Coronary microvascular dysfunction: prevalence and aetiology in patients with suspected myocardial ischaemia.

AIM: To evaluate the prevalence, aetiology, and corresponding morbidity of coronary microvascular dysfunction (CMD) in patients with suspected myocardial ischaemia. MATERIALS AND METHODS: The present study included 115 patients with suspected myocardial ischaemia who underwent stress perfusion cardiac magnetic resonance imaging. CMD was assessed visually based on the myocardial perfusion results. The CMR-derived myocardial perfusion reserve index (MPRI) and left ventricular (LV) strain parameters obtained using the post-processing software CVI42 were employed to evaluate LV myocardial perfusion and deformation. LV strain parameters included global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS), global systolic/diastolic longitudinal, circumferential, and radial strain rates (SLSR, SCSR, SRSR, DLSR, DCSR, and DRSR). RESULTS: Of the 115 patients, 12 patients were excluded and 103 patients were finally included in the study. CMD was observed in 79 % (81 patients, aged 53 ± 12 years) of patients. Regarding aetiology, 91 (88 %) patients had non-obstructive coronary artery disease (CAD), eight (8 %) had obstructive CAD, and four (4 %) had hypertrophic cardiomyopathy (HCM). The incidence of CMD was highest (100 %) in patients with HCM, followed by those with non-obstructive CAD (up to 79 %). There were no statistical differences between CMD and non-CMD groups in GCS, GRS, GLS, SRSR, SCSR, SLSR, DCSR, DRSR and DLSR. CONCLUSION: The incidence of CMD was higher in patients with signs and symptoms of ischaemia. CMD occurred with non-obstructive CAD, obstructive CAD, and HCM, with the highest prevalence of CMD in HCM.

Plaque heterogeneity and the spatial distributions of its components dictate drug-coated balloon therapy.

Drug-coated balloon (DCB) angioplasty is one of the potential approaches to alleviating in-stent restenosis and treating peripheral artery disease. An in-silico model has been developed for sirolimus drug eluted from an inflated balloon in a patient-specific arterial cross-section consisting of fibrous tissue, fibrofatty tissue, dense calcium, necrotic core, and healthy tissue. The convection-diffusion-reaction equation represents the transport of drug, while drug binding, both specific and non-specific, can be modelled as a reaction process. The Brinkman equations describe the interstitial flow in porous tissue. An image processing technique is leveraged for reconstructing the computational domain. The Marker and Cell, and Immersed Boundary Methods are used to solve the set of governing equations. The no-flux interface condition and convection do amplify the tissue content, and the regions of dense calcium and necrotic core limited to or extremely close to the interface pose a clinical threat to DCB therapy. Simulations predict the effects of the positioning and clustering of plaque components in the domain. This study demands extensive intravascular ultrasound-derived virtual histology (VH-IVUS) imaging to understand the plaque morphology and determine the relative positions of different plaque compositions about the lumen-tissue interface, which have a significant impact on arterial pharmacokinetics.

[Comparison among different flushing media for intracoronary imaging with optical coherence tomography].

Objective: To explore the effects and safety of saline mixed 1∶1 with contrast medium (mixed medium) and pure heparinized saline as alternative media for optimal Optical Coherence Tomography (OCT) guided percutaneous coronary intervention (PCI). Methods: This single-center, prospective cohort study enrolled patients who underwent PCI with OCT guidance for chronic stable angina or acute coronary syndrome at the Department of Cardiology, the Second Hospital of Jilin University from October 2021 to August 2022. The target vessels were examined using OCT with three different flushing media at the same anatomical positions: contrast agent, mixed medium, and pure heparinized saline. An independent observer analyzed all imaging results and evaluated the lumen imaging quality, using the proportion of the clear imaging field (CIF%) as a quantitative measure for analysis. The average luminal diameter was compared among different flushing media. The study also assessed the image quality of the luminal anatomical structures, lesion pathologies, and stents. Results: A total of 105 patients were enrolled in the study, including 110 target vessels. The age of the enrolled patients was (60.5±8.4) years, with 60 male patients (57.1%). OCT examinations were successfully completed using all three media, and no related complications were observed in any groups. The three flushing media presented with the same image quality in terms of depicting the lumen anatomical structures, lesion characteristics, and stent-related features. The mixed medium group achieved a comparable CIF% to the contrast group with both right and left coronary arteries (right coronary 100.0% (100.0%, 100.0%) vs. 100.0% (100.0%, 100.0%), P>0.05; left coronary 100.0% (95.9%, 100.0%) vs. 100.0% (100.0%, 100.0%), P>0.05). While the saline group reached a comparable CIF% to the contrast group with right coronary arteries (100.0% (97.6%, 100.0%) vs. 100.0% (95.9%, 100.0%), P>0.05) but showed a significantly lower CIF% with left coronary arteries (84.9% (75.9%, 93.4%) vs. 100.0% (100.0%, 100.0%), P<0.05). For the average diameter of the coronary lumen, there was no statistically significant difference between the mixed medium group and the saline group compared to the contrast group with both right and left coronary arteries (P>0.05). Conclusions: A 1∶1 heparinized saline and contrast mixture can serve as a substitute flushing medium for OCT examination during PCI procedure. Pure saline can also yield good results in OCT examination of the right coronary artery, and both alternatives are safe for use as flushing medium in OCT imaging.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

