Regression Of Percent Atheroma Volume Research Articles

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.

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

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.

Effect of Evolocumab on Coronary Plaque Phenotype and Burden in Statin-Treated Patients Following Myocardial Infarction

BackgroundThe proprotein convertase subtilisin kexin type-9 inhibitor evolocumab produced coronary atheroma regression in statin-treated patients. ObjectivesThe purpose of this study was to determine the effect of evolocumab on optical coherence tomography (OCT) measures of plaque composition. MethodsPatients with a non–ST-segment elevation myocardial infarction were treated with monthly evolocumab 420 mg (n = 80) or placebo (n = 81) for 52 weeks. Patients underwent serial OCT and intravascular ultrasound imaging within a matched arterial segment of a nonculprit vessel. The primary analysis determined the change in the minimum fibrous cap thickness and maximum lipid arc throughout the imaged arterial segment. Additional analyses determined changes in OCT features in lipid-rich plaque regions and plaque burden. Safety and tolerability were evaluated. ResultsAmong treated patients (age 60.5 ± 9.6 years; 28.6% women; low-density lipoprotein cholesterol [LDL-C], 141.3 ± 33.1 mg/dL), 135 had evaluable imaging at follow-up. The evolocumab group achieved lower LDL-C levels (28.1 vs 87.2 mg/dL; P < 0.001). The evolocumab group demonstrated a greater increase in minimum fibrous cap thickness (+42.7 vs +21.5 μm; P = 0.015) and decrease in maximum lipid arc (−57.5o vs. −31.4o; P = 0.04) and macrophage index (−3.17 vs −1.45 mm; P = 0.04) throughout the arterial segment. Similar benefits of evolocumab were observed in lipid-rich plaque regions. Greater regression of percent atheroma volume was observed with evolocumab compared with placebo (−2.29% ± 0.47% vs −0.61% ± 0.46%; P = 0.009). The groups did not differ regarding changes in microchannels or calcium. ConclusionsThe combination of statin and evolocumab after a non–ST-segment elevation myocardial infarction produces favorable changes in coronary atherosclerosis consistent with stabilization and regression. This demonstrates a potential mechanism for the improved clinical outcomes observed achieving very low LDL-C levels following an acute coronary syndrome. (Imaging of Coronary Plaques in Participants Treated With Evolocumab; NCT03570697)

Relationship between arterial remodelling and serial changes in coronary atherosclerosis by intravascular ultrasound: an analysis of the IBIS-4 study.

Arterial remodelling is an important determinant of coronary atherosclerosis. Assessment of the remodelling index, comparing a lesion to a local reference site, is a suboptimal correlate of serial vascular changes. We assessed a novel approach which, unlike the local-reference approach, uses the entire artery's global remodelling as reference. Serial (baseline and 13 months) intravascular ultrasound was performed in 146 non-infarct-related arteries of 82 patients treated with high-intensity statin. Arteries were divided into 3-mm segments (n = 1479), and focal remodelling was characterized in individual segments at both timepoints applying the global arterial reference approach. First, we compared preceding vascular changes in relation to follow-up remodelling. Second, we examined whether baseline remodelling predicts subsequent plaque progression/regression. At follow-up, segments with constrictive vs. compensatory or expansive remodelling had greater preceding reduction of vessel area (-0.67 vs. -0.38 vs. -0.002mm2; P < 0.001) and lumen area (-0.82 vs. -0.09 vs. 0.40mm2; P < 0.001). Overall, we found significant regression in percent atheroma volume (PAV) [-0.80% (-1.41 to -0.19)]. Segments with constrictive remodelling at baseline had greater subsequent PAV regression vs. modest regression in the compensatory, and PAV progression in the expansive remodelling group (-6.14% vs. -0.71% vs. 2.26%; P < 0.001). Lesion-level analyses (n = 118) showed no differences when remodelling was defined by the local reference approach at baseline or follow-up. Remodelling assessment using a global arterial reference approach, but not the commonly used, local reference site approach, correlated reasonably well with serial changes in arterial dimensions and identified arterial segments with subsequent PAV progression despite intensive statin treatment and overall atheroma regression.

