Intimal Lesions Research Articles

Exploring the Connection: Moyamoya Disease and Its Implications for Cardiovascular Health.

Moyamoya disease (MMD) is a vascular disorder characterized by steno-occlusive alterations in cerebral arteries, often resulting in ischemic or hemorrhagic events predominantly affecting the female population and more common in Asian populations. Despite its predominantly neurological manifestations, recent research suggests a potential association between MMD and cardiovascular diseases (CVDs). MMD involves various genetic and environmental factors, with mutations in the RNF213 gene being strongly implicated in disease susceptibility, with histopathological findings revealing intimal lesions and smooth muscle proliferation, contributing to vascular occlusion as well as dysregulation of circulating endothelial and smooth muscle progenitor cells further complicating MMD's pathogenesis. However, the exact nature of the relationship between MMD and CVD remains incompletely understood, and emerging evidence suggests a potential interplay between these pathologies. In this study, we discuss the potential link between MMD and CVD, exploring genetic factors, pathophysiological mechanisms, and studies highlighting cardiac manifestations in MMD patients.

Oxymatrine attenuates chronic allograft rejection by modulating immune responses and inhibiting fibrosis

BackgroundChronic rejection (CR) is a significant obstacle to long-term allograft survival. Oxymatrine (OMT) is a prominent bioactive compound widely utilized in traditional Chinese medicine for the management of inflammatory disorders and it has considerable potential as a therapeutic candidate for the treatment of CR. MethodsWell-established major histocompatibility complex (MHC) class II mismatched B6 mice. C-H-2bm12-to-C57BL/6 mouse transplantation was used as a CR model. Hematoxylin and eosin (H&E) staining, immunohistochemistry, and Masson's trichrome staining were used to assess pathological changes in the grafts, and the percentages of immune cells were determined by flow cytometry. The effects of OMT on the regulation of CD4+ T cell differentiation and cytokine secretion were verified in vitro. ResultsOMT effectively alleviated pathological graft damage, characterized by chronic changes in intimal lesions, vasculopathy, and fibrosis and significantly prolonged cardiac allograft survival. OMT exerted its immunomodulatory effects by inhibiting T helper 1 (Th1) and T helper 17 (Th17) cell differentiation while promoting Treg differentiation both in vivo and in vitro. Further studies revealed that OMT inhibited the phosphorylation of mammalian target of rapamycin (mTOR), which is a potential mechanism underlying its immunosuppressive effects. OMT also inhibited the activation of B cells and the production of donor-specific antibody (DSA). In addition, OMT effectively alleviated chronic changes in fibrosis in cardiac allografts, and these changes may be related to the inhibition of the transforming growth factor-β (TGF-β)-Smad 2/3 pathway. ConclusionsOMT attenuated CR by modulating the immune response and inhibiting graft fibrosis. Further in-depth investigations of OMT may provide valuable insights into the development of novel therapeutic strategies for CR inhibition.

Smooth muscle cells clonally expand in a murine carotid allograft model complicated by immune reactions to reporter transgenes

Background and aimsMost experimental studies of allograft vasculopathy (AV) have relied on transplantation between major histocompatibility complex-mismatched inbred mouse strains, but this leads to the complete eradication of donor smooth muscle cells (SMCs) and lesions formed by recipient cells. This is unlike human AV which is thought to form mainly by donor SMCs. Here, we studied sources of neointimal cells in a minor histocompatibility antigen-mismatched AV model by combining male-to-female orthotopic carotid transplantations and lineage tracing by SMC-specific expression of fluorescent proteins. MethodsTo track SMC-derived cells in allograft vasculopathy, we used male donor mice with SMC-restricted Cre recombination of the mT/mG reporter transgene, which switches expression of membrane-bound red fluorescent protein (RFP) to green fluorescent protein (GFP), or the stochastically recombining Confetti reporter transgene, which yields a mosaic expression of four fluorescent proteins. Donor carotid segments were harvested and orthotopically allografted to female recipients that were wildtype or had non-recombined reporter transgenes. Inhibition of T cell responses by CTLA4Ig was used in some experiments. Sections of lesions harvested after 4 weeks were analyzed by fluorescence microscopy. ResultsDonor-derived SMCs survived and gave rise to part of the neointimal cells in experiments where carotid segments from recombined mT/mG male mice were transplanted into wild-type or non-recombined mT/mG female mice. Sex-mismatched transplants developed significant lesions, increasing the intimal and medial area 4.6-fold (p = 0.038) and 2.0-fold (p = 0.024) compared to sex- and fluorescence-matched controls, respectively. Interestingly, sex-matched fluorescence-positive transplants developed intimal lesions in 50% of fluorescence-naïve recipient controls. To study the clonal structure of the neointimal donor-derived SMC lineage cells, we then transplanted male carotids with heterozygous or homozygous recombined Confetti transgenes into female recipients. These transplants developed lesions with few surviving donor SMCs, indicating that expression of the Confetti reporter increased rejection and donor-specific SMC death. Some of the few remaining donor SMCs underwent clonal expansion. CTLA4Ig administration at the time of surgery did not improve SMC survival in mT/mG or Confetti transplants. ConclusionMale-to-female transplant models feature donor-derived SMCs, some of which undergo clonal expansion, but immune rejection to fluorescence reporters appears to bias results in lineage tracing models. Overcoming these challenges with alternative reporter transgenes or tolerant recipients is necessary to study the mechanisms by which donor SMCs contribute to allograft vasculopathy.