Single-cell RNA sequencing reveals S100a9hi macrophages promote the transition from acute inflammation to fibrotic remodeling after myocardial ischemia‒reperfusion.

Rationale: The transition from acute inflammation to fibrosis following myocardial ischemia‒reperfusion (MIR) significantly affects prognosis. Macrophages play a pivotal role in inflammatory damage and repair after MIR. However, the heterogeneity and transformation mechanisms of macrophages during this transition are not well understood. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) and mass cytometry to examine murine monocyte-derived macrophages after MIR to investigate macrophage subtypes and their roles in the MIR process. S100a9-/- mice were used to establish MIR model to clarify the mechanism of alleviating inflammation and fibrosis after MIR. Reinfusion of bone marrow-derived macrophages (BMDMs) after macrophage depletion (MD) in mice subjected to MIR were performed to further examine the role of S100a9hi macrophages in MIR. Results: We identified a unique subtype of S100a9hi macrophages that originate from monocytes and are involved in acute inflammation and fibrosis. These S100a9hi macrophages infiltrate the heart as early as 2 h post-reperfusion and activate the Myd88/NFκB/NLRP3 signaling pathway, amplifying inflammatory responses. As the tissue environment shifts from proinflammatory to reparative, S100a9 activates transforming growth factor-ß (Tgf-ß)/p-smad3 signaling. This activation not only induces the transformation of myocardial fibroblasts to myofibroblasts but also promotes fibrosis via the macrophage-to-myofibroblast transition (MMT). Targeting S100a9 with a specific inhibitor could effectively mitigate acute inflammatory damage and halt the progression of fibrosis, including MMT. Conclusion: S100a9hi macrophages are a promising therapeutic target for managing the transition from inflammation to fibrosis after MIR.

Assessing the Impact of Long-Term High-Dose Statin Treatment on Pericoronary Inflammation and Plaque Distribution-A Comprehensive Coronary CTA Follow-Up Study.

Computed tomography angiography (CTA) has validated the use of pericoronary adipose tissue (PCAT) attenuation as a credible indicator of coronary inflammation, playing a crucial role in coronary artery disease (CAD). This study aimed to evaluate the long-term effects of high-dose statins on PCAT attenuation at coronary lesion sites and changes in plaque distribution. Our prospective observational study included 52 patients (mean age 60.43) with chest pain, a low-to-intermediate likelihood of CAD, who had documented atheromatous plaque through CTA, performed approximately 1 year and 3 years after inclusion. We utilized the advanced features of the CaRi-Heart® and syngo.via Frontier® systems to assess coronary plaques and changes in PCAT attenuation. The investigation of changes in plaque morphology revealed significant alterations. Notably, in mixed plaques, calcified portions increased (p < 0.0001), while non-calcified plaque volume (NCPV) decreased (p = 0.0209). PCAT attenuation generally decreased after one year and remained low, indicating reduced inflammation in the following arteries: left anterior descending artery (LAD) (p = 0.0142), left circumflex artery (LCX) (p = 0.0513), and right coronary artery (RCA) (p = 0.1249). The CaRi-Heart® risk also decreased significantly (p = 0.0041). Linear regression analysis demonstrated a correlation between increased PCAT attenuation and higher volumes of NCPV (p < 0.0001, r = 0.3032) and lipid-rich plaque volume (p < 0.0001, r = 0.3281). Our study provides evidence that high-dose statin therapy significantly reduces CAD risk factors, inflammation, and plaque vulnerability, as evidenced by the notable decrease in PCAT attenuation, a critical indicator of plaque progression.

