Pub Date : 2024-08-28DOI: 10.1038/s41569-024-01067-1
Ahmed U. Fayyaz, Muhammad Eltony, Larry J. Prokop, Katlyn E. Koepp, Barry A. Borlaug, Surendra Dasari, Melanie C. Bois, Kenneth B. Margulies, Joesph J. Maleszewski, Ying Wang, Margaret M. Redfield
Heart failure with preserved ejection fraction (HFpEF) is a major, worldwide health-care problem. Few therapies for HFpEF exist because the pathophysiology of this condition is poorly defined and, increasingly, postulated to be diverse. Although perturbations in other organs contribute to the clinical profile in HFpEF, altered cardiac structure, function or both are the primary causes of this heart failure syndrome. Therefore, studying myocardial tissue is fundamental to improve pathophysiological insights and therapeutic discovery in HFpEF. Most studies of myocardial changes in HFpEF have relied on cardiac tissue from animal models without (or with limited) confirmatory studies in human cardiac tissue. Animal models of HFpEF have evolved based on theoretical HFpEF aetiologies, but these models might not reflect the complex pathophysiology of human HFpEF. The focus of this Review is the pathophysiological insights gained from studies of human HFpEF myocardium. We outline the rationale for these studies, the challenges and opportunities in obtaining myocardial tissue from patients with HFpEF and relevant comparator groups, the analytical approaches, the pathophysiological insights gained to date and the remaining knowledge gaps. Our objective is to provide a roadmap for future studies of cardiac tissue from diverse cohorts of patients with HFpEF, coupling discovery biology with measures to account for pathophysiological diversity. The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains poorly understood. In this Review, Redfield and colleagues highlight the importance of studying human cardiac tissue in HFpEF, discuss sources, challenges and methods for studying human myocardial samples, summarize pathophysiological insights derived from studies of human myocardium in HFpEF and outline knowledge gaps to guide future research.
{"title":"Pathophysiological insights into HFpEF from studies of human cardiac tissue","authors":"Ahmed U. Fayyaz, Muhammad Eltony, Larry J. Prokop, Katlyn E. Koepp, Barry A. Borlaug, Surendra Dasari, Melanie C. Bois, Kenneth B. Margulies, Joesph J. Maleszewski, Ying Wang, Margaret M. Redfield","doi":"10.1038/s41569-024-01067-1","DOIUrl":"10.1038/s41569-024-01067-1","url":null,"abstract":"Heart failure with preserved ejection fraction (HFpEF) is a major, worldwide health-care problem. Few therapies for HFpEF exist because the pathophysiology of this condition is poorly defined and, increasingly, postulated to be diverse. Although perturbations in other organs contribute to the clinical profile in HFpEF, altered cardiac structure, function or both are the primary causes of this heart failure syndrome. Therefore, studying myocardial tissue is fundamental to improve pathophysiological insights and therapeutic discovery in HFpEF. Most studies of myocardial changes in HFpEF have relied on cardiac tissue from animal models without (or with limited) confirmatory studies in human cardiac tissue. Animal models of HFpEF have evolved based on theoretical HFpEF aetiologies, but these models might not reflect the complex pathophysiology of human HFpEF. The focus of this Review is the pathophysiological insights gained from studies of human HFpEF myocardium. We outline the rationale for these studies, the challenges and opportunities in obtaining myocardial tissue from patients with HFpEF and relevant comparator groups, the analytical approaches, the pathophysiological insights gained to date and the remaining knowledge gaps. Our objective is to provide a roadmap for future studies of cardiac tissue from diverse cohorts of patients with HFpEF, coupling discovery biology with measures to account for pathophysiological diversity. The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains poorly understood. In this Review, Redfield and colleagues highlight the importance of studying human cardiac tissue in HFpEF, discuss sources, challenges and methods for studying human myocardial samples, summarize pathophysiological insights derived from studies of human myocardium in HFpEF and outline knowledge gaps to guide future research.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 2","pages":"90-104"},"PeriodicalIF":41.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085620","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 : 2024-08-07DOI: 10.1038/s41569-024-01064-4
Hossein-Ardeschir Ghofrani, Mardi Gomberg-Maitland, Lan Zhao, Friedrich Grimminger
Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research. In this Review, Ghofrani and colleagues discuss the mechanisms underlying the development of pulmonary arterial hypertension, provide an overview of approved therapies and describe the predominantly non-vasodilatory drugs that are currently being tested in clinical trials.
