Induce Plaque Regression Research Articles

Rethinking atherosclerotic cardiovascular disease prevention in the era of expanding therapies: could plaque stabilization reduce the need for lifelong treatments and polypharmacy?

This review examines current evidence on pharmacologically induced plaque stabilization in the context of a growing range of new therapies. It explores the potential for a paradigm shift in atherosclerotic cardiovascular disease (ASCVD) prevention, where treatments may not need to be lifelong to achieve lasting benefits. Since 2015, over 14 novel therapies have been introduced, each shown to reduce ASCVD risk when added to standard care with statins and aspirin. More than 80% of ischemic heart disease patients are now eligible for one or more of these treatments, increasing the risk of polypharmacy, treatment burden, and adverse side effects. As more therapies become available, this challenge is expected to grow. Many of these treatments have demonstrated plaque regression and stabilization, as evidenced by both intravascular ultrasound and computed tomography angiography, which likely explains much of their efficacy. The increasing number of novel therapies presents challenges in preventing ASCVD without leading to lifelong polypharmacy and increased patient burden. Since many of these drugs act through plaque stabilization, a new approach may be feasible - using these treatments for shorter durations to induce plaque regression, followed by less intensive maintenance therapies to preserve stability. This approach warrants further investigation in future studies.

The role of nanosystems in the delivery of glucose-lowering drugs for the preemption and treatment of diabetes-associated atherosclerosis.

Diabetes is one of the most prevalent diseases worldwide. In recent decades, type-2 diabetes has become increasingly common, particularly in younger individuals. Diabetes leads to many vascular complications, including atherosclerosis. Atherosclerosis is a cardiovascular disease characterized by lipid-rich plaques within the vasculature. Plaques develop over time, restricting blood flow, and can, therefore, be the underlying cause of major adverse cardiovascular events, including myocardial infarction and stroke. Diabetes and atherosclerosis are intrinsically linked. Diabetes is a metabolic syndrome that accelerates atherosclerosis and increases the risk of developing other comorbidities, such as diabetes-associated atherosclerosis (DAA). Gold standard antidiabetic medications focus on attenuating hyperglycemia. Though recent evidence suggests that glucose-lowering drugs may have broader applications, beyond diabetes management. This review mainly evaluates the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide in DAA. These drugs mimic gut hormones (incretins), which inhibit glucagon secretion while stimulating insulin secretion, thus improving insulin sensitivity. This facilitates delayed gastric emptying and increased patient satiety; hence, they are also indicated for the treatment of obesity. GLP-1 RAs have significant cardioprotective effects, including decreasing low-density lipoprotein (LDL) cholesterol and triglycerides levels. Liraglutide and semaglutide have specifically been shown to decrease cardiovascular risk. Liraglutide has displayed a myriad of antiatherosclerotic properties, with the potential to induce plaque regression. This review aims to address how glucose-lowering medications can be applied to treat diseases other than diabetes. We specifically focus on how nanomedicines can be used for the site-specific delivery of antidiabetic medicines for the treatment of diabetes-associated atherosclerosis.

Abstract 307: Targeted Activation Of The Tnfa Pathway Accelerates Atherosclerosis Regression In Mice

Aggressive lipid lowering in mice with established atherosclerosis induces plaque regression and is characterized by reduced monocyte recruitment and increased expression of the motility receptor C-C chemokine receptor 7 (CCR7) to promote macrophage egress from plaques to nearby lymph nodes. Notably, genetic deletion of receptors critical for the recruitment of inflammatory Ly6C high monocytes is necessary to facilitate plaque regression. Our group previously showed that deletion of macrophage LDL receptor-related protein 1 (LRP1) in mice with established atherosclerosis accelerates plaque regression after lipid lowering and is associated with increased inflammation and macrophage CCR7-mediated egress. We tested the hypothesis that targeted activation of inflammation following lipid lowering in atherosclerotic mice accelerates atherosclerosis regression. LC-MS/MS proteomics performed on murine macrophages revealed that the loss of LRP1 upregulated the inflammatory protein tumor necrosis factor alpha (TNFα) 1.48-fold (P<0.05). Apoe -/- mice were fed a Western diet for 12 weeks to establish atherosclerosis and then subjected to bone marrow transplantation (BMT) using wildtype ( Apoe +/+ ) mice as donors to restore plasma APOE and reduce lipids. A cohort was sacrificed two weeks after BMT and used as baseline (N=11). The remaining mice (N=12/group) received intraperitoneal injections of recombinant murine TNFα (0.075mg/kg/day) or saline for 6 weeks on chow diet. After 6 weeks on chow diet, total plasma cholesterol levels ranged 82 -120 mg/dL with no significant differences between treatment cohorts. TNFα-treated mice had elevated spleen-to-body weight ratios compared to saline treated controls (P<0.0001), confirming successful activation of the immune system. Following 6 weeks of lipid lowering, TNFα treatment reduced total plaque area and lipid content 17.0% (P<0.05) and 34.4% (P<0.05), respectively, compared to saline treated controls (P<0.05).Herein, we show that the administration of TNFα, to stimulate inflammation after lipid lowering, significantly reduces plaque size and plaque lipid content in mice with established atherosclerosis.

