medRxiv - Cardiovascular Medicine最新文献

{"title":"Prehabilitation in patients awaiting acute inpatient cardiac surgery: a pilot Study","authors":"Sarah Raut, Aaron Hales, Maureen Twiddy, Lili Dixon, Dumbor Ngaage, David Yates, Gerard Danjoux, Lee Ingle","doi":"10.1101/2024.07.12.24309975","DOIUrl":"https://doi.org/10.1101/2024.07.12.24309975","url":null,"abstract":"Background: The concept of “prehabilitation,” or optimising individual physical and mental wellbeing prior to surgery is well established in cancer and orthopaedic populations. However, amongst the cardiac surgery population, the concept is relatively new. Of the few studies available, all focus on the elective surgical population. This pilot feasibility trial is novel as it will focus on the impact of multimodal prehabilitation on the acute inpatient cardiac surgical population. Methods: This single centre, prospective, single arm pilot feasibility trial will recruit 20 inpatients awaiting cardiac surgery. Measurements will be collected at the start of the trial (baseline), 7 days after intervention, and 14 days after the intervention or before the day of surgery. The primary outcome measure will be feasibility and practicality of the programme in an acute inpatient population. We will be looking into participant eligibility, acceptability, recruitment rates, completion rates and barriers to implementing a prehabilitation programme. Secondary outcomes include incidence of study-related adverse events, improvement in 6 minutes walk test (6MWT), hand grip strength, quality of life, anxiety scores and spirometry. At the end of the trial, we will be seeking the feedback of the participants on key components of the programme to help us inform future work. We hypothesise that light to moderate structured exercise training is low risk and feasible in patients awaiting inpatient cardiac surgery. The study was approved by Health Research Authority and Heath and Care Research Wales (Yorkshire & the Humber- Bradford Leeds Research Ethics Committee: REC reference 23/YH/0255) on the 8th November 2023. Discussion: Multimodal prehabilitation could improve individual physical and mental wellbeing whilst awaiting inpatient cardiac surgery. Prehabilitation can provide individuals with a sense of ownership and control over their condition, improve their motivation and independence, and enhance their mental and physical recovery after surgery. Traditionally, patients waiting for cardiac surgery are discouraged from physical activity/ structured exercise training and receive limited information regarding their health. Appropriate physical and psychological support could improve their confidence to mobilise sooner after surgery. This may then facilitate earlier discharge leading to improved hospital bed utilisation and patient flow.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel monocyte-based biomarker of cardiovascular risk: comparison with QRISK3","authors":"Fatemah Almarri, Soundrie Padayachee, Alexander Kerr, Ashish S Patel, Albert Ferro","doi":"10.1101/2024.07.12.24310323","DOIUrl":"https://doi.org/10.1101/2024.07.12.24310323","url":null,"abstract":"Objective: Circulating monocyte-platelet aggregates (MPA) and CD14+/CD16+ monocytes are elevated in symptomatic patients with atherosclerotic cardiovascular disease. The aim of this study was to investigate their utility in prediction of early atherosclerosis in asymptomatic subjects, in comparison to a traditional cardiovascular risk calculator, QRISK3.\u0000Approach and Results: Asymptomatic patients attending the hypertension clinic at Guy's & St Thomas' Hospitals, London, and healthy volunteer subjects recruited by advertisement, were enrolled (n = 39). Blood (30 mL) was processed for flow cytometry to measure CD14 and CD16 expression on monocytes, and CD14+CD42b+ MPA. Using these measurements, a novel index termed the Monocyte Atherosclerotic Risk Score (MARS) was developed. All subjects also underwent carotid artery ultrasonic angiography. Both QRISK3 and MARS correlated significantly with carotid intima-media thickness (cIMT); however, the correlation was much closer for MARS (r2 = 0.8705, P < 0.0001) than for QRISK3 (r2 = 0.3012, P = 0.0025). ROC analysis revealed MARS to be highly predictive both of cIMT-determined high cardiovascular risk (C-index = 0.9273, P = 0.0001) and presence of carotid plaque (C-index = 0.9385, P = 0.0022), whereas QRISK3 was not. Conclusion: MARS appears superior to QRISK3 in predicting both cIMT and carotid plaque disease. This may help to better identify asymptomatic individuals who would benefit from targeted imaging investigations and prophylactic therapies.