Reduction In Plaque Volume Research Articles

Targeting Interleukin-6 Signaling with Tocilizumab in Atherosclerosis: A Meta-Analysis of Anti-Inflammatory Effects and Plaque Stabilization

Atherosclerosis, a chronic inflammatory disease, is the leading cause of cardiovascular disease. Interleukin-6 (IL-6) plays a crucial role in atherogenesis, making it a potential therapeutic target. Tocilizumab, an IL-6 receptor antagonist, has shown promise in reducing inflammation and stabilizing atherosclerotic plaques. This meta-analysis aimed to evaluate the efficacy and safety of tocilizumab in atherosclerosis by analyzing its impact on inflammatory markers and plaque characteristics. A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted from January 2013 to January 2024. Studies evaluating the effects of tocilizumab on inflammatory markers and plaque characteristics in patients with atherosclerosis were included. Randomized controlled trials (RCTs) and observational studies with a comparative arm were eligible. Data were extracted and pooled using a random-effects model. Nine studies (n=1248 participants) met the inclusion criteria. Tocilizumab significantly reduced CRP levels (standardized mean difference [SMD] -1.23; 95% confidence interval [CI] -1.56 to -0.90; p<0.001) and IL-6 levels (SMD -0.87; 95% CI -1.12 to -0.62; p<0.001) compared to control groups. A significant reduction in plaque volume (SMD -0.45; 95% CI -0.71 to -0.19; p=0.001) and an increase in fibrous cap thickness (SMD 0.38; 95% CI 0.12 to 0.64; p=0.004) were also observed. No significant increase in adverse events was reported in the tocilizumab group. This meta-analysis demonstrates that tocilizumab effectively reduces inflammation and promotes plaque stabilization in atherosclerosis. These findings suggest that tocilizumab may be a promising therapeutic strategy for preventing cardiovascular events in patients with atherosclerosis. Further large-scale RCTs are needed to confirm these findings and establish the long-term safety and efficacy of tocilizumab in this population.

Role of imaging techniques in the assessment of vulnerable plaques and the effectiveness of lipid-lowering therapy

The aim was to evaluate the potential of various imaging methods in the diagnosis of vulnerable coronary plaques and their stabilization using various lipid-lowering therapy regimens.The sources were searched in the PubMed database using the following keywords: "vulnerable (unstable) plaque" AND "PCSK9 inhibitors" AND "intravascular ultrasound" OR "optical coherence tomography" OR "computed tomography angiography". As a result, 8 original clinical trials were selected that corresponded to the review purpose. We assessed the results of following studies on plaque imaging and their regression with various lipid-lowering therapy regimens: GLAGVO, ODYSSEY J, PACMAN-AMI, HUYGENS, ALTAIR, ARCHITECT, etc. The results of most studies have established the advantages of a combined regimen of lipid-lowering therapy (statin+PCSK9 inhibitor) in reducing the rate of cardiovascular events in com­parison with statin monotherapy. The reduction in plaque volume ranged from 0,95% to 2,13% in patients receiving a combination of lipid-lowering drugs, while in monotherapy, it increased from 0,05% to 0,92% (GLAGOV, PACMAN-AMI). The changes of minimum fibrous cap thickness varied from 18,0-62,67 µm with combined therapy and 13,2-33,19 µm with monotherapy (PACMAN-AMI, Gao F). Lipid arc regression was 57,5о in combination therapy (statin+PCSK9 inhibitor) and 31,4о in statin monotherapy (HUYGENS). Imaging diagnostic methods makes it possible to identify vulnerable plaques, which helps in consideration of combination lipid-lowering therapy. In addition, plaque visualization makes it possible to evaluate the treatment effectiveness.

