Lipid-rich Plaques Research Articles

In vivo Predictors of Focal Type In-stent Restenosis: A Clinical, Angiographical and Optical Coherence Tomography Study.

Introduction：Few studies have evaluated different patterns of in-stent restenosis by optical coherence tomography (OCT). This study aims to identify in vivo predictors for focal restenosis in patients with in-stent restenosis (ISR). Methods: The study recruited patients with ISR who underwent OCT examination in the Cardiology Department of the Affiliated Hospital of Zunyi Medical University from October 2018 to December 2022. Based on the angiographic classification of ISR lesions, the patients were divided into two groups: the focal group (n=58) and the non-focal group (n=158). Results： The white blood cell count was higher in the non-focal group than those in focal type (7.8±3.0 vs. 6.6±2.1, P = 0.007). The prevalence of lipid rich plaque was higher in patients with focal ISR (65.5% vs. 42.4%, P = 0.003). The occurrence of red thrombus (27.8% vs. 12.1%, P = 0.016) and white thrombus (41.1% vs. 24.1%, P = 0.021) was higher in the non-focal group. Multivariate analysis showed that low density lipoprotein cholesterol C (odds ratio [OR]:3.341, 95% confidence interval [CI]: 1.714-9.784, P = 0.046) was independently associated with focal restenosis. While white blood cell count (OR: 0.814, 95% CI: 0.657-0.913, P = 0.047) and stent malapposition (OR: 0.228, 95% CI: 0.057-0.896, P = 0.037) were independently associated with non-focal restenosis. Conclusion：There were significant differences in clinical baselines and OCT identified morphological characteristics in patients between focal and non-focal group. Low density lipoprotein cholesterol C was independent associated with focal restenosis. White blood cell count and stent malapposition were correlated with non-focal restenosis.

Coronary Plaque Characteristics Assessed by Optical Coherence Tomography and Plasma Lipoprotein(a) Levels in Patients With Acute Coronary Syndrome.

Lipoprotein(a) [Lp(a)] is associated with increased cardiovascular risk, but its influence on plaque characteristics at optical coherence tomography (OCT) evaluation is not fully understood. This study seeks to explore the impact of Lp(a) levels on plaque morphology as assessed by OCT in a very high-risk subset of patients. Consecutive patients admitted for acute coronary syndrome (ACS) and undergoing OCT-guided percutaneous coronary intervention (PCI) at a large tertiary care center between 2019 and 2022 were deemed eligible for the current analysis. The overall population was categorized into two subgroups according to baseline Lp(a) levels: (1) lower Lp(a) (Lp(a) ≤ 300 mg/L) and (2) elevated Lp(a) (Lp(a) 300 mg/L). Predictors of lipid-rich plaques were identified using multivariable logistic regression with stepwise selection of candidate covariates. A total of 202 patients were included in this study. OCT findings revealed that patients with elevated Lp(a) had a higher prevalence of lipid-rich plaques, a significantly greater mean lipid arc, along with increased macrophage infiltration and thin-cap fibroatheroma (TCFA). In contrast, calcific plaque prevalence was higher in the lower Lp(a) group. Multivariable regression analysis identified low-density lipoprotein cholesterol ≥ 70 mg/dL, and elevated Lp(a) as strong predictors of lipid-rich plaques at OCT. In this observational study including ACS patients undergoing OCT-guided PCI, those with elevated Lp(a) levels exhibited a higher prevalence of lipid-rich plaques, increased macrophage infiltration, and TCFA, thereby indicating a more vulnerable plaque phenotype. Additionally, elevated Lp(a) levels and LDL-C levels ≥ 70 mg/dL were each independently associated with lipid enrichment of coronary plaques. These findings suggest Lp(a), beyond other well-known risk factors, as a key marker for risk stratification, potentially informing optimal medical management strategies.

Relationship Between Coronary Artery Calcium Score and Vulnerability of Culprit Plaque Assessed by OCT in Patients With Established Coronary Artery Disease.

Coronary artery calcium score (CACS) is widely used for risk stratification. However, in patients with established coronary artery disease, its clinical implication and relationship with plaque vulnerability are unclear. We sought to correlate the CACS and plaque vulnerability assessed by optical coherence tomography. Patients with coronary artery disease who had CACS and optical coherence tomography before percutaneous coronary intervention were included. Patients were divided into 5 groups based on CACS: CACS of 0, 1 to 99, 100 to 399, 400 to 999, and ≥1000. Optical coherence tomography-derived vulnerable features in culprit plaque were compared between the groups. In 460 patients, the prevalence of lipid-rich plaque, macrophage, and cholesterol crystal significantly differed among the 5 groups, being lowest in the patients with a CACS of 0. The prevalence of thin-cap fibroatheroma tended to be lower in those with a CACS of 0. No significant difference in vulnerable features was observed between the 4 groups with CACS >0. In the 2-group comparison between the group with a CACS of 0 and the other 4 groups combined, the prevalence of lipid-rich plaque (60.5% versus 85.9%; P<0.001), macrophage (48.8% versus 74.1%; P<0.001), thin-cap fibroatheroma (16.3% versus 35.0%; P=0.013), and cholesterol crystal (11.6% versus 32.9%; P=0.004) was significantly lower in the patients with CACS of 0. CACS of 0 was independently negatively associated with lipid-rich plaque, macrophage, thin-cap fibroatheroma, and cholesterol crystal after adjustment for patient characteristics. Patients with a CACS of 0 have a significantly lower prevalence of vulnerable plaque features compared with those with CACS >0 in patients with established coronary artery disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Association between lipid-rich plaques and thrombus formation after excimer laser coronary angioplasty in in-stent restenosis and de novo lesions.

