Pub Date : 2024-09-17Epub Date: 2024-09-16DOI: 10.1161/CIRCULATIONAHA.124.071870
{"title":"Highlights From the <i>Circulation</i> Family of Journals.","authors":"","doi":"10.1161/CIRCULATIONAHA.124.071870","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071870","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-08-12DOI: 10.1161/CIRCULATIONAHA.124.069047
Amey Vrudhula, Grant Duffy, Milos Vukadinovic, David Liang, Susan Cheng, David Ouyang
Background: Diagnosis of mitral regurgitation (MR) requires careful evaluation by echocardiography with Doppler imaging. This study presents the development and validation of a fully automated deep learning pipeline for identifying apical 4-chamber view videos with color Doppler echocardiography and detecting clinically significant (moderate or severe) MR from transthoracic echocardiograms.
Methods: A total of 58 614 transthoracic echocardiograms (2 587 538 videos) from Cedars-Sinai Medical Center were used to develop and test an automated pipeline to identify apical 4-chamber view videos with color Doppler across the mitral valve and then assess MR severity. The model was tested internally on a test set of 1800 studies (80 833 videos) from Cedars-Sinai Medical Center and externally evaluated in a geographically distinct cohort of 915 studies (46 890 videos) from Stanford Healthcare.
Results: In the held-out Cedars-Sinai Medical Center test set, the view classifier demonstrated an area under the curve (AUC) of 0.998 (0.998-0.999) and correctly identified 3452 of 3539 echocardiography videos as having color Doppler information across the mitral valve (sensitivity of 0.975 [0.968-0.982] and specificity of 0.999 [0.999-0.999] compared with manually curated videos). In the external test cohort from Stanford Healthcare, the view classifier correctly identified 1051 of 1055 manually curated videos with color Doppler information across the mitral valve (sensitivity of 0.996 [0.990-1.000] and specificity of 0.999 [0.999-0.999]). In the Cedars-Sinai Medical Center test cohort, MR moderate or greater in severity was detected with an AUC of 0.916 (0.899-0.932) and severe MR was detected with an AUC of 0.934 (0.913-0.953). In the Stanford Healthcare test cohort, the model detected MR moderate or greater in severity with an AUC of 0.951 (0.924-0.973) and severe MR with an AUC of 0.969 (0.946-0.987).
Conclusions: In this study, a novel automated pipeline for identifying clinically significant MR from full transthoracic echocardiography studies demonstrated excellent performance across large numbers of studies and across multiple institutions. Such an approach has the potential for automated screening and surveillance of MR.
{"title":"High-Throughput Deep Learning Detection of Mitral Regurgitation.","authors":"Amey Vrudhula, Grant Duffy, Milos Vukadinovic, David Liang, Susan Cheng, David Ouyang","doi":"10.1161/CIRCULATIONAHA.124.069047","DOIUrl":"10.1161/CIRCULATIONAHA.124.069047","url":null,"abstract":"<p><strong>Background: </strong>Diagnosis of mitral regurgitation (MR) requires careful evaluation by echocardiography with Doppler imaging. This study presents the development and validation of a fully automated deep learning pipeline for identifying apical 4-chamber view videos with color Doppler echocardiography and detecting clinically significant (moderate or severe) MR from transthoracic echocardiograms.</p><p><strong>Methods: </strong>A total of 58 614 transthoracic echocardiograms (2 587 538 videos) from Cedars-Sinai Medical Center were used to develop and test an automated pipeline to identify apical 4-chamber view videos with color Doppler across the mitral valve and then assess MR severity. The model was tested internally on a test set of 1800 studies (80 833 videos) from Cedars-Sinai Medical Center and externally evaluated in a geographically distinct cohort of 915 studies (46 890 videos) from Stanford Healthcare.</p><p><strong>Results: </strong>In the held-out Cedars-Sinai Medical Center test set, the view classifier demonstrated an area under the curve (AUC) of 0.998 (0.998-0.999) and correctly identified 3452 of 3539 echocardiography videos as having color Doppler information across the mitral valve (sensitivity of 0.975 [0.968-0.982] and specificity of 0.999 [0.999-0.999] compared with manually curated videos). In the external test cohort from Stanford Healthcare, the view classifier correctly identified 1051 of 1055 manually curated videos with color Doppler information across the mitral valve (sensitivity of 0.996 [0.990-1.000] and specificity of 0.999 [0.999-0.999]). In the Cedars-Sinai Medical Center test cohort, MR moderate or greater in severity was detected with an AUC of 0.916 (0.899-0.932) and severe MR was detected with an AUC of 0.934 (0.913-0.953). In the Stanford Healthcare test cohort, the model detected MR moderate or greater in severity with an AUC of 0.951 (0.924-0.973) and severe MR with an AUC of 0.969 (0.946-0.987).</p><p><strong>Conclusions: </strong>In this study, a novel automated pipeline for identifying clinically significant MR from full transthoracic echocardiography studies demonstrated excellent performance across large numbers of studies and across multiple institutions. Such an approach has the potential for automated screening and surveillance of MR.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-02-08DOI: 10.1161/CIRCULATIONAHA.123.067519
Yunqi Jiang, Jinge Gu, Xiaodou Niu, Jiaojiao Hu, Yongzhen Zhang, Dan Li, Yida Tang, Cong Liu, Zijian Li
Background: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF.
