Risk Of Atherosclerotic Disease Research Articles

Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.

Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Magnetic resonance imaging functional imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using cardiac magnetic resonance imaging functional imaging, we evaluated peripheral and coronary endothelial artery structure and function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308.

A User-Centered Data Visualization of Atherosclerotic Heart Disease Risk Factors.

High cholesterol levels significantly contribute to the risk of atherosclerotic cardiovascular disease (ACVD), with a notable portion of ischemic heart disease cases linked to elevated cholesterol levels. Effective graphical displays of lipid panel tests and other cardiac risk factors are crucial for quick and accurate data interpretation, enabling early intervention for individuals with hyperlipidemia. Applying design theories such as Gestalt and distributed cognitive theories is essential for creating user-centered graphical data displays in the context of cardiovascular (CV) risk factors. The proposed dashboard informed by these theories is expected to help healthcare providers better address cardiovascular disease (CVD), enhancing diagnosis, treatment, and prevention. Moreover, this approach may help alleviate clinical provider burnout, improve patient outcomes, and reduce provider stress, thus contributing to safer and more effective healthcare systems.

Explainable artificial intelligence for LDL cholesterol prediction and classification

IntroductionMonitoring LDL-C levels is essential in clinical practice because there is a direct relation between low-density lipoprotein cholesterol (LDL-C) levels and atherosclerotic heart disease risk. Therefore, measurement or estimate of LDL-C is critical. The present study aims to evaluate Artificial Intelligence (AI) and Explainable AI (XAI) methodologies in predicting LDL-C levels while emphasizing the interpretability of these predictions. Materials and methodsWe retrospectively reviewed data from the Laboratory Information System (LIS) of Ankara Etlik City Hospital (AECH). We included 60.217 patients with standard lipid profiles (total cholesterol [TC], high-density lipoprotein cholesterol, and triglycerides) paired with same-day direct LDL-C results. AI methodologies, such as Gradient Boosting (GB), Random Forests (RF), Support Vector Machines (SVM), and Decision Trees (DT), were used to predict LDL-C and compared directly measured and calculated LDL-C with formulas. XAI techniques such as Shapley additive annotation (SHAP) and locally interpretable model-agnostic explanation (LIME) were used to interpret AI models and improve their explainability. ResultsPredicted LDL-C values using AI, especially RF or GB, showed a stronger correlation with direct measurement LDL-C values than calculated LDL-C values with formulas. TC was shown to be the most influential factor in LDL-C prediction using SHAP and LIME. The agreement between the treatment groups based on NCEP ATPIII guidelines according to measured LDL-C and the LDL-C groups obtained with AI was higher than that obtained with formulas. ConclusionsIt can be concluded that AI is not only a reliable method but also an explainable method for LDL-C estimation and classification.

Carotid Intima-Media Thickness, Overweight, and Poor Sleep Quality in Commercial Airline Pilots: A Cross-Sectional Study.

Background Cardiovascular disease is a leading cause of premature career termination in commercial airline pilots (APs). In this cross-sectional study, we sought to investigate the relationship between intima-media thickness (IMT), a marker of subclinical atherosclerosis, and cardiovascular risk factors in APs, focusing on overweight status and sleep quality. Methods A total of 140 male APs were categorized into four groups based on body mass index (BMI) and Pittsburgh Sleep Quality Index (PSQI) score: overweight poor sleepers (OW-PS), overweight good sleepers (OW-GS), normal weight poor sleepers (NW-PS), and normal weight good sleepers (NW-GS). IMT was quantified in the common carotid artery (CCA) and carotid bulb using ultrasound, yielding a composite IMT (IMTcom) measure. Common cardiovascular risk factors were assessed in all participants. Results The prevalence of overweight and poor sleep quality was 43.6% and 32.9%, respectively. The OW-PS group had significantly higher age, heart rate, total cholesterol, and low-density lipoprotein (LDL) cholesterol compared to other groups (p<0.05). Overweight pilots, regardless of sleep quality, had increased IMTcom compared to normal-weight pilots (p<0.001). Age and LDL cholesterol were independent predictors of IMTcom in the OW-PS and OW-GS groups (p<0.05). Conclusions Overweight status, irrespective of sleep quality, is associated with increased IMT in APs, suggesting a higher burden of subclinical atherosclerosis. Interventions focused on reducing LDL cholesterol levels and managing age-related cardiovascular risk factors could be advantageous in mitigating the risk of atherosclerotic vascular disease in overweight pilots.

