Baseline Percent Atheroma Volume Research Articles

Abstract 4137243: Dynamic changes of pericoronary fat attenuation index predicting changes of coronary plaque burden

Background: Percent atheroma volume (PAV) is a validated index of coronary plaque burden, linking to adverse cardiac events. Meanwhile, pericoronary fat attenuation index (FAI) on coronary computed tomography angiography (CCTA) image is a novel prognostic marker of coronary inflammation. Research Questions: It is unknown the impact of coronary inflammation (i.e., FAI) on the progression of coronary PAV in patients at an increased risk of adverse cardiac events. Methods: Patients with type 2 diabetes mellitus (T2DM) who underwent at least two clinically indicated CCTA examinations (time interval > 1 year) at our center were potentially eligible for enrollment. Eligible patients presented with more than one study plaque, defined as non-obstructive stenosis at baseline and not being intervened during serial CCTA. Longitudinal CCTA images were assessed for FAI and compositional plaque characteristics (e.g., PAV) using dedicated post-processing softwares. The relationships between changes in FAI and progression of compositional PAV were examined using the logistic and linear regression analysis. Results: A total of 204 T2DM patients (mean age, 61.2 ± 9.3 years; male, 68.1%) with 366 study plaques were enrolled. All patients were treated with statins, and their time interval between longitudinal CCTAs was 14.1 (12.9, 17.6) months. Compared with patients with improved coronary inflammation (ΔFAI ≤ 0), those with deteriorated coronary inflammation (ΔFAI > 0) had lower high density lipoprotein cholesterol and baseline FAI, whereas higher blood pressure (all p < 0.05). Meanwhile, compared to patients with ΔFAI ≤ 0, those with ΔFAI > 0 had more Δoverall and Δnon-calcified PAV (all p < 0.05). Importantly, these findings were consistent in a dedicated propensity score matching analysis. In logistic regression analysis, ΔFAI > 0 was associated with annual progression of overall PAV and non-calcified PAV, whereas ΔFAI ≤ 0 associated with annual regression of overall PAV and non-calcified PAV after adjusting for cardiac risk factors, baseline PAV and medications (all p < 0.05). Similarly, in linear regression analysis, changes of FAI were independently positively associated with annual changes of overall PAV (β=0.545, p< 0.001) and non-calcified PAV (β=0.461, p< 0.001) (Figure 1). Conclusion: In this longitudinal CCTA study, changes of coronary inflammation are closely correlated with changes of overall and non-calcified PAV among T2DM patients treated with statins.

Angioprotein-like 3 and atheroma progression in statin-treated type 2 diabetic patients with coronary artery disease: the pre-specified analysis from the OPTIMAL randomized controlled trial

