Abstract Aim The negative impacts of in utero tobacco exposure (IUTE) on cardiovascular disease (CVD) have been insufficiently described. This study aims to assess the association between IUTE and the risks of CVD incidence and all-cause mortality, discuss the inter-group difference based on genetic susceptibility and smoking behaviors after birth, and explore the potential mediating factors. Methods Utilizing a total of 375,024 participants from the UK Biobank, the outcomes include myocardial infarction, stroke, chronic ischemic heart disease, nonrheumatic aortic valve disorders, cardiomyopathy, heart failure, atherosclerosis, aortic aneurysm and dissection, and all-cause mortality. Results During a median follow-up period of 14.6 years, 50,434 cases of CVD were recorded. IUTE was significantly associated with increased CVD incidence (HR 1.10, 95% CI 1.08-1.12) and all-cause mortality (HR 1.11, 95% CI 1.09-1.14). Interaction effects between IUTE, smoking behaviors after birth, and genetic risk scores for CVD were observed significant (P for interaction < 0.005). The results of the cross-sectional study revealed a significant positive association between IUTE and smoking behaviors after birth (OR 1.08, 95% CI 1.06-1.09). Mediation analysis indicated that smoking behaviors (Proportion = 12.40%, P < 0.001) and HDL-c levels (Proportion = 14.20%, P < 0.001) partially mediated the IUTE-CVD relationship. Conclusions This study demonstrated that individuals with IUTE have a higher risk of developing CVD, and smoking behaviors after birth have multifaceted influence on this correlation. These findings underscore the importance of mothers avoiding smoking during pregnancy to mitigate adverse effects on their offspring.
摘要子宫内烟草暴露（IUTE）对心血管疾病（CVD）的负面影响尚未得到充分描述。本研究旨在评估子宫内烟草暴露与心血管疾病发病风险和全因死亡率之间的关系，讨论基于遗传易感性和出生后吸烟行为的组间差异，并探讨潜在的中介因素。方法利用英国生物库中的 375,024 名参与者，结果包括心肌梗死、中风、慢性缺血性心脏病、非风湿性主动脉瓣疾病、心肌病、心力衰竭、动脉粥样硬化、主动脉瘤和夹层以及全因死亡率。 结果在中位 14.6 年的随访期间，共记录了 50,434 例心血管疾病。IUTE与心血管疾病发病率增加（HR 1.10，95% CI 1.08-1.12）和全因死亡率增加（HR 1.11，95% CI 1.09-1.14）明显相关。观察发现，IUTE、出生后吸烟行为和心血管疾病遗传风险评分之间存在显著的交互作用（交互作用的 P 为 0.005）。横断面研究结果显示，IUTE 与出生后吸烟行为之间存在显著正相关（OR 1.08，95% CI 1.06-1.09）。中介分析表明，吸烟行为（比例 = 12.40%，P < 0.001）和 HDL-c 水平（比例 = 14.20%，P < 0.001）部分中介了 IUTE 与心血管疾病的关系。这些发现强调了母亲在怀孕期间避免吸烟以减轻对后代不利影响的重要性。
{"title":"The Impact of In Utero Tobacco Exposure on Cardiovascular Disease Risk and All-cause Mortality in Adulthood: a UK Biobank Study","authors":"Yanxu Zheng, Xinyu Xiong, Jing Bao, Jingyu Liu, Jin Wang, Zixi Chen, Fang Zou, Yang Guo, Qingyao Wang, Yixuan Qiu, Zhaowei Zhu","doi":"10.1101/2024.08.19.24312279","DOIUrl":"https://doi.org/10.1101/2024.08.19.24312279","url":null,"abstract":"Abstract\u0000Aim\u0000The negative impacts of in utero tobacco exposure (IUTE) on cardiovascular disease (CVD) have been insufficiently described. This study aims to assess the association between IUTE and the risks of CVD incidence and all-cause mortality, discuss the inter-group difference based on genetic susceptibility and smoking behaviors after birth, and explore the potential mediating factors.\u0000Methods\u0000Utilizing a total of 375,024 participants from the UK Biobank, the outcomes include myocardial infarction, stroke, chronic ischemic heart disease, nonrheumatic aortic valve disorders, cardiomyopathy, heart failure, atherosclerosis, aortic aneurysm and dissection, and all-cause mortality.\u0000Results\u0000During a median follow-up period of 14.6 years, 50,434 cases of CVD were recorded. IUTE was significantly associated with increased CVD incidence (HR 1.10, 95% CI 1.08-1.12) and all-cause mortality (HR 1.11, 95% CI 1.09-1.14). Interaction effects between IUTE, smoking behaviors after birth, and genetic risk scores for CVD were observed significant (P for interaction < 0.005). The results of the cross-sectional study revealed a significant positive association between IUTE and smoking behaviors after birth (OR 1.08, 95% CI 1.06-1.09). Mediation analysis indicated that smoking behaviors (Proportion = 12.40%, P < 0.001) and HDL-c levels (Proportion = 14.20%, P < 0.001) partially mediated the IUTE-CVD relationship.\u0000Conclusions\u0000This study demonstrated that individuals with IUTE have a higher risk of developing CVD, and smoking behaviors after birth have multifaceted influence on this correlation. These findings underscore the importance of mothers avoiding smoking during pregnancy to mitigate adverse effects on their offspring.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218995","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 : 2024-08-20DOI: 10.1101/2024.08.20.24312290
Hui-Qi Qu, Kayleigh Ostberg, Diana J Slater, Fengxiang Wang, James Snyder, Cuiping Hou, John J Connolly, Michael March, Joseph T Glessner, Charlly Kao, Hakon Hakonarson
Background: Single ventricle and hypoplastic left heart syndrome (SV/HLHS) patients require lifelong medical monitoring and management to address potential complications and optimize their health. The consequence of SV/HLHS had detrimental effects on multiple organ systems, including on peripheral blood mononuclear cells (PBMCs) and can weaken the immune system, exacerbating the risk of infection and various cardiovascular complications. Methods: Using single-cell RNA sequencing (scRNA-seq), we studied PBMCs from 33 pediatric patients (10 females and 23 males) with SV/HLHS. By a pair-wide study design, the SV/HLHS patients were compared to 33 controls without heart diseases. Results: Four cell types account for the top 62% cumulative importance of disease effects on gene expression in different cell types, i.e., [T cells, CD4+, Th1/17], [T cells, CD4+, TFH], [NK cells], and [T cells, CD4+, Th2]. Significant sex differences were observed in [T cells, CD4+, TFH], with less prominent effects in female patients. A total of 6659 genes in different cell types were significantly differentially expressed (DE). Hierarchical clustering by WGCNA analysis of the DE genes revealed that DE genes in NK cells are most closely related to those in SV/HLHS. A total of 822 genes showed cell specific DE with opposite directions in different cell types, highlighting overrepresented MYC and IFN-γ activity in T cell and NK cell populations, as well as underrepresentation in monocytes and Treg cells. Conclusion: This study elucidates the complex transcriptome landscape in PBMCs in patients with SV/HLHS, emphasizing the differential impacts on various cell types. New insights are gained into the precise modulation of MYC and IFN-γ activity in SV/HLHS, which may help balance immune responses and reduce harmful inflammation, and promote effective tissue repair and infection control.