Excimer laser coronary angioplasty (ELCA) in percutaneous coronary intervention (PCI) is safe and effective. However, thrombotic complications after ELCA occasionally occur. This study aimed to evaluate the impact of lipid-rich plaque in both in-stent restenosis (ISR) and de novo lesions on thrombus formation and transient no-reflow after ELCA. We conducted a single-center, retrospective, observational study including 27 lesions in 26 patients who underwent PCI with ELCA. Optical coherence tomography (OCT) was performed on all lesions before and immediately after ELCA. We measured the lipid angle per millimeter and lipid length of plaques with signal attenuation. We also recorded ELCA-induced thrombus formation and transient no-reflow. Thrombus formation and transient no-reflow were observed in nine (33%) and four lesions (15%), respectively. The frequency of ISR was significantly higher in the no-thrombus group than in the thrombus group. ISR lesions had a significantly lower lipid index (median [interquartile range] 108° [0°-756°] vs. 2541° [1205°-4336°]; p = 0.004) than de novo lesions. Among ISR lesions, those with ELCA-induced thrombus formation had a significantly higher lipid index (1370° [756°-4992°] vs. 29° [0°-285°]; p = 0.01) and significantly longer lipid length (8mm [7-24mm] vs. 0.5mm [0-2.5mm]; p = 0.01). The findings suggest that thrombus formation was more frequently observed in de novo lesions than in ISR lesions. OCT-detected lipid-rich plaques in ISR lesions were strongly associated with thrombus formation following ELCA.

Evaluating the influence of morphological features on the vulnerability of lipid-Rich plaques during stenting.

Lipid-rich atheromas are linked to plaque rupture in stented atherosclerotic arteries. While fibrous cap thickness is acknowledged as a critical indicator of vulnerability, it is likely that other morphological features also exert influence. However, detailed quantifications of their contributions and intertwined effects in stenting are lacking. Therefore, our goal is to assess the impact of plaque characteristics on the fibrous cap stress and elucidate their underlying mechanisms. We analyzed the stent deployment over a 3D patient-specific coronary artery reconstructed from intravascular optical coherence tomography (IVOCT) through finite element methods. Additionally, we performed sensitivity analysis on 78,000 distinct plaque geometries of two-dimensional arteries for verification. Results from the 3D patient-specific model indicate strong correlations between maximum fibrous cap stress and lipid arc (r=0.769), area stenosis (r=0.550), and lumen curvature (r=0.642). Plaques with lipid arcs > 60°, area stenosis > 75%, and lumen curvatures > 5 mm-1 are at increased rupture risk. While we observed a rise in stress with lipid core thickness, it was less representative than other features. Fibrous cap thickness showed a poor correlation, with the sensitivity analysis revealing its significance only when high stretches are induced by other features, likely due to its J-shaped stress-stretch response. Contrary to physiological pressure, the stent expansion generates unique vulnerable features as the stent load-transferring characteristics modify the plaque?s response. This study is expected to prompt further clinical investigations of other morphological features for predicting plaque rupture in stenting.

Computed tomography versus near-infrared spectroscopy for the assessment of coronary atherosclerosis.

Coronary computed tomography angiography (CCTA) has been proposed as an alternative to intravascular imaging for assessing plaque pathology. We aimed to assess the efficacy of CCTA against near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) in evaluating atheroma burden and composition and for guiding coronary interventions. Seventy patients with a chronic coronary syndrome were recruited and underwent CCTA and NIRS-IVUS. The imaging data were matched, and the estimations of lumen, vessel wall and plaque dimensions and composition of the two modalities were compared. The primary endpoint of the study was the efficacy of CCTA in detecting lipid-rich plaques identified by NIRS-IVUS. Secondary endpoints included the performance of CCTA in evaluating coronary artery pathology in the studied segments and its value in stent sizing, using NIRS-IVUS as the reference standard. In total, 186 vessels were analysed. The attenuated plaque volume on CCTA had weak accuracy in detecting lipid-rich plaques (58%; p=0.029). Compared to NIRS-IVUS, CCTA underestimated the lumen volume (309.2 mm3 vs 420.4 mm3; p=0.001) and plaque dimensions (total atheroma volume 116.1 mm3 vs 292.8 mm3; p<0.001 and percentage atheroma volume 27.67% vs 41.06%; p<0.001) and overestimated the lipid component (lipid core burden index 48.6 vs 33.8; p=0.007). In the 86 lesions considered for revascularisation, CCTA underestimated the reference vessel area (8.16 mm2 vs 12.30 mm2; p<0.001) and overestimated the lesion length (23.5 mm vs 19.0 mm; p=0.029) compared to NIRS-IVUS. CCTA has limited efficacy in assessing plaque composition and quantifying lumen and plaque dimensions and tissue types, which may potentially impact revascularisation planning.