Randomized Comparison of Progression of Atherosclerotic Plaques and Calcification of Coronary Artery in Atrial Fibrillation Patients Treated With Edoxaban Versus Warfarin (The REPRESENT-AF trial)

Although the adverse effects of long-term use of vitamin K oral anticoagulant (OAC), warfarin, on the coronary vasculature are well-established, it remains unknown whether nonvitamin K oral anticoagulants play a role in the attenuation of plaque progression and coronary calcification. This study aimed to compare the changes in atherosclerotic plaques and calcification of the coronary arteries in patients with atrial fibrillation (AF) treated with edoxaban and warfarin. A total of 150 OAC-naïve patients with AF and atherosclerotic lesions on coronary computed tomography angiography (CCTA) were enrolled and randomly assigned to the edoxaban or warfarin treatment groups. All enrolled patients received rosuvastatin 10 mg and 119 patients completed the entire study protocol. A total of 12 months after the assigned OAC treatment, follow-up CCTA was performed and changes in plaque and calcium volumes of the coronary arteries were analyzed. The baseline characteristics of the 2 groups were well-balanced. The percentage of time in therapeutic range in the warfarin group was 61.1%. Compared with the baseline CCTA, there was a significant reduction in plaque volume after 12 months of OAC and rosuvastatin administration in both groups, and the extent of regression did not differ significantly between the groups. The increase in calcium volume was greater in the warfarin group than in the edoxaban group; however, the difference was not significant. In OAC-naïve patients with AF and atherosclerotic coronary lesions who were treated with moderate-intensity statin, edoxaban use did not have a positive effect on atherosclerotic plaques and coronary calcification compared with warfarin use over a 12-month follow-up period.

Cell therapy for male sexual dysfunctions: systematic review and position statements from the European Society for Sexual Medicine.

Cell therapy (CT) is a form of regenerative medicine under investigation for the management of male sexual dysfunction (MSD). We sought to perform a systematic review of published information on CT for MSD and provide an official position statements for the European Society for Sexual Medicine. A comprehensive bibliographic search on the MEDLINE, Web of Science, Scopus, and Cochrane Library databases was conducted in February 2023. Articles were selected based on the Population, Intervention, Comparator, Outcome, Study design (PICOS) model if they included male patients (P) undergoing CT (I) with or without comparison with other treatments (C) and evaluated the impact of CT on sexual function (O). Quantitative data were reported as found in the original studies (S). Level of evidence and grade of recommendation according to the Oxford Centre for Evidence-Based Medicine were assigned to each statement. Outcomes were determined based on assessment of erectile function, ejaculatory function, orgasmic function, sexual desire, and penile curvature. A total of 19 studies and 421 patients were included. Most articles (n = 12, 63%) were case series, whereas a minority of papers (n = 6, 32%) had a comparative group; only 2 articles reported randomized controlled trials (RCTs) and 1 article reported a post hoc analysis of RCTs. Most articles (16, 84%) investigated patients with erectile dysfunction (ED). Improvements in the International Index of Erectile Function-Erectile Function Domain (IIEF-EF) or the IIEF 5-item version (IIEF-5) were found in 11/15 (73%) studies, with mean increases in IIEF-EF, mean IIEF-5, and median IIEF-EF between 8 and 14 points, 2 and 9 points, and 4.5 and 6 points, respectively. Two papers (20%) evaluated men with Peyronie's disease (PD). In both ot these articles penile curvature improvement and plaque volume reduction were described in all patients (n = 16, 100%). Objective measurements were performed in 1 study, which showed 10°-120° (15%-100%) curvature improvement and 90%-100% plaque reduction. Mild transient adverse events at the donor or administration sites were found in 7/16 (44%) papers on ED. Priapism was reported in one case (20%) and mild penile skin complications were reported in the majority of patients after CT for PD. No severe adverse events were described. Although high-quality evidence is lacking, CT appears to have potential benefits from application in patients with ED or PD. This report is to our knowledge the most comprehensive and up-to-date systematic review on the topic of CT for the management of MSD, including the position statements of the European Society for Sexual Medicine. Overall the assessment of available studies demonstrated low quality and significant heterogeneity. Preliminary findings support potential efficacy and safety of CT in patients with ED or PD. Low-quality papers, high methodological heterogeneity, uncertainty about the magnitude of the beneficial effects, and lack of long-term data limit the available evidence.

