Cardiovascular Disease Biomarkers Research Articles

Left ventricular assist devices promote changes in the expression levels of platelet microRNAs.

MicroRNAs (miRs) emerged as promising diagnostic and therapeutic biomarkers in cardiovascular diseases. The potential clinical utility of platelet miRs in the setting of left ventricular assist device (LVAD) support is unexplored. We prospectively measured the expression levels of 12 platelet miRs involved in platelet activation, coagulation, and cardiovascular diseases in LVAD patients by quantitative real-time polymerase chain reaction. Data were longitudinally measured before LVAD implant and after 1, 6, and 12 months of LVAD support, and compared with those measured in healthy volunteers (controls). In silico analysis was also performed to identify pathways targeted by differentially expressed miRs. Data from 15 consecutive patients and 5 controls were analyzed. Pre-implant expression levels of platelet miR-126, miR-374b, miR-223, and miR-320a were significantly different in patients vs. controls. The expression levels of platelet miR-25, miR-144, miR-320, and miR-451a changed significantly over the course of LVAD support; in silico analysis revealed that these miRs are implicated in both cardiac- and coagulation-associated pathways. Furthermore, the patients who suffered from bleeding (n = 5, 33%) had significantly higher pre-implant expression levels of platelet miR-151a and miR-454 with respect to the patients who did not. The same miRs were also differentially expressed in bleeders following LVAD implantation early before the clinical manifestation of the events. This study provides a proof-of-concept evidence of significant modulation of platelet miRs expression driven by LVADs. The possible existence of a platelet miRs signature predictive of the development of bleeding events warrants further validation studies.

Inflammatory and endothelial dysfunction markers in females with metabolic syndrome aged 50–75 years

Introduction: The prevalence of metabolic syndrome (MetS) in Indonesia is 39% and it is higher in females than in males (46% vs. 28%). Features of this syndrome comprise low-grade chronic inflammation and endothelial dysfunction from cardiometabolic abnormalities. High-sensitive C-reactive protein (HsCRP) is a biomarker of cardiovascular disease, whereas ferritin and pentraxin-3 (PTX-3) are markers of chronic inflammation. One of the markers of endothelial dysfunction is an intercellular cell adhesion molecule-1 (ICAM-1). Studies on MetS in women aged 50–70 years and using several markers of inflammation and endothelial dysfunction are rare. The study aimed to determine differences in HsCRP, ferritin, PTX-3, and ICAM-1 level between females with and without MetS aged 50–75 years. Methods: For this cross-sectional study, 160 females aged 50–75 years from South Jakarta were recruited, divided into MetS and non-MetS (control) groups, 80 participants each. Participants that met the inclusion criteria were assessed for vital signs and metabolic parameters (e.g., lipid profile, fasting blood glucose level, and waist circumference [WC]). The groups were compared using an independent t-test for inflammatory (i.e., HsCRP, PTX-3, and ferritin) and endothelial dysfunction (ICAM-1) (p < 0.05) biomarkers. Results: The mean age of the MetS and control groups was 59.6 ± 5.6 and 59.2 ± 5.5 years. MetS criteria included WC of ≥80 cm (95.2%), increased blood pressure level (90.6%); and high-density lipoprotein cholesterol of <50 mg/dL (76.2%). Significant differences were found between the MetS and control groups for ferritin (p = 0.027), PTX-3 (p = 0.045), and ICAM-1 (p = 0.004) but not for HsCRP (p = 0.136). Conclusion: Elevated ferritin, PTX-3 level, and ICAM-1 level are significantly associated with an increased Mets risk in females aged 50–75 years; however, the same is not true for HsCRP.