Negative LDL-C levels with Detectable Apolipoprotein B: Surrogate Markers of Atherosclerotic Disease and Cardiac Event Risk

Negative LDL-C levels with Detectable Apolipoprotein B: Surrogate Markers of Atherosclerotic Disease and Cardiac Event Risk

Diagnosis and Vulnerability Risk Assessment of Atherosclerotic Plaques Using an Amino Acid-Assembled Near-Infrared Ratiometric Nanoprobe.

To reduce the risk of atherosclerotic disease, it is necessary to not only diagnose the presence of atherosclerotic plaques but also assess the vulnerability risk of plaques. Accurate detection of the reactive oxygen species (ROS) level at plaque sites represents a reliable way to assess the plaque vulnerability. Herein, through a simple one-pot reaction, two near-infrared (NIR) fluorescent dyes, one is ROS responsive and the other is inert to ROS, are coassembled in an amphiphilic amino acid-assembled nanoparticle. In the prepared NIR fluorescent amino acid nanoparticle (named FANP), the fluorescent properties and ROS-responsive behaviors of the two fluorescent dyes are well maintained. Surface camouflage through red blood cell membrane (RBCM) encapsulation endows the finally obtained FANP@RBCM nanoprobe with not only further reduced cytotoxicity and improved biocompatibility but also increased immune escape capability, prolonged blood circulation time, and thus enhanced accumulation at atherosclerotic plaque sites. In vitro and in vivo experiments demonstrate that FANP@RBCM not only works well in probing the occurrence of atherosclerotic plaques but also enables plaque vulnerability assessment through the accurate detection of the ROS level at plaque sites in a reliable ratiometric mode, thereby holding great promise as a versatile tool for the diagnosis and risk assessment of atherosclerotic disease.

Highlights of Cardiovascular Disease Prevention Studies Presented at the 2024 American College of Cardiology Conference.

To summarize selected late-breaking science on cardiovascular (CV) disease prevention presented at the 2024 Scientific Session of the American College of Cardiology (ACC) conference. The LIBerate-HR trial showed the efficacy and safety of lerodalcibep, a subcutaneous injection that prevents binding of Pro-Protein Convertase Subtilisin/Kexin (PCSK) 9 to low-density lipoprotein (LDL)-receptors resulting in LDL-cholesterol (LDL-C) lowering in patients at very high risk or high risk of atherosclerotic CV disease (ASCVD). The AEGIS-II randomized patients with type 1 myocardial infarction (MI) with multivessel coronary artery disease and additional CV risk factors and found no benefit in major adverse CV events (MACE) with CSL112, an apolipoprotein A1 infusion shown to increase cholesterol efflux capacity. The Bridge-TIMI 73a trial showed a significant reduction in triglyceride (TG) levels with olezarsen, an antisense mRNA, in patients with moderate hyperTG with elevated CV risk. The BE ACTIVE trial showed significant improvement in step counts in patients given behavioral and financial incentives. The DRIVE study showed a significant increase in the prescription of either sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus (T2DM) at elevated CV or renal risk with a remote team-based, non-licensed navigator and clinical pharmacist approach. The TACTiC trial showed increased and sustained use of statin therapy by patient-driven use of a web-based portal that calculated the ASCVD risk score and gave prompts. The VICTORIAN-INITIATE trial showed efficacy and safety in early use of inclisiran in patients with ASCVD who did not reach target LDL-C < 70mg/dL despite maximally tolerated statin therapy. The ARISE-HF trial showed no difference in change of peak oxygen consumptionwith the use of an oral aldose reductase inhibitor, AT-001, in patients with well-controlled T2DM and diabetic cardiomyopathy with high-risk features compared to placebo. The PREVENT trial showed a significant reduction in target vessel failure at 2years in patients with non-flow limiting vulnerable plaques with percutaneous coronary intervention and optimal medical therapy (OMT) compared to OMT alone. The late-breaking clinical science presented at the 2024 Scientific Session of the ACC paves the way for an evidence-based alternative to statin therapy and provides data on several common clinical scenarios encountered in daily practice.

