Association of a genetic variant in angiopoietin-like 3 with serum HDL-C and risk of cardiovascular disease: A study of the MASHAD cohort over 6 years.

BACKGROUND: Loss-of-function (LOF) variants of the angiopoietin-like 3 (ANGPTL3) gene are reported to be associated with serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations and thereby affect the risk of cardiovascular disease (CVD). OBJECTIVE: In the present study, we examined the association of rs10789117 in the ANGPTL 3 gene locus and the risk of CVD in the group of people who were part of the Mashhad-Stroke and Heart-Atherosclerotic-Disorders (MASHAD) cohort. METHODS: One thousand and two healthy individuals enrolled in this study of whom 849 subjects were healthy and 153 subjects developed CVD outcomes after 6 years of follow-up. After a 12-h overnight fasting, 20 mL of blood samples were collected for the measurement of fasting blood glucose and lipid profile. DNA was extracted, and the Tetra-ARMS PCR (amplification refractory mutation system) was used for genotyping of rs10789117 in the ANGPTL3 gene. The genotype frequencies of the variant of rs10789117 in the ANGPTL3 gene were estimated using χ2 tests. Eventually, the statistical analysis was done by SPSS version 20. RESULTS: Individuals with AC/CC genotypes (rs10789117) were found to have to greater risk of CVD events compared to AA genotype (OR = 1.43, 95%CI = 1.01-2.02, p = 0.041). There was a 1.3-fold increase in cardiovascular events in individuals carrying the C allele of rs10789117 variant compared to non-carriers (OR = 1.32, 95%CI = 1.06-1.72, p value = 0.038). There were significant differences between different genotypes for serum triglyceride levels within the control group, but this difference was not significant in the group with CVD. Moreover, there was a significant association between CC genotype and CVD risk in the individuals with a normal serum HDL-C. CONCLUSION: We have found that a rs10789117 C>A in ANGPTL3 gene polymorphism was associated with incident CVD events, and this may be of value as a risk stratification biomarker in CVD in the Iranian population.

A Bibliometric Analysis of Study of Associations of Certain Genotypes with the Cardiovascular Form of Diabetic Neuropathy.

This bibliometric analysis explores the landscape of research on the associations between specific genotypes and the cardiovascular form of diabetic neuropathy. Diabetes mellitus (DM) is a major contributor to premature mortality, primarily due to increased susceptibility to cardiovascular diseases. The global prevalence of DM is rising, with projections indicating further increases. Diabetic neuropathy, a complication of DM, includes the cardiovascular subtype, posing challenges in diagnosis and management. Understanding the genetic basis of cardiovascular diabetic neuropathy is crucial for targeted therapeutic interventions. The study utilizes bibliometric analysis to synthesize existing literature, identify trends, and guide future research. The Scopus database was searched, applying inclusion criteria for English articles related to genotypes and cardiovascular diabetic neuropathy. The analysis reveals a dynamic field with a notable impact, collaborative efforts, and multidimensional aspects. Publication trends over 1997-2023 demonstrate fluctuating research intensity. Top journals, authors, and affiliations are highlighted, emphasizing global contributions. Keyword analysis reveals thematic trends, and citation analysis identifies influential documents. Limitations include database biases, incomplete metadata, and search query specificity. The urgent need to explore genetic factors in cardiovascular diabetic neuropathy aligns with the increasing global diabetes burden. This analysis provides a comprehensive overview, contributing to the broader discourse on diabetic neuropathy research.

Changes in Sleep Patterns, Genetic Susceptibility, and Incident Cardiovascular Disease in China.

