Novel Cyclic Peptides Trapping Interleukin-1β to Relieve Inflammatory and Atherosclerotic Cardiovascular Disease.

Liver function plays a pivotal role in the initiation and progression of atherosclerotic cardiovascular disease (ASCVD). Exploring the potential associations between liver function assessment indicators and ASCVD is essential for understanding the liver's involvement in ASCVD pathogenesis. However, the specific relationships between these indicators and ASCVD are still debated. This study aims to conduct an in-depth comparative analysis of variations in various liver function assessment indicators among populations of ASCVD patients. A dual-cohort retrospective cross-sectional study design was employed, using data from 15,943 ASCVD patients at the First Hospital of Jilin University and 472 ASCVD patients from the National Health and Nutrition Examination Survey (NHANES) database. Liver function indicators, including enzymatic, protein synthesis, bilirubin metabolism indices, and lipid profile parameters, were analyzed. Inclusion and exclusion criteria were rigorously applied, followed by univariate regression, multivariate regression and stratified subgroup analyses. Hepatocyte damage indicators (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase) and total bilirubin were identified as risk factors for ASCVD. Albumin showed a protective effect. Globulin levels differed significantly between cohorts. Cholinesterase (cohort 1) and total protein, total cholesterol (cohort 2) showed no significant changes in ASCVD patients. Many liver function indicators are correlated with ASCVD. There are differences in these indicators between ASCVD patients and healthy volunteers. Although some indicators may be weakly correlated due to confounding factors, this study still provides a scientific rationale for developing more precise ASCVD prevention and treatment strategies in the future.

Lipoprotein apheresis for lipoprotein(a)-associated progressive atherosclerotic cardiovascular disease: 12-years follow-up.

Background: Complete blood count (CBC) and inflammatory markers derived from hematology parameters, as well as lipid profiles, have emerged as novel biomarkers that aid in predicting the progression of atherosclerotic cardiovascular disease (ASCVD) in people with diabetes. This study aimed to evaluate the alterations in CBC, lipid profiles, and inflammatory markers derived from CBC in Type 2 diabetes mellitus (T2DM)-associated ASCVD and the associations between glycated hemoglobin and hematology, lipid profiles, and inflammatory markers. Methods: Overall, 75 patients with T2DM ASCVD from the National Cardiovascular Center Harapan Kita were investigated. Patients with diabetes were classified into high-risk (HR), very high-risk (VHR), and acute coronary syndrome (ACS) groups. VHR-ASCVD was defined as having ≥2 major ASCVD events, or one major ASCVD event and ≥2 high-risk conditions. HR-ASCVD were patients with >3 major risk factors, diabetes, chronic kidney disease stage 3B or 4, and a very high LDL-C level. ECG and cardiac biomarker tests ensured an ACS diagnosis. CBC, lipid profiles, and IL-6 were estimated in all groups. Results: Patients with T2DM ACS demonstrated significantly different levels of red blood cell distribution width (RDW), leucocytes, basophils, eosinophils, lymphocytes, monocytes, segmented neutrophils, absolute lymphocytes, absolute monocytes, neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), total cholesterol, LDL, HDL/total cholesterol ratio, hemoglobin A1c (HbA1c), and IL-6. HbA1c was significantly correlated with leucocytes (p<0.05), segmented neutrophils (p<0.001), NLR (p<0.05), PLR (p<0,05), total cholesterol (p<0.05), LDL (p<0.05), total cholesterol/ HDL ratio (p<0.05), and IL-6 (p<0.001), eosinophils (p<0.05), lymphocytes (p<0.05), monocytes (p<0.05), and absolute lymphocytes (p<0.05). Logistic regression analysis showed that monocytes, MLR, leucocytes, eosinophils, and absolute monocytes were found to be valuable predictors for T2DM ACS (p<0.05). Conclusions: CBC, inflammatory biomarkers derived from CBC, and lipid ratios were inexpensive parameters that could serve as inflammatory biomarkers of increased risks and complications in T2DM ASCVD.