Abstract 4137414: Uncovering MLKL as a Novel Regulator of Endothelial Cells in the Splenic Niche to Repress Hematopoiesis During Atherosclerosis

Background: Atherosclerosis occurs as lipid and immune cell rich plaques deposit within the arterial wall of the heart. These immune cells are produced from hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) and spleen, a process known as hematopoiesis that is dictated by their microenvironment, including endothelial cells (ECs). Objective: While others have shown adverse remodeling of BM ECs during atherogenesis, whether splenic ECs show a similar dysfunction leading to exacerbated hematopoiesis has not been described. Methods: We analyzed RNA sequencing data from chow fed C57Bl/6 mice and high cholesterol diet (HCD) fed Apoe -/- mouse BM and splenic ECs obtained from published studies, as well as our own. In vivo studies were performed in mice on an atherogenic background ( Apoe -/-&amp; Ldlr -/-) fed a HCD for 4 to 16 weeks. Knockdown of the mixed lineage kinase domain-like protein ( Mlkl KD) was achieved by weekly administration of antisense oligonucleotides (ASOs) or scrambled control (50mg/kg sc.). In vitro studies were performed in primary mouse splenic ECs transfected with siRNA. Results: Pathway analysis revealed remarkable tissue-specific responses to an atherogenic milieu, including dysregulation of Lipid Metabolism, Endocytosis and Cell Death pathways in splenic ECs. Interestingly, we previously showed that the mixed lineage kinase domain-like protein (MLKL) regulates the endocytic trafficking of lipids and cell death in macrophages. Indeed using Mlkl KD Apoe -/- mice, transplantation of Mlkl -/- BM into Ldlr -/- mice or EC-specific Mlkl -/- Apoe -/- mice, we show that loss of MLKL drives myelopoiesis and plaque development through regulation of splenic ECs. Both in vivo and in vitro , silencing Mlkl in splenic but not BM ECs potently increased lipid content and disrupted endocytosis by an accumulation of the multivesicular body marker CHMP4B, which mirror the dysregulated pathways we identified above. Furthermore, co-culture with Mlkl KD splenic ECs increased HSPC activation (pStat5) and myeloid colony formation, an effect that was lost when ECs were pre-treated with the upstream endocytosis inhibitor Dynasore. Conclusions: In conclusion, we establish a novel role for MLKL in regulating the balance of HSPCs, specifically through preservation of splenic, but not BM, ECs that repress hematopoiesis, highlighting the importance of splenic lipid metabolism and endocytosis and its impact on atherogenesis.

Abstract 4132291: Assessing the Efficacy of Preventive Percutaneous Coronary Intervention vs Optimal Medical Therapy for the Treatment of Vulnerable Plaque: A Meta-analysis

Introduction: Rupture and thrombosis of lipid-rich atherosclerotic plaques (vulnerable plaques) contributes to majority of acute coronary syndrome (ACS). Current guidelines recommend optimal medical therapy (OMT) for stabilization of vulnerable plaques. Recent evidence of preventive percutaneous intervention (PCI) as a targeted treatment shows improvement in outcomes in these patients. Hypothesis/Goals/Aims: We aim to evaluate the efficacy of preventive percutaneous coronary intervention (PCI) compared to optimal medical therapy (OMT) for treatment of non-vulnerable plaque within five years of follow up from available selected randomized controlled trials (RCTs). Methods: PubMed, Cochrane, OVID, and NIH Clinical Trials were searched for RCTs evaluating preventive PCI compared to standard of care medical therapy. All trials reported primary common endpoints as death from cardiac cause and myocardial infarction (MI). Secondary outcomes included all-cause mortality, any revascularization, hospitalization for unstable and progressive angina, and composite death (any cause, MI, or any revascularization). Sub analyses for secondary outcomes were included if measured by RCT. A fixed effect model with Mantel-Haenszel statistical method was used to calculate risk ratios, Z scores, and a 95% confidence interval. Results: Ten RCTs (n=15955 patients) were included. Preventive PCI of vulnerable plaques revealed a significant benefit in lowering incidence of MI (RR: 0.86 [0.77, 0.86], p=0.01) and death from cardiac cause (RR: 0.73 [0.62, 0.86], p=0.004). Similarly, patients undergoing preventive PCI had a lower incidence of hospitalization for unstable or progressive angina (RR: 0.75 [0.62, 0.91], p&lt;0.0001) and composite death (RR: 0.55 [0.46, 0.67], p&lt;0.001). No difference was noted in all-cause mortality. Incidence of revascularization had a significant benefit with OMT therapy compared to preventive PCI (RR: 1.84 [1.75, 1.94], p&lt;0.0001). Conclusion: Preventive PCI in vulnerable plaque demonstrates cardiovascular benefit as a result from lower incidence of MI, death from cardiac cause, composite death and fewer hospitalization for unstable or progressive angina.