#3115 THE ASSOCIATION OF FIBROBLAST GROWTH FACTOR-23 AND CARDIORENAL SYNDROME IN PATIENTS WITH DIABETES MELLITUS

Abstract Background and Aims Previous studies suggest that interactions between the heart and the kidney can contribute to the progressive dysfunction of both organs. Recently, there has been an increase in the prevalence of cardiovascular disease (CVD) and chronic kidney disease (CKD) due to increasing diabetes mellitus rate. It is known that fibroblast growth factor-23 (FGF-23) has been found to be related to kidney metabolism especially as a biomarker and a key factor to be used in the kidney field. The aim of our study was to assess potential therapeutic approaches of the use of FGF-23 in clinical settings as a potential circulating biomarker for CVD and CKD. Method A total of 155 patients with DT2, aged 34 to 84 years (60 [60;72]), were examined. Control group included 94 healthy people the same age. All patients underwent standard clinical and laboratory examination, with an assessment of the levels of FGF-23 in baseline plasma samples. Renal function was assessed based on the levels of serum creatinine, cystatin C, eGFR, which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio (A/C). An echocardiographic examination was conducted according to the standard protocol with the calculation of dimensional, volume and speed characteristics. Results The levels of FGF-23 were significantly higher in DT2 patients with CKD 5 in comparison with stages 1–4. There were positive strong significant association between FGF-23 and creatinine (r = 0.71, p<0.001). In both unadjusted and adjusted analyses, probability of decreased eGFR was associated strongly with FGF-23 (COR; 95% CI 1.890; 1.362-2.622, p<0,001). When evaluating the dependence of the probability of decreased eGFR on the FGF-23 using the ROC analysis, the cut-off value of FGF-23 was 0,9 pmol/l. The sensitivity and specificity of the method were 75.3% and 74.5%, respectively (AUC 0.832±0.035 with 95% CI: 0.764-0.901, p<0.001). DT2 patients with left ventricular hypertrophy (LVH) were characterized by higher levels of FGF-23 (2,45 [0,65;7,43] vs 0,57 [0,19;2,19] pmol/l in control group). DT2 patients with LVH and natriuretic peptides levels ≥ 35 pg/ml for BNP and/or ≥125 ng/ml for NT-proBNP had significantly high concentrations of FGF-23 than patients with normal levels of natriuretic peptides (3,22 [1,09;9,55] vs. 0,52 [0,27;1,08] pmol/l, p<0,0001). In order to assess the diagnostic significance of the FGF-23 for predicting left ventricular mass index (LVMI) thickening and increasing the proBNP concentration, a ROC analysis was performed. Thus, at the level of FGF-23 (AUC-0.702) = 0.9 pmol/l, the sensitivity and specificity for LVMI thickening were 66.9% and 67.3%. Conclusion Our study identifies FGF-23 as a promising target of novel therapeutic interventions in cardiorenal syndrome, which should be investigated in future clinical studies.

Progress in the Optical Sensing of Cardiac Biomarkers.

Biomarkers play key roles in the diagnosis, risk assessment, treatment and supervision of cardiovascular diseases (CVD). Optical biosensors and assays are valuable analytical tools answering the need for fast and reliable measurements of biomarker levels. This review presents a survey of recent literature with a focus on the past 5 years. The data indicate continuing trends towards multiplexed, simpler, cheaper, faster and innovative sensing while newer tendencies concern minimizing the sample volume or using alternative sampling matrices such as saliva for less invasive assays. Utilizing the enzyme-mimicking activity of nanomaterials gained ground in comparison to their more traditional roles as signaling probes, immobilization supports for biomolecules and for signal amplification. The growing use of aptamers as replacements for antibodies prompted emerging applications of DNA amplification and editing techniques. Optical biosensors and assays were tested with larger sets of clinical samples and compared with the current standard methods. The ambitious goals on the horizon for CVD testing include the discovery and determination of relevant biomarkers with the help of artificial intelligence, more stable specific recognition elements for biomarkers and fast, cheap readers and disposable tests to facilitate rapid testing at home. As the field is progressing at an impressive pace, the opportunities for biosensors in the optical sensing of CVD biomarkers remain significant.

Lipoprotein(a), family history of cardiovascular disease, and incidence of heart failure

Lipoprotein(a) (Lp(a)) is a largely genetically determined biomarker for cardiovascular disease (CVD), while its potential interplay with family history (FHx) of CVD, a measure of both genetic and environmental exposures, remains unclear. We examined the associations of Lp(a) in terms of circulating concentration or polygenetic risk score (PRS), and FHx of CVD with risk of incident heart failure (HF). Included were 299,158 adults from the UK Biobank without known HF and CVD at baseline. Hazards ratios (HRs) and 95% Cls were estimated by Cox regression models adjusted for traditional risk factors defined by the Atherosclerosis Risk in Communities study HF risk score. During the 11.8-year follow-up, 5,502 incidents of HF occurred. Higher levels of circulating Lp(a), Lp(a) PRS, and positive FHx of CVD were associated with higher risks of HF. Compared with individuals who had lower circulating Lp(a) and no FHx, HRs (95% CIs) of HF were 1.36 (1.25, 1.49), 1.31 (1.19, 1.43), and 1.42 (1.22, 1.67) for those with higher Lp(a) and a positive history of CVD for all family members, parents, and siblings, respectively; similar results were observed by using Lp(a) PRS. The risk estimates for HF associated with elevated Lp(a) and positive FHx were attenuated after excluding those with incident myocardial infarction (MI) during follow-up. Lp(a) and FHx of CVD were independent risk factors for incident HF, and the highest risk of HF was observed among individuals with both risk factors. The association may be partly mediated by myocardial infarction.

