Change In Percent Atheroma Volume Research Articles

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 <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<.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<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

PCSK9 inhibitors and coronary atherosclerotic plaque modification: a meta-analysis

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a promising class of medications, primarily recognized for their potent cholesterol-lowering effects. Beyond their established role in reducing low-density lipoprotein cholesterol levels, recent studies suggest a potential impact of PCSK9 inhibitors on the modification of coronary atherosclerotic plaques. Purpose The purpose of this meta-analysis is to comprehensively synthesize data from relevant clinical studies and trials that have investigated the effects of PCSK9 inhibitors on coronary atherosclerotic plaque characteristics. Methods We performed a literature search for studies assessing the evolution of coronary atherosclerotic plaques after treatment with a PCSK9 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use PCSK9 inhibitors or did not have a control group for comparison. The main outcomes of interest were the changes in percent atheroma volume (PAV), total atheroma volume (TAV), minimal fibrous cap thickness (FCT), lipid arch, as well as the number of patients with improved PAV at follow-up. Effect sizes are presented as standardized mean difference (SMD) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 189 results. After application of the exclusion criteria, a total of 8 studies were selected for data extraction and inclusion in the meta-analysis. Concerning the intravascular ultrasound findings PCSK9 inhibitors induced greater reductions in PAV (SMD -2.70, 95% CI -5.24 to -0.15, p=0.04) (Figure 1) and TAV (SMD -2.46, 95% CI -4.68 to -0.23, p=0.03) (Figure 2), with a greater proportion of patients exhibiting an improvement in PAV (RR 1.30, 95% CI 1.20 to 1.41, p<0.01). Moving to optical coherence tomography parameters, patients treated with PCSK9 inhibitors had an increase in minimal FCT (SMD 2.09, 95% CI 0.12 to 4.07, p=0.04) and a lower lipid arch (SMD -0.64, 95% CI -0.97 to -0.32, p<0.01). Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that PCSK9 inhibitors use is associated with a favorable coronary atherosclerotic plaque remodeling.Figure 1Figure 2

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.

Polygenic Risk Is Associated With Long-Term Coronary Plaque Progression and High-Risk Plaque.

The longitudinal relation between coronary artery disease (CAD) polygenic risk score (PRS) and long-term plaque progression and high-risk plaque (HRP) features is unknown. The goal of this study was to investigate the impact of CAD PRS on long-term coronary plaque progression and HRP. Patients underwent CAD PRS measurement and prospective serial coronary computed tomography angiography (CTA) imaging. Coronary CTA scans were analyzed with a previously validated artificial intelligence-based algorithm (atherosclerosis imaging-quantitative computed tomography imaging). The relationship between CAD PRS and change in percent atheroma volume (PAV), percent noncalcified plaque progression, and HRP prevalence was investigated in linear mixed-effect models adjusted for baseline plaque volume and conventional risk factors. A total of 288 subjects (mean age 58 ± 7 years; 60% male) were included in this study with a median scan interval of 10.2 years. At baseline, patients with a high CAD PRS had a more than 5-fold higher PAV than those with a low CAD PRS (10.4% vs 1.9%; P< 0.001). Per 10 years of follow-up, a 1 SD increase in CAD PRS was associated with a 0.69% increase in PAV progression in the multivariable adjusted model. CAD PRS provided additional discriminatory benefit for above-median noncalcified plaque progression during follow-up when added to a model with conventional risk factors (AUC: 0.73 vs 0.69; P = 0.039). Patients with high CAD PRS had an OR of 2.85 (95%CI: 1.14-7.14; P = 0.026) and 6.16 (95%CI: 2.55-14.91; P< 0.001) for having HRP at baseline and follow-up compared with those with low CAD PRS. Polygenic risk is strongly associated with future long-term plaque progression and HRP in patients suspected of having CAD.

Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial

Background and aimsRandomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. MethodsThe OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). ResultsAll patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to −0.5) vs. −0.4 (-0.6 to −0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to −0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to −1.3) vs. −0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (−0.9 ± 0.25 vs. −0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19–16.30, p = 0.02). ConclusionsIn statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

Atherosclerotic coronary plaque regression from lipid-lowering therapies: A meta-analysis and meta-regression

BackgroundStudies reporting collective and comprehensive data on plaque regression of different lipid-lowering therapies (LLTs) are limited. ObjectivesWe evaluated plaque regression of LLTs based on multiple markers and performed subgroup analyses based on LLT type and post-treatment LDL-C levels MethodsA literature search was performed to identify studies assessing plaque regression from LLTs. The following LLTs groups were included: High-intensity statin (HIS), HIS+ eicosapentaenoic acid (EPA), HIS + ezetimibe, Low-intensity statin (LIS), LIS + EPA, LIS + Ezetimibe, and PCSK9 inhibitors. Our primary outcomes were change in percent atheroma volume (PAV). Secondary outcomes included mean differences in total atheroma volume (TAV), lumen, plaque, and vessel volumes, fibrous cap thickness (FCT), and lipid arc (LA). Subgroup analyses were performed on LLT type and post-treatment LDL-C levels. Meta-regression was performed to control for covariates. ResultsWe identified 51 studies with 9,113 adults (22 % females). LLTs reduced PAV levels (-1.10 % [-1.63, -0.56], p < 0.01), with significant reduction observed with HIS, LIS + ezetimibe, LIS + EPA, and PCSK9 inhibitors. LLTs reduced TAV levels (-5.84 mm3 [-8.64 to -3.04] p < 0.01), mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). LLTs reduced plaque volume and LA and increased FCT. ConclusionThe plaque regression associated with LLTs is observed to be mainly driven by HIS, reducing both TAV and PAV. This suggest that HIS is the most effective LLT for plaque regression Unstructured abstractWe evaluated plaque regression of LLTs from 51 studies. We found that while reduction of PAV (-1.10 % [-1.63, -0.56], p < 0.01) were present across different LLT types, reduction of TAV (-5.84 mm3 [-8.64 to -3.04] p < 0.01) was mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). These results suggest that HIS is the most effective LLT for plaque regression.

Abstract 14816: PCSK9 Inhibitors Modify Plaque and Reduce Plaque Progression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Elevated coronary plaque burden and high-risk plaque characteristics, such as thin fibrous cap, are associated with an increased risk of adverse cardiovascular events. However, there is limited evidence on the effect of PCSK9 inhibitors (PCSK9i) on changes to plaque burden and composition. Hypothesis: We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of standard lipid-lowering therapy with vs. without PCSK9i on plaque burden and phenotype. Methods: We searched PubMed, Embase and Cochrane Central for studies that performed serial intravascular imaging comparing patients with vs. without PCKS9i therapy. Two reviewers independently performed study selection, data extraction and assessment of bias. All outcomes were continuous; thus, we computed pooled mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (CI). Random-effects models were used. Statistical analysis was performed using Review Manager 5.4.1. Results: We included 1,696 patients from 6 RCTs. The mean follow-up ranged from 36 to 76 weeks. Mean age ranged from 58.4 to 61.8 years; 1,246 (65%) were male; and 368 (21.6%) had previous myocardial infarction. Percent atheroma volume (MD -1.05%; 95% CI -1.32, -0.77%; p&lt;0.001), total atheroma volume (MD -6.33 mm 3 ; 95% CI -10.01,-2.66 mm 3 ; p&lt;0.001), and total lipid index (SMD -0.58; 95% CI -0.90,-0.26; p&lt;0.001) were significantly reduced in patients treated with PCSK9i. The minimum fibrous cap thickness (SMD 0.59; 95% CI 0.26,0.93; p&lt;0.001) was also significantly improved in patients randomized to PCSK9i. Conclusions: Our findings suggests that PCSK9i reduce progression of coronary atherosclerosis and stabilizes plaque, as evidence by favorable changes in percent atheroma volume, total atheroma volume, lipid index of the plaque, and minimal fibrous cap thickness.