An arteriovenous fistula model: Carotid artery-posterior facial vein fistula in rats.

To describe an alternative arteriovenous fistula (AVF) model involving anastomosis of the common carotid artery (CCA) with the posterior facial vein (PFV). Twenty-two male Sprague-Dawley rats (age 6-8 weeks) were used to establish the AVF model involving end-to-side anastomosis of PFV and CCA. The peak velocity of the CCA and the diameter of the outflow vein were recorded at 7, 14, and 42 days after the operation using Doppler ultrasound. Pathological examination of the intimal lesions was performed at 14 and 42 days after operation. One rat died within 24 h after surgery related to anesthesia. The patency rates at days 7, 14, and 42 were 85.7%, 81%, and 81%, respectively. The diameter of the carotid artery in rats is approximately 0.8 mm. The diameter of the outflow vein was increased by 1.7-fold and 2.2-fold at 7 days (1.1 ± 0.118 mm) and 14 days (1.4 ± 0.073 mm). At 42 days (1.96 ± 0.101 mm) after operation, the diameter was 3-fold greater compared to the unoperated control rat. The peak systolic flow velocity of the carotid artery at 7 days (593 ± 17.36 mm/s) and 14 days (767 ± 13.64 mm/s) after surgery was significantly greater compared to the control rat (314 ± 15.13 mm/s). The rate of increase was fastest at 7 days and leveled off from 14 to 42 days (875 ± 26 mm/s) after surgery. At 14 days, the intima area showed a nearly 50-fold increase (230 ± 9.93 μm2 × 103) compared to control (area 5 ± 0.37 μm2 × 103). Comparing 6 weeks with 2 weeks (280 ± 10.54 μm2 × 103) after surgery, the intima area increased 1.2 times. The CCA-PFV fistula in rats is a viable alternative AVF model.

Enhanced atherosclerosis in apolipoprotein E knockout rabbits: role of apoB48-rich remnant lipoproteins.

Apolipoprotein E (apoE) acts as a binding molecule for both the low-density lipoprotein receptor and the lipoprotein receptor-related protein and this function is essential for facilitating the hepatocyte uptake of lipoproteins containing apoB. The absence of apoE leads to increased atherogenicity in both humans and mice, although the precise molecular mechanisms remain incompletely understood. This study aimed to investigate the susceptibility of apoE knockout (KO) rabbits, in comparison with wild-type (WT) rabbits, to diet-induced hyperlipidemia and atherosclerosis. ApoE KO rabbits and WT rabbits were fed a diet containing 0.3% cholesterol for 16 weeks. Plasma lipid levels, lipoproteins, and apolipoproteins were analyzed. Atherosclerosis was evaluated at the endpoint of experiments. In addition, we evaluated the oxidizability of those lipoproteins containing apoB to investigate the possible mechanisms of atherosclerosis. Male apoE KO rabbits showed significantly elevated levels of total cholesterol and triglycerides compared to WT rabbits, while female apoE KO rabbits displayed similar high total cholesterol levels, albeit with significantly higher triglycerides levels than WT controls. Notably, both male (2.1-fold increase) and female (1.6-fold increase) apoE KO rabbits exhibited a significantly augmented aortic lesion area compared to WT controls. Pathological examination showed that the increased intimal lesions in apoE KO rabbits were featured by heightened infiltration of macrophages (2.7-fold increase) and smooth muscle cells (2.5-fold increase). Furthermore, coronary atherosclerotic lesions were also increased by 1.3-fold in apoE KO rabbits. Lipoprotein analysis revealed that apoB48-rich beta-very-low-density lipoproteins were notably abundant in apoE KO rabbits, suggesting that these remnant lipoproteins of intestinal origin serve as the primary atherogenic lipoproteins. Moreover, apoB48-rich remnant lipoproteins isolated from apoE KO rabbits exhibited heightened susceptibility to copper-induced oxidation. The findings indicate that apoB48-rich remnant lipoproteins, resulting from apoE deficiency, possess greater atherogenic potential than apoB100-rich remnant lipoproteins, regardless of plasma TC levels.

