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Background: Discordant physiology and anatomy may occur when nonsevere angiographic stenosis has positive physiology as well as the opposite situation., Aim: To underline the reasons behind the discrepancy in physiology and anatomy and to summarize the information that coronary imaging may add to physiology., Methods: A review of the published literature on physiology and intravascular imaging assessment of intermediate lesions was carried out., Results: The limitations of angiography, the possibility of an underlying diffuse disease, the presence of a "grey zone" in both techniques, the amount of myocardial mass that subtends the stenosis, and plaque vulnerability may play a role in such discrepancy. Intracoronary imaging has a poor diagnostic accuracy compared to physiology. However, it may add information about plaque vulnerability that might be useful in deciding whether to treat or not a certain lesion., Conclusions: Coronary revascularization is recommended for patients with ischemia based on physiology. Intracoronary imaging adds information on plaque vulnerability and can help on the decision whether to revascularize or not a lesion., (© 2022 Wiley Periodicals LLC.)

Purpose: Osteocalcin (OC), an osteoblast-derived regulator of metabolic processes, and circulating early endothelial progenitor cells (EPC, CD34 - /CD133 + /KDR +) expressing OC (OC +) are potential candidates linking bone metabolism and the vasculature and might be involved in vascular atherosclerotic calcification. This study aimed at assessing the association of circulating levels of different OC forms and of EPCs count with disease severity in patients with documented coronary atherosclerosis (CAD)., Methods: Patients (n = 59) undergoing coronary angiography were divided, according to stenosis severity, into (1) early coronary atherosclerosis (ECA) (n = 22), and (2) late coronary atherosclerosis (LCA) (n = 37). Total OC (TOC), carboxylated OC (cOC), undercarboxylated OC (unOC) were quantified by ELISA. EPC OC + count was assessed by flow cytometry., Results: EPC OC + counts showed significant differences between ECA and LCA groups. unOC and unOC/TOC ratio were inversely correlated with EPC OC + count. A significant decrease in TOC and unOC plasma levels was associated with higher cardiovascular risk factors (CVRFs) number. EPC OC + count was correlated with LDL-C, total cholesterol, and triglycerides, with a greater significance in the LCA group. No association between the different forms of circulating OC (TOC, ucOC, cOC) and severity of CAD was found., Conclusion: This study showed a significant association between EPCs (CD34 - /CD133 + /KDR + /OC +), CAD severity and CVRFs, suggesting an active role for EPC OC + in the development of CAD. An inverse correlation between TOC, ucOC, and number of CVRFs was observed, suggesting that OC, regardless of its carboxylation status, may be developed as a further cardiovascular risk biomarker., (© 2022. The Author(s).)

Background: Coronary artery disease (CAD) is among prominent causes of death throughout the world. Inflammatory processes participate in the pathogenesis of this disorder., Methods: In the current case-control study, we compared expression levels of three inflammation-associated genes namely Antisense noncoding RNA in the INK4 locus ( ANRIL ), NKILA and IL-1B between CAD patients and matched healthy subjects., Results: ANRIL , IL-1B and NKILA were significantly down-regulated in CAD patients compared with controls ( p values of <.0001, .023 and <.0001, respectively). When evaluating study participants based on their gender, the differences in expression levels of ANRIL and NKILA were significant in both male and female patients compared with the matched controls. However, IL-1B was only down-regulated in female patients compared with female controls., Conclusion: Taken together, our study revealed dysregulation of inflammation-associated genes in the peripheral blood of CAD patients and supported the previously suggested role of inflammation in the pathogenesis of CAD.

Background: Rapid screening and accurate diagnosis of acute myocardial infarction are critical to reduce the progression of myocardial necrosis, in which proteolytic degradation of myocardial extracellular matrix plays a major role. In previous studies, we found that targeting the extracellular matrix metalloprotease inducer (EMMPRIN) by injecting nanoparticles conjugated with the specific EMMPRIN-binding peptide AP9 significantly improved cardiac function in mice subjected to ischemia/reperfusion., Methods: In a porcine model of coronary ischemia/reperfusion, we tested the theragnostic effects of administering 0.1 mg/kg gadolinium-containing nanoparticles conjugated with AP9 (NAP9), a synthetic peptide that targets EMMPRIN or a control nanoparticle (NAPSC). Cardiac magnetic resonance assessment of the infarct progression, ventricular function, and nanoparticle distribution was performed the next 7 days. We also measured the infarcted area of the heart and cardiac remodeling at 7 or 21 days after ischemia/reperfusion., Results: After 21 days of ischemia/reperfusion, NAP9 reduced the extension of cardiac necrosis (14.1±9.7 versus 35.5±1.8) and the levels of collagenolytic activity of MMPs (matrix metalloproteases), along with a significant reduction in collagen deposition (7.5±4.5 versus 41.3±20); including the ratio of type I versus III collagen fibers in the necrotic myocardium. In terms of cardiac function, the response to NAP9 administration resulted in a significant improvement of cardiac performance overtime, as evidenced by the left ventricle ejection fraction (64.0±7.8), when compared with those present in the NAPSC group (47.3±4.7). As shown by magnetic resonance imaging, noninvasive molecular imaging of NAP9 enabled us to find a significant reduction in cardiac necrosis, myocardial edema, hemorrhage, and microvascular obstruction, suggesting that NAP9 may reduce myocardial injury and preserve left ventricular function, at least, by preventing the effect of EMMPRIN on extracellular matrix degradation., Conclusions: Our data point towards NAP9 as a promising theragnostic tool in managing acute myocardial infarction, by inhibiting EMMPRIN-induced extracellular matrix degradation and allowing noninvasive visualization of cardiac necrosis progression over time.

Background: Despite the significant decline in cardiovascular mortality in women over the past several decades, sex differences in the underlying pathology of acute coronary syndromes remain poorly understood. Previous postmortem studies have demonstrated sex differences in coronary plaque morphology with a higher prevalence of plaque erosion in young women and more plaque rupture in older women after menopause, whereas men showed no increase in prevalence of plaque rupture with age. However, in vivo data are limited., Methods: This study included patients who presented with acute coronary syndrome and underwent preintervention optical coherence tomography imaging of the culprit lesion. The culprit plaque was categorized as plaque rupture, plaque erosion or culprit plaque with calcification, and stratified by age. Features of plaque vulnerability at culprit lesion were also analyzed., Results: In 1368 patients (women=286), women and men had a similar distribution of culprit plaque morphology (plaque rupture versus plaque erosion). However, significant sex differences were found in the underlying mechanisms of acute coronary syndrome among different age groups: women showed a significant ascending trend with age in plaque rupture ( P <0.001) and the features of plaque vulnerability such as lipid plaque ( P <0.001), thin-cap fibroatheroma ( P =0.005), and microstructures including macrophages, cholesterol crystals, and calcification ( P =0.026). No trend was observed in men., Conclusions: Age related sex differences in culprit plaque morphology and vulnerability were identified in patients with acute coronary syndrome: prevalence of plaque rupture and vulnerability increased with age in women but not in men., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01110538 and NCT03479723.

Left main coronary artery disease is associated with an unfavorable prognosis. Evidence-based decision making regarding the optimal revascularization strategy in patients with left main disease has become a challenge, in view of the recently published data. An improvement in outcomes following left main percutaneous interventions could be achieved by reducing the rate of repeat target lesion revascularization through stent optimization techniques. In the setting of left main disease, procedural guidance by intravascular ultrasound or optical coherence tomography is essential for good long-term results, in such a way that intravascular imaging has gained more of a therapeutic connotation. Besides stent optimization, intracoronary imaging quantifies lesion severity, guides lesion preparation through morphological data, facilitates stent selection through accurate vessel sizing, identifies the landing zones, diagnoses acute vessel wall complications such as stent-related edge dissection or intramural hematoma, and defines procedural success.This review focuses on the two main intracoronary imaging techniques used for diagnostic evaluation and procedural guidance in left main coronary artery disease: intravascular ultrasound and optical coherence tomography. Based on the most recently published data, the review discusses each technique's advantages and pitfalls, and summarizes their indications.

