Progression Of Atherosclerotic Cardiovascular Disease Research Articles

Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities.

Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.

Awareness of smoking cessation amongst German vascular surgeons.

Background: Smoking represents the well-known enemy of vascular well-being. Numerous previous studies emphasised the important role of smoking on the development and progression of atherosclerotic cardiovascular disease. The current study aimed to identify hurdles and barriers for an insufficient implementation of secondary prevention in the treatment of lower extremity peripheral arterial disease (PAD). Methods: All members of the German Society for Vascular Surgery and Vascular Medicine (DGG) with valid email addresses were invited to participate in an electronic survey on smoking. Results are descriptively presented. Results: Amongst 2716 invited participants, 327 (12%) submitted complete responses, thereof 33% women and 80% between 30 and 59 years old (87% board certified specialists). 83% were employed by hospitals (56% teaching hospital, 14% university, 13% non-academic) and 16% by outpatient facilities. 6% are active smokers (63% never) while a mean of five medical education activities on smoking cessation were completed during the past five years of practice. Only 27% of the institutions offered smoking cessation programs and 28% of the respondents were aware of local programs while a mean of 46% of their patients were deemed eligible for participation. 63% of the respondents deemed outpatient physicians primarily responsible for smoking cessation, followed by medical insurance (26%). Conclusions: The current nationwide survey of one scientific medical society involved in the care of patients with vascular disease revealed that smoking cessation, although being commonly accepted as important pillar of comprehensive holistic care, is not sufficiently implemented in everyday clinical practice.

Complete blood count, lipid profiles, and inflammatory markers associated with atherosclerotic cardiovascular disease in patients with diabetes

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.

Sirtuin-1 directly binds and deacetylates hepatic PCSK9 to inhibit low-density lipoprotein receptor degradation

Abstract Background Low-density lipoprotein cholesterol (LDL-C) is causally involved in atherosclerotic cardiovascular disease (ASCVD). We have previously shown that pharmacological activation of Sirtuin-1 (SIRT1), a NAD+-dependent deacetylase, reduces plasma LDL-C levels by decreasing PCSK9 and increasing hepatic LDLR expression, thus exerts atheroprotective effects in mice; however, the mechanism of SIRT1 action remains elusive. Purpose We found diminished levels of circulating SIRT1 in atherosclerotic mice compared to wild-type healthy controls. We hypothesized that this decrease in SIRT1 levels may promote dysregulated lipid metabolism and ASCVD in humans. Herein, we aimed to restore the reduced systemic Sirtuin-1 plasma levels in ASCVD by injecting recombinant murine Sirtuin-1 (rmSIRT1) in atherosclerotic mice. Methods Twelve-week-old apolipoprotein E-deficient (ApoE-/-) male mice fed a high-cholesterol diet (1.25% w/w) were randomized to receive rmSIRT1 (n=6; 0.3mg/kg BW i.p.) or vehicle treatment (n=6) every third day over 4-weeks. Mice were euthanized and organs were harvested to study lipid metabolism and ASCVD progression. Human hepatocytes (Huh7) cells were used to perform radioactive assays to study cellular uptake of radioiodinated LDL, surface plasmon resonance to study binding and site-directed mutagenesis to dissect the underlying molecular mechanism exerted by circulating SIRT1. Results Boosting circulating SIRT1 levels increased hepatic LDLR expression, reduced plasma LDL-C levels and progression of plaques in ApoE-/- mice (Figure 1). rmSIRT1 treatment did not change hepatic expression of total PCSK9 but increased its deacetylated status. Mechanistically, rmSIRT1 directly bound to hepatic PCSK9 and deacetylated PCSK9 at 3 sites: Lys243, Lys421 and Lys506 as shown by Surface Plasmon Resonance and mass spectrometry, respectively. In vitro mutagenesis to triple deacetylation mimetic (3KR) in hepatocytes (Huh7 cells) reduced SIRT1-induced PCSK9 activity, as evidenced by increased cellular binding and association of 125I-LDL through LDLR in Huh7cells. Finally, plasma levels of SIRT1 and PCSK9 were assessed at baseline in patients with acute coronary syndromes (ACS) where plasma SIRT1 showed an inverse correlation with PCSK9 and conferred a reduced risk of major adverse cardiovascular events. Conclusion SIRT1 directly binds PCSK9 and decreases its activity by deacetylation, thereby enhancing LDL-C clearance by hepatic LDLR upregulation. Increased circulating SIRT1 exerts atheroprotective effects and is associated with improved prognosis in patients with ACS.Figure 1

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts

BackgroundResearch suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. ObjectivesWe evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. MethodsOmega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. ResultsIn the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. ConclusionThis study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

HbA1c control in type 2 diabetes mellitus patients with coronary artery disease: a retrospective study in a tertiary hospital in South Africa.