Treatment of renal artery fibromuscular dysplasia with drug-eluting balloon angioplasty and intravascular imaging: a case report

Fibromuscular dysplasia (FD) is a segmental, non-inflammatory and non-atherosclerotic disease of vascular smooth muscle of unknown etiology, which leads to stenosis of smalland medium-sized arteries. The choice of surgical treatment tactics for renal artery FD depends on the severity of clinical manifestations and the response to the conservative drug treatment used. Young age, female sex, high blood pressure with failure to achieve target values with therapy, as well as the absence of atherosclerotic involvement of other arterial systems gives reason to suspect renal artery FD. According to modern guidelines, the invasive treatment of hemodynamically significant renal artery stenoses includes transluminal drug-eluting balloon angioplasty. In this disease, renal artery stenting is not recommended. However, stent implantation is required if balloon angioplasty did not give the optimal result or in case of periprocedural complications, such as arterial dissection. Open reconstructive surgery is indicated for complex anatomy of the related artery, macroaneurysms in which stent grafts are ineffective, refractory intimal fibroplastic lesions, increased risk of endovascular treatment, or after unsuccessful endovascular intervention. The article presents a case of a young patient with renal artery FD, renovascular arterial hypertension, who successfully underwent renal artery transluminal drugeluting balloon angioplasty.

MiR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling.

Diabetes leads to dysregulated macrophage immunometabolism, contributing to accelerated atherosclerosis progression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet goal. MicroRNAs orchestrate multiple signalling events in macrophages, yet their therapeutic potential in diabetes-associated atherosclerosis remains unclear. miRNA profiling revealed significantly lower miR-369-3p expression in aortic intimal lesions from Ldlr-/- mice on a high-fat sucrose-containing (HFSC) diet for 12 weeks. miR-369-3p was also reduced in peripheral blood mononuclear cells from diabetic patients with coronary artery disease (CAD). Cell-type expression profiling showed miR-369-3p enrichment in aortic macrophages. In vitro, oxLDL treatment reduced miR-369-3p expression in mouse bone marrow-derived macrophages (BMDMs). Metabolic profiling in BMDMs revealed that miR-369-3p overexpression blocked the oxidized low density lipoprotein (oxLDL)-mediated increase in the cellular metabolite succinate and reduced mitochondrial respiration (OXPHOS) and inflammation [Interleukin (lL)-1β, TNF-α, and IL-6]. Mechanistically, miR-369-3p targeted the succinate receptor (GPR91) and alleviated the oxLDL-induced activation of inflammasome signalling pathways. Therapeutic administration of miR-369-3p mimics in HFSC-fed Ldlr-/- mice reduced GPR91 expression in lesional macrophages and diabetes-accelerated atherosclerosis, evident by a decrease in plaque size and pro-inflammatory Ly6Chi monocytes. RNA-Seq analyses showed more pro-resolving pathways in plaque macrophages from miR-369-3p-treated mice, consistent with an increase in macrophage efferocytosis in lesions. Finally, a GPR91 antagonist attenuated oxLDL-induced inflammation in primary monocytes from human subjects with diabetes. These findings establish a therapeutic role for miR-369-3p in halting diabetes-associated atherosclerosis by regulating GPR91 and macrophage succinate metabolism.

Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis

Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr-/- mice on a high-fat, high-sucrose-containing (HFSC) diet identifies a macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in HFSC diet-fed Ldlr-/- mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro-inflammatory responses. These findings unveil a regulatory mechanism whereby amacrophage-enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.

Arterial histology in amputated limbs with chronic limb-threatening ischemia and cadaver limbs

ObjectiveThe study objectives were to: (1) elucidate the histopathological and structural alterations in the femoral to popliteal arteries and tibial or more distal arteries in patients with chronic limb-threatening ischemia through detailed histomorphological and histopathological examinations of the lower limb arteries in the amputated limbs; and (2) elucidate the basic structure of the entire lower extremity, from the external iliac artery to the digital artery, based on histomorphological examinations of cadaver limbs. MethodsWe examined the histopathology and histomorphology of lower limb arteries harvested from 22 amputated limbs and that from 11 cadavers without lower limb issues. Sixty-three sections from the amputated limbs were categorized into femoropopliteal, tibial, and distal segments. Five hundred ten sections (from the external iliac artery to the digital artery) from the cadavers were categorized as femoropopliteal segments, tibial and distal segments, and others. The modified American Heart Association classification was used for the histopathological analysis, and the advanced lesion was defined as the presence of progressive atherosclerotic lesion. In the histomorphological analyses, we calculated % stenosis, % medial area as the medial area divided by the area within the external elastic lamina × 100, and % intimal area as the intimal area divided by the area within the external elastic lamina × 100. ResultsIn amputated limbs, advanced lesions and calcification in the medial area were more prevalent in the femoropopliteal segments than in the tibial and distal segments (advanced lesion: 8/10 vs 18/42; P = .048; calcification: 10/10 vs 28/42; P = .037), whereas % stenosis and prevalence of luminal thrombi were comparable. Significant inverse correlations were noted between % medial area and external elastic lamina diameter in both amputated (r = −0.641; P < .001) and cadaver limbs (r = −0.775; P < .001). In the femoropopliteal segments of the amputated limbs, luminal stenosis was solely caused by intimal lesions, whereas in the tibial and distal segments, medial area thickening contributed to luminal stenosis when intimal lesions were less pronounced. When the external elastic lamina diameter was entered as a covariate, the medial area of the 178 cadaver tibial and distal segments with minimal intimal lesions (<40% intimal area) was significantly greater when >75% stenosis was present in the femoropopliteal segments (P < .001). ConclusionsAdvanced lesions in the tibial and distal segments are less prevalent compared with the femoropopliteal segments. Medial area thickening may contribute to luminal stenosis in the tibial and distal segments when intimal lesions were less pronounced, which may be secondary to a significant proximal occlusive lesion.

Antibiofilm and antithrombotic hydrogel coating based on superhydrophilic zwitterionic carboxymethyl chitosan for blood-contacting devices

Blood-contacting devices must be designed to minimize the risk of bloodstream-associated infections, thrombosis, and intimal lesions caused by surface friction. However, achieving effective prevention of both bloodstream-associated infections and thrombosis poses a challenge due to the conflicting nature of antibacterial and antithrombotic activities, specifically regarding electrostatic interactions. This study introduced a novel biocompatible hydrogel of sodium alginate and zwitterionic carboxymethyl chitosan (ZW@CMC) with antibacterial and antithrombotic activities for use in catheters. The ZW@CMC hydrogel demonstrates a superhydrophilic surface and good hygroscopic properties, which facilitate the formation of a stable hydration layer with low friction. The zwitterionic-functionalized CMC incorporates an additional negative sulfone group and increased negative charge density in the carboxyl group. This augmentation enhances electrostatic repulsion and facilitates the formation of hydration layer. This leads to exceptional prevention of blood clotting factor adhesion and inhibition of biofilm formation. Subsequently, the ZW@CMC hydrogel exhibited biocompatibility with tests of in vitro cytotoxicity, hemolysis, and catheter friction. Furthermore, in vivo tests of antithrombotic and systemic inflammation models with catheterization indicated that ZW@CMC has significant advantages for practical applications in cardiovascular-related and sepsis treatment. This study opens a new avenue for the development of chitosan-based multifunctional hydrogel for applications in blood-contacting devices.

Ultrasound-Assessed Lesion Morphology and Drug-Coated Balloon Treatment for de novo Dysfunctional Arteriovenous Fistula in Hemodialysis Patients.

