Lipoprotein Metabolism, Dyslipidemia, and Lipid-Lowering Therapy in Women: A Comprehensive Review.

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk.

Prunus yedoensis Bark Downregulates the Expression of Cell Adhesion Molecules in Human Endothelial Cell Lines and Relaxes Blood Vessels in Rat Aortic Rings.

The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension.

Humoral and Cellular Response Induced by Primary Series and Booster Doses of mRNA Coronavirus Disease 2019 Vaccine in Patients with Cardiovascular Disease: A Longitudinal Study.

Preexisting cardiovascular disease (CVD) is a pivotal risk factor for severe coronavirus disease 2019 (COVID-19). We investigated the longitudinal (over 1 year and 9 months) humoral and cellular responses to primary series and booster doses of mRNA COVID-19 vaccines in patients with CVD. Twenty-six patients with CVD who received monovalent mRNA COVID-19 vaccines were enrolled in this study. Peripheral blood samples were serially drawn nine times from each patient. IgG against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) was measured using an enzyme-linked immunosorbent assay. The numbers of interferon-γ-releasing cells in response to SARS-CoV-2 peptides were measured using an enzyme-linked immunospot assay. The RBD-IgG titers increased 2 weeks after the primary series and booster vaccination and waned 6 months after vaccination. The S1-specific T cell responses in patients aged < 75 years were favorable before and after booster doses; however, the Omicron BA.1-specific T cell responses were poor. These results suggest that regular vaccination is useful to maintain long-term antibody levels and has implications for booster dose strategies in patients with CVD. Additional booster doses, including Omicron variant-adapted mRNA vaccines, may be recommended for patients with CVD, regardless of age.

Formaldehyde and the Transient Receptor Potential Ankyrin-1 Contribute to Electronic Cigarette Aerosol-induced Endothelial Dysfunction in Mice.

Electronic Nicotine Delivery Systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and 'respiratory braking' - biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or formaldehyde (FA, 5 ppm). Short-term exposures to PG: VG and FA induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N  -1,3-thiazolidine-4-carboxylic acid, TCA; N  -1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h).13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0-3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS.

Physical performance changes as clues to late-life blood pressure changes with advanced age: the osteoporotic fractures in men study.

OBJECTIVES: This study examined whether changes in late-life physical performance are associated with contemporaneous changes in blood pressure (BP) in older men. DESIGN: prospective cohort study over 7 years. SETTING AND PARTICIPANTS: Physical performance (gait speed, grip strength, chair stand performance) and clinic-measured BP at baseline and at least one follow-up (year 7 or 9) were assessed in 3,135 men aged ≥65 y enrolled in the Osteoporotic Fractures in Men Study (MrOS). METHODS: Generalized estimating equation analysis of multivariable models with standardized point estimates (ß [95% CI]) described longitudinal associations between physical performance and BP changes in participants overall, and stratified by baseline cardiovascular disease (CVD), antihypertensive medication use (none, ≥1), and enrollment age (<75 years; ≥75 years). RESULTS: Overall, positive associations (z-score units) were found between each increment increase in gait speed and systolic (SBP) (0.74 [0.22, 1.26]) and grip strength (0.35 [0.04, 0.65]) or gait speed (0.55 [0.24, 0.85]) with diastolic (DBP). Better grip strength and chair stand performance over time were associated with 1.83 [0.74, 2.91] and 3.47 [0.20, 6.74] mmHg higher SBP, respectively in men with CVD at baseline (both interaction P < .05). Gait speed increases were associated with higher SBP in men without CVD (0.76 [0.21, 1.32]), antihypertensive medication non-users (0.96 [0.30, 1.62]), aged <75 years (0.73 [0.05, 1.41]) and ≥75 years (0.76 [0.06, 1.47]). Similar positive, but modest associations for DBP were observed with grip strength in men with CVD, antihypertensive medication non-users, and aged <75 years, and with gait speed in men without CVD, aged <75 years, and irrespective of antihypertensive medication use. CONCLUSION: In older men, better physical performance is longitudinally associated with higher BP. Mechanisms and implications of these seemingly paradoxical findings, which appears to be modified by CVD status, antihypertensive medication use, and age, requires further investigation.