Abstract Introduction Despite guideline-recommended control of LDL-C with a statin, type 2 diabetic patients more likely cause cardiovascular events. This indicates the need to identify additional therapeutic targets in those patients. Angioprotein-like 3 (ANGPTL3) is an inhibitor of lipoprotein and endothelial lipase, which increases the levels of LDL-C and other atherogenic lipoproteins. These properties suggest ANGPTL3 as a potential driver associated with diabetic atherosclerosis. The OPTIMAL randomized controlled trial (jRCT1052180152) compared the efficacy of continuous glucose monitoring-guided versus HbA1c-guided glycemic control on coronary atherosclerosis in statin-treated type 2 diabetic patients by using serial intravascular ultrasound (IVUS) imaging. This pre-specified analysis of the OPTIMAL study was designed to evaluate whether ANGPTL3 affects progression of coronary atheroma in statin-treated type 2 diabetic patients. Purpose To elucidate the association of serial change in ANGPTL3 with the degree of atheroma progression in statin-treated type 2 diabetic patients. Methods 59 patients (59 lesions) with serial ANGPTL3 levels at baseline and week 48 were included into the current analysis. Clinical demographics and IVUS-derived measure were compared in patients with and without any increase in ANGPTL3. Results All of study subjects received a statin, and over 60% of them were treated with high-intensity statin. Under these lipid-lowering therapies, any increase in ANGPTL3 levels at week 48 was observed in 52.5% of study participants. Patients with any increase in ANGPTL3 were more likely to have a history of hypertension (90.0% vs. 64.3%, p=0.02), whereas there was no significant difference in on-treatment LDL-C levels between the two groups (1.8 ± 0.4 vs. 1.6 ± 0.6 mmol/L, p=0.25) (Table). On IVUS imaging analysis, baseline percent atheroma volume (PAV) did not differ in those with and without any increase in ANGPTL3. However, patients with any increase in ANGPTL3 presented a greater progression of PAV (0.08 ± 0.28 vs. -0.74 ± 0.29, p=0.04). There was a trend toward a lower frequency of PAV regression in those exhibiting any increase in ANGPTL3 (48.4% vs. 57.1%), but this comparison did not meet statistical significance (p=0.50) (Figure). Multivariate analysis adjusting clinical characteristics demonstrated that any increase in ANGPTL3 level was not independently associated with PAV progression (β=0.16, 95%CI=-0.01 – 0.18, p=0.27). Conclusion Over 50% of statin-treated type 2 diabetic patients with coronary atherosclerosis showed any increase in ANGPTL3 levels at week 48. Serial IVUS imaging revealed that patients with any increase in ANGPTL3 more likely presented a greater atheroma progression. However, this relationship did not exist after adjusting clinical characteristics. Our findings suggest that ANGPTL3 may not be a pivotal driver associated with atheroma progression in statin-treated type 2 diabetic patients.

Rapid Plaque Progression Is Independently Associated With Hyperglycemia and Low HDL Cholesterol in Patients With Stable Coronary Artery Disease: A PARADIGM Study.

We assessed whether combinations of cardiometabolic risk factors independently predict coronary plaque progression (PP) and major adverse cardiovascular events in patients with stable coronary artery disease. Patients with known or suspected stable coronary artery disease (60.9±9.3 years, 55.4% male) undergoing serial coronary computed tomography angiographies (≥2 years apart), with clinical characterization and follow-up (N=1200), were analyzed from the PARADIGM study (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging). Plaque volumes measured in coronary segments (≥2 mm in diameter) were summed to provide whole heart plaque volume (mm3) and percent atheroma volume (plaque volume/vessel volume×100; %) per patient at baseline and follow-up. Rapid PP was defined as a percent atheroma volume increase of ≥1.0%/y. Major adverse cardiovascular events included nonfatal myocardial infarction, death, and unplanned coronary revascularization. In an interscan period of 3.2 years (interquartile range, 1.9), rapid PP occurred in 341 patients (28%). At multivariable analysis, the combination of cardiometabolic risk factors defined as metabolic syndrome predicted rapid PP (odds ratio, 1.51 [95% CI, 1.12-2.03]; P=0.007) together with older age, smoking habits, and baseline percent atheroma volume. Among single cardiometabolic variables, high fasting plasma glucose (diabetes or fasting plasma glucose >100 mg/dL) and low HDL-C (high-density lipoprotein cholesterol; <40 mg/dL in males and <50 mg/dL in females) were independently associated with rapid PP, in particular when combined (odds ratio, 2.37 [95% CI, 1.56-3.61]; P<0.001). In a follow-up of 8.23 years (interquartile range, 5.92-9.53), major adverse cardiovascular events occurred in 201 patients (17%). At multivariable Cox analysis, the combination of high fasting plasma glucose with high systemic blood pressure (treated hypertension or systemic blood pressure >130/85 mm Hg) was an independent predictor of events (hazard ratio, 1.79 [95% CI, 1.10-2.90]; P=0.018) together with family history, baseline percent atheroma volume, and rapid PP. In patients with stable coronary artery disease, the combination of hyperglycemia with low HDL-C is associated with rapid PP independently of other risk factors, baseline plaque burden, and treatment. The combination of hyperglycemia with high systemic blood pressure independently predicts the worse outcome beyond PP. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02803411.