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Principal Component Analysis to Heterogenous Fontan Registry Data Identifies Independent Contributing Factors to Decline","authors":"Margaret Ferrari, Michal Schafer, Kendall Hunter, Michael DiMaria","doi":"10.1101/2024.07.11.24310309","DOIUrl":"https://doi.org/10.1101/2024.07.11.24310309","url":null,"abstract":"Single ventricle heart disease is a severe and life-threatening illness, and improvements in clinical outcomes of those with Fontan circulation have not yet yielded acceptable survival over the past two decades. Patients are at risk of developing a diverse variety of Fontan-associated comorbidities that ultimately requires heart transplant. Our study goal was to determine if principal component analysis (PCA) applied to data collected from a substantial Fontan cohort can predict functional decline (N=140). Heterogeneous data broadly consisting of measures of cardiac and vascular function, exercise (VO2max), lymphatic biomarkers, and blood biomarkers were collected over 11 years at a single site; in that time, 16 events occurred that are considered here in a composite outcome measure. After standardization and PCA, principal components (PCs) representing >5% of total variance were thematically labeled based on their constituents and tested for association with the composite outcome. Our main findings suggest that the 6th PC (PC6), representing 7.1% percent of the total variance in the set, is greatly influenced by blood serum biomarkers and superior vena cava flow, is a superior measure of proportional hazard compared to EF, and displayed the greatest accuracy for classifying Fontan patients as determined by AUC. In bivariate hazard analysis, we found that models combining systolic function (EF or PC5) and lymphatic dysfunction (PC6) were most predictive, with the former having the greatest AIC, and the latter having the highest c-statistic. Our findings support our hypothesis that a multifactorial model must be considered to improve prognosis in the Fontan population.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Medical Therapy on Reducing the Risk of Pacing Induced Cardiomyopathy","authors":"Mahdi S Agha, Christopher L Schaich, Rishi Rikhi, Krupal Hari, George M Bodziock, Prashant D Bhave","doi":"10.1101/2024.07.10.24310243","DOIUrl":"https://doi.org/10.1101/2024.07.10.24310243","url":null,"abstract":"Background: High right ventricular (RV) pacing burden can result in pacing-induced cardiomyopathy (PICM). Objectives: To investigate whether ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta blockers (BB) reduce the risk of PICM in patients with high RV pacing burden. Methods: This was a single center, retrospective study which included patients with normal ejection fraction (EF) and complete heart block who underwent pacemaker implantation between 1992 and 2013. The medical therapy group included patients who received ACEI/ARB, BB, or combination of these classes. The control group received neither ACEI/ARB nor BB. The primary endpoint was PICM, defined as upgrade to a biventricular device or reduction in EF to ?40% without another etiology identified. Fine-Gray subdistribution hazard models accounting for death as a competing risk were used to determine the relationship between medical therapy (ACEI/ARB, BB, or combination) and cumulative incidence of PICM. Results: The study included 642 patients (mean [SD] age 71 [14] years; 51% women). Over 10 years of follow-up, 76 (11.8%) patients received ACEI/ARB therapy only; 49 (7.6%) received BB therapy only; and 86 (13.4%) were exposed to both. PICM occurred in 10 of 211 patients in the medical therapy group (4.7%) and in 30 of 431 in the control group (7.0%). In adjusted analyses weighted for group-switching, the risk of PICM was significantly lower in the medical therapy group compared to the control group (HR 0.59, 95% CI 0.45 - 0.77). Patients exposed to combination therapy had the lowest risk (HR 0.46, 95% CI 0.31 - 0.69). Conclusion: In patients with high RV pacing burden, BB therapy alone or in combination with ACEI/ARBs appears to reduce the risk of PICM within 10 years of pacemaker implantation.