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BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Vital organs like the heart are affected by the occlusion of blood vessels due to atherosclerotic plaque formation. However, the role of infectious agents has always been an essential subject of investigation. This study investigated the presence of microorganisms, including nanobacteria, in atherosclerotic plaques removed from human carotid arteries by microbiological and metagenomic examination. METHODS: Atheroma plaque samples were obtained from 20 patients with carotid artery stenosis who had atherectomy by surgery or percutaneous intervention. Nanobacteria were grown by culturing homogenates of the atheroma plaques. Whole genome sequencing was done for samples. Because of the high percentage of Toxoplasma gondii (T. gondii) DNA, PCR investigation was applied to detect T. gondii DNA in the samples. RESULTS: A molecular analysis of nanobacteria revealed them to be made of human proteins, supporting the theory that they are not living organisms. According to sequencing results, samples showed that more than 50 % of the metagenomic sequences belonged to Toxoplasma gondii. PCR investigation indicated that T. gondii DNA was positive in 8 (40 %) of 20 plaques. CONCLUSIONS: Further evidence regarding the role of T. gondii in the etiology of plaque formation may help determine the strategy for prevention and treatment of infections in preventing atheroma plaque formation in the future.

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BACKGROUND: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke. METHODS: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile. RESULTS: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups. CONCLUSIONS: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban.

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INTRODUCTION: In patients with obstructive sleep apnea (OSA), novel metrics such as hypoxic burden (HB) and sleep apnea-specific pulse-rate response (ΔHR) may better correlate with cardiovascular diseases (CVD) than the apnea-hypopnea index (AHI). This manuscript aims to assess the correlation between ΔHR and HB with subclinical atherosclerosis in patients with OSA, testing the hypothesis that elevated ΔHR and HB are associated with subclinical atherosclerosis development. METHODS: In a prospective study, individuals aged 20-65 years with suspected OSA without known comorbidities were consecutively recruited and defined as OSA (AHI≥5events/h) or healthy controls. Using bilateral carotid ultrasonography, common carotid intima-media thickness (CIMT) was assessed and the identification of at least one atheromatous plaque defined the presence of subclinical atherosclerosis. ΔHR, and HB were derived from pulse-oximetry. RESULTS: We studied 296 patients of age 45±10 years old, of whom 28% were women, and with a BMI of 30.3±5.3kg/m2. Overall, 245 had OSA and 51 were healthy controls. After controlling for confounding variables higher ΔHR but not HB, was associated with higher CIMT (p=0.006) and higher time spent with oxygen saturation below 90% (T90) was associated with an increase in carotid atheroma plaques (p=0.032). When stratifying OSA based on HB tertiles, we observed that within tertile 2 of HB, an increase in ΔHR was associated with larger CIMT (p=0.017). CONCLUSION: A higher ΔHR is associated with an increase in CIMT among adult patients with OSA. This study suggests that ΔHR could be a biomarker of risk for CVD in patients with OSA.

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This study aimed to investigate the relationship between complex aortic plaque (CAP) and short-term as well as long-term outcomes following cardioembolic stroke. CAP is a known risk factor for occurrence and recurrence of ischemic stroke. However, the association of CAP on cardioembolic stroke remains unclear. This was retrospective study using prospective cohort of consecutive patients with cardioembolic stroke who underwent transesophageal echocardiography. The functional outcome was evaluated using the modified Rankin Scale score at 3 months, and long-term outcomes were assessed by recurrence of ischemic stroke and occurrence of major adverse cardiovascular events (MACE). Among 759 patients with cardioembolic stroke, 91 (12.0%) had CAP. Early ischemic stroke recurrence within 3 months was associated with CAP (p = 0.025), whereas CAP was not associated with functional outcome at 3 months (odd ratio 1.01, 95% confidence interval [CI] 0.57-1.84, p = 0.973). During a median follow-up of 3.02 years, CAP was significantly associated with ischemic stroke recurrence (hazard ratio = 2.68, 95% CI 1.48-4.88, p = 0.001) and MACE occurrence (hazard ratio = 1.61, 95% CI 1.03-2.51, p = 0.039). In conclusion, CAP was associated with early ischemic stroke recurrence and poor long-term outcomes in patients with cardioembolic stroke. It might be helpful to consider transesophageal echocardiography for patients with cardioembolic stroke to identify CAP.