Preliminary results on temporal evolution and clinical implications of atherosclerotic plaque in branch atheromatous disease after statin treatment.

Branch atheromatous disease (BAD) is a primary cause of early neurological deterioration (END) in penetrating artery occlusion, leading to poor functional outcomes. While it has been proposed to classify BAD under large artery atherosclerosis, uncertainty exists regarding the optimal treatment strategy, including cholesterol-lowering targets. We aimed to assess the clinical implications and temporal changes of atherosclerotic plaques before and after high-intensity statin treatment. This is a high-resolution vessel-wall imaging sub-analysis of the trial of Statin and Dual Antiplatelet Therapy in Preventing Early Neurological Deterioration in Branch Atheromatous Disease (SATBRAD). In this prospective, single-group cohort study, participants in the treatment arm of the SATBRAD trial received early dual antiplatelet therapy and high-intensity statin treatment. The majority of these participants subsequently underwent high-resolution vessel-wall magnetic resonance imaging (MRI). Those with atheromatous plaques in the parent artery continued high-intensity statin treatment for 6 months, followed by a repeat MRI to monitor plaque changes. There were 57 patients who underwent vessel-wall imaging and 24 exhibited contrast-enhanced plaques. Patients with contrast-enhanced plaques showed higher rates of END (29.2% vs 6.1%, p = 0.027), perfusion defects (62.5% vs 24.2%, p = 0.004), and lower rates of good outcomes at 3 months (50.0% vs 81.8%, p = 0.011). After adjusting for confounding factors, contrast-enhanced plaque had a negative impact on achieving a good outcome at 3 months (adjusted odds ratio = 0.04; 95% confidence interval = <0.01-0.60). Following high-intensity statin treatment in 36 patients, there was a notable reduction in stenosis (33.7% vs 29.3%, p = 0.005) and contrast-enhanced plaque volume (16.3 vs 11.6 mm3, p = 0.015). The study highlighted the association between contrast-enhanced atherosclerotic plaques, END, and poor functional outcomes, with high-intensity treatment leading to plaque volume reduction. These results underscore the shared pathology between BAD and intracranial atherosclerosis, emphasizing the necessity for further research and tailored treatment strategies for BAD. ClinicalTrials.gov; Identifier: NCT04824911 (https://clinicaltrials.gov/study/NCT04824911).

GLP-2 predicts cardiovascular outcomes in patients with myocardial infarction and increases atherosclerosis in mice

Abstract Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones that are co-secreted from intestinal L-cells in response to food intake and inflammatory stimuli. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 enhances intestinal nutrient absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to investigate the role of GLP-2 for cardiovascular disease (CVD). Methods Total GLP-2 levels were assessed at time of admission in 918 patients with myocardial infarction presenting with acute chest pain, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. To induce atherosclerosis, Glp2r−/− or WT mice were injected with PCSK9 virus and fed a diet high in cholesterol (HCD) for 12 weeks. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 pM) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (3-P-MACE and all-cause mortality; logarithmized GLP-2 values HR: 2.87; p&amp;lt;.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterinemia, previous CVD and diabetes mellitus did not affect this association (logarithmized GLP-2 values HR: 2.66; p=0.0055). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for early events (area under the curve of the combined endpoint at 7 days: 0.74; 14 days: 0.76; 30 days: 0.76; 6 months: 0.72), which proved to be superior to Troponin T and hs-CRP. To asses the functional role of GLP-2 in CVD in an experimental approach we injected Glp2r−/− or WT mice PCSK9 virus (to induce functional Ldlr-deficiency and hypercholesterolemia) and fed these mice a HCD. After 12 weeks Glp2r−/− mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and circulating leukocyte numbers (FACS analysis) were unaffected, Glp2r−/− mice had lower cholesterol levels. Conclusion Circulating GLP-2 levels are associated with cardiovascular events in patients with acute myocardial infarction while inactivation of the GLP-2 system reduces atherosclerosis in mice. Future studies are needed to investigate whether the GLP-2 receptor might provide a novel therapeutic target for cardiovascular disease.

