Atherosclerotic Complications Research Articles

Activation of heme oxygenase-1 by laminar shear stress ameliorates high glucose-induced endothelial cell and smooth muscle cell dysfunction.

High glucose (HG)-induced endothelial cell (EC) and smooth muscle cell (SMC) dysfunction is critical in diabetes-associated atherosclerosis. However, the roles of heme oxygenase-1 (HO-1), a stress-response protein, in hemodynamic force-generated shear stress and HG-induced metabolic stress remain unclear. This investigation examined the cellular effects and mechanisms of HO-1 under physiologically high shear stress (HSS) in HG-treated ECs and adjacent SMCs. We found that exposure of human aortic ECs to HSS significantly increased HO-1 expression; however, this upregulation appeared to be independent of adenosine monophosphate-activated protein kinase, a regulator of HO-1. Furthermore, HSS inhibited the expression of HG-induced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and reactive oxygen species (ROS) production in ECs. In an EC/SMC co-culture, compared with static conditions, subjecting ECs close to SMCs to HSS and HG significantly suppressed SMC proliferation while increasing the expression of physiological contractile phenotype markers, such as α-smooth muscle actin and serum response factor. Moreover, HSS and HG decreased the expression of vimentin, an atherogenic synthetic phenotypic marker, in SMCs. Transfecting ECs with HO-1-specific small interfering (si)RNA reversed HSS inhibition on HG-induced inflammation and ROS production in ECs. Similarly, reversed HSS inhibition on HG-induced proliferation and synthetic phenotype formation were observed in co-cultured SMCs. Our findings provide insights into the mechanisms underlying EC-SMC interplay during HG-induced metabolic stress. Strategies to promote HSS in the vessel wall, such as continuous exercise, or the development of HO-1 analogs and mimics of the HSS effect, could provide an effective approach for preventing and treating diabetes-related atherosclerotic vascular complications.

The predictive value of plasma uridine for type 2 diabetes and its atherosclerotic complications.

Uridine might be a common link between pathological pathways in diabetes and cardiovascular diseases. This study aimed to investigate the predictive value of plasma uridine for type 2 diabetes and type 2 diabetes with atherosclerosis. Individuals with type 2 diabetes (T2D) and healthy controls (n=218) were randomly enrolled in a cross-sectional study. Patients with T2D were divided into two groups based on carotid ultrasound: patients with carotid atherosclerosis (CA) (group DCA), and patients without CA (group D). Plasma uridine was determined using high-performance liquid chromatography-tandem mass spectrometry. Correlation and logistic regression analyses were used to analyze the results. Fasting and postprandial uridine were significantly increased in patients with T2D compared with healthy individuals. Logistic regression suggested that fasting and postprandial uridine were independent risk factors for T2D. The receiver operating characteristic (ROC) curve showed that fasting uridine had a predictive value on T2D (95% CI,0.686-0.863, sensitivity 74.3%, specificity 71.8%). Fasting uridine was positively correlated with LDL-c, FBG, and PBG, and negatively correlated with CP-0h and HOMA-IS. The change in postprandial uridine from fasting baseline (Δ uridine) was smaller in T2D patients with CA compared with those without (0.80(0.04-2.46) vs. 2.01(0.49-3.15), P=0.010). Δuridine was also associated with T2D with CA and negatively correlated with BMI, CP-0h, and HOMA-IR. Fasting uridine has potential as a predictor of diabetes. Δuridine is closely associated with carotid atherosclerosis in patients with T2D.

STATINS IN THE TREATMENT OF PATIENTS WITH PERIPHERAL ARTERY DISEASES: STRATEGY AND TACTICS OF APPOINTMENT

The article presents a review of the literature on the relationship of peripheral artery diseases and cardiovascular complications. According to modern concepts, peripheral artery diseases are classified as markers of very high cardiovascular risk. The most important aspect of the therapy of patients in this category, in addition to correcting specific symptoms of vascular lesions of the lower extremities, is to reduce the risk of developing cardiovascular diseases and their prevention, and treatment of patients in this category should be carried out in accordance with the recommendations for secondary prevention of cardiovascular complications, the most important part of which is the control of serum lipids. Statins are the most widely used class of drugs for the correction of hypercholesterolemia, but the frequency of their appointment as a strategically important class of drugs to prevent the development of atherosclerotic cardiovascular complications in high- and very high-risk individuals in the Russian Federation, as in other countries, remains low. The basic principles of lipid-lowering therapy in patients with peripheral artery diseases are described: strategies, goals and issues of therapy control.