Morphological characterization of coronary plaques in young indian patients with acute coronary syndrome: A multicentric study

ObjectivesThe prevalence of atherosclerosis and acute coronary syndrome (ACS) is increasing in young Indians (18–50 years of age). However, the characteristics of atherosclerotic plaques in such individuals are poorly understood, presenting distinct challenges for the management of ACS. This study aims to analyze plaque characteristics in young Indian patients with ACS who underwent percutaneous coronary intervention (PCI) using optical coherence tomography (OCT) imaging. MethodsThis was a prospective, multicentric, non-interventional study on patients aged 18–50 years presenting with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction, or unstable angina, and were scheduled to undergo OCT-guided PCI. Major adverse cardiac events (MACE) were assessed post-procedure and at the 6-month and 12-month follow-ups. ResultsThe study included 100 ACS patients (mean age = 43.6 ± 5.2 years), with 51% presenting with STEMI. Pre-PCI OCT assessment showed that fibrous plaques (75%) were most common followed by plaques containing macrophages (27%), microchannels (20%), and calcified nodules (14%). In addition, plaque rupture, plaque erosion, and lipid-rich plaques, along with red, white, and mixed thrombi, were observed in 31%, 25%, 24%, 21%, 14%, and 17% (total thrombus occurrence = 52%) of the patients, respectively. At 12 months, the MACE (coronary artery bypass graft) rate was 1%. ConclusionsYoung Indian patients with ACS displayed a range of plaque morphologies identified through pre-PCI OCT. Among these, fibrous plaques were the most prominent type, followed by plaques containing macrophages. Additionally, plaque rupture, plaque erosion, and lipid-rich plaques were also observed in this population.

The impact of lipid rich plaque on coronary-microvascular-dysfunction evaluated by near-infrared spectroscopy IVUS and angiography-derived index of microcirculatory resistance after percutaneous-coron

Abstract Background Coronary microvascular dysfunction (CMD) after percutaneous coronary intervention (PCI) has been reported to be associated not only with periprocedural myocardial infarction, but also with poor prognosis. While index of microcirculatory resistance using pressure wire (invasive IMR) has been conventionally used to evaluate CMD, angio-derived IMR (angio-IMR) has recently emerged as a noninvasive method and has shown good correlation with invasive IMR. Previous investigations have already shown that the maximum value of LCBI for any of the 4-mm segments (maxLCBI4mm) by near-infrared spectroscopy IVUS (NIRS-IVUS) represents the degree of lipid rich plaque (LRP) and can predict microvascular obstruction after PCI. However, few studies have examined the relationship between maxLCBI4mm values assessed by NIRS-IVUS and the degree of CMD from physiological assessment, or the optimal maxLCBI4mm cut-off values to predict CMD after PCI. Purpose The purpose of this study was to define the relationship between LRP identified by NIRS-IVUS and CMD assessed by angio-IMR in coronary artery disease (CAD) patients and to determinate the optimal diagnostic cut-off values of maxLCBI4mm. Methods We retrospectively evaluated 101 consecutive patients who underwent PCI using NIRS-IVUS for CAD, excluding STEMI, at our hospital from November 2021 to January 2024. MaxLCBI4mm and angio-IMR were measured in culprit vessel before and after PCI. CMD was defined as angio-IMR≥25. ROC curve analysis was performed to determine the optimal cut-off values of maxLCBI4mm for angio-IMR≥25. Plaques with maxLCBI4mm values above the cut-off were defined as the LRP group. Results Of 101 patients, CMD after PCI occurred in 37 patients (37%). MaxLCBI4mm values were significantly higher in the CMD group compared to the non-CMD group (659±198 vs. 403±226, P&amp;lt;0.001). Figure 1 shows the results of ROC analysis for predicting the incidence of CMD after PCI. ROC analysis determined maxLCBI4mm≥579 (LRP group) as an optimal cut-off value associated with incidence of CMD (AUC=0.80, P&amp;lt;0.01, sensitivity=0.78, specificity=0.75). LRP group had significantly higher angio-IMR values and incidence of CMD than non-LRP group (24.7±7.8 vs. 19.1±7.2, P&amp;lt;0.01, 64% vs. 14%, P&amp;lt;0.01). Furthermore, Δangio-IMR (post PCI-Pre PCI) of the LRP group was significantly higher than that of the non-LRP group (Figure 2). On multivariable analysis, maxLCBI4mm≥579 emerged as the independent predictor of the incidence of CMD after PCI (OR=10.6, 95% CI=2.29-48.8, P&amp;lt;0.01). Conclusions The results of this study indicate that NIRS-IVUS-guided PCI is a useful predictor of the incidence of CMD after PCI.Figure 1Figure 2