Chronic inflammation plays a key role in the development and progression of atherosclerotic cardiovascular disease (ASCVD) and its complications. Despite the use of blood pressure-, lipid- and glucose-lowering therapies as well as antithrombotic agents, the lifetime residual cardiovascular (CV) risk in patients with ASCVD remains high. Because chronic inflammation remains an unaddressed risk factor, anti-inflammatory therapy has the potential to further lower residual CV risk in these patients. Low dose colchicine (0.5 mg daily) has emerged as a promising low-cost oral anti-inflammatory therapy for this indication. In patients with chronic coronary syndrome (CCS), low dose colchicine was well tolerated and reduced the risk of myocardial infarction, stroke, coronary revascularization and CV death. However, trials in patients with acute coronary syndromes (ACS) yielded conflicting results, and two trials in patients with ischemic stroke did not show a benefit. In patients with peripheral artery disease (PAD), preliminary observational data suggested a potential benefit and a randomized trial is currently underway to examine its efficacy in reducing CV and limb events. The long-term safety data for low dose colchicine in ASCVD are reassuring. Although pooled data from trials in ASCVD show a small (0.55%) absolute increase in the risk of hospitalization for gastrointestinal events, adverse signals were not observed for serious infection, cancer or severe myotoxicity. In this article, we review the clinical studies of colchicine that examined its risk-benefit for the prevention of CV events in patients with ASCVD, discuss clinical and research implications, and highlight knowledge gaps.

Comparison of the 2017 Taiwan lipid guidelines and the Western lipid guidelines for high risk patients

The initiation and progression of atherosclerotic cardiovascular disease (ASCVD) has always been associated with a series of risk factors. Evidences of statin therapy from randomized clinical trials are abundant, whereas discussions regarding patients with ASCVD without evidence-based risk factors are rare. Here, we describe a case of a 58-year-old woman who was diagnosed with ASCVD with none of these evidence-based risk factors. After four years of medical interventions, including atorvastatin, the patient recovered completely from severe chest pain with significant regression of atherosclerotic plaques in coronary arteries.

Low density lipoprotein-cholesterol (LDL-C) is the main etiologic factor for the development and progression of atherosclerotic cardiovascular disease (ASCVD) and LDL-C reduction is a central tenet of ASCVD treatment and prevention. Moreover, ASCVD risk reduction is proportional to the magnitude of LDL-C lowering. Recent European guidelines have recommended a goal of <55 mg/dL (<1.4 mmol/L) for patients at very-high cardiovascular risk, while the U.S. guideline considers an LDL-C ≥70 mg/dL (≤1.8 mmol/L) as a threshold to intensify therapy with the addition of a non-statin therapy to statins. To reach these lower LDL-C goals of <55 mg/dL or <70 mg/dL, combination therapy is necessary in the majority of these patients. Drug combinations, and in particular single-pill combinations, may substantially increase adherence to therapy. Adherence is essential for achieving a clinical benefit and, as many patients discontinue medications, the long-term adherence to lipid-lowering therapy represents a major issue in ASCVD prevention. Secondary prevention or high-risk primary prevention patients, such as those with familial hypercholesterolemia in whom maximally-tolerated statin doses alone would not be anticipated to sufficiently lower LDL-C, would benefit from combination therapy. In current clinical practice, statins with ezetimibe, statins plus PCSK9 inhibitors (with or without ezetimibe), and, most recently statins or ezetimibe with bempedoic acid are the most commonly used combination therapies for LDL-C-lowering. This review outlines the importance of using combination therapy for the achievement of LDL-C treatment

Chapter 14 - Glucagon-like peptide-1 receptor agonists: role in the prevention and treatment of diabetes-related cardiovascular complications

Introduction: Resolvin D2 (RvD2), a mediator that helps resolve inflammation, plays a role in stopping the progression of atherosclerotic cardiovascular disease (ASCVD). Understanding how RvD2 levels relate to ASCVD risk could reveal its potential as both a treatment target and a biomarker. Methods: We examined the research by Liu et al., which used an analytical method that combined restricted cubic splines with multivariable Cox proportional hazard models. This approach aimed to uncover the link between plasma RvD2 levels and ASCVD risk considering linear patterns. The study also examined how serum cholesterol might influence this relationship through sensitivity analyses. Results: Liu et al. discovered an inverted U-shaped relationship between plasma RvD2 levels and ASCVD risk. They found that while high levels of RvD2 are protective, moderate levels could raise the risk of ASCVD. Additionally, the study suggested that serum cholesterol might play a mediating role in this connection. Conclusion: These results indicate that the dynamics of RvD2 levels in relation to ASCVD risk are intricate and challenge conventional views on how inflammation resolves in heart health. The study emphasizes the importance of exploring the basis for this threshold effect occurrence and how RvD2 could serve as a biomarker for ASCVD. Further studies should explore conducting long-term research, including randomized controlled trials, to confirm the effectiveness and safety of using RvD2 as a treatment option.