Atherosclerotic Coronary Plaque Regression and Risk of Adverse Cardiovascular Events

The association between changes in atherosclerotic plaque induced by lipid-lowering therapies (LLTs) and reduction in major adverse cardiovascular events (MACEs) remains controversial. To evaluate the association between coronary plaque regression assessed by intravascular ultrasound (IVUS) and MACEs. A comprehensive, systematic search of publications in PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science was performed. Clinical prospective studies of LLTs reporting change in percent atheroma volume (PAV) assessed by IVUS and describing MACE components were selected. Reporting was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The association between mean change in PAV and MACEs was analyzed by meta-regression using mixed-effects, 2-level binomial logistic regression models, unadjusted and adjusted for clinical covariates, including mean age, baseline PAV, baseline low-density lipoprotein cholesterol level, and study duration. Mean PAV change and MACE in intervention and comparator arms were assessed in an updated systematic review and meta-regression analysis of IVUS trials of LLTs that also reported MACEs. This meta-analysis included 23 studies published between July 2001 and July 2022, including 7407 patients and trial durations ranging from 11 to 104 weeks. Mean (SD) patient age ranged from 55.8 (9.8) to 70.2 (7.6) years, and the number of male patients from 245 of 507 (48.3%) to 24 of 26 (92.3%). Change in PAV across 46 study arms ranged from -5.6% to 3.1%. The number of MACEs ranged from 0 to 72 per study arm (17 groups [37%] reported no events, 9 [20%] reported 1-2 events, and 20 [43%] reported ≥3 events). In unadjusted analysis, a 1% decrease in mean PAV was associated with 17% reduced odds of MACEs (unadjusted OR, 0.83; 95% CI, 0.71-0.98; P = .03), and with a 14% reduction in MACEs in adjusted analysis (adjusted OR, 0.86; 95% CI, 0.75-1.00; P = .050). Further adjustment for cardiovascular risk factors showed a 19% reduced risk (adjusted OR, 0.81; 95% CI, 0.68-0.96; P = .01) per 1% decrease in PAV. A 1% reduction of PAV change between intervention and comparator arms within studies was also associated with a significant 25% reduction in MACEs (OR, 0.75; 95% CI, 0.56-1.00; P = .046). In this meta-analysis, regression of atherosclerotic plaque by 1% was associated with a 25% reduction in the odds of MACEs. These findings suggest that change in PAV could be a surrogate marker for MACEs, but given the heterogeneity in the outcomes, additional data are needed.

Effect of High-Intensity Statin Therapy on Atherosclerosis (IBIS-4): Manual Versus Automated Methods of IVUS Analysis

AimsStandard manual analysis of IVUS to study the impact of anti-atherosclerotic therapies on the coronary vessel wall is done by a core laboratory (CL), the ground truth (GT). Automatic segmentation of IVUS with a machine learning (ML) algorithm has the potential to replace manual readings with an unbiased and reproducible method. The aim is to determine if results from a CL can be replicated with ML methods. MethodsThis is a post-hoc, comparative analysis of the IBIS-4 (Integrated Biomarkers and Imaging Study-4) study (NCT00962416). The GT baseline and 13-month follow-up measurements of lumen and vessel area and percent atheroma volume (PAV) after statin induction were repeated by the ML algorithm. ResultsThe primary endpoint was change in PAV. PAV as measured by GT was 43.95 % at baseline and 43.02 % at follow-up with a change of −0.90 % (p = 0.007) while the ML algorithm measured 43.69 % and 42.41 % for baseline and follow-up, respectively, with a change of −1.28 % (p < 0.001). Along the most diseased 10 mm segments, GT-PAV was 52.31 % at baseline and 49.42 % at follow-up, with a change of −2.94 % (p < 0.001). The same segments measured by the ML algorithm resulted in PAV of 51.55 % at baseline and 47.81 % at follow-up with a change of −3.74 % (p < 0.001). ConclusionsPAV, the most used endpoint in clinical trials, analyzed by the CL is closely replicated by the ML algorithm. ML automatic segmentation of lumen, vessel and plaque effectively reproduces GT and may be used in future clinical trials as the standard.