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulations in Cardiogenic Mechanisms by TGF-beta and Angiotensin II in Cardiac Remodeling Post-Ischemic Injury: a systematic review","authors":"Ovais Shafi, Kashaf Zahra, Haider Hussain Shah","doi":"10.1101/2024.07.11.24310260","DOIUrl":"https://doi.org/10.1101/2024.07.11.24310260","url":null,"abstract":"Objective:\u0000The objective of this study is to look into how TGF-beta and Angiotensin II disrupt cardiogenic regulators (Isl1, Brg1/Baf60-Smarcd3 complex, Nkx2-5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt-signaling pathway, Notch, FGF, BMPs) during cardiac remodeling post-ischemic injury.\u0000Background:\u0000Cardiac remodeling post-ischemic injury, influenced by TGF-beta and Angiotensin II, disrupts critical cardiogenic regulators essential for heart function. Understanding these disruptions is crucial for developing targeted therapies and biomarkers to assess disease severity. This research addresses a crucial gap in cardiovascular treatment by focusing on mechanisms underlying remodeling processes, aiming to improve therapeutic strategies and outcomes for ischemic heart disease patients.\u0000Methods: Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription based journals were searched for published articles without any date restrictions, to look into how TGF beta and Angiotensin II disrupt cardiogenic regulators in cardiac remodeling post-ischemic. Based on the criteria mentioned in the methods section, studies were systematically reviewed with focus on objectives of the study. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).\u0000Results:\u0000Cardiac remodeling post-ischemic injury involves complex disruptions of cardiogenic regulators, prominently influenced by TGF-beta and Angiotensin II. Our study reveals these factors significantly alter critical regulators like Isl1, Nkx2.5, and GATA4, impacting myocardial repair mechanisms. TGF-beta induces fibrosis and inflammatory responses, while Angiotensin II exacerbates hypertrophic pathways and oxidative stress. Interactions between these pathways amplify remodeling through Smad, MAPK, and other signaling cascades. These findings point to the crucial roles of TGF-beta and Angiotensin II in pathological cardiac remodeling, highlighting potential targets for therapeutic interventions.\u0000Conclusion:\u0000Cardiac remodeling post-ischemic injury, influenced by TGF-beta and Angiotensin II, disrupts vital cardiogenic regulators like Isl1, Brg1/Baf60/Smarcd3 complex, Nkx2.5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt-signaling pathway, Notch, FGF, and BMPs. These disruptions, involving altered receptor expression, signaling pathway interference, hypertrophic responses, and fibrosis promotion, compromise cardiac development and repair mechanisms. Targeting these pathways could enhance therapeutic strategies for ischemic heart disease by restoring normal regulator function and promoting effective cardiac repair and regeneration, thereby improving clinical outcomes.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of PCSK-9 Inhibitors on Lipoprotein(a): A Meta-analysis and Meta-regression of Randomized Controlled Trials","authors":"FREDERICK BERRO RIVERA, Sung Whoy Cha, John Vincent Magalong, Vincent Anthony Tang, Mary Grace Enriquez, Martha Gulati, Enkhmaa Byambaa, Neha J. Pagidipati, Nishant P Shah","doi":"10.1101/2024.07.10.24310245","DOIUrl":"https://doi.org/10.1101/2024.07.10.24310245","url":null,"abstract":"Background: Lipoprotein(a) [Lp(a)] has been independently associated with increased cardiovascular risk. We examined the effect of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on plasma Lp(a) levels across multiple clinical trials. Methods: Studies were retrieved comparing the effect of PCSK9i vs. placebo on Lp(a) levels. The primary outcome was percent change in Lp(a) levels. Secondary outcomes included percent change in additional cholesterol markers. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on comparator, PCSK9i type, treatment duration, and presence of familial hypercholesterolemia (FH). Results: 47 studies with 67,057 patients were analyzed. PCSK9i reduced Lp(a) levels by -27% (95% CI: -29.8 to -24.1, p<0.00?). Concurrent reduction in LDL-C, non-HDL-C, total cholesterol, triglycerides ApoB, ApoA-1, and increased HDL-C were also observed with PCSK9i use. Factors associated with the treatment effect included mean percent change in LDL-C (p=0.02, tau2=177.1, R2 analog=0.00) and Apo-B (p<0.00, tau2=114.20, R=1.42). Subgroup analyses revealed consistent treatment effect amongst comparators (vs. placebo: -27.69% (95% CI: -30.85 to -24.54, p<0.00), vs. ezetimibe: -24.0% (95% CI: -29.95% to -18.01, p<0.00), type of PCSK9i, evolocumab: -29.35% (95% CI: -33.56 to -25.14, p<0.00) vs. alirocumab: -24.50% (95% CI: -27.96 to -21.04, p<0.00), and presence of FH: -25.63% (95% CI: -31.96% to -19.30, p<0.00 vs. no FH: -27.22% (95% CI: -30.34. to -24.09, p<0.00). Varying treatment effects were noted in the duration of treatment (12 weeks or shorter: -32.43% (95% CI: -36.63 to -28.23 vs. >12 weeks: -22.31% (95% CI: -25.13 to -19.49, p<0.00), p interaction <0.01. Conclusion: PCSK9 inhibitors reduce Lp(a) levels up to 27%. Mean percent change in LDL-C and Apo-B were associated with treatment effect. PCSK9i also significantly reduced other atherogenic lipoproteins. Across multiple clinical trials, PCSK9i has a consistent effect of significantly lowering Lp(a) levels.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NETosis is an important component of chronic inflammation in patients with heart failure","authors":"Sawa Kostin, Manfred Richter, Florian Krizanic, Benjamin Sasko Sasko, Theodoros Kelesidis, Nikolaos Pagonas","doi":"10.1101/2024.07.09.24310187","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310187","url":null,"abstract":"Background and aim. We have previously demonstrated that heart failure (HF) is characterized by low-grade myocardial inflammation. However, the role of neutrophils (N), neutrophil extracellular traps (NETs) and neutrophil cell death by NETosis in the myocardium of patients with HF remains largely unknown. The present study investigated the number of neutrophils (N) and their proportion undergoing NETosis and developing NETs in HF.\u0000Methods. We used quantitative confocal microscopy and NETosis markers in the left ventricular biopsies obtained from 5 control and from patients with HF due to dilated (DCM, n=7), inflammatory (infCMP, n=7) and ischemic cardiomyopathy (ICM, n=7). We used immunolabeling for CD45, CD66b and CD11b for (N) and citrullinated histone3 (citH3), peptidylarginine deiminase-4 (PAD-4), neutrophil elastase (NE) and myeoloperoxidase (MPO) for NETosis. These proteins were investigated also by quantitative fluorescence intensity analysis, Western blot and quantitative polymerase chain reaction (qPCR).\u0000Results. Compared to control, the number of N was increased 3-4 fold in HF. We found that using a single marker for NETosemarkers, 43.2% of N in DCM, 46.7% in ICM and 57.3% in infCMP experienced NETosis. The use of double labeling (NE with CitH3) showed that 55.6% (47.2-60.9) of N developed NETosis in DCM, 57.9% (52.2-64.8) in ICM and 79.4% (71.1-84.9) in infCMP. The difference between the N who underwent NETosis in infCMP and those in DCM was statistically different (p<0.01). The proportion of N who developed NETosis or formed NETs in control tissue was less than 5% and differed significantly from that in HF patients, regardless of etiology (p<0.01). These results were confirmed by quantitative fluorescence analysis, Western blot and qPCR.\u0000Conclusions: This is the first study to show the occurrence of NETosis in human hearts in situ indicating that NETosis is an important component of low-grade myocardial inflammation in HF.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141588434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine-Learning based Prediction Models for Healthcare Outcomes in Patients Participating in Cardiac Rehabilitation: A Systematic Review","authors":"Xiarepati Tieliwaerdi, Kathryn Manalo, Sana Khan, Edmund Appiahkubi, Andrew Oehler","doi":"10.1101/2024.07.09.24310007","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310007","url":null,"abstract":"Purpose: CR has been proven to reduce mortality and morbidity in patients with CVD. ML techniques are increasingly used to predict healthcare outcomes in various fields of medicine including CR. This systemic review aims to perform critical appraisal of existing ML based prognosis predictive model within CR and identify key research gaps in this area. Review methods: A systematic literature search was conducted in Scopus, PubMed, Web of Science and Google Scholar from the inception of each database to 28th January 2024. The data extracted included clinical features, predicted outcomes, model development and validation as well as model performance metrics. Included studies underwent quality assessments using the IJMEDI.