Cardiovascular and Kidney Risks in Individuals With Type 2 Diabetes: Contemporary Understanding With Greater Emphasis on Excess Adiposity.

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways-e.g., hemodynamic, cellular overnutrition, and inflammatory-could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium-glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes.

Effect of atherosclerosis on the relationship between atrial fibrillation and ischemic stroke incidence among patients on hemodialysis

In patients undergoing hemodialysis, the impact of atrial fibrillation (AF) through cardiac thromboembolism on the development of ischemic stroke may be influenced by the severity of atherosclerosis present. However, there are no large-scale reports confirming whether the severity of atherosclerosis influences the relationship between AF and stroke development in patients requiring hemodialysis. We aimed to investigate the effects of atherosclerotic disease on the relationship between AF and new-onset ischemic stroke. This nationwide longitudinal study based on dialysis facilities across Japan used data collected from the Japanese Renal Data Registry at the end of 2019 and 2020. The exposure was AF at the end of 2019, identified using a resting 12-lead electrocardiography. The primary outcome was the incidence of cerebral infarction (CI) after 1 year. To examine whether the number of atherosclerotic diseases modified the association between AF and the outcome, we estimated the odds ratios (ORs) using a logistic regression model and then assessed the presence of global interaction using Wald test. Following the study criteria, data from 151,350 patients (mean age, 69 years; men, 65.2%; diabetic patients, 48.7%) were included in the final analysis. A total of 9841 patients had AF (prevalence, 6.5%). Between 2019 and 2020, 4967 patients (3.2%) developed ischemic stroke. The adjusted OR of AF for new-onset CI was 1.5, which showed a decreasing trend with an increasing number of atherosclerotic diseases; the interaction was not significant (P = 0.34). While age, diabetes mellitus, smoking, systolic blood pressure, and serum C-reactive protein concentration were positively associated with CI, intradialytic weight gain, body mass index, and serum albumin level were negatively associated. While we demonstrated the association between AF and new-onset CI among Japanese patients on hemodialysis, we failed to demonstrate the evidence that the association was attenuated with an increasing numbers of atherosclerotic complications.