Methods: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on β-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF.
Results: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the β-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF.
Conclusions: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.
{"title":"Phosphorylation-Regulated Dynamic Phase Separation of HIP-55 Protects Against Heart Failure.","authors":"Yunqi Jiang, Jinge Gu, Xiaodou Niu, Jiaojiao Hu, Yongzhen Zhang, Dan Li, Yida Tang, Cong Liu, Zijian Li","doi":"10.1161/CIRCULATIONAHA.123.067519","DOIUrl":"10.1161/CIRCULATIONAHA.123.067519","url":null,"abstract":"<p><strong>Background: </strong>Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF.</p><p><strong>Methods: </strong>Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac-specific overexpression of HIP-55 were used to examine the role of HIP-55 on β-adrenergic receptor hyperactivation-induced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF.</p><p><strong>Results: </strong>Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the β-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF.</p><p><strong>Conclusions: </strong>Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11404759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-08-15DOI: 10.1161/CIR.0000000000001266
Sidney C Smith, Dhruv S Kazi, Cheryl A M Anderson, Craig Beam, Douglas S Boyle, Kelly Griesenbeck Carter, Mitchell S V Elkind, Pooja Khatri, John Meiners, Louise Morgan, Puja Patel, Melanie B Turner, Nanette K Wenger
The American Heart Association (AHA), founded in 1924, is anchored in the core belief that scientific research can lead the way to better prevention, treatment, recovery, and ultimately a cure for cardiovascular disease. Historically, the association's involvement in international efforts centered on scientific cooperation. Activities mostly involved AHA leadership presenting at international scientific meetings and leaders from other countries sharing scientific and medical information at AHA meetings. Although the AHA's and American Stroke Association's international efforts have expanded substantially since those early days, global knowledge exchange remains the bedrock of its international endeavors. As the AHA turns 100, we reflect on the successful global efforts in prevention, resuscitation, global advocacy, quality improvement, and health equity that have guided the organization to a place of readiness for "advancing health and hope, for everyone, everywhere." Motivated by the enormous potential for population health gains in an aging world, the AHA is entering its second century with redoubled commitment to improving global cardiovascular and cerebrovascular health for all.