Role of ADAR2-mediated innate immune responses in vascular inflammation and atherosclerosis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG) Background Adenosine-to-inosine (A-to-I) RNA editing is an epitranscriptional regulator of RNA metabolism, catalyzed by the adenosine deaminases acting on RNA-1/-2 (ADAR1/2). Whether ADAR2 play a role in atherosclerotic processes remains elusive. Aim We examined the role of ADAR2 in vascular endothelial cell (EC) immunomodulatory responses and its biological relevance in murine and human atherosclerosis. Methods The role of ADAR2 in atherosclerosis was determined in a double ADAR2 and ApoE knockout mice fed with Western diet for 20 weeks. Three mouse genetic models (global and inducible vascular endothelial cell (iEC)-restricted ADAR2 and IL6ST knockout) were used to determine the role of ADAR2 in IL-6-related innate immunity. Expression levels of ADAR2 were measured in peripheral blood mononuclear cells derived from 533 individuals at risk for atherosclerotic vascular disease. Structural vascular measurements were used, including intima-media thickness (IMT), carotid wall maximum thickness (maxWT), and the number of atheromatous plaques by carotid and femoral artery ultrasonography as surrogate markers of subclinical arterial disease. Study participants were followed for major adverse cardiovascular events (MACE). Results Genetic ablation of ADAR2 resulted in a reduction of atherosclerotic plaque burden and necrotic core in the aorta and brachiocephalic trunk as well as reduced leukocyte infiltration in atherosclerotic plaques without affecting cholesterol levels in mice. Blood analysis revealed decreased pro-inflammatory cytokine levels including IL-6 after treatment of ADAR2/APOE KO mice compared to littermate control mice. Intravital imaging of IL-6-inflamed vascular endothelium showed that rolling and adhesion of leukocyte subsets to vascular wall were impaired by 2-fold in ADAR2-/- or iEC-ADAR2-/- KO mice. In vivo and ex vivo histological examination revealed that endothelial ADAR2 controls endothelial vascular adhesion molecule expression induced by gp130 signaling. ADAR2-deficient transcriptome revealed a selective upregulation of a conserved group of miRNAs targeting the IL6ST mRNA. Multilayered rescue studies including miR-inhibitors restored IL6ST levels after ADAR2 deficiency. In humans, increased ADAR2 expression was independently associated with the presence of CAD, higher C-reactive protein and mean carotid IMT after adjustment for traditional risk factors. Increased ADAR2 at baseline was prospectively associated with accelerated progression of subclinical atherosclerosis reflected by the increased number of carotid plaques at follow-up (OR=3.74, P&amp;lt;0.05). Finally, high ADAR2 levels were independently associated with higher MACE incidence across a median follow-up period of 54 months. Conclusion Posttranscriptional control of vascular inflammation by ADAR2 is integral for the development and progression of atherosclerosis in mice and humans. Our findings suggest that ADAR2 may serve as a promising therapeutic target for atherosclerosis.Role of ADAR2 in atherosclerosis

Predictive models of high risk of heart failure, atherosclerotic diseases and CKD in patients with type 2 diabetes mellitus

