Risk Of Adverse Cardiovascular Events Research Articles

Renal Dysfunction Increases Risk of Adverse Cardiovascular Events in 5-Year Follow-Up Study of Intermediate Coronary Artery Lesions.

BACKGROUND Progression of chronic coronary syndrome (CCS) is influenced by chronic kidney disease (CKD). This 5-year follow-up study aimed to assess 100 patients with 118 intermediate coronary artery lesions evaluated by fractional flow reserve (FFR) and intravascular imaging stratified according to renal function. MATERIAL AND METHODS This prospective study enrolled patients with intermediate coronary stenosis identified by coronary angiogram. Patients with severe renal dysfunction (estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m²) were excluded from the study. The remaining were divided into 2 groups according to eGFR: 45-60 ml/min/1.73 m² for mild-to-moderate renal dysfunction and >60 ml/min/1.73 m² for no renal dysfunction. We analyzed intermediate-grade stenoses (40-80% as assessed in coronary angiography) with the use of optical coherence tomography (OCT), FFR, and intravascular ultrasound (IVUS). RESULTS Renal dysfunction patients were older (67.7±8.1 vs 63.6±9.7 years, P=0.044). Lesion characteristics, including plaque type and minimal lumen area in OCT, showed no significant differences between the renal dysfunction and no renal dysfunction groups. Thin-cap fibroatheroma, calcific plaques, lipidic plaques, and fibrous plaques had similar prevalence. FFR values and IVUS parameters did not significantly differ between the groups. Over a 5-year follow-up, individuals with mild-to-moderate renal dysfunction had an elevated risk of all-cause mortality and major adverse cardiovascular events in multivariate analyses adjusted for age and sex. CONCLUSIONS Mild-to-moderate renal dysfunction was not associated with significant differences in OCT- and IVUS-derived plaque morphology nor with functional indices characterizing intermediate-grade coronary stenoses. Renal dysfunction was related to a higher risk of all-cause mortality and major adverse cardiovascular events prevalence in 5-year follow-up.

MASKED HYPERTENSION IN PATIENTS WITH METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE – AN UNDERESTIMATED RISK?

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension are major cardiovascular risk factors sharing a bi-directional relationship. Although nearly half of MASLD patients are suffering from arterial hypertension, data on the prevalence of different hypertension phenotypes (e.g. masked hypertension) in this patient population are scarce. Masked hypertension, which is defined by normal office blood pressure but elevated blood pressure in the ambulatory 24-hour blood pressure measurement (24-h-ABPM), often remains undetected, although it has a comparable risk for adverse cardiovascular events as sustained hypertension. Therefore, the identification of this hypertension phenotype in MASLD patients seems highly relevant. Design and method: To analyze the prevalence of masked hypertension and to improve hypertension management in MASLD patients we integrated a 24-h-ABPM-based hypertension screening and control program among MASLD patients in our outpatient liver department. A total of 226 MASLD patients were recruited during regular follow-up visits and recording of office blood pressure and 24-h-ABPM measurements were performed according to a standardized protocol. Results: For the final analysis, 218 data sets were evaluated. The median age of the included 218 patients was 51 years, 48.2% were female. 101 (46.3%) MASLD patients had prior history of hypertension. At the time of ABPM 93 (92.1%) of these patients received antihypertensive treatment. Masked hypertension was identified in 46 (21.1%) MASLD patients, 20 (43.5%) of whom were receiving antihypertensive treatment (masked uncontrolled hypertension). Interestingly, 14 (30.4%) MASLD patients with masked hypertension had isolated nocturnal masked hypertension. Furthermore, a non-dipping blood pressure pattern was recognized in 28 (60.9%) MASLD patients with masked hypertension. Conclusions: Due to the high rates of masked hypertension and abnormal nocturnal blood pressure dipping, which both represent important risk factors for adverse cardiovascular events, the establishment of hypertension screening and management programs in this high-risk population seems urgently needed. Controlled hypertension reduces the risk of cardiovascular events in this vulnerable population and, due to the strong link between MASLD and hypertension, possibly also slow the progression of MASLD to advanced liver fibrosis or cirrhosis.

Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

Utility of the ACD-GENE-CLI Score in Asian Patients with Critical Limb Ischemia Undergoing Endovascular Interventions.

Critical limb ischemia (CLI) is an emerging public health threat and lacks a reliable score for predicting the outcomes. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD-GENE) risk score helps identify patients with coronary artery disease who have cytochrome P450 2C19 (CYP2C19) polymorphism-related drug resistance and are at risk for cardiovascular adverse events. However, its application to CLI remains unknown. In this study, we aim to validate a modified ACD-GENE-CLI score to improve the prediction of major adverse limb events (MALEs) in patients with CLI receiving clopidogrel. Patients with CLI receiving clopidogrel post-endovascular intervention were enrolled prospectively in two medical centers. Amputation and revascularization as MALEs were regarded as the outcomes. A total of 473 patients were recruited, with a mean follow-up duration of 25 months. Except for obesity, old age, diabetes, chronic kidney disease (CKD), and CYP2C19 polymorphisms were significantly associated with MALEs. Using bootstrap regression analysis, we established a modified risk score (ACD-GENE-CLI) that included old age (≥ 65 years), diabetes, CKD, and CYP2C19 polymorphisms. At a cutoff value of 8, the ACD-GENE-CLI score was superior to the CYP2C19 deficiency only, and the conventional ABCD-GENE score in predicting MALEs (area under the curve: 0.69 vs. 0.59 vs. 0.67, p=0.01). The diagnostic ability of the ACD-GENE-CLI score was consistent in the external validation. Also, Kaplan-Meier curves showed that in CYP2C19 deficiency, the ABCD-GENE and ACD-GENE-CLI scores could all differentiate patients with CLI who are free from MALEs. The modified ACD-GENE-CLI score could differentiate patients with CLI receiving clopidogrel who are at risk of MALEs. Further studies are required to generalize the utility of the score.

The impact of renal tubulointerstitial dysfunction on the early and long-term prognosis in chronic heart failure patients with preserved left ventricular ejection fraction