Objectives: The aim of this study was to compare the level of coronary inflammation between plaque rupture and plaque erosion using pericoronary adipose tissue (PCAT) attenuation., Background: Vascular inflammation plays a key role in plaque rupture, while the role of inflammation in plaque erosion remains less well defined. PCAT attenuation determined using computed tomography has emerged as a marker specific for coronary artery inflammation., Methods: Patients with non-ST-segment elevation acute coronary syndromes who underwent preintervention coronary computed tomographic angiography and optical coherence tomographic culprit lesion imaging were enrolled. PCAT attenuation was measured around the culprit lesion and in the proximal 40 mm of all coronary arteries., Results: Among 198 patients, plaque rupture was the underlying mechanism in 107 (54.0%) and plaque erosion in 91 (46.0%). Plaque rupture had higher PCAT attenuation than plaque erosion both at the culprit plaque level (-65.8 ± 7.5 HU vs -69.5 ± 11.4 HU; P = 0.010) and at the culprit vessel level (-67.1 ± 7.1 HU vs -69.6 ± 8.2 HU; P = 0.024). The mean PCAT attenuation of all 3 coronary arteries was also significantly higher in patients with plaque rupture than in plaque erosion, indicating a higher level of inflammation (-67.9 ± 5.7 HU vs -69.9 ± 6.8 HU; P = 0.030). In multivariable analysis, plaque rupture was significantly associated with high PCAT attenuation., Conclusions: PCAT attenuation in culprit plaque, culprit vessel, and all 3 coronary arteries was higher in plaque rupture than in plaque erosion. The results suggest that pancoronary inflammation plays a more significant role in plaque rupture than in plaque erosion. (Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration; NCT04523194)., Competing Interests: Funding Support and Author Disclosures Dr Jang’s research was supported by Mr and Mrs Allan and Gill Gray and by Mr and Mrs Michael and Kathryn Park. Dr Dey is supported by National Heart, Lung, and Blood Institute grants (1R01HL148787-01A1 and 1R01HL151266). The funders had no role in the design or conduct of this research. Dr Jang has received educational grant support from Abbott Vascular; and consulting fees from Svelte Medical Systems and Mitobridge. Outside the present study, Dr Dey has received software royalties from Cedars-Sinai Medical Center; and has a patent. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Guidelines recommend intracoronary optical coherence tomography (OCT) to assess stent failure and guide percutaneous coronary intervention (PCI) but OCT may be useful for other indications in routine clinical practice., Methods/materials: We conducted an international registry of OCT cases at two large tertiary care centers to assess clinical indications and the potential impact on decision making of OCT in clinical routine. Clinical indications, OCT findings, and their impact on interventional or medical treatment strategy were retrospectively assessed., Results: OCT was performed in 810 coronary angiography cases (1928 OCT-pullbacks). OCT was used for diagnostic purposes in 67% (N = 542) and OCT-guided percutaneous coronary intervention in 50% (N = 404, 136 cases with prior diagnostic indication). Most frequent indications for diagnostic OCT were culprit lesion identification in suspected ACS (29%) and stent failure assessment (28%). OCT findings in the diagnostic setting influenced patient management in 74%. OCT-guided PCIs concerned ACS patients in 45%. Among the 55% with chronic coronary syndrome, long lesions >28 mm (19%), left main PCI (16%), and bifurcation PCI with side-branch-stenting (5%) were the leading indications for PCI-guidance. Post-procedural OCT findings led to corrective measures in 52% (26% malapposition, 14% underexpansion, 6% edge dissection, 3% intrastent mass, 3% geographic plaque miss)., Conclusions: OCT was most frequently performed to identify culprit lesions in suspected ACS, for stent failure assessment, and PCI-guidance. OCT may impact subsequent treatment strategies in two out of three patients., Competing Interests: Declaration of competing interest JH received a travel-grant from Bayer. GCMS reported receiving honoraria from Abbott outside the submitted work. SB reports a research grant to the institution from Medis Medical Imaging Systems. SS has received research grants to the institution from Edwards Lifesciences, Medtronic, Abbott Vascular and Boston Scientific, serves as consultant for BTG and Teleflex and has received speaker fees from BTG and Boston Scientific. PM serves as consultant for St Jude Medical / Abbott and Terumo. SW reports research and educational grants to the institution from Abbott, Amgen, Bayer, BMS, Boston Scientific, Biotronik, Cardinal Health, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet AG, Johnson&Johnson, Medtronic, Sanofi-Aventis, and Terumo. SW serves as unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Polares, Sinomed, V-Wave, and Xeltis, but has not received personal payments by any pharmaceutical company or device manufacturer. SW is member of the steering/executive committee group of several investigated-initiated trials that receive funding by industry without impact on his personal remuneration. GS serves as consultant for St Jude Medical / Abbott and Terumo. LR received research grants to the institution by Abbott, Biotronik, BostonScientific, Medis, Infraredx, Sanofi, Regeneron and consultation/speaker fees by Abbott, Amgen, AstraZeneca, Canon, Sanofi, Vifor. All other author have nothing to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autopsy studies have established that thin-cap fibroatheromas (TCFAs) are the most frequent cause of fatal coronary events. In living patients, optical coherence tomography (OCT) has sufficient resolution to accurately differentiate TCFA from thick-cap fibroatheroma (ThCFA) and not lipid rich plaque (non-LRP). However, the impact of OCT-detected plaque phenotype of nonischemic lesions on future adverse events remains unknown. Therefore, we studied the natural history of OCT-detected TCFA, ThCFA, and non-LRP in patients enrolled in the prospective multicenter COMBINE FFR-OCT trial (Combined Optical Coherence Tomography Morphologic and Fractional Flow Reserve Hemodynamic Assessment of Non-Culprit Lesions to Better Predict Adverse Event Outcomes in Diabetes Mellitus Patients)., Methods: In the COMBINE FFR-OCT trial, patients with diabetes and ≥1 lesion with a fractional flow reserve >0.80 underwent OCT evaluation and were clinically followed for 18 months. A composite primary end point of cardiac death, target vessel-related myocardial infarction, target-lesion revascularization, and hospitalization for unstable angina was evaluated in relation to OCT-based plaque morphology., Results: A total of 390 patients (age 67.5±9 years; 63% male) with ≥1 nonischemic lesions underwent OCT evaluation: 284 (73%) had ≥1 LRP and 106 (27%) non-LRP lesions. Among LRP patients, 98 (34.5%) had ≥1 TCFA. The primary end point occurred in 7% of LRP patients compared with 1.9% of non-LRP patients (7.0% versus 1.9%; hazard ratio [HR], 3.9 [95% CI, 0.9-16.5]; P =0.068; log rank- P =0.049). However, within LRP patients, TCFA patients had a much higher risk for primary end point compared with ThCFA (13.3% versus 3.8%; HR, 3.8 [95% CI, 1.5-9.5]; P <0.01), and to non-LRP patients (13.3% versus 1.9%; HR, 7.7 [95% CI, 1.7-33.9]; P <0.01), whereas ThCFA patients had risk similar to non-LRP patients (3.8% versus 1.9%; HR, 2.0 [95% CI, 0.42-9.7]; P =0.38). Multivariable analyses identified TCFA as the strongest independent predictor of primary end point (HR, 6.79 [95% CI, 1.50-30.72]; P =0.013)., Conclusions: Among diabetes patients with fractional flow reserve-negative lesions, patients carrying TCFA lesions represent only one-third of LRP patients and are associated with a high risk of future events while patients carrying LRP-ThCFA and non-LRP lesions portend benign outcomes., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02989740.

Background: Coronary artery disease (CAD) is the single most common cause of death worldwide. Recent technological developments with coronary cardiovascular magnetic resonance angiography (CCMRA) allow high-resolution free-breathing imaging of the coronary arteries at submillimeter resolution without contrast in a predictable scan time of ~ 10 min. The objective of this study was to determine the diagnostic accuracy of high-resolution CCMRA for CAD detection against the gold standard of invasive coronary angiography (ICA)., Methods: Forty-five patients (15 female, 62 ± 10 years) with suspected CAD underwent sub-millimeter-resolution (0.6 mm 3 ) non-contrast CCMRA at 1.5T in this prospective clinical study from 2019-2020. Prior to CCMR, patients were given an intravenous beta blockers to optimize heart rate control and sublingual glyceryl trinitrate to promote coronary vasodilation. Obstructive CAD was defined by lesions with ≥ 50% stenosis by quantitative coronary angiography on ICA., Results: The mean duration of image acquisition was 10.4 ± 2.1 min. On a per patient analysis, the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 95% (75-100), 54% (36-71), 60% (42-75) and 93% (70-100), respectively. On a per vessel analysis the sensitivity, specificity, positive predictive value and negative predictive value (95% confidence intervals) were 80% (63-91), 83% (77-88), 49% (36-63) and 95% (90-98), respectively., Conclusion: As an important step towards clinical translation, we demonstrated a good diagnostic accuracy for CAD detection using high-resolution CCMRA, with high sensitivity and negative predictive value. The positive predictive value is moderate, and combination with CMR stress perfusion may improve the diagnostic accuracy. Future multicenter evaluation is now required., (© 2022. The Author(s).)

Coronary artery ectasia (CAE) is associated with increased risk of mortality, equivalent to that of patients with obstructive coronary artery disease (CAD). Considering the role of inflammation in the pathogenesis of CAE, we aimed to investigate whether there is an association between systemic immune-inflammation index (SII) and isolated CAE. The study population included 510 patients of which 170 patients with isolated CAE, 170 patients with obstructive CAD and 170 patients with normal coronary angiograms (NCA). The severity of CAE was determined according to the Markis classification. Patients with isolated CAE had significantly higher SII values compared to those with obstructive CAD and NCA [median 550 IQR (404-821), median 526 IQR (383-661), and median 433 IQR (330-555), respectively, p  < .001]. In multivariate analysis, SII (OR 1.032, 95% CI 1.020-1.044, p  = .003), male gender (OR 2.083, p  = .008), eGFR (OR 0.979, p  = .016), and CRP (OR 1.105, p  = .005) were independent factors of isolated CAE. Moreover, in the Spearman correlation analysis, there was a moderate but significant positive correlation between SII and CRP ( r  = 0.379, p  < .001). In conclusion, higher SII levels were independently associated with the presence of isolated CAE. This result suggests that a more severe inflammatory process may play a role in the development of this variant of CAD.