Inclisiran-containing low-density lipoprotein cholesterol reduction effectively stabilizes atherosclerotic plaques

Abstract Background/Introduction Near-infrared spectroscopy (NIRS) allows to quantify lipid composition of coronary artery lesions. High plaque lipid content has been associated with increased adverse cardiovascular event risk. Purpose Aim of this study was to evaluate atherosclerotic plaque lipid content reduction in association with low-density lipoprotein (LDL-C) lowering on the background of intensive hypolipidaemic therapy. Methods NIRS investigation was performed in stable coronary artery disease patients having 20-50% stenosis in the proximal or middle third of a coronary artery. Segment of interest was repeatedly evaluated after 15 months. Lipid-rich plaques (LRPs) were defined as lesions with maximum lipid-core burden index within 4 mm (maxLCBI4 mm) &amp;gt;250. Study participants were taking high-intensity statin (atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg) with or without ezetimibe for a run-in period of 4-6 weeks. Afterwards, in patients not achieving LDL-C level &amp;lt;1.8 mmol/l, add-on inclisiran was started. Baseline LDL-C was defined as the level at the time of initiation of optimal lipid-lowering therapy. Statistical significance level of 0.05 was set. Results Data of 36 patients was analyzed. Mean baseline maxLCBI4 mm was 203.9, reduced by 39.8% (-81.1, 95%CI -129.2 to -33.0) at 15-month follow-up (P=0.003). In 15 patients LRPs were detected with mean baseline maxLCBI4 mm 363.5, which was decreased by 35.8% (-130.3, 95%CI -235.0 to -25.7) (P=0.020). Mean LDL-C level at baseline was 2.5 mmol/l among all participants, lowered by 32.0% (-0.8, 95%CI -1.1 to -0.5) after 15 months of treatment (P&amp;lt;0.001). 19 patients received inclisiran in addition to high-dose statin and optional ezetimibe therapy. In 24 patients achieving LDL-C target &amp;lt;1.8 mmol/l at 15-month follow-up, a significant maxLCBI4 mm reduction from 208.5 by 48.4% (-101.0, 95%CI -169.3 to -32.7) was established (P=0.010). Among those having LDL-C &amp;gt;1.8 mmol/l, maxLCBI4 mm reduction from 194.7 by 21.2% (-41.25, 95%CI -94.7 to 12.2) was observed, however the change was not statistically significant (P=0.114). Conclusion LDL-C lowering with high-intensity hypolipidaemic therapy, including escalation to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, demonstrated atherosclerotic plaque stabilization by NIRS-detected lipid content decrease.

Relationship between coronary artery calcium score and plaque vulnerability in patients with established coronary artery disease

Abstract Introduction Coronary artery calcium (CAC) score is widely used for risk stratification. However, in patients with established coronary artery disease (CAD), its clinical implication and relationship with plaque vulnerability have not been fully investigated. Purpose We sought to investigate the relationship between CAC score and plaque vulnerability assessed by optical coherence tomography (OCT). Methods Patients with CAD who had both CAC score and OCT prior to percutaneous coronary intervention were included. The patients with a prior history of coronary revascularization were excluded. Patients were divided into five groups based on CAC score; CAC score of 0, 1-99, 100-399, 400-999, and over 1000. Vulnerable features in culprit plaque assessed by OCT were compared among these five groups. Results In 460 patients, the prevalence of lipid-rich plaque, macrophage, and cholesterol crystal significantly differed among the five groups: lowest in the patients with a CAC score of zero. The prevalence of thin-cap fibroatheroma (TCFA) tended to be lower in those with a CAC score of zero (Figure). In the two-group comparison between the group with a CAC score of zero and the other four groups, the prevalence of lipid-rich plaque (60.5 vs. 85.9%, p &amp;lt; 0.001), macrophage (48.8 vs. 74.1%, p &amp;lt; 0.001), TCFA (16.3 vs. 35.0%, p = 0.013), and cholesterol crystal (11.6 vs. 32.9%, p = 0.004) was significantly lower in the patients with CAC score of zero. No significant difference in vulnerable features was observed among the four groups with CAC scores &amp;gt; 0. CAC score of zero was independently negatively associated with the lipid-rich plaque (odds ratio [OR] 0.246, p &amp;lt; 0.001), macrophage (OR 0.348, p = 0.003), TCFA (OR 0.285, p = 0.006), and cholesterol crystal (OR 0.273, p = 0.010) after adjustment with patient characteristics. Conclusion This is the first study that investigated the relationship between CAC score and plaque vulnerability assessed by OCT in patients with known CAD. Patients with CAC score of zero have a significantly lower prevalence of vulnerable plaque features compared to those with CAC score &amp;gt; 0.