Type 2 diabetes mellitus (T2DM) patients with coronary artery disease (CAD) have an increased risk of recurrent cardiovascular events. These patients require optimal glucose control to prevent the progression of atherosclerotic cardiovascular disease (ASCVD). Contemporary guidelines recommend an HbA1c ≤7% to mitigate this risk. The aim of this study was to evaluate HbA1c control in T2DM patients with angiographically proven ASCVD. We conducted a cross-sectional, retrospective study on consecutive T2DM patients with acute and chronic coronary syndromes managed in a tertiary academic hospital in South Africa. Glycaemic control was assessed by evaluating the glycated haemoglobin (HbA1c) level measured at index presentation with acute and chronic coronary syndromes and during the most recent follow-up visit. The study population comprised 262 T2DM patients with a mean age of 61.3 ± 10.4 years. At index presentation, 110 (42.0%) T2DM patients presented with ST-segment elevation myocardial infarction, 69 (26.3%) had non-ST-segment elevation myocardial infarction, 43 (16.4%) had unstable angina, and 40 (15.3%) had stable angina. After a median duration of 16.5 months (IQR: 7-29), 28.7% of the study participants had an HbA1c ≤7%. On multivariable logistic regression analysis, females were less likely to have poor glycaemic control (HbA1c above 7%) [odds ratio (OR): 0.42, 95% confidence interval (CI): 0.19-0.95, p=0.038]. Also, T2DM patients prescribed metformin monotherapy (OR: 0.34, 95% CI: 0.14-0.82, p=0.017) and patients with ST-segment depression on the electrocardiogram (OR: 0.39, 95% CI: 0.16-0.96, p=0.041) were less likely to have poor glycaemic control. After a median duration of 16.5 months, only 28.7% of T2DM patients with CAD had an HbA1c ≤7%. This finding underscores the substantial unmet need for optimal diabetes control in this very high-risk group.

Stress-Mediated Abnormalities in Regional Myocardial Wall Motion in Young Women with a History of Psychological Trauma.

Psychosocial stress has been associated with the development and progression of atherosclerotic cardiovascular disease (CVD). Previously, we reported subtle differences in global longitudinal strain in somatically healthy women with a psychiatric diagnosis of borderline personality disorder (BPD). This study aimed to investigate the impact of BPD on segmental myocardial wall motion using speckle tracking echocardiography (STE) analysis. A total of 100 women aged between 18 and 38 years were included in this study. Fifty patients meeting the diagnostic criteria for BPD were recruited from the Department of Psychiatry (LWL-University Hospital Bochum) and compared with fifty age-matched healthy control subjects without previous cardiac disease. Laboratory tests and STE were performed with segmental wall motion analysis. The BPD group had a higher prevalence of risk factors for CVD, with smoking and obesity being predominant, when compared with the control group. Other cardiovascular parameters such as blood pressure, glucose, and cholesterol levels were also elevated, even though not to pathological values. Moreover, in the STE analysis, the BPD group consistently exhibited decreased deformation in nine myocardial wall regions compared with the control group, along with a shift toward higher values in the distribution of peak pathological segments. Additionally, significantly higher values of free thyroxine concentration and thyroid's secretory capacity were observed in the BPD group, despite falling within the (high-) normal range. BPD is associated with chronic stress, classical risk factors, and myocardial wall motion abnormalities. Further exploration is warranted to investigate the relationship between high-normal thyroid metabolism, these risk factors, and myocardial function in BPD patients. Long-term follow-up studies would be valuable in confirming the potential for predicting adverse events.

The Role of Triglyceride-rich Lipoproteins and Their Remnants in Atherosclerotic Cardiovascular Disease.