Importance: The associations of changes in sleep patterns with incident cardiovascular disease (CVD) are not fully elucidated, and whether these associations are modified by genetic susceptibility remains unknown. Objectives: To investigate the associations of 5-year changes in sleep patterns with incident CVD and whether genetic susceptibility modifies these associations. Design, Setting, and Participants: This prospective cohort study of the Dongfeng-Tongji cohort was conducted from 2008 to 2018 in China. Eligible participants included those with complete sleep information at baseline survey (2008-2010) and the first follow-up survey (2013); participants who had no CVD or cancer in 2013 were prospectively assessed until 2018. Statistical analysis was performed in November 2023. Exposures: Five-year changes in sleep patterns (determined by bedtime, sleep duration, sleep quality, and midday napping) between 2008 and 2013, and polygenic risk scores (PRS) for coronary heart disease (CHD) and stroke. Main Outcomes and Measures: Incident CVD, CHD, and stroke were identified from 2013 to 2018. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% CIs. Results: Among 15 306 individuals (mean [SD] age, 65.8 [7.4] years; 8858 [57.9%] female and 6448 male [42.1%]), 5474 (35.78%) had persistent unfavorable sleep patterns and 3946 (25.8%) had persistent favorable sleep patterns. A total of 3669 incident CVD cases were documented, including 2986 CHD cases and 683 stroke cases, over a mean (SD) follow-up of 4.9 (1.5) years. Compared with those with persistent unfavorable sleep patterns, individuals with persistent favorable sleep patterns over 5 years had lower risks of incident CVD (HR, 0.80; 95% CI, 0.73-0.87), CHD (HR, 0.84; 95% CI, 0.76-0.92), and stroke (HR, 0.66; 95% CI, 0.54-0.82) in the subsequent 5-year period. No significant effect modification by PRS was observed for sleep pattern change and CHD or stroke risk. However, sleep pattern changes and PRS were jointly associated with the CHD and stroke risk in a dose-dependent manner, with the lowest risk being among those with persistent favorable sleep patterns combined with low PRS (HR for CHD, 0.65; 95% CI, 0.52-0.82 and HR for stroke, 0.48; 95% CI, 0.29-0.79). Conclusions and Relevance: In this cohort study of middle-aged and older Chinese adults, individuals with persistent favorable sleep patterns had a lower CVD risk, even among those with higher genetic risk. These findings highlight the importance of maintaining favorable sleep patterns for CVD prevention.

A Comparison of 5 Measures of Accelerated Biological Aging and Their Association With Incident Cardiovascular Disease: The CARDIA Study.

BACKGROUND: Accelerated biological aging is an increasingly popular way to track the acceleration of biology over time that may not be captured by calendar time. Biological aging has been linked to external and internal chronic stressors and has the potential to be used clinically to understand a person's personalized functioning and predict future disease. We compared the association of different measures of biological aging and incident cardiovascular disease (CVD) overall and by race. METHODS AND RESULTS: We used multiple informants models to compare the strength of clinical marker-derived age acceleration, 5 measures of epigenetic age acceleration (intrinsic and extrinsic epigenetic age acceleration, GrimAge acceleration, and PhenoAge acceleration), and 1 established clinical predictor of future CVD, Framingham 10-year risk score, with incident CVD over an 11-year period (2007-2018). Participants were 913 self-identified Black or White (41% and 59%, respectively) female or male (51% and 49%, respectively) individuals enrolled in the US-based CARDIA (Coronary Artery Risk Development in Young Adults) cohort study. The analytic baseline for this study was the 20-year follow-up examination (2005-2006; median age 45 years). We also included race-specific analysis. We found that all measures were modestly correlated with one another. However, clinical marker-derived age acceleration and Framingham 10-year risk score were more strongly associated with incident CVD than all the epigenetic measures. Clinical marker-derived age acceleration and Framingham 10-year risk score were not significantly different than one another in their association with incident CVD. CONCLUSIONS: The type of accelerated aging measure should be taken into consideration when comparing their association with clinical outcomes. A multisystem clinical composite shows associations with incident CVD equally to a well-known clinical predictor.

State of Gene Therapy for Monogenic Cardiovascular Diseases.