The natural history and prediction of 10-year plaque progression on serial coronary CT angiography

Abstract Background Several studies have shown that plaque subcomponents such as low-attenuation or non-calcified plaque volume from coronary CT angiography (CCTA) are associated with the occurrence of major adverse cardiovascular events. However, it remains unknown how plaque morphology progresses over the long-term. Furthermore, it is unknown which plaque characteristics put patients at increased risk of plaque progression which would require more intensive image-guided follow-up. This study investigated the natural history and predictors of long-term coronary plaque progression in a serial CCTA cohort of patients with suspected coronary artery disease (CAD). Methods In this follow-up study, 539 patients from an earlier published CCTA cohort (Diemen, 2021) were invited for repeat CCTA imaging per-protocol, regardless of symptoms. A total of 299 patients underwent follow-up CCTA imaging with a median scan interval of 10.2 [8.7-11.2] years. Patients who underwent coronary artery bypass grafting (CABG) between baseline and follow-up imaging were excluded. All scans were analyzed using artificial intelligence-guided quantitative CCTA (AI-QCT). Revascularized vessels were excluded. Quantitative plaque volumes (total, low-density, non-calcified and calcified plaque) depicted by AI-QCT were divided by the total vessel volume to represent percent atheroma volume (PAV). PAV progression was calculated subtracting baseline PAV from follow-up PAV. The association of the plaque components with PAV progression was evaluated in a multivariate linear regression model adjusted for clinical risk characteristics (age, sex, hypertension, hypercholesterolemia, diabetes, BMI, smoking, family history of CAD and statin use). Results In total, 274 patients without CABG were used for the serial analysis, mean age was 57 years, 42% were women. At baseline, median PAV was 2.5% [IQR 0.7-8.1], which increased to 6.1% [IQR 1.2-12.9] at follow-up (Figure). The mean PAV progression was 0.4±0.5% per year. Adjusted for clinical risk characteristics and other plaque volumes, baseline percent non-calcified plaque volume (NCP) was the only plaque volume associated with PAV progression (0.5% PAV progression increase per % increase in baseline non-calcified plaque volume). Conclusion Using an unique long-term serial CCTA cohort undergoing per-protocol repeat imaging with a 10-year scan interval, we found that coronary plaque burden more than doubled. Interestingly, the amount of non-calcified plaque volume at baseline was the only predictor for disease progression.Figure

Effects of renin-angiotensin-aldosterone-system inhibitors on coronary atherosclerotic plaques: The PARADIGM registry

Background and aimsInhibition of Renin-Angiotensin-Aldosterone-System (RAAS) has been hypothesized to improve endothelial function and reduce plaque inflammation, however, their impact on the progression of coronary atherosclerosis is unclear. We aim to study the effects of RAAS inhibitor on plaque progression and composition assessed by serial coronary CT angiography (CCTA). MethodsWe performed a prospective, multinational study consisting of a registry of patients without history of CAD, who underwent serial CCTAs. Patients using RAAS inhibitors were propensity matched to RAAS inhibitor naïve patients based on clinical and CCTA characteristics at baseline. Atherosclerotic plaques in CCTAs were quantitatively analyzed for percent atheroma volume (PAV) according to plaque composition. Interactions between RAAS inhibitor use and baseline PAV on plaque progression were assessed in the unmatched cohort using a multivariate linear regression model. ResultsOf 1248 patients from the registry, 299 RAAS inhibitor taking patients were matched to 299 RAAS inhibitor naïve patients. Over a mean interval of 3.9 years, there was no significant difference in annual progression of total PAV between RAAS inhibitor naïve vs taking patients (0.75 vs 0.79%/year, p = 0.66). With interaction testing in the unmatched cohort, however, RAAS inhibitor use was significantly associated with lower non-calcified plaque progression (Beta coefficient −0.100, adjusted p = 0.038) with higher levels of baseline PAV. ConclusionsThe use of RAAS inhibitors over a period of nearly 4 years did not significantly impact on total atherosclerotic plaque progression or various plaque components. However, interaction testing to assess the differential effect of RAAS inhibition based on baseline PAV suggested a significant decrease in progression of non-calcified plaque in patients with a higher burden of baseline atherosclerosis, which should be considered hypothesis generating.