Atherosclerotic cardiovascular disease (ASCVD) is the world's leading cause of death. ASCVD has multiple mediators that therapeutic interventions target, such as dyslipidaemia, hypertension, diabetes and heightened systemic inflammatory tone, among others. LDL cholesterol is one of the most well-studied and established mediators targeted for primary and secondary prevention of ASCVD. However, despite the strength of evidence supporting LDL cholesterol reduction by multiple management strategies, ASCVD events can still recur, even in patients whose LDL cholesterol has been very aggressively reduced. Hypertriglyceridaemia and elevated levels of triglyceride-rich lipoproteins (TRLs) may be key contributors to ASCVD residual risk. Several observational and genetic epidemiological studies have highlighted the causal role of triglycerides within the TRLs and/or their remnant cholesterol in the development and progression of ASCVD. TRLs consist of intestinally derived chylomicrons and hepatically synthesised very LDL. Lifestyle modification has been considered the first line intervention for managing hypertriglyceridaemia. Multiple novel targeted therapies are in development, and have shown efficacy in the preclinical and clinical phases of study in managing hypertriglyceridaemia and elevated TRLs. This comprehensive review provides an overview of the biology, pathogenicity, epidemiology, and genetics of triglycerides and TRLs, and how they impact the risk for ASCVD. In addition, we provide a summary of currently available and novel emerging triglyceride-lowering therapies in development.

Immunometabolism and immune response regulate macrophage function in atherosclerosis.

Macrophages are crucial in the progression of atherosclerotic cardiovascular disease (ASCVD). In the atherosclerotic lesions, macrophages play a central role in maintaining inflammatory response, promoting plaque development, and facilitating thrombosis. Increasing studies indicate that metabolic reprogramming and immune response mediate macrophage functional changes in all stages of atherosclerosis. In this review article, we explain how metabolic changes in glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, fatty acid synthesis, fatty acid oxidation, and cholesterol metabolism regulate macrophage function in atherosclerosis. We discuss how immune response to oxidized lipids regulate macrophage function in atherosclerosis. Additionally, we explore how abnormal metabolism leads to macrophage mitochondrial dysfunction in atherosclerosis.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome.

Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.

Primordial Prevention of Atherosclerotic Cardiovascular Disease

The primordial prevention of atherosclerotic cardiovascular disease (ASCVD) involves the prevention of the onset of its risk factors. This review explores the associations between early modifiable risk factors and the development of ASCVD in adulthood, as well as evidence-based interventions to prevent them. A review was conducted on the basis of an in-depth literature search including longitudinal observational data, systematic reviews and meta-analyses published in 2012 or later, clinical trials, and additional manual searches of recent literature based on reference lists of other reviews and relevant guidelines. ASCVD is a disease that begins in childhood; hence, primordial prevention is an important target for improving cardiovascular morbidity and mortality later in life. Data from large-scale population studies have consistently identified the following modifiable risk factors for the development of ASCVD: smoking, overweight and obesity, high cholesterol, high blood pressure, hyperglycemia, poor diet, and physical inactivity. These risk factors originate during the prenatal, childhood, and adolescent stages of life. Various successful interventions to prevent the onset of each risk factor have been evaluated at the individual, community, and population levels. Implementation of a heart-healthy dietary pattern and regular exercise early in life are large components of many successful interventions.

Evolocumab treatment reduces carotid intima-media thickness in paediatric patients with heterozygous familial hypercholesterolaemia

Abstract Background Familial hypercholesterolemia (FH) is characterised by high plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Previous studies show that carotid intima-media thickness (cIMT) is increased in children with FH, an indicator of early ASCVD. Add-on treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, evolocumab, substantially reduced atherosclerotic lipid levels in children with heterozygous FH (HeFH) and was safe and well tolerated. The effect of evolocumab on cIMT in paediatric patients (pts) has not been investigated. Purpose To investigate the effect of evolocumab treatment on cIMT progression in paediatric pts with HeFH. Methods HAUSER-RCT was a multicenter, randomised, placebo-controlled study in which paediatric FH pts (ages 10–17 years) received monthly subcutaneous injections of evolocumab 420 mg or placebo. Of 157 pts, 150 continued to an open-label extension study (HAUSER-OLE) during which all received up to 80 weeks of monthly evolocumab 420 mg on top of stable background statin therapy. cIMT was measured by B-mode ultrasound scanning at baseline, week 24 of the RCT, and weeks 24, 48, and 80 of the OLE. cIMT was measured on anterior, lateral, and posterior imaging angles of the right and left common carotid artery. Mean thickness at each visit and mean changes from baseline were summarised by treatment received during the RCT and artery location. In addition, the largest measurements (anterior, lateral, or posterior) from a patient's left and right carotid artery were averaged to calculate a summary score. Results Mean baseline cIMT summary score was 0.568 mm (SD=0.06) for 46 placebo pts and 0.586 mm (SD=0.06) for 82 evolocumab pts. During the RCT, 37 placebo pts had a mean increase of 0.006 mm (SD=0.05) from baseline to week 24; in contrast, 76 evolocumab pts had a mean decrease of 0.003 mm (SD=0.05). Although this treatment group difference was not statistically significant (P=0.403), the pattern of increased cIMT for placebo and decreased cIMT for evolocumab was consistent across artery locations (Table). During the OLE, for pts who initially received placebo, mean cIMT summary score decreased by 0.019 mm (SD=0.04, n=34) from baseline to week 80 (P=0.007) (Figure). Pts who received evolocumab in both the RCT and OLE showed continued improvement during the OLE; at week 80, mean cIMT summary score decreased by 0.012 mm (SD=0.05, n=59) from baseline (P=0.067). For all pts at week 80 (n=128), the mean decrease in LDL-C from baseline was 35.3% (SD=28.0). Conclusions Open-label evolocumab treatment for up to 80 weeks led to reductions in mean cIMT. In this small sample of pts with FH, the data suggest that the addition of PCSK9 inhibition to background lipid-lowering therapy has the potential to reduce the risk of ASCVD progression and future cardiovascular events in this vulnerable paediatric population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen, Inc.

