Pub Date : 2024-07-12DOI: 10.1101/2024.07.12.24309975
Sarah Raut, Aaron Hales, Maureen Twiddy, Lili Dixon, Dumbor Ngaage, David Yates, Gerard Danjoux, Lee Ingle
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.
{"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":"115 1","pages":""},"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}
Pub Date : 2024-07-12DOI: 10.1101/2024.07.12.24310323
Fatemah Almarri, Soundrie Padayachee, Alexander Kerr, Ashish S Patel, Albert Ferro
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. Approach 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.
{"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":"62 1","pages":""},"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}
Pub Date : 2024-07-12DOI: 10.1101/2024.07.11.24310309
Margaret Ferrari, Michal Schafer, Kendall Hunter, Michael DiMaria
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.
单心室心脏病是一种严重的危及生命的疾病，在过去二十年里，丰坦循环患者的临床治疗效果尚未得到改善，存活率也不尽人意。患者有可能患上各种与丰坦相关的并发症，最终需要进行心脏移植。我们的研究目标是确定将主成分分析（PCA）应用于从大量丰坦队列中收集的数据能否预测功能衰退（N=140）。我们在一个地点收集了11年的异质数据，这些数据广泛包括心脏和血管功能、运动（VO2max）、淋巴生物标记物和血液生物标记物的测量值；在此期间，共发生了16起事件，这些事件在综合结果测量中被考虑在内。经过标准化和 PCA 后，代表总方差 5%的主成分（PCs）根据其组成成分进行了主题标注，并测试了其与综合结果的关联性。我们的主要研究结果表明，第 6 个主成分（PC6）占主成分集总方差的 7.1%，受血清生物标志物和上腔静脉血流的影响很大，与 EF 相比，它是比例危险性的更优测量指标，而且根据 AUC 值对 Fontan 患者进行分类的准确性最高。在双变量危险分析中，我们发现结合收缩功能（EF 或 PC5）和淋巴功能障碍（PC6）的模型最具预测性，前者的 AIC 最大，后者的 c 统计量最高。我们的研究结果支持了我们的假设，即必须考虑采用多因素模型来改善Fontan人群的预后。
{"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":"46 1","pages":""},"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}
Pub Date : 2024-07-11DOI: 10.1101/2024.07.10.24310243
Mahdi S Agha, Christopher L Schaich, Rishi Rikhi, Krupal Hari, George M Bodziock, Prashant D Bhave
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.
{"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":"40 1","pages":""},"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}
Pub Date : 2024-07-11DOI: 10.1101/2024.07.11.24310260
Ovais Shafi, Kashaf Zahra, Haider Hussain Shah
Objective: The 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. Background: Cardiac 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. Methods: 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). Results: Cardiac 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. Conclusion: Cardiac 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.