Epigenetic Modifications as Predictive Biomarkers for Cardiovascular Disease: A Longitudinal Study on DNA Methylation Patterns and Disease Risk

Cardiovascular disease (CVD) is a leading cause of death worldwide, and early detection and prevention are essential to reduce its burden. Although traditional risk factors such as hypertension and lipid levels are standard predictors, they tend to identify the risk of disease at a later date There is an urgent need to develop more accurate, leading-edge biomarkers indicating molecular changes that occur before the onset of clinical symptoms. Epigenetic changes, in particular DNA methylation, provide a promising approach to identify individuals at risk for CVD. Despite advances in understanding the genetic underpinnings of CVD, little is known about how dynamic epigenetic modifications influenced by environmental and lifestyle factors can serve as early predictive biomarkers the risk of the disease. This study aims to address this gap by investigating whether DNA methylation patterns can predict future CVD risk before clinical manifestations. The primary objective of this study was to systematically investigate the association between DNA methylation patterns and CVD risk. Specifically, the study seeks to identify regions where DNA methylation changes are associated with cardiovascular outcomes and investigate the predictive potential of these epigenetic changes for future disease. 1,000 participants aged 30-75 years were followed for 5 to 10 years. Periodic blood samples were collected for DNA methylation analysis by bisulfite sequencing and microarrays. Major CVD risk factors such as adiposity, hypertension and smoking status were also controlled. Comprehensive statistical models were used to assess the association between DNA methylation changes and CVD incidence. Participants who developed CVD showed significant differences in DNA methylation in regions associated with lipid metabolism (e.g., APOA5) and inflammation (e.g., TNF-α) Over time, those who developed heart disease and vascular events revealed progressive hyper methylation of key genes, with 85% sensitivity 78 to predict future CVD risk % and specificity skin. These methylation patterns were discovered years before the appearance of conventional clinical pathology. This study shows that DNA methylation patterns are determinants of acute cardiovascular risk, providing a novel approach for early detection and prevention The findings suggest the inclusion of epigenetic biomarkers in routine risk assessment about may improve the identification of individuals at high risk for CVD It is important to inform individuals at high risk of CVD of the diagnosis and to explore possible interventions that can alter change a occurs in this epigenetic and reduced CVD risk.

Diagnosis of acute myocardial infarction using a combination of circulating circular RNA cZNF292 and clinical information based on machine learning.

Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof-of-concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia-induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non-AMI patients. Based on feature selection by using lasso with 10-fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM+cZNF292 can separate AMI and non-AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non-ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti-apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model "CM+cZNF292."

Volunteering and Changes in Cardiovascular Biomarkers: Longitudinal Evidence From the Health and Retirement Study.

Growing body of research shows that volunteering is beneficial for those served, the volunteers, and the larger communities. However, major challenges remain that hinder the practical implications for volunteer activity as a public health intervention, including potential selection effects, lack of longitudinal studies that adjust for baseline characteristics, and a paucity of studies that consider multiple physical health outcomes in a single model. Data from 2006 to 2016 waves of the Health and Retirement Study (2006-2016) were used (N = 18,847). Outcome-wide analyses were utilized to evaluate if changes in volunteering between 2006/2008 (t0) and 2010/2012 (t1) were associated with 7 cardiovascular disease biomarkers 4 years later (2014/2016, t2). These models were adjusted for demographic factors, socioeconomic status, health behaviors, chronic conditions, baseline biomarkers, and volunteering. Additionally, selection into volunteering and attrition were taken into account. Compared with nonvolunteers, volunteering more than 200 hr a year was associated with a lower risk for clinically high diastolic blood pressure. In addition, increased volunteering effort (change from 1 to 99 hr at t0 to >100 hr at t1) was associated with a lower likelihood of clinically high systolic and diastolic blood pressure levels. Sustained high volunteering (>100 hr at both t0 and t1) was associated with lower diastolic blood pressure. The current study adds to the evidence on the health benefits of volunteering for adults 50 and older by inferring a potential causal link between high-intensity volunteering and reduced blood pressure.