The Effects of Statin Treatment on Serum Ferritin Levels: A Systematic Review and Meta-Analysis

Background: Statins are the most widely used drugs for decreasing elevated serum LDL-cholesterol (LDL-C) and thus for the prevention of atherosclerotic cardiovascular disease (ASCVD), but they have also some pleiotropic effects, including anti-inflammatory properties. Atherosclerosis is a low-grade inflammatory disease, and elevated ferritin is considered to be one of the markers of inflammation. Since the results of studies on the effects of statins on serum ferritin levels are conflicting, this meta-analysis was performed. Methods: A literature search was performed using major electronic databases (MEDLINE/PubMed, Scopus, Embase, and ISI Web of Science) from inception up to 5 March 2022 to find studies evaluating the effect of different statins on serum ferritin levels. The effect size was determined using weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs). Results: The meta-analysis of nine studies (1611 patients) analyzing the effects of statins on serum ferritin levels that were included showed a significant decrease in circulating ferritin levels caused by statins. The results did not suggest any significant association between the changes in concentrations of serum ferritin and the duration of treatment with statins. Conclusions: Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD. This effect might be explained by the anti-inflammatory effects and maybe some other pleiotropic effects of statins and not by their lipid-lowering effects.

Low-density lipoprotein particles in atherosclerosis.

Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Low-density lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i.

U-Shaped Relationship of Non-HDL Cholesterol With All-Cause and Cardiovascular Mortality in Men Without Statin Therapy.

BackgroundNon-HDL-C is well established causal risk factor for the progression of atherosclerotic cardiovascular disease. However, there remains a controversial pattern of how non-HDL-C relates to all-cause and cardiovascular mortality, and the concentration of non-HDL-C where the risk of mortality is lowest is not defined.MethodsA population-based cohort study using data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014. Male participants without statin therapy were divided into the six groups according to non-HDL-C levels (<100, 100–129, 130–159, 160–189, 190–219, ≥220 mg/dl). Multivariable Cox proportional hazards models were conducted with a hazard ratio (HR) and corresponding 95% confidence interval (CI). To further explore the relationship between non-HDL-C and mortality, Kaplan–Meier survival curves, restricted cubic spline curves, and subgroup analysis were performed.ResultsAmong 12,574 individuals (average age 44.29 ± 16.37 years), 1,174(9.34%) deaths during a median follow-up 98.38 months. Both low and high non-HDL-C levels were significantly associated with increased risk of all-cause and cardiovascular mortality, indicating a U-shaped association. Threshold values were detected at 144 mg/dl for all-cause mortality and 142 mg/dl for cardiovascular mortality. Below the threshold, per 30 mg/dl increase in non-HDL-C reduced a 28 and 40% increased risk of all-cause (p < 0.0001) and cardiovascular mortality (p = 0.0037), respectively. Inversely, above the threshold, per 30 mg/dl increase in non-HDL-C accelerated risk of both all-cause mortality (HR 1.11, 95% CI 1.03–1.20, p = 0.0057) and cardiovascular mortality (HR 1.30, 95% CI 1.09–1.54, p = 0.0028).ConclusionsNon-HDL-C was U-shaped related to all-cause and cardiovascular mortality among men without statin therapy.