Lesion-level changes induced by low-density lipoprotein cholesterol lowering therapy in patients with acute myocardial infarction: the pre-specified PACMAN-AMI lesion-level analysis

Abstract Background Previous intracoronary imaging studies investigated atherosclerotic changes induced by lipid-lowering therapy in extensive coronary segments, based on anatomical landmarks and irrespective of the baseline atheroma burden. The effects of lipid-lowering therapy focusing on coronary lesions with advanced atherosclerotic features and at presumably higher risk for future events remains largely unknown. Purpose To provide a lesion-level analysis reporting changes in high-risk atherosclerotic features and plaque phenotypes induced by alirocumab versus placebo in addition to high-intensity statin therapy in nonculprit coronary lesions of patients admitted with acute myocardial infarction (AMI). Methods In this pre-specified lesion-level analysis of the PACMAN-AMI trial, coronary lesions were identified as segments with plaque burden ≥40% defined by intravascular ultrasound (IVUS). IVUS, near-infrared spectroscopy (NIRS) and optical coherence tomography (OCT) images at baseline and 52-week follow-up were manually matched and lesion-level imaging outcome measures were calculated by analysts blinded to treatment allocation and patient clinical data. The evolution of high-risk plaque phenotypes as defined by each imaging modality (IVUS-defined plaque burden ≥70%, NIRS-defined maximum LCBI 4 mm ≥400, OCT-defined thin-cap fibroatheroma &amp;lt;65µm) was investigated. Results Overall, 591 lesions with available baseline and follow-up imaging were included. Of these, 287 were identified in 118 patients (214 vessels) in the alirocumab arm, and 304 lesions were identified in 127 patients (239 vessels) in the placebo arm. At lesion-level, mean change in percent atheroma volume (PAV) by IVUS was -4.86% with alirocumab vs -2.78% with placebo (difference, -2.02 [-3.00 to -1.05], p&amp;lt;.001), substantially greater than that at vessel-level (Figure 1). At the minimum lumen area (MLA) site, mean change in PAV was -10.14% with alirocumab vs -6.70% with placebo (difference, -3.36 (-4.98 to -1.75, p&amp;lt;0.001). MLA increased by 0.15 mm2 with alirocumab and decreased by 0.07 mm2 in the placebo arm (difference, +0.21, 0.01 to 0.41, p=0.036), whereas arterial remodeling was similar between arms (-0.73±1.61 in alirocumab vs -0.63±1.31 in placebo group, p=0.482). Among lesions with high-risk plaque phenotypes at baseline, those in the alirocumab arm more frequently showed a more stable and less lipid-rich plaque phenotype at follow-up than those in the placebo arm (Figure 2). Conclusions At lesion-level, intense lipid-lowering therapy with alirocumab in addition to high-intensity statin therapy induced extensive PAV regression, substantially greater than described in previous vessel-level analyses. Compared to statin therapy alone, alirocumab treatment was associated with a greater enlargement of the lesion MLA, similar negative arterial remodeling, and a more frequent transition of high-risk plaque phenotypes into more stable, less lipid-rich plaque phenotypes.Figure 1.Figure 2

Cellular communication network factor 2 regulates smooth muscle cell transdifferentiation and lipid accumulation in atherosclerosis.

Accruing evidence illustrates an emerging paradigm of dynamic vascular smooth muscle cell (SMC) transdifferentiation during atherosclerosis progression. However, the molecular regulators that govern SMC phenotype diversification remain poorly defined. This study aims to elucidate the functional role and underlying mechanisms of cellular communication network factor 2 (CCN2), a matricellular protein, in regulating SMC plasticity in the context of atherosclerosis. In both human and murine atherosclerosis, an up-regulation of CCN2 is observed in transdifferentiated SMCs. Using an inducible murine SMC CCN2 deletion model, we demonstrate that SMC-specific CCN2 knockout mice are hypersusceptible to atherosclerosis development as evidenced by a profound increase in lipid-rich plaques along the entire aorta. Single-cell RNA sequencing studies reveal that SMC deficiency of CCN2 positively regulates machinery involved in endoplasmic reticulum stress, endocytosis, and lipid accumulation in transdifferentiated macrophage-like SMCs during the progression of atherosclerosis, findings recapitulated in CCN2-deficient human aortic SMCs. Our studies illuminate an unanticipated protective role of SMC-CCN2 against atherosclerosis. Disruption of vascular wall homeostasis resulting from vascular SMC CCN2 deficiency predisposes mice to atherosclerosis development and progression.

Effect of Colchicine on Coronary Plaque Stability in Acute Coronary Syndrome as Assessed by Optical Coherence Tomography: The COLOCT Randomized Clinical Trial.