Abstract 704: Autophagy Activation Promotes Atherosclerosis Regression

Atherosclerosis is characterized by the deposition of cholesterol-rich plaques within the artery wall that are primarily comprised of macrophage and vascular smooth muscle cell (VSMC) foam cells. Atherogenesis is associated with a progressive defect in autophagy, a cell process that promotes cellular cholesterol homeostasis by degrading excess lipids and promoting cholesterol efflux. We recently showed that during atherosclerosis progression, autophagy and cholesterol efflux to HDL was particularly defective in VSMC foam cells as compared to macrophage foam cells. While previous studies have shown that autophagy activation of transcription factor EB by trehalose protects against atherosclerosis, the ability of this therapeutic compound to shrink pre-existing atherosclerotic plaque (atherosclerosis regression ) is unknown. We hypothesized that activating autophagy with trehalose would promote atherosclerosis regression in mice by enhancing macrophage and VSMC reverse cholesterol transport. Mice were injected with a gain of function PCSK9 adeno-associated virus and fed a Western Diet for 16 weeks to promote atherosclerotic plaque progression, followed by a switch to chow diet for 6 weeks to induce plaque regression. During the regression phase, mice received sub-cutaneous injections of saline or trehalose biweekly. Aortic sinuses were evaluated for changes in plaque size and lipid content. Circulating immune cells were quantified by flow cytometry. A switch to chow diet decreased circulating inflammatory and patrolling monocytes as compared to baseline, although no changes between the trehalose and saline treatment groups were observed. Oil Red O staining revealed a decrease in plaque lipid content in trehalose-treated mice as compared to the saline group, suggesting that autophagy activation in mice during atherosclerosis regression promotes favorable plaque remodeling. Our data demonstrates the therapeutic potential of autophagy activation in reducing atherosclerotic plaque burden. Further analysis of autophagy and inflammatory markers to characterize the mechanisms by which trehalose improves atherosclerosis regression is ongoing.

Macrophage polarization as a potential therapeutic target for atherosclerosis: a dynamic stochastic modelling study.

We proposed a dynamic stochastic mathematical model to evaluate the role of macrophage polarization in plaque development. The dynamic process of macrophages from proliferation to death was simulated under different lipid microenvironments. The probability of macrophage phenotypic switching was described using a Bernoulli distribution where the stochastic variable was determined by the local lipid level. Moreover, the interactions between macrophages and microenvironmental factors vary with macrophage phenotype. We investigated the distribution of key microenvironmental factors, the dynamics of macrophage polarization and its influence on foam cell formation. M1 macrophages were found to predominate in advanced plaque corresponding to the exacerbated inflammation observed in mice experiments. The imbalance between the deposition of oxidized low-density lipoprotein and phagocytic effects of macrophages governed the formation of foam cells. Furthermore, we simulated targeted therapies by either directly inhibiting the polarization probability to M1 macrophages or indirectly regulating macrophage polarization due to high-density lipoprotein levels. Comparison of simulation results with experimental findings in both therapies indicated that the intervention and regulation of macrophage polarization could influence plaque microenvironment and subsequently induce plaque regression, especially in the early stage. The proposed modelling system can facilitate the evaluation of novel therapies targeting macrophage polarization.

Alirocumab induces plaque regression.

Alirocumab induces plaque regression.

New insights in statins affecting atheromatous plaque macrophages.

Macrophages are key protagonists of atherosclerotic plaque development and hence represent targets of therapeutic intervention. Statins are the most potent widely used atheroprotective drugs. Therefore, whether and how statins influence atheromatous plaque macrophages has remained at the center of cardiovascular research for decades. Because statins are capable of regulating macrophage functions in cell culture, largely independent of their cholesterol-lowering effect, it was assumed that these pleiotropic effects operate in vivo as well. Recent experimental data, in line with clinical observations, indicate, however, that statins do not interact with macrophages in atherosclerotic plaques, directly, and instead control their functions and assembly indirectly via changes to circulating lipid levels and endothelial activation. Statin-mediated lipid lowering induces plaque regression which is characterized by a decline in plaque macrophage content. Understanding how statins provoke this protective phenotype may inspire conceptually new therapeutic approaches in cardiovascular medicine.

CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography.

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide d-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64Cu radiolabeling showed extended blood circulation of 64Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE-/-) showed that the three 64Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE-/- mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.

Abstract 14770: Reduction With Evolocumab in Complex Coronary Disease Requiring Revascularization: Insights From the FOURIER Trial

Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P<0.001) and the risk of complex revascularization by 29% (HR 0.71; 95%CI 0.61-0.84; P<0.001), including complex PCI by 33% (HR 0.67; 95%CI 0.54-0.84; P<0.001) and CABG by 24% (HR 0.76; 95%CI 0.60-0.96; P=0.019; Figure). The incidence of reported PCI complications tended to be lower with evolocumab (HR 0.74; 95% CI 0.49-1.11). Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to <1 mmol/L has beneficial effects on coronary atherosclerosis burden, anatomical complexity, and the need for intervention.

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization

ObjectivesThis study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization. BackgroundPCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall. MethodsFOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG). ResultsIn this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years). ConclusionsAdding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.)

Ezetimibe and Improving Cardiovascular Outcomes: Current Evidence and Perspectives.

Low-density lipoprotein lowering with statins has convincingly and consistently proven to reduce cardiovascular events in both primary and secondary prevention. However, despite high-dose statin therapy, residual cardiovascular risk remains and many patients also do not tolerate statins. Ezetimibe was initially projected as a frontline alternative to statin. It is an intestinal cholesterol absorption inhibitor with modest LDL lowering effects. But, major studies failed to demonstrate any beneficial effect of CV outcomes, and the drug was relegated to oblivion. IMPROVE-IT, a contemporary, large, and well-designed trial, unequivocally demonstrated reduction in CV outcomes with ezetimibe when added to statin therapy. The benefits are seen in both sexes, elderly, CKD, diabetes mellitus, and in patients with prior CABG. It also reduces biomarkers and induces plaque regression like statins. The drug has now established itself as an add-on therapy to statin when monotherapy fails to achieve LDL goals and when it is not tolerated. The combination therapy has excellent safety and efficacy record. It has now been endorsed by major guidelines too in management of dyslipidemia. Yes, ezetimibe can indeed improve cardiovascular outcomes!

P733Cholesterol uptake triggers macrophage proliferation in the plaque

Abstract Background Guidelines recommend cholesterol lowering for primary and secondary prevention of cardiovascular disease. While lipid lowering has been reported to induce plaque regression, the underlying mechanisms have remained speculative. Purpose We hypothesize that lipid uptake triggers local macrophage proliferation in the plaque, and conversely, statin treatment inhibits local macrophage proliferation leading to plaque regression. Methods Mixed bone marrow chimeras were generated in LDLR−/− mice reconstituted with wild type and scavenger receptor deficient or cholesterol exporter deficient bone marrow cells to study cell autonomous effects on macrophage proliferation. APOE*3-Leiden.huCETP mice with established atherosclerosis were randomized to three groups: Continued cholesterol diet, cholesterol diet supplemented with 0.01% atorvastatin, and cholesterol free diet for 4 weeks to study mechanisms of plaque regression. Results Proliferation of scavenger receptor A and CD36 deficient macrophages with impaired lipid uptake was reduced by 30–50% in the plaque, while ABCA1/ABCG1 exporter deficiency resulted in cholesterol overloading and apoptosis. Oral atorvastatin treatment decreased total plasma cholesterol levels by 50% to the same extend as cholesterol free diet feeding in APOE*3-Leiden.huCETP. Cholesterol lowering resulted in a 50% reduction in local macrophage proliferation and plaque regression with reduced macrophage and lipid contents and increased collagen. GFP bone marrow reconstitution of APOE*3-Leiden.huCETP mice in which the aortas were shielded from irradiation showed infiltrating monocytes to contribute only 11% to the plaque macrophage pool during plaque progression, thereby underscoring the relevance of targeting macrophage proliferation for plaque regression. Finally, rates of macrophage proliferation in human carotid artery plaques correlated with serum LDL-cholesterol levels, in line with our experimental studies. Conclusion Foam cell formation in atherosclerotic plaques triggers their proliferation. Targeting macrophage proliferation leads to plaque regression.