HIV and cardiovascular disease: the role of inflammation.

HIV and antiretroviral therapy (ART) use are linked to an increased incidence of atherosclerotic cardiovascular disease (ASCVD). Immune activation persists in ART-treated people with HIV (PWH), and markers of inflammation (i.e. IL-6, C-reactive protein) predict mortality in this population. This review discusses underlying mechanisms that likely contribute to inflammation and the development of ASCVD in PWH. Persistent inflammation contributes to accelerated ASCVD in HIV and several new insights into the underlying immunologic mechanisms of chronic inflammation in PWH have been made (e.g. clonal haematopoiesis, trained immunity, lipidomics). We will also highlight potential pro-inflammatory mechanisms that may differ in vulnerable populations, including women, minorities and children. Mechanistic studies into the drivers of chronic inflammation in PWH are ongoing and may aid in tailoring effective therapeutic strategies that can reduce ASCVD risk in this population. Focus should also include factors that lead to persistent disparities in HIV care and comorbidities, including sex as a biological factor and social determinants of health. It remains unclear whether ASCVD progression in HIV is driven by unique mediators (HIV itself, ART, immunodeficiency), or if it is an accelerated version of disease progression seen in the general population.

Lipid-lowering for the prevention of cardiovascular disease in the new era: A practical approach to combination therapy: Lipid-lowering and combination therapy

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 &lt;55 mg/dL (&lt;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 &lt;55 mg/dL or &lt;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

Arterial stiffness in rheumatoid arthritis: Current knowledge and future perspectivess

Rheumatoid arthritis (RA) is characterized by the excess cardiovascular risk that remains essentially unaltered despite current medical advances. The introduction of reliable markers towards early identification and subsequently effective management of high-risk patients with RA are urgently needed. Arterial stiffness represents an early indicator of cardiovascular morbidity and mortality and has emerged as a surrogate marker of cardiovascular disease. From a pathophysiological perspective, it is significantly accelerated by the accumulation of cardiovascular risk factors and is considered an intermediate process towards the development and progression of atherosclerotic cardiovascular disease. The aim of this review is to critically upraise current knowledge on arterial stiffness in patients with RA. Although not all studies concur, increased Pulse Wave Velocity (PWV) has been repeatedly reported in patients with RA. However, results need to be interpreted with caution as most studies enrolled patients with multiple cardiovascular risk factors and/or established cardiovascular disease, or with uncontrolled RA with high levels of systemic inflammation. Whether and to which extent increased arterial stiffness among patients with RA is associated with the disease per se, or rather represents the composite effect of hypertension and other classical cardiovascular risk factors, warrants further investigation. The impact of antirheumatic drugs on arterial stiffness is also discussed. Considering the well-established predictive value of increased PWV both in the general population and patients at high cardiovascular risk, future studies need to focus on the clinical utility of this surrogate risk marker specifically in patients with RA.

Bisphenol S exposure accelerates the progression of atherosclerosis in zebrafish embryo-larvae

Bisphenol S (BPS), widely utilized in manufacturing of daily necessities, is a toxicant with potential to induce atherosclerotic cardiovascular disease (ASCVD). However, the mode of action by which BPS exposure induces ASCVD remains unknown. Here, macrophages that were exposed to BPS in combination with oxidized low-density lipoprotein (oxLDL) exhibited enhanced formation of foam cells, a hallmark of ASCVD. Furthermore, zebrafish embryo-larvae were exposed to BPS (0, 1, 10 and 100 μg/L) for 15 days (d) and the characteristic symptoms of ASCVD including an inflammatory response, macrophage recruitment around blood vessels, and accumulation of oxLDL on vascular endothelium, were induced in 15-d larvae. After zebrafish were exposed to BPS for 45 d, BPS mobilized fatty acid metabolism and activated peroxisome proliferator-activated receptor signaling in larval liver, the hub of endogenous lipid metabolism, causing an increase in plasma LDL. Driven by high plasma LDL levels, the caudal artery of zebrafish larvae exhibited lipid accumulation and a thickened area with a large number of collagen fibers, accompanied by characteristic lesions, as well as hyperlipidemia, erythrocyte aggregation, thinner blood vessel walls and increased levels of leukocytes and thromboocytes in plasma. Our data demonstrate that BPS accelerates the progression of ASCVD using zebrafish embryo-larvae as a model.