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Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients' blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings. [ABSTRACT FROM AUTHOR]

Atherosclerotic plaque development constitutes the primary substrate of coronary artery disease (CAD) and is the outcome of an intricate process involving endothelial damage, inflammation, and lipid retention. The clinical efficacy of many lipid-lowering therapies in patients with CAD has been well established. Over the past few decades, a substantial and significant advance regarding the use of invasive and non-invasive imaging modalities has been observed. Numerous studies have been conducted using these imaging techniques and have investigated the changes in morphology (e.g., atheroma volume) and composition (e.g., lipid burden, fibrous cap thickness, macrophage accumulation) at the plaque level that explain the improved clinical outcomes by various pharmacological interventions. Lipid-lowering agents, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, demonstrate direct effects on plaque volume and composition that enhance plaque stabilization and/or regression beyond the reduction of low-density lipoproteins. An increasing amount of clinical research is also focused on the role of inflammation in plaque vulnerability and future adverse cardiac events. Consequently, there is a pressing need to explore therapeutic strategies that are capable of disrupting the inflammatory response as well as reducing atheroma burden and modifying high-risk plaque characteristics. This review provides a comprehensive analysis of the current evidence regarding the effects of traditional and novel therapeutic strategies targeting modification of the lipid profile and inflammatory processes on reversing plaque growth and attenuating vulnerable features, thereby promoting plaque stabilization and passivation. [ABSTRACT FROM AUTHOR]

Abstract Background The current clinical management of carotid atherosclerosis is based on the control of risk factors and medicine. However, the risk of adverse events associated with the medicine resulting in concerns and low medication compliance makes it necessary to seek a safer alternative therapy. This study assessed the effectiveness and safety of acupuncture as a treatment for carotid atherosclerosis. Methods In this randomized controlled trial, patients with carotid atherosclerotic plaques were included and randomly assigned (1:1) to receive real acupuncture or sham acupuncture for 12 weeks. The follow-up period was 12 weeks. The primary outcome included carotid intima-media thickness (cIMT), plaque score (PS), plaque volume (PV) and grey-scale median (GSM). Secondary outcome was pulse wave velocity (PWV). Adverse events results were recorded as safety outcomes. Results From January 2021 to February 2022, 60 eligible patients were included. 55 patients (91.7%) completed the intervention and the 12-week follow-up and there was no statistical difference in demographics between the groups. At the end of treatment, the real acupuncture group had significantly reduced PS (P = 0.002), PV (P = 0.000), and improved GSM (P = 0.044). There was no significant difference in the reduction in cIMT (Left cIMT: P = 0.338, Right cIMT: P = 0.204) and PWV between the groups (the left BS: P = 0.429; the left ES: P = 0.701; the right BS: P = 0.211; the right ES: P = 0.083). Three mild adverse reactions occurred during the study. Conclusion This study found that acupuncture had a certain effect on reducing the thickness and volume of carotid plaque and improving the stability of plaque with minor side effects. These findings suggest that acupuncture may be a potential alternative therapy for carotid atherosclerosis. Trial registration This trial has been registered at ClinicalTrials.gov (ChiCTR2100041762). Submitted 30 December 2020, Registered 4 January 2021 Prospectively registered.

Background: The current clinical management of carotid atherosclerosis is based on the control of risk factors and medicine. However, the risk of adverse events associated with the medicine resulting in concerns and low medication compliance makes it necessary to seek a safer alternative therapy. This study assessed the effectiveness and safety of acupuncture as a treatment for carotid atherosclerosis. Methods: In this randomized controlled trial, patients with carotid atherosclerotic plaques were included and randomly assigned (1:1) to receive real acupuncture or sham acupuncture for 12 weeks. The follow-up period was 12 weeks. The primary outcome included carotid intima-media thickness (cIMT), plaque score (PS), plaque volume (PV) and grey-scale median (GSM). Secondary outcome was pulse wave velocity (PWV). Adverse events results were recorded as safety outcomes. Results: From January 2021 to February 2022, 60 eligible patients were included. 55 patients (91.7%) completed the intervention and the 12-week follow-up and there was no statistical difference in demographics between the groups. At the end of treatment, the real acupuncture group had significantly reduced PS (P = 0.002), PV (P = 0.000), and improved GSM (P = 0.044). There was no significant difference in the reduction in cIMT (Left cIMT: P = 0.338, Right cIMT: P = 0.204) and PWV between the groups (the left BS: P = 0.429; the left ES: P = 0.701; the right BS: P = 0.211; the right ES: P = 0.083). Three mild adverse reactions occurred during the study. Conclusion: This study found that acupuncture had a certain effect on reducing the thickness and volume of carotid plaque and improving the stability of plaque with minor side effects. These findings suggest that acupuncture may be a potential alternative therapy for carotid atherosclerosis. Trial registration: This trial has been registered at ClinicalTrials.gov (ChiCTR2100041762). Submitted 30 December 2020, Registered 4 January 2021 Prospectively registered. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients’ blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings.

