en pacientes que reciben heparina permite el diagnóstico precoz de la TIH. La demostración de la activación plaquetaria dependiente de heparina con métodos antigénicos o funcionales confirma el diagnóstico. Una vez que se confirma serológicamente el diagnóstico de TIH o la sospecha es alta, se debe suspender el tratamiento con heparina y valorar el tratamiento con anticoagulantes alternativos. En esta revisión se discute los aspectos diagnósticos y el manejo de este síndrome (AU)

Hemorrhage is the most common and best-recognized complication of heparin treatment. However, a potentially more dangerous complication is the development of heparin-induced thrombocytopenia (HIT). All patients exposed to heparin, irrespective of the dose and route of administration, are at risk of developing HIT. It is due to the formation of antibodies against the heparin­platelet factor 4 complex, which cause secondary activation of platelets, coagulation and, finally, increased thrombin production. The main symptom is the sudden onset of thrombocytopenia involving a drop in the platelet count to less than 50% of the basal level, with or without the appearance of thrombotic complications some 5 to 14 days after the start of heparin therapy. Heparin-induced thrombocytopenia can be detected early in patients receiving heparin by monitoring the platelet count. Demonstration of heparin-dependent platelet activation using an antigen or functional assay confirms the clinical diagnosis. Once the diagnosis of HIT has been confirmed serologically or there is a high level of suspicion of HIT, heparin must be suspended and treatment with an alternative anticoagulant should be considered. This review contains a discussion of the diagnosis and treatment of this syndrome (AU)