Aim. To study the dependence of the early-term (1 year) and long-term (5 years) prognosis in patients with chronic heart failure (CHF) of ischemic origin with preserved left ventricular ejection fraction (LVEF) depending on renal tubulointerstitial functional disorders. Materials and methods. The study involved 88 patients (men – 46.6 % (n = 41); women – 53.4 % (n = 47)) with CHF of ischemic origin, stage II A–B, stage II–IV according to NYHA, 67 % (n = 59) with sinus rhythm, and 33 % (n = 29) with atrial fibrillation. Patients with sinus rhythm and atrial fibrillation were matched in age (p = 0.483), height (p = 0.345), weight (p = 0.317), body surface area (p = 0.153). NGAL levels were analyzed using an ELISA kit (E-EL-H0096, Elabscience, USA). NAG levels were analyzed using an ELISA kit (SEA 069 Hu, Cloud-Clone Corp., USA). KIM-1 levels were analyzed using an ELISA kit (SEA 785 Hu, Cloud-Clone Corp., USA). Kaplan–Meier curves and Cox proportional hazards regression analysis were performed. Results. No significant difference was found in the frequency of the cumulative endpoint during the first-year follow-up from the initial level of two markers of tubulointerstitial injury – KIM-1 (Log-Rank Test: p = 0.57529) and NAG (Log-Rank Test: p = 0.86001). According to the results of analysis of the Cox proportional hazards, only a tendency to increase in the risk factors of adverse events were observed in case of elevated KIM-1 (HR = 1.66; p = 0.5795) and NAG levels (HR = 1.1712; p = 0.8626) in this CHF patients’ cohort. Kaplan–Meier analysis revealed a probable (Log-Rank Test; p = 0.00141) increase in the frequency of the cumulative endpoint during the first year of follow-up in CHF patients with preserved LVEF due to increased serum NGAL level more than 168 ng/ml. According to the univariate model, an elevated serum NGAL level is associated with an increase in the relative risk by 4.2 times (95 % CI 1.78–16.89; p = 0.014). A reduced sodium level less than 142.5 mmol/l was associated with an increase in number of adverse cardiovascular events during the first-year follow- ups by 22 % (HR = 1.22, p = 0.029). After 5 years of follow-up, a decrease in sodium level less than 142.3 mmol/l is also characterized by a probable difference of the cumulative Kaplan–Meier’s curves (Cox–Mantel F-Test, p = 0.00287). According to the univariate model of Cox proportional hazards, the relative risk of adverse cardiovascular events in patients with CHF during the 5-year follow-up has a tendency to increase by 1.04 times (95 % CI 0.85–1.27; p = 0.72). Serum NGAL, a marker of renal tubulo-interstitial injury, doesn’t lose its properties as a powerful marker of an unfavorable long-term prognosis in patients with CHF with preserved LVEF (HR = 5.96; 95 % CI 1.17–30.50; p = 0.032). Conclusions. The most powerful factors of the early (1-year) prognosis of adverse cardiovascular events in CHF patients with preserved left ventricular ejection fraction are the marker of tubulointerstitial injury, serum NGAL over 168 ng/ml, as well as the marker of tubulointerstitial dysfunction – the serum sodium level less than 142.5 mmol/l. The electrolyte imbalance, decreased sodium level less than 142.3 mmol/l, remains a powerful marker of an unfavorable long-term 5-year prognosis in CHF patients with preserved left ventricular ejection fraction, meanwhile serum NGAL, a marker of renal tubulointerstitial injury, besides doesn’t lose its prognostic value (HR = 5.96; 95 % CI 1.17–30.50; p = 0.032), but also is independent from the parameters of the age (p = 0.409) and gender (p = 0.397) in such patients.

Atherosclerosis Residual Lipid Risk-Overview of Existing and Future Pharmacotherapies.

Patients with atherosclerotic disease remain at increased risk of future events despite receiving optimal medical treatment. This residual risk is widely heterogeneous, but lipoprotein particles and their content play a major role in determining future cardiovascular events. Beyond low-density lipoprotein cholesterol (LDL-c), other lipoprotein particles have not demonstrated similar contribution to the progression of atherosclerosis. Statins, ezetimibe, and more recently, proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors and bempedoic acid have confirmed the causal role of LDL-c in the development of atherosclerosis. Data on high-density lipoprotein cholesterol (HDL-c) suggested a possible causal role for atherosclerosis; nonetheless, HDL-c-raising treatments, including cholesteryl-ester transfer protein (CETP) inhibitors and niacin, failed to confirm this relationship. On the other hand, mendelian randomisation revealed that triglycerides are more implicated in the development of atherosclerosis. Although the use of highly purified eicosapentaenoic acid (EPA) was associated with a reduction in the risk of adverse cardiovascular events, this beneficial effect did not correlate with the reduction in triglycerides level and has not been consistent across large phase 3 trials. Moreover, other triglyceride-lowering treatments, such as fibrates, were not associated with a reduction in future cardiovascular risk. Studies assessing agents targeting angiopoietin-like 3 (lipoprotein lipase inhibitor) and apolipoprotein C3 antisense will add further insights into the role of triglycerides in atherosclerosis. Emerging lipid markers such as lipoprotein (a) and cholesterol efflux capacity may have a direct role in the progression of atherosclerosis. Targeting these biomarkers may provide incremental benefits in reducing cardiovascular risk when added to optimal medical treatment. This Review aims to assess available therapies for current lipid biomarkers and provide mechanistic insight into their potential role in reducing future cardiovascular risk.