Atherosclerotic plaque development constitutes the primary substrate of coronary artery disease (CAD) and is the outcome of an intricate process involving endothelial damage, inflammation, and lipid retention. The clinical efficacy of many lipid-lowering therapies in patients with CAD has been well established. Over the past few decades, a substantial and significant advance regarding the use of invasive and non-invasive imaging modalities has been observed. Numerous studies have been conducted using these imaging techniques and have investigated the changes in morphology (e.g., atheroma volume) and composition (e.g., lipid burden, fibrous cap thickness, macrophage accumulation) at the plaque level that explain the improved clinical outcomes by various pharmacological interventions. Lipid-lowering agents, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, demonstrate direct effects on plaque volume and composition that enhance plaque stabilization and/or regression beyond the reduction of low-density lipoproteins. An increasing amount of clinical research is also focused on the role of inflammation in plaque vulnerability and future adverse cardiac events. Consequently, there is a pressing need to explore therapeutic strategies that are capable of disrupting the inflammatory response as well as reducing atheroma burden and modifying high-risk plaque characteristics. This review provides a comprehensive analysis of the current evidence regarding the effects of traditional and novel therapeutic strategies targeting modification of the lipid profile and inflammatory processes on reversing plaque growth and attenuating vulnerable features, thereby promoting plaque stabilization and passivation.

Background: Studies reporting collective and comprehensive data on plaque regression of different lipid-lowering therapies (LLTs) are limited. Objectives: We evaluated plaque regression of LLTs based on multiple markers and performed subgroup analyses based on LLT type and post-treatment LDL-C levels Methods: A literature search was performed to identify studies assessing plaque regression from LLTs. The following LLTs groups were included: High-intensity statin (HIS), HIS+ eicosapentaenoic acid (EPA), HIS + ezetimibe, Low-intensity statin (LIS), LIS + EPA, LIS + Ezetimibe, and PCSK9 inhibitors. Our primary outcomes were change in percent atheroma volume (PAV). Secondary outcomes included mean differences in total atheroma volume (TAV), lumen, plaque, and vessel volumes, fibrous cap thickness (FCT), and lipid arc (LA). Subgroup analyses were performed on LLT type and post-treatment LDL-C levels. Meta-regression was performed to control for covariates. Results: We identified 51 studies with 9,113 adults (22 % females). LLTs reduced PAV levels (-1.10 % [-1.63, -0.56], p < 0.01), with significant reduction observed with HIS, LIS + ezetimibe, LIS + EPA, and PCSK9 inhibitors. LLTs reduced TAV levels (-5.84 mm3 [-8.64 to -3.04] p < 0.01), mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). LLTs reduced plaque volume and LA and increased FCT. Conclusion: The plaque regression associated with LLTs is observed to be mainly driven by HIS, reducing both TAV and PAV. This suggest that HIS is the most effective LLT for plaque regression Unstructured abstract: We evaluated plaque regression of LLTs from 51 studies. We found that while reduction of PAV (-1.10 % [-1.63, -0.56], p < 0.01) were present across different LLT types, reduction of TAV (-5.84 mm3 [-8.64 to -3.04] p < 0.01) was mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). These results suggest that HIS is the most effective LLT for plaque regression.

Several previous studies have demonstrated that aged garlic extract (AGE) inhibits the progression of coronary artery calcification and non-calcified plaque (NCP) in the general population. However, its effects on plaque progression in patients with diabetes have not yet been investigated, at least to the best of our knowledge. This study investigated whether AGE reduces the coronary plaque volume measured by cardiac computed tomography angiography (CCTA) in patients with diabetes mellitus (DM). A total of 80 participants with DM with a median age of 57 years were prospectively assigned to consume 2,400 mg AGE/day (after completion, 37 participants) or placebo (after completion, 29 participants) orally. Both groups underwent CCTA at baseline and follow-up 365 days apart. In total, 66 participants completed the study. Coronary plaque volume, including total plaque (TP), dense calcium (DC), fibrous, fibro-fatty and low-attenuation plaque (LAP) volumes were measured based upon pre-defined intensity cut-off values using semi-automated software (QAngio CT). Changes in various plaque types were normalized to the total coronary artery length. The non-parametric Wilcoxon rank-sum test was performed to examine the differences in plaque formation between the 2 groups. No significant differences were found in the baseline characteristics between the AGE and placebo groups. Compared with the placebo group, the AGE group exhibited a statistically significant regression in normalized LAP [median and standard deviation (SD) -0.2 (18.8) vs. 2.5 (69.3), P=0.0415]. No differences were observed in TP, fibrous, or fibrofatty plaque volumes between the AGE and placebo group. On the whole, this study indicated that the %LAP change in the AGE group was significantly greater than that in the placebo group in patients with diabetes. However, further studies are warranted to evaluate whether AGE has the ability to stabilize vulnerable plaque and decrease adverse cardiovascular events.

Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH. Case summary The present case describes a long-term (>10 years) follow-up of a 52-year-old woman with severe HoFH, who was treated with conventional lipid-lowering medications (i.e. statins and ezetimibe) for several years before experiencing the risks and benefits that were encountered with the use of LDL-receptor-independent agents (MTP and ANGPTL3 inhibitors). This combination therapy demonstrated a good long-term safety and efficacy profile, while continuous monitoring of hepatic enzymes (sometimes requiring dose adjustments) and fat accumulation is recommended when using lomitapide. Discussion Treating this HoFH patient with an LLT involving the combination of MTP and ANGPTL3 LDL-receptor-independent inhibitors (lomitapide and evinacumab, respectively) showed remarkable improvement in LDL-C levels, disappearance of xanthomatosis and regression in atherosclerotic plaques. In addition to safety and efficacy, one should question the affordability and access hurdle that emerging combination of expensive therapies might constitute in the future for the payers. These challenges could eventually limit the clinical use of those innovative treatments despite their clinical benefit. [ABSTRACT FROM AUTHOR]

Anti-atherosclerotic effects of early intervention with dipeptidyl peptidase-4 inhibitors remain poorly defined. In a prospective, single-center, randomized trial, 66 patients with acute coronary syndrome (ACS) and mild dysglycemia (HbA1c 6.0 (5.7, 6.3)%, 58% of impaired glucose tolerance) were randomly assigned to receive alogliptin (n = 33) or placebo (n = 33) in addition to standard treatments. Serial intravascular ultrasound (IVUS) was performed at baseline and 10 months to evaluate changes in coronary percent plaque volumes (%PV) and plaque tissue components of non-culprit lesions (NCLs). Baseline clinical and IVUS characteristics, as well as decreases in HbA1c and lipid variables during 10 months, did not differ significantly between the 2 groups. In contrast, with respect to vascular responses, the alogliptin group showed significantly greater decreases in plaque volumes (−0.3 ± 0.6 vs. −0.04 ± 0.7 mm3/mm, p = 0.03) and %PV (−0.9 ± 2.8 vs. 1.2 ± 3.6%, p = 0.01), with a tendency toward smaller lumen loss (−0.1 ± 0.7 vs. −0.4 ± 0.8 mm3/mm, p = 0.07) compared with the placebo group. Significantly decreased percent necrotic volumes (%NV) (−1.9 ± 3.8 vs. 0.3 ± 3.7%, p = 0.03) and increased fibrotic volumes (2.5 ± 5.0 vs. −0.3 ± 5.3%, p = 0.05) were or tended to be seen in alogliptin versus placebo groups at 10 months. In multiple regression analysis, alogliptin use was a statistically significant determinant of changes in %PV (β = −0.33, p = 0.004) and %NV (β = −0.28, p = 0.03) at 10 months. Alogliptin treatment, independently of glycemic and lipid status, resulted in significant plaque regression and stabilization in NCLs in patients with ACS and mild dysglycemia, suggesting the potential utility of early intervention with incretin-based treatments for this patients' subset. [Display omitted] • Alogliptin reduced coronary plaque volumes in acute coronary syndrome (ACS) patients with dysglycemia. • Alogliptin also decreased necrotic and lipid volumes and increased fibrous volume. • Beneficial effects of alogliptin were independent of lipid and glucose status. • Early intervention with incretin-based drug may be useful for secondary prevention. [ABSTRACT FROM AUTHOR]

Lipid-lowering therapy plays a central role in reducing cardiovascular events. Over the past few decades, clinical trials utilizing several imaging techniques have consistently shown that lipid-lowering therapy can reduce the coronary plaque burden and improve plaque composition. Although intravascular ultrasound has been the most extensively used modality to assess plaque burden, other invasive modalities, such as optical coherence tomography and near-infrared spectroscopy, provide relevant data on plaque vulnerability, and computed tomography angiography detects both plaque volume and characteristics non-invasively. A large body of evidence supports the notion that reducing low-density lipoprotein cholesterol using statins combined with ezetimibe and proprotein convertase subtillisin/kexin type 9 inhibitors consistently shows improvements in plaque burden and favorable morphological changes. This review summarizes previously obtained data on the impact of lipid-lowering treatment strategies on atherosclerotic plaque regression, as assessed using several imaging modalities.

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features—such as fibrous cap thickness and large lipid accumulation—beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk assessment and management strategies. Although significant progress has been made recently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health. [Display omitted] • Recent advancements in ASCVD management focus on identifying at-risk individuals and plaque regression strategies. • ASCVD can manifest without traditional risk factors, necessitating a paradigm shift in preventive approaches. • Targeting plaque progression rather than just traditional risk factors is crucial for preventing adverse events. • Personalised medicine, advanced imaging, and biomarker research offer new avenues for refining risk stratification. • Integrating genetic, imaging, and biomarker data, alongside AI tools, promises to optimize cardiovascular risk management. [ABSTRACT FROM AUTHOR]

Traditionally atherosclerosis was thought to be progressive and medical treatment solely focused on delaying the progression of atherosclerosis rather than treating the disease itself. Multiple recent studies, however, have demonstrated a significant decrease in cardiovascular mortality with the use of additional anti-atherosclerotic therapies beyond statins. Consistent with these observations, mechanistic studies indicate that these additional anti-atherosclerotic therapies have a positive effect on both halting and reversing the course of atherosclerosis. We examine the progression of atherosclerosis and the efficacy of various anti-atherosclerotic treatment classes in this review utilizing multimodality imaging techniques. Searches were conducted in electronic databases: PubMed and EMBASE for all peer reviewed publications that examined coronary plaque progression, regression and stabilization using different imaging modalities and antiatherosclerosis therapies. All relevant published articles on this topic were identified and their reference lists were screened for relevance. Though lipoprotein levels have traditionally been the target for antiatherosclerosis medication, several newer strategies have emerged creating novel targets in the treatment of coronary atherosclerosis. Using a combination of antiatherosclerosis therapies in conjunction with noninvasive imaging modalities like CCTA to directly visualize the plaque, is currently the focus of the future, with the aim of preventing and reversing atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims 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. Methods and results 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. −0.002 mm2; P  < 0.001) and lumen area (−0.82 vs. −0.09 vs. 0.40 mm2; 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. Conclusion 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. [ABSTRACT FROM AUTHOR]

Both plasma low-density lipoprotein (LDL) cholesterol levels and risk for premature cardiovascular disease are extremely elevated in patients with homozygous familial hypercholesterolemia (HoFH), despite the use of multiple cholesterol lowering treatments. Given its inborn nature, atherosclerotic plaques are commonly observed in young HoFH patients. Whether intensive lipid lowering strategies result in plaque regression in adolescent patients is unknown. Two HoFH patients with null/null LDLR variants, who participated in the R1500-CL-1629 randomized clinical trial (NCT03399786) evaluating the LDL cholesterol lowering effect of evinacumab (a human antibody directed against ANGPTL3; 15 mg/kg intravenously once monthly), were included in this study. Patients underwent coronary computed tomography angiography (CCTA) before randomization and after 6 months of treatment. Both patient A (aged 12) and B (aged 16) were treated with a statin, ezetimibe and weekly apheresis. Evinacumab decreased mean pre-apheresis LDL cholesterol levels from 5.51 ± 0.75 and 5.07 ± 1.45 mmol/l to 2.48 ± 0.31 and 2.20 ± 0.13 mmol/l and post-apheresis LDL levels from 1.45 ± 0.26 and 1.37 ± 39 mmol/l to 0.80 ± 0.16 and 0.78 ± 0.13 mmol/l in patient A and B, respectively. Total plaque volumes were reduced by 76% and 85% after 6 months of evinacumab treatment in patient A and B, respectively. We describe two severely affected young HoFH patients in whom profound plaque reduction was observed with CCTA after intensive lipid lowering therapy with statins, ezetimibe, LDL apheresis, and evinacumab. This shows that atherosclerotic plaques possess the ability to regress at young age, even in HoFH patients. [Display omitted] • Homozygous familial hypercholesterolemia (HoFH) is characterized by the presence of coronary plaques at a young age. • Two adolescent HoFH patients with profound plaques received aggressive low-density lipoprotein (LDL) lowering. • Profound coronary plaque regression was observed on CCTA imaging. • Atherosclerotic plaques possess the ability to regress at young age, even in HoFH. [ABSTRACT FROM AUTHOR]

Reversal of atherosclerosis has been well documented in humans on intensive lifestyle changes or lipid-lowering therapies. The development of mouse models has greatly advanced our understanding of molecular mechanisms underlying this biological process. I seek to summarize the established mouse models and highlight the recent therapeutic progress on plaque regression. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Background: Studies reporting collective and comprehensive data on plaque regression of different lipid-lowering therapies (LLTs) are limited., Objectives: We evaluated plaque regression of LLTs based on multiple markers and performed subgroup analyses based on LLT type and post-treatment LDL-C levels., Methods: A literature search was performed to identify studies assessing plaque regression from LLTs. The following LLTs groups were included: High-intensity statin (HIS), HIS+ eicosapentaenoic acid (EPA), HIS + ezetimibe, Low-intensity statin (LIS), LIS + EPA, LIS + Ezetimibe, and PCSK9 inhibitors. Our primary outcomes were change in percent atheroma volume (PAV). Secondary outcomes included mean differences in total atheroma volume (TAV), lumen, plaque, and vessel volumes, fibrous cap thickness (FCT), and lipid arc (LA). Subgroup analyses were performed on LLT type and post-treatment LDL-C levels. Meta-regression was performed to control for covariates., Results: We identified 51 studies with 9,113 adults (22 % females). LLTs reduced PAV levels (-1.10 % [-1.63, -0.56], p < 0.01), with significant reduction observed with HIS, LIS + ezetimibe, LIS + EPA, and PCSK9 inhibitors. LLTs reduced TAV levels (-5.84 mm3 [-8.64 to -3.04] p < 0.01), mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). LLTs reduced plaque volume and LA and increased FCT., Conclusion: The plaque regression associated with LLTs is observed to be mainly driven by HIS, reducing both TAV and PAV. This suggest that HIS is the most effective LLT for plaque regression., Unstructured Abstract: We evaluated plaque regression of LLTs from 51 studies. We found that while reduction of PAV (-1.10 % [-1.63, -0.56], p < 0.01) were present across different LLT types, reduction of TAV (-5.84 mm3 [-8.64 to -3.04] p < 0.01) was mainly driven by HIS (-7.60 mm3 [-11.89, -3.31] p < 0.01). These results suggest that HIS is the most effective LLT for plaque regression., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

A paradigm shift from preventive therapy to aggressive plaque regression and eventual eradication is much needed to address increasing atherosclerotic burden and risks. Herein, we report a biologically inspired dual-targeting multifunctional recombinant high-density lipoprotein (rHDL)-mimicking core-shell nanoplatform. It is composed of an ATP-responsive ternary polyplexes core for SR-A siRNA and catalase complexation, and a phosphatidylserine-modified rHDL-based outer shell for SR-BI and CD36 targeting, in which pitavastatin is packaged. We demonstrated that dual-targeting biomimetic core-shell nanoparticles dynamically enhanced macrophage CD36 targeting in the plaques by establishing a positive feedback loop via the reciprocal regulation of SR-A and CD36. Positive feedback-enabled accumulation of the nanoparticles in the atherosclerotic plaques increased by 3.3-fold following 4-week repeated administration. A 3-month dosage regimen of the dual-targeting rHDL-mimicking nanoparticles reduced plaque areas by 65.8%, and decreased macrophages by 57.3%. Collectively, this work shows that dynamically enhancing plaque targeting via a positive feedback loop and dual action of cholesterol deposition inhibition and efflux enhancement accomplished with our novel multifunctional biomimetic nanoparticles provides a new way to regress plaques and alleviate the atherosclerotic burden. Unlabelled Image • ApoA-I/PS-NP2 S/P/C dynamically enhanced plaque targeting via positive feedback loop. • 3-month dosage regimen of apoA-I/PS-NP2 S/P/C achieved a plaque reduction of 65.8%. • Catalase triggered ROS elimination, ATP generation, and accelerated siRNA release. [ABSTRACT FROM AUTHOR]

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

View large Download slide View large Download slide Aims The focal distribution of atherosclerotic plaques suggests that local biomechanical factors may influence plaque development. Methods and results We studied 40 patients at baseline and over 12 months by virtual-histology intravascular ultrasound and bi-plane coronary angiography. We calculated plaque structural stress (PSS), defined as the mean of the maximum principal stress at the peri-luminal region, and wall shear stress (WSS), defined as the parallel frictional force exerted by blood flow on the endothelial surface, in areas undergoing progression or regression. Changes in plaque area, plaque burden (PB), necrotic core (NC), fibrous tissue (FT), fibrofatty tissue, and dense calcium were calculated for each co-registered frame. A total of 4029 co-registered frames were generated. In areas with progression, high PSS was associated with larger increases in NC and small increases in FT vs. low PSS (difference in ΔNC: 0.24 ± 0.06 mm2; P  < 0.0001, difference in ΔFT: −0.15 ± 0.08 mm2; P  = 0.049). In areas with regression, high PSS was associated with increased NC and decreased FT (difference in ΔNC: 0.15 ± 0.04; P  = 0.0005, difference in ΔFT: −0.31 ± 0.06 mm2; P  < 0.0001). Low WSS was associated with increased PB vs. high WSS in areas with progression (difference in ΔPB: 3.3 ± 0.4%; P  < 0.001) with a similar pattern observed in areas with regression (difference in ΔPB: 1.2 ± 0.4%; P  = 0.004). Plaque structural stress and WSS were largely independent of each other (R 2 = 0.002; P  = 0.001). Conclusion Areas with high PSS are associated with compositional changes consistent with increased plaque vulnerability. Areas with low WSS are associated with more plaque growth in areas that progress and less plaque loss in areas that regress. The interplay of PSS and WSS may govern important changes in plaque size and composition. [ABSTRACT FROM AUTHOR]

The relationship between plaque regression induced by dyslipidemia therapies and occurrence of major adverse cardiovascular events (MACE) is controversial. We performed a systematic review and meta-regression of dyslipidemia therapy studies reporting MACE and intravascular ultrasound (IVUS) measures of change in coronary atheroma. Prospective studies of dyslipidemia therapies reporting percent atheroma volume (PAV) measured by IVUS and reporting death, myocardial infarction, stroke, unstable angina or transient ischemic attack (MACE) were included. The association between mean change in PAV and MACE was examined using meta-regression via mixed-effects binomial logistic regression models, unadjusted and adjusted for mean age, baseline PAV, baseline low density lipoprotein-cholesterol and study duration. The study included 17 prospective studies published between 2001 and 2018 totaling 6333 patients. Study duration varied from 11 to 104 weeks. Mean change in PAV, across the study arms, ranged from −5.6% to 3.1%. MACE ranged from 0 to 72 events per study arm: 13 study arms (38%) reported no events, 8 (24%) reported 1–2 events and 13 (38%) reported 3 or more events. Meta-regression demonstrated a decline in the odds of MACE associated with reduction in mean PAV: unadjusted odds ratio (OR): 0.78, 95% Confidence Interval (CI): [0.63, 0.96], p = 0.018; adjusted OR: 0.82, 95% CI: [0.70, 0.95], p = 0.011, per 1% decrease in mean PAV. A 1% reduction in mean PAV as induced by dyslipidemia therapies was associated with a 20% reduction in the odds of MACE. • Meta-regression analysis of trials using intravascular ultrasound to assess regression induced by lipid medications was performed. • A 1% decrease in percent atheroma volume was associated with approximately a 20% reduction in the odds of incurring a major cardiovascular event. • Percent atheroma volume changes represent a surrogate measure of cardiovascular events. [ABSTRACT FROM AUTHOR]

Highlights • The ENTERPRISE study will evaluate the effects of CPAP on coronary plaque in SDB. • Plaque regression/progression will be assessed with using serial near-infrared spectroscopy-intravascular ultrasound study. • The results will provide new insights into CPAP for SDB and residual risk. Abstract Background Sleep-disordered breathing (SDB) is a novel cardiovascular risk factor. To date, the effects of continuous positive airway pressure (CPAP) on coronary plaque atheroma in SDB patients with coronary artery disease (CAD) have remained unclear. The CPAP Effects on Atherosclerotic Plaques in Patients with Sleep-Disordered Breathing and Coronary Artery Disease (ENTERPRISE) trial was designed to evaluate the effects of CPAP treatment in addition to optimal medical treatment on coronary plaque regression in SDB patients. Methods This study is planned as a prospective, randomized, open-label, single-center study. The presence of SDB is defined as a 3% oxygen desaturation index (ODI) of ≥15 events/h as measured by nocturnal pulse oximetry. A total of 100 eligible SDB patients undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention will be randomly assigned to either CPAP as add-on therapy or no CPAP for SDB (1:1 ratio for CPAP vs. no CPAP). The intervention will consist of 12 months of CPAP treatment. The primary endpoint will be percentage changes in plaque atheroma volume of the non-culprit lesion segment as measured by IVUS. A specialist sleep cardiology team will carefully monitor patients receiving CPAP treatment in order to quickly detect and resolve problems, and to motivate patients to continue treatment. Conclusion This study will provide novel information on the effects of SDB and its treatment with CPAP on coronary plaque stability with regard to secondary prevention of CAD. [ABSTRACT FROM AUTHOR]

Despite recent therapeutic advances, there is an unmet need in cardiovascular disease prevention. Clinical trials and meta-analyses have established that LDL-C lowering, particularly by statin therapy, reduces the progression of coronary atherosclerosis and the risk of coronary events. Insufficient LDL-C reduction and high residual risk in a significant proportion of statin-treated patients signify that additional therapies are required to deliver more effective coronary care. Pharmacological inhibition of cholesterol absorption (with ezetimibe) and PCSK9 activity (with evolocumab or alirocumab) provides potentially useful approaches for the therapeutic modulation of LDL-C metabolism in statin-treated patients. In recent trials, combination strategies involving a statin and non-statin agent (ezetimibe or evolocumab) have been shown to promote coronary atherosclerosis regression and improve cardiovascular outcomes in patients with moderate-to-high cardiovascular risk. This review summarizes recent evidence on the effects of dual lipid-lowering therapy on coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Purpose of Review Atherosclerosis has major morbidity and mortality implications globally. While it has often been considered an irreversible degenerative process, recent evidence provides compelling proof that atherosclerosis can be reversed. Plaque regression is however difficult to appraise and quantify, with competing diagnostic methods available. Given the potential of evidence synthesis to provide clinical guidance, we aimed to review recent meta-analyses on diagnostic methods for atherosclerotic plaque regression. Recent Findings We identified 8 meta-analyses published between 2015 and 2017, including 79 studies and 14,442 patients, followed for a median of 12 months. They reported on atherosclerotic plaque regression appraised with carotid duplex ultrasound, coronary computed tomography, carotid magnetic resonance, coronary intravascular ultrasound, and coronary optical coherence tomography. Overall, all meta-analyses showed significant atherosclerotic plaque regression with lipid-lowering therapy, with the most notable effects on echogenicity, lipid-rich necrotic core volume, wall/plaque volume, dense calcium volume, and fibrous cap thickness. Significant interactions were found with concomitant changes in low density lipoprotein cholesterol, high density lipoprotein cholesterol, and C-reactive protein levels, and with ethnicity. Summary Atherosclerotic plaque regression and conversion to a stable phenotype is possible with intensive medical therapy and can be demonstrated in patients using a variety of non-invasive and invasive imaging modalities. [ABSTRACT FROM AUTHOR]

Introduction: Lipid-lowering therapy effectively decreases cardiovascular risk on a population level, but it remains difficult to identify an individual patient’s personal risk reduction while following guideline directed medical therapy, leading to overtreatment in some patients and cardiovascular events in others. Recent improvements in cardiac CT technology provide the ability to directly assess an individual’s atherosclerotic disease burden, which has the potential to personalize risk assessment for lipid-lowering therapy. Areas covered: We review the current unmet need in identifying patients at elevated residual risk despite guideline directed medical therapy, the evidence behind plaque regression as a potential marker of therapeutic response, and highlight state-of-the-art advances in coronary computed tomographic angiography (CCTA) for measurement of quantitative and qualitative changes in coronary atherosclerosis over time. Literature search was performed using PubMed and Google Scholar for literature relevant to statin therapy and residual risk, coronary plaque regression measurement, and CCTA assessment of quantitative and qualitative change in coronary atherosclerosis. Expert commentary: We discuss the potential ability of CCTA to guide lipid-lowering therapy as a bridge between population and personalized medicine in the future, as well as the potential barriers to its use. [ABSTRACT FROM PUBLISHER]

Atherosclerosis is characterized by formation of plaques on the inner walls of arteries that threatens to become the leading cause of death worldwide via its sequelae of myocardial infarction and stroke. Endothelial dysfunction leads to cholesterol uptake and accumulation of infl ammatory markers within the plaque. The stability of a plaque eventually depends on the balance between vascular smooth muscle cells that stabilize it and the infl ammatory cells like macrophages and T lymphocytes that make it prone to rupture. The current approach to manage atherosclerosis focuses on the treatment of a ruptured plaque and efforts have been made to reduce the risk of plaque rupture by identifying vulnerable plaques and treating them before they precipitate into clinical events. New diagnostic approaches such as IVUS and CIMT ultrasound are now being preferred over traditional coronary angiography because of their better accuracy in measuring plaque volume rather than the level of stenosis caused. The present review highlights the literature available on two prevalent approaches to manage a vulnerable plaque, namely, plaque stabilization and plaque regression, and their validation through various treatment modalities in recent plaque management studies. Plaque stabilization focuses on stabilizing the content of plaque and strengthening the overlying endothelium, while plaque regression focuses on the overall reduction in plaque volume and to reverse the arterial endothelium to its normal functional state. Although earlier studies contemplated the practicality of plaque regression and focused greatly on stabilization of a vulnerable plaque, our review indicated that, aided by the use of superior diagnostics tools, more intensive lipid modifying therapies have resulted in actual plaque regression.

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features-such as fibrous cap thickness and large lipid accumulation-beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.

This study aimed to clarify the relationships between arterial remodeling patterns and plaque volume regression or stabilization. The TOGETHAR trial is a prospective open-label trial designed to assess coronary plaque regression and stabilization with multiple plaque imaging modalities following 52 weeks of pitavastatin treatment (2 mg/day). Coronary plaques were observed in 46 patients with both angioscopy and intravascular ultrasound at baseline and after 52 weeks of drug treatment. We divided these patients into three groups according to their remodeling indices (RI). Group P consisted of patients with a baseline RI >1.05, Group M of patients with a baseline RI of 0.95-1.05, and Group N of patients with a baseline RI <0.95 and then evaluated differences in coronary plaque volume changes and yellow grade among the three groups. In the positive remodeling group, whose remodeling index (RI) exceeded 1.05 at baseline, RI and percent atheroma volume (PAV) were significantly reduced (RI 1.14 ± 0.07 to 1.05 ± 0.10, p = 0.010, PAV 47.3 ± 8.3 to 45.3 ± 7.3 mm, p = 0.048). There was no relationship between baseline RI and the change in yellow grade of plaque. RI increased without significant change of PAV or a decrease in lumen volume in group N, with RI below 0.95 at baseline. Plaques with positive remodeling were more likely to have plaque volume regression by pitavastatin than those without in patients with coronary artery disease. Moreover, plaques with positive and negative remodeling were changed into those with intermediate remodeling by pitavastatin. Pitavastatin might induce not only plaque regression or stabilization, but also conformational normalization of vessel structure. [ABSTRACT FROM AUTHOR]

Aims To evaluate the relationship between lipid content and plaque morphometry as well as the process of lesion progression and regression in patients with significant coronary artery disease. Methods and results The present study, using data from the YELLOW trial, was conducted in patients having significant coronary lesions (fractional flow reserve <0.8) who underwent serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) at baseline and after 7 weeks. For each coronary plaque (≥50% plaque burden that was ≥5 mm in length), we evaluated plaque characteristics and the extent of lipid-rich plaque [LRP, defined as the 4 mm long segment with the maximum lipid-core burden index (maxLCBI4mm)] on NIRS. Among 66 patients (age 63.0 ±10.1 years; 82% statin use at baseline), 94 plaques were identified. The extent of LRP at baseline was positively correlated with IVUS plaque burden (r = 0.317, P = 0.002). A large LRP (maxLCBI4mm ≥500) was present only in plaques with a large plaque burden (≥70%). Multivariate analysis demonstrated that plaque burden was the best predictor of the extent of LRP (P < 0.001). In lesions with a large plaque burden and a large amount of LRP at baseline, a reduction in LRP was seen in all lesions in patients receiving intensive statin therapy (P = 0.004) without a significant change in plaque burden. Conclusions Coronary lesions containing a large amount of LRP also had a large plaque burden. Short-term regression of LRP (without a change in plaque burden) was observed mainly in plaques with a large plaque burden and a large amount of LRP at baseline. [ABSTRACT FROM AUTHOR]

Accumulation of lipid-laden macrophage foam cells in arterial wall is the hallmark of atherosclerosis, the underlying cause of cardiovascular disease (CVD). Increased uptake of cholesteryl ester-rich modified low-density lipoprotein (LDL) is thought to be responsible for lipid accumulation and strong inverse correlation exists between plasma LDL and CVD. However, despite reaching the target LDL levels significant residual risk for CVD remains. Furthermore, current therapeutic strategies do not lead to regression of existing plaques. This review discusses a change in paradigm emphasizing the importance of removal of cholesterol from macrophage foam cells and final elimination of cholesterol from the body. Intracellular processes involved in this process are described to provide insight into the development of new therapies for CVD. [ABSTRACT FROM AUTHOR]

Evolution of atheroma usually take many years and this process is stimulated by a high dietary intake of cholesterol and both, saturated and trans fatty acids, added to accelerating factors such as tobacco, stress, diabetes, arterial hypertension, sedentary life style and obesity. Histopathology of the plaque reveals recruitment of Th 1 helper lymphocytes which destabilizes the atheroma, making it vulnerable to occlusion because of erosions and fissures; then adhering platelets and blood cells to its surface ensuing a myocardial infarction. On the contrary, plaque stabilization avoids its rupture, a result that can be achieved through reduction of the inflammatory activity in the plaque with medications that reduce its lipid content or by impairing macrophage activity inside the plaque. The former objectives can be obtained by 1) stoping LDL-c deposit 2) increasing reverse cholesterol transport with HDL-c 3) promoting foam cells death or macrophage migration or 4) remotion of the necrotic core of the atheroma. Studies of pharmacological regression of the atheromatous plaque in humans started several years ago with niacin; then with simvastatin (a HMG CoA reductase inhibitor) combined to niacin that increased by 26% HDL-c and reduced 42% LDL-c, a finding associated to 0,4% reduction of angiographically demonstrated coronary stenosis and surprisingly to 87% lowering of acute coronary risk events. On the other hand, recombinant apoA-I Milano, intravenously injected, also induce 4,2% regression of the atheroma volume in comparison to 0,14% decreased volume reduction with placebo. It is worth to consider renin-angiotensin-aldosterone system actively participate in atheroma development because olmesartan, an angiotensin II antagonist molecule (ARA II), reduce in 5,4% coronary atheroma volume, compared to 0,6% reduction obtained with a control treatment; this change was associated to a longer survival of patients without major cardiovascular events in comparison to the control group. This result points to an important cardiovascular protecting effect of ARA II agents. [ABSTRACT FROM AUTHOR]