Predictors of percutaneous coronary intervention derived from CCTA in patients with chronic coronary syndrome.

BACKGROUND: To identify anatomical and morphological plaque features predictors of PCI and create a multiparametric score to increase the predictive yield. Moreover, we assessed the incremental predictive value of FFRCT (Fractional Flow Reserve derived from CCTA) trans-lesion gradient (ΔFFRCT) when integrated into the score. METHODS: Observational cohort study including patients undergoing CCTA for suspected coronary artery disease, with FFRCT available, referred to invasive coronary angiogram and assessment of fractional flow reserve. Plaque analysis was performed using validated semi-automated software. Logistic regression was performed to identify anatomical and morphological plaque features predictive of PCI. Optimal thresholds were defined by area under the receiver-operating characteristics curve (AUC) analysis. A scoring system was developed in a derivation cohort (70 â€‹% of the study population) and tested in a validation cohort (30 â€‹% of patients). RESULTS: The overall study population included 340 patients (455 vessels), among which 238 patients (320 vessels) were included in the derivation cohort. At multivariate logistic regression analysis, absence of left main disease, diameter stenosis (DS), non-calcified plaque (NCP) volume, and percent atheroma volume (PAV) were independent predictors of PCI. Optimal thresholds were: DS â€‹≥ â€‹50 â€‹%, volume of NCP>113 â€‹mm3 and PAV>17 â€‹%. A weighted score (CT-PCI Score) ranging from 0 to 11 was obtained. The AUC of the score was 0.80 (95%CI 0.74-0.86). The integration of ΔFFRCT in the CT-PCI score led to a mild albeit not significant increase in the AUC (0.82, 95%CI 0.77-0.87, p â€‹= â€‹0.328). CONCLUSIONS: Plaque anatomy and morphology derived from CCTA could aid in identifying patients amenable to PCI.

Clinical Impact of In-Stent Calcification in Coronary Arteries: Optical Coherence Tomography Study.

In-stent restenosis with neoatherosclerosis has been known as the predictor of target lesion revascularization (TLR) after percutaneous coronary intervention. However, the impact of in-stent calcification (ISC) alone on clinical outcomes remains unknown since neoatherosclerosis by optical coherence tomography includes in-stent lipid and calcification. We aimed to assess the effect of ISC on clinical outcomes and clinical differences among different types of ISC. We included 126 lesions that underwent optical coherence tomography-guided percutaneous coronary intervention and divided those into the ISC group (n = 38) and the non-ISC group (n = 88) according to the presence of ISC. The cumulative incidence of clinically driven TLR (CD-TLR) was compared between the ISC and non-ISC groups. The impact of in-stent calcified nodule and nodular calcification on CD-TLR was evaluated using the Cox hazard model. The incidence of CD-TLR was significantly higher in the ISC group than in the non-ISC group (p = 0.004). In the multivariate Cox hazard model, ISC was significantly associated with CD-TLR (hazard ratio [HR] 3.58, 95% confidence interval [CI] 1.33 to 9.65, p = 0.01). In-stent calcified nodule/nodular calcification and in-stent nodular calcification alone were also the factors significantly associated with CD-TLR (HR 3.34, 95%CI 1.15 to 9.65, p = 0.03 and HR 5.21, 95%CI 1.82 to 14.91, p = 0.002, respectively). ISC without in-stent calcified nodule/nodular calcification, which was defined as in-stent smooth calcification, was not associated with CD-TLR. In conclusion, ISC was associated with a higher rate of CD-TLR. The types of calcifications that led to a high rate of CD-TLR were in-stent calcified nodule/nodular calcification and in-stent nodular calcification alone but not in-stent smooth calcification. In-stent calcified nodule and nodular calcification should be paid more attention.

Expression of PCT, BNP and Inflammatory Factors in Children with Kawasaki Disease and Their Correlation with Coronary Artery Lesions.