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.

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

Measurement of compensatory arterial remodelling over time with serial coronary computed tomography angiography and 3D metrics.

The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA). From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI -0.37 to -0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281). Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis.

Progression of whole-heart Atherosclerosis by coronary CT and major adverse cardiovascular events

BackgroundThe current study aimed to examine the independent prognostic value of whole-heart atherosclerosis progression by serial coronary computed tomography angiography (CCTA) for major adverse cardiovascular events (MACE). MethodsThe multi-center PARADIGM study includes patients undergoing serial CCTA for symptomatic reasons, ≥2 years apart. Whole-heart atherosclerosis was characterized on a segmental level, with co-registration of baseline and follow-up CCTA, and summed to per-patient level. The independent prognostic significance of atherosclerosis progression for MACE (non-fatal myocardial infarction [MI], death, unplanned coronary revascularization) was examined. Patients experiencing interval MACE were not omitted. ResultsThe study population comprised 1166 patients (age 60.5 ​± ​9.5 years, 54.7% male) who experienced 139 MACE events during 8.2 (IQR 6.2, 9.5) years of follow up (15 death, 5 non-fatal MI, 119 unplanned revascularizations). Whole-heart percent atheroma volume (PAV) increased from 2.32% at baseline to 4.04% at follow-up. Adjusted for baseline PAV, the annualized increase in PAV was independently associated with MACE: OR 1.23 (95% CI 1.08, 1.39) per 1 standard deviation increase, which was consistent in multiple subpopulations. When categorized by composition, only non-calcified plaque progression associated independently with MACE, while calcified plaque did not. Restricting to patients without events before follow-up CCTA, those with future MACE showed an annualized increase in PAV of 0.93% (IQR 0.34, 1.96) vs 0.32% (IQR 0.02, 0.90), P ​< ​0.001. ConclusionsWhole-heart atherosclerosis progression examined by serial CCTA is independently associated with MACE, with a prognostic threshold of 1.0% increase in PAV per year.

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

Intravascular ultrasound (IVUS) imaging can visualize vulnerable plaque features including attenuation (AP) and echolucency (ELP). While IVUS-derived vulnerable plaque features associate with microvascular obstruction during percutaneous coronary intervention, the relationship between these plaque features and clinical outcomes has not been established. This analysis aimed to evaluate the association of AP/ELP with cardiovascular events. Serial IVUS imaging was reviewed in 1497 patients, followed for 18-24 months, with coronary artery disease from two clinical trials. Attenuated plaque and ELP were identified to measure each characteristics (AP arc, ELP area, and lengths), which permitted calculation of an AP index (API) and ELP volume. Attenuated plaque/ELP progression was defined as patients with any increase of API or ELP volume on serial imaging. The major cardiovascular events (MACEs) were defined as death, myocardial infarction, stroke, and coronary revascularization. AP or ELP was identified in 282 patients (18.8%) at baseline and 160 (10.7%) patients demonstrated an increase in AP or ELP at follow-up. The incidence of MACE was higher in patients with baseline AP/ELP than those without (8.2% vs. 3.9%, P = 0.002). Patients with AP/ELP progression were more likely to be acute coronary syndrome (41.9 vs. 33.2%, P = 0.03) and have greater baseline percent atheroma volume (40.0% vs. 35.8%, P < 0.001) than those without. On multivariable analysis, AP/ELP progression was more strongly associated with MACE [baseline AP/ELP: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.05-2.97, AP/ELP progression: HR 2.19, 95% CI 1.24-3.86]. Attenuation/ELP progression was associated with a higher prevalence of cardiovascular events, supporting a potential role for the identification of high-risk vulnerable plaques in patients with coronary artery disease.