BP classification using the 2017 ACC/AHA guideline with risk of cardiovascular events in older individuals.

BACKGROUND: The association between stage 1 hypertension and the risk of cardiovascular disease (CVD) has not been established in older adults. Furthermore, little is known about whether lowering blood pressure (BP) is beneficial in older adults with stage 1 hypertension. METHODS: This cohort study analyzed nationwide data collected from the Japanese DeSC database, including 476,654 individuals aged ≥60 years. Individuals were categorized into four groups according to the 2017 ACC/AHA BP guidelines: normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension. The primary outcome was a composite CVD event, including myocardial infarction, angina pectoris, stroke, and heart failure. RESULTS: During a mean follow-up of 3.1 years, 53,946 composite CVD events were recorded. Hazard ratios of stage 1 hypertension for composite CVD events, myocardial infarction, angina pectoris, stroke, and heart failure were 1.10 (95 % CI, 1.07-1.13), 1.16 (95 % CI, 1.03-1.31), 1.06 (95 % CI, 1.01-1.10), 1.13 (95 % CI, 1.08-1.18), and 1.13 (95 % CI, 1.09-1.16), respectively. Individuals with a ≥ 5 mmHg decrease in systolic BP over one year had a lower risk of stroke among individuals with stage 1 hypertension. The positive association between stage 1 hypertension and composite CVD events was attenuated in individuals aged ≥75 years. CONCLUSIONS: Stage 1 hypertension is associated with a higher risk of developing CVD events among older adults. The 2017 ACC/AHA BP guidelines could be applied to older populations; however, the applicability of these guidelines to older adults aged ≥75 years requires further investigations.

Association of a Low-Carbohydrate High-Fat Diet With Plasma Lipid Levels and Cardiovascular Risk.

Background: Low-carbohydrate high-fat (LCHF) diets have attracted interest for a variety of conditions. In some individuals, these diets trigger hypercholesterolemia. There are limited data on their effects on cardiovascular disease risk. Objectives: The purpose of this study was to investigate the association between LCHF dietary patterns, lipid levels, and incident major adverse cardiovascular events (MACE). Methods: In a cohort from the UK Biobank, participants with ≥1 24-hour dietary questionnaire were identified. A LCHF diet was defined as <100 g/day and/or <25% total daily energy from carbohydrates/day and >45% total daily energy from fat, with participants on a standard diet (SD) not meeting these criteria. Each LCHF case was age- and sex-matched 1:4 to SD individuals. Results: Of the 2034 LCHF and 8136 SD identified participants, 305 LCHF and 1220 SD individuals completed an enrollment assessment concurrently with lipid collection. In this cohort, low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B levels were significantly increased in the LCHF vs SD group (P < 0.001). 11.1% of LCHF and 6.2% of SD individuals demonstrated severe hypercholesterolemia (LDL-C >5 mmol/L, P < 0.001). After 11.8 years, 9.8% of LCHF vs 4.3% of SD participants experienced a MACE (P < 0.001). This difference remained significant after adjustment for cardiovascular risk factors (HR: 2.18, 95% CI: 1.39-3.43, P < 0.001). Individuals with an elevated LDL-C polygenic risk score had the highest concentrations of LDL-C on a LCHF diet. Similar significant changes in lipid levels and MACE associations were confirmed in the entire cohort and in ≥2 dietary surveys. Conclusions: Consumption of a LCHF diet was associated with increased LDL-C and apolipoprotein B levels, and an increased risk of incident MACE.

Nirmatrelvir-Ritonavir for Acute COVID-19 in Patients With Cardiovascular Disease and Postacute Sequelae of SARS-CoV-2 Infection.