Background: Kawasaki disease (KD), as one of the most common vascular diseases in children, will cause the risk of coronary artery lesions (CAL) without treatment. This study is to explore the expression of procalcitonin (PCT), brain natriuretic peptide (BNP), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6) in children with KD and their correlation with CAL. Methods: 86 KD children in Baoding Hospital of Beijing Children's Hospital were selected as the study subjects from January 2020 to June 2021. According to whether CAL occurred, they were divided into the CAL group (n=30) and NCAL group (n=56). The clinical data of the two groups were collected from the medical record system. The levels of PCT and BNP were detected by chemiluminescence microparticle assay, the CRP level was detected by immunoturbidimetry, and the levels of TNF-α and IL-6 were detected by flow immunofluorescence method. The relationship of PCT, BNP, and inflammatory factors with CAL in KD children was explored by Pearson correlation analysis. Results: The comparative result of clinical data showed no overt difference in gender, disease types, age and blood routine indexes between the two groups, except for coronary artery diameter (P >.05). The levels of PCT, BNP, CRP, TNF-α and IL-6 in CAL group were (1.70±0.39) µg/L, (289.21±29.78) ng/L, (83.16±17.35) mg/L, (9.38±1.23) pg/mL and (59.97±0.97) ng/mL, respectively. The levels of PCT, BNP, CRP, TNF-α and IL-6 in NCAL group were (1.04±0.18) µg/L, (170.85±23.58) ng/L, (69.70±16.64) mg/L, (6.32±0.73) pg/mL and (44.16±11.97) ng/mL, respectively. The levels of each index in the CAL group were notably higher than in the NCAL group (P < .001). Pearson correlation analysis revealed that PCT, BNP, CRP, TNF-α and IL-6 were positively correlated with CAL in KD children (r=0.829, 0.865, 0.823, 0.894, 0.784, P < .001). Conclusion: The increase of PCT, BNP, and inflammatory factors has a certain warning effect on CAL in KD children. In clinical practice, health care professionals should strengthen the detection of PCT, BNP and inflammatory factors in KD children, carry out early monitoring of CAL in children with high expression of biomarkers, and formulate personalized preventive intervention based on the disease progress, so as to reduce the risk of cardiovascular disease. However, due to the limitations of research conditions and methods, the sample size of this study is small, which may affect the reliability and representativeness of the conclusion. In order to provide a new direction for the clinical prevention and treatment of the disease, future work will improve the research design, expand the sample size, and carry out more in-depth exploration on the prediction of CAL in KD children.

Polygenic Risk Score Associates With Atherosclerotic Plaque Characteristics at Autopsy.

BACKGROUND: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically. METHODS: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD. RESULTS: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P<0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P=0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P=0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P<0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P<0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P<0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates. CONCLUSIONS: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects.

Angiographic Severity of the Nonculprit Lesion and the Efficacy of Fractional Flow Reserve-Guided Complete Revascularization in Patients With AMI: FRAME-AMI Substudy.

BACKGROUND: The benefit of fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) for noninfarct-related artery (IRA) lesions with angiographically severe stenosis in patients with acute myocardial infarction is unclear. METHODS: Among 562 patients from the FRAME-AMI trial (Fractional Flow Reserve Versus Angiography-Guided Strategy for Management of Non-Infraction Related Artery Stenosis in Patients With Acute Myocardial Infarction) who were randomly allocated into either FFR-guided or angiography-guided PCI for non-IRA lesions, the current study evaluated the relationship between non-IRA stenosis measured by quantitative coronary angiography (QCA) and the efficacy of FFR-guided PCI. The incidence of the primary end point (death, myocardial infarction, or repeat revascularization) was compared between FFR- and angiography-guided PCI according to non-IRA stenosis severity (QCA stenosis ≥70% or <70%). RESULTS: A total of 562 patients were assigned to FFR-guided (n=284) versus angiography-guided PCI (n=278). At a median follow-up of 3.5 years, the primary end point occurred in 14 of 181 patients with FFR-guided PCI and 31 of 197 patients with angiography-guided PCI among patients with QCA stenosis ≥70% (8.5% versus 19.2%; hazard ratio, 0.41 [95% CI, 0.22-0.80]; P=0.008), while occurred in 4 of 103 patients with FFR-guided PCI and 9 of 81 patients with angiography-guided PCI among those with QCA stenosis <70% (3.9% versus 11.1%; P=0.315). There was no significant interaction between treatment strategy and non-IRA stenosis severity (P for interaction=0.636). FFR-guided PCI was associated with the reduction of death and myocardial infarction in both patients with QCA stenosis ≥70% (6.7% versus 15.1%; P=0.008) and those with QCA stenosis <70% (1.0% versus 9.6%; P=0.042) compared with angiography-guided PCI. CONCLUSIONS: In patients with acute myocardial infarction and multivessel disease, FFR-guided PCI tended to have a lower risk of primary end point than angiography-guided PCI regardless of non-IRA stenosis severity without significant interaction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02715518.