PROGNOSTIC VALUE OF MICRORNA-126-3P FOR CARDIOVASCULAR EVENTS IN A GENERAL POPULATION

Objective: Endothelial dysfunction is a forerunner of atherosclerosis, leading to cardiovascular disease, and albuminuria is a marker of endothelial dysfunction. Measurement of circulating levels of microRNAs is emerging as potential biomarkers for cardiovascular disease. We aimed to estimate the predictive value of a plasma microRNAs signature associated with albuminuria in the incidence of cardiovascular events. Design and method: The first study phase was to identify the plasma miRNAs associated with albuminuria in patients with HTN and controls. In a second step, a predictive model of miRNAs to assess the risk to develop CV events was analyzed in a retrospective study of the general population (HORTEGA Follow-up Study), on those who did not have previous CVD and had complete basal information on relevant covariates. Plasma miRNAs quantified in hypertensive patients by next generation sequencing were validated in a cohort of patients and controls by real-time quantitative PCR. The microRNAs associated with albuminuria were tested and their prognostic value for cardiovascular event incidence were analyzed on a retrospective, population-based study using Cox proportional hazard models. Results: A plasma microRNA profile was identified in the discovery cohort (n = 48) associated with albuminuria and three microRNAs (miR-126-3p, miR-1260b and miR-374a-5p) were confirmed in the validation cohort (n = 98). The microRNA signature discriminates urinary albumin excretion at baseline (n = 1025), and predicts the incidence of cardiovascular events and coronary heart disease and stroke in a general population retrospective study within a 14-year follow-up (n = 926). Thus, high miR-126-3p levels were associated with a shorter time free of both cardiovascular events (HR = 1.48, (1.36–1.62), p < 0.0001), as well as coronary artery disease and stroke combined (HR = 2.49, (2.19–2.83), p < 0.0001) (Figure). Conclusions: An increased plasma microRNAs profile was identified in hypertensive patients with albuminuria. Increased miR-126-3p emerges as a prognostic marker for cardiovascular events in a long-term general population. Further studies will assess the potential role of miR-126-3p as a guide for the status of endothelial dysfunction.

0126 CVD biomarker profiling reveals distinct responses to acute exercise under conditions of recurrent sleep loss in healthy humans

Abstract Introduction Physical exercise impacts a plethora of signaling pathways, which mediate the acute and long-term benefits of exercise. Whereas the acute effects of exercise on overall metabolism and cardiovascular disease (CVD) risk factors have been extensively studied in humans, little is known about how a wider range of CVD biomarkers change in response to acute exercise under conditions of sleep loss. Thus, here we examined whether a few nights of short sleep alter the diurnal and exercise-induced levels of a range of CVD biomarkers. Methods In a randomized two-condition crossover study, 16 men partook in two sessions, comprising three consecutive nights of full-night sleep (NS, 8.5 hours sleep/night) and three nights of partial sleep restriction (SR, 4.25 hours/night). In both conditions, blood was repeatedly sampled in the evening and about 12 hours later (for evening-to-morning analysis) as well as repeatedly before and after a 30-min bout of high-intensity exercise (at 75% VO2maxReserve). Olink's CVD II panel and ELISAs were used to measure 92 CVD protein biomarkers. Results Under pre-exercise sedentary conditions, the diurnal changes of several CVD biomarkers differed in response to SR compared with NS. However, several proteins exhibited diurnal changes regardless of sleep condition (as also confirmed in a separate a cohort with overnight wakefulness). In response to exercise, we observed that most proteins increased vs. decreased in their relative levels, including inflammatory markers. Furthermore, some proteins exhibited an early vs. more delayed increase. However, following SR, the exercise-induced induction of CVD biomarkers was markedly dampened, compared with the NS condition, and SR resulted in an altered exercise-induced response for several inflammatory-related CVD biomarkers. Conclusion Recurrent sleep restriction impacts the evening-to-morning dynamics of several CVD biomarkers, and the extent to which blood-based CVD biomarkers are induced by acute, high-intensity exercise. This may indicate that some of the cardiometabolic responses to vigorous exercise differ under conditions of sleep loss. Whether such changes alter the long-term benefits of aerobic exercise under conditions of chronic sleep loss, and whether these changes differ in e.g. older subjects or CVD, remains to be investigated. Support (if any) Swedish Society for Medical Research, Swedish Cancer Foundation, Diabetesfonden, Göran Gustafsson, Hjärnfonden