Interrelation between baseline plaque characteristics and changes in coronary atherosclerosis with the PCSK9-inhibitor alirocumab: insights from the PACMAN-AMI randomized trial

Abstract Background Patients with acute myocardial infarction (AMI) frequently experience recurrent atherothrombotic events, largely attributable to non-culprit lesions with high-risk characteristics. Statins can halt the progression of coronary atherosclerosis, and addition of protein convertase subtilisin/kexin type 9-inhibitors (PCSK9i) results in incremental low-density lipoprotein cholesterol (LDL-C) lowering and atheroma regression. Purpose We sought to examine the interrelation between baseline imaging characteristics, on-treatment LDL-C levels, and changes in coronary atherosclerosis as assessed by serial, multi-modality intracoronary imaging in patients with AMI. Methods This is a post hoc analysis from the PACMAN-AMI randomized trial. Patients were randomly allocated to biweekly alirocumab 150 mg vs. placebo on top of high-intensity statin initiated within 24h of presentation with AMI, and underwent serial imaging of the two non-infarct-related arteries at baseline and after 52 weeks. The primary endpoint was percent atheroma volume (PAV) by intravascular ultrasound (IVUS). Powered secondary endpoints were maximal lipid core burden index (maxLCBI4mm) by near-infrared spectroscopy (NIRS) and minimum fibrous cap thickness (FCTmin) by optical coherence tomography (OCT). Results Of 300 randomized patients (mean age 58.5±9.8 years, 18.7% women, baseline LDL-C 3.94±0.87 mmol/L), IVUS was serially performed in 265 patients (537 arteries). LDL-C levels decreased to 1.92±0.79 mmol/L with placebo and 0.61±0.61 mmol/L with alirocumab (p&amp;lt;0.001). Compared with placebo (statin alone), alirocumab added to statin resulted in greater PAV reduction (−2.13% vs. −0.92%; p&amp;lt;0.001), greater maxLCBI4mm reduction (−79.42 vs. −37.60; p=0.006), and greater increase in FCTmin (62.67 vs. 33.19 μm; p=0.001). Changes in PAV and maxLCBI4mm were inversely related to on-treatment LDL-C levels, and change in FCTmin was positively related to on-treatment LDL-C levels (Figure 1). Across all patients, we found significant, inverse relationships between change in PAV and baseline PAV [slope: −0.072 (95% CI −0.101 to −0.042); p&amp;lt;0.001], between change in maxLCBI4mm and baseline maxLCBI4mm [slope: −0.437 (95% CI −0.505 to −0.369); p&amp;lt;0.001], and between change in FCTmin and baseline FCTmin [slope: −0.436 (95% CI −0.541 to −0.332); p&amp;lt;0.001]; these findings indicate greater PAV and maxLCBI4mm regression in lesions with greater PAV and LCBI4mm at baseline, and greater fibrous cap thickening in lesions with thinner fibrous caps at baseline. Conclusion In this study of intensive LDL-C lowering treatment initiated in the acute AMI setting, more favorable plaque changes were observed in patients with lower on-treatment LDL-C levels and in lesions with more adverse baseline plaque characteristics. Whether AMI patients with high-risk plaque features might derive greater clinical benefit from early initiation of intensive LDL-C-lowering therapies requires further investigation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi, Regeneron

Dynamic natural morphologies and component changes in nonculprit subclinical atherosclerosis in patients with acute coronary syndrome at 1-year follow-up and clinical significance at 3-year follow-up