Circulating galectin-3 level association with cardiovascular risk factors during peritoneal dialysis

ObjectiveCardiovascular disease (CVD) represents the primary cause of mortality in patients afflicted with end-stage renal disease and undergoing peritoneal dialysis (PD) treatment. Galectin-3 (Gal-3), a molecule known to exhibit a correlation with CVD mortality garners considerable interest. The objective of this study was to explore the potential association between serum Gal-3 levels and other CVD risk factors among PD patients.MethodsIn this cross-sectional study, a total of 114 PD patients with a minimum of 3 months of PD treatment were enrolled. Serum Gal-3 levels were quantified using an enzyme-linked immunosorbent assay. The data of patients with Gal-3 levels higher and lower than 26.744 pg/ml were compared using Mann–Whitney U tests or t tests. Pearson’s correlation or Spearman’s correlation analysis and multivariate regression were used to assess the associations between the known risk factors for CVD and Gal-3.ResultsIn comparison to the inter-group baseline data, the low Gal-3 group exhibited a higher glomerular filtration rate (GFR). Gal-3 levels correlate positively with PD duration, B-type natriuretic peptide (BNP), growth differentiation factor 15 (GDF-15), interventricular septal thickness in diastolic (IVST), and left ventricular mass index (LVMI). Conversely, Gal-3 exhibited a negative correlation with albumin levels. Multivariate linear regression analysis demonstrated a positive correlation between Gal-3 levels and BNP, GDF-15, PD duration, IVST and LVMI. Gal-3 levels were negatively correlated with albumin levels.ConclusionsGal-3 was strongly associated with BNP, GDF-15, IVST and LVMI in patients undergoing PD treatment. Prospective studies should be carried out to determine whether Gal-3 can be a promising biomarker in predicting increased risk of adverse cardiovascular events in PD patients.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions

Background and objectiveEndothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients.MethodsA total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro.ResultsEndothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05).ConclusionNP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

An Updated Review of the Management of Chronic Heart Failure in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is common in patients with heart failure (HF) and is associated with high morbidity and mortality. There has been remarkable progress in the treatment of HF over recent years with the establishment of guideline-directed medical therapies including: (1) Beta-blockers, (2) renal angiotensin aldosterone system (RAAS) inhibition (i.e., angiotensin-converting enzyme inhibitor [ACEi], aldosterone receptor blocker [ARB] or angiotensin receptor-neprilysin inhibitor [ARNI]); (3) mineralocorticoid receptor antagonists (MRA), and (4) sodium-glucose cotransporter-2 inhibitors (SGLT2i). However, there are challenges to the implementation of these medications in patients with concomitant CKD due to increased vulnerability to common side-effects (including worsening renal function, hyperkalaemia, hypotension), and most of the pivotal trials which provide evidence of the efficacy of these medications excluded patients with severe CKD. Patients with CKD and HF often have regular healthcare encounters with multiple professionals and can receive conflicting guidance regarding their medication. Thus, despite being at higher risk of adverse cardiovascular events, patients who have both HF and CKD are more likely to be under-optimised on evidence-based therapies. This review is an updated summary of the evidence available for the management of HF (including reduced, mildly reduced and preserved left ventricular ejection fraction) in patients with various stages of CKD. The review covers the evidence for recommended medications, devices such as implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT), intravenous (IV) iron, and discusses how frailty affects the management of these patients. It also considers emerging evidence for the prevention of HF in the cohort of patients with CKD. It synthesises the available evidence regarding when to temporarily stop, continue or rechallenge medications in this cohort. Chronic HF in context of CKD remains a challenging scenario for clinicians to manage, which is usually complicated by frailty, multimorbidity and polypharmacy. Treatment should be tailored to a patients individual needs and management in specialised cardio-renal clinics with a multi-disciplinary team approach has been recommended. This review offers a concise summary on this expansive topic.

Cardiovascular events among patients with prostate cancer treated with abiraterone and enzalutamide.