背景：单心室和左心室发育不全综合征（SV/HLHS）患者需要终生接受医学监测和管理，以应对潜在的并发症并优化其健康状况。单心室和左心室发育不全综合征（SV/HLHS）的后果会对多个器官系统造成有害影响，包括外周血单核细胞（PBMCs），并会削弱免疫系统，加剧感染和各种心血管并发症的风险：我们利用单细胞 RNA 测序技术（scRNA-seq）研究了 33 名 SV/HLHS 儿科患者（10 名女性和 23 名男性）的 PBMCs。通过配对研究设计，将 SV/HLHS 患者与 33 名无心脏病的对照者进行了比较。研究结果在疾病对不同细胞类型基因表达影响的累积重要性中，有四种细胞类型占了前62%，即[T细胞，CD4+，Th1/17]、[T细胞，CD4+，TFH]、[NK细胞]和[T细胞，CD4+，Th2]。在[T细胞、CD4+、TFH]方面观察到了显著的性别差异，女性患者的影响较小。不同细胞类型中共有 6659 个基因存在显著差异表达（DE）。通过对 DE 基因进行 WGCNA 层次聚类分析，发现 NK 细胞中的 DE 基因与 SV/HLHS 中的 DE 基因关系最为密切。共有 822 个基因在不同细胞类型中显示出方向相反的细胞特异性 DE，突显出 MYC 和 IFN-γ 活性在 T 细胞和 NK 细胞群中代表性过高，而在单核细胞和 Treg 细胞中代表性过低。结论本研究阐明了 SV/HLHS 患者 PBMCs 中复杂的转录组情况，强调了对各种细胞类型的不同影响。研究人员对 SV/HLHS 中 MYC 和 IFN-γ 活性的精确调节有了新的认识，这可能有助于平衡免疫反应、减少有害炎症、促进有效的组织修复和感染控制。
{"title":"Single-cell RNA Sequencing of Peripheral Blood Mononuclear Cells in Patients with Single Ventricle/Hypoplastic Left Heart Syndrome","authors":"Hui-Qi Qu, Kayleigh Ostberg, Diana J Slater, Fengxiang Wang, James Snyder, Cuiping Hou, John J Connolly, Michael March, Joseph T Glessner, Charlly Kao, Hakon Hakonarson","doi":"10.1101/2024.08.20.24312290","DOIUrl":"https://doi.org/10.1101/2024.08.20.24312290","url":null,"abstract":"Background: Single ventricle and hypoplastic left heart syndrome (SV/HLHS) patients require lifelong medical monitoring and management to address potential complications and optimize their health. The consequence of SV/HLHS had detrimental effects on multiple organ systems, including on peripheral blood mononuclear cells (PBMCs) and can weaken the immune system, exacerbating the risk of infection and various cardiovascular complications.\u0000Methods: Using single-cell RNA sequencing (scRNA-seq), we studied PBMCs from 33 pediatric patients (10 females and 23 males) with SV/HLHS. By a pair-wide study design, the SV/HLHS patients were compared to 33 controls without heart diseases. Results: Four cell types account for the top 62% cumulative importance of disease effects on gene expression in different cell types, i.e., [T cells, CD4+, Th1/17], [T cells, CD4+, TFH], [NK cells], and [T cells, CD4+, Th2]. Significant sex differences were observed in [T cells, CD4+, TFH], with less prominent effects in female patients. A total of 6659 genes in different cell types were significantly differentially expressed (DE). Hierarchical clustering by WGCNA analysis of the DE genes revealed that DE genes in NK cells are most closely related to those in SV/HLHS. A total of 822 genes showed cell specific DE with opposite directions in different cell types, highlighting overrepresented MYC and IFN-γ activity in T cell and NK cell populations, as well as underrepresentation in monocytes and Treg cells. Conclusion: This study elucidates the complex transcriptome landscape in PBMCs in patients with SV/HLHS, emphasizing the differential impacts on various cell types. New insights are gained into the precise modulation of MYC and IFN-γ activity in SV/HLHS, which may help balance immune responses and reduce harmful inflammation, and promote effective tissue repair and infection control.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218996","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}
Our study investigates the persistent cardiovascular symptoms observed in individuals long after contracting SARS-CoV-2, a condition commonly referred to as ?Long COVID?, which has significantly affected millions globally. We meticulously describe the cardiovascular outcomes in five patients, encompassing a range of severe conditions such as sudden cardiac death during exercise, coronary atherosclerotic heart disease, acute inferior myocardial infarction, and acute myocarditis. All five patients were diagnosed with myocarditis, confirmed through endomyocardial biopsy and histochemical staining, which identified inflammatory cell infiltration in their heart tissue. Crucially, electron microscopy revealed widespread mitochondrial vacuolations and the presence of myofilament degradation within the cardiomyocytes of these patients. These findings were mirrored in SARS-CoV-2-infected mice, suggesting a potential underlying cellular mechanism for the cardiac effects associated with Long COVID. Our report sheds light on the cardiovascular implications of Long COVID and underscores the importance of further research to understand its cellular underpinnings.