Background and aimsWe aimed to explore the dynamic natural morphologies and main components of nonculprit subclinical atherosclerotic changes underlying lesion regression (LR) or lesion progression (LP) in patients with acute coronary syndrome. MethodsThe primary endpoints were changes in percent atheroma volume (ΔPAV), normalized total atheroma volume (ΔTAVn) and each component in nonculprit subclinical atherosclerosis from baseline to 1 year measured by optical flow ratio (OFR) software. LR or LP was defined by an increase or decrease in PAV. Secondary endpoints included the correlation between changes in the lipid profile and ΔPAV/ΔTAVn and major adverse cardiac events (MACEs) related to nonculprit subclinical atherosclerosis at 3 years. ResultsThis was a subgroup analysis of our previous randomized trial with a total of 161 nonculprit lesions analysed. In the LR (approximately 55.3% of the lesions) group, ΔTAVn was positively correlated only with lipid ΔTAVn (r = 0.482, p < 0.001) but not fibrous and calcium ΔTAVn, and ΔPAV was positively correlated with lipid ΔPAV (r = 0.315, p = 0.003) but not fibrous and calcium ΔPAV. The percent reduction in low-density lipoprotein cholesterol (LDL-C) was an independent predictor of LR in multivariate logistic regression analysis (OR = 3.574, 95% CI: 1.125–11.347, p = 0.031). The incidence of MACEs related to nonculprit lesions at 3 years was higher in the LP group than the LR group (9.9% vs. 2.2%, p = 0.040). ConclusionsLR of nonculprit subclinical atherosclerosis at 1-year follow-up was mainly caused by regression of the lipid component, which was correlated with the degree of LDL-C reduction and fewer MACEs at 3-year follow-up.

Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction

Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown. To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction. The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals. Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg). Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non-infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy-derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography-derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52. Among 300 randomized patients (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] low-density lipoprotein cholesterol level, 152.4 [33.8] mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001). Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo. Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population. ClinicalTrials.gov Identifier: NCT03067844.

HbA1c, Coronary atheroma progression and cardiovascular outcomes

Background and aimsWe tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. MethodsWe performed a post-hoc pooled analysis of data from seven prospective, randomized trials involving serial coronary intravascular ultrasonography (IVUS). The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque. Using multivariable mixed modeling, we determined the association of on-treatment HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. ResultsAmong 3,312 patients (mean age 58.6±9years, 28.4%women) average on-treatment HbA1c was 6.2±1.1%. Overall, there was no net significant annualized change in PAV (0.12±0.19%, p = 0.52). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index, systolic blood pressure, smoking, low- and high-density lipoprotein cholesterol, triglyceride levels, peripheral vascular disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13(0.08, 0.19), p < 0.001]. On-treatment HbA1c levels were independently associated with MACE [hazard ratio (95% confidence interval): 1.13(1.04, 1.23), p = 0.005]. ConclusionsIndependent of achieved cardiovascular risk factor control, greater HbA1c levels significantly associate with coronary atheroma progression rates and clinical outcomes. These results support the notion of a direct, specific effect of glycemic control upon coronary atheroma and atherosclerotic events, supporting the rationale of therapies designed to directly modulate it.

HbA1c, coronary atheroma progression and cardiovascular events

Abstract Background Hemoglobin A1c (HbA1c) reflects long-term glycemic control and is associated with an increased risk of cardiovascular events among diabetic and non-diabetic patients. The specific impact of HbA1c upon atheroma progression and incident cardiovascular events relative to the presence of other cardiovascular risk factors remains uncertain. Purpose We tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression measured with serial intravascular ultrasonography (IVUS) and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. Methods We performed a post-hoc pooled analysis of data from eight prospective, randomized trials involving serial coronary IVUS. HbA1c was measured at baseline and the average of the follow-up values was taken. The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest. Using multivariable mixed modeling, we determined the association of HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. Results Among 2,791 patients, mean age was 58.9±9 years and 29.1% were women. Mean on-treatment low-density lipoprotein (LDL)-cholesterol was 80.2±33.7 mg/dl and median on-treatment triglycerides (TG) were 125.5 (94.7, 170.2) mg/dl. Mean baseline and follow-up HbA1c was 6.2±1.2% and 6.3±1.2%, respectively. Overall, there was no net significant annualized change in PAV (0.15±0.21, p=0.47). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index (BMI), systolic blood pressure, smoking, LDL- and high-density lipoprotein cholesterol, TG levels, peripheral artery disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13 (0.07, 0.19), p&amp;lt;0.001]. On-treatment HbA1c levels were significantly and independently associated with incidence of MACE [hazard ratio (95% confidence interval): 1.17 (1.07, 1.28), p&amp;lt;0.001]. Conclusions Independent of achieved cholesterol levels, vascular risk factors and BMI, greater HbA1c levels significantly associate with coronary atheroma progression and clinical outcomes. These results support the notion of a direct, specific effect of glycemic control upon the natural history of coronary atheroma and atherosclerotic events, supporting the rationale of therapies designed to directly modulate it. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation

Usefulness of MCP-1 Chemokine in the Monitoring of Patients with Coronary Artery Disease Subjected to Intensive Dietary Intervention: A Pilot Study.

Monocyte chemotactic protein-1 (MCP-1) plays an important role in the entire atherosclerotic process, from atherogenesis to destabilisation of the atherosclerotic plaque. The purpose of this study is to evaluate the effect of the dietary approaches to stop hypertension (DASH) diet in patients with coronary artery disease on the MCP-1 plasma concentration and to evaluate the potential usefulness of this chemokine as a marker of change in the volume and composition of coronary plaque. Material and method. As part of the dietary intervention to stop coronary atherosclerosis in computed tomography (DISCO-CT) study, patients were randomised to an intervention group (n = 40) in which the DASH diet was introduced, and to a control group (n = 39) with no dietary intervention. In the DASH group, dietary counselling was provided at all follow-up visits within 12 months of the follow-up period. MCP-1 plasma concentration was determined using enzyme-linked immunosorbent assay (ELISA). Coronary plaque analysis was performed using a semi-automated plaque analysis software system (QAngioCT, Medis, The Netherlands). Results. In the DASH group, MCP-1 plasma concentration significantly decreased by 34.1 pg/mL (p = 0.01), while in the control group, the change in MPC-1 was not significant. Significant inverse correlations were revealed for the change in MCP-1 plasma concentration and change in the consumption of vitamin C and dietary fibre both in the DASH (r = −0.519, p = 0.0005; r = −0.353, p = 0.025, respectively) and in the control group (r = −0.488 p = 0.001; r = −0.502, p = 0.001, respectively). In patients with the highest decrease in percent atheroma volume (PAV), a significant positive correlation was observed between the change in MCP-1 plasma concentration and changes in PAV (r = 0.428, p = 0.033) and calcified plaque component (r = 0.468, p = 0.018), while the change in noncalcified plaque component correlated inversely with change in MCP1 (r = −0.459, p = 0.021). Conclusion. Dietary intervention based on the DASH diet model reduces the MCP-1plasma concentration, mostly due to an increased intake of plant-derived, fibre-rich foods and antioxidants. The change in MCP-1 plasma concentration seems to reflect changes in the atheroma volume and proportions between the calcified and non-calcified plaque elements.

Effect of Atorvastatin (10 mg) and Ezetimibe (10 mg) Combination Compared to Atorvastatin (40 mg) Alone on Coronary Atherosclerosis