Differences in Progression to Obstructive Lesions per High-Risk Plaque Features and Plaque Volumes With CCTA

ObjectivesThis study explored whether the pattern of nonobstructive lesion progression into obstructive lesions would differ according to the presence of high-risk plaque (HRP). BackgroundIt is still debatable whether HRP simply represents a certain phase during the natural history of coronary atherosclerotic plaques or if disease progression would differ according to the presence of HRP. MethodsPatients with nonobstructive coronary artery disease, defined as percent diameter stenosis (%DS) <50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. HRP was defined as lesions with ≥2 features of positive remodeling, spotty calcification, or low-attenuation plaque. Quantitative total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions. ResultsA total of 3,049 nonobstructive lesions were identified from 1,297 patients (mean age 60.3 ± 9.3 years; 56.8% men). There were 2,624 non-HRP and 425 HRP lesions. HRP lesions had a greater total PAV and all noncalcified components of PAV and %DS at baseline compared with non-HRP lesions. However, the annualized total PAV changes were greater in non-HRP lesions than in HRP lesions. On multivariate analysis adjusted for clinical risk factors, drug use, change in lipid level, total PAV, %DS, and HRP, only the baseline total PAV and %DS independently predicted the development of obstructive lesions (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.07, and HR: 1.07; 95% CI: 1.04 to 1.10, respectively, all p < 0.05), whereas the presence of HRP did not (p > 0.05). ConclusionsThe pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV, not the presence of HRP features, was the most important predictor of lesions developing into obstructive lesions. (Progression of Atherosclerotic Plaque Determined By Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)

P6162Difference in progression to obstructive lesions according to the presence of high-risk plaque features

Abstract Background It is still debatable whether the so-called high-risk plaque (HRP) simply represents a certain phase during the natural history of coronary atherosclerotic plaques or the disease progression would differ according to the presence of HRP. Purpose We determined whether the pattern of non-obstructive lesion progression into obstructive lesions would differ according to the presence of HRP. Methods Patients with non-obstructive coronary artery disease, defined as % diameter stenosis (%DS) ≥50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an inter-scan interval of ≥2 years. HRP was defined as lesions with ≥2 of positive remodelling, spotty calcification, and low-attenuation plaque. The total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions. Results A total of 1,115 non-obstructive lesions were identified from 327 patients (61.1±8.9 years old, 66.0% male). There were 690 non-HRP and 425 HRP lesions. HRP lesions possessed greater PAV and %DS at baseline compared to non-HRP lesions. However, the annualized total and non-calcified PAV change were greater in non-HRP lesions than in HRP lesions. On multivariate analysis, addition of baseline PAV and %DS to clinical risk factors improved the predictive power of the model (Table). When clinical risk factors, PAV, %DS, and HRP were all adjusted on Model 3, only baseline PAV and %DS independently predicted the development of obstructive lesions (hazard ratio (HR) 1.046 [95% confidence interval (CI): 1.026–1.066] and HR 1.087 [95% CI: 1.055–1.119], respectively, all p&lt;0.001), while HRP did not (p&gt;0.05). Comparison of C-statistics of per-lesion analysis to predict progression to obstructive lesion C-statistics (95% CI) P Model 1: Baseline PAV 0.880 (0.879–0.884) – Model 2: Model 1 + baseline %DS 0.938 (0.937–0.939) vs. Model 1: &lt;0.001 Model 3: Model 2 + HRP 0.935 (0.934–0.937) vs. Model 2: 0.004 Adjusted for age, male sex, hypertension, diabetes mellitus, hyperlipidemia, family history of coronary artery disease, smoking, body mass index, and statin use. Conclusion The pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV was the most important predictor for lesions developing into obstructive lesions rather than the presence of HRP features at baseline. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

Clinical significance of non-culprit plaque regression following acute coronary syndrome: A serial intravascular ultrasound study