目的：本研究旨在探讨 TGF-beta 和血管紧张素 II 如何在缺血损伤后心脏重塑过程中破坏心源性调节因子（Isl1、Brg1/Baf60-Smarcd3 复合物、Nkx2-5、GATA4、Tbx5、Mef2c、HAND1/2、MYOCD、MSX2、HOPX、Wnt 信号通路、Notch、FGF、BMPs）。背景：缺血损伤后的心脏重塑受 TGF-beta 和血管紧张素 II 的影响，破坏了对心脏功能至关重要的关键心源性调节因子。了解这些干扰对于开发靶向疗法和评估疾病严重程度的生物标记物至关重要。这项研究关注重塑过程的内在机制，旨在改善缺血性心脏病患者的治疗策略和疗效，从而填补心血管治疗领域的重要空白：方法：在包括PubMed、MEDLINE、Google Scholar和开放获取/订阅期刊在内的数据库中搜索已发表的文章，没有任何日期限制，以研究TGF beta和血管紧张素II如何破坏缺血后心脏重塑过程中的心源性调节因子。根据 "方法 "部分中提到的标准，对研究进行了系统性审查，重点关注研究目标。结果：缺血损伤后的心脏重塑涉及复杂的心源性调节因子干扰，主要受 TGF-beta 和血管紧张素 II 的影响。我们的研究发现，这些因素极大地改变了Isl1、Nkx2.5和GATA4等关键调节因子，影响了心肌修复机制。TGF-beta诱导纤维化和炎症反应，而血管紧张素II则加剧肥大途径和氧化应激。这些途径之间的相互作用通过 Smad、MAPK 和其他信号级联扩大了重塑。这些研究结果表明了 TGF-beta 和血管紧张素 II 在病理性心脏重塑中的关键作用，突出了治疗干预的潜在靶点。结论：缺血损伤后的心脏重塑受到 TGF-beta 和血管紧张素 II 的影响，破坏了重要的致心调节因子，如 Isl1、Brg1/Baf60/Smarcd3 复合物、Nkx2.5、GATA4、Tbx5、Mef2c、HAND1/2、MYOCD、MSX2、HOPX、Wnt 信号通路、Notch、FGF 和 BMPs。这些干扰涉及受体表达改变、信号通路干扰、肥大反应和纤维化促进，损害了心脏发育和修复机制。以这些通路为靶点，可恢复正常调节器功能，促进有效的心脏修复和再生，从而改善临床疗效，从而加强缺血性心脏病的治疗策略。
{"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":"32 1","pages":""},"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}
Pub Date : 2024-07-11DOI: 10.1101/2024.07.10.24310245
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
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.
背景：脂蛋白（a）[Lp(a)]与心血管风险的增加有独立关联。我们研究了多项临床试验中单克隆抗体丙蛋白转换酶亚基酶/kexin 9 型抑制剂（PCSK9i）对血浆脂蛋白（a）水平的影响。方法：检索比较 PCSK9i 与安慰剂对脂蛋白（a）水平影响的研究。主要结果是脂蛋白（a）水平变化的百分比。次要结果包括其他胆固醇指标的变化百分比。通过元回归分析确定了与治疗效果相关的因素。还进行了亚组分析，以探讨基于比较者、PCSK9i类型、治疗持续时间和是否存在家族性高胆固醇血症（FH）的潜在治疗效果差异。研究结果共分析了 47 项研究、67,057 名患者。PCSK9i可将脂蛋白（a）水平降低-27%（95% CI：-29.8 至 -24.1，p<0.00?）。使用 PCSK9i 还可同时降低低密度脂蛋白胆固醇、非高密度脂蛋白胆固醇、总胆固醇、甘油三酯 ApoB、ApoA-1，并增加高密度脂蛋白胆固醇。与治疗效果相关的因素包括低密度脂蛋白胆固醇的平均百分比变化（p=0.02，tau2=177.1，R2 analog=0.00）和载脂蛋白-B（p<0.00，tau2=114.20，R=1.42）。亚组分析显示，比较者之间的治疗效果一致（vs.安慰剂：-27.69% (95% CI: -30.85 to -24.54，p<0.00)，vs.依折麦布：-24.0% (95% CI: -29.95% to -18.01，p<0.00)，PCSK9i类型，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), 以及是否存在 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)。治疗效果因治疗时间长短而异（12 周或更短：-32.43%（95% CI：-36.63 至 -28.23 vs. >12周：-22.31%（95% CI：-25.13 至 -19.49，p<0.00），p 交互作用<0.01。结论PCSK9抑制剂最多可降低27%的脂蛋白（a）水平。低密度脂蛋白胆固醇和载脂蛋白-B的平均百分比变化与治疗效果有关。PCSK9i 还能显著降低其他致动脉粥样硬化脂蛋白。在多项临床试验中，PCSK9i 在显著降低脂蛋白（a）水平方面具有一致的效果。
{"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":"52 1","pages":""},"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}
Pub Date : 2024-07-10DOI: 10.1101/2024.07.09.24310187
Sawa Kostin, Manfred Richter, Florian Krizanic, Benjamin Sasko Sasko, Theodoros Kelesidis, Nikolaos Pagonas
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. Methods. 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). Results. 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. Conclusions: 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.