\u0000Summary: 22 ML-based clinical models from 7 studies across multiple phases of CR were included. Most models were developed using smaller patient cohorts from 41 to 227, with one exception involving 2280 patients. The prediction objectives ranged from patient intention to initiate CR to graduate from outpatient CR along with interval physiological and psychological response to CR. The best-performing ML models reported AUC between 0.82 and 0.91, sensitivity from 0.77 to 0.95, indicating good prediction capabilities. However, none of them underwent calibration or external validation. Most studies raised concerns for bias. Readiness of these models for implement into practice is questionable. External validation of existing models and development of new models with robust methodology based on larger populations and targeting diverse clinical overcomes in CR are needed.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141574991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling","authors":"Kevin D Mangum, Qinmengge Li, Tyler Bauer, Sonya Wolf, James Shadiow, Jadie Yoonjoo Moon, Emily Barrett, Amrita Joshi, Zara Ahmed, Rachael Wasikowski, Kylie Boyer, Andrea Tara Obi, Frank M Davis, Lin Chang, Lam C Tsoi, Johann E. Gudjonsson, Katherine Ann Gallagher","doi":"10.1101/2024.07.09.24310178","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310178","url":null,"abstract":"Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141574992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestry specific distribution of LPA Kringle IV-Type-2 genetic variants highlight associations to apo(a) copy number, glucose and hypertension.","authors":"Yihao Li, Florian Kronenberg, Stefan Coassin, Badri Vardarajan, Gissette Reyes-Soffer","doi":"10.1101/2024.07.09.24310176","DOIUrl":"https://doi.org/10.1101/2024.07.09.24310176","url":null,"abstract":"Background: High Lp(a) levels contribute to atherosclerotic cardiovascular disease and are tightly regulated by the LPA gene . Lp(a) levels have an inverse correlation with LPA Kringle IV Type-2 (KIV-2) copy number (CN). Black (B) and Hispanic (H) individuals exhibit higher levels of Lp(a) and rates of CVD compared to non-Hispanic Whites (NHW). Therefore, we investigated genetic variations in the LPA KIV-2 region across three ancestries and their associations with metabolic risk factors. Methods: Using published pipelines we analyzed a multi-ethnic whole exome dataset comprising 3,817 participants from the Washington Heights and Inwood Columbia Aging Project (WHICAP): 886 [NHW (23%), 1,811 Caribbean (C) H (47%), and 1,120 B individuals (29%). Rare and common variants (alternative allele carrier frequency, CF < 0.01 or > 0.99 and 0.01 < CF < 0.99, respectively) were identified and KIV-2 CN estimated. The associations of variants and CN with: history of heart disease, hypertension (HTN), stroke, lipid levels and, clinical diagnosis of Alzheimer?s disease (AD) wasassessed. A small pilot provided in-silico validation of study findings. Results: We report 1421 variants in the LPA KIV-2 repeat region, comprising 267 exonic and 1154 intronic variants. 61.4% of the exonic variants have not been previously described. Three novel exonic variants significantly increase the risk of HTN across all ethnic groups: 4785-C/A (frequency = 78%, odds ratio [OR] = 1.45, p = 0.032), 727-T/C (frequency = 96%, OR = 2.11, p = 0.032), and 723-A/G (frequency = 96%, OR = 1.97, p = 0.038). Additionally, six intronic variants showed associations with HTN: 166-G/A, 387-G/C, 402-G/A, 4527-A/T, 4541-G/A, and 4653-A/T. One intronic variant, 412-C/T, was associated with decreased blood glucose levels (frequency = 72%, ? = -14.52, p = 0.02).\u0000Three of the associations were not affected after adjusting for LPA KIV-2 CN: 412-C/T (? = -14.2, p = 0.03), 166-G/A (OR = 1.41, p = 0.05), and 387-G/C (OR = 1.40, p = 0.05). KIV CN itself was significantly associated with 314 variants and was negatively correlated with plasma total cholesterol levels.\u0000Conclusions: In three ancestry groups, we identify novel rare and common LPA KIV-2 region variants. We report new associations of variants with HTN and Glucose levels. These results underscore the genetic complexity of the LPA KIV-2 region in influencing cardiovascular and metabolic health, suggesting potential genetic regulation of pathways that can be studied for research and therapeutic interventions.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141574990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}