{"title":"SARS-CoV-2 Damages Cardiomyocytes Mitochondria and Implicates Long COVID-associated Cardiovascular Manifestations","authors":"Wenliang Che, Shuai Guo, Yanqun Wang, Xiaohua Wan, Bingyu Tan, Hailing Li, Jiasuer Ailipu, Mengyun Zhu, Zesong Chen, Peiyao Li, Zhaoyong Zhang, Yiliang Wang, Xiaohan Huang, Xinsheng Wang, Jian Zhu, Xijiang Pan, Fa Zhang, Peiyi Wang, Jincun Zhao, Yawei Xu, Zheng Liu","doi":"10.1101/2024.08.18.24311961","DOIUrl":"https://doi.org/10.1101/2024.08.18.24311961","url":null,"abstract":"Our study investigates the persistent cardiovascular symptoms observed in individuals long after contracting SARS-CoV-2, a condition commonly referred to as ?Long COVID?, which has significantly affected millions globally. We meticulously describe the cardiovascular outcomes in five patients, encompassing a range of severe conditions such as sudden cardiac death during exercise, coronary atherosclerotic heart disease, acute inferior myocardial infarction, and acute myocarditis. All five patients were diagnosed with myocarditis, confirmed through endomyocardial biopsy and histochemical staining, which identified inflammatory cell infiltration in their heart tissue. Crucially, electron microscopy revealed widespread mitochondrial vacuolations and the presence of myofilament degradation within the cardiomyocytes of these patients. These findings were mirrored in SARS-CoV-2-infected mice, suggesting a potential underlying cellular mechanism for the cardiac effects associated with Long COVID. Our report sheds light on the cardiovascular implications of Long COVID and underscores the importance of further research to understand its cellular underpinnings.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219002","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}
Background: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2 *2), affecting around 8% world population and 40% East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2 and ferroptosis in MI. Methods: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2 *2 were enrolled. MI mouse model of left anterior descending coronary artery ligation (LAD) was conducted on wild type, ALDH2 *2, and mice with cardiomyocyte-specific knock down of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma and mouse serum samples as well as in mouse heart tissues. Results: Human ALDH2 *2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in blood samples through lipidomic analysis, including increased levels of multiple classes of oxidized phospholipids, and decreased levels of antioxidants, such as Coenzyme Q-10 (Co-Q10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2 *2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2 *2 led to significantly decreased protein levels of ALDH2, whereas ferroptosis related proteins including Transferrin receptor (TFRC), Acyl-CoA synthetase long chain family member 4 (ACSL4), and Heme oxygenase 1 (HMOX1) were upregulated specifically in the infarct heart tissues. Mechanistically, ALDH2 physically interacted with eIF3E to modulate translation of critical proteins involved in ferroptosis, and ALDH2 deficiency in ALDH2 *2 mutant predisposes cardiomyocytes to ferroptosis by promoting Tfrc/Acsl4/Hmox1 translation. Consistently, cardiomyocytes-specific eIF3E knock down restored ALDH2 *2 cardiac function by attenuating ferroptosis in MI. Conclusions: ALDH2 *2 aggravates acute heart failure in MI through promoting cardiomyocytes ferroptosis, and targeting ferroptosis may be a potential therapeutic target for treating AMI, especially for ALDH2 *2 carriers.