O-09 A rare cause of acute pancreatitis: Werner Syndrome

Abstract Introduction Lipodystrophies are rare disorders characterized by loss of body fat resulting in leptin deficiency. Patients are predisposed to metabolic complications such as severe insulin resistance, hypertriglyceridemia, and hepatic steatosis. Werner syndrome (WS) is among the progeroid syndromes in the classification of lipodystrophy. Due to its extremely rare occurrence, it can often be overlooked by the clinician. Clinical Case A 19 years old male patient hospitalized for non-biliary acute pancreatitis was consulted for hypertriglyceridemia and hyperglycemia. He had no history of any disease or medication use. His sister was diagnosed with type 2 diabetes mellitus at age 29. She was using linagliptin and gliclazide for 3 years. She had short stature (147 cm) and low body weight (40 kg) and had scleroderma-like skin findings. The patient also had short stature (157 cm) and low body weight (41 kg). He had scleroderma-like skin findings and generalized loss of subcutaneous adipose tissue. The laboratory results were; glucose, 261 mg/dl; creatinine, 0.46 mg/dl; ALT, 24 U/l; lipase, 161 U/l; HbA1c, 9.6%; triglyceride, 799 mg/dl; HDL, 9.6 mg/dl; LDL, 75 mg/dl; c-peptide, 4.3 ng/dl. The thyroid function test results (TSH: 29.7 µIU/ml, fT4: 6.81 pmol/L, Anti-TPO: negative) were consistent with primary hypothyroidism. Hepatosteatosis was observed in abdominal ultrasonography. We initiated intensive insulin, metformin as well as fenofibrate and levothyroxine treatment. The patient needed high insulin doses (60 IU/day). Measured serum leptin levels were found to be low (2.11 ng/ml) in suspicion of lipodystrophy. Genetic analysis of the patient and his sister showed homozygous mutation in the WRN gene (c.1105C>T p.Arg369Ter, Homozygous) which was compatible with WS. The patient was started on leptin analog therapy in a clinical trial. Conclusion WS is an exceptionally rare autosomal recessive genetic disorder characterized by premature aging and multisystemic complications. The clinical features encompass scleroderma-like skin changes, short stature, low body weight, alopecia, cataracts, osteoporosis, and a propensity for atherosclerotic complications and malignancies. Impaired glucose tolerance is reported in 15%–20% of WS subjects, diabetes mellitus in 55%–70%, and dyslipidemia in 60%–85%. The presence of hypertriglyceridemia, diabetes mellıtus and generalized lack of subcutaneous adipose tissue led us to suspect from lipodystrophy. Although acute pancreatitis due to hypertriglyceridemia can be seen in lipodystrophy (15-20%), first presentation of WS presenting with acute pancreatitis is very rare in the literature. The most common mutation in non-Japanese patients in WRN gene is c.1105 C>T (18.6%). Metreleptin, an analog of human leptin, is shown to ameliorate the metabolic derangements. WS remains a diagnostic challenge due to its rarity, atypical presentation, and should be kept in mind in patients with severe dyslipidemia and insulin resistance.

Cardiovascular Complications in Pheochromocytoma and Paraganglioma: Does Phenotype Matter?

Adrenaline-producing tumors are mostly characterized by a sudden release of catecholamines with episodic symptoms. Noradrenergic ones are usually less symptomatic and characterized by a continuous overproduction of catecholamines that are released into the bloodstream. Their effects on the cardiovascular system can thus be different. The aim of this study was to determine the prevalence of cardiovascular complications by catecholamine phenotype. We retrospectively analyzed data on the prevalence of cardiovascular events in 341 consecutive patients with pheochromocytoma and paraganglioma treated from 1995 to 2023. Biochemical catecholamine phenotype was determined based on plasma or urinary catecholamines and metanephrines. According to the phenotype, 153 patients had noradrenergic pheochromocytoma and paraganglioma and 188 had adrenergic pheochromocytoma and paraganglioma. In the whole sample, the incidence of serious cardiovascular complications was 28% (95 patients), with no difference between the phenotypes or sexes. The noradrenergic phenotype had significantly more atherosclerotic complications (composite end point of type 1 myocardial infarction and symptomatic peripheral artery disease; odds ratio, 3.58 [95% CI, 1.59-8.83]; P=0.003), while the adrenergic phenotype more often had type 2 myocardial infarction and takotsubo-like cardiomyopathy (OR, 0.24 [95% CI, 0.09-0.57]; P=0.002). These changes remained even after adjustment for conventional risk factors of atherosclerosis. We found a 28% incidence of cardiovascular complications in a consecutive group of patients with pheochromocytoma and paraganglioma. Patients presenting with a noradrenergic phenotype have a higher incidence of atherosclerotic complications, while the adrenergic phenotype is associated with a higher incidence of acute myocardial damage due to takotsubo-like cardiomyopathy.

Interleukin-1β gene rs1143634 polymorphism and cardiovascular complications in patients with coronary artery atherosclerosis