Serial Coronary Plaque Assessment Using Computed Tomography Coronary Angiography

Serial Coronary Plaque Assessment Using Computed Tomography Coronary Angiography

Effect of Evolocumab on Coronary Plaque Composition

BackgroundIncremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. ObjectivesThe purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. MethodsA total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. ResultsCompared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001). ConclusionsThe addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422)

Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial

Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. To determine the effect of infusing MDCO-216 on coronary atherosclerosis progression. This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20 mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measures were the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patients who demonstrated plaque regression. Safety and tolerability were also evaluated. Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93 men [76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5] mg/dL [to convert to millimoles per liter, multiply by 0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levels were comparable with the placebo and MDCO-216 (68.6 vs 70.5 mg/dL; difference, -2.5 mg/dL; 95% CI, -10.1 to 5.0; P = .51). A reduction in high-density lipoprotein cholesterol levels was observed in MDCO, but not placebo patients (-3.3 vs 3.0 mg/dL [to convert to millimoles per liter, multiply by 0.0259]; difference, -6.3 mg/dL; 95% CI, -8.5 to -4.1; P < .001). Percent atheroma volume, which was adjusted for baseline values, decreased 0.94% with the placebo and 0.21% with MDCO-216 (difference, 0.73%; 95% CI, -0.07 to 1.52; P = .07). Normalized TAV decreased 7.9 mm3 with the placebo and 6.4 mm3 with MDCO-216 (difference, 1.6 mm3; 95% CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8 mm3 with the placebo and 2.2 mm3 with MDCO-216 (difference 0.4 mm3; 95% CI, -4.4 to 3.5; P = .83). A similar percentage of patients demonstrated a regression of PAV (67.2% vs 55.8%; P = .21) and TAV (68.9% vs 71.2%; P = .79) in the placebo and MDCO-216 groups, respectively. Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy. ClinicalTrials.gov Identifier: NCT02678923.

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.

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 623: Effect of High-intensity Statin Therapy on High-density Lipoprotein (HDL) Subfractions and Regression of Coronary Atheroma: The SATURN Trial

Aim: Statin therapy can slow the progression of coronary atherosclerosis. However, the clinical factors underlying the beneficial effects of statin therapy on disease progression remain poorly understood. We examined the relationship of circulating HDL subfractions with measures of coronary atheroma following long-term high-intensity statin therapy. Methods: Serial coronary intravascular ultrasound (IVUS) was utilized in SATURN to monitor changes in atheroma burden [percent atheroma volume (PAV)] in 915 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Results: Baseline levels of total HDL-C, apo E-containing HDL-C (apoE HDL-C), HDL 3 -C and HDL 2 -C did not differ significantly between treatment groups. Compared with the atorvastatin-treated group, rosuvastatin-treated patients demonstrated greater increases in levels of total HDL-C (4.4% vs. -1.8%, p&lt;0.001), apoE HDL-C (8.5% vs. -3.3%, p&lt;0.001), HDL 3 -C (3.3% vs. -2.7%, p&lt;0.001) and HDL 2 -C (7.0% vs. -0.7%, p&lt;0.001). The alterations in apo E HDL-C and HDL 3 -C levels were associated with PAV regression in rosuvastatin-treated patients (β=-0.84, p=0.018 and β=-1.10, p=0.056, respectively) but not in the atorvastatin-treated group (β=0.41, p=0.22 and β=0.71, p=0.22 for apo E HDL-C and HDL 3 -C, respectively). Conclusions: Rosuvastatin therapy resulted in favorable changes in HDL subfractions and on-treatment levels of apoE HDL-C and HDL 3 -C were associated with greater disease regression.

Changes of coronary plaque composition correlate with C-reactive protein levels in patients with ST-elevation myocardial infarction following high-intensity statin therapy

ObjectivesLevels of inflammatory biomarkers associate with changes of coronary atheroma burden in statin-treated patients with stable coronary artery disease. This study sought to determine changes of plaque composition in vivo in relation to high-sensitivity C-reactive protein (hs-CRP) levels in patients with ST-elevation myocardial infarction (STEMI) receiving high-intensity statin therapy. MethodsThe IBIS-4 study performed serial (baseline and 13-month), 2-vessel intravascular ultrasound (IVUS) and radiofrequency-IVUS of the non-infarct-related arteries in patients with STEMI treated with high-intensity statin therapy. The present analysis included 44 patients (80 arteries) with serial measurements of hs-CRP. ResultsAt follow-up, median low-density lipoprotein cholesterol (LDL-C) levels decreased from 126 to 77 mg/dl, HDL-C increased from 44 to 47 mg/dl, and hs-CRP decreased from 1.6 to 0.7 mg/L. Regression of percent atheroma volume (−0.99%, 95% CI −1.84 to −0.14, p = 0.024) was accompanied by reduction of percent fibro-fatty (p = 0.04) and fibrous tissue (p < 0.001), and increase in percent necrotic core (p = 0.006) and dense calcium (p < 0.001). Follow-up levels of hs-CRP, but not LDL-C, correlated with changes in percent necrotic core (p = 0.001) and inversely with percent fibrous tissue volume (p = 0.008). Similarly, baseline-to-follow-up change of hs-CRP correlated with the change in percent necrotic core volume (p = 0.02). ConclusionsIn STEMI patients receiving high-intensity statin therapy, stabilization of VH-IVUS–defined necrotic core was confined to patients with lowest on-treatment levels and greatest reduction of hs-CRP. Elevated CRP levels at follow-up may identify progression of high-risk coronary plaque composition despite intensive statin therapy and overall regression of atheroma volume.