Background: The vast majority of sudden and unexpected natural deaths are related to cardiovascular diseases, especially coronary artery diseases., Aims: In this study, we aimed to reveal the epidemiological differences between men and women and to investigate the most common pathologies that cause cardiac deaths., Methods: Five thousand seven hundred sixty-eight autopsy cases that were done in 2016 were reviewed for the autopsy information and histopathological findings. Of the 5768 autopsies performed, 866 were due to cardiac causes. Eight hundred thirty-two cases were reviewed due to lack of autopsy information in 34 cases., Results: One hundred sixteen (13.9%) were female, and 716 (86.1%) were male. Coronary artery disease was detected in 760 of 832 cases. There were findings of acute or previous myocardial infarction in 595 (71.5%), perivascular and interstitial fibrosis in 159 (19.1%), myocardial rupture and tamponade in 31 (%3.7), valvular disease in 6 (0.7%), cardiomyopathy in 4 (0.5%), and congenital heart disease in 3 (0.4%). In the study, it was observed that the mean age of death due to cardiac pathology other than coronary artery disease was significantly lower than deaths due to coronary artery disease (p < 0.05). The presence of coronary artery disease in men was found to be significantly higher than in women (p < 0.001)., Conclusion: In our study, it was found that deaths due to coronary artery disease are seen at an older age than cardiac deaths other than coronary artery disease. In addition, in line with current knowledge, it has been confirmed that the mortality rate of coronary artery disease is higher in men than in women., (© 2021. Royal Academy of Medicine in Ireland.)

Background: Optical coherence tomography (OCT) is a high-resolution imaging modality that provides a precise evaluation of coronary anatomy. However, the presence of severe coronary lesions can prevent the required adequate distal contrast flushing resultting in inadequate blood clearance and poor image quality or complete blood shadowing of the underlying vessel wall., Objectives: The aim of this prospective study was to evaluate the feasibility and safety of a novel "double injection technique" (DIT) to overcome the limitations of the conventional technique (CT) in patients with severely stenotic lesions., Methods: Twenty-three patients with severe angiographic lesions were sequentially imaged before intervention with OCT with the CT and then with DIT. A total of 5125 OCT frames were carefully matched and analyzed by an independent central core lab. A semiquantitative image quality score was used to grade the number of quadrants (0-4) with vessel wall visualization., Results: Optimal OCT visualization (Grades 3-4) significantly improved by the DIT (68% vs. 38% of frames, p < 0.001). The DIT also improved the mean score (3.1 ± 0.6 vs. 2.0 ± 0.8; p < 0.05; mean improvement of 1.1 ± 0.5 per patient). There were no complications associated with the DIT., Conclusion: The DIT significantly improved preintervention image quality of OCT in severe coronary lesions., (© 2022 Wiley Periodicals LLC.)

Background: Radial artery (RA) atherosclerosis in acute coronary syndrome (ACS) patients has not been systematically observed in vivo. The study aims to characterize plaque morphology and intimal hyperplasia of the RA in patients with ACS, using optical coherence tomography (OCT)., Methods: In this retrospective study involving 239 ACS patients underwent RA OCT without guidewire shadow, 3 groups were divided according to the following criteria: radial artery plaque (RAP) group included patients with fibrous, lipid or calcified plaque; patients without RAP were further classified into radial intimal hyperplasia (RIH) group (intima media thickness ratio [IMR] ≥ 1) or normal group (IMR < 1). The presence and characteristics of RAP and its related risk factors were identified., Results: The RAP, RIH and normal groups included 76 (31.8%), 69 (28.9%) and 94 (39.3%) patients, respectively. Patients in RAP group were the oldest, compared with those in the RIH and normal groups (p < 0.001), and more frequently had triple vessel disease (p = 0.004). The percentage of plaque rupture (72.4% vs. 56.4%, p = 0.018) and calcification (42.1% vs. 27.6%, p = 0.026) at culprit lesion were significantly higher in patients with RAP than those without RAP. A total of 148 RAP were revealed by OCT, including fibrous (72, 48.6%), lipid (50, 33.8%) and calcified plaques (26, 17.6%). The microvessels were also frequently observed in the RAP group than that in RIH and normal groups (59.2% vs. 8.7% vs. 9.6%, p < 0.001). Multivariate logistic regression analysis showed that age, diabetes, and smoking history (all p < 0.05) were independent risk factors for RAP., Conclusions: In terms of insights gained from OCT, RA atherosclerosis is not uncommon in ACS patients by OCT, sharing several morphological characters with early coronary atherosclerosis. Aging, diabetes, and smoking are risk factors for RAP., (© 2022. The Author(s).)

Background Inflammation of the perivascular adipose tissue (PvAT) may be related to atherosclerosis; however, the association of polarized macrophages in the pericoronary PvAT with measurements of atherosclerosis components in humans has not been fully investigated. Methods and Results Coronary arteries were dissected with surrounding PvAT. We evaluated the percentage of arterial obstruction, intima-media thickness, fibrous cap thickness, plaque components, and the number of vasa vasorum. The number of proinflammatory (M1) and anti-inflammatory (M2) macrophages in the periplaque and control PvAT were evaluated using immunohistochemistry. Regression models adjusted for sociodemographic and clinical variables were used. In 319 segments from 82 individuals, we found a correlation of the M1/M2 macrophage density ratio with an increase in arterial obstruction ( P =0.02) and lipid content ( P =0.01), and a decrease in smooth muscle cells ( P =0.02). M1 and the ratio of M1/M2 macrophages were associated with an increased risk of thrombosis ( P =0.03). In plaques with thrombosis, M1 macrophages were correlated with a decrease in fibrous cap thickness ( P =0.006), an increase in lipid content ( P =0.008), and the number of vasa vasorum in the adventitia layer ( P =0.001). M2 macrophages were correlated with increased arterial obstruction ( P =0.01), calcification ( P =0.02), necrosis ( P =0.03) only in plaques without thrombosis, and decrease of the number of vasa vasorum in plaques with thrombosis ( P =0.003). Conclusions M1 macrophages in the periplaque PvAT were associated with a higher risk of coronary thrombosis and were correlated with histological components of plaque progression and destabilization. M2 macrophages were correlated with plaque size, calcification, necrotic content, and a decrease in the number of vasa vasorum in the adventitia layer.

Atherosclerotic plaque instability could occur on the basis of healed plaque which has a layered appearance on optical coherence tomography. This study aimed to investigate pancoronary plaque features of layered plaque rupture (LPR) and layered plaque erosion (LPE) in patients with acute myocardial infarction. Among 388 patients with acute myocardial infarction who underwent preintervention optical coherence tomography imaging of three coronary arteries, 190 patients with layered culprit plaque (49.0%) were identified and further divided into 2 groups: LPR group and LPE group. Clinical characteristics, pancoronary plaque features and clinical outcomes were compared between the 2 groups. Patients with LPR were older, less often male and current smoker, and had a lower coronary flow grade than those with LPE. At the culprit lesion, LPR group had a higher prevalence of lipid plaque, thin-cap fibroatheroma (TCFA), macrophage, and microchannel, and presented with more severe lumen area stenosis than LPE group. At nonculprit lesions, LPR group had a higher prevalence of TCFA and had greater layered tissue thickness and area than LPE group. The ischemia-driven revascularization rate was higher in LPR group. Moreover, we found that TCFA, diameter stenosis >56.5%, and mean lipid arc >179.1° were predictors for layered culprit plaque. In conclusion, patients with LPR had more vulnerable plaque features at culprit and nonculprit lesions and had higher incidence of ischemia-driven revascularization than those with LPE. TCFA, diameter stenosis >56.5%, and mean lipid arc >179.1° were predictors of layered culprit plaque., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The ideal treatment strategy for stable three-vessel coronary artery disease (CAD) patients are difficult to determine and for patients undergoing conservative treatment, imaging evidence of coronary atherosclerotic severity progression remains limited. Epicardial fat volume (EFV) on coronary CT angiography (CCTA) has been considered to be associated with coronary atherosclerosis. Therefore, this study aims to evaluate the relationship between EFV level and coronary atherosclerosis severity in three-vessel CAD., Methods: This retrospective study enrolled 252 consecutive patients with three-vessel CAD and 252 normal control group participants who underwent CCTA between January 2018 and December 2019. A semi-automatic method was developed for EFV quantification on CCTA images, standardized by body surface area. Coronary atherosclerosis severity was evaluated and scored by the number of coronary arteries with ≥ 50% stenosis on coronary angiography. Patients were subdivided into groups on the basis of lesion severity: mild (score = 3 vessels, n = 85), moderate (3.5 vessels ≤ score < 4 vessels, n = 82), and severe (4 vessels ≤ score ≤ 7 vessels, n = 85). The independent sample t-test, analysis of variance, and logistic regression analysis were used to evaluate the associations between EFV level and severity of coronary atherosclerosis., Results: Compared with normal controls, three-vessel CAD patients had significantly higher EFV level (65 ± 22 mL/m 2 vs. 48 ± 19 mL/m 2 ; P < 0.001). In patients with three-vessel CAD, there was a progressive decline in EFV level as the score of coronary atherosclerosis severity increased, especially in those patients with a body mass index (BMI) ≥ 25 kg/m 2 (75 ± 21 mL/m 2 vs. 72 ± 22 mL/m 2 vs. 62 ± 17 mL/m 2 ; P < 0.05). Multivariable regression analysis showed that both BMI (OR 3.40, 95% CI 2.00-5.78, P < 0.001) and the score of coronary atherosclerosis severity (OR 0.49, 95% CI 0.26-0.93, P < 0.05) were independently related to the change of EFV level., Conclusion: Three-vessel CAD patients do have higher EFV level than the normal controls. While, there may be an inverse relationship between EFV level and the severity of coronary atherosclerosis in patients with three-vessel CAD., (© 2022. The Author(s).)

