Effects of statin therapy on coronary plaque volume by decreasing CRP/hsCRP levels: A meta-regression of randomized controlled trials

Background and aims: Several clinical trials have indicated that statins stabilize and reverse atherosclerotic plaque. However, different studies have provided inconsistent findings regarding mechanisms and influencing factors of plaque regression under statin therapy. In this study, meta-analysis and meta-regression were used to determine the effect of statin medication on coronary plaque volume as determined by intravenous ultrasound. Meanwhile, the impact of statins on CRP/hsCRP reduction on plaque regression was discussed. Methods: Up to May 28, 2021, a systematic PubMed, EMBASE, and Cochrane search was performed for randomized controlled trials that assessed treatment effect using total atheroma volume (TAV), percent atheroma volume (PAV), or plaque volume (PV). Only CRP/hsCRP and LDL-C values reported before and after treatment were considered. Results: 12 studies fulfilled the inclusion criteria and were included in the systematic review. Compared with control groups, meta-analysis of 15 statin-treated arms reported change of TAV/PV showed standardized mean difference (SMD) at -0.27 (95% confidence intervals [CI]: -0.42, -0.12). Meta-analysis of 7 studies reported change of PAV revealed SMD at -0.16 (95% CI: -0.29, -0.03). Meta-regression analysis revealed percent change of CRP/hsCRP statistically influences SMD in change of TAV/PVafter adjusting for percent change of LDL-C, age and gender. Meta-regression analysis showed that percent change of CRP/hsCRP statistically influences SMD in change of PAV. Conclusion: In conclusion, statin therapy is beneficial for plaque regression. Statins promote plaque regression through their anti-inflammatory ability while lowering LDL-C is unaffected. Keywords: Statins; Reduction of atherosclerosis; C-reactive protein; Randomized controlled trial; Meta-analysis

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression

Rationale: Therapeutic efforts to decrease atherosclerotic cardiovascular disease risk have focused largely on reducing atherogenic lipoproteins, yet lipid lowering therapies alone are insufficient to fully regress plaque burden. We postulate that arterial repair requires resolution of a maladaptive immune response, and that targeting factors that hinder inflammation resolution will facilitate plaque regression. Objective: The guidance molecule netrin-1 is secreted by macrophages in atherosclerotic plaques, where it sustains inflammation by enhancing macrophage survival and blocking macrophage emigration. We tested whether silencing netrin-1 in advanced atherosclerosis could resolve arterial inflammation and regress plaques. Methods and Results: To temporally silence netrin-1 in myeloid cells, we generated genetically modified mice in which Ntn1 could be selectively deleted in monocytes and macrophages using a tamoxifen-induced CX3CR1-driven cre-recombinase ( Ntn1 fl/fl Cx3cr1 creERT2+ ) and littermate control mice ( Ntn1 fl/fl Cx3cr1 WT ). Mice were fed western diet in the setting of hepatic PCSK9 overexpression to render them atherosclerotic, and then treated with tamoxifen to initiate deletion of myeloid netrin-1 (Mø ΔNtn1 ) or not in controls (Mø WT ). Morphometric analyses performed 4 weeks later showed that myeloid Ntn1 silencing reduced plaque burden in the aorta (-50%) and plaque complexity in the aortic root. Monocyte-macrophage tracing experiments revealed lower monocyte recruitment, macrophage retention, and proliferation in Mø ΔNtn1 compared to Mø WT plaques, indicating a restructuring of monocyte-macrophage dynamics in the artery wall upon netrin-1 silencing. Single cell RNA-sequencing of aortic immune cells prior to and after netrin-1 silencing revealed upregulation of gene pathways involved in macrophage phagocytosis and migration, including the Ccr7 chemokine receptor signaling pathway required for macrophage emigration from plaques and atherosclerosis regression. Additionally, plaques from Mø ΔNtn1 mice showed hallmarks of inflammation resolution, including higher levels of pro-resolving macrophages, interleukin-10, and efferocytosis, as compared to plaques from Mø WT mice. Conclusions: Our data show that targeting netrin-1 in advanced atherosclerosis ameliorates atherosclerotic inflammation and promotes plaque regression.