{"title":"ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury","authors":"Xin Chen, Xiujian Yu, Xiaodong Xu, Rui Li, Ningning Liang, Lili Zhang, Luxiao Li, Jingyu Zhang, Mingyao Zhou, Tongwei Lv, Haoran Ma, Yongqiang Wang, Yanwen Ye, Chunzhao Yin, Shiting Chen, Hui Huang, Jinwei Tian, Aijun Sun, Weiyuan Wang, Dewen Yan, Pan Li, Huang-Tian Yang, Shanshan Zhong, Huiyong Yin","doi":"10.1101/2024.08.19.24312276","DOIUrl":"https://doi.org/10.1101/2024.08.19.24312276","url":null,"abstract":"Background: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2 *2), affecting around 8% world population and 40% East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2 and ferroptosis in MI.\u0000Methods: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2 *2 were enrolled. MI mouse model of left anterior descending coronary artery ligation (LAD) was conducted on wild type, ALDH2 *2, and mice with cardiomyocyte-specific knock down of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma and mouse serum samples as well as in mouse heart tissues. Results: Human ALDH2 *2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in blood samples through lipidomic analysis, including increased levels of multiple classes of oxidized phospholipids, and decreased levels of antioxidants, such as Coenzyme Q-10 (Co-Q10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2 *2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2 *2 led to significantly decreased protein levels of ALDH2, whereas ferroptosis related proteins including Transferrin receptor (TFRC), Acyl-CoA synthetase long chain family member 4 (ACSL4), and Heme oxygenase 1 (HMOX1) were upregulated specifically in the infarct heart tissues. Mechanistically, ALDH2 physically interacted with eIF3E to modulate translation of critical proteins involved in ferroptosis, and ALDH2 deficiency in ALDH2 *2 mutant predisposes cardiomyocytes to ferroptosis by promoting Tfrc/Acsl4/Hmox1 translation. Consistently, cardiomyocytes-specific eIF3E knock down restored ALDH2 *2 cardiac function by attenuating ferroptosis in MI.\u0000Conclusions: ALDH2 *2 aggravates acute heart failure in MI through promoting cardiomyocytes ferroptosis, and targeting ferroptosis may be a potential therapeutic target for treating AMI, especially for ALDH2 *2 carriers.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142218997","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 : 2024-08-20DOI: 10.1101/2024.08.14.24311020
Hannah Kleppe, Anastasia Budan, Lucas Zhang, Marie Majetic, Reva Shenwai, Alan Levinson, Olga Cisne-Thompson, Farshad Farshidifar, Jonathan Tsui, Sylwia Figarska, Timothy Hoey, James Priest, Rebecca Slater
Background: The I-bar protein MTSS1 is a known modifier of heart failure and contractile phenotypes but its role in modulating contractile dysfunction in genetic forms of Mendelian dilated cardiomyopathy (DCM) is not known. Methods: The potential role of cardiac MTSS1 in TTN DCM was explored using time-to-event models in observational human datasets. Using induced siRNA and mutant forms of pluripotent stem cell cardiomyocytes (iPSC-CMs) the impact of siRNA knockdown of MTSS upon sarcomere and Cardiomyocyte biology was assessed via quantitative high-content microscopy, and the impact and mechanism of MTSS1 knockdown upon contractility was assessed using engineered heart tissues (EHTs). Results: Amongst individuals affected with TTN DCM, a variant conferring lower cardiac levels of MTSS1 was associated with significantly improved event-free survival from cardiovascular death or heart transplant (HR 0.29, p=0.0016). Knockdown of MTSS1 by siRNA significantly improved the appearance of iPSC-CM models of TTN (p=2.9e-06), CSRP3 (p=3.1e-14), and RBM20 (p=4.4e-04) DCM as assessed by quantitative microscopy. Correspondingly, siRNA knockdown of MTSS1 increased contractility in EHT models of TTN DCM (p=0.003), CSRP3 DCM (p=0.008), and RBM20 DCM (p<2e-16). Across all genetic backgrounds, knockdown of MTSS1 was observed to increase the number of sarcomeres (p<0.0001), and in co-immunoprecipitation experiments MTSS1 physically interacts with MYO18A a key determinant of early sarcomere formation. Knockdown of MTSS1 resulted in increased transcription of MYH7 (0.29 log2FC, p=2.9e-06) along with other sarcomere genes. Conclusions: In iPSC-CMs Knockdown of MTSS1 by siRNA increased number of sarcomeres and was observed to increase twitch force in select in vitro models, suggesting MTSS1 may have a previously unrecognized role in modulating sarcomere production or turnover. Human observational and iPSC-CM experimental data supports the hypothesis that reduced expression of MTSS1 may be beneficial in Mendelian DCM caused by TTN, RBM20, and CSRP3.
{"title":"Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM","authors":"Hannah Kleppe, Anastasia Budan, Lucas Zhang, Marie Majetic, Reva Shenwai, Alan Levinson, Olga Cisne-Thompson, Farshad Farshidifar, Jonathan Tsui, Sylwia Figarska, Timothy Hoey, James Priest, Rebecca Slater","doi":"10.1101/2024.08.14.24311020","DOIUrl":"https://doi.org/10.1101/2024.08.14.24311020","url":null,"abstract":"Background: The I-bar protein MTSS1 is a known modifier of heart failure and contractile phenotypes but its role in modulating contractile dysfunction in genetic forms of Mendelian dilated cardiomyopathy (DCM) is not known. Methods: The potential role of cardiac MTSS1 in TTN DCM was explored using time-to-event models in observational human datasets. Using induced siRNA and mutant forms of pluripotent stem cell cardiomyocytes (iPSC-CMs) the impact of siRNA knockdown of MTSS upon sarcomere and Cardiomyocyte biology was assessed via quantitative high-content microscopy, and the impact and mechanism of MTSS1 knockdown upon contractility was assessed using engineered heart tissues (EHTs). Results: Amongst individuals affected with TTN DCM, a variant conferring lower cardiac levels of MTSS1 was associated with significantly improved event-free survival from cardiovascular death or heart transplant (HR 0.29, p=0.0016). Knockdown of MTSS1 by siRNA significantly improved the appearance of iPSC-CM models of TTN (p=2.9e-06), CSRP3 (p=3.1e-14), and RBM20 (p=4.4e-04) DCM as assessed by quantitative microscopy. Correspondingly, siRNA knockdown of MTSS1 increased contractility in EHT models of TTN DCM (p=0.003), CSRP3 DCM (p=0.008), and RBM20 DCM (p<2e-16). Across all genetic backgrounds, knockdown of MTSS1 was observed to increase the number of sarcomeres (p<0.0001), and in co-immunoprecipitation experiments MTSS1 physically interacts with MYO18A a key determinant of early sarcomere formation. Knockdown of MTSS1 resulted in increased transcription of MYH7 (0.29 log2FC, p=2.9e-06) along with other sarcomere genes. Conclusions: In iPSC-CMs Knockdown of MTSS1 by siRNA increased number of sarcomeres and was observed to increase twitch force in select in vitro models, suggesting MTSS1 may have a previously unrecognized role in modulating sarcomere production or turnover. Human observational and iPSC-CM experimental data supports the hypothesis that reduced expression of MTSS1 may be beneficial in Mendelian DCM caused by TTN, RBM20, and CSRP3.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219007","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 : 2024-08-20DOI: 10.1101/2024.08.19.24312280