Phenotyping coronary plaque by computed tomography in premature coronary artery disease.

AIMS: Premature coronary artery disease (CAD) is an aggressive disease with multiple recurrences mostly related to new coronary lesions. This study aimed to compare coronary plaque characteristics of individuals with premature CAD with those of incidental plaques found in matched individuals free of overt cardiovascular disease, using coronary computed tomography angiography (CCTA). METHODS AND RESULTS: Of 1552 consecutive individuals who underwent CCTA, 106 individuals with history of acute or stable obstructive CAD ≤45 years were matched by age, sex, smoking status, cardiovascular heredity, and dyslipidaemia with 106 controls. CCTA were analysed for Coronary Artery Disease Reporting and Data System score, plaque composition, and high-risk plaque (HRP) features, including spotty calcification, positive remodelling, low attenuation, and napkin-ring sign. The characteristics of 348 premature CAD plaques were compared with those of 167 incidental coronary plaques of matched controls. The prevalence of non-calcified plaques was higher among individuals with premature CAD (65.1 vs. 30.2%, P < 0.001), as well as spotty calcification (42.5 vs. 17.9%, P < 0.001), positive remodelling (41.5 vs. 9.4%, P < 0.001), low attenuation (24.5 vs. 3.8%, P < 0.001), and napkin-ring sign (1.9 vs. 0.0%). They exhibited an average of 2.2 (2.7) HRP, while the control group displayed 0.4 (0.8) HRP (P < 0.001). Within a median follow-up of 24 (16, 34) months, individuals with premature CAD and ischaemic recurrence (n = 24) had more HRP [4.3 (3.9)] than those without ischaemic recurrence [1.5 (1.9)], mostly non-calcified with low attenuation and positive remodelling. CONCLUSION: Coronary atherosclerosis in individuals with premature CAD is characterized by a high and predominant burden of non-calcified plaque and unusual high prevalence of HRP, contributing to disease progression with multiple recurrences. A comprehensive qualitative CCTA assessment of plaque characteristics may further risk stratify our patients, beyond cardiovascular risk factors.

LncRNA-mediated Modulation of Endothelial Cells: Novel Progress in the Pathogenesis of Coronary Atherosclerotic Disease.

Coronary atherosclerotic disease (CAD) is a common cardiovascular disease and an important cause of death. Moreover, endothelial cells (ECs) injury is an early pathophysiological feature of CAD, and long noncoding RNAs (lncRNAs) can modulate gene expression. Recent studies have shown that lncRNAs are involved in the pathogenesis of CAD, especially by regulating ECs. In this review, we summarize the novel progress of lncRNA-modulated ECs in the pathogenesis of CAD, including ECs proliferation, migration, adhesion, angiogenesis, inflammation, apoptosis, autophagy, and pyroptosis. Thus, as lncRNAs regulate ECs in CAD, lncRNAs will provide ideal and novel targets for the diagnosis and drug therapy of CAD.

Higher triglyceride levels are associated with the higher prevalence of layered plaques in non-culprit coronary plaques.