Frequency, predictors and clinical outcomes of AMI patients with triple regression of coronary atherosclerosis: A sub-analysis of the PACMAN AMI trial

Abstract Background Recent studies have shown that coronary artery disease regression is not limited to atheroma reduction but also includes plaque stabilization in patients treated with high-intensity lipid-lowering therapy. The frequency and characteristics of patients who simultaneously show atheroma volume reduction and plaque stabilization defined as reduction in plaque lipid content and increase in fibrous cap thickness (i.e., triple regression) are unknown. Purpose This study sought to determine the percentage and determinants of both plaque volume reduction and plaque stabilization in patients with acute myocardial infarction (MI) and treated wiTh alirocumab or placebo added to high-intensity statin therapy. Methods The PACMAN-AMI trial employed serial intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography to compare the effects of alirocumab vs. placebo (1:1) in 265 patients (537 non–infarct-related coronary arteries) receiving high-intensity statin therapy. Triple regression was defined by the combined presence of reduction in percent atheroma volume (PAV), reduction in maximum lipid core burden index (maxLCBI4mm) and increase in minimal fibrous cap thickness (FCT). Clinical outcomes of patients with or without triple regression were assessed at one year follow-up. Results Overall, 199 (75.1%) patients showed PAV reduction, 180 (67.7%) maxLCBI4mm reduction and 172 (77.6%) minimal FCT increase, with a total of 84 (31.7%) patients having triple regression (40.8% in the alirocumab group vs. 23.0% in the placebo group, p=0.002). The percentage of patients with triple regression was similar among the groups with PAV reduction, maxLCBI4mm reduction or minimal FCT thickening (42%, 51% or 49%, respectively, p=0.30). Similar baseline clinical features and a higher reduction in low-density lipoprotein cholesterol (LDL-C, -27.1 [37.7 to -16.6] mg/dl, p&amp;lt;0.001) and apolipoprotein B levels (-18.5 [-26.0 to -11.0] p&amp;lt;0.001) were observed patienst with vs. without triple regression. A higher reduction in PAV (-1.54 [-2.14 to -0.95] %, p&amp;lt;0.001), maxLCBI4mm (-111.24 [-140.46 to -82.02], p&amp;lt;0.001) and a higher increase in minimal FCT (56.39 [38.67 to 74.11] µm, p&amp;lt;0.001) were found in patients with triple regression. At multivariable analysis, factors independently associated with triple regression included higher baseline maxLCBI4mm (1.03, 1.01 to 1.06, p=0.013) and alirocumab treatment (2.83, 1.57 to 5.16, p=0.001). The composite clinical endpoint of death, MI and ischemia-driven revascularization occurred less frequently in patients with versus without triple regression (8.3% vs 18.2%, p=0.042). Conclusions Triple regression occurred among one third of acute AMI patients receiving high-intensity lipid lowering therapy. Alirocumab treatment and higher baseline lipid accumulation were independent predictors of triple regression. Triple regression was associated with a reduced rate of adverse cardiovascular events.

Abstract 686: Glp-2 Predicts Cardiovascular Outcomes In Patients With Myocardial Infarction And Increases Atherosclerosis In Mice