Background: In recent years, several trials investigated the role of anti-inflammatory agents in reducing cardiovascular events. Trehalose is a natural disaccharide able to reduce inflammation by enhancing macrophage autophagic activity. This action has been demonstrated to attenuate atherosclerotic plaque development in various pro-atherogenic animal models. However, at present, no data about the efficacy of this compound in human subjects have been published., Methods: We performed a randomized, double-blind trial involving 15 patients with history of myocardial infarction and evidence of systemic inflammation (defined as C-reactive protein > 2 mg/L). The patients were randomly assigned, in 2:1 ratio, to receive either intravenous trehalose (15 g once weekly) or placebo for 12 weeks. The primary efficacy end-point was the change in arterial wall inflammation, assessed by quantifying 18 F-FDG PET/CT uptake in carotid arteries and ascending aorta., Results: The MDS TBR change of the index vessel at 3-month follow-up was not significant in treatment and placebo groups. Furthermore, we could not demonstrate any significant difference between the trehalose group and control group in changes of cIMT from baseline to 3 months in the overall population. No significant changes in echocardiographic measurement were noted after trehalose treatment. Except for the change in urea level in placebo group (31.00 ± 6.59 vs. 25.60 ± 6.402 P = 0.038) no other changes were detected after treatment. Also, there was a significant difference between changes in alanine aminotransferase (ALT) trehalose and placebo groups., Conclusion: This was the first study that specifically assessed the effects of intravenous trehalose on atherogenesis in human subjects. Trehalose treatment was characterized by an optimal safety profile, but no significant reduction in arterial wall inflammation could be observed. This might be a consequence of the small sample size of this trial. Larger studies are needed to better assess the efficacy of this compound in this clinical context., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background and Aims: Accurate classification of plaque composition is essential for treatment planning. Intravascular ultrasound (IVUS) has limited efficacy in assessing tissue types, while near-infrared spectroscopy (NIRS) provides complementary information to IVUS but lacks depth information. The aim of this study is to train and assess the efficacy of a machine learning classifier for plaque component classification that relies on IVUS echogenicity and NIRS-signal, using histology as reference standard., Methods: Matched NIRS-IVUS and histology images from 15 cadaveric human coronary arteries were analyzed (10 vessels were used for training and 5 for testing). Fibrous/pathological intimal thickening (F-PIT), early necrotic core (ENC), late necrotic core (LNC), and calcific tissue regions-of-interest were detected on histology and superimposed onto IVUS frames. The pixel intensities of these tissue types from the training set were used to train a J48 classifier for plaque characterization (ECHO-classification). To aid differentiation of F-PIT from necrotic cores, the NIRS-signal was used to classify non-calcific pixels outside yellow-spot regions as F-PIT (ECHO-NIRS classification). The performance of ECHO and ECHO-NIRS classifications were validated against histology., Results: 262 matched frames were included in the analysis (162 constituted the training set and 100 the test set). The pixel intensities of F-PIT and ENC were similar and thus these two tissues could not be differentiated by echogenicity. With ENC and LNC as a single class, ECHO-classification showed good agreement with histology for detecting calcific and F-PIT tissues but had poor efficacy for necrotic cores (recall 0.59 and precision 0.29). Similar results were found when F-PIT and ENC were treated as a single class (recall and precision for LNC 0.78 and 0.33, respectively). ECHO-NIRS classification improved necrotic core and LNC detection, resulting in an increase of the overall accuracy of both models, from 81.4% to 91.8%, and from 87.9% to 94.7%, respectively. Comparable performance of the two models was seen in the test set where the overall accuracy of ECHO-NIRS classification was 95.0% and 95.5%, respectively., Conclusions: The combination of echogenicity with NIRS-signal appears capable of overcoming limitations of echogenicity, enabling more accurate characterization of plaque components., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A coronary artery calcium score (CACS) of 0 is associated with a very low risk of cardiac event. However, the Agatston CACS may fail to detect very small or less dense calcifications. We investigated if an alteration of the Agatston criteria would affect the ability to detect such plaques., Methods: We evaluated 322 patients, 161 who had a baseline scan with CACS ​= ​0 and a follow-up scan with CACS>0 and 161 with two serial CACS ​= ​0 scans (control group), to identify subtle calcification not detected in the baseline scan because it was not meeting the Agatston size and HU thresholds (≥1 ​mm 2 and ≥130HU). Size threshold was set to <1 ​mm 2 and the HU threshold modified in a stepwise manner to 120, 110, 100 and 90. New lesions were classified as true positive or false positive(noise) using the follow-up scan., Results: We identified 69 visually suspected subtle calcified lesions in 65/322 (20.2%) patients with CAC ​= ​0 by the Agatston criteria. When size threshold was set as <1 ​mm 2 and HU ​≥ ​130, 36 lesions scored CACS>0, 34 (94.4%) true positive and 2 (5.6%) false positive. When decrease in HU (120HU, 110HU, 100HU, and 90HU) threshold was added to the reduced size threshold, the number of lesions scoring>0 increased (46, 55, 59, and 69, respectively) at a cost of increased false positive rate (8.7%, 20%, 22%, and 30.4% respectively). Eliminating size or both size and HU threshold to ≥120HU correctly reclassified 9.6% and 12.1% of patients respectively., Conclusion: Eliminating size and reducing HU thresholds to ≥120HU improved the detection of subtle calcification when compared to the Agatston CACS method., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest relevant to this study., (Copyright © 2021 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Prior coronary optical coherence tomography (OCT)-near infrared auto-fluorescence (NIRAF) imaging data has shown a correlation between high-risk morphological features and NIRAF signal intensity. This study aims to understand the histopathological origins of NIRAF in human cadaver coronary arteries., Methods: Ex vivo intracoronary OCT-NIRAF imaging was performed on coronary arteries prosected from 23 fresh human cadaver hearts. Arteries with elevated NIRAF were formalin-fixed and paraffin-embedded. Microscopic images of immunostained Glycophorin A (indicating intraplaque hemorrhage) and Sudan Black (indicating ceroid after fixation) stained slides were compared with confocal NIRAF images (ex. 635 nm, em. 655-755 nm) from adjacent unstained slides in each section. Different images from the same section were registered via luminal morphology. Confocal NIRAF-positive 45° sectors were compared to immunohistochemistry and colocalization between NIRAF and intraplaque hemorrhage or ceroid was quantified by Manders' overlap and Dice similarity coefficients., Results: Thirty-one coronary arteries from 14 hearts demonstrated ≥1.5 times higher NIRAF signal than background, and 429 sections were created from them, including 54 sections (12.6%) with high-risk plaques. Within 112 confocal NIRAF-positive 45° sectors, 65 sectors (58.0%) showed both Glycophorin A-positive and Sudan Black-positive, while 7 sectors (6.3%) and 40 sectors (33.6%) only showed Glycophorin A-positive or Sudan black-positive, respectively. A two-tailed McNemar's test showed that Sudan Black more closely corresponded to confocal NIRAF than Glycophorin A (p < 1.0 × 10 -6 ). NIRAF was also found to spatially associate with both Glycophorin A and Sudan Black, with stronger colocalization between Sudan Black and NIRAF (Manders: 0.19 ± 0.15 vs. 0.13 ± 0.14, p < 0.005; Dice: 0.072 ± 0.096 vs. 0.060 ± 0.090, p < 0.01)., Conclusions: As ceroid associates with oxidative stress and intraplaque hemorrhage is implicated in rapid lesion progression, these results suggest that NIRAF provides additional, complementary information to morphologic imaging that may aid in identifying high-risk coronary plaques via translatable intracoronary OCT-NIRAF imaging., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Improvement of non-invasive identification of high-risk plaque may increase the preventive options of acute coronary syndrome. To describe the characteristics of thin-cap fibroatheroma (TCFA) in a post mortem model in comparison to characteristics of culprit lesions in patients with non-ST-elevation-myocardial-infarction (NSTEMI) using the dual energy computed tomography (DECT). Three post mortem hearts were prepared with iodine-contrast, inserted in a Kyoto phantom and scanned by DECT. Six TCFA were identified using histopathological analysis (cap thickness < 65 μm and necrotic core > 10% of the plaque area). In the NSTEMI group, 29 patients were scheduled to DECT prior to coronary angiography and invasive treatment. Culprit lesions were identified blinded for the patient history by two independent invasive cardiologists using the coronary angiography. The DECT analysis of TCFA and culprit lesions was performed retrospectively with determination of effective atomic number (Effective-Z), Hounsfield Unit (HU), plaque type (non-calcified, predominantly non-calcified, predominantly calcified or calcified), spotty calcification,, plaque length, plaque volume and plaque burden and the remodeling index. The Effective-Z, HU and plaqueburden were significantly different between TCFA and culprit lesions (P < 0.05).The TCFA plaques were more calcified in comparison to culprit lesions (P < 0.05). No significant difference in the other plaque characteristics was observed. The use of DECT demonstrated different Effective-Z values and different characteristics of post mortem TCFA in comparison to in vivo culprit lesions. This finding may highlight, that not all TCFA should be considered as vulnerable., (© 2021. Springer Japan KK, part of Springer Nature.)