There is growing concern about the adverse metabolic and cardiovascular effects of abiraterone acetate (AA) and enzalutamide (ENZ), two standard hormonal therapies for prostate cancer. We analysed the risk of cardiovascular adverse events among patients treated with AA and ENZ. We used Kythera Medicare data from January 2019 to June 2023 to identify patients with at least one pharmacy claim for AA or ENZ. The index date was the first prescription claim date. Patients were required to have 1 year of data pre- and post-index date. New users excluded those with prior AA or ENZ claims and pre-existing cardiovascular comorbidities. Demographic and clinical variables, including age, socioeconomic status (SES), comorbidity score, prostate-specific comorbidities, and healthcare costs, were analysed . Propensity score matching was employed for risk adjustment. Of the 8,929 and 8,624 patients in the AA and ENZ cohorts, respectively, 7,647 were matched after adjusting for age, sociodemographic, and clinical factors. Between the matched cohorts (15.54% vs. 14.83%, p < 0.05), there were no statistically significant differences in any cardiovascular event after adjusting for these factors. The most common cardiovascular event in both cohorts was heart failure (5.20% vs. 4.49%), followed by atrial fibrillation (4.42% vs. 3.60%) and hypotension (2.93% vs. 2.48%). This study provides real-world evidence of the cardiovascular risk of AA and ENZ that may not appear in clinical trial settings. Adjusting for age, baseline comorbidities, and SES, the likelihood of a cardiovascular event did not differ between treatment groups.

Bile Acids and Risk of Adverse Cardiovascular Events and All-Cause Mortality in Patients with Acute Coronary Syndrome.

The relationship between bile acids (BAs) and adverse cardiovascular events following acute coronary syndrome (ACS) have been little investigated. We aimed to examine the associations of BAs with the risk of cardiovascular events and all-cause mortality in ACS. We conducted a prospective study on 309 ACS patients who were followed for 10 years. Plasma BAs were quantified by liquid chromatography coupled to tandem mass spectrometry. Cox regression analyses with elastic net penalties were performed to associate BAs with MACE and all-cause mortality. Weighted scores were computed using the 100 iterated coefficients corresponding to each selected BA, and the associations of these scores with these adverse outcomes were assessed using multivariable Cox regression models. A panel of 10 BAs was significantly associated with the increased risk of MACE. The hazard ratio of MACE per SD increase in the estimated BA score was 1.35 (95% CI 1.12-1.63). Furthermore, four BAs were selected from the elastic net model for all-cause mortality, although their weighted score was not independently associated with mortality. Our findings indicate that primary and secondary BAs may play a significant role in the development of MACE. This insight holds potential for developing strategies to manage ACS and prevent adverse outcomes.

The Differential Impact of Medical Therapy and Lifestyle Modification on Cardiovascular Health and Risk of Adverse Cardiovascular Events: A Narrative Review.

Cardiovascular diseases (CVDs) continueto be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive collaboration between medical therapy and lifestyle modifications in the management of CVDs, aiming to interpret whether a single approach holds the key to reducing major cardiovascular events. In the realm of pharmaceutical therapy, statins, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and antiplatelet agents have shown significant effectiveness, as evidenced by landmark trials such as Scandinavian Simvastatin Survival Study (4S) and Heart Outcomes Prevention Evaluation (HOPE). Concurrently, lifestyle adjustments, encompassing physical activity, dietary changes,and management of stress, emerge as indispensable elements in cardiovascular care. The article discusses the pivotal role of patient adherence, tailored approaches, and the synergistic impact of combining medical therapy and lifestyle modifications. Challenges, such as socioeconomic disparities and uncertainties in lipid management, underscore the need for ongoing research and precision medicine. Digital health interventions offer novel avenues for personalized care. Despite advancements, uncertainties persist regarding the optimal balance between medical and lifestyle interventions in lowering major cardiovascular event risks. This article emphasizes the ongoing evolution of cardiovascular care, highlighting the imperative need for evidence-based guidelines tailored to individual patient needs.

Value of DUSP6 in peripheral blood mononuclear cells in predicting adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy.