BackgroundThe use of serial intravascular ultrasound (IVUS) for coronary atherosclerosis has offered valuable insight into plaque regression (PR) or progression. However, the beneficial effects of PR on the long-term clinical outcomes in patients with acute coronary syndrome (ACS) remain unclear. We aimed to evaluate the impact of coronary plaque change in patients following primary percutaneous coronary intervention. MethodsWe retrospectively analyzed data from 4 prospective clinical trials involving 173 patients with ACS who underwent serial IVUS of non-culprit lesions on statin treatment at baseline and at 6 or 8 months of follow-up. The relationship of the IVUS findings with the change in percent atheroma volume (PAV), on-treatment low-density lipoprotein cholesterol (LDL-C), and major adverse cardiac and cerebrovascular events (MACCE) were investigated. ResultsIn our serial IVUS analysis, baseline plaque volume and PAV were 79.6mm3 and 46.0%, respectively. The overall change in PAV was −1.5% [interquartile range (IQR): −4.1% to 1.0%], and PR (i.e. PAV change from baseline <0) was observed in 67.1% of patients. They were followed up observationally for a mean of 3.5 years and a total of 37 MACCE occurred. The rate of MACCE tended to be lower in patients with PR than in those without PR (18.1% vs. 28.7%, p=0.14). A multivariate Cox hazard model analysis demonstrated that achievement of both PR and on-treatment low LDL-C levels (<70mg/dL) was the only significant independent predictor of MACCE (hazard ratio: 0.42, 95% confidence interval: 0.19–0.88; p=0.02). ConclusionsAchievement of both PR and sufficient lowering of the LDL-C was clinically important in post-ACS management.

Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial

CER-001 is a negatively charged, engineered pre-β high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P = .15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (-0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. ClinicalTrials.gov Identifier: NCT2484378.

Regression of coronary atherosclerosis with infusions of the high-density lipoprotein mimetic CER-001 in patients with more extensive plaque burden.

CER-001 is an engineered pre-beta high-density lipoprotein (HDL) mimetic, which rapidly mobilizes cholesterol. Infusion of CER-001 3 mg/kg exhibited a potentially favorable effect on plaque burden in the CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study. Since baseline atheroma burden has been shown as a determinant for the efficacy of HDL infusions, the degree of baseline atheroma burden might influence the effect of CER-001. CHI-SQUARE compared the effect of 6 weekly infusions of CER-001 (3, 6 and 12 mg/kg) vs. placebo on coronary atherosclerosis in 369 patients with acute coronary syndrome (ACS) using serial intravascular ultrasound (IVUS). Baseline percent atheroma volume (B-PAV) cutoff associated with atheroma regression following CER-001 infusions was determined by receiver-operating characteristics curve analysis. 369 subjects were stratified according to the cutoff. The effect of CER-001 at different doses was compared to placebo in each group. A B-PAV ≥30% was the optimal cutoff associated with PAV regression following CER-001 infusions. CER-001 induced PAV regression in patients with B-PAV ≥30% but not in those with B-PAV <30% (-0.45%±2.65% vs. +0.34%±1.69%, P=0.01). Compared to placebo, the greatest PAV regression was observed with CER-001 3mg/kg in patients with B-PAV ≥30% (-0.96%±0.34% vs. -0.25%±0.31%, P=0.01), whereas there were no differences between placebo (+0.09%±0.36%) versus CER-001 in patients with B-PAV <30% (3 mg/kg; +0.41%±0.32%, P=0.39; 6 mg/kg; +0.27%±0.36%, P=0.76; 12 mg/kg; +0.32%±0.37%, P=0.97). Infusions of CER-001 3 mg/kg induced the greatest atheroma regression in ACS patients with higher B-PAV. These findings identify ACS patients with more extensive disease as most likely to benefit from HDL mimetic therapy.

Atrial fibrillation, progression of coronary atherosclerosis and myocardial infarction.