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.

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.

Impact of Statins on Serial Coronary Calcification During Atheroma Progression and Regression

BackgroundStatins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can modulate coronary atheroma calcification in vivo. ObjectivesThis study compared changes in coronary atheroma volume and calcium indices (CaI) in patients receiving high-intensity statin therapy (HIST), low-intensity statin therapy (LIST), and no-statin therapy. MethodsIn a post-hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume (PAV) and CaI were measured across matched coronary segments in patients with coronary artery disease. ResultsFollowing propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline (−0.6 ± 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 ± 0.1% and +1.0 ± 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median [interquartile range] HIST, +0.044 [0.0–0.12]; LIST, +0.038 [0.0–0.11]; no-statin, +0.020 [0.0–0.10]; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no-statin group. ConclusionsIndependent of their plaque-regressive effects, statins promote coronary atheroma calcification. These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression.

Sex-Related Differences of Coronary Atherosclerosis Regression Following Maximally Intensive Statin Therapy: Insights From SATURN

ObjectivesThe study sought to explore sex-related differences in coronary atheroma regression following high-intensity statin therapy. BackgroundGuidelines now recommend high-intensity statins in all individuals with atherosclerotic cardiovascular disease. MethodsSATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) employed serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. The treatment groups did not differ significantly in change from baseline of percent atheroma volume (PAV) or total atheroma volume (TAV) on intravascular ultrasound, nor in safety or clinical outcomes. ResultsCompared with men (n = 765), women (n = 274) were older (p < 0.001) and more likely to have hypertension (p < 0.001), diabetes (p = 0.002), and higher low-density lipoprotein cholesterol (LDL-C) (p = 0.01), high-density lipoprotein cholesterol (p < 0.001), and C-reactive protein (CRP) (p = 0.004) levels. At follow-up, women had higher high-density lipoprotein cholesterol (p < 0.001) and CRP (p < 0.001), but similar LDL-C (p = 0.46) levels compared with men. Compared with men, women had lower baseline PAV (34.0 ± 8.0% vs. 37.2 ± 8.2%, p < 0.001) and TAV (122.4 ± 55 mm3 vs. 151.9 ± 63 mm3, p < 0.001), yet demonstrated greater PAV regression (–1.52 ± 0.18% vs. –1.07 ± 0.10%, p = 0.03) and TAV regression (–8.27 ± 0.9 mm3 vs. –6.59 ± 0.50 mm3, p = 0.11) following treatment. Greater PAV regression in women versus men occurred with rosuvastatin (p = 0.004), those with diabetes (p = 0.01), stable coronary disease (p = 0.01), higher baseline LDL-C (p = 0.02), and higher CRP (p = 0.04) levels. On multivariable analysis, female sex was independently associated with PAV regression (p = 0.01), and a sex-treatment interaction was found (p = 0.036). For participants with on-treatment LDL-C levels <70 mg/dl, women achieved greater PAV regression (–1.81 ± 0.22% vs. –1.12 ± 0.13%, p = 0.007) and TAV regression (–10.1 ± 1.1 mm3 vs. –7.16 ± 0.65 mm3, p = 0.023) than men, whereas PAV and TAV regression did not differ by sex, with LDL-C levels ≥70 mg/dl. ConclusionsWomen with coronary disease demonstrate greater coronary atheroma regression than men when empirically prescribed guideline-driven potent statin therapy. This benefit appears in the setting of lower on-treatment LDL-C levels. (CRESTOR Athero Imaging Head to Head IVUS Study [SATURN]; NCT000620542)

Progression of coronary atherosclerosis in stable patients with ultrasonic features of high-risk plaques.