Urinary 11-dehydro-thromboxane B2 levels are associated with vascular inflammation and prognosis in atherosclerotic cardiovascular disease

Familial hypercholesterolemia (FH) is an autosomal semi-dominant condition, characterized by excessive circulating low-density lipoprotein cholesterol (LDL-C) from birth that substantially accelerates the onset and progression of atherosclerotic cardiovascular disease (ASCVD), classically coronary artery disease (CAD). Elevated plasma LDL-C integrated over time is unequivocally the major determinant of ASCVD in heterozygous FH (HeFH); however, the wide variation in incidence and progression of ASCVD suggests a role for a wide spectrum of risk modifiers. We reviewed recent evidence describing the features of an ASCVD-free entity referred to as resilient FH among patients with HeFH. Compared with nonresilient FH patients, resilient patients are more likely to be female, and have a lower prevalence of ASCVD comorbidities, higher levels of HDL-C and larger HDL particles, as well as a lower level of lipoprotein(a). A lower SAFEHEART risk score is also an independent predictor of resilient FH. Gene expression studies also demonstrate that resilient FH patients are associated with a less atherogenic gene expression profile in relation to HDL metabolism and immune responses, as reflected by higher expression of ABCA1 and ABCG1, and lower expression of STAT2 and STAT3, respectively. A group of HeFH patients, referred as resilient FH, can survive to advance ages without experiencing any ASCVD events. Several key contributors to the event-fee CAD in HeFH patients have been identified. This could not only improve risk stratification and management for FH but also be of major importance for the general population in primary and secondary prevention. However, resilient FH remains an under-investigated area and requires further research.

Background: Among the modifiable risk factors, diet plays an important role in the risks and progression of atherosclerotic cardiovascular disease (ASCVD). However, few studies have examined this association in people with type 1 diabetes (T1D) who are at a greater risk of developing ASCVD than nondiabetic (non-DM) controls. Methods: We conducted cross-sectional and longitudinal analyses of data from CACTI study [n=1257; T1D: n=568; non-DM: n=689] collected between March 2000 and April 2002. Participants completed a validated food frequency questionnaire, a physical examination and fasting biochemical analyses (12h fast), and coronary artery calcification (CAC) was measured using electron beam computed tomography. At baseline, dietary patterns based on variations in food group intake were created with principal components analysis (PCA). Logistic regression was used to examine associations of dietary patterns with the CAC prevalence in a model adjusted for age and sex and stratified by diabetes status. Results: Three dietary patterns were identified using PCA as follows: ‘fruits, veggies, meats, cereal’, ‘baked desserts’ and ‘convenience foods and alcohol’ patterns. At baseline, no significant associations of dietary patterns with CAC prevalence were observed. At year-6, ‘baked dessert’ pattern was significantly associated with increased risk of CAC (<0 vs. 0) in T1D [odds ratios (OR) and 95% CI: 2.05 (1.19, 3.51)], but not in non-DM [0.74 (0.51, 1.06)] when adjusted for age, sex and baseline total calories, as well as duration of diabetes for T1D. Conclusions: Habitual intake of a dietary pattern that is characterized by an increased intake of added sugar and fats, such as in baked desserts may increase risks of atherosclerosis in T1D. Thus, dietary adjustments to improve this pattern may be atheroprotective. Disclosure A. Basu: None. A.C. Alman: None. J.K. Snell-Bergeon: None. Funding American Diabetes Association (7-13-CD-10 to J.K.S-B.)

Purpose of the reviewMacrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease.Recent findingsDysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function.Summary, Insights and PerspectiveTargeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.Graphical

BackgroundLiterature supports the “response-to-retention” hypothesis—that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance.Methods and ResultsArteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls.ConclusionsIncreased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.

There is a growing body of evidence that cumulative hyperglycemic exposure plays a central role in the development and progression of atherosclerotic cardiovascular disease in diabetic patients. Monosaccharides, such as glucose, fructose, and glyceraldehyde can react non-enzymatically with amino groups of proteins, lipids, nucleic acids to form senescent macromolecules termed advanced glycation end products (AGEs), whose formation and accumulation has been known to progress in diabetic patients, especially in those with a long history of disease. The sustained accumulation of AGEs could contribute to the phenomenon of metabolic memory or legacy effects observed in long-term follow-up clinical studies of diabetic patients. AGE modification alters the structural integrity and function of various types of macromolecules, and interaction of AGEs with a receptor for AGEs (RAGE) has been shown to evoke inflammatory and thrombotic reactions. Therefore, the AGE–RAGE axis is a novel therapeutic target of atherosclerotic cardiovascular disease in diabetic patients. In this paper, we briefly review the pathological role of AGEs and their receptor RAGE system in atherosclerotic cardiovascular disease, including peripheral artery disease and discuss the clinical utility of measuring AGEs in evaluating the severity of atherosclerosis in patients with diabetes.