Background: GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones that are co-secreted from intestinal L-cells in response to food. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 is a local intestinal growth factor enhancing intestinal nutrient absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to investigate the role of GLP-2 for cardiovascular disease (CVD). Methods: Circulating GLP-2 levels were assessed at time of hospital admission in 1929 patients with myocardial infarction. The primary outcome of the study was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE). To induce atherosclerosis, Glp2r –/– or WT mice were injected with PCSK9 virus and fed a HCD for 12 weeks. Results: Kaplan-Meier survival plots and univariable cox regression analyses found GLP-2 to be associated with adverse outcome (3-P-MACE and all-cause mortality; log. GLP-2 values HR: 2.87; p&lt;.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterinemia, previous CVD and diabetes mellitus did not affect this association (log. GLP-2 values HR: 2.66; p=0.0055). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for early events, which proved to be superior to Troponin T and hs-CRP. To asses the functional role of GLP-2 in CVD in an experimental approach we injected Glp2r –/– or WT mice PCSK9 virus and fed these mice a HCD. After 12 weeks Glp2r –/– mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and leukocyte numbers in various organs were unaffected, Glp2r –/– mice had significantly lower cholesterol levels. Conclusion: Circulating GLP-2 levels are independently associated with cardiovascular events in patients with myocardial infarction while inactivation of the GLP-2 system reduces atherosclerosis in mice. Future studies are needed to investigate whether the GLP-2 receptor might provide a novel therapeutic target for cardiovascular disease.

Directional versus orbital atherectomy of femoropopliteal artery lesions: Angiographic and intravascular ultrasound outcomes.

The aim of this study was to compare the ability of two different atherectomy modalities, the directional atherectomy system (DAS) and the orbital atherectomy system (OAS), to modify plaque and augment luminal gain as evaluated by angiography and intravascular ultrasound (IVUS) in patients with symptomatic femoro-popliteal peripheral arterial disease (PAD). Atherectomy is frequently utilized in the treatment of complex PAD. To date, there are no head-to-head comparisons of existing devices and their selection is based mostly on operator preference rather than on supportive data. This was a single-center, prospective, randomized trial designed to assess the impact of DAS in comparison to OAS on atherosclerotic plaque. Pre- and postatherectomy lesion characterization was performed by angiography and IVUS. Drug-coated balloon (DCB) angioplasty was performed after atherectomy with similar analysis repeated. Sixty patients were randomized to undergo either DAS or OAS. Pretreatment angiographic and IVUS characteristics were similar in the DAS and OAS groups. DAS led to a greater reduction in plaque volume throughout the entire lesion (5.9% vs. 1.1%, p = 0.003). This corresponded to a greater increase in total vessel and lumen volume by IVUS (161.5 mm3 vs. 50.2 mm3 , p = 0.001; 178.6 mm3 vs. 47.0 mm3 , p = 0.004, respectively), as well as a reduction in angiographic stenosis (40% vs. 70%, p < 0.001). After DCB, 10 patients required stenting for suboptimal results in the OAS group compared with twoin the DAS group (p = 0.021). Compared to OAS, DAS demonstrated a greater plaque volume reduction and luminal gain with significantly fewer stents needed post-DCB.

The Relationship Between Coronary Calcification and the Natural History of Coronary Artery Disease

The aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease. Coronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy. This analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume)× 100 at a per-plaque and per-patient level (summation of all individual plaques). CPV was strongly correlated with plaque volume (r=0.780; p<0.001) at baseline and with plaque progression (r=0.297; p<0.001); however, this association was reversed after accounting for plaque volume at baseline (r=-0.146; p<0.001). In contrast, PCPV was an independent predictor of a reduction in plaque volume (r=-0.11; p<0.001) in univariable and multivariable linear regression analyses. Patient-level analysis showed that high CPV was associated with incident major adverse cardiac events (hazard ratio: 3.01: 95% confidence interval: 1.58 to 5.72), whereas high PCPV was inversely associated with major adverse cardiac events (hazard ratio: 0.529; 95% confidence interval: 0.229 to 0.968) in multivariable analysis. Calcified plaque is a marker for risk of adverse events and disease progression due to its strong association with the total plaque burden. When considered as a percentage of the total plaque volume, increasing PCPV is a marker of plaque stability and reduced risk at both a lesion and patient level. (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411).

Plaque volume reduction after drug-coated balloon angioplasty for superficial femoral artery lesion.