Large plaque burden, expansive vascular remodelling, and spotty calcification have been considered as important morphologies of high-risk plaques causing acute coronary events. Although non-occlusive rupture of high-risk plaques has been proposed as a mechanism for disease progression in post-mortem studies, the natural history of coronary atherosclerosis in stable patients with high-risk plaques has not been fully elucidated. We sought to evaluate coronary atheroma progression in stable patients with greyscale intravascular ultrasound (IVUS)-derived high-risk plaques. We analysed 4477 patients with stable coronary artery disease underwent serial greyscale IVUS imaging in eight clinical trials. We compared volumetric intravascular ultrasound (IVUS) data in the non-culprit segments between patients with and without high-risk plaques, defined as the combination of per cent atheroma volume (PAV) >63%, positive remodelling and spotty calcification. High-risk plaques were observed in 201 (4.5%) of patients. Patients with high-risk plaques exhibited a greater PAV (47.1 ± 8.4 vs. 37.7 ± 8.7%, P < 0.001) at baseline. On serial evaluation, however, regression of PAV (-0.26 ± 0.39 vs. 0.24 ± 0.32%, P = 0.03) was observed. In patients with high-risk plaques, the non-statin use was associated with the accelerated atheroma progression, whereas atheroma regression was observed under statin therapy (change in PAV: 1.87 ± 0.68% vs. -0.83 ± 0.53%, P = 0.01). Patients with high-risk plaques exhibit extensive atheroma burden, which is modifiable with anti-atherosclerotic therapies. These findings underscore risk modification using a statin in patients with high-risk plaques.

Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN

To evaluate the effect of long-term maximally intensive statin therapy on indices of coronary atheroma composition in a randomized trial, and how these changes relate to modifications of serum lipoproteins and systemic inflammation. The Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months. Seventy-one patients underwent serial assessment of indices of plaque composition by spectral analysis of the radiofrequency IVUS signal. Changes in low-density lipoprotein cholesterol [LDL-C; -52 (-72, -33) mg/dL, P < 0.001], C-reactive protein [CRP -0.2 (-1, 0.1) mg/L, P = 0.01], and high-density lipoprotein cholesterol [HDL-C; +2.8 (-0.3, 7.8) mg/dL, P < 0.001] were associated with regression of percent atheroma volume (PAV: -1.6 ± 3.6%, P < 0.001). A reduction in estimated fibro-fatty tissue volume accompanied atheroma regression (P < 0.001), while dense calcium tissue volume increased (P = 0.002). There were no changes in fibrous or necrotic core tissue volumes. Volumetric changes in necrotic core tissue correlated with on-treatment HDL-C (r = -0.27, P = 0.03) and CRP (r = 0.25, P = 0.03) levels. A per-lesion analysis showed a reduction in the number of pathological intimal thickening lesions (defined by ≥3 consecutive IVUS frames containing PAV of ≥40%, predominantly fibro-fatty plaque, with <10% confluent necrotic core and <10% confluent dense calcium) at follow-up (67 vs. 38, P = 0.001). Fibroatheromas and fibrotic lesions remained static in number. Changes in indices of atheroma composition accompany regression of coronary atheroma with maximally intensive statin therapy, and associate with anti-inflammatory effects of statins. NCT000620542.

Effect of Aliskiren on Progression of Coronary Disease in Patients With Prehypertension

Blood pressure reduction and renin-angiotensin-aldosterone system inhibition are targets for treatment of atherosclerosis. The effect of renin inhibition on coronary disease progression has not been investigated. To determine the effects of renin inhibition with aliskiren on progression of coronary atherosclerosis. A double-blind, randomized, multicenter trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) comparing aliskiren with placebo in 613 participants with coronary artery disease, systolic blood pressure between 125 and 139 mm Hg (prehypertension range), and 2 additional cardiovascular risk factors conducted at 103 academic and community hospitals in Europe, Australia, and North and South America (enrollment from March 2009 to February 2011; end of follow-up: January 31, 2013). Participants underwent coronary intravascular ultrasound (IVUS) imaging and were randomized to receive 300 mg of aliskiren (n = 305) or placebo (n = 308) taken orally daily for 104 weeks. Disease progression was measured by repeat IVUS examination after at least 72 weeks of treatment. The primary efficacy parameter was the change in percent atheroma volume (PAV) from baseline to study completion. Secondary efficacy parameters included the change in normalized total atheroma volume (TAV) and the percentage of participants with atheroma regression. Safety and tolerability were also assessed. Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (-0.33%; 95% CI, -0.68% to 0.02%) and placebo (0.11%; 95% CI, -0.24% to 0.45%) (between-group difference, -0.43% [95% CI, -0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, TAV, did not differ between participants treated with aliskiren (-4.1 mm3; 95% CI, -6.27 to -1.94 mm3) and placebo (-2.1 mm3; 95% CI, -4.21 to 0.07 mm3) (between-group difference, -2.04 mm3 [95% CI, -5.03 to 0.95 mm3]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively. Among participants with prehypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. These findings do not support the use of aliskiren for regression or prevention of progression of coronary atherosclerosis. clinicaltrials.gov Identifier: NCT00853827.

Factors underlying regression of coronary atheroma with potent statin therapy

Statins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy. SATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs. -4.4 mm(3), P = 0.01), but not PAV (-1.22 vs. -0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P-value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P-value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV -0.25, P < 0.001; PAV -0.23, P < 0.001). Higher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy.