The changing landscape of atherosclerosis.

Emerging evidence has spurred a considerable evolution of concepts relating to atherosclerosis, and has called into question many previous notions. Here I review this evidence, and discuss its implications for understanding of atherosclerosis. The risk of developing atherosclerosis is no longer concentrated in Western countries, and it is instead involved in the majority of deaths worldwide. Atherosclerosis now affects younger people, and more women and individuals from a diverse range of ethnic backgrounds, than was formerly the case. The risk factor profile has shifted as levels of low-density lipoprotein (LDL) cholesterol, blood pressure and smoking have decreased. Recent research has challenged the protective effects of high-density lipoprotein, and now focuses on triglyceride-rich lipoproteins in addition to low-density lipoprotein as causal in atherosclerosis. Non-traditional drivers of atherosclerosis-such as disturbed sleep, physical inactivity, the microbiome, air pollution and environmental stress-have also gained attention. Inflammatory pathways and leukocytes link traditional and emerging risk factors alike to the altered behaviour of arterial wall cells. Probing the pathogenesis of atherosclerosis has highlighted the role of the bone marrow: somatic mutations in stem cells can cause clonal haematopoiesis, which represents a previously unrecognized but common and potent age-related contributor to the risk of developing cardiovascular disease. Characterizations of the mechanisms that underpin thrombotic complications of atherosclerosis have evolved beyond the 'vulnerable plaque' concept. These advances in our understanding of the biology of atherosclerosis have opened avenues to therapeutic interventions that promise to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.

High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.

High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional regulator ATF3, as an HDL-inducible target gene in macrophages that downregulates the expression of Toll-like receptor (TLR)-induced proinflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of new HDL-based therapies.

Extracellular vesicles in atherothrombosis: From biomarkers and precision medicine to therapeutic targets.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up-to-date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.

Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease.

The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.

Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

BACKGROUND: VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. METHODS: Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). RESULTS: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. CONCLUSIONS: VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

Epidemiology of Diabetes and Atherosclerotic Cardiovascular Disease Among Asian American Adults: Implications, Management, and Future Directions: A Scientific Statement From the American Heart Association.

Asian American individuals make up the fastest growing racial and ethnic group in the United States. Despite the substantial variability that exists in type 2 diabetes and atherosclerotic cardiovascular disease risk among the different subgroups of Asian Americans, the current literature, when available, often fails to examine these subgroups individually. The purpose of this scientific statement is to summarize the latest disaggregated data, when possible, on Asian American demographics, prevalence, biological mechanisms, genetics, health behaviors, acculturation and lifestyle interventions, pharmacological therapy, complementary alternative interventions, and their impact on type 2 diabetes and atherosclerotic cardiovascular disease. On the basis of available evidence to date, we noted that the prevalences of type 2 diabetes and stroke mortality are higher in all Asian American subgroups compared with non-Hispanic White adults. Data also showed that atherosclerotic cardiovascular disease risk is highest among South Asian and Filipino adults but lowest among Chinese, Japanese, and Korean adults. This scientific statement discusses the biological pathway of type 2 diabetes and the possible role of genetics in type 2 diabetes and atherosclerotic cardiovascular disease among Asian American adults. Challenges to provide evidence-based recommendations included the limited data on Asian American adults in risk prediction models, national surveillance surveys, and clinical trials, leading to significant research disparities in this population. The large disparity within this population is a call for action to the public health and clinical health care community, for whom opportunities for the inclusion of the Asian American subgroups should be a priority. Future studies of atherosclerotic cardiovascular disease risk in Asian American adults need to be adequately powered, to incorporate multiple Asian ancestries, and to include multigenerational cohorts. With advances in epidemiology and data analysis and the availability of larger, representative cohorts, furthering refining the Pooled Cohort Equations, in addition to enhancers, would allow better risk estimation in segments of the population. Last, this scientific statement provides individual- and community-level intervention suggestions for health care professionals who interact with the Asian American population.

Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference.

PURPOSE OF REVIEW: RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation. RECENT FINDINGS: RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the 'Lp(a) hypothesis' that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway. SUMMARY: Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.

Development of stem cell therapy for atherosclerosis.

Cardiovascular disease (CVD) has a high incidence and low cure rate worldwide, and atherosclerosis (AS) is the main factor inducing cardiovascular disease, of which lipid deposition in the vessel wall is the main marker of AS. Currently, although statins can be used to lower lipids and low-density lipoprotein (LDL) in AS, the cure rate for AS remains low. Therefore, there is an urgent need to develop new therapeutic approaches, and stem cells are now widely studied, while stem cells are a class of cell types that always maintain the ability to differentiate and can differentiate to form other cells and tissues, and stem cell transplantation techniques have shown efficacy in the treatment of other diseases. With the establishment of cellular therapies and continued research in stem cell technology, stem cells are also being used to address the problem of AS. In this paper, we focus on recent research advances in stem cell therapy for AS and briefly summarize the relevant factors that induce the formation of AS. We mainly discuss the efficacy and application prospects of mesenchymal stem cells (MSCs) for the treatment of AS, in addition to the partial role and potential of exosomes in the treatment of AS. Further, provide new ideas for the clinical application of stem cells.

Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression.

BACKGROUND: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. METHODS: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. RESULTS: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1, Col3a1, Col1a2, Fn1, etc) and tissue inhibitor of metalloproteinase 3 (Timp3) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. CONCLUSIONS: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.

Angiography-based hemodynamic features predict recurrent ischemic events after angioplasty and stenting of intracranial vertebrobasilar atherosclerotic stenosis.

OBJECTIVES: To assess the predictive value of hemodynamic features for stroke relapse in patients with intracranial vertebrobasilar atherosclerotic stenosis treated with percutaneous transluminal angioplasty and stenting (PTAS) using quantitative digital subtraction angiography (q-DSA). METHODS: In this retrospective longitudinal study, patients with intracranial vertebrobasilar atherosclerotic stenosis and who underwent PTAS treatment between January 2012 and May 2020 were enrolled. The q-DSA assessment was performed before and after PTAS. ROIs 1-4 were placed along the vertebral artery, proximal and distal basilar artery, and posterior cerebral artery; ROIs 5-8 were in 5 mm and 10 mm proximal and distal to the lesion, respectively. Relative time to peak (rTTP) was defined as the difference in TTP between ROIs. Cox regression analyses were performed to determine risk factors for recurrent stroke. RESULTS: A total of 137 patients (mean age, 62 years ± 10 [standard deviation], 83.2% males) were included, and 26 (19.0%) patients had stroke relapse during follow-up (median time of 42.6 months [interquartile range, 19.7-60.7]). Preprocedural rTTP4-1 (adjusted hazard ratio (HR) = 2.270; 95% CI 1.371-3.758; p = 0.001) and preprocedural rTTP8-5 (adjusted HR = 0.240; 95% CI 0.088-0.658; p = 0.006) were independently associated with the recurrent stroke. These hemodynamic parameters provided an incremental prognostic value for stroke relapse (AUC, 0.817 [0.704-0.931]; the net reclassification index, 0.431 [0.057-0.625]; and the integrated discrimination index, 0.140 [0.035-0.292]). CONCLUSIONS: In patients with intracranial vertebrobasilar atherosclerosis treated with PTAS, preprocedural prolonged TTP of the target vessel and shortened trans-stenotic TTP difference were associated with stroke relapse. Q-DSA-defined hemodynamic parameters provided incremental predictive value over conventional parameters for stroke recurrence. CLINICAL RELEVANCE STATEMENT: Quantitative DSA analysis enables intuitive observation and semi-quantitative evaluation of peri-therapeutic cerebral blood flow. More importantly, quantitative DSA-defined hemodynamic parameters have the potential for risk stratification of patients with intracranial atherosclerotic stenosis. KEY POINTS: Semi-quantitative angiography-based parameters can reflect pre- and postprocedural subtle changes in blood flow in patients with intracranial atherosclerotic stenosis. Although angioplasty procedures can significantly improve blood flow status, patients with more restricted baseline blood flow still show a higher risk of stroke recurrence. Angiography-based hemodynamic features possess prognostic value and can serve as clinical markers to assess stroke risk of patients with intracranial atherosclerotic stenosis.

Multiomic Analysis and CRISPR Perturbation Screens Identify Endothelial Cell Programs and Novel Therapeutic Targets for Coronary Artery Disease.

Endothelial cells (EC) are an important mediator of atherosclerosis and vascular disease. Their exposure to atherogenic risk factors such as hypertension and serum cholesterol leads to endothelial dysfunction and many disease-associated processes. Identifying which of these multiple EC functions is causally related to disease risk has been challenging. There is evidence from in vivo models and human sequencing studies that dysregulation of nitric oxide production directly affects risk of coronary artery disease. Human genetics can help prioritize the other EC functions with causal relationships because germline mutations are acquired at birth and serve as a randomized test of which pathways affect disease risk. Though several coronary artery disease risk variants have been linked to EC function, this process has been slow and laborious. Unbiased analyses of EC dysfunction using multiomic approaches promise to identify the causal genetic mechanisms responsible for vascular disease. Here, we review the data from genomic, epigenomic, and transcriptomic studies that prioritize EC-specific causal pathways. New methods that CRISPR (clustered regularly interspaced short palindromic repeats) perturbation technology with genomic, epigenomic, and transcriptomic analysis promise to speed up the characterization of disease-associated genetic variation. We summarize several recent studies in ECs which use high-throughput genetic perturbation to identify disease-relevant pathways and novel mechanisms of disease. These genetically validated pathways can accelerate the identification of drug targets for the prevention and treatment of atherosclerosis.

Effect of endovascular treatment on patients with basilar artery occlusion presenting with different pathologic mechanisms: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to summarize the clinical outcomes of endovascular treatment in patients with basilar artery occlusion (BAO) with different pathologic mechanisms. METHODS: Two independent reviewers searched PubMed/MEDLINE, Embase and Cochrane Library database up to December 2022, patients with different BAO pathological mechanisms (BAO with in situ atherosclerosis vs. embolism alone without vertebral artery steno-occlusion vs. embolism from tandem vertebral artery steno-occlusion) were collected and analyzed. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) to assess the associations between clinical outcomes and BAO pathological mechanisms. RESULTS: A total of 1163 participants from 12 studies were identified. Compared with embolism alone, patients with in situ atherosclerotic BAO had a lower favorable outcome rate (modified Rankin score [mRS] 0-2: 34.5% vs. 41.2%; OR 0.83, 95% CI 0.70-0.98; P = 0.03) and moderate outcome rate (mRS 0-3: 45.8% vs. 55.4%; OR 0.65, 95% CI 0.47-0.90; P = 0.01) at 3 months and a higher risk of mortality (29.9% vs. 27.2%; OR 1.31, 95% CI 0.96-1.79, P = 0.09; adjusted OR 1.46, 95% CI 1.08-1.96). Tandem BAO had a comparable mortality risk to that of in situ atherosclerotic BAO (OR 1.37, 95% CI 0.84-2.22; P = 0.48) or embolism alone (OR 1.44, 95% CI 0.65-3.21; P = 0.43), and there were no significant differences in favorable or moderate outcomes between tandem BAO and each of the other two BAO mechanisms. CONCLUSION: Among BAO patients with endovascular treatment, embolism mechanism had better clinical outcomes than in situ atherosclerosis, and atherosclerotic mechanism was associated with a higher mortality at 3 months. RCTs are needed to further confirm clinical outcomes of BAO by different mechanisms.

Cognition of diet quality and dietary management in elderly patients with coronary and other atherosclerotic vascular disease in western China, a qualitative research study.

BACKGROUND: Healthy eating is one of the most important nonpharmacologic treatments for patients with atherosclerosis(AS). However, it is unclear how elderly AS patients in western China perceive their dietary status and which type of nutritional assistance they would be willing to receive. Therefore, the primary purpose of this study was to understand the level of knowledge about current dietary habits and healthy eating habits among elderly AS patients in western China, and the secondary purpose was to identify acceptable nutritional assistance measures or pathways for those patients to help them manage disease progression. METHODS: An implementation study approach was used to recruit elderly patients with AS-related diseases in western China for semistructured interviews. RESULTS: 14 participants were included in the study, and the following three themes were identified from the interviews:(1) the diet with regional characteristics; (2) low nutrition-related health literacy; (3) complex attitudes towards nutritional assistance. Most participants had misconceptions about healthy eating, and the sources of their knowledge might not be trustworthy. Participants expressed a preference for personalized nutritional assistance, especially that provided by medical-nursing combined institutions. CONCLUSION: Patients in western China need nutritional assistance for their regional dietary habits; therefore, healthy dietary patterns consistent with the regional culture are proposed to improve the prevailing lack of knowledge about healthy diets, improve the dietary structure of patients, and control the development of the disease.

Bulk and single-cell characterisation of the immune heterogeneity of atherosclerosis identifies novel targets for immunotherapy.

BACKGROUND: Immune cells that infiltrate lesions are important for atherosclerosis progression and immunotherapies. This study was aimed at gaining important new insights into the heterogeneity of these cells by integrating the sequencing results of multiple samples and using an enhanced single-cell sequencing workflow to overcome the limitations of a single study. RESULTS: Integrative analyses identified 28 distinct subpopulations based on gene expression profiles. Further analysis demonstrated that these cells manifested high heterogeneity at the levels of tissue preferences, genetic perturbations, functional variations, immune dynamics, transcriptional regulators, metabolic changes, and communication patterns. Of the T cells, interferon-induced CD8+ T cells were involved in the progression of atherosclerosis. In contrast, proinflammatory CD4+ CD28null T cells predicted a poor outcome in atherosclerosis. Notably, we identified two subpopulations of foamy macrophages that exhibit contrasting phenotypes. Among them, TREM2- SPP1+ foamy macrophages were preferentially distributed in the hypoxic core of plaques. These glycolytic metabolism-enriched cells, with impaired cholesterol metabolism and robust pro-angiogenic capacity, were phenotypically regulated by CSF1 secreted by co-localised mast cells. Moreover, combined with deconvolution of the bulk datasets, we revealed that these dysfunctional cells had a higher proportion of ruptured and haemorrhagic lesions and were significantly associated with poor atherosclerosis prognoses. CONCLUSIONS: We systematically explored atherosclerotic immune heterogeneity and identified cell populations underlying atherosclerosis progression and poor prognosis, which may be valuable for developing new and precise immunotherapies.

The Molecular Mechanisms and Therapeutic Targets of Atherosclerosis: From Basic Research to Interventional Cardiology.

The goal of this Special Issue was to collect original pieces as well as state-of-the-art review articles from scientists and research groups with specific interests in atherosclerosis research [...].

A review of the signaling pathways of aerobic and anaerobic exercise on atherosclerosis.

Atherosclerosis (AS), a chronic inflammatory vascular disease with lipid metabolism abnormalities, is one of the major pathological bases of coronary heart disease. As people's lifestyles and diets change, the incidence of AS increases yearly. Physical activity and exercise training have recently been identified as effective strategies for lowering cardiovascular disease (CVD) risk. However, the best exercise mode to ameliorate the risk factors related to AS is not clear. The effect of exercise on AS is affected by the type of exercise, intensity, and duration. In particular, aerobic and anaerobic exercise are the two most widely discussed types of exercise. During exercise, the cardiovascular system undergoes physiological changes via various signaling pathways. The review aims to summarize signaling pathways related to AS in two different exercise types and provide new ideas for the prevention and treatment of AS in clinical practice.

AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk.

BACKGROUND: Whereas several interventions can effectively lower lipid levels in people at risk for atherosclerotic cardiovascular disease (ASCVD), cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to cardiovascular event risk. Monocytes and macrophages play central roles in atherosclerosis, but studies have yet to provide a detailed view of macrophage populations involved in increased ASCVD risk. METHODS: A novel macrophage foaming analytics tool, AtheroSpectrum, was developed using 2 quantitative indices depicting lipid metabolism and the inflammatory status of macrophages. A machine learning algorithm was developed to analyze gene expression patterns in the peripheral monocyte transcriptome of MESA participants (Multi-Ethnic Study of Atherosclerosis; set 1; n=911). A list of 30 genes was generated and integrated with traditional risk factors to create an ASCVD risk prediction model (30-gene cardiovascular disease risk score [CR-30]), which was subsequently validated in the remaining MESA participants (set 2; n=228); performance of CR-30 was also tested in 2 independent human atherosclerotic tissue transcriptome data sets (GTEx [Genotype-Tissue Expression] and GSE43292). RESULTS: Using single-cell transcriptomic profiles (GSE97310, GSE116240, GSE97941, and FR-FCM-Z23S), AtheroSpectrum detected 2 distinct programs in plaque macrophages-homeostatic foaming and inflammatory pathogenic foaming-the latter of which was positively associated with severity of atherosclerosis in multiple studies. A pool of 2209 pathogenic foaming genes was extracted and screened to select a subset of 30 genes correlated with cardiovascular event in MESA set 1. A cardiovascular disease risk score model (CR-30) was then developed by incorporating this gene set with traditional variables sensitive to cardiovascular event in MESA set 1 after cross-validation generalizability analysis. The performance of CR-30 was then tested in MESA set 2 (P=2.60×10-4; area under the receiver operating characteristic curve, 0.742) and 2 independent data sets (GTEx: P=7.32×10-17; area under the receiver operating characteristic curve, 0.664; GSE43292: P=7.04×10-2; area under the receiver operating characteristic curve, 0.633). Model sensitivity tests confirmed the contribution of the 30-gene panel to the prediction model (likelihood ratio test; df=31, P=0.03). CONCLUSIONS: Our novel computational program (AtheroSpectrum) identified a specific gene expression profile associated with inflammatory macrophage foam cells. A subset of 30 genes expressed in circulating monocytes jointly contributed to prediction of symptomatic atherosclerotic vascular disease. Incorporating a pathogenic foaming gene set with known risk factors can significantly strengthen the power to predict ASCVD risk. Our programs may facilitate both mechanistic investigations and development of therapeutic and prognostic strategies for ASCVD risk.

Remote Ischemic Conditioning and Outcomes in Acute Ischemic Stroke With Versus Without Large Artery Atherosclerosis.

BACKGROUND: RICAMIS trial (The Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) has demonstrated efficacy of remote ischemic conditioning (RIC) in acute ischemic stroke. We conducted a post hoc analysis of RICAMIS to investigate whether large artery atherosclerosis (LAA) subtype contributed to the outcomes. METHODS: This is a post hoc analysis of the RICAMIS trial. Patients randomized to RIC group and Control group in full analysis set of RICAMIS were classified into LAA and non-LAA subtypes. The primary outcome was excellent functional outcome at 90 days, defined as modified Rankin Scale score of 0 to 1. Compared with patients receiving usual care, we investigated the association of RIC effect with outcomes in stroke subtypes and the interaction between RIC effect and stroke subtypes. The primary analysis was adjusted analysis. RESULTS: Among 1773 patients, 516 were assigned to LAA subtype (229 in the RIC group and 287 in the control group) and 1257 to non-LAA subtype (633 in the RIC group and 624 in the control group). Median age was 65 years, and 34.2% were women. A higher proportion of primary outcome was found to be associated with RIC treatment in LAA subtype (adjusted risk difference, 11.4% [95% CI, 3.6%-19.2%]; P=0.004), but not in non-LAA subtype (adjusted risk difference, 4.1% [95% CI, -1.1% to 9.3%]; P=0.12). There was no significant interaction between RIC effect and stroke subtypes (P=0.12). CONCLUSIONS: Patients with LAA subtype may benefit from RIC after stroke with respect to excellent functional outcome at 90 days. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740971.

Vascular Electrical Stimulation with Wireless, Battery-Free, and Fully Implantable Features Reduces Atherosclerotic Plaque Formation Through Sirt1-Mediated Autophagy.