Adverse cardiovascular events are the leading cause of death in peritoneal dialysis patients. Identifying indicators that can predict adverse cardiovascular events in these patients is crucial for prognosis. This study aims to assess the value of dual-specificity phosphatase 6 (DUSP6) in peripheral blood mononuclear cells as a predictor of adverse cardiovascular events after peritoneal dialysis in diabetic nephropathy patients. A total of 124 diabetic nephropathy patients underwent peritoneal dialysis treatment at the Department of Nephrology of the First Affiliated Hospital of Hebei North University from June to September 2022 were selected as study subjects. The levels of DUSP6 in peripheral blood mononuclear cells were determined using Western blotting. Patients were categorized into high-level and low-level DUSP6 groups based on the median DUSP6 level. Differences in body mass index, serum albumin, high-sensitivity C-reactive protein, and dialysis duration were compared between the 2 groups. Pearson, Spearman, and multiple linear regression analyses were performed to examine factors related to DUSP6. Patients were followed up to monitor the occurrence of adverse cardiovascular events, and risk factors for adverse cardiovascular events after peritoneal dialysis were analyzed using Kaplan-Meier and Cox regression. By the end of the follow-up, 33 (26.61%) patients had experienced at least one adverse cardiovascular event. The high-level DUSP6 group had higher body mass index, longer dialysis duration, and higher high-sensitivity C-reactive protein, but lower serum albumin levels compared to the low-level DUSP6 group (all P<0.05). DUSP6 was negatively correlated with serum albumin levels (r=-0.271, P=0.002) and positively correlated with dialysis duration (rs=0.406, P<0.001) and high-sensitivity C-reactive protein (rs=0.367, P<0.001). Multiple linear regression analysis revealed that dialysis duration and high-sensitivity C-reactive protein were independently correlated with DUSP6 levels (both P<0.05). The cumulative incidence of adverse cardiovascular events was higher in the high-level DUSP6 group than in the low-level DUSP6 group (46.67% vs 7.81%, P<0.001). Cox regression analysis indicated that low serum albumin levels (HR=0.836, 95% CI 0.778 to 0.899), high high-sensitivity C-reactive protein (HR=1.409, 95% CI 1.208 to 1.644), and high DUSP6 (HR=6.631, 95% CI 2.352 to 18.693) were independent risk factors for adverse cardiovascular events in peritoneal dialysis patients. Dialysis duration and high-sensitivity C-reactive protein are independently associated with DUSP6 levels in peripheral blood mononuclear cells of diabetic nephropathy patients undergoing peritoneal dialysis. High DUSP6 levels indicate a higher risk of adverse cardiovascular events.

Quantitative and structural changes of blood platelet cytoskeleton proteins in multiple sclerosis (MS)

Epidemiological studies show that cardiovascular events related to platelet hyperactivity remain the leading causes of death among multiple sclerosis (MS) patients. Quantitative or structural changes of platelet cytoskeleton alter their morphology and function. Here, we demonstrated, for the first time, the structural changes in MS platelets that may be related to their hyperactivity. MS platelets were found to form large aggregates compared to control platelets. In contrast to the control, the images of overactivated, irregularly shaped MS platelets show changes in the cytoskeleton architecture, fragmented microtubule rings. Furthermore, MS platelets have long and numerous pseudopodia rich in actin filaments. We showed that MS platelets and megakaryocytes, overexpress β1-tubulin and β-actin mRNAs and proteins and have altered post-translational modification patterns. Moreover, we identified two previously undisclosed mutations in the gene encoding β1-tubulin in MS. We propose that the demonstrated structural changes of platelet cytoskeleton enhance their ability to adhere, aggregate, and degranulate fueling the risk of adverse cardiovascular events in MS.

The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout.