This study aimed to evaluate the effect of ultrasound-assessed lesion morphology on the outcomes of drug-coated balloon (DCB) versus plain old balloon angioplasty (POBA) treatment for de novo dysfunctional arteriovenous fistulas (AVF) lesions. This single-center retrospective study enrolled 114 consecutive patients (mean age, 73 ± 10 years; male, 69%) with de novo dysfunctional AVF lesions who underwent percutaneous transluminal angioplasty (PTA) using DCB (n = 48) and POBA (n = 66). The morphology of the stenotic lesions, evaluated using ultrasonography, was classified into intimal hyperplasia and shrinking types. The outcome measure was 12-month primary patency. Factors associated with loss of primary patency were evaluated using Cox proportional hazards models. The baseline characteristics were not significantly different between the 2 treatment groups. The 12-month primary patency rate was significantly higher in the DCB group than in the POBA group (66.8 ± 7.1% versus 35.9 ± 6.3%, P = .006). The 12-month primary patency rate in the lesions with intimal hyperplasia type was not significantly different (DCB: 70.3 ± 9.5% versus POBA: 45.9 ± 8.0%; P = .310), whereas that in the shrinking type was significantly higher in the DCB group than in the POBA group (61.9 ± 10.6% versus 15.2 ± 8.1%; P < .001). The interaction analysis demonstrated that lesion morphology had a significantly different hazard ratio (HR) for restenosis between the POBA and DCB groups (P for interaction = .031). The multivariate analysis revealed that DCB usage (adjusted hazard ratio [aHR], 0.49; 95% confidence interval [CI]: [0.28, 0.87]; P = .015), ultrasound-assessed lesion morphology (shrinking type: aHR, 1.77; 95% CI: [1.07, 2.93]; P = .026), and location of stenosis (aHR, 2.26; 95% CI: 1.15, 4.46; P = .018) were significantly associated with AVF patency after PTA. This study revealed that lesion morphology evaluated using ultrasonography had a differential impact on DCB and POBA outcomes. The therapeutic effect of DCB was unexpectedly confirmed in the shrinking type. The effectiveness of DCB in inhibiting smooth muscle cell proliferation in intimal hyperplasia lesions was expected based on the known mechanism of action of paclitaxel. However the therapeutic effect of DCB was unexpectedly confirmed in the shrinking type too. We may not need to hesitate usage of DCB for shrinking type.

Arteriovenous Fistula Stenosis: Correlating Degree of Neointimal Hyperplasia With Reduction in Volume Flow Measured on Ultrasound and Ultrasound Characterization Based on Stenosis Morphology

Introduction: Duplex ultrasound (DUS) is commonly used to diagnose and grade arteriovenous fistula (AVF) stenosis. Duplex ultrasound may also be used to examine stenosis type based on measurement of intimal-medial thickness (IMT). There are, as yet, no criteria in use to define the different stenosis types based on measurement of percentage IMT (%IMT). In this study, we have examined stenosis morphology using ultrasound. We have examined consecutive DUS examinations to assess the incidence and degree of IMT and correlated %IMT with volume flow as an indicator of AVF dysfunction. Methods: Duplex ultrasound was performed as per standard of care. Volume flow was measured within the ipsilateral brachial artery. Measurements of luminal diameter and vessel wall diameter were used to calculate %IMT. Results: The study group included 156 consecutive DUS examinations demonstrating a greater than 50% AVF stenosis. Mean %IMT was 45%. There were 17 (11%) lesions where there was no measurable IMT; the remainder had measurable IMT. On receiver-operating characteristic (ROC) analysis, a %IMT of 54% predicted low flow with 62.5% sensitivity and 62.7% specificity. Conclusion: Intimal-medial thickness has a moderate predictive value in predicting volume flow. Based on our results, there are 4 lesion types: (1) lesions with no measurable intimal hyperplasia, (2) a predominantly intimal hyperplastic lesion, (3) those with nonpredominant intimal hyperplasia, and (4) those with a valve type stenosis. A value based on correlation with volume flow could be considered based on our results at 54%IMT or based on morphology at 45%IMT to distinguish between predominant and nonpredominant intimal hyperplasia groups. Including measurements of %IMT in clinical trials could further our knowledge of how lesions with no measurable IMT and those with different degrees of intimal hyperplasia respond to different percutaneous interventions. This could potentially improve outcomes for patients and target more costly treatment options where there is most benefit.