Due to the high prevalence of complications from the cardiovascular system and kidneys in patients with type 2 diabetes mellitus (DM) already in the early stages of the disease, it is interesting to identify predictors that could be used for early diagnosis and prevention of cardio-renal complications in patients with type 2 diabetes.Objective: to develop prognostic models for the development of ASCVD, CHF, and CKD in patients with type 2 diabetes, identifying predictors and determining the contribution of each factor in the development of these diseases.Material and methods: A one-time observational study was conducted on a sample of patients hospitalized in the endocrinology department of the State Budgetary Healthcare Institution of the City Clinical Hospital named after V.P. Demikhov. Statistical analysis was carried out using Jamovi and IBM SPSS Statistics 23 (IBM. USA). Differences were considered statistically significant at p &lt;0.05. The construction of a prognostic model of the probability of a certain outcome was carried out using the logistic regression method with reverse stepwise exclusion of collinear factors, calculation of the odds ratio (OR) and 95% confidence interval (CI).Results: The study included 1150 patients with type 2 diabetes, whose median age was 65 [57;74] years, median BMI - 31.2 [26.3; 35.8] kg/m2. According to logistic regression analysis, the most significant factors associated with the development of ASCVD in the population of patients with type 2 diabetes were: duration of diabetes more than 10 years (OR 4.16 (95% CI: 3.01-5.76) (p&gt;0.001) ) and hypertension (OR 3.92 (95% CI: 2.17-7.08). Age over 60 years (OR 2.12 (95% CI: 1.46-3.06) (p&gt;0.001), male gender (OR 1.61 95% CI: 1.14-2.26) (p&gt;0.006)). Predictors increasing the likelihood of CHF were: patient age over 60 years (OR 4.05 (95% CI: 2). .70-6.06), (p&gt;0.001)), previous MI (OR 3.71 (95%(2.58-5.33), p&lt;0.001), presence of AF 2.93 (OR 2.93 (95 % CI: 1.79-4.78), p&lt;0.001), hypertension (OR 2.45 (95% CI: 1.29-4.65), p&lt;0.006) and female gender (OR 1.58 ( 95% 1.09-2.28), p&lt;0.014). Factors increasing the odds of CKD were: age over 60 years (OR 2.36 (95% CI: 1.61-3.47), p &lt;0.001), the presence of CHF was associated with an increase in the odds of CKD by 1.86 times (p &lt;0.001), previous MI by 1.55 times (p&lt;0.008), female gender by 1.62 times (p&lt;0.004) and diabetes duration of more than 10 years by 1.44 times (p&gt;0.037).Conclusion: The universal predictors of the development of cardiorenal complications in patients with type 2 diabetes were: age over 60 years and hypertension. Predictors of the development of ASCVD, in addition to universal ones, were: duration of diabetes and male gender; the likelihood of developing CHF increased in patients with a history of myocardial infarction, the presence of AF, and in females. The presence of obesity increased the chances of developing CHF, but was not associated with ASCVD and CKD. The odds of developing HF were similar regardless of the duration of diabetes, while the duration of diabetes was closely associated with the development of ASCVD and renal dysfunction. The following factors were associated with the development of CKD: duration of diabetes, female gender, history of CVD and female gender.

Prediction model based on artificial intelligence for identifying risk of coronary atherosclerotic heart disease in computed tomography

ObjectiveTo analyze the application value of artificial intelligence (AI) in coronary computed tomography angiography (CCTA) image processing and diagnosis of coronary atherosclerotic heart disease (CHD). MethodsA total of 80 patients with suspected CHD in our hospital were selected for CCTA examination and blood lipid examination. The convolutional neural networks (CNN) model of coronary artery plaque detection was constructed, and the data set was randomly divided into training set and test set after pretreatment of lipid characteristics and image characteristics. The prediction efficiency and accuracy of the model were evaluated. ResultsIn the data set, the lipid indexes LDL-C, TC, and TG of patients in the CHD group were significantly higher than those in the Non-CHD group (P < 0.05). The average processing and diagnosis time of the AI model was (187.19 ± 18.79) s, which was significantly shorter than the average time of doctors (989.07 ± 50.40) s, and the difference was statistically significant (P < 0.05). There was no significant difference in the detection of calcified plaque, non-calcified plaque, and mixed plaque between doctors and AI models (P > 0.05). However, 5 plaques were misdiagnosed in the AI model (3.38%). The area under the curve (AUC) value of the CNN recognition model-based AI and manual recognition of doctors for the CHD were 0.870 (95% CI: 0.698–0.931) and 0.870 (95% CI: 0.691–0.926) (P < 0.001). ConclusionAI integrated with lipid parameters has certain clinical value in CCTA image processing efficiency and plaque diagnosis, and can be used as an effective auxiliary tool to analyze and diagnose CHD.

Acute coronary syndromes in patients with cancer: Recent advances.

Coronary artery disease is presently one of the leading causes of death among cancer survivors. Due to the number of cancer survivors projected to reach 26 million by 2040 managing coronary disease in this population presents a unique challenge. Cancer patients face an elevated risk of atherosclerotic disease due to shared cardiovascular risk factors and the cardiotoxic effects of cancer therapies, predisposing them to acute coronary syndromes. Challenges in treating cancer patients presenting with acute coronary syndromes include atypical presentations, obscured symptoms, and the impact of cancer-related processes on traditional biomarkers. This review explores the complexities of acute coronary syndrome management in cancer patients, addressing challenges involved, recent advances in percutaneous strategies, pharmacology, and considerations for these high-risk individuals. This review discusses a balance between invasive vs. medical strategy, technical advances in multimodal imaging, intravascular physiology, intracoronary imaging, and evolving stent options, highlighting the need for tailored approaches in this complex patient population.