Background: There is limited evidence of association of nirmatrelvir-ritonavir (NMV-r) and incidence of postacute sequelae of SARS-CoV-2 infection (PASC) in patients with pre-existing cardiovascular disease (CVD). Objectives: The objective of this study was to assess the association of NMV-r in nonhospitalized, vaccinated patients with pre-existing CVD and occurrence of PASC. Methods: We conducted a retrospective cohort study utilizing the TriNetX research network, including vaccinated patients with pre-existing CVD who developed COVID-19 between December 2021 and December 2022. Two cohorts were created based on NMV-r administration within 5 days of diagnosis: NMV-r and non-NMV-r cohort. The main outcome was presence of PASC, assessed between 30 to 90 days and 90 to 180 days after index COVID-19 infection. After propensity score matching, both cohorts were compared using t-test and chi-square test for continuous and categorical variables, respectively. Results: A total of 26,953 patients remained in each cohort after propensity score matching. Broadly defined PASC occurred in 6,925 patients (26%) in the NMV-r cohort vs 8,150 patients (30.6%) in the non-NMV-r cohort (OR: 0.80; 95% CI: 0.76-0.82; P < 0.001) from 30 to 90 days and in 6,692 patients (25.1%) as compared to 8,910 patients (33.5%) (OR: 0.25, 95% CI: 0.23-0.29; P < 0.001) from 90 to 180 days. Similarly, narrowly defined PASC occurred in 5,335 patients (20%) in the NMV-r cohort vs 6,271 patients (23.6%) in the non-NMV-r cohort between 30 and 90 days (OR: 0.81, 95% CI: 0.78-0.84, P < 0.001) and in 5,121 patients (19.2%) as compared to 6,964 patients (26.1%) (OR: 0.67, 95% CI: 0.64-0.70, P < 0.001) between 90 and 180 days. Conclusions: NMV-r in nonhospitalized vaccinated patients with pre-existing CVD with COVID-19 was associated with a reduction in PASC and health care utilization.

Effects of Once-Weekly Semaglutide on Kidney Disease Outcomes by KDIGO Risk Category in the SUSTAIN 6 Trial.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are recommended by Kidney Disease: Improving Global Outcomes (KDIGO) as risk-based treatment for hyperglycemia, weight management, and cardiovascular (CV) risk reduction in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). The aim of this post hoc analysis was to assess treatment effects of once weekly semaglutide on kidney disease outcomes by KDIGO risk category and on changes in KDIGO risk category, compared with placebo. Methods: Participants with T2D and established CV disease or at high CV risk treated with once weekly semaglutide or placebo in SUSTAIN 6 (NCT01720446) were stratified by baseline KDIGO risk category (low [n = 1596], moderate [n = 831], high [n = 445], very high [n = 366]). Treatment effect was analyzed for a kidney disease composite end point (macroalbuminuria, serum creatinine doubling and estimated glomerular filtration rate [eGFR] < 45 ml/min per 1.73 m2, kidney replacement therapy, or death due to kidney disease) from baseline to 2 years. Results: The treatment effect of semaglutide versus placebo was consistent across KDIGO categories for the kidney disease composite end point (hazard ratio [95% confidence interval (CI)]: 0.35 [0.07-1.72], 0.42 [0.25-0.72], 0.87 [0.45-1.71], and 0.72 [0.42-1.23] for low, moderate, high, and very high risk categories, respectively; P interaction = 0.28). Participants receiving semaglutide were more likely to move to a lower KDIGO risk category (odds ratio: 1.69; 95% CI: [1.32-2.16]) and less likely to move to a higher KDIGO risk category versus placebo (odds ratio: 0.71; 95% CI: [0.59-0.86]). Conclusion: Once weekly semaglutide versus placebo reduced risks of kidney disease end points and improved risk categories irrespective of baseline KDIGO risk.

Understanding the roles of salt-inducible kinases in cardiometabolic disease.

Salt-inducible kinases (SIKs) are serine/threonine kinases of the adenosine monophosphate-activated protein kinase family. Acting as mediators of a broad array of neuronal and hormonal signaling pathways, SIKs play diverse roles in many physiological and pathological processes. Phosphorylation by the upstream kinase liver kinase B1 is required for SIK activation, while phosphorylation by protein kinase A induces the binding of 14-3-3 protein and leads to SIK inhibition. SIKs are subjected to auto-phosphorylation regulation and their activity can also be modulated by Ca2+/calmodulin-dependent protein kinase in response to cellular calcium influx. SIKs regulate the physiological processes through direct phosphorylation on various substrates, which include class IIa histone deacetylases, cAMP-regulated transcriptional coactivators, phosphatase methylesterase-1, among others. Accumulative body of studies have demonstrated that SIKs are important regulators of the cardiovascular system, including early works establishing their roles in sodium sensing and vascular homeostasis and recent progress in pulmonary arterial hypertension and pathological cardiac remodeling. SIKs also regulate inflammation, fibrosis, and metabolic homeostasis, which are essential pathological underpinnings of cardiovascular disease. The development of small molecule SIK inhibitors provides the translational opportunity to explore their potential as therapeutic targets for treating cardiometabolic disease in the future.