Colchicine has been approved to reduce cardiovascular risk in patients with coronary heart disease on the basis of its potential benefits demonstrated in the COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low-Dose Colchicine 2) studies. Nevertheless, there are limited data available about the specific impact of colchicine on coronary plaques. This was a prospective, single-center, randomized, double-blind clinical trial. From May 3, 2021, until August 31, 2022, a total of 128 patients with acute coronary syndrome aged 18 to 80 years with lipid-rich plaque (lipid pool arc >90°) detected by optical coherence tomography were included. The subjects were randomly assigned in a 1:1 ratio to receive either colchicine (0.5 mg once daily) or placebo for 12 months. The primary end point was the change in the minimal fibrous cap thickness from baseline to the 12-month follow-up. Among 128 patients, 52 in the colchicine group and 52 in the placebo group completed the study. The mean age of the 128 patients was 58.0±9.8 years, and 25.0% were female. Compared with placebo, colchicine therapy significantly increased the minimal fibrous cap thickness (51.9 [95% CI, 32.8 to 71.0] μm versus 87.2 [95% CI, 69.9 to 104.5] μm; difference, 34.2 [95% CI, 9.7 to 58.6] μm; P=0.006), and reduced average lipid arc (-25.2° [95% CI, -30.6° to -19.9°] versus -35.7° [95% CI, -40.5° to -30.8°]; difference, -10.5° [95% CI, -17.7° to -3.4°]; P=0.004), mean angular extension of macrophages (-8.9° [95% CI, -13.3° to -4.6°] versus -14.0° [95% CI, -18.0° to -10.0°]; difference, -6.0° [95% CI, -11.8° to -0.2°]; P=0.044), high-sensitivity C-reactive protein level (geometric mean ratio, 0.6 [95% CI, 0.4 to 1.0] versus 0.3 [95% CI, 0.2 to 0.5]; difference, 0.5 [95% CI, 0.3 to 1.0]; P=0.046), interleukin-6 level (geometric mean ratio, 0.8 [95% CI, 0.6 to 1.1] versus 0.5 [95% CI, 0.4 to 0.7]; difference, 0.6 [95% CI, 0.4 to 0.9]; P=0.025), and myeloperoxidase level (geometric mean ratio, 1.0 [95% CI, 0.8 to 1.2] versus 0.8 [95% CI, 0.7 to 0.9]; difference, 0.8 [95% CI, 0.6 to 1.0]; P=0.047). Our findings suggested that colchicine resulted in favorable effects on coronary plaque stabilization at optical coherence tomography in patients with acute coronary syndrome. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04848857.

Relationship Between Calcified Plaque Burden, Vascular Inflammation, and Plaque Vulnerability in Patients With Coronary Atherosclerosis

BackgroundCoronary artery calcification is an integral part of atherosclerosis. It has been suggested that early coronary artery calcification is associated with active inflammation, and advanced calcification forms as inflammation subsides. Inflammation is also an important factor in plaque vulnerability. However, the relationship between coronary artery calcium burden, vascular inflammation, and plaque vulnerability has not been fully investigated. ObjectivesThis study aimed to correlate calcified plaque burden (CPB) at the culprit lesion with vascular inflammation and plaque vulnerability. MethodsPatients with coronary artery disease who had both computed tomography angiography and optical coherence tomography were included. The authors divided the patients into 4 groups: 1 group without calcification at the culprit lesion; and 3 groups based on the CPB tertiles. CPB was calculated as calcified plaque volume divided by vessel volume in the culprit lesion. The authors compared pericoronary adipose tissue (PCAT) attenuation for vascular inflammation and optical coherence tomography–derived vulnerable features among the 4 groups. ResultsAmong 578 patients, the highest CPB tertile showed significantly lower PCAT attenuation of culprit vessel compared with the other groups. The prevalence of features of plaque vulnerability (including lipid-rich plaque, macrophage, and microvessel) was also lowest in the highest CPB tertile. In the patients with calcification, higher age, statin use, and lower PCAT attenuation were independently associated with CPB. ConclusionsGreater calcium burden is associated with a lower level of vascular inflammation and plaque vulnerability. A greater calcium burden may represent advanced stable plaque without significant inflammatory activity. (Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration; NCT04523194)

Lesion-Level Effects of LDL-C–Lowering Therapy in Patients With Acute Myocardial Infarction