Lecithin: cholesterol acyltransferase (LCAT) is the only enzyme in plasma which is able to esterify cholesterol and boost cholesterol esterify with phospholipid-derived acyl chains. In order to better understand the progress of LCAT research, it is always inescapable that it is linked to high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). Because LCAT plays a central role in HDL metabolism and RCT, many animal studies and clinical studies are currently aimed at improving plasma lipid metabolism by increasing LCAT activity in order to find better treatment options for familial LCAT deficiency (FLD), fish eye disease (FED), and cardiovascular disease. Recombinant human LCAT (rhLCAT) injections, cells and gene therapy, and small molecule activators have been carried out with promising results. Recently rhLCAT therapies have entered clinical phase II trials with good prospects. In this review, we discuss the diseases associated with LCAT and therapies that use LCAT as a target hoping to find out whether LCAT can be an effective therapeutic target for coronary heart disease and atherosclerosis. Also, probing the mechanism of action of LCAT may help better understand the heterogeneity of HDL and the action mechanism of dynamic lipoprotein particles., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Genome-wide association studies (GWAS) have implicated 58 loci in coronary artery disease (CAD). However, the biological basis for these associations, the relevant genes, and causative variants often remain uncertain. Since the vast majority of GWAS loci reside outside coding regions, most exert regulatory functions. Here we explore the complexity of each of these loci, using tissue specific RNA sequencing data from GTEx to identify genes that exhibit altered expression patterns in the context of GWAS-significant loci, expanding the list of candidate genes from the 75 currently annotated by GWAS to 245, with almost half of these transcripts being non-coding. Tissue specific allelic expression imbalance data, also from GTEx, allows us to uncover GWAS variants that mark functional variation in a locus, e.g., rs7528419 residing in the SORT1 locus, in liver specifically, and rs72689147 in the GUYC1A1 locus, across a variety of tissues. We consider the GWAS variant rs1412444 in the LIPA locus in more detail as an example, probing tissue and transcript specific effects of genetic variation in the region. By evaluating linkage disequilibrium (LD) between tissue specific eQTLs, we reveal evidence for multiple functional variants within loci. We identify 3 variants (rs1412444, rs1051338, rs2250781) that when considered together, each improve the ability to account for LIPA gene expression, suggesting multiple interacting factors. These results refine the assignment of 58 GWAS loci to likely causative variants in a handful of cases and for the remainder help to re-prioritize associated genes and RNA isoforms, suggesting that ncRNAs maybe a relevant transcript in almost half of CAD GWAS results. Our findings support a multi-factorial system where a single variant can influence multiple genes and each genes is regulated by multiple variants., Competing Interests: The authors have declared that no competing interests exist.

We investigated the changes in subfoveal choroidal thickness and choroidal vascularity index (CVI) and their relationship with the severity of coronary artery stenosis in patients with cardiovascular risk factors and symptoms suggestive of coronary artery disease (CAD). Ninety patients who underwent coronary angiography (CAG) for evaluation of their coronary artery status and cardiac symptoms were included. Forty-two patients showed no evidence of CAD; 31 patients had one to two vessel disease; and 17 had a triple vessel disease. There were no significant differences in the subfoveal choroidal thickness among the three groups; however, the CVI in the triple vessel disease group was lower than those in the other groups. The CVI values were good predictors of the presence of triple-vessel disease (p = 0.020). Multivariate logistic regression analysis results revealed that male sex (odds ratio 5.4, p = 0.049), hypertension (odds ratio 4.9, p = 0.017), and CVI (%, odds ratio 0.8, p = 0.016) were significant factors associated with the presence of triple vessel disease. Although CVI may not be a sensitive marker for detecting early changes in the coronary artery, it may be helpful in indicating severe CAD., (© 2022. The Author(s).)

Aims: The Non-adherence Academic Research Consortium (NARC) has recently developed a consensus-based standardized classification for medication non-adherence in cardiovascular clinical trials. We aimed to assess the prevalence of NARC-defined self-reported non-adherence to P2Y12 inhibitors and its impact on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: Using a standardized questionnaire administered at 1 year after PCI, we assessed the 4 NARC-defined non-adherence levels including type, decision-maker, reasons, and timing within the Bern PCI registry. The primary endpoint was the patient-oriented composite endpoint (POCE) defined as a composite of death, myocardial infarction, stroke, and any revascularization at 1 year. The recommended P2Y12 inhibitor duration was 12 months. Among 3,896 patients, P2Y12 inhibitor non-adherence was observed in 647 (17%) patients. Discontinuation was permanent in the majority of patients (84%). The decision was mainly driven by a physician (94%), and rarely by patients (6%). The most frequent reason was risk profile change (43%), followed by unlisted reasons (25%), surgery (17%), and adverse events (14%). Non-adherence occurred early (<30 days) in 21%, late (30-180 days) in 45%, and very late (>180 days) in 33%. The majority of POCE events (n = 421/502, 84%) occurred during adherence to the prescribed P2Y12 inhibitor. Permanent discontinuation, doctor-driven non-adherence, and risk profile change emerged as independent predictors for POCE., Conclusions: In real-world PCI population treated with 1-year DAPT, non-adherence was observed in nearly one-fifth of patients. Non-adherence to P2Y12 inhibitors was associated with worse clinical outcomes, while the risk was related to underlying contexts., Clinicaltrials.gov Identifier: NCT02241291., Competing Interests: The authors have read the journal’s policy and have the following competing interests to declare: YU reports personal fees from Infraredex, outside the submitted work. GCMS reports personal fees from Abbott Vascular, outside the submitted work. JH reports personal fees from Bayer, outside the submitted work. SS reports grants from Edwards Lifesciences, grants from Medtronic, grants from Abbott Vascular, grants and personal fees from Boston Scientific, personal fees from BTG, outside the submitted work. TP reports grants and personal fees from Biotronik, grants and personal fees from Symetis/Boston Scientific, grants from Edwards Lifesciences, and personal fees from HighLife SAS outside the submitted work. MV reports grants and personal fees from Terumo, grants from Medicure, grants and personal fees from Abbott, grants and personal fees from Astrazeneca, personal fees from Chisei, personal fees from Bayer, personal fees from Daiichi Sankyo, personal fees from Amgen, personal fees from Alvimedica, personal fees from Biosensors, outside the submitted work. SW reports research and educational grants to the institution from Abbott, Amgen, BMS, Bayer, Boston Scientific, Biotronik, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Johnson&Johnson, Medtronic, Querbet, Polares, Sanofi, Terumo, Sinomed. SW serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigated-initiated trials that receive funding by industry without impact on his personal remuneration. SW is an unpaid member of the Pfizer Research Award selection committee in Switzerland. LR reports grants and personal fees from Abbott Vascular, personal fees from Amgen, personal fees from Astra Zeneca, grants and personal fees from Biotronik, grants and personal fees from Sanofi, grants from Heartflow, personal fees from Canon, personal fees from Occlutech, outside the submitted work. The other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Body mass index (BMI) is a complex disease risk factor known to be influenced by genes acting via both metabolic pathways and appetite regulation. In this study, we aimed to gain insight into the phenotypic consequences of BMI-associated genetic variants, which may be mediated by their expression in different tissues. First, we harnessed meta-analyzed gene expression datasets derived from subcutaneous adipose (n = 1257) and brain (n = 1194) tissue to identify 86 and 140 loci, respectively, which provided evidence of genetic colocalization with BMI. These two sets of tissue-partitioned loci had differential effects with respect to waist-to-hip ratio, suggesting that the way they influence fat distribution might vary despite their having very similar average magnitudes of effect on BMI itself (adipose = 0.0148 and brain = 0.0149 standard deviation change in BMI per effect allele). For instance, BMI-associated variants colocalized with TBX15 expression in adipose tissue (posterior probability [PPA] = 0.97), but not when we used TBX15 expression data derived from brain tissue (PPA = 0.04) This gene putatively influences BMI via its role in skeletal development. Conversely, there were loci where BMI-associated variants provided evidence of colocalization with gene expression in brain tissue (e.g., NEGR1, PPA = 0.93), but not when we used data derived from adipose tissue, suggesting that these genes might be more likely to influence BMI via energy balance. Leveraging these tissue-partitioned variant sets through a multivariable Mendelian randomization framework provided strong evidence that the brain-tissue-derived variants are predominantly responsible for driving the genetically predicted effects of BMI on cardiovascular-disease endpoints (e.g., coronary artery disease: odds ratio = 1.05, 95% confidence interval = 1.04-1.07, p = 4.67 × 10 -14 ). In contrast, our analyses suggested that the adipose tissue variants might predominantly be responsible for the underlying relationship between BMI and measures of cardiac function, such as left ventricular stroke volume (beta = 0.21, 95% confidence interval = 0.09-0.32, p = 6.43 × 10 -4 )., Competing Interests: Declaration of interests T.G.R. is a part-time employee of Novo Nordisk outside of the work presented in this manuscript. All other co-authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Depression is associated with thrombotic risk and arterial events, its proper management is strongly recommended in coronary artery disease (CAD) patients. We have previously shown that the Brain-Derived Neurotrophic Factor (BDNF)Val66Met polymorphism, related to depression, is associated with arterial thrombosis in mice, and with an increased risk of acute myocardial infarction in humans. Herein, expanding the previous findings on BDNFVal66Met polymorphism, we show that desipramine, a norepinephrine reuptake-inhibitor, rescues behavioral impairments, reduces the arterial thrombosis risk, abolishes pathological coagulation and platelet hyper-reactivity, normalizes leukocyte, platelet, and bone marrow megakaryocyte number and restores physiological norepinephrine levels in homozygous knock-in BDNF Val66Met (BDNF Met/Met ) mice. The in vitro data confirm the enhanced procoagulant activity and the alpha 2A -adrenergic receptor (α 2A -ADR) overexpression found in BDNF Met/Met mice and we provide evidence that, in presence of Met variant, norepinephrine is crucial to up-regulate procoagulant activity and to enhance platelet generation. The α 2 -ADR antagonist rauwolscine rescues the prothrombotic phenotype in BDNF Met/Met mice and reduces procoagulant activity and platelet generation in cells transfected with BDNF Met plasmid or exposed to pro-BDNF Met peptide. Finally, we show that homozygous BDNF Met/Met CAD patients have hyper-reactive platelets overexpressing abundant α 2A -ADR. The great proplatelet release from their megakaryocytes well reflects their higher circulating platelet number compared to BDNF Val/Val patients. These data reveal an unprecedented described role of Met allele in the dysregulation of norepinephrine/α 2A -ADR pathway that may explain the predisposition to arterial thrombosis. Overall, the development of α 2A -ADR inhibitors might represent a pharmacological treatment for depression-associated thrombotic conditions in this specific subgroup of CAD patients., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background The pericoronary fat attenuation index (FAI) is assessed using standard coronary computed tomography angiography, and it has emerged as a novel imaging biomarker of coronary inflammation. The present study assessed whether increased pericoronary FAI values on coronary computed tomography angiography were associated with vulnerable plaque components and their intracellular cytokine levels in patients with non-ST elevation acute coronary syndrome. Methods and Results A total of 195 lesions in 130 patients with non-ST elevation acute coronary syndrome were prospectively included. Lesion-specific pericoronary FAI, plaque components and other plaque features were evaluated by coronary computed tomography angiography. Local T cell subsets and their intracellular cytokine levels were detected by flow cytometry. Lesions with pericoronary FAI values >-70.1 Hounsfield units exhibited spotty calcification (43.1% versus 25.0%, P =0.015) and low-attenuation plaques (17.6% versus 4.2%, P =0.016) more frequently than lesions with lower pericoronary FAI values. Further quantitative plaque compositional analysis showed that increased necrotic core volume (Pearson's r=0.324, P <0.001) and fibrofatty volume (Pearson's r=0.270, P <0.001) were positively associated with the pericoronary FAI, and fibrous volume (Pearson's r=-0.333, P <0.001) showed a negative association. An increasing proinflammatory intracellular cytokine profile was found in lesions with higher pericoronary FAI values. Conclusions The pericoronary FAI may be a reliable indicator of local immune-inflammatory response activation, which is closely related to plaque vulnerability. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04792047.