美国心脏协会(AHA)成立于 1924 年,其核心理念是科学研究能够引领人们更好地预防、治疗和康复心血管疾病,并最终治愈疾病。从历史上看,协会参与的国际活动主要集中在科学合作方面。活动主要包括 AHA 领导在国际科学会议上发表演讲,以及其他国家的领导人在 AHA 会议上分享科学和医学信息。尽管美国心脏病学会和美国卒中协会的国际工作自早期以来已大幅扩展,但全球知识交流仍是其国际工作的基石。在 AHA 成立 100 周年之际,我们回顾了在预防、复苏、全球宣传、质量改进和健康公平方面所做的成功的全球努力,这些努力引导该组织为 "促进健康和希望,造福世界各地的每一个人 "做好了准备。在老龄化世界人口健康收益的巨大潜力的推动下,美国心脏协会正以加倍的承诺进入第二个世纪,致力于改善全球所有人的心脑血管健康。
{"title":"International Initiatives of the American Heart Association: Original Concepts, Present Programs, and Future Focus: A Science Advisory From the American Heart Association.","authors":"Sidney C Smith, Dhruv S Kazi, Cheryl A M Anderson, Craig Beam, Douglas S Boyle, Kelly Griesenbeck Carter, Mitchell S V Elkind, Pooja Khatri, John Meiners, Louise Morgan, Puja Patel, Melanie B Turner, Nanette K Wenger","doi":"10.1161/CIR.0000000000001266","DOIUrl":"10.1161/CIR.0000000000001266","url":null,"abstract":"<p><p>The American Heart Association (AHA), founded in 1924, is anchored in the core belief that scientific research can lead the way to better prevention, treatment, recovery, and ultimately a cure for cardiovascular disease. Historically, the association's involvement in international efforts centered on scientific cooperation. Activities mostly involved AHA leadership presenting at international scientific meetings and leaders from other countries sharing scientific and medical information at AHA meetings. Although the AHA's and American Stroke Association's international efforts have expanded substantially since those early days, global knowledge exchange remains the bedrock of its international endeavors. As the AHA turns 100, we reflect on the successful global efforts in prevention, resuscitation, global advocacy, quality improvement, and health equity that have guided the organization to a place of readiness for \"advancing health and hope, for everyone, everywhere.\" Motivated by the enormous potential for population health gains in an aging world, the AHA is entering its second century with redoubled commitment to improving global cardiovascular and cerebrovascular health for all.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-09-16DOI: 10.1161/CIRCULATIONAHA.123.068415
Martin S Maron, Ethan J Rowin, Barry J Maron
{"title":"Letter by Maron et al Regarding Article, \"Sudden Cardiac Death in National Collegiate Athletic Association Athletes\".","authors":"Martin S Maron, Ethan J Rowin, Barry J Maron","doi":"10.1161/CIRCULATIONAHA.123.068415","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.123.068415","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-06-05DOI: 10.1161/CIRCULATIONAHA.123.064747
Christine Quast, Florian Bönner, Amin Polzin, Verena Veulemans, Ramesh Chennupati, Isabella Gyamfi Poku, Susanne Pfeiler, Nicolas Kramser, Magdalena Nankinova, Nicole Staub, Elric Zweck, Juliane Jokiel, Fabian Keyser, Jasmina Hoffe, Sven Witkowski, Katrin Becker, Pia Leuders, Saif Zako, Ralf Erkens, Christian Jung, Ulrich Flögel, Tianai Wang, Michael Neidlin, Ulrich Steinseifer, Sven Thomas Niepmann, Sebastian Zimmer, Norbert Gerdes, Miriam M Cortese-Krott, Martin Feelisch, Tobias Zeus, Malte Kelm
Background: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown.
Methods: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system.
Results: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress.
Conclusions: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns.
Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739.