Paclitaxel has a potentially beneficial effect on atherosclerotic plaque volume reduction; however, data about plaque volume reduction in real-world practice are scarce. We herein report a case whose plaque volume of superficial femoral artery was analyzed using high-definition intravascular ultrasound just after endovascular treatment using drug-coated balloon and at 6months after the procedure. From analysis using a quantitative intravascular ultrasound analysis system, the lumen volume was enlarged (from 2909.2 to 4944.1mm3) as a result of not only vessel volume enlargement (from 7242.0 to 8296.3mm3) but also plaque volume reduction (from 4332.8 to 3352.2mm3).

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, Reality or Dream in Managing Patients with Cardiovascular Disease

Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond 'normal' or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.

Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome.

The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial. We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53; between-group difference, 16.9%, P<0.0001). The percent change in PV was -5.1% in the combination therapy group and -6.2% in the statin alone group (P=0.66), although both groups had reduction of PV compared with baseline (both P<0.01). The percent change in lipid PV did not differ between the groups (4.3 vs. -3.0%, P=0.37). In statin-naïve patients with ACS, combined therapy with ezetimibe and statin did not result in a significant change in coronary plaque regression or tissue component compared with statin alone. [Clinical Trial Registration: www.clinicaltrials.gov (NCT00549926)].

Cardiovascular Immunotherapy and the Role of Imaging.

Despite significant advances in prevention and treatment, cardiovascular diseases (CVDs) remain the most common cause of death in the United States.1–3 In part, and compared with treatment developments in oncology, this is because of the lack of current generation CVD precision therapies.4–6 Most CVDs are caused by atherosclerosis, a disease process that causes thickening of the arterial wall because of inflammation and lipid accumulation, resulting in plaque formation.7,8 Macrophage dynamics plays a central role in atherosclerosis progression, vessel wall destabilization, and—as has been recently discovered—plaque aggravation because of myocardial infarction.9–11 Therefore, and despite current standardized treatments, ≈25% of patients who had myocardial infarction or stroke will experience secondary major adverse cardiovascular events, often more harmful than the primary event.12–14 To break this vicious cycle, innovative and tailored therapeutic strategies are needed. Various targeted immunotherapies that showed anticancer potential in in vitro screens also displayed in vivo potential in mouse models. Such proof-of-concept studies in validated syngeneic mouse tumor models not only provide information on in vivo efficacy but also disclose the targeted immunotherapies’ underlying mechanism of action and safety profile. However, immunotherapies’ high costs and the identification of amendable patients compromise clinical translation.15,16 Continued and focused efforts are needed to understand patient responsiveness and reduce high dropout rates in trials. A parallel effort focused on the development of novel imaging tools that can guide patient selection may offer a potential solution. Positron emission tomography (PET) can be used to trace immunotherapies. So-called immunoPET uses antibodies, developed for cancer treatment, that selectively recognize a specific epitope on target cells. The antibodies are labeled with radioactive isotopes, such as zirconium-89 or iodine-124, with relatively long decay half-lives of 3.27 and 4.18 days, respectively, to …

Effect of Ezetimibe on Stabilization and Regression of Intracoronary Plaque - The ZIPANGU Study.

Diminishing yellow color is associated with plaque stabilization. We assessed the hypothesis that a combination of ezetimibe and statin provides more effective plaque stabilization and regression than statin alone as assessed by plaque color. Stable coronary artery disease patients (n=131) who underwent elective percutaneous coronary intervention and had yellow plaques were randomized to combination therapy (atorvastatin 10-20 mg and ezetimibe 10 mg/day; Group C) or statin monotherapy (atorvastatin 10-20 mg; Group M). Changes in plaque color and plaque volume during 9 months were assessed by angioscopy and intravascular ultrasound. Low-density lipoprotein cholesterol (LDL-C) decreased from 103±28 to 63±18 mg/dL in Group C (P<0.001) and from 100±28 to 75±17 mg/dL in Group M (P<0.001). Yellow color grade decreased significantly in both Group M (2.1±1.1 vs. 1.7±1.0, P=0.005) and Group C (2.2±1.2 vs. 1.8±1.2, P=0.002), but did not differ between the groups. %plaque volume did not change in Group M (48.5±10.2% vs. 48.2±10.4%, P=0.4), but decreased significantly in Group C (50.0±9.8% vs. 49.3±9.8%, P=0.03). Compared with statin monotherapy, combination therapy with ezetimibe further reduced LDL-C levels. Significant plaque volume reduction was achieved by the combination therapy, but not statin monotherapy; however, plaque stabilization was similarly achieved by both therapies. Furthermore, reduction in plaque volume was dependent on reduction in LDL-C, regardless of whether it was achieved by statin alone or statin plus ezetimibe.