Two randomized controlled trials of nudges to encourage referrals to centralized pharmacy services for evidence-based statin initiation in high-risk patients: Rationale and design of the SUPER LIPID program

In patients with or at risk for atherosclerotic vascular disease, statins reduce the incidence of major adverse cardiovascular events, but the majority of US adults with an indication for statin therapy are not prescribed statins at guideline-recommended intensity. Clinicians' limited time to address preventative care issues is cited as one factor contributing to gaps in statin prescribing. Centralized pharmacy services can fulfill a strategic role for population health management through outreach, education, and statin prescribing for patients at elevated ASCVD risk, but best practices for optimizing referrals of appropriate patients are unknown. SUPER LIPID (NCT05537064) is a program consisting of two pragmatic clinical trials testing the effect of nudges in increasing referrals of appropriate patients to a centralized pharmacy service for lipid management, conducted within 11 primary care practices in a large community health system. In both trials, patients were eligible for inclusion if they had an assigned primary care provider (PCP) in a participating practice and were not prescribed a high- or moderate-intensity statin despite an indication, identified via an electronic health record (EHR) algorithm. Trial #1 was a stepped wedge trial, conducted at a single practice with randomization at the PCP level, of an interruptive EHR message that appeared during eligible patients' visits and facilitated referral to the pharmacy service. For the first 3 months, no PCPs received the message; for the second 3 months, half were randomly selected to receive the message; and for the last 3 months, all PCPs received the message. Trial #2 was a cluster-randomized trial conducted at 10 practices, with randomization at the practice level. Practices were randomized to usual care or to have eligible patients automatically referred to centralized pharmacy services via a referral order placed in PCPs EHR inboxes for co-signature. In both trials, when a patient was referred to centralized pharmacy services, a pharmacist reviewed the patient's chart, contacted the patient, and initiated statin therapy if the patient agreed. The primary endpoint of both trials was the proportion of patients prescribed a statin; secondary endpoints include the proportion of patients prescribed a statin at guideline-recommended intensity, the proportion of patients filling a statin prescription, and serum low-density lipoprotein level. SUPER LIPID is a pair of pragmatic clinical trials assessing the effectiveness of two strategies to encourage referral of appropriate patients to a centralized pharmacy service for lipid management. The trial results will develop the evidence base for simple, scalable, EHR-based strategies to integrate clinical pharmacists into population health management and increase appropriate statin prescribing. clinicaltrials.gov; NCT05537064.

C-reactive protein, cardiovascular issues of an acute-phase protein: an update for theclinician

Inflammation is an important pathogenic factor for the development of atherosclerotic cardiovascular disease. Currently, the most frequently used biomarker reflecting systemic inflammation is C-reactive protein (CRP), an acute-phase protein produced primarily by hepatocytes under the influence of interleukin-6, interleukin-1 beta, and tumor necrosis factor. Growing evidence from epidemiological studies has shown a robust association between elevated serum or plasma CRP concentrations and the incidence of a first cardiovascular adverse event (including acute myocardial infarction, ischemic stroke, and sudden cardiac death) in the general population, as well as recurrence of major adverse cardiovascular events among patients with established disease. The additive value that CRP measurement gives to traditional risk factors is reflected in novel cardiovascular risk calculators and in current intervention regimens, which already consider CRP as a target therapeutic. However, the variations in CRP levels, that depend on sex, ethnicity, hormonal status, and some peculiarities of the measurement assays, must be taken into consideration when deciding to implement CRP as a useful biomarker in the study and treatment of atherosclerotic cardiovascular disease. This review aims to offer an updated vision of the importance of measuring CRP levels as a biomarker of cardiovascular risk beyond the traditional factors that estimate the risk of atherosclerotic disease.