Over the past 2 decades, significant efforts have been made to advance gene therapy into clinical practice. Although successful examples exist in other fields, gene therapy for the treatment of monogenic cardiovascular diseases lags behind. In this review, we (1) highlight a brief history of gene therapy, (2) distinguish between gene silencing, gene replacement, and gene editing technologies, (3) discuss vector modalities used in the field with a special focus on adeno-associated viruses, (4) provide examples of gene therapy approaches in cardiomyopathies, channelopathies, and familial hypercholesterolemia, and (5) present current challenges and limitations in the gene therapy field.

The Senescent Heart-"Age Doth Wither Its Infinite Variety".

Cardiovascular diseases are a leading cause of morbidity and mortality world-wide. While many factors like smoking, hypertension, diabetes, dyslipidaemia, a sedentary lifestyle, and genetic factors can predispose to cardiovascular diseases, the natural process of aging is by itself a major determinant of the risk. Cardiac aging is marked by a conglomerate of cellular and molecular changes, exacerbated by age-driven decline in cardiac regeneration capacity. Although the phenotypes of cardiac aging are well characterised, the underlying molecular mechanisms are far less explored. Recent advances unequivocally link cardiovascular aging to the dysregulation of critical signalling pathways in cardiac fibroblasts, which compromises the critical role of these cells in maintaining the structural and functional integrity of the myocardium. Clearly, the identification of cardiac fibroblast-specific factors and mechanisms that regulate cardiac fibroblast function in the senescent myocardium is of immense importance. In this regard, recent studies show that Discoidin domain receptor 2 (DDR2), a collagen-activated receptor tyrosine kinase predominantly located in cardiac fibroblasts, has an obligate role in cardiac fibroblast function and cardiovascular fibrosis. Incisive studies on the molecular basis of cardiovascular aging and dysregulated fibroblast function in the senescent heart would pave the way for effective strategies to mitigate cardiovascular diseases in a rapidly growing elderly population.

Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review.

The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.

Cardiovascular Risk Factors Among First-Degree Relatives of Patients with Premature Cardiovascular Disease in Malta. Baseline Findings from the CRISO Project.

Purpose: A family history of premature atherosclerotic cardiovascular disease (ASCVD) confers a greater risk of developing ASCVD. However, the prevalence of ASCVD risk factors among asymptomatic Maltese adults with parental or fraternal history of premature ASCVD is unknown. The study aimed to evaluate and compare their risk with the general population. Patients and Methods: Posters to market the project were distributed in cardiac rehabilitation areas. Patients with premature cardiovascular disease facilitated recruitment by informing their relatives about the project. Medical doctors and cardiac rehabilitation nurses referred first-degree relatives. Posters were put up in community pharmacies, and an explanatory video clip was shared on social media for interested individuals to contact researchers. Those eligible were enrolled in a preventive cardiology lifestyle intervention. Their data were compared with the risk in the general population. Results: Many first-degree relatives had a suboptimal risk profile, with 60% (N = 89) having a total cholesterol level of >5.0 mmol/L; 54% having a low-density lipoprotein-cholesterol level of >3 mmol/L; 70.5% being overweight/obese, with 62% having a waist circumference greater than the recommended values; 34.8% having hypertension; 56.2% being inadequately adherent to the Mediterranean diet; 62% being underactive, with 18% being sedentary; and 25.8% being smokers. First-degree relatives had significantly higher proportions of underactive lifestyle (p = 0.00016), high body mass index (>25kg/m2) (p = 0.006), and systolic blood pressure (p = 0.001) than the general population, with 30% having metabolic syndrome. Conclusion: This study determined the prevalence of lifestyle, biochemical, physiological, and anthropometric cardiovascular risk factors among asymptomatic first-degree relatives of Maltese patients with premature ASCVD. First-degree relatives had considerable prevalences of an underactive lifestyle, hypertension, and obesity, suggesting better screening and early risk factor intervention are needed to modify their risk of ASCVD.

This study was done to evaluate factors that can increase the risk of heart disease in siblings and offspring of Maltese patients who developed atherosclerotic cardiovascular disease (ASCVD) at a young age. Relatives were invited to meetings during which a risk evaluation was performed. The researchers found that relatives had a high prevalence of cardiometabolic risk factors, meaning they were at increased risk of developing the disease. The researchers have concluded that reducing the risk of ASCVD in individuals at increased risk requires developing and testing potentially sustainable risk factor modification strategies.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

Causal associations of particulate matter 2.5 and cardiovascular disease: A two-sample mendelian randomization study.