Pathologic Intimal Thickening Plaque Phenotype: Not as Innocent as Previously Thought. A Serial 3D Intravascular Ultrasound Virtual Histology Study

Pathologic intimal thickening (PIT) has been considered a benign plaque phenotype. We report plaque phenotypic changes in a baseline/follow-up intravascular ultrasound-based virtual histology study. A total of 61 patients with stable coronary artery disease were analyzed from the HEAVEN trial (89 patients randomized between routine statin therapy vs atorvastatin 80mg and ezetimibe 10mg) with serial intravascular ultrasound imaging of nonculprit vessels. We compared changes in 693 baseline and follow-up 5-mm long segments in a novel risk score, Liverpool Active Plaque Score (LAPS), plaque parameters, and plaque composition. The PIT showed the highest increase of risk score and, with fibrous plaque, also the LAPS. Necrotic core (NC) abutting to the lumen increased in PIT (22 ± 51.7; P = .0001) and in fibrous plaque (17.9 ± 42.6; P = .004) but decreased in thin cap fibroatheroma (TCFA) (⿿15.14 ± 52.2; P = .001). The PIT was the most likely of all nonthin cap fibroatheroma plaque types to transform into TCFA at follow-up (11% of all TCFA found during follow-up and 35.9% of newly-developed TCFA), but showed (together with fibrous plaque) the lowest stability during lipid-lowering therapy (24.7% of PIT remained PIT and 24.5% of fibrous plaque remained fibrous plaque). Over the 1-year follow-up, PIT was the most dynamic of the plaque phenotypes and was associated with an increase of risk score and LAPS (together with fibrous plaque), NC percentage (together with fibrous plaque) and NC abutting to the lumen, despite a small reduction of plaque volume during lipid-lowering therapy. The PIT was the main source for new TCFA segments.

Fenotipo del engrosamiento intimal patológico: no tan inocente como se pensaba. Estudio de la histología virtual de una serie de casos con ecografía intravascular 3D

Resumen Introduccion y objetivos Se ha considerado que el engrosamiento intimal patologico (EIP) es un fenotipo de placa benigno. Se presentan los cambios fenotipicos de la placa en un estudio comparativo entre situacion basal y seguimiento mediante un estudio de reconstruccion histologica virtual por ecografia intravascular. Metodos Se estudio a 61 pacientes con enfermedad coronaria estable del ensayo HEAVEN (89 pacientes aleatorizados al tratamiento estandar con estatinas o atorvastatina 80 mg y ezetimiba 10 mg) por ecografia intravascular seriada de las arterias no culpables. Se compararon los cambios examinando al inicio del estudio y durante el seguimiento 693 segmentos de 5 mm de longitud mediante una nueva puntuacion de riesgo, la Liverpool Active Plaque Score (LAPS), los parametros de la placa y la composicion de esta. Resultados El EIP es el tipo que mostro mayor aumento de la puntuacion de riesgo y, junto con las placas fibrosas, tambien de la LAPS. El core necrotico (CN) proximo a la luz aumento tanto en las placas con EIP (22 ± 51,7; p = 0,0001) como en las placas fibrosas (17,9 ± 42,6; p = 0,004), pero disminuyo en el fibroateroma de capa fina (FCF) (–15,14 ± 52,2; p = 0,001). El EIP es el tipo de placa de fibroateroma de capa no fina con mayor probabilidad de transformacion a FCF durante el seguimiento (el 11% del total de FCF hallados durante el seguimiento y el 35,9% de los FCF de nueva aparicion), pero tambien el que mostro (junto con las placas fibrosas) menor estabilidad durante el tratamiento hipolipemiante (el 24,7% de los EIP y el 24,5% de las placas fibrosas se mantuvieron estables). Conclusiones En 1 ano de seguimiento, el EIP fue el fenotipo de placa mas dinamico y se asocio a un aumento de la puntuacion de riesgo y de la LAPS (junto con la placa fibrosa), el porcentaje de CN (junto con la placa fibrosa) y el CN proximo a la luz, a pesar de una pequena reduccion del volumen de la placa durante el tratamiento hipolipemiante. El EIP fue el principal origen de los nuevos segmentos con FCF.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