Association between triglyceride glucose body mass index and cardiovascular disease in adults: evidence from NHANES 2011- 2020.

Background: The association between insulin resistance and cardiovascular diseases (CVD) is of significant interest. However, there is limited published research on the relationship between CVD and the triglyceride glucose-body mass index (TyG-BMI). This study aims to examine the association between TyG-BMI and CVD in US adults. Method: We analyzed data from 11016 adults collected through the 2011-2020 NHANES. Employing weighted generalized linear models, subgroup analysis, sensitivity analysis, and receiver operating characteristic curves, we examined the association between the TyG-BMI index and CVD. Nonlinear associations were investigated using restricted cubic splines. Results: Higher TyG-BMI values were significantly associated with an increased prevalence of CVD (P<0.001). Weighted generalized linear models consistently demonstrated a positive association across all models. Specifically, individuals in the highest tertile of TyG-BMI had a 38% higher CVD prevalence than those in the lowest quartile (OR=1.380; 95% CI=1.080, 1.763). Unweighted logistic regression models further confirmed these findings. Sex, race, education, family income to poverty ratio, smoking, hypertension, and diabetes did not modify this positive association (P for interaction >0.05). Incorporating the TyG-BMI index into traditional risk factor models marginally improved the prediction of CVD prevalence (P for comparison <0.05). Conclusions: The TyG-BMI index, an indicator of insulin resistance, is significantly positive associated with a higher prevalence of CVD. These findings underscore the importance of managing insulin resistance to prevent CVD and highlight the need for further research into the underlying mechanisms of this association.

Cost-effectiveness analysis of low-sodium potassium-rich salt substitutes in Indonesia: an equity modelling study.

Background: Evidence suggests low-sodium potassium-rich salt substitutes (LSSS) are effective in reducing blood pressure (BP). However, the health and economic impacts of LSSS in Indonesia are currently unknown. Methods: We developed a proportional multistate lifetable Markov model to assess a government-led strategy implementing the use of LSSS compared to current regular salt consumption. BP data were derived from the Indonesian Basic Health Research Survey (RISKESDAS 2018), while epidemiological data were from the Global Burden of Disease 2019 study. We estimated implementation costs and the impact of changes in BP on disease events and healthcare costs, and incremental cost-effectiveness ratios. Outcomes were simulated over different time horizons for the 2019 Indonesian population overall, and by income quintiles. Probabilistic sensitivity analysis was done to capture uncertainty. Findings: Over the first 10 years, LSSS could prevent 1.5 million non-fatal cardiovascular disease (CVD) events (8.3%-19.4% reduction) and 643,000 incident chronic kidney disease (CKD) cases (8.2% reduction), while averting over 200,000 CVD and CKD deaths (0.2%-5.2% reduction). This translated to over 24.6 million health-adjusted life years (HALYs) gained over the lifetime of the population, and reduced CVD-related health inequalities (concentration index, -0.075, 95% CI: -0.088 to -0.062). Implementation cost (US$ 1.2 billion [IDR 17.2 trillion] total; US$ 4.5 [IDR 63,665] per capita, as of July 2019) was outweighed by the net health expenditure savings (∼US$ 2 billion [IDR 27.7 trillion] total; US$ 7.3 [IDR 103,300] per capita) in the first 10 years. LSSS were cost-saving over the lifetime, and very cost-effective even with a high LSSS price. Interpretation: Scaling the use of LSSS nationally could be a cost-saving strategy to prevent substantial cardiovascular and kidney disease burden in Indonesia. Funding: Griffith University Postdoctoral Fellowship.

One-size-fits-all versus risk-category-based screening interval strategies for cardiovascular disease prevention in Chinese adults: a prospective cohort study.