Alexandra Janowski, Finley Mueller, Shreya Agarwal, Scott H Visovatti, Rebecca R Vanderpool
Background: RV strain associates with mortality in pulmonary hypertension (PH) but time-resolved strain is not typically assessed. The aim was to evaluate phasic changes in RV strain using cardiac magnetic resonance (CMR) images. We hypothesized that phasic changes in ejection and filling RV strain significantly associate with outcomes in PH. Methods: Participants were identified from the Ohio State University CMR PH registry (n=96). RV endocardial areas were segmented from 4-chamber CMR Cine images. Time-resolved strains were calculated for RV global, free wall and septal strain. Ventricular dynamics were assessed during the ejection, early filling and late filling cardiac phases to quantify phasic changes in function. RV contractility, afterload and diastolic stiffness were quantified using the single-beat method. Outcomes were evaluated at one year. Results: In this retrospective, single-center study, 96 participants with and without pulmonary hypertension were included. Cohort was predominately female (n=53, 55%) with elevated mean pulmonary arterial pressure (38[26-48] mmHg) and reduced RV function (RVEF: 42[31-54] %, TAPSE of 19[15-23] cm). Filling strain patterns described changes in ventricular dynamics but did not associate with RV dilation or other measures characteristic of RV dysfunction. In comparison, decreased free wall strain and increased diastolic stiffness both associated with RV dysfunction but there were no significant differences in strain patterns. Participants with strain pattern 3, decreased free wall strain or increased Eed had increased one-year mortality. When investigated together, participants with decreased free wall strain, RVEF and increased Eed had greatly reduced one-year survival. Conclusions: Assessment of phasic changes in ventricular function does provide additional pathophysiological information but assessment of strain patterns alone are not sufficient for identifying reduced function. Deep phenotyping using a combination of RV strain and diastolic stiffness is highly selective of participants with increased one-year mortality.
{"title":"Cardiac MRI Phasic Assessment of Strain in Right Ventricular Dysfunction","authors":"Alexandra Janowski, Finley Mueller, Shreya Agarwal, Scott H Visovatti, Rebecca R Vanderpool","doi":"10.1101/2024.08.19.24312280","DOIUrl":"https://doi.org/10.1101/2024.08.19.24312280","url":null,"abstract":"Background: RV strain associates with mortality in pulmonary hypertension (PH) but time-resolved strain is not typically assessed. The aim was to evaluate phasic changes in RV strain using cardiac magnetic resonance (CMR) images. We hypothesized that phasic changes in ejection and filling RV strain significantly associate with outcomes in PH. Methods: Participants were identified from the Ohio State University CMR PH registry (n=96). RV endocardial areas were segmented from 4-chamber CMR Cine images. Time-resolved strains were calculated for RV global, free wall and septal strain. Ventricular dynamics were assessed during the ejection, early filling and late filling cardiac phases to quantify phasic changes in function. RV contractility, afterload and diastolic stiffness were quantified using the single-beat method. Outcomes were evaluated at one year. Results: In this retrospective, single-center study, 96 participants with and without pulmonary hypertension were included. Cohort was predominately female (n=53, 55%) with elevated mean pulmonary arterial pressure (38[26-48] mmHg) and reduced RV function (RVEF: 42[31-54] %, TAPSE of 19[15-23] cm). Filling strain patterns described changes in ventricular dynamics but did not associate with RV dilation or other measures characteristic of RV dysfunction. In comparison, decreased free wall strain and increased diastolic stiffness both associated with RV dysfunction but there were no significant differences in strain patterns. Participants with strain pattern 3, decreased free wall strain or increased Eed had increased one-year mortality. When investigated together, participants with decreased free wall strain, RVEF and increased Eed had greatly reduced one-year survival. Conclusions: Assessment of phasic changes in ventricular function does provide additional pathophysiological information but assessment of strain patterns alone are not sufficient for identifying reduced function. Deep phenotyping using a combination of RV strain and diastolic stiffness is highly selective of participants with increased one-year mortality.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227463","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 : 2024-08-20DOI: 10.1101/2024.08.16.24312145
Sooyun Caroline Tavolacci, Kenji Okumura, Ameesh Isath, Gabriel Rodriguez, Corazon Belisario De La Pena, Junichi Shimamura, Steven L Lansman, Suguru Ohira
Objective: Heart transplants utilizing donors from circulatory death (DCD) allografts are rapidly growing with the potential to expand the donor pool. However, little is known about the use of DCD donors for simultaneous heart and kidney transplants (SHKT) compared to SHKT using brain death donors (DBD). Methods: From May 22, 2020, to September 30, 2023, 1,129 adult patients received SHKT (DCD, N=91 vs. DBD, N=1,038), identified using the United Network for Organ Sharing database, excluding other multi-organ transplants and re-transplants. A 1:3 ratio propensity score matching was performed using 17 recipient characteristics and 7 donor characteristics. A total of 91 DCD and 273 DBD matched cases were compared. Results: In the unmatched cohort, DCD recipients were older (DCD: 60 vs. DBD: 58 years, p=0.03) and had a lower rate of dialysis at transplant (27% vs. 40%, p=0.03) and status 1 to 2 patients (43% vs. 72%, p<.001). Donors were younger (30 vs. 32 years, p=0.02) in the DCD group. In the matched cohort, kidney delayed graft function (27% vs. 22%, p=0.29) was comparable, as were recipient survival (p=0.19), heart graft survival (p=0.19), and kidney graft survival (p=0.17). In multivariate Cox proportional hazards analysis, donor type (DCD) was not associated with an increased risk of mortality (HR=1.69, 95% Cl 0.90-3.16, p=0.10). Sub-group analysis showed that survival and freedom from graft failures were comparable between different modes of DCD recovery. The centers performing both DCD- and DBD-SHKT showed significantly shorter waitlist days with comparable transplant outcomes compared to centers that only performed DBD-SHKT. Conclusions: SHKT using DCD donors yields comparable survival and graft outcomes to those using DBD donors. These findings will guide treatment strategies for heart transplant candidates with kidney dysfunction, including the selection of donors and patients and safety net policy options.