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD., (© 2022. The Author(s).)

Aims: Chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease (CAD). For both, CKD and CAD, the intercellular transfer of microRNAs (miRs) through extracellular vesicles (EVs) is an important factor of disease development. Whether the combination of CAD and CKD affects endothelial function through cellular crosstalk of EV-incorporated miRs is still unknown., Methods and Results: Out of 172 screened CAD patients, 31 patients with CAD + CKD were identified and matched with 31 CAD patients without CKD. Additionally, 13 controls without CAD and CKD were included. Large EVs from CAD + CKD patients contained significantly lower levels of the vasculo-protective miR-130a-3p and miR-126-3p compared to CAD patients and controls. Flow cytometric analysis of plasma-derived EVs revealed significantly higher numbers of endothelial cell-derived EVs in CAD and CAD + CKD patients compared to controls. EVs from CAD + CKD patients impaired target human coronary artery endothelial cell (HCAEC) proliferation upon incubation in vitro. Consistent with the clinical data, treatment with the uraemia toxin indoxyl sulfate (IS)-reduced miR-130a-3p levels in HCAEC-derived EVs. EVs from IS-treated donor HCAECs-reduced proliferation and re-endothelialization in EV-recipient cells and induced an anti-angiogenic gene expression profile. In a mouse-experiment, intravenous treatment with EVs from IS-treated endothelial cells significantly impaired endothelial regeneration. On the molecular level, we found that IS leads to an up-regulation of the heterogenous nuclear ribonucleoprotein U (hnRNPU), which retains miR-130a-3p in the cell leading to reduced vesicular miR-130a-3p export and impaired EV-recipient cell proliferation., Conclusion: Our findings suggest that EV-miR-mediated vascular intercellular communication is altered in patients with CAD and CKD, promoting CKD-induced endothelial dysfunction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Epicardial Adipose Tissue (EAT) surrounds the epicardium and can mediate harmful effects related to Coronary Artery Disease (CAD)., Objective: We explored the regional differences between adipose stores surrounding diseased and non-diseased segments of coronary arteries in patients with advanced CAD., Methods: We enrolled 32 patients with known CAD who underwent coronary artery bypass graft (CABG) surgery. Inflammatory mediators were measured in EAT biopsies collected from a region of the Left Anterior Descending Artery (LAD) with severe stenosis (diseased segment) and without stenosis (non-diseased segment)., Results: Mean age was 64.3±11.1 years, and mean EAT thickness was 7.4±1.9 mm. Dyslipidemia was the most prevalent comorbidity (81% of the patients). Out of a total of 11 cytokines, resistin (p=0.039), matrix metallopeptidase 9 (MMP-9) (p=0.020), C-C motif chemokine ligand 5 (CCL-5) (p=0.021), and follistatin (p=0.038) were significantly increased in the diseased compared with the non-diseased EAT segments. Indexed tumor necrosis factor-alpha (TNF-α), defined as the diseased to non-diseased cytokine levels ratio, was significantly correlated with increased EAT thickness both in the whole cohort (p=0.043) and in a subpopulation of patients with dyslipidemia (p=0.009). Treatment with lipid-lowering agents significantly decreased indexed TNF-α levels (p=0.015). No significant alterations were observed in the circulating levels of these cytokines with respect to CAD-associated comorbidities., Conclusion: Perivascular EAT is a source of cytokine secretion in distinct areas surrounding the coronary arteries in patients with advanced CAD. Adipocyte-derived TNF-α is a prominent mediator of local inflammation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Fibromuscular dysplasia (FMD), a nonatherosclerotic, noninflammatory disease of medium-sized arteries, is an underdiagnosed disease. We investigated the urinary proteome and developed a classifier for discrimination of FMD from healthy controls and other diseases. We further hypothesized that urinary proteomics biomarkers may be associated with alterations in medium-sized, but not large artery geometry and mechanics. The study included 33 patients with mostly multifocal, renal FMD who underwent in depth arterial exploration using ultra-high frequency ultrasound. The cohort was separated in a training set of 23 patients with FMD from Belgium and an independent test set of 10 patients with FMD from Italy. For each set, controls matched 2:1 were selected from the Human Urinary Proteome Database. The specificity of the classifier was tested in 700 additional controls from general population studies, patients with chronic kidney disease (n=66) and coronary artery disease (n=31). Three hundred thirty-five urinary peptides, mostly related to collagen turnover, were identified in the training cohort and combined into a classifier. When applying in the test cohort, the area under the receiver operating characteristic curve was 1.00, 100% specificity at 100% sensitivity. The classifier maintained a high specificity in additional controls (98.3%), patients with chronic kidney (90.9%) and coronary artery (96.8%) diseases. Furthermore, in patients with FMD, the proteomic score was positively associated with radial wall thickness and wall cross-sectional area. In conclusion, a proteomic score has the potential to discriminate between patients with FMD and controls. If confirmed in a wider and more diverse cohort, these findings may pave the way for a noninvasive diagnostic test of FMD.

Context: A personalized antiplatelet therapy guided by a novel platelet function testing (PFT), PL-12, is considered an optimized treatment strategy in stable coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI). However, the safety and efficacy of any dual-antiplatelet therapy (DAPT) strategy may differ in relation to diabetes status., Objective: The aim of this study was to compare the outcomes of PFT-guided personalized DAPT in stable CAD patients with and without diabetes mellitus., Methods: The PATH-PCI trial randomly assigned 2285 stable CAD patients to either personalized antiplatelet therapy or standard antiplatelet treatment. We investigated the association and interaction of diabetes on clinical outcomes across 2 treatment groups., Results: We did not find a significant difference between the personalized group and the standard group in net adverse clinical events in either diabetes patients (10.3% vs 13.4%, P = .224) or in the nondiabetic group (3.1% vs 5.0%, P = .064). In diabetes patients (n = 646, 28.3%), the overall ischemic event rates were significantly low (6.8% vs 11.3%, HR = 0.586, 95% CI, 0.344-0.999, P = .049) and the bleeding event rates did not differ between the 2 groups (3.5% vs 3.3%, HR = 1.066, 95% CI, 0.462-2.458, P = .882). Similarly, in nondiabetic patients, the overall ischemic event rates were significantly low (1.8% vs 4.2%, HR = 0.428, 95% CI, 0.233-0.758, P = .006) and the bleeding event rates did not differ between the 2 groups (1.6% vs 0.9%, HR = 1.802, 95% CI: 0.719-4.516, P = .209)., Conclusion: The present study suggests that personalized antiplatelet therapy according to PFT can reduce ischemic events but not increase bleedings in stable CAD patients with or without diabetes who have undergone PCI., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Given its close anatomical location to the heart and its endocrine properties, attention on epicardial adipose tissue (EAT) has increased., Objective: This study investigated the expression profiles of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) in EAT derived from patients with coronary artery disease (CAD)., Methods: EAT samples from 8 CAD, and 8 non-CAD patients were obtained during open-heart surgery, respectively. The expression of lncRNAs and mRNAs in each EAT sample was investigated using microarray analysis and further verified using reverse transcription-quantitative polymerase chain reaction., Results: Overall, 1,093 differentially expressed mRNAs and 2,282 differentially expressed lncRNAs were identified in EAT from CAD vs. non-CAD patients. Analysis using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes showed that these differentially expressed genes were mainly enriched in various inflammatory, immune, and metabolic processes. They were also involved in osteoclast differentiation, B cell receptor and adipocytokine signaling, and insulin resistance pathways. Additionally, lncRNA-mRNA and lncRNA-target pathway networks were built to identify potential core genes (e.g., Lnc-CCDC68-2:1, AC010148.1, NONHSAT104810) involved in atherosclerotic pathogenesis., Conclusion: In summary, lncRNA and mRNA profiles in EAT were markedly different between CAD and non-CAD patients. Our study identifies several potential key genes and pathways that may participate in atherosclerosis development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Comparing first and second wave MIS-C cohorts at our quaternary pediatric institution, second wave were older, presented more frequently with shortness of breath, higher maximum troponin and N-terminal BNP, and more frequently required advanced respiratory and inotropic support. Despite increased severity in the second cohort, both cohorts had similar rates of coronary artery abnormalities, systolic dysfunction, and length of stay., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Polymorphisms at LPA , LDLR , APOE , APOC1 , MYLIP and ABCG2 are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated whether polymorphisms at these genes are associated with the risk of coronary artery disease (CAD) development, and reduction of atherogenic lipids and carotid intima-media thickness (CIMT) in CAD patients, taking rosuvastatin. Materials & methods: 190 CAD patients and 1697 subjects were enrolled in pharmacogenetic and genetic association study, respectively. SNP genotyping was done using the MassARRAY-4 system. Results: MYLIP rs6924995, rs3757354, APOC1 rs445925, LDLR rs6511720, APOE rs7412, ABCG2 rs2199936, rs1481012 variants were significantly associated with CAD susceptibility (p = 0.016, 0.0003, <0.0001, <0.0001, 0.013, 0.016, 0.0035, respectively), as well as with CIMT regression (except ABCG2 variants; p = 0.05, 0.039, 0.039, 0.016, 0.0065), and changes in plasma lipids during rosuvastatin therapy. Conclusion: The studied polymorphisms possess pleiotropic effects on plasma lipids and CIMT, CAD susceptibility, and determine lipid-lowering response to rosuvastatin.