It remains inconclusive whether the additional low-density lipoprotein cholesterol (LDL-C) lowering effects of ezetimibe added to statin on coronary atherosclerosis and clinical outcomes are similar to those of statin monotherapy in the setting of comparable LDL-C reduction. We aimed to determine whether there were distinguishable differences in their effects on coronary atherosclerosis with intermediate stenosis between the combination of moderate-intensity statin plus ezetimibe and high-intensity statin monotherapy. Forty-one patients with stable angina undergoing percutaneous coronary intervention were randomized to receive either atorvastatin 10 mg plus ezetimibe 10 mg (ATO10/EZE10) or atorvastatin 40 mg alone (ATO40). The intermediate lesions were evaluated using a near-infrared spectroscopy-intravascular ultrasonography at baseline and after 12 months in 37 patients. The primary endpoint was percent atheroma volume (PAV). Mean LDL-C levels were significantly reduced by 40% and 38% from baseline in the ATO10/EZE10 group (n=18, from 107 mg/dL to 61 mg/dL) and ATO40 group (n=19, from 101 mg/dL to 58 mg/dL), respectively, without between-group difference. The absolute change of PAV was -2.9% in the ATO10/EZE10 group and -3.2% in the ATO40 group. The mean difference (95% confidence interval) for the absolute change in PAV between the 2 groups was 0.5% (-2.4% to 2.8%), which did not exceed the pre-defined non-inferiority margin of 5%. There was no significant reduction in lipid core burden index in both groups. In conclusion, the combination of atorvastatin 10 mg and ezetimibe 10 mg showed comparable LDL-C lowering and regression of coronary atherosclerosis in the intermediate lesions, compared with atorvastatin 40 mg alone.

Progression of coronary atherosclerosis in patients without standard modifiable risk factors

Background and aimsThe outcome of patients with clinical coronary artery disease despite traditional risk factors is poorly understood. MethodsClinical characteristics and plaque burden on serial intravascular ultrasonography were compared in patients without (n ​= ​165) and with (n ​= ​492) standard modifiable risk factors after matching on age, sex and use of statins from a database of 5823 patients participating in clinical trials of anti-atherosclerotic therapies. ResultsPatients without standard modifiable risk factors had lower baseline systolic blood pressure (118 ​± ​12 vs. 129 ​± ​17 ​mmHg, p ​< ​0.001), low-density lipoprotein cholesterol (87 ​± ​21 vs. 104 ​± ​34 ​mg/dl, p ​< ​0.001), triglycerides [106 vs. 136 ​mg/dl, p ​< ​0.001)] and C-reactive protein [1.5 vs. 2.1 ​mg/l, p ​= ​0.001]. At baseline, patients without modifiable risk factors had a lower percent atheroma volume (35.7 ​± ​8.6 vs. 38 ​± ​8.8%, p ​= ​0.004) and total atheroma volume (174.7 ​± ​80 vs. 190.9 ​± ​84 ​mm3, p ​= ​0.03) and less images with calcification (22.2 vs. 26.5%, p ​= ​0.025). The use of aspirin and statin prior to and during the trials was similar. The use of ACE inhibitors and beta blockers was lower in the no risk factor group prior to and during the trials. The change in percent atheroma volume (−0.2 ​± ​2.8 vs. −0.1 ​± ​3.6%, p ​= ​0.71), total atheroma volume (−5.5 ​± ​23.4 vs. −3.8 ​± ​22.7 ​mm3, p ​= ​0.42), and the percentage of patients demonstrating any degree of progression (50.9% vs 45.1%, p ​= ​0.20) were similar in those without and with standard modifiable risk factors, respectively. ConclusionPatients who develop clinical coronary atherosclerosis without standard modifiable risk factors have similar rates of plaque progression to those with traditional risk factors.

The efficacy of a PCSK9 inhibitor for the plaque stabilization in the non-culprit lesion of ACS patients by using near-infrared intravascular ultrasonography