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OBJECTIVES: Morphometric information of the structures within the borders of the aortic root is a guide for surgical interventions. It is essential to determine the effects of aortic calcification and atheroma plaque findings on the structures of this region. This study aims to establish the normal values of aortic root structures and to investigate the impact of pathologic findings in order to guide diagnosis and treatment in the clinic. METHODS: The aortic root structures were morphometrically analyzed in fresh hearts of 110 patients (89 males, 21 females) brought to the forensic medicine institution. The distances between the bases of the aortic sinuses, their widths and heights, and the lengths of the commissures were measured to differentiate between pathologic and non-pathologic aortic classes. Parameters were compared according to gender, age, body mass index, and body surface area. RESULTS: The mean age was 44.71 ± 15.57 years in 21 female patients and 53.66 ± 15.67 years in 89 male patients. The results of the pathologic aorta group with calcification and atheroma plaque findings were higher than the non-pathologic aorta group in all parameters (P < .05). CONCLUSIONS: Calcification and the presence of atheroma plaque in the aorta increase the size of the structures at the aortic root. Gender, age, body mass index, and body surface area are among the criteria that will cause changes in the structures of this region. These results will help surgeons to know the normal values of aortic root structures and to consider the effects of pathologic findings in aortic valve repair operations.

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Background: Evidence indicates that the addition of ezetimibe to statin therapy reduces cardiovascular events. However, the impact of ezetimibe-statin combination therapy on coronary plaque regression, plaque stabilization, and diameter stenosis remains a matter of controversy. Methods: We performed electronic searches in PubMed, Web of Knowledge, and the Cochrane Central Register of Controlled Trials to identify eligible trials assessing the effects of ezetimibe-statin combination therapy versus statin monotherapy reporting at least one outcome among total atheroma volume (TAV), minimum fibrous cap thickness (FCT), lumen volume (LV), and lumen area (LA) derived from intravascular imaging modalities of intravascular ultrasound (IVUS) and optical coherence tomography (OCT). We used the random-effects model and performed trial sequential analysis (TSA) during this meta-analysis. Results: Eleven articles with a total of 926 individuals (460 in the dual-lipid-lowering therapy group and 466 in the statin monotherapy group) were included in the final meta-analysis. Compared to statin monotherapy, ezetimibe-statin combination therapy was associated with significantly decreased TAV [WMD = -3.17, 95% CI (-5.42 to -0.92), and p = 0.006], with no effect on the LV of the coronary artery [WMD = -0.52, 95% CI (-2.24 to 1.21), and p = 0.56], the LA of the coronary artery [WMD = 0.16, 95% CI (-0.10-0.42), and p = 0.22], or minimum FCT thickness [WMD = 19.11, 95%CI (-12.76-50.97)]. Conclusion: In patients with coronary artery disease, ezetimibe-statin combination therapy resulted in a significant regression in TAV compared to statin monotherapy, whereas no overall improvements of minimum FCT or lumenal stenosis were observed.

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OBJECTIVE: Atherosclerosis is a chronic lipid-driven inflammatory disease of the arterial wall. Due to its cardiovascular ischemic complications, it is one of the most common causes of death in people. However, atherosclerosis is seldomly reported in dogs. ANIMAL: A 10-year-old male mixed-breed dog. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: Severe acute kidney injury associated with thrombosis of the abdominal aorta. TREATMENT AND OUTCOME: Treatment included renal replacement therapy, antithrombotic therapy, and supportive care. However, the dog developed neurological and respiratory complications and was euthanized due to worsening kidney function and lack of improvement of the thrombosis. Postmortem examination confirmed the presence of aortic thromboembolism and renal infarcts. Histology revealed severe chronic-active atherosclerosis of the distal aorta and renal arteries. CLINICAL RELEVANCE: Aortic thrombosis is uncommon in dogs, and it is often associated with underlying conditions such as protein-losing nephropathy, endocrine disorders, cardiac disease, or hypercoagulability. In this case, no specific underlying cause was identified and atherosclerosis was considered the primary cause of the thrombosis.