The atherogenic index of plasma and carotid atherosclerosis in a community population: a population-based cohort study in China

BackgroundThe atherogenic index of plasma (AIP) is an important alternative metabolic biomarker of atherosclerosis and cardiovascular diseases. Nevertheless, the correlation between the AIP and carotid atherosclerosis is unknown among the general population.MethodsA total of 52,380 community residents, aged ≥ 40 years who underwentcervical vascular ultrasound from December 2017 to December 2020 in Hunan China, were selected for retrospective analysis. The AIP was calculated as a logarithmically converted ratio of triglycerides (TG) to high-density lipoprotein-cholesterol (HDL-C). The participants were divided into AIP quartile groups (Q1-Q4). Logistic regression models and restricted cubic spline analyses were used to examine the association of the AIP with carotid atherosclerosis. Stratified analyses were applied to control for confounding factors. The incremental predictive value of the AIP was further assessed.ResultsAfter adjusting for traditional risk factors, an increased AIP was associated with a higher rate of carotid atherosclerosis (CA), increased carotid intima-media thickness (CIMT), and plaques [odds ratio, OR (95% confidence interval, CI): 1.06 (1.04, 1.08), 1.07 (1.05, 1.09), and 1.04 (1.02, 1.06) per 1-SD increase in the AIP, respectively]. Compared with those participants in the quartile 1 group, those in the quartile 4 group had a greater risk of CA [OR 1.18, 95% CI (1.12, 1.25)], increased CIMT [OR 1.20, 95% CI (1.13, 1.26)], and plaques [OR 1.13, 95% CI (1.06, 1.19)]. However, we did not observe an association between the AIP and stenosis [0.97 (0.77, 1.23), p for trend = 0.758]. Restricted cubic spline analyses also showed a cumulative increase in the risk of CA, increased CIMT, and plaques but not stenosis severity (> 50%) with an increase of the AIP. Subgroup analyses showed that a more significant association between the AIP and the prevalence of increased CA was detected in younger subjects (aged < 60 years) with a body mass index (BMI) of ≥ 24 and fewer comorbidities. Additionally, the AIP provided incremental predictive capacity over established risk factors for CA, as shown by an improvement in the net reclassification index (NRI) and integrated discrimination index (IDI) (all P < 0.05).ConclusionsAn elevated AIP in a community-based population is associated with a higher rate of CA. the AIP could serve as a potential biomarker for CA risk assessment.

DNA methylation as a biomarker for cardiometabolic disease risk

Abstract Funding Acknowledgements Type of funding sources: None. Cardiovascular disease (CVD) is the leading cause of death in most countries [1]. Risk factors known to predispose to the development of CVD include increasing age, male gender, diabetes mellitus, high blood cholesterol, tobacco smoking, high blood pressure (hypertension), obesity, physical inactivity, and family history [2]. Elevated plasma homocysteine is also an independent risk factor for CVD [2,3]. The mechanism by which elevated homocysteine contributes to CVD risk is not well understood, but it is well-established that dietary folate and vitamin B supplementation can reduce serum homocysteine levels by facilitating remethylation of homocysteine to methionine [4]. DNA methylation can modulate gene expression in response to exposure to various substances, such as nutrients, smoking, and environmental chemicals.Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. The remethylation cycle is essential for the systemic methyl donor supply, which is used for important biological processes, such as cytosine-5 methylation of genomic DNA, an epigenetic modification that plays an important role in maintaining genomic stability, chromatin structure, and in controlling transcriptional capacity [2,4]. Methodology/Principal Findings In this prospective study, we examined both gender patients, aged 40-50 years. Relationship between prevalence of Cardiometabolic risk factors (metabolic syndrome, oxidative stress and arterial hypertension) or its predisposing conditions (hypertrigliceridemia, dislipedimia, inusline resistance, D vitamin hipovitaminosis)) and DNA hydroximethylation was investigated. Hydroxymethylation measurement was done using a gold standard technique (liquid chromatography + mass spectrometry), the biological age equivalent was calculated by LC-MS in laboratories Reunis, to verify the potential value of DNA methylation as a CVD biomarker. Results Generally, 296 both gender patients were analyzed regarding metabolic syndrome and oxidative stress, age group 40-50 years (Me=47,1). MethylAge (DNA-hydroxymethylation) in analyzed group has average age 40,1 years old. DNA Hydroxymethylation is higher in those individuals, who has increased waist circumference, as well as, statistically significant correlation was observed between MethylAge waist circumference, metabolic syndrome and hypertriglyceridemia (p&amp;lt;0,05). Conclusion The evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, iron deficiency, dyslipidemia). Our data showed a link between premature biological ageing and waist circumference, hypertrigliceridimia. Hydroxymethylation of DNA is a good epigenetic marker for aging and risk assessment, especially in alliance with AGEs and oxidative stress research.