BACKGROUND: According to epidemiological studies, particulate matter 2.5 (PM2.5) is a significant contributor to cardiovascular disease (CVD). However, making causal inferences is difficult due to the methodological constraints of observational studies. In this study, we used two-sample Mendelian randomization (MR) to examine the causal relationship between PM 2.5 and the risk of CVD. METHODS: Genome-wide association study (GWAS) statistics for PM2.5 and CVD were collected from the FinnGen and UK Biobanks. Mendelian randomization analyses were applied to explore the causal effects of PM2.5 on CVD by selecting single-nucleotide polymorphisms(SNP) as instrumental variables. RESULTS: The results revealed that a causal effect was observed between PM2.5 and coronary artery disease(IVW: OR 2.06, 95% CI 1.35, 3.14), and hypertension(IVW: OR 1.07, 95% CI 1.03, 1.12). On the contrary, no causal effect was observed between PM2.5 and myocardial infarction(IVW: OR 0.73, 95% CI 0.44, 1.22), heart failure(IVW: OR 1.54, 95% CI 0.96, 2.47), atrial fibrillation(IVW: OR 1.03, 95% CI 0.71, 1.48), and ischemic stroke (IS)(IVW: OR 0.98, 95% CI 0.54, 1.77). CONCLUSION: We discovered that there is a causal link between PM2.5 and coronary artery disease and hypertension in the European population, using MR methods. Our discovery may have the significance of public hygiene to improve the understanding of air quality and CVD risk.

THE EFFECT OF NUTRITIONAL GENOMICS ON CARDIOVASCULAR SYSTEM.

The idea that obesity and cardiovascular diseases together are considered for a sizable share of adult global morbidity and mortality is supported by epidemiological data. They have intricate systems in which environmental and genetic variables interact, including nutrition. As an environmental component, nutrition has a major and well-known role in managing health and preventing obesity and disorders connected to obesity, such as cardiovascular disease (CVD). Nonetheless, people with the same food pattern but obese exhibit a notable difference in CVD. This variance might be explained by the various genetic polymorphisms which gave rise to the field of nutrigenetics. The discipline known as nutritional genomics, or nutrigenetics, examines and describes gene variants linked to varying reactions to particular nutrients and links these variations to various disorders, including obesity-related cardiovascular disease (CVD). Therefore, tailored nutrition advice depending on a person's genetic background could enhance the results of a particular dietary intervention and offer a novel dietary technique to enhance health by lowering obesity and cardiovascular disease. With these suppositions, it seems reasonable to assume that understanding food and gene interactions will provide more targeted and efficacious dietary treatments in preventing obesity and CVD by nutrigenetics-based personalized nutrition. In addition to elucidating the connection between diet and gene expression and the major nutrition-related genes involved in obesity and CVD, this research seeks to provide a concise summary of the greater significant genes linked to obesity and CVD.

Characterizing the polygenic overlap and shared loci between rheumatoid arthritis and cardiovascular diseases.

BACKGROUND: Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. METHODS: Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. RESULTS: Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15-1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. CONCLUSIONS: This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.

Serum albumin and cardiovascular disease: a Mendelian randomization study.