High triglyceride (TG) levels have been recognized as a risk factor for cardiovascular events in patients with coronary artery disease (CAD). This study aimed to clarify the association between TG levels and characteristics of non-culprit coronary plaques in patients with CAD. A total of 531 consecutive patients with stable CAD who underwent percutaneous coronary intervention for culprit lesions and optical coherence tomography (OCT) assessment of non-culprit plaques in the culprit vessel were included in this study. The morphology of the non-culprit plaques assessed by OCT imaging were compared between the higher TG (TG ≥ 150 mg/dL, n = 197) and lower TG (TG < 150 mg/dL, n = 334) groups. The prevalence of layered plaques (40.1 vs. 27.5%, p = 0.004) was significantly higher in the higher TG group than in the lower TG group, although the prevalence of other plaque components was comparable between the two groups. High TG levels were an independent factor for the presence of layered plaques (odds ratio 1.761, 95% confidence interval 1.213-2.558, p = 0.003) whereas high low-density lipoprotein cholesterol levels (≥ 140 mg/dL) and low eicosapentaenoic acid/arachidonic acid ratios (< 0.4) were independently associated with a higher prevalence of thin-cap fibroatheroma and macrophages. Higher TG levels were associated with a higher prevalence of layered plaques in non-culprit plaques among patients with stable CAD. These results may partly explain the effect of TG on the progression of coronary plaques and the increased incidence of recurrent events in patients with CAD.

Coronary CT angiography for the assessment of atherosclerotic plaque inflammation: postmortem proof of concept with histological validation.

OBJECTIVES: To evaluate the diagnostic utility of multiphase postmortem CT angiography (PMCTA) to detect plaque enhancement as a surrogate marker of inflammation, using fatal coronary plaques obtained from autopsies following sudden cardiac death. METHODS: In this retrospective study, we included 35 cases (12 women, 34%; median [IQR] age, 52 [11] years), with autopsy-proven coronary thrombosis, histological examination, and multiphase PMCTA. Two radiologists blinded towards histological findings assessed PMCTA for plaque enhancement of the culprit lesion in consensus. Two forensic pathologists determined the culprit lesion and assessed histological samples in consensus. Cases with concomitant vasa vasorum density increase and intraplaque and periadventital inflammation were considered positive for plaque inflammation. Finally, we correlated radiology and pathology findings. RESULTS: All 35 cases had histological evidence of atherosclerotic plaque disruption and thrombosis; 30 (85.7%) had plaque inflammation. Plaque enhancement at multiphase PMCTA was reported in 21 (60%) and resulted in a PPV of 95.2% (77.3-99.2%) and an NPV of 28.6% (17-43.9%). Median histological ratings indicated higher intraplaque inflammation (p = .024) and vasa vasorum density (p = .032) in plaques with enhancement. We found no evidence of a difference in adventitial inflammation between CT-negative and CT-positive plaques (p = .211). CONCLUSIONS: Plaque enhancement was found in 2/3 of fatal atherothrombotic occlusions at coronary postmortem CT angiography. Furthermore, plaque enhancement correlated with histopathological plaque inflammation and increased vasa vasorum density. Plaque enhancement on multiphase CT angiography could potentially serve as a noninvasive marker of inflammation in high-risk populations. CLINICAL RELEVANCE STATEMENT: Phenotyping coronary plaque more comprehensively is one of the principal challenges cardiac imaging is facing. Translating our ex vivo findings of CT-based plaque inflammation assessment into clinical studies might help pave the way in defining high-risk plaque better. KEY POINTS: • Most thrombosed coronary plaques leading to fatality in our series had histological signs of inflammation. • Multiphase postmortem CT angiography can provide a noninvasive interrogation of plaque inflammation through contrast enhancement. • Atherosclerotic plaque enhancement at multiphase postmortem CT angiography correlated with histopathological signs of plaque inflammation and could potentially serve as an imaging biological marker of plaque vulnerability.

Whole-Blood Transcriptome Unveils Altered Immune Response in Acute Myocardial Infarction Patients With Aortic Valve Sclerosis.