{"title":"Mechanisms and treatment of pulmonary arterial hypertension","authors":"Hossein-Ardeschir Ghofrani, Mardi Gomberg-Maitland, Lan Zhao, Friedrich Grimminger","doi":"10.1038/s41569-024-01064-4","DOIUrl":"10.1038/s41569-024-01064-4","url":null,"abstract":"Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research. In this Review, Ghofrani and colleagues discuss the mechanisms underlying the development of pulmonary arterial hypertension, provide an overview of approved therapies and describe the predominantly non-vasodilatory drugs that are currently being tested in clinical trials.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 2","pages":"105-120"},"PeriodicalIF":41.7,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899446","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 : 2024-08-07DOI: 10.1038/s41569-024-01069-z
Irene Fernández-Ruiz
Acute ischaemic stroke induces persistent innate immune memory through epigenetic changes in myeloid progenitors in the bone marrow, and this innate immune training contributes to cardiac remodelling and dysfunction in the long term, according to a new study.
{"title":"Stroke triggers an innate immune memory that drives cardiac dysfunction","authors":"Irene Fernández-Ruiz","doi":"10.1038/s41569-024-01069-z","DOIUrl":"10.1038/s41569-024-01069-z","url":null,"abstract":"Acute ischaemic stroke induces persistent innate immune memory through epigenetic changes in myeloid progenitors in the bone marrow, and this innate immune training contributes to cardiac remodelling and dysfunction in the long term, according to a new study.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"21 10","pages":"663-663"},"PeriodicalIF":41.7,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899445","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 : 2024-07-29DOI: 10.1038/s41569-024-01066-2
Irene Fernández-Ruiz
A new small-molecule inhibitor of vasohibins reduces myocardial stiffness and improves diastolic relaxation in a rat model of HFpEF.
一种新的血管抑制素小分子抑制剂可降低心肌僵硬度并改善高频心衰大鼠模型的舒张松弛。
{"title":"Potential new therapeutic target for HFpEF","authors":"Irene Fernández-Ruiz","doi":"10.1038/s41569-024-01066-2","DOIUrl":"10.1038/s41569-024-01066-2","url":null,"abstract":"A new small-molecule inhibitor of vasohibins reduces myocardial stiffness and improves diastolic relaxation in a rat model of HFpEF.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"21 10","pages":"664-664"},"PeriodicalIF":41.7,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792887","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 : 2024-07-25DOI: 10.1038/s41569-024-01058-2
Luisa C. C. Brant, J. Jaime Miranda, Rodrigo M. Carrillo-Larco, David Flood, Vilma Irazola, Antonio Luiz P. Ribeiro
In Latin America and the Caribbean (LAC), sociodemographic context, socioeconomic disparities and the high level of urbanization provide a unique entry point to reflect on the burden of cardiometabolic disease in the region. Cardiovascular diseases are the main cause of death in LAC, precipitated by population growth and ageing together with a rapid increase in the prevalence of cardiometabolic risk factors, predominantly obesity and diabetes mellitus, over the past four decades. Strategies to address this growing cardiometabolic burden include both population-wide and individual-based initiatives tailored to the specific challenges faced by different LAC countries, which are heterogeneous. The implementation of public policies to reduce smoking and health system approaches to control hypertension are examples of scalable strategies. The challenges faced by LAC are also opportunities to foster innovative approaches to combat the high burden of cardiometabolic diseases such as implementing digital health interventions and team-based initiatives. This Review provides a summary of trends in the epidemiology of cardiometabolic diseases and their risk factors in LAC as well as context-specific disease determinants and potential solutions to improve cardiometabolic health in the region. Cardiovascular diseases are the leading cause of death in Latin America and the Caribbean (LAC), precipitated by the unique milieu of population growth, rapid urbanization, socioeconomic disparities and prevalent cardiometabolic risk factors. Brant and colleagues summarize trends in cardiometabolic health in LAC and discuss tailored, innovative solutions to address the growing burden of disease in the region.