Atherogenesis in Apoe−/− and Ldlr−/− Mice with a Genetically Resistant Background

Apoe-deficient (Apoe-/-) and Ldlr-deficient (Ldlr-/-) mice are two common animal models of hypercholesterolemia and atherosclerosis. The two models differ in lipid and glucose metabolism and other mechanisms involved in atherogenesis. Here we examined atherosclerotic lesion formation in the two models with an atherosclerosis-resistant C3H/HeJ (C3H) background. 3-month-old C3H-Ldlr-/- and C3H-Apoe-/- mice developed minimal atherosclerotic lesions in the aortic root when fed a chow diet. After 12 weeks on a Western diet, C3H-Ldlr-/- mice developed 3-fold larger lesions than C3H-Apoe-/- mice in the aortic root (127,386 ± 13,439 vs. 41,542 ± 5075 μm2/section; p = 0.00028), but neither knockout formed any lesion in the carotid artery. After being ligated near its bifurcation, the common carotid artery developed intimal lesions in both knockouts 4 weeks after ligation, significantly larger in C3H-Ldlr-/- than C3H-Apoe-/- mice (68,721 ± 2706 vs. 47,472 ± 8146 μm2/section; p = 0.028). Compared to C3H-Apoe-/- mice, C3H-Ldlr-/- mice showed a 50% reduction in plasma MCP-1 levels, similar levels of malondialdehyde, an oxidative stress biomarker, on both chow and Western diets, but higher small dense LDL levels on the Western diet. These results suggest a more significant role for small dense LDL than inflammation and oxidative stress in the different susceptibility of the mouse models to atherosclerosis.

Adherence to Mediterranean Diet: A Population-Based Longitudinal Cohort Study.

Adherence to the Mediterranean diet (MedDiet) is recommended for cardiovascular disease prevention. However, recent epidemiological studies report a shift toward lower adherence to MedDiet. We have conducted a prospective cohort study to evaluate changes in individual determinants of MedDiet adherence over time. Clinical information and MedDiet adherence score (MEDAS) were collected in 711 subjects (mean age 68 ± 10 years; 42% males), enrolled in the PLIC study (Progression of Intimal Atherosclerotic Lesions in Carotid arteries), during two visits conducted, on average, 4.5 years apart. MEDAS score worsening and improvements (absolute change, ΔMEDAS) and the variation in the proportion of subjects reporting to meet each MEDAS criteria were assessed. Overall, 34% of the subjects improved their MedDiet adherence (ΔMEDAS: +1.87 ± 1.13), by consuming more olive oil, legumes and fish and use of dishes seasoned with sofrito and 48% subjects worsened their MedDiet adherence (ΔMEDAS: -2.02 ± 1.14) by consuming less fruit, legumes, fish and nuts, with higher rates of worsening in women and subjects aged 50-65 years. Subjects who improved the score were more obese, had higher plasma glucose levels, and metabolic syndrome at the basal visit. In summary, we report an overall decrease in MedDiet adherence, evaluated during a timeframe heavily affected by the COVID-19 pandemic, underlining the need for better dietary interventions.

Macrophage elastase derived from adventitial macrophages modulates aortic remodeling.

Abdominal aortic aneurysm (AAA) is pathologically characterized by intimal atherosclerosis, disruption and attenuation of the elastic media, and adventitial inflammatory infiltrates. Although all these pathological events are possibly involved in the pathogenesis of AAA, the functional roles contributed by adventitial inflammatory macrophages have not been fully documented. Recent studies have revealed that increased expression of matrix metalloproteinase-12 (MMP-12) derived from macrophages may be particularly important in the pathogenesis of both atherosclerosis and AAA. In the current study, we developed a carrageenan-induced abdominal aortic adventitial inflammatory model in hypercholesterolemic rabbits and evaluated the effect of adventitial macrophage accumulation on the aortic remodeling with special reference to the influence of increased expression of MMP-12. To accomplish this, we compared the carrageenan-induced aortic lesions of transgenic (Tg) rabbits that expressed high levels of MMP-12 in the macrophage lineage to those of non-Tg rabbits. We found that the aortic medial and adventitial lesions of Tg rabbits were greater in degree than those of non-Tg rabbits, with the increased infiltration of macrophages and prominent destruction of elastic lamellae accompanied by the frequent appearance of dilated lesions, while the intimal lesions were slightly increased. Enhanced aortic lesions in Tg rabbits were focally associated with increased dilation of the aortic lumens. RT-PCR and Western blotting revealed high levels of MMP-12 in the lesions of Tg rabbits that were accompanied by elevated levels of MMP-2 and -3, which was caused by increased number of macrophages. Our results suggest that adventitial inflammation constitutes a major stimulus to aortic remodeling and increased expression of MMP-12 secreted from adventitial macrophages plays an important role in the pathogenesis of vascular diseases such as AAA.