Previous studies investigated atherosclerotic changes induced by lipid-lowering therapy in extensive coronary segments irrespective of baseline disease burden (a vessel-level approach). To investigate the effects of lipid-lowering therapy on coronary lesions with advanced atherosclerotic plaque features and presumably higher risk for future events. The PACMAN-AMI randomized clinical trial (enrollment: May 2017 to October 2020; final follow-up: October 2021) randomized patients with acute myocardial infarction to receive alirocumab or placebo in addition to high-intensity statin therapy. In this post hoc lesion-level analysis, nonculprit lesions were identified as segments with plaque burden 40% or greater defined by intravascular ultrasound (IVUS). IVUS, near-infrared spectroscopy, and optical coherence tomography images at baseline and the 52-week follow-up were manually matched by readers blinded to treatment allocation. Data for this study were analyzed from October 2022 to November 2023. Alirocumab or placebo in addition to high-intensity statin therapy. Lesion-level imaging outcome measures, including high-risk plaque characteristics and phenotypes. Of the 245 patients in whom lesions were found, 118 were in the alirocumab group (mean [SD] age, 58.2 [10.0] years; 101 [85.6%] male and 17 [14.4%] female) and 127 in the placebo group (mean [SD] age, 57.7 [8.8] years; 104 [81.9%] male and 23 [18.1%] female). Overall, 591 lesions were included: 287 lesions (118 patients, 214 vessels) in the alirocumab group and 304 lesions (127 patients, 239 vessels) in the placebo group. Lesion-level mean change in percent atheroma volume (PAV) was -4.86% with alirocumab vs -2.78% with placebo (difference, -2.02; 95% CI, -3.00 to -1.05; P < .001). At the minimum lumen area (MLA) site, mean change in PAV was -10.14% with alirocumab vs -6.70% with placebo (difference, -3.36; 95% CI, -4.98 to -1.75; P < .001). MLA increased by 0.15 mm2 with alirocumab and decreased by 0.07 mm2 with placebo (difference, 0.21; 95% CI, 0.01 to 0.41; P = .04). Among 122 lipid-rich lesions, 34 of 55 (61.8%) in the alirocumab arm and 27 of 67 (41.8%) in the placebo arm showed a less lipid-rich plaque phenotype at follow-up (P = .03). Among 63 lesions with thin-cap fibroatheroma at baseline, 8 of 26 (30.8%) in the alirocumab arm and 3 of 37 (8.1%) in the placebo arm showed a fibrous/fibrocalcific plaque phenotype at follow-up (P = .02). At the lesion level, very intensive lipid-lowering therapy induced substantially greater PAV regression than described in previous vessel-level analyses. Compared with statin therapy alone, alirocumab treatment was associated with greater enlargement of the lesion MLA and more frequent transition of presumably high-risk plaque phenotypes into more stable, less lipid-rich plaque phenotypes. ClinicalTrials.gov Identifier: NCT03067844.

Value of Combined Optical Coherence Tomography and Optical Flow Ratio Measurements After Percutaneous Coronary Intervention

BackgroundOptical flow ratio (OFR) is a novel computational fractional flow reserve derived from optical coherence tomography (OCT). However, the impact of combining post-stenting morphology (OCT) and physiology (OFR) remains largely unknown. MethodsOCT and OFR were analysed at an independent core laboratory. Target lesion failure (TLF) was defined as the composite of cardiac death, target lesion myocardial infarction, and target lesion revascularisation. Suboptimal stent deployment was identified with at least 1 TLF-related OCT or OFR characteristic. ResultsA total of 448 patients with acute coronary syndrome (459 vessels) were assessed. Stent expansion < 80%, minimal stent area < 4.5 mm2, stent edge lipid-rich plaque and OFR < 0.90 were independent predictors of TLF (all P < 0.001). Patients with OCT-suboptimal (adjusted hazard ratio [aHR] 7.88, 95% CI 2.73-22.72,-P < 0.001) or OFR-suboptimal (aHR 5.78, 95% CI 2.54-13.14; P < 0.001) stent deployment showed significantly higher risk of TLF compared with those with optimal stent deployment, with a significant interaction (Pinteraction < 0.001). OCT and OFR both–suboptimal stent deployment was confirmed as an independent predictor of TLF (aHR 9.39, 95% CI 4.25-20.76; P < 0.001). ConclusionsCombined OCT and OFR conferred an optimal reclassification of stent deployment, which may aid in decision making regarding a tailored PCI strategy for optimal stent deployment.

Optical coherence tomography assessment of the impact of colchicine on non-culprit coronary plaque composition after myocardial infarction.

Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT). COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery which contained at least one lipid-rich plaque causing ≥20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0±35.1% vs. colchicine +62.4±38.1%, P=0.18) or absolute changes in minimum FCT (+29.2±20.9 µm vs. +37.2±21.3 µm, P=0.18), or change in maximum lipid arc (-38.8±32.2° vs. -54.8±46.9°, P=0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P=0.03). In post-hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7±25.4% vs. colchicine +64.7±34.1%, P=0.005). In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post-hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT. Australian New Zealand Clinical Trials Registry Identifier, ACTRN12618000809235, registered on the 11th of May 2018.

Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome.

Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45-180 μm] vs. 50 μm [IQR: 0-110 μm]; P = 0.032}. Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Adage-Joto study, UMIN ID No. 26516.