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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.

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(1) Background: Non-stenotic complicated plaques are a neglected cause of stroke, in particular in young patients. Atherosclerosis has some preferential sites in extracranial arteries and the prepetrous segment of the internal carotid artery has been rarely described as site of atheroma in general and of complicated atheroma in stroke patients. The aim of this study is to describe the rate of the prepetrous internal carotid artery's (ICA) involvement in a single-center case series of young stroke patients. (2) Methods: All patients < 50 years old with acute ischemic stroke admitted to a single-center Stroke Unit during two time periods (the first one from 1 January 2018 to 31 December 2019, and the second one from 1 January 2021 to 30 June 2022), were prospectively investigated as part of a screening protocol of the Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) study [ClinicalTrials.gov ID NCT01934725], including extracranial vascular examination by using computed tomography (CT) or magnetic resonance imaging (MRI). (3) Results: Two out of ninety-three consecutive patients (2.15%) had a complicated atheroma in the prepetrous ICA as the cause of stroke and both CT angiography and high-resolution vessel wall MRI were applied to document the main features of positive remodeling, cap rupture, ulceration, intraplaque hemorrhage, and a transient thrombus superimposed on the atheroma. The two patients had a different evolution of healing in the first case and a persisting ulceration at 12 months in the second case. (4) Conclusions: The prepetrous ICA is a rarely described location of complicated atheroma in stroke patients at all ages and it represents roughly 2% of causes of acute stroke in this single-center case series in young people.

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Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE-/- mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis.

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Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identification of molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of global gene expression data focusing on two TF genes, ZNF385D and HAND2, whose polymorphisms have been recently reported to show association with CIMT. Genome-wide gene expression data were measured from pieces of carotid endarterectomy collected from 34 hypertensive patients (atheroma plaque of stages IV and above according to the Stary classification) each paired with one sample of distant macroscopically intact tissue (stages I and II). Transcriptional regulation networks or the regulons were reconstructed for ZNF385D (5644 target genes) and HAND2 (781 target genes) using network inference. Their association with the progression of carotid atheroma was examined using gene-set enrichment analysis with extremely high statistical significance for regulons of both ZNF385D and HAND2 (p < 6.95 × 10-7) suggesting the involvement of expression quantitative loci (eQTL). Functional annotation of the regulon genes found heavy involvement in the immune system's response to inflammation and infection in the development of atherosclerosis. Detailed examination of the regulation and correlation patterns suggests that activities of the two TF genes could have high clinical and interventional impacts on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.

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Ketogenic diets (KDs) are very high-fat low-carbohydrate diets that promote nutritional ketosis and are widely used for weight loss, although concerns about potential adverse cardiovascular effects remain. We investigated a very high-fat KD's vascular impact and plasma metabolic signature compared to a non-ketogenic high-fat diet (HFD). Apolipoprotein E deficient (ApoE -/-) mice were fed a KD (%kcal:81:1:18, fat/carbohydrate/protein), a non-ketogenic high-fat diet with half of the fat content (HFD) (%kcal:40:42:18, fat/carbohydrate/protein) for 12 weeks. Plasma samples were used to quantify the major ketone body beta-hydroxybutyrate (BHB) and several pro-inflammatory cytokines (IL-6, MCP-1, MIP-1alpha, and TNF alpha), and to targeted metabolomic profiling by mass spectrometry. In addition, aortic atherosclerotic lesions were quantified ex-vivo by magnetic resonance imaging (MRI) on a 14-tesla system. KD was atherogenic when compared to the control diet, but KD mice, when compared to the HFD group (1) had markedly higher levels of BHB and lower levels of cytokines, confirming the presence of ketosis that alleviated the well-established fat-induced systemic inflammation; (2) displayed significant changes in the plasma metabolome that included a decrease in lipophilic metabolites and an increase in hydrophilic metabolites; (3) had significantly lower levels of several atherogenic lipid metabolites, including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides; and (4) presented significantly lower aortic plaque burden. KD was atherogenic and was associated with specific metabolic changes but alleviated the fat-induced inflammation and lessened the progression of atherosclerosis when compared to the HFD.