Background Despite atrial fibrillation representing an established risk factor for stroke, the association between atrial fibrillation and both progression of coronary atherosclerosis and major adverse cardiovascular events is not well characterized. We assessed the serial measures of coronary atheroma burden and cardiovascular outcomes in patients with and without atrial fibrillation. Methods Data were analyzed from nine clinical trials involving 4966 patients with coronary artery disease undergoing serial intravascular ultrasonography at 18-24 month intervals to assess changes in percent atheroma volume (PAV). Using a propensity weighted analysis, and following adjustment for baseline variables, patients with ( n = 190) or without ( n = 4776) atrial fibrillation were compared with regard to coronary plaque volume and major adverse cardiovascular events (death, myocardial infarction, and stroke). Results Atrial fibrillation patients demonstrated lower baseline PAV (36.0 ± 8.9 vs. 38.1 ± 8.9%, p = 0.002) and less PAV progression (-0.07 ± 0.34 vs. + 0.23 ± 0.34%, p = 0.001) compared with the non-atrial fibrillation group. Multivariable analysis revealed atrial fibrillation to independently predict both myocardial infarction [HR, 2.41 (1.74,3.35), p<0.001] 2.41 (1.74, 3.35), p < 0.00) and major adverse cardiovascular events [HR, 2.2, (1.66, 2.92), p<0.001] 2.20 (1.66, 2.92), p < 0.001]. Kaplan-Meier analysis showed that atrial fibrillation compared with non-atrial fibrillation patients had a significantly higher two-year cumulative incidence of overall major adverse cardiovascular events (4.4 vs. 2.0%, log-rank p = 0.02) and myocardial infarction (3.3 vs. 1.5%, log-rank p = 0.05). Conclusions The presence of atrial fibrillation independently associates with a heightened risk of myocardial infarction despite a lower baseline burden and progression rate of coronary atheroma. Further studies are necessary to define the pathogenesis of myocardial infarction in the setting of atrial fibrillation.

Coronary atheroma progression rates in men and women following high-intensity statin therapy: A pooled analysis of REVERSAL, ASTEROID and SATURN

Background and aimsHigh-intensity statin therapy (HIST) reduces cardiovascular events, however, sex-related differences in treatment effects are not well characterized. MethodsA patient-level post hoc pooled analysis of 3 randomized trials utilizing serial coronary intravascular ultrasound was undertaken, testing the anti-atherosclerotic effects of HIST in coronary disease patients. Sex-related differences in changes (Δ) in coronary percent atheroma volume (PAV) were ascertained following 18–24 months of HIST (atorvastatin 80 mg or rosuvastatin 40 mg daily), and further characterized according to on-treatment lipid and lipoprotein levels. ResultsIn women (n = 451) compared with men (n = 1190), on-treatment levels of LDL-C (68 ± 24 vs. 67 ± 22 mg/dl, p=0.62) and apoB (77 ± 23 vs. 76 ± 20 mg/dL, p=0.51) were similar; levels of HDL-C (53 ± 12 vs. 47 ± 11 mg/dl, p < 0.001), apoA1 (154 ± 26 vs. 140 ± 24 mg/dl, p < 0.001), triglycerides [122 (95, 158) vs. 114 (89, 154) mg/dl, p=0.012] and CRP [1.7 (0.9, 3.8) vs. 1.1 (0.6, 2.7) mg/l, p < 0.001] were higher; while the total cholesterol/HDL-C (TC/HDL-C) ratio was lower (2.9 ± 0.8 vs. 3.1 ± 0.8, p < 0.001). Compared with men, women harbored significantly lower baseline PAV (34.8 ± 8.7 vs. 38.3 ± 8.8%, p < 0.001), yet demonstrated significantly greater PAV regression (ΔPAV -1.07 ± 0.26 vs. -0.66 ± 0.23%, p=0.02). When achieved on-treatment levels of LDL-C were <64 mg/dl, apoB <73 mg/dl, non-HDL-C <88.8 mg/dl, and TC/HDL-C <2.99, women demonstrated significantly greater PAV regression than men. Multivariable analysis revealed female sex to independently associate with PAV regression (coefficient −0.66, p=0.02). ConclusionsWomen demonstrate greater degrees of coronary plaque regression compared with men following long-term HIST, especially in the setting of lower achieved atherogenic lipoprotein levels.