Heart and blood: clonal hematopoiesis

Cardiovascular diseases are among the leading causes of death worldwide, with well-known modifiable risk factors, such as smoking, overweight, lipid metabolism disorders, lack of physical activity and high blood pressure playing asignificant role. Recent studies have now identified "clonal hematopoiesis" as anovel blood-based risk factor. Clonal hematopoiesis arises from mutations in hematopoietic stem cells, which lead to the expansion of mutated blood cells. Mutated cell clones can be detected in over 40% of individuals over 50years old, with more than 15% of those over 90years old harboring large clones. Surprisingly, mutated cells predispose to the development of leukemia only to a minor extent, leading to the term clonal hematopoiesis of indeterminate potential (CHIP); however, it has been shown that CHIP is associated with an increased risk of cardiovascular diseases. Individuals with CHIP-associated gene mutations have an elevated risk of atherosclerotic vascular diseases, stroke and thrombosis. Patients with heart failure with reduced ejection fraction (HFrEF), whether of ischemic or non-ischemic origin and patients with heart failure with preserved ejection fraction (HFpEF) exhibit an increased number of mutated cells in the blood. The presence of CHIP mutations is linked to apoorer prognosis in patients with existing cardiovascular diseases. Future research should aim at a better understanding of the specific effects of different mutations, clone sizes and combinations to develop personalized therapeutic approaches. Various anti-inflammatory therapeutic drugs are available, which can be tested in controlled studies.

Unclosing Premature Mortality Gap Among Patients With Gout in the US General Population, Independent of Serum Urate and Atherosclerotic Cardiovascular Risk Factors.

Gout flares are followed by transient major cardiovascular (CV) risk, implicating the role of inflammation; the aim of this study was to determine whether premature mortality rates in patients with gout and CV risk are independent of serum urate (SU) and atherosclerotic CV disease (ASCVD) risk factors. Using serial US nationwide prospective cohorts, we evaluated the independent association of prevalent gout with all-cause and CV mortality, adjusting for SU, ASCVD risk factors, comorbidities, medications, and kidney function and compared mortality rates between the early (1988-1994 baseline) and late cohorts (2007-2016 baseline). We replicated late cohort findings among patients with gout in a nationwide UK cohort (2006-2010 baseline). Adjusted hazard ratios (HRs) for mortality rates in patients with prevalent gout were similar in early and late US cohorts (1.20 [1.03-1.40] and 1.19 [1.04-1.37], respectively); HRs with further adjustment for SU were 1.19 (1.02-1.38) and 1.19 (1.03-1.37), respectively. Adjusted HR among patients with gout from the UK late cohort was 1.61 (1.47-1.75); these associations were larger among women (P = 0.04) and prominent among Black individuals. Adjusted HR for CV mortality rates in the late US cohort was 1.39 (1.09-1.78); those for circulatory, CV, and coronary heart disease deaths among UK patients with incident gout were 1.48 (1.24-1.76), 1.49 (1.20-1.85), and 1.59 (1.26-1.99), respectively. Patients with gout experience a persistent mortality gap in all-cause and CV deaths, even adjusting for SU and ASCVD risk factors, supporting a role for gout-specific pathways (eg, flare inflammation). These findings suggest gaps in current care, particularly in women and possibly among Black patients.

Clot or Not? Reviewing the Reciprocal Regulation Between Lipids and Blood Clotting.

Both hyperlipidemia and thrombosis contribute to the risks of atherosclerotic cardiovascular diseases, which are the leading cause of death and reduced quality of life in survivors worldwide. The accumulation of lipid-rich plaques on arterial walls eventually leads to the rupture or erosion of vulnerable lesions, triggering excessive blood clotting and leading to adverse thrombotic events. Lipoproteins are highly dynamic particles that circulate in blood, carry insoluble lipids, and are associated with proteins, many of which are involved in blood clotting. A growing body of evidence suggests a reciprocal regulatory relationship between blood clotting and lipid metabolism. In this review article, we summarize the observations that lipoproteins and lipids impact the hemostatic system, and the clotting-related proteins influence lipid metabolism. We also highlight the gaps that need to be filled in this area of research.

PCSK9 genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations.

Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition. In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI. The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections. Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication.

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.