目的：利用循环死亡（DCD）供体同种异体移植的心脏移植手术正在迅速增加，有可能扩大供体库。然而，与使用脑死亡供体（DBD）进行心脏和肾脏同时移植（SHKT）相比，人们对使用 DCD 供体进行心脏和肾脏同时移植（SHKT）的情况知之甚少。方法：从2020年5月22日至2023年9月30日，1129名成年患者接受了SHKT（DCD，N=91 vs. DBD，N=1,038），这些患者是通过器官共享联合网络数据库确定的，不包括其他多器官移植和再移植。使用 17 个受者特征和 7 个供者特征进行了 1:3 比例倾向得分匹配。共比较了 91 例 DCD 和 273 例 DBD 匹配病例。结果：在非匹配队列中，DCD 受者年龄较大（DCD：60 岁 vs. DBD：58 岁，p=0.03），移植时透析率较低（27% vs. 40%，p=0.03），状态 1 至 2 的患者比例较低（43% vs. 72%，p<.001）。DCD组的捐献者更年轻（30岁对32岁，P=0.02）。在配对队列中，肾脏延迟移植物功能（27% 对 22%，P=0.29）与受者存活率（P=0.19）、心脏移植物存活率（P=0.19）和肾脏移植物存活率（P=0.17）相当。在多变量考克斯比例危险分析中，供体类型（DCD）与死亡率风险增加无关（HR=1.69，95% Cl 0.90-3.16，P=0.10）。分组分析表明，不同的 DCD 恢复模式的存活率和移植物失败率相当。与只进行DBD-SHKT的中心相比，同时进行DCD-SHKT和DBD-SHKT的中心的等待天数明显较短，移植结果也相当。结论：使用DCD供体的SHKT与使用DBD供体的SHKT可获得相当的存活率和移植结果。这些发现将指导肾功能不全心脏移植候选者的治疗策略，包括供体和患者的选择以及安全网政策选择。
{"title":"Simultaneous Heart and Kidney Transplantation utilizing Circulatory Death Donors in the United States","authors":"Sooyun Caroline Tavolacci, Kenji Okumura, Ameesh Isath, Gabriel Rodriguez, Corazon Belisario De La Pena, Junichi Shimamura, Steven L Lansman, Suguru Ohira","doi":"10.1101/2024.08.16.24312145","DOIUrl":"https://doi.org/10.1101/2024.08.16.24312145","url":null,"abstract":"Objective: Heart transplants utilizing donors from circulatory death (DCD) allografts are rapidly growing with the potential to expand the donor pool. However, little is known about the use of DCD donors for simultaneous heart and kidney transplants (SHKT) compared to SHKT using brain death donors (DBD). Methods: From May 22, 2020, to September 30, 2023, 1,129 adult patients received SHKT (DCD, N=91 vs. DBD, N=1,038), identified using the United Network for Organ Sharing database, excluding other multi-organ transplants and re-transplants. A 1:3 ratio propensity score matching was performed using 17 recipient characteristics and 7 donor characteristics. A total of 91 DCD and 273 DBD matched cases were compared. Results: In the unmatched cohort, DCD recipients were older (DCD: 60 vs. DBD: 58 years, p=0.03) and had a lower rate of dialysis at transplant (27% vs. 40%, p=0.03) and status 1 to 2 patients (43% vs. 72%, p<.001). Donors were younger (30 vs. 32 years, p=0.02) in the DCD group. In the matched cohort, kidney delayed graft function (27% vs. 22%, p=0.29) was comparable, as were recipient survival (p=0.19), heart graft survival (p=0.19), and kidney graft survival (p=0.17). In multivariate Cox proportional hazards analysis, donor type (DCD) was not associated with an increased risk of mortality (HR=1.69, 95% Cl 0.90-3.16, p=0.10). Sub-group analysis showed that survival and freedom from graft failures were comparable between different modes of DCD recovery. The centers performing both DCD- and DBD-SHKT showed significantly shorter waitlist days with comparable transplant outcomes compared to centers that only performed DBD-SHKT. Conclusions: SHKT using DCD donors yields comparable survival and graft outcomes to those using DBD donors. These findings will guide treatment strategies for heart transplant candidates with kidney dysfunction, including the selection of donors and patients and safety net policy options.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219003","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 : 2024-08-19DOI: 10.1101/2024.08.18.24312189
Hui-Qi Qu, Kushagra Goel, Kayleigh Ostberg, Diana J Slater, Fengxiang Wang, James Snyder, Cuiping Hou, John J Connolly, Michael March, Joseph T Glessner, Charlly Kao, Hakon Hakonarson
We utilized single-cell RNA sequencing (scRNA-seq) to examine peripheral blood mononuclear cells (PBMCs) from patients with Single Ventricle/Hypoplastic Left Heart Syndrome (SV/HLHS), and demonstrated a more pronounced correlation between gene expression in Natural Killer (NK) cells and SV/HLHS compared to other PBMC cell types. Our scRNA-seq analysis of NK cells in this study identified two distinct clusters with gene expression patterns linked to immune responsiveness and adaptation to stress. While this finding underscores the heterogeneity of NK cells, it provides new insights into fine-tuning of immune modulation that could prevent complications in SV/HLHS. Specifically, our study suggests that while NK cells in SV/HLHS are adapting to support survival in a challenging physiological environment, these adaptations may compromise their ability to manage additional stresses such as infections and inflammation.