Abstract Background and purpose In acute coronary syndrome (ACS) patients, major cardiovascular events during follow-up were equally attributable to recurrence at the site of culprit lesions and to non-culprit lesions, and mostly occurred within one year. Recent studies showed that Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor significantly reduces the risk of cardiovascular events. However, the rigorous effects of PCSK9 inhibitor in patients with ACS, especially for the stabilization of plaque in the non-culprit lesions has not been identified. The purpose of this study was to evaluate the efficacy of a PCSK9 inhibitor for the plaque stabilization in the non-culprit lesion of ACS patients. Methods We retrospectively analyzed the 10 ACS patients (STEMI:5 cases, NSTEMI:1 case, and UAP:4 cases) who had non-culprit lesions and were injected with a PCSK9 inhibitor. We analyzed 11 non-culprit lesions before and after PSCK9 injections by using a near-infrared intravascular ultrasonography (NIRS-IVUS). Results The follow up intervals were 229.4±82.9 days. Major cardiovascular events did not occur in all patients. The serum low-density lipoprotein (LDL) cholesterol levels were significantly decreased form 128±36.7 mg/dl to 26.7±7.4 mg/dl (P&amp;lt;0.01; Figure 1A). There were no significant changes in percent atheroma volume before and after PCSK9 injections. However, the max lipid core burden index (LCBI) were significantly improved from 392.5±155.8 to 209.4±116 (P&amp;lt;0.01; Figure 1B). Although the lesion characteristics did not change in the images, by IVUS, the LCBI of the lesion was significantly decreased after PCSK9 injections. This study suggested that NIRS-IVUS had the possibility of detection for the slight changes in the plaque characteristics, which could not be detected by only an IVUS. Conclusion This study suggested that the plaque morphology can be altered by the aggressive lipid lowering therapy by using a PCSK9 inhibitor, and NIRS-IVUS can detect these plaque stabilizations of non-culprit lesion in ACS patients. The authors have no financial conflicts of interest to disclose concerning the presentation. Figure 1 Funding Acknowledgement Type of funding source: None

Effects of Statin Plus Ezetimibe on Coronary Plaques in Acute Coronary Syndrome Patients with Diabetes Mellitus: Sub-Analysis of PRECISE-IVUS Trial.

Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM.Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9–12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL.Results: In DM patients, the monotherapy group (n = 13) and the DLLT group (n = 12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: −2.77 ± 3.47% vs. −0.77 ± 2.51%, P = 0.11; non-DM: −2.01 ± 3.36% vs. −0.08 ± 2.66%, P = 0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r = 0.52, P = 0.008).Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.

Sitagliptin attenuates the progression of coronary atherosclerosis in patients with coronary disease and type 2 diabetes

Background and aimsType 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for ASCVD, the aim of this study was to investigate the effects of a dipeptidyl peptidase-4 inhibitor, sitagliptin, on prevention of progression of coronary atherosclerosis assessed by three-dimensional quantitative coronary angiography (3D-QCA) in T2DM patients with coronary artery disease (CAD). MethodsThis was a prospective, randomized, double-center, open-label, blinded end point, controlled 18-month study in patients with CAD and T2DM. A total of 149 patients, who had at least 1 atherosclerotic plaque with 20%–80% luminal narrowing in a coronary artery, and had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to sitagliptin group (n = 74) or control group (n = 75). Atherosclerosis progression was measured by repeat 3D-QCA examination in 88 patients at study completion. The primary outcome was changes in percent atheroma volume (PAV) from baseline to study completion measured by 3D-QCA. Secondary outcomes included change in 3D-QCA-derived total atheroma volume (TAV) and late lumen loss (LLL). ResultsThe primary outcome of PAV increased of 1.69% (95%CL, −0.8%–4.2%) with sitagliptin and 5.12% (95%CL, 3.49%–6.74%) with the conventional treatment (p = 0.023). The secondary outcome of change in TAV in patients treated with sitagliptin increased of 6.45 mm3 (95%CL,-2.46 to 6.36 mm3) and 9.45 mm3 (95%CL,-4.52 to 10.14 mm3) with conventional treatment (p = 0.023), however, no significant difference between groups was observed (p = 0.175). Patients treated with sitagliptin had similar LLL as compared with conventional antidiabetics (−0.06, 95%CL, −0.22 to 0.03 vs. −0.08, −0.23 to −0.03 mm, p = 0.689). ConclusionsIn patients with type 2 diabetes and coronary artery disease, treatment with sitagliptin resulted in a significantly lower rate of progression of coronary atherosclerosis compared with conventional treatment.