BACKGROUND: An increasing body of evidence suggests that serum albumin levels play a role in cardiovascular diseases. However, the specific causal relationship between serum albumin levels and cardiovascular disease remains partially unknown. METHODS: Mendelian randomization (MR) was employed in this study to examine potential causal relationships between instrumental variables and cardiovascular diseases. Specifically, we utilized genetic variants of serum albumin levels within the reference range as our instrumental variables. To acquire data on genetic associations with cardiovascular diseases, we sourced information from renowned genome-wide association studies such as UK BioBank, EMBL-EBI, and FinnGen. Notably, our study leveraged summary statistics from large cohorts that have been previously described. RESULTS: We explored the association between serum albumin levels and various conditions, including heart failure (HF), venous thromboembolism (VTE), stroke, atrial fibrillation (AF), coronary artery disease (CAD), type 2 diabetes (T2DM), and pulmonary heart disease (PHD). Genetically predicted serum albumin levels were associated with PHD (odds ratio = 0.737, 95% CI = 0.622 - 0.874, P < 0.001), AF (odds ratio = 0.922, 95% CI = 0.870 - 0.977, P = 0.006), VTE (odds ratio = 0.993, 95% CI = 0.991 - 0.995, P < 0.001), and Stroke (odds ratio = 0.997, 95% CI = 0.995 - 0.999, P = 0.002). However, genetically predicted serum albumin level traits were not associated with HF, CAD and T2DM. CONCLUSION: Our study demonstrates a significant association between serum albumin levels and cardiovascular disease, underscoring the crucial role of low serum albumin as a predictive factor in patients with cardiovascular disease.

[Epigenetic modifications and cardiovascular diseases : new Eldorado]. / Modifications épigénétiques et maladies cardiovasculaires : nouvel Eldorado.

As the risk of developing cardiovascular disease (CVD) is strongly dependent on the environment, the study of associated epigenetic modifications is a potentially promising axe of research given that they are affected by both the environment and disease development. Importantly, it is possible to identify and characterize specific epigenetic modifications in association with a disease, or risk factors for a disease, to create a so-called "epigenetic signature". Epigenetic signatures thus provide a summary of associated epigenetic changes and have the potential for several clinical applications including diagnosis, prognosis, as well as patient monitoring. However, although epigenetics has been successfully applied in cancer, efforts are still required to make their clinical use in CVD a reality.

Les maladies cardiovasculaires (MCV) dépendant fortement de l'environnement, l'étude des changements épigénétiques associés constitue un axe de recherche prometteur. En effet, ils sont affectés à la fois par l'environnement et par la survenue de maladies. En particulier, des changements épigénétiques spécifiques ou « signatures épigénétiques ¼ permettent de caractériser certains facteurs de risque des MCV. Les signatures épigénétiques ont de nombreuses applications potentielles dans le domaine du diagnostic, du pronostic et du suivi des patients. Cependant, malgré leur potentiel avéré pour le cancer, des efforts restent à faire pour concrétiser leur utilisation clinique dans le cadre des MCV.

Translational bioinformatics approach to combat cardiovascular disease and cancers.

Bioinformatics is an interconnected subject of science dealing with diverse fields including biology, chemistry, physics, statistics, mathematics, and computer science as the key fields to answer complicated physiological problems. Key intention of bioinformatics is to store, analyze, organize, and retrieve essential information about genome, proteome, transcriptome, metabolome, as well as organisms to investigate the biological system along with its dynamics, if any. The outcome of bioinformatics depends on the type, quantity, and quality of the raw data provided and the algorithm employed to analyze the same. Despite several approved medicines available, cardiovascular disorders (CVDs) and cancers comprises of the two leading causes of human deaths. Understanding the unknown facts of both these non-communicable disorders is inevitable to discover new pathways, find new drug targets, and eventually newer drugs to combat them successfully. Since, all these goals involve complex investigation and handling of various types of macro- and small- molecules of the human body, bioinformatics plays a key role in such processes. Results from such investigation has direct human application and thus we call this filed as translational bioinformatics. Current book chapter thus deals with diverse scope and applications of this translational bioinformatics to find cure, diagnosis, and understanding the mechanisms of CVDs and cancers. Developing complex yet small or long algorithms to address such problems is very common in translational bioinformatics. Structure-based drug discovery or AI-guided invention of novel antibodies that too with super-high accuracy, speed, and involvement of considerably low amount of investment are some of the astonishing features of the translational bioinformatics and its applications in the fields of CVDs and cancers.

Impact of genetic background as a risk factor for atherosclerotic cardiovascular disease: A protocol for a nationwide genetic case-control (CV-GENES) study in Brazil.

Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).

Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.

BACKGROUND: To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents. METHODS: We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar. We assessed the regional density of these variants by defining a regional clustering index. We then combined a highly active base editor with prime editing to demonstrate the feasibility of a P/LP hotspot-directed genome engineering therapeutic strategy in vitro. RESULTS: P/LP variants in cardiovascular disease genes display higher regional density than rare variants found in the general population. P/LP missense variants displayed higher average regional density than P/LP truncating variants. Following hypermutagenesis at a pathogenic hotspot, mean prime editing efficiency across introduced variants was 57±27%. CONCLUSIONS: Designing therapeutics that target pathogenic hotspots will not only address known missense P/LP variants but also novel P/LP variants identified in these hotspots as well. Moreover, the clustering of P/LP missense rather than truncating variants in these hotspots suggests that prime editing technology is particularly valuable for dominant negative disease. Although prime editing technology in relation to cardiac health continues to improve, this study presents an approach to targeting the most impactful regions of the genome for inherited cardiovascular disease.

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression.

Cardiovascular diseases (CVDs) are multifactorial chronic diseases and have the highest rates of morbidity and mortality worldwide. The ubiquitin-proteasome system (UPS) plays a crucial role in posttranslational modification and quality control of proteins, maintaining intracellular homeostasis via degradation of misfolded, short-lived, or nonfunctional regulatory proteins. Noncoding RNAs (ncRNAs, such as microRNAs, long noncoding RNAs, circular RNAs and small interfering RNAs) serve as epigenetic factors and directly or indirectly participate in various physiological and pathological processes. NcRNAs that regulate ubiquitination or are regulated by the UPS are involved in the execution of target protein stability. The cross-linked relationship between the UPS, ncRNAs and CVDs has drawn researchers' attention. Herein, we provide an update on recent developments and perspectives on how the crosstalk of the UPS and ncRNAs affects the pathological mechanisms of CVDs, particularly myocardial ischemia/reperfusion injury, myocardial infarction, cardiomyopathy, heart failure, atherosclerosis, hypertension, and ischemic stroke. In addition, we further envision that RNA interference or ncRNA mimics or inhibitors targeting the UPS can potentially be used as therapeutic tools and strategies.

Air pollution, APOE genotype and risk of dementia among individuals with cardiovascular diseases: A population-based longitudinal study.

Individuals with cardiovascular disease (CVD) are particularly vulnerable to dementia, but it remains unclear whether air pollution exposure links with higher risk of dementia among those with CVD. The data were derived from the UK Biobank study (UKB). Dementia-free participants with CVD at baseline were included. Air pollution exposure was assessed through land use regression models, including particulate matter (PM2.5, PM2.5-10, and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOX). A Cox proportional hazards model was used to investigate the associations between air pollution exposure and incident dementia among individuals with CVD. Air pollution was associated with dementia among individuals with CVD, and the hazard ratios of dementia associated with each interquartile range (IQR) µg/m3 increase in air pollution were 1.07 (95% CI: 1.02, 1.12) for PM2.5, 1.10 (95% CI: 1.04, 1.15) for PM10, 1.08 (95% CI: 1.03, 1.14) for NO2 and 1.05 (95% CI: 1.00, 1.09) for NOx. Associations between air pollution and all-cause dementia were found to be significant among individuals with hypertension. Adverse effects of air pollution were also observed for Alzheimer's dementia (AD) and vascular dementia (VaD), with a higher effect for AD. Observed associations remained similar in subgroups of APOE ε4 carriers and noncarriers, although there was a higher risk difference across different air pollution concentration among these individuals carrying APOE ε4. Air pollution emerges as a critical risk factor for dementia among individuals with CVD, regardless of genetic susceptibility indicated by the APOE genotype. Notably, individuals with hypertension might be susceptible to the adverse effects of air pollution, leading to a higher incidence of dementia. Understanding these impacts on dementia among individuals with CVD may promote better targeted prevention and clinical management strategies.