The course of heart failure, regardless of its etiology, is associated with local and systemic activation of inflammatory signaling cascades. Identification of the association of candidate cytokine genes with the risk of developing coronary heart disease and chronic heart failure remains a subject of interest for many researchers. The review presents an analysis of studies of the rs1143634 polymorphism of the IL-β gene in relation to the risk of atherosclerotic cardiovascular complications. The presence of the minor allele T is associated with an increase in the concentration of IL-1β in the blood serum. Data on the role of the rs1143634 polymorphism of the IL-β gene in atherosclerotic coronary heart disease, including in combination with chronic heart failure syndrome, are presented, taking into account ethnic characteristics and gender of patients. The carriage of the T allele was associated with the risk of developing atherosclerosis and myocardial infarction. At the same time, it is reported that the C allele and the CC genotype of the rs1143634 polymorphism of the IL-1β gene were a genetic risk factor for the development and progression of heart failure. In a number of studies and meta-analyses, the association of this polymorphism with diseases of the cardiovascular system was not confirmed, but certain trajectories of the risk of complications were identified due to differences in the rs1143634 polymorphism of the IL-β gene in heart failure.

Effect of oral versus parenteral vitamin D3 supplementation on nuclear factor-κB and platelet aggregation in type 2 diabetic patients.

Platelet hyperactivity is one of the key factors implicated in the development and progression of diabetic vascular complications. Activated platelets mediate leukocyte recruitment that further enhances inflammatory responses in vascular wall ultimately resulting in atherosclerotic complications. Since vitamin D insufficiency is highly prevalent in diabetics, we aimed to evaluate the effect of three dosage forms of vitamin D supplementation on lipid profile, NF-κB, platelet aggregation, and platelet calcium content in type 2 diabetic patients. Type 2 diabetic patients were randomized to receive daily (4000 IU/day) or weekly (50 000 IU/week) oral vitamin D3 for 3 months. Another group received a single parenteral dose (300 000 IU) of vitamin D3, whereas the control group received their antidiabetic drug(s) alone. Serum 25(OH)D, total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol, NF-κB, and platelet aggregation were measured at the beginning and 3 months after vitamin D supplementation. Platelet calcium content was evaluated by measuring the fluorescence intensity of Rhod-2-stained platelets by confocal fluorescence microscopy. Results showed that serum 25(OH)D3 levels significantly increased in all vitamin D3-treated groups. However, the mean level for parenteral treated group was significantly lower than oral-treated groups. Oral and parenteral treatment were also able to decrease NF-κB level, platelet aggregation, and platelet calcium content. However, both oral doses of vitamin D3 were superior to the single parenteral dose. In conclusion, restoring normal levels of vitamin D is an important determinant to maintain normal platelet function and reduce inflammation. Nevertheless, further long-term studies are still needed.

Atherosclerotic Cardiovascular Disease in Diabetes Patients.

Diabetes mellitus (DM) is a metabolic disorder characterized by abnormally elevated levels of blood glucose. The hyperglycemic condition is caused by abnormalities in either insulin secretion, insulin action, or both. Two-thirds of diabetes-related deaths are caused by atherosclerotic cardiovascular disease (ASCVD). The purpose of this study was to determine the risk of ASCVD and related factors in type 2 DM patients in Medan, North Sumatra. We conducted a cross-sectional observational study. A total of 252 DM patients visiting primary health centers in Medan were recruited after fulfilling the inclusion and exclusion criteria. The level of risk of atherosclerotic cardiovascular disease (ASCVD) was determined by using ASCVD Risk Calculator. Data required to use this calculator are age, sex, race, total cholesterol, HDL-C, systolic blood pressure, diastolic blood pressure, history of diabetes, history of hypertension treatment, smoking history, and use of statins for anti-hyperlipidemia. The data were then analyzed with Chi-square Test (p < 0.0%) and processed with SPSS. There were 59 (23.41%), 140 (55.56%), and 53 (21.03%) participants who had high, moderate, and low risks of ASCVD, respectively. Bivariate analysis showed significant association between risk of ASCVD with age, SBP, total cholesterol level, HDL-C levels, and duration of diabetes (p < 0.05). Meanwhile, gender and familial history not related to ASCVD risks among DM patients (p > 0.05). The risks for atherosclerotic complications of cardiovascular disease in type 2 DM patients in Medan were predominantly high. The variables related to ASCVD risks included age, gender, HbA1C, systolic blood pressure (SBP), total cholesterol levels, HDL-C, and LDL-C levels.

Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis invitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease.