Gout is the most common form of inflammatory arthritis worldwide and is characterized by painful recurrent flares of inflammatory arthritis that are associated with a transiently increased risk of adverse cardiovascular events. Furthermore, gout is associated with multiple cardiometabolic-renal comorbidities such as type 2 diabetes, chronic kidney disease and cardiovascular disease. These comorbidities, potentially combined with gout flare-related inflammation, contribute to persistent premature mortality in gout, independently of serum urate concentrations and traditional cardiovascular risk factors. Although better implementation of standard gout care could improve gout outcomes, deliberate efforts to address the cardiovascular risk in patients with gout are likely to berequired to reduce mortality. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are approved for multiple indications owing to their ability to lower the risk of all-cause and cardiovascular death, hospitalizations for heart failure and chronic kidney disease progression, making them an attractive treatment option for gout. These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

SGLT2 Inhibitors vs GLP-1 Receptor Agonists and Clinical Outcomes in Patients With Diabetes With/Without Atrial Fibrillation.

The coexistence of diabetes mellitus and atrial fibrillation (AF) is associated with substantial risks of adverse cardiovascular events. The relevant outcomes associated with the use of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) vs glucagon-like peptide-1 receptor agonists (GLP-1RAs) among patients with type 2 diabetes (T2D) with/without concomitant AF remain unknown. In this nationwide retrospective cohort study from the Taiwan National Health Insurance Research Database, there were 344 392 and 31 351 patients with T2D without AF, and 11 462 and 816 T2D patients with AF treated with SGLT2is and GLP-1RAs, respectively, from May 1, 2016, to December 31, 2019. Patients were followed from the drug index date until the occurrence of study events, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. We used propensity score-stabilized weight to balance covariates across the 2 medication groups. The incidence rate of all study outcomes in patients with concomitant AF was much higher than in those without concomitant AF. For the AF cohort, SGLT2i vs GLP-1RA was associated with a lower risk of hospitalization for heart failure (HF) (2.32 vs 4.74 events per 100 person-years; hazard ratio [HR] 0.48, 95% CI 0.36-0.66), with no benefit seen for the non-AF cohort (P for homogeneity < .01). SGLT2i vs GLP-1RA was associated with a lower risk of composite kidney outcomes both in the AF (0.38 vs 0.79 events per 100 person-years; HR 0.47; 95% CI 0.23-0.96) and the non-AF cohorts (0.09 vs 0.18 events per 100 person-years; HR 0.53; 95% CI 0.43-0.64). There were no significant differences in the risk of major adverse cardiovascular events and all-cause mortality in those who received SGLT2i compared with GLP-1RA for the AF or non-AF cohorts. Considering the high risk of developing HF and/or high prevalence of concomitant HF in patients with concomitant diabetes and AF, whether SGLT2is should be the preferred treatment to GLP-1RAs for such a high-risk population requires further investigation.

Carbamazepine, lamotrigine, valproate: comparing risks of adverse cardiovascular events

Carbamazepine, lamotrigine, valproate: comparing risks of adverse cardiovascular events

Constitutive Modeling of Mouse Arteries Suggests Changes in Directional Coupling and Extracellular Matrix Remodeling That Depend on Artery Type, Age, Sex, and Elastin Amounts.

Arterial stiffening occurs during natural aging, is associated with an increased risk of adverse cardiovascular events, and can follow different timelines in males and females. One mechanism of arterial stiffening includes remodeling of the extracellular matrix (ECM), which alters the wall material properties. We used elastin haploinsufficient (Eln+/-) and wildtype (Eln+/+) mice to investigate how material properties of two different arteries (ascending aorta and carotid artery) change with age, sex, and ECM composition. We used a constitutive model by Dong and Sun that is based on the Holzapfel-Gasser-Ogden (HGO) type, but does not require a discrete number of fibrous ECM families and allows varied deformation coupling. We find that the amount of deformation coupling for the best fit model depends on the artery type. We also find that remodeling to maintain homeostatic (i.e., young, wildtype) values of biomechanical parameters with age, sex, and ECM composition depends on the artery type, with ascending aorta being more adaptable than carotid artery. Fitted material constants indicate sex-dependent remodeling that may be important for determining the time course of arterial stiffening in males and females. We correlated fitted material constants with ECM composition measured by biochemical (ascending aorta) or histological (carotid artery) methods. We show significant correlations between ECM composition and material parameters for the mean values for each group, with biochemical measurements correlating more strongly than histological measurements. Understanding how arterial stiffening depends on age, sex, ECM composition, and artery type may help design effective, personalized clinical treatment strategies.