BACKGROUND: Aortic valve sclerosis (AVSc) presents similar pathogenetic mechanisms to coronary artery disease and is associated with short- and long-term mortality in patients with coronary artery disease. Evidence of AVSc-specific pathophysiological traits in acute myocardial infarction (AMI) is currently lacking. Thus, we aimed to identify a blood-based transcriptional signature that could differentiate AVSc from no-AVSc patients during AMI. METHODS: Whole-blood transcriptome of AVSc (n=44) and no-AVSc (n=66) patients with AMI was assessed by RNA sequencing on hospital admission. Feature selection, differential expression, and enrichment analyses were performed to identify gene expression patterns discriminating AVSc from no-AVSc and infer functional associations. Multivariable Cox regression analysis was used to estimate the hazard ratios of cardiovascular events in AVSc versus no-AVSc patients. RESULTS: This cross-sectional study identified a panel of 100 informative genes capable of distinguishing AVSc from no-AVSc patients with 94% accuracy. Further analysis revealed significant mean differences in 143 genes, of which 30 genes withstood correction for age and previous AMI or coronary interventions. Functional inference unveiled a significant association between AVSc and key biological processes, including acute inflammatory responses, type I IFN (interferon) response, platelet activation, and hemostasis. Notably, patients with AMI with AVSc exhibited a significantly higher incidence of adverse cardiovascular events during a 10-year follow-up period, with a full adjusted hazard ratio of 2.4 (95% CI, 1.3-4.5). CONCLUSIONS: Our findings shed light on the molecular mechanisms underlying AVSc and provide potential prognostic insights for patients with AMI with AVSc. During AMI, patients with AVSc showed increased type I IFN (interferon) response and earlier adverse cardiovascular outcomes. Novel pharmacological therapies aiming at limiting type I IFN response during or immediately after AMI might improve poor cardiovascular outcomes of patients with AMI with AVSc.

Association of multiple blood metals and systemic atherosclerosis: A cross-sectional study in the CAD population.

BACKGROUND: Coronary atherosclerotic disease (CAD) is often accompanied by peripheral atherosclerosis, resulting in a higher risk of ischemia and cardiovascular death. Exposure to metals is associated with atherosclerotic plaques at specific sites. However, less is known about the effects of mixed metals on systemic atherosclerotic burden in CAD patients. OBJECTIVES: To investigate the association of metal mixtures with systemic atherosclerotic burden in a CAD population. METHODS: A cross-sectional study including 1562 CAD patients from Southwest China was conducted. The levels of 10 blood metals were measured via inductively coupled plasma spectrometry. More than one vessel with a stenosis ≥50% vessel diameter was defined as CAD. Carotid and lower limb atherosclerosis was assessed by using ultrasound, and coronary atherosclerosis was quantified via arterial angiography. Systemic atherosclerosis was scored according to the presence or absence of lesions at the three sites and the total number of lesions. To investigate the combined impacts and interaction effects of metals, Bayesian kernel machine regression was used. Weighted quantile regression was used to identify the contributions of the metals. RESULTS: Significant overall associations of mixed metals with systemic atherosclerotic burden were found. These positive overall associations were mainly driven by Cd, Cu and Pb in systemic atherosclerosis. The main contributing factors were As and Cu for coronary atherosclerosis as well as Cd, Cu and Pb for carotid and lower limb atherosclerosis. Cd and Pb or Cr can interact, and Pb interacts with age, sex and alcohol. CONCLUSIONS: In CAD patients, exposure to combinations of metals was highly positively associated with systemic atherosclerotic burden. These significant trends were more pronounced in the peripheral arteries and carotid arteries. Controlling environmental metal exposure can contribute to reducing systemic atherosclerosis in CAD patients.

Subclinical Atherosclerosis: Part 1: What Is it? Can it Be Defined at the Histological Level?

While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location.

The effect of miR-223-3p on endothelial cells in coronary artery disease.

Endothelial cell damage and dysfunction are crucial factors in the development and early stages of coronary artery disease (CAD) and apoptosis plays a significant role in this process. In this study, We aimed to simulate the CAD vascular microenvironment by treating endothelial cells with tumor necrosis factor alpha (TNF-α) to construct an endothelial cell apoptosis model. Our findings revealed that the TNF-α model resulted in increased micro-RNA 223-3p (miR-223-3p) mRNA and Bax protein expression, decreased kruppel-like factor 15 (KLF15) and Bcl-2 protein expression, and decreased cell viability. More importantly, in the TNF-α-induced endothelial cell apoptosis model, transfection with the miR-223-3p inhibitor reversed the effects of TNF-α on Bcl-2, Bax expression. We transfected miRNA-223-3p mimics or inhibitors into endothelial cells and assessed miR-223-3p levels using RT-PCR. Cell viability was detected using CCK8. Western blot technology was used to detect the expression of Bcl-2, Bax, and KLF15. In summary, this study demonstrates the role and possible mechanism of miR-223-3p in endothelial cells during CAD, suggesting that miR-223-3p may serve as a promising therapeutic target in CAD by regulating KLF15.