Abstract 12156: Greater Regression of Coronary Atherosclerosis With the Pre-Beta High-Density Lipoprotein Mimetic CER-001 in Patients With More Extensive Plaque Burden

Introduction: Infusing high-density lipoprotein (HDL) has been shown to promote plaque regression in patients with acute coronary syndrome (ACS). The factors associated with a greater propensity to regression have not been elucidated. We hypothesized greater plaque regression with HDL infusion would be observed in patients with greater baseline plaque burden. Methods: The CHI-SQUARE study compared the effect of infusing the pre-beta HDL mimetic CER-001 (3 to 12 mg/kg) versus placebo weekly for 5 weeks in patients with a recent ACS on plaque burden using serial intravascular ultrasound. Receiver operating characteristics curve analysis determined that a baseline percent atheroma volume (PAV) ≥30% optimally associated with greater regression. Clinical and imaging characteristics were compared in patients with baseline PAV &lt;30% (n=74) or ≥30% (n=271). Results: There were no differences between the groups apart from greater use of statin in patients with baseline PAV ≥30% (100 v. 90%, p=0.01). Patients with a greater baseline PAV were more likely to demonstrate echolucency (20 v. 9%, p=0.02) and ultrasound attenuation (21 v. 7%, p=0.01), consistent with lipidic and inflammatory material. On serial evaluation, PAV decreased with CER-001 infusion in patients with baseline PAV ≥30% by -0.27% (p=0.01 v. baseline), but not in those with baseline PAV &lt;30% (+0.43%, p=0.15 v. baseline, p=0.01 between plaque burden groups). The greatest PAV regression was observed with infusing CER-001 3 mg/kg in patients with baseline PAV ≥30% by 0.96% (p=0.04 v. baseline, p=0.02 v. placebo) (Table), but not in those patients with baseline PAV &lt;30% (+0.08%, p=0.55 v. baseline, p=0.004 for comparison between plaque burden groups). Conclusions: Greater plaque regression with CER-001 3 mg/kg was observed in ACS patients with greater atheroma burden and more vulnerable features. The findings identify ACS patients with high-risk plaque features most likely to benefit from HDL mimetic therapy.

Abstract 16913: Greater Coronary Atheroma Regression in Women Compared With Men: A Pooled Analysis of Serial Intravascular Ultrasonography Trials Utilizing High-intensity Statin Therapy

Introduction: High-intensity statin therapy (HIST) reduces cardiovascular events, however sex-related differences in treatment effects are not well characterized, possibly contributing to gender disparities in HIST use. Hypothesis: Sex-related differences in coronary atheroma regression exist following HIST. Methods: We undertook a patient-level post-hoc pooled analysis of 3 randomized trials utilizing serial coronary IVUS to test the anti-atherosclerotic effects of HIST in patients with coronary disease. Sex-related differences in changes (Δ) in coronary percent atheroma volume (PAV) were ascertained following 18-24 months of either atorvastatin 80 mg or rosuvastatin 40 mg. Results: In women (n=451) compared with men (n=1190), levels of on-treatment LDL-C (68±24 vs. 68±22mg/dl, p=0.62) were similar, however HDL-C (53±12 vs. 47±11 mg/dl, p&lt;0.01) and CRP [1.7 (0.9, 3.8) vs. 1.1 (0.6, 2.7) mg/l, p&lt;0.01] were higher. Compared with men, women harbored lower baseline PAV (34.8±8.7 vs. 38.3±8.8%, p&lt;0.001), yet demonstrated greater PAV regression (ΔPAV -1.07±0.26 vs. -0.66±0.23%, p=0.02). When achieved on-treatment LDL-C levels were &lt;70mg/dl, women demonstrated greater PAV regression than men (-1.49±0.21 vs. -0.97±0.13%, p=0.035), however had similar rates of PAV regression with on-treatment LDL-C levels ≥70 mg/dl (-0.63±0.25 vs. -0.42±0.16%, p=0.47). Sex-related differences in atheroma regression did not differ according to achieved levels of HDL-C, non-HDL-C or CRP (Figure). Multivariable analysis revealed female sex to independently associate with PAV regression (coefficient -0.66, p=0.017). Conclusion: Women systematically demonstrate greater degrees of coronary plaque regression compared with men following long-term HIST, especially in the setting of lower achieved LDL-C levels. Further research is required for elucidating mechanisms underpinning sex-related variations in plaque progression-regression.