Nephrotic syndrome: pathophysiology and consequences.

In patients with kidney disease, nephrotic syndrome can lead to several complications including progressive kidney dysfunction. Proteinuria may lead to the formation of cellular or fibrous crescents with reciprocal development of rapidly progressive glomerulonephritis or focal glomerulosclerosis. Proteinuria may also cause overload and dysfunction of tubular epithelial cells, eventually resulting in tubular atrophy and interstitial fibrosis. Hypoalbuminemia is usually associated with increased risk of mortality and kidney dysfunction. Dyslipidemia may increase the risk of atherosclerotic complications, cause podocyte dysfunction and contribute to vascular thrombosis. Urinary loss of anticoagulants and overproduction of coagulation factors may facilitate a hypercoagulable state. Edema, hypogammaglobulinemia, loss of complement factors, and immunosuppressive therapy can favor infection. Treatment of these complications may reduce their impact on the severity of NS. Nephrotic syndrome is a kidney disorder that can worsen the quality of life and increase the risk of kidney disease progression.

Catestatin in diagnosing cardiovascular and metabolic disorders in patients with comorbid hypertension

Background. Hypertension is the major pandemic in human history, which determines the structure of cardiovascular morbidity and mortality. There is an obvious relationship between hypertension and various diseases that largely determine its development and increase the risk of cardiovascular complications. Neuropeptides appear to have a major impact on the progression of these complications. Catestatin (CST) is one of them, which deserves special scientific and practical concern, as it has a wide range of biological effects in the body. The aim of the study: to determine the place of CST in the early diagnosis of cardiovascular and metabolic complications in patients with comorbid hypertension among the Ukrainian population. Materials and methods. One hundred and eleven patients with hypertension, type 2 diabetes mellitus, obesity (men/women — 50/61) and 20 controls were examined. All patients with hypertension, type 2 diabetes mellitus, and obesity were aged 54.37 ± 1.18 years. Following a thorough examination and supervision, they were divi­ded into 2 groups depending on the median CST level of 2.45 ng/ml. The first group included 55 (49.5 %) patients who had a CST level below 2.45 ng/ml, the second one consisted of 56 patients (50.5 %) who had a CST level above 2.45 ng/ml. In all patients, we measured body weight, height, calculated body mass index, evaluated glycated hemoglobin levels, lipid metabolism (serum concentrations of total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein cholesterol); systolic and diastolic blood pressure. The content of CST, cardiotrophin 1, leptin, cystatin C, neutrophil gelatinase-associated lipocalin, N-terminal prohormone of brain natriuretic peptide, 25(OH)D, β2-microglobulin, and insulin levels in the blood serum were determined by enzyme-linked immunosorbent assay. Results. A reliable difference between the groups was found by β2-microglobulin (p = 0.008). Univariate and multivariate linear regression analysis revealed a negative correlation between CST and cardiotrophin 1, N-terminal prohormone of brain natriuretic peptide, neutrophil gelatinase-associated lipocalin, and 25(OH)D. A positive correlation was found between CST and the level of glycated hemoglobin, body mass index, and triglycerides. A statistically significant correlation was found between CST and creatinine (R = –0.21, p = 0.029), high-density lipoprotein cholesterol (R = 0.207, p = 0.029), and β2-microglobulin (R = 0.279, p = 0.0029) in the patients with hypertension. Conclusions. It has been proven that a decrease in serum catestatin concentration can be a risk factor for the development of more severe comorbidities in patients with hypertension. The detected relationships of catestatin with creatinine, urea, and β2-microglobulin suggest that CST is a predictor of chronic kidney disease in patients with comorbidities. The revealed correlation of CST with high-density lipoprotein, obesity, and body mass index suggests its importance in the prevention of atherosclerotic and metabolic complications in patients with hypertension, type 2 diabetes mellitus, and obesity.