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Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice. Next, we examined the relevance to humans by analyzing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey. We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr-/- mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.

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BACKGROUND: Atherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. OBJECTIVE: To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. MATERIAL AND METHODS: Seven hundred and forty-six individuals from the metropolitan area of Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed. RESULTS: Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. CONCLUSIONS: High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.

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Background: The aim of this study was to determine the reliability of panoramic radiograph (PR) as a screening tool for the detection of calcified carotid atheroma (CCA) in comparison with Doppler ultrasonography (DU) examination. Materials and Methods: In this study, DU was performed for 52 patients who had carotid calcification or other differential diagnoses of carotid calcification on PR routine screening. The data relating to the presence or absence of calcified atheroma in DU and PR were evaluated using SPSS software. Results: In the 52 stated patients, CCA of 9 (18%) patients was diagnosed in the PR. Significant differences in CCA between the two sexes were not found. Also, considerable differences between the left and right sides (P = 0/906) were not found. Moreover, the positive cases who are diagnosed using ultrasonography and PR were 2.25% and 6.5%, respectively. Conclusion: PR method is not a good choice for the primary diagnosis method for the carotid artery calcifications due to its less positive diagnosing ratio compared to DU.

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BACKGROUND: Carotid free-floating thrombus (CFFT) is an uncommon disorder. The aim of this study was to describe a French cohort of CFFT patients. METHODS: We conducted a retrospective monocentric study from a Stroke Center among patients admitted for stroke with CFFT. RESULTS: Between January 2017 to December 2019, 2038 ischemic strokes were recorded. A total of 50 patients with CFFT were consecutively included (32 men/18 women). The mean age was 58.2 years (±11.7). Their etiologies were atheroma (46%), carotid dissection and web (20%), hypercoagulability disorders (16%) and arrhythmia (10%). Exclusive medical management was performed in 38 patients (76%): 29 (59.2%) were anticoagulated and 9 (18.4%) received antiplatelets alone in the first week. Surgical intervention was performed in the first 30 days for 11 patients (22%). The main surgical indication was a residual carotid stenosis over 70%. Only three patients had a recurrent stroke in the medical group with anticoagulants. No patients in the antiplatelet group or the surgical group had a recurrent stroke. CONCLUSIONS: Our study summarized a large cohort of 50 patients with CFFT. This diagnosis implies the need to search for a local arterial disease and to screen for hypercoagulability states. An initial medical strategy followed by a delayed carotid surgery if the follow-up imaging shows a residual stenosis appears to be safe.