POS0216 GREATER HIGH-DENSITY LIPOPROTEIN LEVELS OVER TIME ARE LINKED TO DECREASED CORONARY PLAQUE FORMATION AND REGRESSION AND STABILIZATION OF HIGH-RISK LESIONS IN RHEUMATOID ARTHRITIS

Background:The relationship between serum lipoproteins and cardiovascular disease risk in rheumatoid arthritis (RA) is complex1. Their levels and function may vary based on disease activity and medication use. Beneficial effects on high-density lipoprotein (HDL-C) levels, structure and behavior, in response to treatment have been described. However, the impact of HDL-C levels over time on coronary atherosclerosis progression in RA is unknown.Objectives:We here evaluated the influence of HDL-C levels over time on long-term coronary plaque formation and progression in patients with RA.Methods:One hundred one RA patients without symptoms or history of cardiovascular disease who participated in a computed tomography angiography study of coronary atherosclerosis had repeat assessments after 6.9±0.3 years to evaluate plaque progression. Clinical, laboratory and medication data were recorded at baseline and regular outpatient follow-up visits thereafter. Time-averaged HDL-C was calculated for each patient using available consecutive HDL measurements between baseline and follow-up. Robust logistic regression assessed the association between time-averaged HDL-C and likelihood of new plaque formation in segments without plaque at baseline, and transition of prevalent mixed plaque to calcified plaque. Robust multinomial logistic regression evaluated the effect of time-averaged HDL-C on likelihood of new non-calcified, mixed or calcified plaque formation in segments without plaque (compared to remaining without plaque), and non-calcified plaque regression or transition to mixed or calcified plaque at follow-up (compared to remaining non-calcified). All models accounted for clustering of coronary segments within patients and adjusted for Framingham D’Agostino risk score, proximal segment location, time-averaged CRP, cumulative prednisone dose, bDMARD duration, statin duration, waist-to-height ratio, and time-averaged triglycerides.Results:Participants were mostly female (n=87, 86.1%), with a mean ± standard deviation (SD) age of 51.5±10.3 years and time-averaged HDL-C of 51.7±13.9. Ninety-seven new plaques formed in segments without plaque at baseline; 20 were noncalcified, 21 were mixed, and 56 were calcified. Time-averaged HDL-C had no effect on new total plaque formation (adjusted odds ratio-OR 0.88 [95% CI 0.64-1.21]). However, each 1-SD increase in time-averaged HDL-C associated with a 44% reduced likelihood of new non-calcified plaque formation at follow-up (adjusted OR 0.56 [95% CI 0.35-0.92], Figure 1). In contrast, there was no effect of time-averaged HDL-C on new mixed or calcified plaque formation. Of 98 non-calcified plaques at baseline, 42 did not change at follow-up, 32 regressed (disappeared), 16 transitioned to mixed and 8 to calcified plaques. Each SD increase in time-averaged HDL-C yielded a 2.2-fold greater likelihood of non-calcified plaque regression (adjusted OR 2.21 [95% CI 1.02-4.83]). Sixteen of 52 mixed plaques present at baseline transitioned to more stable calcified lesions, and time-averaged HDL-C (per 1-SD increment) predicted a 3.5-fold increased likelihood of transition of mixed to fully calcified plaque (adjusted OR 3.56 [95% CI 1.25-10.17]).Conclusion:Higher HDL-C over time predicted regression of existing and decreased formation of new higher-risk non-calcified plaque. It also associated with transition of vulnerable mixed plaque to more stable fully calcified plaque. These effects were independent of RA treatment duration, prednisone dose and statin exposure.References:[1]Toms TE et al. Curr Vasc Pharmacol. 2010;8:301–326.Figure 1.Impact of HDL-C over time on coronary plaque progression in RADisclosure of Interests:George Karpouzas Speakers bureau: Sanofi/Genzyme/Regeneron, Consultant of: Sanofi/Genzyme/Regeneron, Grant/research support from: Pfizer, Sarah Ormseth: None declared, Elizabeth Hernandez: None declared, Matthew Budoff: None declared

The effects of lipid-lowering therapy on coronary plaque regression: a systematic review and meta-analysis

To assess the influence of lipid-lowering therapy on coronary plaque volume, and to identify the LDL and HDL targets for plaque regression to provide a comprehensive overview. The databases searched (from inception to 15 July 2020) to identify prospective studies investigating the impact of lipid-lowering therapy on coronary plaque volume and including quantitative measurement of plaque volume by intravascular ultrasound after treatment. Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001).Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001). Our meta-analysis suggests that not only should LDL be reduced to a target level of < 80 mg/dL, but HDL should be increased to a target level of > 45 mg/dL to regress coronary plaques.Trial Registration PROSPERO identifier: CRD42019146170.