Are acute type A aortic dissections atherosclerotic?

Type A aortic dissections (TAAD) are devastating aortic complications. Patients with Marfan syndrome, a bicuspid aortic valve or a thoracic aortic aneurysm have an increased risk to develop a TAAD. These predisposing conditions are characterized by a histologically thin intimal layer and hardly any atherosclerosis. Little is known about the susceptibility for atherosclerosis in patients with a type A aortic dissection. We aim to systematically describe atherosclerotic lesions in TAAD patients. A total of 51 patients with a TAAD (mean age 62.5 ± 10.8 years, 49% females) and 17 control patients (mean age 63 ± 5.5 years, 53% females) were included in this study. Cardiovascular risk factors were assessed clinically. All sections were stained with Movat pentachrome and hematoxylin eosin. Plaque morphology was classified according to the modified AHA classification scheme proposed by Virmani et al. In the TAAD group thirty-seven percent were overweight (BMI > 25). Diabetes and peripheral arterial disease were not present in any of the patients. Fifty-nine percent of the patients had a history of hypertension. The intima in TAAD patients was significantly thinner as compared to the control group (mean thickness 143 ± 126.5 μm versus 193 ± 132 μm, p < 0.023). Seven TAAD patients had a normal intima without any form of adaptive or pathological thickening. Twenty-three TAAD patients demonstrated adaptive intimal thickening. Fourteen had an intimal xanthoma, also known as fatty streaks. A minority of 7 TAAD patients had progressive atherosclerotic lesions, 4 of which demonstrated pathological intimal thickening, 3 patients showed early fibroatheroma, late fibroatheroma and thin cap fibroatheroma. In the control group the majority of the patients exhibited progressive atherosclerotic lesions: three pathologic intimal thickening, two early fibroatheroma, six late fibroatheroma, one healed rupture and two fibrotic calcified plaque. This study shows that TAAD patients hardly exhibit any form of progressive atherosclerosis. The majority of TAAD patients showcase non-progressive intimal lesions, whereas the control group mostly demonstrated progressive intimal atherosclerotic lesions. Findings are independent of age, sex, or the presence of (a history of) hypertension.

Clinical characteristics and outcomes of Stanford type B aortic intramural hematoma: A single centre experience.

To compare the clinical characteristics of Stanford type B aortic intramural hematoma (IMH) and Stanford type B aortic dissection (AD), and to identify the differences between thoracic endovascular aortic repair (TEVAR) and medical management (MM) in the Stanford type B IMH patients. A retrospective observational study was conducted in patients treated between January 2015 and December 2016. The clinical characteristics and CT images of patients with type B IMH and type B AD were compared, and the clinical characteristics and CT images of patients in the type B IMH group who were treated with TEVAR and MM were compared. A total of 176 patients were included in this study, including 62 patients of type B IMH and 114 patients of type B AD. Five patients died in the IMH group and three in the AD group. The proximal hematoma or entry tear in both groups was mainly located in the descending aorta, and the proportion of the iliac artery involved in the AD group was significantly higher than that in the IMH group (31.6% vs. 8.1% P < 0.05). There were 50 MM patients and 12 TEVAR patients in the IMH group. No death occurred in the TEVAR group, while five patients in the MM group died. Seven patients in the MM group had disease progression vs. 12 in the TEVAR group (P < 0.05). The patients in the TEVAR group had more intima lesions than those in the MM group (83.3% vs. 30.0%, P < 0.05). TEVAR group involved more iliac artery hematoma than MM group (33.3% vs. 2.0%, P < 0.05). The maximum thickness of hematoma in TEVAR group was 14.9 ± 3.4 mm, which was significantly larger than that of MM group (10.2 ± 2.8 mm) (P < 0.05). In the diagnosis of IMH, patients' symptoms and high-risk signs of CTA should be paid attention to. TEVAR therapy should be actively considered on the basis of effective medical management when there are intima lesions (ULP/PAU), increased aortic diameter and hematoma thickness, extensive hematoma involvement, and pleural effusion.