OBJECTIVE:The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis.METHODS:This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed.RESULTS:The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group.CONCLUSION:Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Combined Lipid Lowering by Ezetimibe and Statin and Coronary Plaque Regression: A Meta- Analysis of Randomized Controlled Trials

Background: It is not clear whether the addition of ezetimibe to statin will result in greater reduction in coronary plaque. We aimed to perform a meta-analysis of all RCTs and prospective studies that evaluated role of dual lipid lowering strategy in atherosclerosis regression. Methods: We searched PubMed, EMBASE, Cochrane CENTRAL, Scopus and relevant references for RCTs (inception through December 20, 2015 without language restrictions) and performed meta-analysis using random effects model. Percentage change in plaque volume, change in lumen volume, percentage change in LDL, HDL and hsCRP were measured outcomes. Results: 3 RCTs and 1 prospective non randomized trial with a total population of 554 comprising mostly of Asian population were analyzed. Statin plus ezetimibe showed significantly greater lowering of plaque volume than statin alone (WMD -4.13 mm3 range of -7.42 mm3 to 0.85 mm3; p=0.01); there was a trend towards increased lumen volume in combination group without statistical significance [WMD 1.90 mm3 (-4.61 to 8.40); p=0.57).Combination strategy resulted in significantly higher percentage lowering of LDL at the end of follow up [WMD: -16.16(-22.47 to -9.85) p ≤ 0.00001]. No differences in percentage change in HDL and hsCRP were observed between two groups. Conclusion: Combination lipid lowering by statin plus ezetimibe causes significantly greater reduction in plaque volume and lowering of LDL cholesterol. Further larger studies are needed to validate the findings in all population groups.

Impact of Total Risk Management on Coronary Plaque Regression in Diabetic Patients with Acute Coronary Syndrome.

Diabetic patients with coronary artery disease have a high incidence of cardiovascular events, which was associated with increased coronary plaque volume. Low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) play pivotal roles in the progression of coronary plaque. Several trials have shown that intervention for a single risk factor reduced the development of coronary plaque progression. However, it remained uncertain whether total risk management for LDL-C, BP, and glycosylated Hb (HbA1c) has a beneficial effect on coronary plaque volume in diabetic patients. This study was a sub-study of the JAPAN-ACS that was a prospective, randomized, open-label trial that evaluated the impact of intensive lipid-lowering therapy on coronary plaque volume in patients with acute coronary syndrome (ACS). Among a total of 252 patients, 73 diabetic patients were analyzed. We examined the impact of total risk management (LDL-C ＜80 mg/dL, systolic BP ＜130 mmHg, and HbA1c ＜6.5%) on changes in coronary plaque volume. The patients were divided into four groups according to the number of risk factors that achieved the target value. Baseline characteristics were similar among the groups. The degree of coronary plaque regression was greater in patients who achieved total risk management. The number of risk factors that achieved the target level was associated with the extent of the coronary plaque volume reduction in a dose-dependent manner. Total risk management that focused on LDL-C, BP, and HbA1c had a beneficial impact on the coronary plaque regression in diabetic patients with ACS.