我们利用单细胞 RNA 测序（scRNA-seq）技术检测了单心室/左心室肥大综合征（SV/HLHS）患者的外周血单核细胞（PBMC），结果表明，与其他 PBMC 细胞类型相比，自然杀伤（NK）细胞和 SV/HLHS 的基因表达之间存在更明显的相关性。在这项研究中，我们对 NK 细胞进行了 scRNA-seq 分析，发现了两个不同的基因簇，其基因表达模式与免疫反应性和应激适应性有关。这一发现强调了 NK 细胞的异质性，同时也为预防 SV/HLHS 并发症的免疫调节微调提供了新的见解。具体来说，我们的研究表明，虽然 SV/HLHS 中的 NK 细胞正在进行调整，以支持在具有挑战性的生理环境中生存，但这些调整可能会损害它们管理感染和炎症等额外压力的能力。
{"title":"Characterization of Natural Killer Cell Subpopulations in the Blood of Single Ventricle/Hypoplastic Left Heart Syndrome Patients Using Single-Cell RNA Sequencing","authors":"Hui-Qi Qu, Kushagra Goel, Kayleigh Ostberg, Diana J Slater, Fengxiang Wang, James Snyder, Cuiping Hou, John J Connolly, Michael March, Joseph T Glessner, Charlly Kao, Hakon Hakonarson","doi":"10.1101/2024.08.18.24312189","DOIUrl":"https://doi.org/10.1101/2024.08.18.24312189","url":null,"abstract":"We utilized single-cell RNA sequencing (scRNA-seq) to examine peripheral blood mononuclear cells (PBMCs) from patients with Single Ventricle/Hypoplastic Left Heart Syndrome (SV/HLHS), and demonstrated a more pronounced correlation between gene expression in Natural Killer (NK) cells and SV/HLHS compared to other PBMC cell types. Our scRNA-seq analysis of NK cells in this study identified two distinct clusters with gene expression patterns linked to immune responsiveness and adaptation to stress. While this finding underscores the heterogeneity of NK cells, it provides new insights into fine-tuning of immune modulation that could prevent complications in SV/HLHS. Specifically, our study suggests that while NK cells in SV/HLHS are adapting to support survival in a challenging physiological environment, these adaptations may compromise their ability to manage additional stresses such as infections and inflammation.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219027","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 : 2024-08-19DOI: 10.1101/2024.08.17.24311901
Alexandra Janiszewski, Julia Christina Lueg, Daniel Schulze, Benjamin Juri, Louis Morell, Maria Hajduczenia, Pierre Hennig, Aslihan Erbay, Alexander Lembcke, Stefan Markus Niehues, Ulf Landmesser, Karl Stangl, David Manuel Leistner, Henryk Dreger, Verena Tscholl
Background: The need for permanent pacemaker implantation (PPMI) remains one of the most frequent complications after transcatheter aortic valve implantation (TAVI). This study aimed to develop a novel, two-step risk score to predict PPMI probability after TAVI and to implement it into a user-friendly website. Our risk score addresses the gap in existing data on current prosthesis generations and provides a new and clinically motivated approach to calculating the risk for PPMI. Methods: Between January 2019 and December 2020, 1039 patients underwent TAVI at our institution. We retrospectively evaluated clinical, electrocardiographic, echocardiographic, computed tomographic, and periprocedural data. Patients with prior PPMI were excluded. We developed a prediction model for the occurrence of PPMI, initially using 55 patient and procedural characteristics. Results: We included 836 patients (mean age 80.2 ± 9.1 years, 50.5% female), among whom 140 patients (16.6%) needed PPMI within 30 days after TAVI. In the first step, the TAVI PACER score calculates an individual risk for PPMI, including 14 preprocedural risk factors such as preexisting right bundle branch block, atrioventricular block, left bundle branch block, bradycardia, interventricular septum thickness in diastole, NYHA class, and aortic annulus perimeter. In the second step, intraprocedural variables are included to demonstrate how PPMI risk can vary based on the chosen valve type and implantation depth. The TAVI PACER score can predict PPMI with a sensitivity of 76% and specificity of 72% (AUC = 0.8). Conclusions: The TAVI PACER score provides a novel tool for daily clinical practice, which predicts the individual risk for PPMI after TAVI based on various patient and two procedural characteristics.