Background: In non-high-risk individuals, risk-category-based atherosclerotic cardiovascular disease (ASCVD) screening strategies may be more cost-effective than one-size-fits-all approaches. However, current decisions are constrained by a lack of research evidence. We aimed to explore appropriate risk-category-based screening interval strategies for non-high-risk individuals in ASCVD primary prevention in the Chinese population. Methods: We used data from 28,624 participants in the China Kadoorie Biobank (CKB) who had completed at least two field surveys. The risk assessment tools were the 10-year ASCVD risk prediction models developed based on the CKB cohort. We constructed multistate Markov models to model disease progression and estimate transition probabilities between different risk categories. The total person-years spent unidentified in the high-risk state over a 10-year period were calculated for each screening interval protocol. We also estimated the number of ASCVD events prevented, quality-adjusted life years (QALYs) gained, and costs saved when compared to the 3-yearly screening protocol. Findings: When compared to the uniform 3-yearly protocol, most risk-category-based screening interval protocols would identify more high-risk individuals timely, thus preventing more ASCVD events and gaining QALYs. A few of them would reduce total health-care costs. The protocol, which used 6-year, 3-year, and 2-year screening intervals for low-risk, intermediate-low-risk, and intermediate-high risk individuals, was optimal, and would reduce the person-years spent unidentified in the high-risk category by 17.9% (95% CI: 13.1%-21.9%), thus preventing an estimated 113 thousand (95% CI: 83-138) hard ASCVD events for Chinese adults aged 30-79 over a 10-year period. When using a lower cost of statin therapy, more screening protocols would gain QALYs while saving costs. Interpretation: For the primary prevention of ASCVD, risk-category-based screening protocols outperformed the one-size-fits-all approach in the Chinese population. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82388102, 82192900) and grants (2023YFC2509400) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303, 81941018), and Chinese Ministry of Science and Technology (2011BAI09B01).

Association between gait video information and general cardiovascular diseases: a prospective cross-sectional study.

Aims: Cardiovascular disease (CVD) may not be detected in time with conventional clinical approaches. Abnormal gait patterns have been associated with pathological conditions and can be monitored continuously by gait video. We aim to test the association between non-contact, video-based gait information and general CVD status. Methods and results: Individuals undergoing confirmatory CVD evaluation were included in a prospective, cross-sectional study. Gait videos were recorded with a Kinect camera. Gait features were extracted from gait videos to correlate with the composite and individual components of CVD, including coronary artery disease, peripheral artery disease, heart failure, and cerebrovascular events. The incremental value of incorporating gait information with traditional CVD clinical variables was also evaluated. Three hundred fifty-two participants were included in the final analysis [mean (standard deviation) age, 59.4 (9.8) years; 25.3% were female]. Compared with the baseline clinical variable model [area under the receiver operating curve (AUC) 0.717, (0.690-0.743)], the gait feature model demonstrated statistically better performance [AUC 0.753, (0.726-0.780)] in predicting the composite CVD, with further incremental value when incorporated with the clinical variables [AUC 0.764, (0.741-0.786)]. Notably, gait features exhibited varied association with different CVD component conditions, especially for peripheral artery disease [AUC 0.752, (0.728-0.775)] and heart failure [0.733, (0.707-0.758)]. Additional analyses also revealed association of gait information with CVD risk factors and the established CVD risk score. Conclusion: We demonstrated the association and predictive value of non-contact, video-based gait information for general CVD status. Further studies for gait video-based daily living CVD monitoring are promising.

Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA2 Prostanoids/TP Axis.

BACKGROUND: Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown. METHODS: Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored. RESULTS: PGF2α, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level. CONCLUSIONS: Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.

Cardiovascular Disease, Genetic Susceptibility, and Risk of Psychiatric Disorders and Suicide Attempt: A Community-Based Matched Cohort Study Based on the UK Biobank.