Effect of Moringa Leaves Ethanolic Extract (Moringa oleifera, Lam.) on Testicles Histopathological Structure in Metabolic Syndrome Rat Model

&lt;p&gt;&lt;strong&gt;Introduction:&lt;/strong&gt; Metabolic syndrome was a collection of various disorders that can significantly increase the risk of experiencing insulin resistance, atherosclerotic cardiovascular disease, vascular complications, and diabetes mellitus. The detrimental effect of this condition has led to the development of various treatments options, such as Moringa leaves extract (Moringa oleifera), which was suspected to have ameliorative effects. Therefore, this study aimed to determine the effect of Moringa leaves extract on the histopathological appearance of the testes of Wistar rats induced with metabolic syndrome.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This was an experimental design study, with a post-test-only control group, involving 30 Wistar rats (Rattus norvegicus). Metabolic syndrome was induced in the samples through the administration of high-fat and fructose feeds along with streptozotocin and nicotinamide. Furthermore, the moringa leaves extract was administered to the treatment groups in different doses of 150, 250, and 350 mg/kg BW. Testicular histopathological damage scores were then assessed on each group. The Kruskal-Wallis test which followed by Mann-Whitney test was used to determine the significant differences between the groups, while the correlation was analyzed using Spearman test.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; There were significant differences in the histopathological scores between the treatment and control groups. Furthermore, the Wistar rats treated with Moringa extract showed better histopathological scores (2.1±0.64) compared to those without the treatment (2.7±0.54), p&amp;lt;0.05. The results also showed that higher doses of the extract significantly correlated with better outcome in testicular histopathological structure of metabolic syndrome rat model (p=0.000, r=-0.396).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; Moringa leaves ethanolic extract treatment improved testicular histopathological appearance in Wistar rats induced with metabolic syndrome.&lt;/p&gt;

Anti-inflammation nanomedicine shots through atherosclerotic plaques for targeted treatment and precise diagnosis

Atherosclerosis, formed by fibrofatty lesions in the artery wall, underpins myocardial infarctions, strokes and disabling peripheral artery diseases. Inflammation with multiple maladaptive roles runs through atherosclerotic inception, propagation, and complications. Given degree of inflammation differing among atherosclerotics, inflammation-targeted nanomedicine may produce individualized monitoring and manipulation of inflammatory regulators beyond traditionally slowing down atherosclerosis progression. Equipped with biomimetic membrane, microenvironment-responsive and targeting structures, nanomedicines could escape from the innate immune system and autonomously navigate to targeted lesions, thereby muting inflammation in atherosclerotic sites. Moreover, nanoparticles’ advantages go beyond advancing pharmacology. The optimal physicochemical properties of nanoparticles favor noninvasive imaging function to provide diagnostic and prognostic information of atherosclerotic plaques. Despite efficacious ability of the preclinical anti-inflammation nanotherapeutics to reduce atherosclerotic risks, future translation of inflammation-targeted nanomedicines requires to comprehensively refine the strategies that the nanomedicines forestall inflammatory pathways via systemic exposure, drug-cell interactions, and endothelial barrier reconstruction. In this review, we outline the development of diverse nanomedicines to specifically identify pathophysiological changes and combat advanced atherosclerosis along with dynamically tracing inflammatory markers. Finally, challenges and opportunities of inflammation-targeted nanomedicines are highlighted to pave avenues toward personalized medicine for atherosclerosis to stem the growing global burden of cardiovascular diseases.

Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study.

The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.

Sex-specific association between adipose tissue inflammation and vascular and metabolic complications of obesity.