Total carotene plasma concentrations are inversely associated with atherosclerotic plaque burden: A post-hoc analysis of the DIABIMCAP cohort

Atherosclerosis is the major risk factor for cardiovascular disease (CVD), the first cause of death worldwide. Chronic low-grade inflammation and a sustained oxidative milieu are causatively related to atherosclerosis onset and progression, and therefore, dietary patterns rich in bioactive compounds with anti-inflammatory and antioxidant activities might likely contribute to revert or slowing the progression of atherosclerosis. The aim of this study is to analyse the association between fruit and vegetables intake, quantitatively measured through carotene plasma concentrations, and atherosclerotic burden, as a surrogate biomarker of CVD, in free-living subjects from the DIABIMCAP cohort study. The 204 participants of the DIABIMCAP Study cohort (Carotid Atherosclerosis in Newly Diagnosed Type 2 Diabetic Individuals, ClinicalTrials.gov Identifier: NCT01898572), were included in this cross-sectional study. Total, α-, and β-carotenes were quantified by HPLC-MS/MS. Lipoprotein analysis in serum was performed by 2D- 1H NMR- DOSY, and atherosclerosis and intima media thickness (IMT) were measured through standardized bilateral carotid artery ultrasound imaging. Subjects with atherosclerosis (n=134) had lower levels of large HDL particles than subjects without atherosclerosis. Positive associations were found between α-carotene and both large and medium HDL particles, and inverse associations were found between β- and total carotene, and VLDL and its medium/small particles. Subjects with atherosclerosis presented significantly lower plasma concentrations of total carotene compared with subjects without atherosclerosis. Plasma concentrations of carotene decreased as the number of atherosclerotic plaques increased, although after multivariate adjustment, the inverse association between β- and total carotene with plaque burden remained significant only in women. A diet rich in fruit and vegetables results in higher plasmatic carotene concentrations, which are associated with a lesser atherosclerotic plaque burden.

Effects of high-intensity interval training on physical morphology, cardiorespiratoryfitness and metabolic risk factors of cardiovascular disease in children and adolescents: A systematic review and meta-analysis.

To systematically evaluate the safety and efficacy of high-intensity interval training in children and adolescents. Eight databases were searched. Descriptive analysis of the efficacy and safety of high-intensity interval training on body shape, cardiorespiratory fitness, and metabolic risk markers of cardiovascular disease in children and adolescents. Subgroup analysis was performed using age, participants, intervention time, and exercise frequency as covariates. 47 studies included 2995 children and adolescents. The results of the meta-analysis showed that high-intensity interval training significantly improved cardiorespiratory fitness indicators (VO2max, SBP, DBP and HRmax) and cardiovascular disease biomarkers (TC and HDL-C). HIIT had no significant effect on body shape indicators (BMI, BF% and WC) or cardiovascular disease biomarkers (TG and LDL-C). Currently, there is insufficient evidence that HIIT with interval running as the predominant form improves physical indicators in children and adolescents. However, HIIT can be promoted in children and adolescents to improve cardiorespiratory fitness and reduce some metabolic risk of cardiovascular disease.

Association Between Life's Simple 7 and Biomarkers of Cardiovascular Disease: Aldosterone, Interleukin-6, C-Reactive Protein.

Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)-achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C-reactive protein), and IL-6 (interleukin-6). Methods and Results We analyzed 379 individuals (age 18-66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14-point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3-14), we classified participants as "inadequate" (3-6), "average" (7-10), and "optimal" (11-14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone (Ptrend<0.001 and Ptrend=0.001, respectively), lower plasma renin activity (Ptrend<0.001), and a blunted increase in serum aldosterone with angiotensin II infusion (Ptrend=0.023). Being in the "optimal" LS7 score group was associated with lower serum CRP (Ptrend=0.001) and IL-6 (Ptrend=0.001). Conclusions A higher LS7 score was associated with a lower activity of the renin-angiotensin-aldosterone system and lower levels of the inflammatory markers CRP and IL-6. These findings offer a possible link between ideal cardiovascular health targets and biomarkers known to play a central role in the development of cardiovascular disease.

Detection and quantification of breast arterial calcifications on mammograms: a deep learning approach

ObjectiveBreast arterial calcifications (BAC) are a sex-specific cardiovascular disease biomarker that might improve cardiovascular risk stratification in women. We implemented a deep convolutional neural network for automatic BAC detection and quantification.MethodsIn this retrospective study, four readers labelled four-view mammograms as BAC positive (BAC+) or BAC negative (BAC−) at image level. Starting from a pretrained VGG16 model, we trained a convolutional neural network to discriminate BAC+ and BAC− mammograms. Accuracy, F1 score, and area under the receiver operating characteristic curve (AUC-ROC) were used to assess the diagnostic performance. Predictions of calcified areas were generated using the generalized gradient-weighted class activation mapping (Grad-CAM++) method, and their correlation with manual measurement of BAC length in a subset of cases was assessed using Spearman ρ.ResultsA total 1493 women (198 BAC+) with a median age of 59 years (interquartile range 52–68) were included and partitioned in a training set of 410 cases (1640 views, 398 BAC+), validation set of 222 cases (888 views, 89 BAC+), and test set of 229 cases (916 views, 94 BAC+). The accuracy, F1 score, and AUC-ROC were 0.94, 0.86, and 0.98 in the training set; 0.96, 0.74, and 0.96 in the validation set; and 0.97, 0.80, and 0.95 in the test set, respectively. In 112 analyzed views, the Grad-CAM++ predictions displayed a strong correlation with BAC measured length (ρ = 0.88, p < 0.001).ConclusionOur model showed promising performances in BAC detection and in quantification of BAC burden, showing a strong correlation with manual measurements.Clinical relevance statementIntegrating our model to clinical practice could improve BAC reporting without increasing clinical workload, facilitating large-scale studies on the impact of BAC as a biomarker of cardiovascular risk, raising awareness on women’s cardiovascular health, and leveraging mammographic screening.Key Points• We implemented a deep convolutional neural network (CNN) for BAC detection and quantification.• Our CNN had an area under the receiving operator curve of 0.95 for BAC detection in the test set composed of 916 views, 94 of which were BAC+ .• Furthermore, our CNN showed a strong correlation with manual BAC measurements (ρ = 0.88) in a set of 112 views.

Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers

Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.

Abstract 695: Serine Hydroxymethyltransferase 2 Regulates Mitochondrial Function And Ceramide Metabolism In Macrophages During Atherosclerosis

Increasing evidence suggests a critical role for amino acid metabolism in cardiovascular disease, highlighting potential therapeutic targets and our need for further understanding. Plasma serine has been found to be a biomarker for cardiovascular disease, while glycine is negatively correlated with coronary artery disease. Furthermore, attenuated plasma glycine:serine is associated with unstable atherosclerotic plaques. Mitochondrial Serine hydroxymethyl transferase (SHMT) catalyzes the bulk formation of glycine from serine in most cell types and drives one-carbon metabolism in the cytosol (SHMT1) or mitochondria (SHMT2). SHMT2 is necessary for mitochondrial protein translation and critical in development since global knockout mice are nonviable. We found LPS-treated macrophages have reduced SHMT2 expression concomitant with attenuated intracellular glycine:serine. Deletion of macrophage SHMT2 in vitro enhanced intracellular serine, which contributes to the rate-limiting step of ceramide de novo biosynthesis. C16:0 ceramide is highly abundant in atherosclerotic plaques and is positively associated with plaque severity, and SHMT2-deleted macrophages treated with C16:0 fatty acid enhances intracellular ceramide. Furthermore, deletion of SHMT2 reduced mitochondrial respiration and enhanced glycolysis similar to LPS-treated macrophages. Moreover, we found SHMT2 is highly expressed in plaque-associated macrophages in both human and mouse atherosclerotic plaques. We therefore hypothesized that SHMT2 regulates macrophage inflammatory phenotype in atherosclerosis through alterations in mitochondrial function and ceramide biosynthesis. To determine whether macrophage-expressed SHMT2 contributes to atherosclerosis, we developed a novel Shmt2 -floxed mouse crossed with LysM-Cre ( Shmt2 MKO ) and Apoe -/- mice. After 12 weeks on Western diet, we observed no differences in plasma glycine:serine or circulating lipids. Nevertheless, Shmt2 MKO / Apoe -/- mice had significantly enhanced plaque area compared to littermate controls. Our findings, representing the first investigation of conditional SHMT2 knockout mice, suggest a novel immunometabolic role for SHMT2 in macrophages in atherosclerosis.