Objectives: To do a quantitative comparison of saline and contrast Frequency domain optical coherence tomography (FD-OCT) during percutaneous coronary intervention (PCI) optimisation., Methods: 13 pairs of OCT runs were analysed, wherein each pair consisted of a contrast run and a heparinized saline run taken in the same coronary artery at the same position. Quantitative analysis was done comparing minimal lumen area (MLA), proximal reference diameter (PRD), distal reference diameter (DRD) and percentage area stenosis (AS) at the same anatomical location. Lesion morphologies, rendered stent view and 3D reconstruction were compared for image clarity., Result: The saline OCT runs resulted in comparable MLA (3.88 ± 2.59 mm 2 with saline run vs 3.88 ± 2.71 mm 2 with contrast run; p = 0.650), PRD (3.66 ± 0.52 mm with saline vs 3.65 ± 0.52 mm with contrast; p = 0.463), DRD (2.97 ± 0.22 mm with saline vs 2.99 ± 0.88 mm with contrast; p = 0.433), and AS (59.60 ± 18.62% with saline vs 59.18 ± 19.11% with contrast; p = 0.753) with respect to the contrast runs. The Bland Altman plots of the measured parameters indicate good agreement between saline and contrast OCT. Linear regression analysis indicated the absence of proportional bias All lesion morphologies (calcified, fibrotic, thin cap fibroatheroma, macrophages, cholesterol crystals and edge dissection), 3D reconstruction and rendered stent view were clearly demonstrable in the saline OCT runs., Conclusions: Using heparinized saline as flushing media in coronary FD-OCT may result in vessel dimensions that are comparable with contrast. Heparinized saline may be used as a contrast saving alternative for FD-OCT during PCI optimization., Competing Interests: Declaration of competing interest None., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: This research study has been carried out to study the various morphological changes in the heart in medicolegal autopsies and to compile data for the frequency of heart diseases found in autopsy cases., Methods: The present study comprised 430 medicolegal autopsy cases. Details of the cases were entered in a proforma prepared for the study. The heart was fixed in 10% formalin, and then, opened along the flow of blood. The findings were based on gross and microscopic examinations., Results: Out of 430 adult hearts, 211 (49.0%) cases showed 253 cardiac lesions; 35 (8.1%) cases of coronary atherosclerosis and 196 (45.5%) aortic atherosclerosis were noted; 7 cases of ischemic lesions (1.6%) were identified; 12 (2.7%) cases of hypertrophy; 2 cases of valve calcification; and 1 of cardiomyopathy were noted., Conclusion: In the present study, among medicolegal autopsies, atherosclerotic disease was the most frequently encountered lesion followed by hypertrophy. The incidence of atherosclerosis was found to be 47.6%. This study shows the high prevalence of atherosclerosis in the population., Competing Interests: None

Background: Growth-differentiation factor-15 (GDF-15) is a biomarker belonging to the transforming growth factor-beta cytokine superfamily, which is linked to many pathological conditions, including inflammation and myocardial injury. Pulse wave velocity (cfPWV) and augmentation index (AIx) are indices of arterial stiffness, which are associated with the severity of coronary artery disease (CAD). Flow-mediated dilatation (FMD) is a well-studied surrogate marker of endothelial-dependent dysfunction and systemic inflammation., Objective: In this proof-of-concept study, we aimed to investigate the relationship between circulating GDF-15, endothelial dysfunction, and indices of arterial stiffness in different settings of coronary artery disease and myocardial injury., Methods: In this cross-sectional single-center study, we enrolled patients (n = 22) after interventional treatment for acute myocardial infarction (AMI), patients (n = 11) admitted with chest pain and elevated cardiac enzymes but without evidence of obstructing CAD (MI-NOCAD) in percutaneous coronary angiography (CAG), and patients (n = 20) who underwent CAG according to indications without evident obstructive CAD in CAG (NOCAD). FMD was assessed at the brachial artery. AIx of the central aortic pressure and cfPWV were estimated by applanation tonometry at the radial and carotid-femoral site, respectively, with a validated acquisition system (Sphygmo- Cor, AtCor Medical, Sydney (NSW), Australia). ELISA was used to determine circulating GDF- 15 serum levels (R&D Systems, Minneapolis, MN). Clinical and demographic data and values of routine biochemical biomarkers were obtained. The highest high-sensitive cardiac Troponin I (hsTpnI) value during hospitalization was also recorded. Left ventricular ejection fraction (LVEF) was assessed with a transthoracic echocardiogram., Results: Patients with AMI were older, had worse LVEF, higher values of hsTpnI and increased circulating GDF-15 levels. Importantly, AMI patients had increased cfPWV values, deteriorated AIx values, blunted FMD and worse serum creatinine levels compared to MI-NOCAD and NOCAD patients, respectively, whereas MI-NOCAD and NOCAD did not differ from each other significantly on these biomarkers. Both AMI and MI-NOCAD patients presented a higher but comparable white blood cell count than NOCAD patients. A strong linear correlation between GDF-15 and cfPWV, hsTpnI, AIx, white blood cell count and creatinine but not with FMD was demonstrated in the general study population., Conclusion: This proof-of-concept study showed that higher circulating levels of GDF-15, an inflammatory biomarker, were associated significantly with increased arterial stiffness only in AMI patients, whereas elevated GDF-15 demonstrated a linear relationship with the severity of the myocardial injury., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Percutaneous coronary intervention (PCI) is an expanding treatment option for patients with coronary artery disease (CAD). It is considered the default strategy for the unstable presentation of CAD. PCI techniques have evolved over the last 4 decades with significant improvements in stent design, an increase in functional assessment of coronary lesions, and the use of intra-vascular imaging. Nonetheless, the morbidity and mortality related to CAD remain significant. Advances in technology have allowed a better understanding of the nature and progression of CAD. New tools are now available that reflect the pathophysiological changes at the level of the myocardium and coronary atherosclerotic plaque. Certain changes within the plaque would render it more prone to rupture leading to acute vascular events. These changes are potentially detected using novel tools invasively, such as near infra-red spectroscopy, or non-invasively using T2 mapping cardiovascular magnetic resonance imaging (CMR) and 18 F-Sodium Fluoride positron emission tomography/ computed tomography. Similarly, changes at the level of the injured myocardium are feasibly assessed invasively using index microcirculatory resistance or non-invasively using T1 mapping CMR. Importantly, these changes could be detected immediately with the opportunity to tailor treatment to those considered at high risk. Concurrently, novel therapeutic options have demonstrated promising results in reducing future cardiovascular risks in patients with CAD. This Review article will discuss the role of these novel tools and their applicability in employing a mechanical and pharmacological treatment to mitigate cardiovascular risk in patients with CAD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Cognitive impairment has been suggested to be associated with coronary artery disease [CAD]; however, the underlying mechanism is not fully understood. Our current study aimed to explore the brain activity in CAD patients compared to healthy controls [HCs]., Methods: Twenty-two CAD patients and 23 HCs were enrolled in our study. A low-frequency oscillation at the voxel level in all participants based on the amplitude of low-frequency fluctuations [ALFF] was measured using resting-state functional magnetic resonance imaging. All participants underwent neuropsychological examinations [Mini-Mental State Examination, MMSE and Montreal Cognitive Assessment, MoCA] and visual acuity examination., Results: CAD patients showed significantly lower ALFF values [P < 0.05] in the right precuneus gyrus [Precuneus&#95;R], left supramarginal gyrus [Supramarginal&#95;L], left angular gyrus [Angular&#95;L], and left middle cingulum gyrus [Cingulum&#95;Mid&#95;L] than healthy controls. Lower MoCA scores in CAD patients significantly correlated with lower Supramarginal&#95;L [P = 0.001] and Cingulate&#95; Mid&#95;L [P = 0.004] ALFF values. Reduced visual acuity significantly correlated with lower Precuneus&#95;R [P = 0.019] and Cingulate&#95;Mid&#95;L [P = 0.011] ALFF values in CAD patients., Conclusion: These findings may provide further insight into the underlying neuropathophysiology of CAD with cognitive impairment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Bilateral internal thoracic arteries (BITA) are uncommonly used in the every-day practice due to safety concerns and technical challenges with Y-grafts. We hypothesized that in-situ BITA use during coronary artery by-pass grafting (CABG) for two vessel disease is equally safe to standard strategy with left internal thoracic artery-left anterior descending artery revascularization and venous graft to other target vessels., Methods: A propensity score matched analysis was used to compare elective on-pump CABG patients who received in-situ BITA (BITA-group), versus left internal thoracic artery graft to the left anterior descending artery plus vein (SITA-group). Primary end points were 30-days all-cause-mortality, major adverse cardiac events and incidents and deep sternal wound infections., Results: A total of 50 matched pairs (c-statistics 0.769) were selected from patients operated on between January 2015 and April 2020 using BITA (n = 50) and SITA (n = 2170). There were no inter-group differences in demographics and basic clinical characteristics. The total operation time was longer in the BITA-group (4.0 vs 3.6 hours; p = 0.004). The rate of complete revascularization was similar, as was median aortic cross-clamp time, median extracorporeal circulation time, rate of re-explorations for bleeding, deep sternal wound infections or length of stay. One patient died in BITA group, 3 days after surgery, from a non-cardiac cause. After 36 months, the survival rate was 98% for BITA-group and 96% for controls (log-rank, p = 0.577)., Conclusions: In-situ use of BITA during coronary revascularization for two-vessel disease is as safe and effective, as use of single ITA and vein graft. In-situ strategy abolishes allows to avoid the technically demanding composite graft configuration., Competing Interests: The authors have declared that no competing interests exist.