Adipose tissue (AT) inflammation predisposes to insulin resistance and metabolic syndrome in obesity. To investigate the association between adipocyte size, AT inflammation, systemic inflammation, and metabolic and atherosclerotic complications of obesity in a sex-specific manner. Cross-sectional cohort study. University hospital in the Netherlands. 302 adult subjects with a BMI ≥ 27 kg/m2. We obtained subcutaneous abdominal fat biopsies and systematically assessed, in a sex-specific manner, associations of several parameters of AT inflammation (including adipocyte size, macrophage content, crown like structures (CLS), and gene expression) to biomarkers of systemic inflammation, leukocyte number and function, and to the presence of metabolic syndrome, insulin resistance, and carotid atherosclerotic plaques, assessed with ultrasound. Adipocyte size was associated with metabolic syndrome and AT macrophage content with insulin resistance. In contrast, none of the AT parameters were associated with carotid atherosclerosis, although mRNA expression of the anti-inflammatory IL-37 was associated with a lower intima-media thickness. We revealed profound sex-specific differences, with an association between BMI and adipocyte size, and between adipocyte size and metabolic syndrome only in men. Also, only men showed an association between adipocyte size, AT expression of leptin and MCP-1, and AT macrophage numbers), and between AT inflammation (CLS number) and several circulating inflammatory proteins, including hsCRP, and IL-6. Inflammation in abdominal subcutaneous adipose tissue is more related to the metabolic than the atherosclerotic complications of obesity, and there are profound sex-specific differences in the association between BMI, adipocyte size, AT inflammation, and systemic inflammation, which are much stronger in men than women.

The effect of extracts of fruits of different cultivars of Cornus mas L. on plasma lipid profile in experimental diabetes mellitus

Background. Diabetes mellitus with impaired transport of glucose from the blood into the cells against the background of absolute or relative hypoinsulinemia is accompanied by the development of dyslipidemia. Therefore, it is important to find therapeutic agents capable of alleviating the symptoms and, as a result, the course of diabetes. Screening of antidiabetic agents indicates that one of their main potential sources is natural products of plant origin. However, although a wide range of plant extracts are known to be used to treat diabetes, the use of only some of them has been scientifically proven. The aim of the study was to investigate the influence of biologically active substances available in the extracts of fruits of different cultivars of Cornus mas L. on plasma lipid profile in experimental diabetes mellitus. Materials and methods. Wistar male rats with starting weight of 140–170 g were used for all experiments. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg of body weight). The animals were divided into five groups. The first (control) and the second (diabetic control) groups orally received 1 mL of water daily for 14 days. Diabetic animals of the third to fifth groups were orally administered extracts of red and yellow fruits of Cornus mas L. and the “Loganic acid” extract, respectively, in the amount of 20 mg/kg of body weight for 14 days. The concentration of low-density lipoproteins, high-density lipoproteins, triglycerides, and cholesterol was determined in the rats’ blood plasma. Atherogenic indices were calculated based on lipid profile in blood plasma. Results. The total cholesterol content in diabetic rats’ blood plasma was reliably reduced when the extract of the red fruits of the Cornus mas L. “Podolski” cultivar was administered. “Loganic acid” extract, obtained from the yellow fruits of the “Yantarnyi” and “Flava” cultivars of Cornus mas L., decreased the concentration of total cholesterol, triglycerides, and the content of low-density lipoproteins against the background of an increase in the content of high-density lipoproteins in blood plasma. The atherogenic indexes made it possible to establish that the degree of risk of cardiovascular complications due to diabetes is significantly reduced against the background of the administration of extracts of cornelian cherry fruits. Conclusions. Extracts of the fruits of the “Podolski”, “Yantarnyi” and “Flava” cultivars of Cornus mas L. correct the lipid profile of blood plasma in streptozotocin-induced diabetes animals and, as a result, may potentially prevent the development of atherosclerotic changes and cardiovascular complications. The fruits of Cornus mas L. may be potential agents in the therapy of dyslipidemia in diabetes.

The Relevance of Thrombo-Inflammatory Biomarkers and Their Relationship with Circulating Glycosaminoglycans in End-Stage Renal Disease Patients