背景和目的。我们以前曾证实，心力衰竭（HF）以低度心肌炎症为特征。然而，嗜中性粒细胞（N）、嗜中性粒细胞胞外捕获物（NET）和嗜中性粒细胞NETosis导致的嗜中性粒细胞死亡在心力衰竭患者心肌中的作用在很大程度上仍然未知。本研究调查了心房颤动患者中性粒细胞（N）的数量及其发生NETosis和NETs的比例。我们使用定量共聚焦显微镜和NETosis标记物对5名对照组和因扩张型（DCM，n=7）、炎症型（infCMP，n=7）和缺血性心肌病（ICM，n=7）导致的HF患者的左心室活检组织进行了检测。我们使用 CD45、CD66b 和 CD11b 免疫标记法检测（N），使用瓜氨酸组蛋白 3（citH3）、肽精氨酸脱氨酶-4（PAD-4）、中性粒细胞弹性蛋白酶（NE）和麦芽过氧化物酶（MPO）免疫标记法检测 NETosis。还通过荧光强度定量分析、Western 印迹和定量聚合酶链反应（qPCR）对这些蛋白质进行了研究。与对照组相比，高频患者的 N 数量增加了 3-4 倍。我们发现，使用单一标记物作为 NETosemarkers，43.2% 的 DCM、46.7% 的 ICM 和 57.3% 的 infCMP N 出现 NETosis。使用双重标记（NE 与 CitH3）显示，DCM 中 55.6% （47.2-60.9）的 N 出现 NETosis，ICM 中 57.9% （52.2-64.8），infCMP 中 79.4%（71.1-84.9）。在 infCMP 中接受 NETosis 的 N 与在 DCM 中接受 NETosis 的 N 之间存在统计学差异（p<0.01）。在对照组织中发生 NETosis 或形成 NET 的 N 所占比例低于 5%，与高频患者相比，无论病因如何，均有显著差异（p<0.01）。这些结果得到了荧光定量分析、Western blot 和 qPCR 的证实：这是首次在人体心脏原位发现NETosis的研究，表明NETosis是HF低度心肌炎症的重要组成部分。
{"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":"27 1","pages":""},"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}
Pub Date : 2024-07-10DOI: 10.1101/2024.07.09.24310007
Xiarepati Tieliwaerdi, Kathryn Manalo, Sana Khan, Edmund Appiahkubi, Andrew Oehler
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. Summary: 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.
目的：事实证明，CR 可以降低心血管疾病患者的死亡率和发病率。包括 CR 在内的各个医学领域越来越多地使用 ML 技术来预测医疗结果。本系统综述旨在对 CR 中现有的基于 ML 的预后预测模型进行批判性评估，并找出该领域的主要研究空白。综述方法：在 Scopus、PubMed、Web of Science 和 Google Scholar 上进行了系统的文献检索，检索时间从各数据库建立之初至 2024 年 1 月 28 日。提取的数据包括临床特征、预测结果、模型开发和验证以及模型性能指标。摘要：共纳入了 7 项研究中的 22 个基于 ML 的临床模型，涉及 CR 的多个阶段。大多数模型都是使用较小的患者群（41 到 227 人）开发的，只有一个例外涉及 2280 名患者。预测目标从患者启动 CR 的意向到从门诊 CR 毕业，以及对 CR 的间歇性生理和心理反应不等。表现最好的 ML 模型的 AUC 在 0.82 到 0.91 之间，灵敏度在 0.77 到 0.95 之间，显示了良好的预测能力。但是，这些模型都没有经过校准或外部验证。大多数研究都提出了偏差问题。这些模型是否可用于实践值得怀疑。有必要对现有模型进行外部验证，并针对 CR 的不同临床结果，以更大的人群为基础，用可靠的方法开发新的模型。
{"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":"72 1","pages":""},"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}
Pub Date : 2024-07-10DOI: 10.1101/2024.07.09.24310178
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
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.
{"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":"41 1","pages":""},"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}
Pub Date : 2024-07-10DOI: 10.1101/2024.07.09.24310176
Yihao Li, Florian Kronenberg, Stefan Coassin, Badri Vardarajan, Gissette Reyes-Soffer
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). Three 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. Conclusions: 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.
{"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":"38 1","pages":""},"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}
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