BACKGROUND: The associations between cardiovascular disease (CVD) and multiple psychiatric disorders and suicide attempt, and whether different genetic susceptibilities affect such links, have not been investigated clearly. METHODS AND RESULTS: Based on the UK Biobank, we conducted a matched cohort study involving 63 923 patients who were first hospitalized with a CVD diagnosis between 1997 and 2020, and their 127 845 matched unexposed individuals. Cox models were used to examine the subsequent risk of psychiatric disorders and suicide attempt (ie, anxiety, depression, stress-related disorder, substance misuse, psychotic disorder, and suicide behaviors) following CVD. We further performed stratified analyses by polygenic risk score for each studied psychiatric condition to detect the possible effects of genetic susceptibility on the observed associations. We found an increased risk of any psychiatric disorders and suicide attempt among CVD patients, compared with matched unexposed individuals, particularly within 1 year following the CVD (fully adjusted hazard ratio [HR] within 1 year, 1.83 [95% CI, 1.58-2.12]; HR after 1 year, 1.24 [95% CI, 1.16-1.32]). By subtype, the risk elevations existed for any psychiatric disorders and suicide attempt following most categories of CVDs. Analyses stratified by polygenic risk score revealed little impact of genetic predisposition to studied psychiatric conditions on these observed links. CONCLUSIONS: Patients hospitalized for CVD were at increased subsequent risk of multiple types of psychiatric disorders and suicide attempt, especially in the first year after hospitalization, irrespective of their genetic susceptibilities to studied psychiatric conditions, and these findings underscore the necessity of developing timely psychological interventions for this vulnerable population.

Lipoprotein (a) and cerebrovascular disease.

The role of lipoprotein (a) [Lp(a)] in cerebrovascular disease is a topic of importance. In this narrative review, pertinent studies have been leveraged to comprehensively examine this relationship from diverse perspectives.Lp(a) shares structural traits with low-density lipoprotein cholesterol. Lp(a) is synthesized by hepatocytes, and its plasma levels are genetically determined by the LPA gene, which produces apolipoprotein (a).Numerous epidemiological studies have confirmed the positive correlation between elevated serum Lp(a) levels and the occurrence or recurrence of cerebrovascular events, especially ischemic strokes, in adults. It should be noted that the correlation strength varies among studies and is marginal in Mendelian randomization studies.Regarding pediatric patients, screening is currently limited to those with a relevant medical history. Lp(a) seems to play a significant role in the pathogenesis of arterial ischemic stroke in children because environmental thrombotic and atherogenic factors are generally not present.Phase 3 trials of novel Lp(a) targeting agents, such as pelacarsen and olpasiran, are anticipated to demonstrate their efficacy in reducing the incidence of stroke. Given the richness of the literature, new guidelines regarding Lp(a) screening and management in targeted populations are warranted to provide more effective primary and secondary prevention.

Sociodemographic Correlates of High Cardiovascular Health Across Childhood and Adolescence: A Prospective Study Among 2 Cohorts in the ECHO Consortium.

BACKGROUND: This study seeks to characterize cardiovascular health (CVH) from early childhood to late adolescence and identify sociodemographic correlates of high CVH that serve as levers for optimizing CVH across early life. METHODS AND RESULTS: Among 1530 youth aged 3 to 20 years from 2 cohorts in the ECHO (Environmental Influences on Child Health Outcomes) consortium, we first derived CVH scores on the basis of the Life's Essential 8 construct comprising 4 behavioral (nicotine use/exposure, physical activity, sleep, and diet) and 4 health factors (body mass index, blood pressure, non-high-density lipoprotein cholesterol, and fasting glucose) during early childhood (mean age, 3.5 years), middle childhood (8.0 years), early adolescence (13.3 years), and late adolescence (17.8 years). Next, we used generalized regression to estimate the probability of high (versus not high) CVH with respect to sociodemographic characteristics. Overall CVH score was stable across life stages: 81.2±7.6, 83.3±8.0, and 81.7±8.9 of 100 possible points in early childhood, middle childhood, and early adolescence, respectively. Accordingly, during these life stages, most children (63.3%-71.5%) had high CVH (80 to <100). However, CVH declined by late adolescence, with an average score of 75.5±10.2 and 39.4% high CVH. No children had optimal CVH (score=100) at any time. Correlates of high CVH include non-Hispanic White race and ethnicity, maternal college education, and annual household income >$70 000. These associations were driven by behavioral factors. CONCLUSIONS: Although most youth maintained high CVH across childhood, the decline by late adolescence indicates that cardiovascular disease prevention should occur before the early teen years. Disparities in high CVH over time with respect to sociodemographic characteristics were explained by behavioral factors, pointing toward prevention targets.