Electrical stimulation (ES) is a safe and effective procedure in clinical rehabilitation with few adverse effects. However, studies on ES for atherosclerosis (AS) are scarce because ES does not provide a long-term intervention for chronic disease processes. Battery-free implants and surgically mounted them in the abdominal aorta of high-fat-fed Apolipoprotein E (ApoE-/- ) mice are used, which are electrically stimulated for four weeks using a wireless ES device to observe changes in atherosclerotic plaques. Results showed that there is almost no growth of atherosclerotic plaque at the stimulated site in AopE-/- mice after ES. RNA-sequencing (RNA-seq) analysis of Thp-1 macrophages reveal that the transcriptional activity of autophagy-related genes increase substantially after ES. Additionally, ES reduces lipid accumulation in macrophages by restoring ABCA1- and ABCG1-mediated cholesterol efflux. Mechanistically, it is demonstrated that ES reduced lipid accumulation through Sirtuin 1 (Sirt1)/Autophagy related 5 (Atg5) pathway-mediated autophagy. Furthermore, ES reverse autophagic dysfunction in macrophages of AopE-/- mouse plaques by restoring Sirt1, blunting P62 accumulation, and inhibiting the secretion of interleukin (IL)-6, resulting in the alleviation of atherosclerotic lesion formation. Here, a novel approach is shown in which ES can be used as a promising therapeutic strategy for AS treatment through Sirt1/Atg5 pathway-mediated autophagy.

Retrieval of renal function after renal artery stenting improves event-free survival in a subgroup analysis of the Cardiovascular Outcomes in Renal Atherosclerotic Lesions trial.

OBJECTIVE: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, a multicenter randomized controlled trial with 947 patients, concluded that there was no benefit of renal artery stenting (RAS) over medical therapy. However, patients with chronic kidney disease (CKD) were not analyzed separately in the CORAL trial. CKD is a risk factor for cardiovascular and renal morbidity. We hypothesized that improved renal function after RAS would be associated with increased long-term survival and a lower risk of cardiovascular and renal events in patients with CKD. METHODS: This post hoc analysis of the CORAL trial included 842 patients with CKD stages 2 to 4 at baseline who were randomized to optimal medical therapy alone (OMT; n = 432) or RAS plus OMT (RAS + OMT; n = 410). Patients were categorized as responders or nonresponders based on the change in the estimated glomerular filtration rate (eGFR) from baseline to last follow-up (median, 3.6 years; interquartile range, 2.6-4.6 years). Responders were defined by a 20% or greater increase in eGFR from baseline; all others were designated as nonresponders. Event-free survival was defined as freedom from death and multiple cardiovascular and renal complications. Event-free survival was analyzed using the Kaplan-Meier method and log-rank test. Multivariable Cox proportional hazards regression analysis was used to identify independent predictors of event-free survival. RESULTS: The RAS + OMT group had a higher proportion of patients with improved renal function (≥20% increase in eGFR over baseline), compared with the OMT group (25.6% vs 17.1%; P = .003). However, event-free survival was no different for the two cohorts (P = .18 by the log-rank test). Multivariable Cox proportional hazards regression analysis identified four variables that independently correlated with event-free survival for the stented cohort. Higher preoperative eGFR (hazard ratio, 0.98; 95% confidence interval [CI], 0.96-0.99; P = .002) and being a responder to stenting (hazard ratio, 0.49; 95% CI, 0.26-0.95; P = .033) increased event-free survival, whereas a history of congestive heart failure (hazard ratio, 2.52; 95% CI, 1.46-4.35; P < .001) and a higher preoperative systolic BP (hazard ratio, 1.02; 95% CI, 1.01-1.03; P = .002) decreased event-free survival. Within the stented group, 105 of 410 patients (25.6%) were responders. Event-free survival was superior for responders, compared with nonresponders (P = .009 by log-rank test). The only independent preoperative negative predictor of improved renal function after stenting was diabetes (odds ratio, 0.37; 95% CI, 0.16-0.84; P = .017), which decreased the probability of improved renal function after RAS + OMT. A subset of patients (23.4%) after RAS had worsened renal function, but OMT alone produced an equivalent incidence of worsened renal function. An increased urine albumin/creatinine ratio was an independent predictor of worsened renal function after RAS. CONCLUSIONS: CORAL participants who demonstrated improved kidney function after RAS + OMT demonstrated improved event-free survival. This finding reinforces the need for predictors of outcome to guide patient selection for RAS.