En-stage renal disease (ESRD) is a growing public health problem. The atherosclerotic cardiovascular complications are the leading causes of mortality and morbidity in the ESRD. In this study, we sought to quantify the levels of thrombo-inflammatory biomarkers in an ESRD patients in comparison to healthy controls to determine their relevance in thrombo-inflammation and adverse outcomes. The levels of D-Dimer, C-reactive protein (CRP), plasminogen activator inhibitor 1 (PAI-1) antigen, functional PAI-1, thrombin activatable fibrinolysis inhibitor, tissue plasminogen activator, von Willebrand factor, and anti-PF4 IgG and microparticle (MP) activity were quantified by using commercially available ELISA immunoassays for each of the ESRD (n = 73) and control plasma samples (n = 10). The levels of endogenous glycosaminoglycans (GAGs) were quantified by utilizing a Heparin Red Probe (Redprobes UG, Germany). The collected data were analyzed to demonstrate the relationship between various parameters. All the tested biomarkers were increased in ESRD patients in comparison to healthy controls (p < 0.05). These biomarkers have shown significant correlations within each other except for anti-PF4 Ig G and MPs. The CRP levels were significantly higher in patients who had coronary artery disease (CAD) (p < 0.05), but there was no significant difference in other biomarkers according to the cardiovascular outcomes. In the multivariate analysis, the CRP (odds ratio: 1.19; 95% confidence interval: 1.01-1.41; p: 0.03) value was an independent predictor of CAD. In this study, we demonstrated increased levels of 10 different biomarkers in ESRD patients. The CRP levels can be a good predictor of CAD in ESRD patients.

Circulating CD31 reflects endothelial activity and is associated with a lower risk for cardiovascular complications

Abstract Background CD31 is a membrane receptor expressed by leucocytes, platelets and endothelial cells. CD31 regulates endothelial leukocyte transmigration and is key in maintaining endothelial homeostasis. An increased endothelial activation is suggested to contribute to atherosclerotic plaque inflammation but studies focusing on CD31 in atherosclerosis have provided evidence for both pro- and anti-atherosclerotic effects. However, which biological processes that are reflected by circulating soluble CD31 (sCD31) in human atherosclerosis remain unknown. Purpose Here, we aimed to explore 1) which biological processes circulating sCD31 reflects in the human atherosclerotic plaque and circulation 2) if sCD31 levels predicts cardiovascular death in individuals with carotid atherosclerosis and 3) if circulating sCD31 is causally associated to coronary artery disease (CAD) and ischemic stroke, in order to investigate its role as a biomarker of atherosclerotic disease and complications. Methods Cardiovascular associated plasma proteins (n=543) and carotid plaque proteins (n=197) were assessed by a proximity extension assay (Olink, SciLife) in the Carotid Plaque Imaging Project biobank. Plaques were phenotyped by immunohistochemistry. CD31 was located by immunofluorescence. Human carotid artery endothelial cells (HCtAECs) were stimulated with IL-6 and TNF-α to assess sCD31 release. National registries were used to identify cardiovascular death during follow up. All patients gave written informed consent. The study was approved by the local ethical review board and followed the declaration of Helsinki. Causal effects for sCD31 on stroke and CAD were examined by Mendelian randomization (MR). Summary statistics for GWAS of circulating CD31, coronary artery disease and stroke were retrieved from the SCALLOP study, the CARDIoGRAMplusC4D and the MEGASTROKE consortia. Results Plasma sCD31 correlated to plaque sCD31, TNF-α, MMP-2, MMP-9 levels and CD68+ plaque area. Plasma sCD31 also correlated to plasma CSF-1, MCP-1 and IL-8 levels. Clustering and enrichment analyses revealed that plasma sCD31 was associated to angiogenesis, cell migration and inflammatory responses. CD31 was pre-dominantly expressed on the plaque endothelium. TNF-α and IL-6 induced HCtAECs sCD31 release in vitro. Furthermore, low levels of circulating sCD31 predicted cardiovascular death and our MR analyses suggested that low circulating sCD31 levels were causally associated with a higher risk of stroke and CAD. Conclusions The present study shows that circulating sCD31 is released from endothelial cells due to inflammatory stimuli and reflects plaque inflammation. However, our follow-up data and MR analyses suggest that circulating sCD31 is associated with a lower risk for cardiovascular complications. This indicates that circulating sCD31 is not only a marker of an inflammatory response but also a marker of a functional endothelium, able to maintain the endothelial homeostasis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Swedish Society for Medical Research, The Swedish Research Council, Crafoord foundation, The Swedish Society of Medicine, The Swedish Heart and Lung Foundation, The Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University and Region Skåne.