ZeXieYin formula alleviates atherosclerosis by inhibiting the MAPK/NF-κB signaling pathway in APOE−/− mice to attenuate vascular inflammation and increase plaque stability

Ethnopharmacological relevanceZexieyin formula (ZXYF), a traditional Chinese herbal formula recorded in the Huangdi Neijing to have efficacy in relieving spleen dampness and heat accumulation syndrome, which is also the key pathogenesis of atherosclerosis (AS). The efficacy has demonstrated by our previous studies. However, the intrinsic mechanism of ZXYF for treating vascular inflammation and the effect of inflammatory response on plaque are not known. Currently, plaque stabilization is crucial for the prognosis of AS. Aim of the studyOur study mainly focused on the therapeutic effects of ZXYF on high-fat diet (HFD)-induced vascular inflammation and vulnerable plaques (VP) in mice and explored its underlying mechanism. Methods and materialsMale apolipoprotein E knockout (APOE−/−) mice were fed HFD for 8 weeks to establish a VP model. During this period, the mice were also administered ZXYF, while atorvastatin (ATO) was used as a positive control. Aortic plaque area and morphology were detected by oil red staining and HE staining. Aortic plaque collagen content was detected by Masson staining. M1/M2 type macrophages were detected using immunofluorescence (IF). The study analyzed the levels of inflammation-related cytokines (IL-1β, IL-10, IL-6), MAPK/NF-κB pathway proteins, and NLRP3 inflammasomes (NLRP3, Caspase-1) using Western blot. Additionally, the levels of matrix metalloproteinase (MMP)-2 and MMP-9 and α-smooth muscle actin (α-SMA) in the aorta were analyzed using immunohistochemistry (IHC). The plaque instability index was calculated for each group using the vulnerable plaque formula. ResultsIn this study, APOE−/− mice were fed high-fat diet for 8 weeks. The results of oil-red and HE staining indicated a significant increase in the aortic plaque area of the mice, which exhibited a typical VP phenotype. ZXYF and ATO significantly improved AS plaques and prevented plaque rupture. HFD exacerbated vascular inflammation, stimulated macrophage conversion to M1-type through the MAPK/NF-κB signaling pathway, and released pro-inflammatory factors such as interleukin (IL)-1β, IL-1α, and IL-6. These factors activated NLRP3 inflammasome, leading to cellular death. However, ZXYF could reverse this trend and promote the conversion of macrophages to the anti-inflammatory M2 type. The anti-inflammatory effect of ATO was not significant. Moreover, HFD promoted the release of MMP-2 and MMP-9 from macrophages, which degraded plaque collagen, and induced a decrease in plaque SMC content, resulting in a thinning of the plaque fibrous cap. In contrast, ZXYF inhibited the decomposition of plaque collagen and increased the content of plaque smooth muscle cells (SMC) by reducing macrophage secretion of MMPs, thereby stabilizing plaques. Although ATO could reverse the decrease in plaque collagen and SMC content, its effect on MMPs was not significant. Finally, we calculated the vulnerability index to assess the overall risk of the plaque vulnerability phenotype. In line with these findings, ZXYF and ATO were able to effectively reverse the increase in the vulnerability index caused by HFD and lower the risk of adverse cardiovascular events. ConclusionOur results suggested that ZXYF could reduce inflammation and increase plaque stability by inhibiting the MAPK/NF-κB signaling pathway, which provided a theoretical basis for clinical application and subsequent research.

Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: Asystematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.