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BACKGROUND/OBJECTIVES: Dyslipidemia causes metabolic disorders such as atherosclerosis and fatty liver syndrome due to abnormally high blood lipids. Purple perilla frutescens extract (PPE) possesses various bioactive compounds such as α-asarone, chlorogenic acid and rosmarinic acid. This study examined whether PPE and α-asarone improved dyslipidemia-associated inflammation and inhibited atheroma formation in apolipoprotein E (apoE)-deficient mice, an experimental animal model of atherosclerosis. MATERIALS/METHODS: ApoE-deficient mice were fed on high cholesterol-diet (Paigen's diet) and orally administrated with 10-20 mg/kg PPE and α-asarone for 10 wk. RESULTS: The Paigen's diet reduced body weight gain in apoE-deficient mice, which was not restored by PPE or α-asarone. PPE or α-asarone improved the plasma lipid profiles in Paigen's diet-fed apoE-deficient mice, and despite a small increase in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL)-cholesterol, and very LDL were significantly reduced. Paigen's diet-induced systemic inflammation was reduced in PPE or α-asarone-treated apoE-deficient mice. Supplying PPE or α-asarone to mice lacking apoE suppressed aorta atherogenesis induced by atherogenic diet. PPE or α-asarone diminished aorta accumulation of CD68- and/or F4/80-positive macrophages induced by atherogenic diet in apoE-deficient mice. Treatment of apoE-deficient mice with PPE and α-asarone resulted in a significant decrease in plasma cholesteryl ester transfer protein level and an increase in lecithin:cholesterol acyltransferase reduced by supply of Paigen's diet. Supplementation of PPE and α-asarone enhanced the transcription of hepatic apoA1 and SR-B1 reduced by Paigen's diet in apoE-deficient mice. CONCLUSIONS: α-Asarone in PPE inhibited inflammation-associated atheroma formation and promoted hepatic HDL-C trafficking in dyslipidemic mice.

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Background and aim: The complex dynamic interplay between different biological pathways involved in atherosclerosis development has rendered the identification of specific therapeutic targets a challenging quest. We aimed to identify specific genes and mechanistic pathways associated with the early development of fibro-atheromas in a swine model of atherosclerosis. Methods: The Wisconsin Miniature Swine™ model of Familial Hypercholesterolemia (WMS-FH, n = 11) and genetically related WMS controls (WMS-N, n = 11) were used. The infrarenal aorta was harvested from both groups for histopathologic and transcriptomic profiling at 12 months. Bioinformatic analysis was performed to identify hub genes and pathways central to disease pathophysiology. The expression of ITGB2, the top ranked hub gene, was manipulated in cell culture and the expression of interconnected genes was tested. Results: Fibro-atheromatous lesions were documented in all WMS-FH aortic tissues and displayed internal elastic lamina (IEL) disruption, significant reduction of myofibroblast presence and disorganized collagen deposition. No fibro-atheromas were observed in the control group. A total of 266 differentially expressed genes (DEGs) were upregulated in WMS-FH aortic tissues, while 29 genes were downregulated. Top identified hub genes included ITGB2, C1QA, LCP2, SPI1, CSF1R, C5AR1, CTSS, MPEG1, C1QC, and CSF2RB. Overexpression of ITGB2 resulted in elevated expression of other interconnected genes expressed in porcine endothelial cells. Conclusion: In a swine translational model of atherosclerosis, transcriptomic analysis identified ITGB2 as a central hub gene associated inflammation and early fibroatheroma development making it a potential therapeutic target at this stage of disease.

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INTRODUCTION: Lipid-laden foam cells within atherosclerotic plaques are key players in all phases of lesion development including its progression, necrotic core formation, fibrous cap thinning, and eventually plaque rupture. Manipulating foam cell biology is thus an attractive therapeutic strategy at early, middle, and even late stages of atherosclerosis. Traditional therapies have focused on prevention, especially lowering plasma lipid levels. Despite these interventions, atherosclerosis remains a major cause of cardiovascular disease, responsible for the largest numbers of death worldwide. AREAS COVERED: Foam cells within atherosclerotic plaques are comprised of macrophages, vascular smooth muscle cells, and other cell types which are exposed to high concentrations of lipoproteins accumulating within the subendothelial intimal layer. Macrophage-derived foam cells are particularly well studied and have provided important insights into lipid metabolism and atherogenesis. The contributions of foam cell-based processes are discussed with an emphasis on areas of therapeutic potential and directions for drug development. EXERT OPINION: As key players in atherosclerosis, foam cells are attractive targets for developing more specific, targeted therapies aimed at resolving atherosclerotic plaques. Recent advances in our understanding of lipid handling within these cells provide insights into how they might be manipulated and clinically translated to better treat atherosclerosis.

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