Lifestyle Interventions and Carotid Plaque Burden: A Comparative Analysis of Two Lifestyle Intervention Programs in Patients with Coronary Artery Disease

The cardioprotective effects of intensive lifestyle regimens in primary prevention have been elucidated; however, there is a paucity of data comparing the effects of different lifestyle regimens in patients with established coronary artery disease (CAD) or CAD equivalent, specifically vis-à-vis carotid plaque regression. We performed a randomized, single-center, single-blind study in 120 patients with established CAD. Patients were randomly assigned to either 9 months of the Complete Health Improvement Program (CHIP), an outpatient lifestyle enrichment program that focuses on improving dietary choices, enhancing daily exercise, increasing support systems, and decreasing stress; or to 9 months of an ad hoc, nonsequential combination of various healthy living classes offered separately through a health maintenance organization and referred to as the Healthy Heart program. Baseline and 9-month change in carotid intima-media thickness (CIMT) were measured. Among 120 participants, data were analyzed for 79, of which 68 (86%) completed the study. Both average CIMT and average maximum CIMT increased over 9 months, but the changes between groups were insignificant. There were marked differences in the mean body mass index favoring the CHIP group (-1.9 [standard deviation = 1.9]; p < 0.001) and statistically significant within-group improvements in blood pressure, triglyceride level, 6-minute walk test result, self-assessment well-being score, and Patient Health Questionnaire-9 score that were not observed between groups. Neither the CHIP nor Healthy Heart was effective in inducing plaque regression in patients with established CAD after a 9-month period. However, both were effective in improving several CAD risk factors, which shows that the nonsequential offering of healthy lifestyle programs can lead to similar outcomes as a formal, sequential, established program (CHIP) in many aspects. These results have important implications as to how lifestyle changes will be implemented as tertiary prevention measures in the future.

Oral Atorvastatin Induces Plaque Regression By Inhibiting Macrophage Proliferation

Background and Aims: Statins induce plaque regression, but the underlying mechanisms remain speculative. We hypothesize that atorvastatin treatment, by lowering systemic cholesterol levels in vivo, inhibits local macrophage proliferation in the plaque, leading to its regression.

Abstract 583: Targeting of Macrophage Netrin-1 Expression Promotes Plaque Regression and Resolution of Chronic Inflammation in Atherosclerosis

Chronic inflammation in atherosclerosis is driven by the accumulation of cholesterol-laden macrophages in the arterial wall. These pro-inflammatory macrophages persist in this site, and sustain local and systemic inflammation. Recently, we reported that the neuronal guidance protein netrin-1 plays a pivotal role in the retention of macrophages in plaques and the progression of atherosclerosis. To test whether targeting netrin-1 in established atherosclerotic plaques could promote the resolution of chronic inflammation in atherosclerosis and/or induce plaque regression, we developed mice in which macrophage netrin-1 expression could be inducibly deleted by tamoxifen administration (Ntn1 fl/fl CX3CR1 CreER2+ mice). We first induced atherosclerosis in Ntn1 fl/fl CX3CR1 CreER2+ and control Ntn1 fl/fl CX3CR1 CreER2- using a recombinant AAV-vector overexpressing PSCK9 and Western diet feeding. After 20 weeks, 10 mice from each group were sacrificed for baseline plaque measurements, while the remaining mice were switched to chow diet to stop further progression of atherosclerosis and treated with tamoxifen (n=14/group). After 4 weeks, mice were sacrificed to assess the effects of macrophage-specific netrin-1 deletion on plaque size and composition. Analysis of peritoneal macrophages confirmed robust deletion of netrin-1 in tamoxifen treated Ntn1 fl/fl CX3CR1 CreER2+ but not control Ntn1 fl/fl CX3CR1 CreER2- mice. Macrophage-specific deletion of netrin-1 caused a 30% reduction in plaque burden in the aortic arch as measured by en face analysis, compared to control mice. While we observed no change in aortic macrophage content, macrophage-specific netrin-1 deletion was associated with a shift in effector T cell populations in the aorta: we observed a decrease in Th1 cells and an enrichment of Th2 and Treg cells in aortic plaques of Ntn1 fl/fl CX3CR1 CreER2+ compared to control Ntn1 fl/fl CX3CR1 CreER2- . Furthermore, deletion of macrophage netrin-1 expression was associated with a reduction of systemic IL-1β levels. Collectively, these data suggest that targeting macrophage expression of netrin-1 in established atherosclerosis fosters a local pro-resolving and atheroprotective T cell phenotype in plaques and reduces systemic inflammation.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients

Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV). Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. clinicaltrials.gov Identifier: NCT01813422.

The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice

IntroductionWe investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition. MethodsForty-eight apolipoprotein E-deficient (ApoE-/-) mice were kept on a 16-week high-fat diet. Mice were then placed on a normal diet and were randomized to the following groups with n=12 mice for 6 more weeks: 1) Control (Co) - no intervention; 2) Exercise (Ex) - exercise training on treadmill; 3) Rimonabant (Ri) - oral administration of rimonabant (10 mg/kg/day); or 4) Rimonabant+Exercise (RiEx) - combination of Ri and Ex groups treatment. At the end, all animals were sacrificed, and blood samples, as well as aortic root specimens, were obtained for histomorphometric analysis and quantification of the serum and plaque content of matrix metalloproteinases (MMPs). ResultsThe mean plaque area was significantly smaller (RiEx: 43.18±1.72%, Ri: 44.66±3.1%, Ex: 49±4.10%, Co: 70.43±2.83%) in all active treatment groups relative to the Co group (p<0.01). Conversely, the relative concentrations of collagen and elastin were increased significantly across all treatment groups compared to Co (p<0.05). Immunohistochemical analysis revealed significantly reduced macrophage content within plaques after all interventions, with the most pronounced effect observed after combined treatment (RiEx: 9.4±3.92%, Ri: 15±2.45%, Ex: 19.78±2.79%, Co: 34.25±4.99%; p<0.05). Within plaques, the TIMP-1 concentration was significantly upregulated in exercise-treated groups. MMP-3 and MMP-9 concentrations were equivalently decreased in all three active treatment groups compared to controls (p<0.001). DiscussionBoth exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.

Acute ApoA-I Milano administration induces plaque regression and stabilisation in the long term

Acute ApoA-I Milano administration induces plaque regression and stabilisation in the long term -

Virtual Histology Findings and Effects of Varying Doses of Atorvastatin on Coronary Plaque Volume and Composition in Statin-Naive Patients

While statin induces plaque regression, its effects, particularly with different doses on plaque virtual histology composition, remain unknown. In this prospective, randomized, double-blinded study, 40 consecutive statin-naive patients with stable angina requiring percutaneous coronary intervention (PCI) were randomized to 2 arms (20 patients each) receiving 6 months of atorvastatin 10 mg or 40 mg daily. The primary end-point was (VH-IVUS) changes from baseline to 6 months, as assessed by a core laboratory. Fifty-four VH-IVUS lesions were analyzed from the 10 mg group and 57 from the 40 mg group. Overall, plaque volume was reduced by 4.28% (-5.10±14.93 mm(3), P<0.001), absolute VH-IVUS fibrous volume by 10.54% (-4.87±10.74 mm(3), P<0.001), and relative percentage fibrous component by 3.29±7.84% (P<0.001), while relative percentage dense calcium increased by 1.50±3.08% (P<0.001), and necrotic core by 3.19±7.82% (P<0.001). Beneficial changes were more substantial in the higher dose (40 mg) group, with significantly more percentage plaque volume regression (-1.50±3.85% vs. 0.38±4.05% increase in the 10 mg group, P=0.014), less relative percentage necrotic core expansion (1.68±7.57% vs. 4.78±7.82% in the 10 mg group, P=0.037), and without occurrence of major adverse cardiac events (vs. 6 patients in the 10 mg group, P=0.020). In statin-naive patients requiring PCI, 6 months of atorvastatin induced a significant percentage of plaque volume reduction and substantial modification of VH-IVUS composition. In addition, these effects appeared to vary with different doses of atorvastatin, showing significantly better limitation of relative percentage necrotic core expansion at a higher dose.