Rapid Rise in Cardio-Ankle Vascular Index as a Predictor of Impending Cardiovascular Events -Smooth Muscle Cell Contraction Hypothesis for Plaque Rupture.

Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.

Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca2+ signaling.

The pulmonary circulation is a low-resistance, low-pressure, and high-compliance system that allows the lungs to receive the entire cardiac output. Pulmonary arterial pressure is a function of cardiac output and pulmonary vascular resistance, and pulmonary vascular resistance is inversely proportional to the fourth power of the intraluminal radius of the pulmonary artery. Therefore, a very small decrease of the pulmonary vascular lumen diameter results in a significant increase in pulmonary vascular resistance and pulmonary arterial pressure. Pulmonary arterial hypertension is a fatal and progressive disease with poor prognosis. Regardless of the initial pathogenic triggers, sustained pulmonary vasoconstriction, concentric vascular remodeling, occlusive intimal lesions, in situ thrombosis, and vascular wall stiffening are the major and direct causes for elevated pulmonary vascular resistance in patients with pulmonary arterial hypertension and other forms of precapillary pulmonary hypertension. In this review, we aim to discuss the basic principles and physiological mechanisms involved in the regulation of lung vascular hemodynamics and pulmonary vascular function, the changes in the pulmonary vasculature that contribute to the increased vascular resistance and arterial pressure, and the pathogenic mechanisms involved in the development and progression of pulmonary hypertension. We focus on reviewing the pathogenic roles of membrane receptors, ion channels, and intracellular Ca2+ signaling in pulmonary vascular smooth muscle cells in the development and progression of pulmonary hypertension.

Abstract 13700: LncRNA MERRICAL Controls Macrophage Chemotaxis and Vascular Inflammation by In-cis Regulation of CCL3/4 via H3k4me3 in Diabetes-Associated Atherosclerosis

Introduction: Diabetes-associated atherosclerosis is characterized by excessive vascular wall inflammation, including impaired lipid deposition, increased immune cell infiltration and plaque formation in the vessel wall. Macrophages are instrumental for lesion formation, however the mechanisms underlying their impaired functional capacity remain poorly understood in diabetes. Herein, we identify a unique role of a macrophage-enriched lncRNA MERRICAL (Macrophage Enriched lncRNA Regulates Inflammation, Chemotaxis, and AtheroscLerosis) in the development of diabetes-associated atherosclerosis. Methods: Transcriptomic analysis of the aortic intima from Ldlr -/- mice was performed at 4 time points along the continuum of lesion progression and regression under a high fat, high sucrose-containing (HFSC) or chow diet, respectively, to identify differentially expressed lncRNAs. Gain- and loss-of-function cell-based assays, RNA-protein interactions, and in vivo knockdown were performed to uncover the role of a top lncRNA candidate. Results: LncRNA MERRICAL is nuclear localized and increased by 249% in intimal lesions during progression. Transcriptomic analysis of MERRICAL -deficient bone marrow-derived macrophages showed decreased chemokine and inflammatory gene expression for Ccl3, Ccl4, and Il1β, with reduced chemotaxis and inflammatory-associated gene ontology pathways. Gain- and loss-of-function studies demonstrated the role of lncRNA MERRICAL in cis -regulation of its neighboring genes Ccl3 and Ccl4, an effect that is mediated in part via interaction with the histone modification enzyme H3K4me3. Remarkably, systemic knockdown of MERRICAL in HFSC-fed mice strongly reduced lesion formation by 73% in the aortic sinus by inhibiting the pro-inflammatory and Ccl3 - and Ccl4 -associated chemotactic response and decreasing the recruitment of leukocytes into the aortic wall. Conclusions: These findings establish a cis -regulatory mechanism by which a macrophage-specific lncRNA, MERRICAL , potently inhibits pro-inflammatory and chemotactic responses to alleviate lesion progression in diabetes, with implications for a broad range of diabetes-associated vascular disease states.