背景:主动脉瓣狭窄(AS)是否会对全身内皮功能产生不利影响?主动脉瓣狭窄(AS)是否会独立于标准的可改变的心血管风险因素而对全身内皮功能产生不利影响尚不清楚:因此,我们研究了无标准可改变心血管风险因素的主动脉瓣狭窄小鼠实验模型和计划进行经导管主动脉瓣置换术的主动脉瓣狭窄患者队列中的内皮和心脏功能。内皮功能通过使用超声波进行血流介导的扩张来测定。通过酶联免疫吸附法和化学发光法测定了小鼠和人类血浆中的细胞外血红蛋白(eHb)浓度和 NO 消耗量。此外,还利用磁共振成像和计算流体动力学模拟对主动脉血流进行了四维流动采集测量。在小鼠血管舒张生物测定系统的转移实验中,确定了血浆和红细胞悬浮液对血管功能的影响:结果:在小鼠体内,诱导强直性脊柱炎会导致全身内皮功能障碍。在左心室收缩功能正常和轻度肥厚的情况下,跨瓣梯度的增加与红细胞增多症、eHb 增加和血浆 NO 消耗有关;血红蛋白螯合 eHb 可恢复内皮功能。由于强直性脊柱炎患者的主动脉瓣口面积减小,瓣后中央升主动脉的机械应力增加。这与 eHb 升高、循环 RBC 衍生的微囊泡、红细胞、无临床相关贫血的血红蛋白水平降低以及连续的内皮功能障碍有关。转移实验表明,通过使用血红蛋白治疗降低 eHb,或通过经导管主动脉瓣置换术消除流体动力应力,可恢复内皮功能。在患有强直性脊柱炎和亚临床红细胞破碎的患者中,经导管主动脉瓣置换术前后剩余的循环红细胞表现出完整的膜功能、变形能力以及对渗透和缺氧应力的抵抗力:强直性脊柱炎增加了升主动脉中央瓣膜后的漩涡血流,引发红细胞破碎,血浆中的血红蛋白积聚。这增加了血液中 NO 的消耗,从而限制了血管 NO 的生物利用率。因此,强直性脊柱炎本身会促进系统性内皮功能障碍,而不受其他既定风险因素的影响。经导管主动脉瓣置换术能够限制NO清除,并通过将瓣膜后血流重新调整到接近生理模式来挽救内皮功能:URL: https://www.clinicaltrials.gov; 唯一标识符:NCT05603520。URL: https://www.clinicaltrials.gov; Unique identifier:NCT01805739。
{"title":"Aortic Valve Stenosis Causes Accumulation of Extracellular Hemoglobin and Systemic Endothelial Dysfunction.","authors":"Christine Quast, Florian Bönner, Amin Polzin, Verena Veulemans, Ramesh Chennupati, Isabella Gyamfi Poku, Susanne Pfeiler, Nicolas Kramser, Magdalena Nankinova, Nicole Staub, Elric Zweck, Juliane Jokiel, Fabian Keyser, Jasmina Hoffe, Sven Witkowski, Katrin Becker, Pia Leuders, Saif Zako, Ralf Erkens, Christian Jung, Ulrich Flögel, Tianai Wang, Michael Neidlin, Ulrich Steinseifer, Sven Thomas Niepmann, Sebastian Zimmer, Norbert Gerdes, Miriam M Cortese-Krott, Martin Feelisch, Tobias Zeus, Malte Kelm","doi":"10.1161/CIRCULATIONAHA.123.064747","DOIUrl":"10.1161/CIRCULATIONAHA.123.064747","url":null,"abstract":"<p><strong>Background: </strong>Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown.</p><p><strong>Methods: </strong>We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system.</p><p><strong>Results: </strong>In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress.</p><p><strong>Conclusions: </strong>AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-09-16DOI: 10.1161/CIRCULATIONAHA.124.071728
Walter K Clair, Anne E Sumner, Eldrin F Lewis
{"title":"Expanding Opportunities by Adding Accessibility to Diversity, Equity, and Inclusion.","authors":"Walter K Clair, Anne E Sumner, Eldrin F Lewis","doi":"10.1161/CIRCULATIONAHA.124.071728","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071728","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-09-16DOI: 10.1161/CIRCULATIONAHA.124.070246
Kimberly G Harmon, Timothy W Churchhill, Nathaniel Moulsen, Stephanie A Kliethermes, Aaron L Baggish, Jonathan A Drezner, Manesh R Patel, Michael J Ackerman, David M Siebert, Lauren Salerno, Monica Zigman Suchsland, Irfan M Asif, Joseph J Maleszewski, Bradley J Petek
{"title":"Response from Harmon et al to Letter Regarding Article, \"Sudden Cardiac Death in National Collegiate Athletic Association Athletes\".","authors":"Kimberly G Harmon, Timothy W Churchhill, Nathaniel Moulsen, Stephanie A Kliethermes, Aaron L Baggish, Jonathan A Drezner, Manesh R Patel, Michael J Ackerman, David M Siebert, Lauren Salerno, Monica Zigman Suchsland, Irfan M Asif, Joseph J Maleszewski, Bradley J Petek","doi":"10.1161/CIRCULATIONAHA.124.070246","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070246","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17Epub Date: 2024-09-16DOI: 10.1161/CIRCULATIONAHA.124.070541
Jeffrey I Weitz
{"title":"Arterial Thrombosis: Present and Future.","authors":"Jeffrey I Weitz","doi":"10.1161/CIRCULATIONAHA.124.070541","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070541","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":null,"pages":null},"PeriodicalIF":35.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}