Aging increases the risk of atherosclerotic vascular disease and its complications. Macrophages are pivotal in the pathogenesis of vascular aging, driving inflammation and atherosclerosis progression. NOX4 (NADPH oxidase 4) expression increases with age, correlating with mitochondrial dysfunction, inflammation, and atherosclerosis. We hypothesized that the NOX4-dependent mitochondrial oxidative stress promotes aging-associated atherosclerosis progression by causing metabolic dysfunction and inflammatory phenotype switch in macrophages. We studied atherosclerotic lesion morphology and macrophage phenotype in young (5-month-old) and aged (16-month-old) Nox4 -/-/Apoe -/- and Apoe -/- mice fed Western diet. Young Nox4-/-/Apoe-/- and Apoe-/- mice had comparable aortic and brachiocephalic artery atherosclerotic lesion cross-sectional areas. Aged mice showed significantly increased lesion area compared with young mice. Aged Nox4-/-/Apoe-/- had significantly lower lesion areas than Apoe-/- mice. Compared with Apoe-/- mice, atherosclerotic lesions in aged Nox4-/-/Apoe-/- showed reduced cellular and mitochondrial ROS and oxidative DNA damage, lower necrotic core area, higher collagen content, and decreased inflammatory cytokine expression. Immunofluorescence and flow cytometry analysis revealed that aged Apoe-/- mice had a higher percentage of classically activated pro-inflammatory macrophages (CD38+CD80+) in the lesions. Aged Nox4-/-/Apoe-/- mice had a significantly higher proportion of alternatively activated pro-resolving macrophages (EGR2+/CD163+CD206+) in the lesions, with an increased CD38+/EGR2+ cell ratio compared with Apoe-/- mice. Mitochondrial respiration assessment revealed impaired oxidative phosphorylation and increased glycolytic ATP production in macrophages from aged Apoe-/- mice. In contrast, macrophages from Nox4-/-/Apoe-/- mice were less glycolytic and more aerobic, with preserved basal and maximal respiration and mitochondrial ATP production. Macrophages from Nox4-/-/Apoe-/- mice also had lower mitochondrial ROS levels and reduced IL1β secretion; flow cytometry analysis showed fewer CD38+ cells after IFNγ+LPS treatment and more EGR2+ cells after IL4 treatment than in Apoe-/- macrophages. In aged Apoe-/- mice, inhibition of NOX4 activity using GKT137831 significantly reduced macrophage mitochondrial ROS and improved mitochondrial function, resulting in decreased CD68+CD80+ and increased CD163+CD206+ lesion macrophage proportion and attenuated atherosclerosis. Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity.

Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study.

Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases. A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes (HMGCR, PCKS9, NPC1L1, LDLR, APOB, CETP, LPL, APOC3, and ANGPTL3) were extracted as exposures from the summary data of Global Lipids Genetics Consortium Genome-Wide Association Studies (GWAS). GWAS summary data of cancers and noncancerous diseases were used as outcomes. The inverse-variance weighted method was applied as the main statistical approach. Sensitivity tests were conducted to evaluate the robustness, pleiotropy, and heterogeneity of the results. In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of PCKS9, CETP, LPL, LDLR, and APOC3 were associated with longer human lifespans (q<0.05). Lipid-lowering variants of ANGPTL3 and LDLR were associated with reduced risks of colorectal cancer, and ANGPTL3 was also associated with lower risks of gastric cancer (q<0.05). Lipid-lowering LPL variants were associated with decreased risks of hypertension, type 2 diabetes, nonalcoholic fatty liver disease, and bladder cancer (q<0.05). Lipid-lowering variants of PCKS9 and HMGCR were associated with decreased risks of osteoporosis (q<0.05). Lipid-lowering APOB variants were associated with a decreased risk of thyroid cancer (q<0.05). Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies.

Evaluation of intracranial atherosclerotic disease risk factors in patients with acute ischemic stroke

Background &amp; Objective: Intracranial atherosclerotic disease (ICAD) is a prevalent cause of ischemic stroke and is related to recurrent strokes. In this study, we aim to identify the ICAD rate and establish the risk factors in patients with acute ischemic stroke (AIS) in our population in Turkey. Methods: Eight hundred sixty-two patients diagnosed with AIS in our tertiary centre between 01-01.2019 and 01.01.2021 were retrospectively included in this study. Results: We detected ICAD in 172 (20%) patients. While the independent risk factors of anterior ICAD were hypertension and diabetes mellitus, the risk factors of posterior ICAD were advanced age, diabetes mellitus, hyperlipidaemia and vertebral artery hypoplasia. There were more frequent posterior ICAD. Conclusion: There was difference in the risk factors for anterior ICAD and posterior ICAD in this Turkish study.