{"title":"TAVI PACER: A two-step risk score for prediction of permanent pacemaker implantation after TAVI.","authors":"Alexandra Janiszewski, Julia Christina Lueg, Daniel Schulze, Benjamin Juri, Louis Morell, Maria Hajduczenia, Pierre Hennig, Aslihan Erbay, Alexander Lembcke, Stefan Markus Niehues, Ulf Landmesser, Karl Stangl, David Manuel Leistner, Henryk Dreger, Verena Tscholl","doi":"10.1101/2024.08.17.24311901","DOIUrl":"https://doi.org/10.1101/2024.08.17.24311901","url":null,"abstract":"Background: The need for permanent pacemaker implantation (PPMI) remains one of the most frequent complications after transcatheter aortic valve implantation (TAVI). This study aimed to develop a novel, two-step risk score to predict PPMI probability after TAVI and to implement it into a user-friendly website. Our risk score addresses the gap in existing data on current prosthesis generations and provides a new and clinically motivated approach to calculating the risk for PPMI.\u0000Methods: Between January 2019 and December 2020, 1039 patients underwent TAVI at our institution. We retrospectively evaluated clinical, electrocardiographic, echocardiographic, computed tomographic, and periprocedural data. Patients with prior PPMI were excluded. We developed a prediction model for the occurrence of PPMI, initially using 55 patient and procedural characteristics.\u0000Results: We included 836 patients (mean age 80.2 ± 9.1 years, 50.5% female), among whom 140 patients (16.6%) needed PPMI within 30 days after TAVI. In the first step, the TAVI PACER score calculates an individual risk for PPMI, including 14 preprocedural risk factors such as preexisting right bundle branch block, atrioventricular block, left bundle branch block, bradycardia, interventricular septum thickness in diastole, NYHA class, and aortic annulus perimeter. In the second step, intraprocedural variables are included to demonstrate how PPMI risk can vary based on the chosen valve type and implantation depth. The TAVI PACER score can predict PPMI with a sensitivity of 76% and specificity of 72% (AUC = 0.8). Conclusions: The TAVI PACER score provides a novel tool for daily clinical practice, which predicts the individual risk for PPMI after TAVI based on various patient and two procedural characteristics.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219004","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 : 2024-08-19DOI: 10.1101/2024.08.17.24312157
Mehrtash Hashemzadeh, Arman Soltani Moghadam, Saman Soltani Moghadam, Mohammad Reza Movahed
Introduction: The obesity paradox has been seen in many cardiovascular conditions. The goal of this study was to evaluate whether it exists in patients with a diagnosis of aortic stenosis. Method: We used the Nationwide Inpatients Sample (NIS) database and ICD-10 coding for adults in different weight categories and with aortic stenosis diagnoses for 2016-2020. We evaluated the effect of weight on mortality using multivariate adjustment and the cox-regression model. Results: A total of 2,330,584 patients were diagnosed with aortic stenosis. Mortality was lowest in overweight followed by obesity and morbid obesity (1.74% vs. 2.43% vs 3.2% in comparison to normal weight mortality of 4.4%, p<0.001) and it was highest in patients with cachexia (mortality of 14.5%). After adjusting for baseline characteristics and comorbid conditions, the relation between mortality and weights remained unaltered. Multivariate adjusted odds ratios (OR) were as follows: Overweight OR 0.4, CI 0.31-0.6, p<0.001, Obesity: OR 0.64, CI 06-0.68, p<0.001, morbid obesity OR: 0.88, CI 0.83-0.94, P<0.001, Cachexia OR 3.31 CI: 3.04-3.62, p<0.001). Conclusion: Using the largest database, we found that in patients with a diagnosis of aortic stenosis, overweight followed by obesity and morbid obesity have the lowest mortality whereas cachexia has the highest mortality compared to normal-weight patients.
导言肥胖悖论在许多心血管疾病中都曾出现过。本研究旨在评估主动脉瓣狭窄患者是否存在肥胖悖论。研究方法：我们使用了全国住院患者样本（NIS）数据库和 ICD-10 编码，对 2016-2020 年期间不同体重类别且诊断为主动脉瓣狭窄的成人进行了分析。我们使用多变量调整和 cox 回归模型评估了体重对死亡率的影响。结果如下共有 2,330,584 名患者被诊断为主动脉瓣狭窄。超重患者的死亡率最低，其次是肥胖和病态肥胖（1.74% vs. 2.43% vs. 3.2%，而正常体重患者的死亡率为 4.4%，p<0.001），恶病质患者的死亡率最高（14.5%）。在对基线特征和合并症进行调整后，死亡率与体重之间的关系仍保持不变。多变量调整后的几率（OR）如下：超重 OR 0.4，CI 0.31-0.6，p<0.001，肥胖：OR：0.64，CI：06-0.68，P<0.001，病态肥胖 OR：0.88，CI：0.83-0.94，P<0.001，头痛 OR：3.31，CI：3.04-3.62，P<0.001）：通过使用最大的数据库，我们发现在确诊为主动脉瓣狭窄的患者中，超重患者的死亡率最低，其次是肥胖和病态肥胖，而与正常体重患者相比，恶病质患者的死亡率最高。
{"title":"Mortality is lowest in overweight followed by obese and morbid obese patients and is highest in cachexia compared to normal weight in patients with the diagnosis of aortic stenosis.","authors":"Mehrtash Hashemzadeh, Arman Soltani Moghadam, Saman Soltani Moghadam, Mohammad Reza Movahed","doi":"10.1101/2024.08.17.24312157","DOIUrl":"https://doi.org/10.1101/2024.08.17.24312157","url":null,"abstract":"Introduction: The obesity paradox has been seen in many cardiovascular conditions. The goal of this study was to evaluate whether it exists in patients with a diagnosis of aortic stenosis. Method: We used the Nationwide Inpatients Sample (NIS) database and ICD-10 coding for adults in different weight categories and with aortic stenosis diagnoses for 2016-2020. We evaluated the effect of weight on mortality using multivariate adjustment and the cox-regression model. Results: A total of 2,330,584 patients were diagnosed with aortic stenosis. Mortality was lowest in overweight followed by obesity and morbid obesity (1.74% vs. 2.43% vs 3.2% in comparison to normal weight mortality of 4.4%, p<0.001) and it was highest in patients with cachexia (mortality of 14.5%). After adjusting for baseline characteristics and comorbid conditions, the relation between mortality and weights remained unaltered. Multivariate adjusted odds ratios (OR) were as follows: Overweight OR 0.4, CI 0.31-0.6, p<0.001, Obesity: OR 0.64, CI 06-0.68, p<0.001, morbid obesity OR: 0.88, CI 0.83-0.94, P<0.001, Cachexia OR 3.31 CI: 3.04-3.62, p<0.001).\u0000Conclusion: Using the largest database, we found that in patients with a diagnosis of aortic stenosis, overweight followed by obesity and morbid obesity have the lowest mortality whereas cachexia has the highest mortality compared to normal-weight patients.","PeriodicalId":501297,"journal":{"name":"medRxiv - Cardiovascular Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219020","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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