The relationship between the in-stent neoatherosclerosis (ISNA) formation and the plaque's characteristic changes in the non-culprit lesion is unclear. We aim to investigate the plaque characteristics changes at non-culprit lesions between patients with ISNA and without ISNA formation at 1-year follow-up. We retrospectively enrolled patients who had DES implantation in de novo lesion and underwent immediately after stenting and 1-year follow-up optical coherence tomography (OCT) examination. OCT-defined ISNA was defined as the presence of lipid-laden neointima or calcification within the culprit stent with a longitudinal extension of ≥1 mm. Non-culprit lesions were divided into two groups: ISNA group (with ISNA) and non-ISNA group (without ISNA). Plaque characteristics of non-culprit lesions were evaluated at baseline and 1-year follow-up. In total, 89 patients with 89 non-culprit lesions (ISNA: n = 37; non-ISNA: n = 52) were included in the analyses. The lesions in the ISNA group show a smaller minimum lumen area compared to the non-ISNA group at 1-year follow-up (2.57 ± 1.08 mm 2 versus 3.20 ± 1.62 mm 2 , p = 0.044). The lesions of the ISNA group show a significant decrease in minimum lumen area changes percent (-7.25% versus 6.46%, p = 0.039). And there are more lesions with minimum lumen area (64.9% versus 38.5%, p = 0.014) and minimum lumen diameter (64.9% versus 40.4%, p = 0.023) decrease in the ISNA group. Furthermore, the lesions in ISNA group have more plaques with lipid core length increase (25.0% versus 10.0%, p = 0.040), more plaques with FCT decrease (50.0% versus 74.0%, p = 0.027) and less TCFA change to non-TCFA (33.3% versus 87.5%, p = 0.010). The plaque characteristic changes in non-culprit lesions are closely related to ISNA formation. The ISNA formation may accompany by a tardier plaque stabilization process in non-culprit lesions., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Considerable progress has been made in the treatment of coronary bifurcation stenosis. Anatomical characteristics of the vessel and lesion, however, fail to give information about the functional significance of the bifurcation stenosis. To the best of our knowledge, there is no study that systematically establishes the baseline functional significance of coronary stenosis and its effect on procedural and clinical outcomes. Patients with significant angiographic bifurcation lesions defined as diameter stenosis > 50% in main vessel and/or side branch were included. FFR was performed in main vessel (MV) and side branch (SB) before and after percutaneous coronary intervention (PCI). 169 patients from Fiesta study (derivation cohort) and 555 patients from prospective bifurcation registry (clinical effect cohort) were analyzed to validate angiographic prediction score (BFSS) used to determine the potentially functional significance of coronary bifurcation stenosis. Bifurcation functional significance score (including the following parameters-SYNTAX ≥ 11, SB/MB BARI score, MV %DS ≥ 55%, main branch (MB) %DS ≥ 65%, lesion length ≥ 25 mm) with a maximum value of 11 was developed. A cut-off value of 6.0 was shown to give the best discriminatory ability-with accuracy 87% (sensitivity 77%, specificity 96%, p < 0.001). There was also a significant difference in all-cause mortality between patients with BFSS ≥ 6.0 vs. BFSS < 6.0-25.5% vs. 18.4%, log-rank p = 0.001 as well as cardiac mortality: BFSS ≥ 6.0 vs. BFSS < 6.0-17.7% vs. 14.5%, log-rank (p = 0.016). The cardiac mortality was significantly lower in patients with smaller absolute SB territory, p = 0.023. An angiographic score (BFSS) with good discriminatory ability to determine the functional significance of coronary bifurcation stenosis was developed. The value for BFSS ≥ 6.0 can be used as a discriminator to define groups with higher risk for all-cause and cardiac mortality. Also, we found that the smaller side branches pose greater mortality risk., (© 2021. The Author(s).)

Objective: A high coronary artery calcification score (CACS) may be associated with high mortality in patients undergoing hemodialysis (HD). Recently, effects of iron on vascular smooth muscle cell calcification have been described. We aimed to investigate the relationships between iron, CACS, and mortality in HD patients., Methods: We studied 173 consecutive patients who were undergoing maintenance HD. Laboratory data and Agatston's CACS were obtained at baseline for two groups of patients: those with CACS ≥400 ( n  = 109) and those with CACS <400 ( n  = 64). Logistic regression analyses for CACS ≥400 and Cox proportional hazard analyses for mortality were conducted., Results: The median (interquartile range) age and duration of dialysis of the participants were 67 (60-75) years and 73 (37-138) months, respectively. Serum iron (Fe) and transferrin saturation (TSAT) levels were significantly lower in participants with CACS ≥400 than in those with CACS <400, although the serum ferritin concentration did not differ between the groups. TSAT ≥21% was significantly associated with CACS ≥400 (odds ratio 0.46, p< 0.05). TSAT ≥17%, Fe ≥63 µg/dL, and ferritin ≥200 ng/mL appear to protect against 5-year all-cause mortality in HD patients, independent of conventional risk factors of all-cause mortality ( p  < 0.05)., Conclusion: We have identified associations between iron, CACS, and mortality in HD patients. Lower TSAT was found to be an independent predictor of CACS ≥400, and iron deficiency (low TSAT, iron, or ferritin) was a significant predictor of 5-year all-cause mortality in HD patients.

Kawasaki disease (KD) causes cardiovascular system injury in children. However, the pathogenic mechanisms of KD have not been well defined. Recently, strong correlation between aberrant microRNAs and KD nosogenesis has been revealed. A role of microRNA-197-3p (miR-197-3p) in the pathogenesis of KD is identified in the present study. Cell proliferation assay showed human coronary artery endothelial cells (HCAECs) were suppressed by serum from KD patients, which was correlated with high levels of miR-197-3p in both KD serum and HCAECs cultured with KD serum. The inhibition of HCAECs by miR-197-3p was confirmed by cells expressing miR-197-3p mimic and miR-197-3p inhibitor. Comparative proteomics analysis and Ingenuity Pathway Analysis (IPA) revealed TIMP3 as a potential target of miR-197-3p, which was demonstrated by western blot and dual-luciferase reporter assays. Subsequently, by detecting the endothelium damage markers THBS1, VWF, and HSPG2, the role of miR-197-3p/TIMP3 in KD-induced damage to HCAECs was confirmed, which was further validated by a KD mouse model in vivo. The expressions of miR-197-3p and its target, TIMP3, are dramatically variational in KD serum and HCAECs cultured with KD serum. Increased miR-197-3p induces HCAECs abnormal by restraining TIMP3 expression directly. Hence, dysregulation of miR-197-3p/TIMP3 expression in HCAECs may be an important mechanism in cardiovascular endothelium injury in KD patients, which offers a feasible therapeutic target for KD treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chronic kidney disease (CKD) is associated with an increased risk of the progression of coronary artery disease (CAD). However, there are few data on the relationship between CAD severity and the duration of CKD. This study assessed the predictive value of the duration of kidney dysfunction in CKD patients with CAD severity., Methods: In 145 patients (63.4% male, n  = 92; mean age, 68.8 ± 12.8 years) with CKD, severity of CAD was assessed by coronary angiography and quantified by SYNTAX scores, and duration of kidney dysfunction was either assessed by checking historical biochemical parameters of individuals or was based on enquiries., Results: Patients with high SYNTAX scores (≥ 22) had a greater prevalence of cardiovascular risk factors including age, gender, history of heart failure and smoking. In CKD patients, SYNTAX scores were positively correlated to duration of CKD and serum uric acid (UA), and negatively correlated to high-density lipoprotein-cholesterol (HDL-C) and ApoA1 levels. Univariate binary logistic regression and multivariate logistic analyses showed that SYNTAX scores correlated significantly with CKD duration, UA, and HDL-C. Receiver-operating characteristic analysis was used to explore a time point when coronary angiography application was economical and effective and yielded a Youden index of 6.5 years., Conclusions: Together, our results demonstrated that the duration of kidney dysfunction was an independent correlate of the severity of CAD in patients with CKD. Our findings suggest that coronary angiography should be considered for CKD patients with renal insufficiency having lasted for more than 6.5 years.