Abstract 483: Monocyte-derived Dll4 Is A Novel Contributor To Persistent Systemic Inflammation In HIV Patients

Background: In HIV patients on combination antiretroviral therapy (cART), persistent systemic inflammation is a driving force for the progression of comorbidities, such as cardiovascular diseases. Monocyte and macrophage-related inflammation rather than T cell activation is a major cause of chronic inflammation. However, the underlying mechanism of how monocytes cause persistent inflammation is multifaceted. Methods and Results: In vitro, we demonstrated that lipopolysaccharides (LPS) or tumor necrosis factor alpha (TNFα), induced a robust increase of Delta-like ligand 4 (Dll4) mRNA and protein expression in human monocytes and Dll4 secretion (extracellular Dll4, exDll4) from monocytes. Enhanced Dll4 expression in monocytes triggered Notch1 activation to promote pro-inflammatory factors expression. Dll4 silencing and inhibition of Nocth1 activation diminished the LPS or TNFα -induced inflammation. exDll4 releases in response to cytokines occurred in monocytes but not endothelial cells or T cells. In clinical specimens, we found that people living with HIV (PLWH), both male and female, on cART showed a significant increase in membrane-bound Dll4 (mDll4) expression, activation of Dll4-Notch1 signaling, and inflammation in monocytes. Surprisingly, plasma exDll4 was remarkably elevated in HIV male patients but not female patients, and its levels paralleled with monocytes mDll4 in HIV male patients. In addition, circulating exDll4 was positively associated with pro-inflammatory monocytes and negatively associated with classic monocytes in HIV male patients. Conclusion: Pro-inflammatory stimuli increase Dll4 expression and Dll4-Notch1 signaling activation in monocytes and enhance monocyte inflammation, contributing to persistent systemic inflammation in PLWH. Plasma exDll4 is mainly released from monocytes and could act as a potential biomarker of HIV-related cardiovascular diseases caused by monocyte-mediated inflammation in HIV male patients. mDll4 in monocytes could be a potential biomarker of inflammation for both genders of HIV patients.

Trimethylamine N-Oxide (TMAO) Inducing Endothelial Injury: UPLC-MS/MS-Based Quantification and the Activation of Cathepsin B-Mediated NLRP3 Inflammasome.

TMAO is a new risk biomarker for cardiovascular disease. With trimethylammonium as its main chemical skeleton, TMAO is structurally similar to many endogenous metabolites, such as acetylcholine, carnitine, phosphorylcholine, etc. The mechanism of TMAO on the pathological process of CVD is still unclear. In this study, the quantitative analysis of plasma TMAO is conducted, and the contribution of Cathepsin B and NLRP3 inflammasome during the process of TMAO-induced endothelial injury was proposed and investigated at animal and cellular levels. Immunofluorescence assay was applied to represent the protein expression of Cathepsin B and NLRP3 inflammasome located at endothelial cells. The results showed that TMAO could disrupt endothelial cells permeability to induce endothelial injury, meanwhile, TMAO could increase NLRP3 inflammasome activation and promote the activity and expression of Cathepsin B in vitro and in vivo, whereas inhibition of NLRP3 inflammasome activation by MCC950 could protect the endothelial cells from TMAO associated endothelial injury via Cathepsin B. The study reveals that TMAO can cause endothelial injury via Cathepsin B-dependent NLRP3 inflammasome, and inhibition of Cathepsin B and NLRP3 inflammasome can reduce the TMAO-induced damage. The results provide new insight into the role of TMAO in CVD, which can be a potential therapeutic target for disease treatment and drug design.