{"title":"Epidemiology of cardiometabolic health in Latin America and strategies to address disparities","authors":"Luisa C. C. Brant, J. Jaime Miranda, Rodrigo M. Carrillo-Larco, David Flood, Vilma Irazola, Antonio Luiz P. Ribeiro","doi":"10.1038/s41569-024-01058-2","DOIUrl":"10.1038/s41569-024-01058-2","url":null,"abstract":"In Latin America and the Caribbean (LAC), sociodemographic context, socioeconomic disparities and the high level of urbanization provide a unique entry point to reflect on the burden of cardiometabolic disease in the region. Cardiovascular diseases are the main cause of death in LAC, precipitated by population growth and ageing together with a rapid increase in the prevalence of cardiometabolic risk factors, predominantly obesity and diabetes mellitus, over the past four decades. Strategies to address this growing cardiometabolic burden include both population-wide and individual-based initiatives tailored to the specific challenges faced by different LAC countries, which are heterogeneous. The implementation of public policies to reduce smoking and health system approaches to control hypertension are examples of scalable strategies. The challenges faced by LAC are also opportunities to foster innovative approaches to combat the high burden of cardiometabolic diseases such as implementing digital health interventions and team-based initiatives. This Review provides a summary of trends in the epidemiology of cardiometabolic diseases and their risk factors in LAC as well as context-specific disease determinants and potential solutions to improve cardiometabolic health in the region. Cardiovascular diseases are the leading cause of death in Latin America and the Caribbean (LAC), precipitated by the unique milieu of population growth, rapid urbanization, socioeconomic disparities and prevalent cardiometabolic risk factors. Brant and colleagues summarize trends in cardiometabolic health in LAC and discuss tailored, innovative solutions to address the growing burden of disease in the region.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"21 12","pages":"849-864"},"PeriodicalIF":41.7,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759956","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 : 2024-07-24DOI: 10.1038/s41569-024-01062-6
Livia L. Camargo, Francisco J. Rios, Augusto C. Montezano, Rhian M. Touyz
Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin–angiotensin–aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension. In this Review, Touyz and colleagues discuss the role of reactive oxygen species in the pathophysiology of hypertension, focusing on the mechanisms of reactive oxygen species generation and oxidative stress in hypertension, as well as the alterations in redox signalling. They also discuss potential therapeutic strategies for targeting oxidative stress in hypertension.
{"title":"Reactive oxygen species in hypertension","authors":"Livia L. Camargo, Francisco J. Rios, Augusto C. Montezano, Rhian M. Touyz","doi":"10.1038/s41569-024-01062-6","DOIUrl":"10.1038/s41569-024-01062-6","url":null,"abstract":"Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin–angiotensin–aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension. In this Review, Touyz and colleagues discuss the role of reactive oxygen species in the pathophysiology of hypertension, focusing on the mechanisms of reactive oxygen species generation and oxidative stress in hypertension, as well as the alterations in redox signalling. They also discuss potential therapeutic strategies for targeting oxidative stress in hypertension.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 1","pages":"20-37"},"PeriodicalIF":41.7,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754745","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 : 2024-07-22DOI: 10.1038/s41569-024-01060-8
Emily Y. Chew, Stephen A. Burns, Alison G. Abraham, Mathieu F. Bakhoum, Joshua A. Beckman, Toco Y. P. Chui, Robert P. Finger, Alejandro F. Frangi, Rebecca F. Gottesman, Maria B. Grant, Henner Hanssen, Cecilia S. Lee, Michelle L. Meyer, Damiano Rizzoni, Alicja R. Rudnicka, Joel S. Schuman, Sara B. Seidelmann, W. H. Wilson Tang, Bishow B. Adhikari, Narasimhan Danthi, Yuling Hong, Diane Reid, Grace L. Shen, Young S. Oh
The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging ‘pipelines’, and integrating advanced imaging with ‘omics’, lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds. In this Roadmap arising from an NHLBI workshop, Chew and colleagues explore the use of retinal imaging biomarkers for the prediction, diagnosis and monitoring of systemic cardiovascular diseases. The authors identify knowledge gaps and research opportunities to translate retinal imaging biomarkers into clinical practice.
{"title":"Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop","authors":"Emily Y. Chew, Stephen A. Burns, Alison G. Abraham, Mathieu F. Bakhoum, Joshua A. Beckman, Toco Y. P. Chui, Robert P. Finger, Alejandro F. Frangi, Rebecca F. Gottesman, Maria B. Grant, Henner Hanssen, Cecilia S. Lee, Michelle L. Meyer, Damiano Rizzoni, Alicja R. Rudnicka, Joel S. Schuman, Sara B. Seidelmann, W. H. Wilson Tang, Bishow B. Adhikari, Narasimhan Danthi, Yuling Hong, Diane Reid, Grace L. Shen, Young S. Oh","doi":"10.1038/s41569-024-01060-8","DOIUrl":"10.1038/s41569-024-01060-8","url":null,"abstract":"The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging ‘pipelines’, and integrating advanced imaging with ‘omics’, lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds. In this Roadmap arising from an NHLBI workshop, Chew and colleagues explore the use of retinal imaging biomarkers for the prediction, diagnosis and monitoring of systemic cardiovascular diseases. The authors identify knowledge gaps and research opportunities to translate retinal imaging biomarkers into clinical practice.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 1","pages":"47-63"},"PeriodicalIF":41.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736901","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 : 2024-07-22DOI: 10.1038/s41569-024-01065-3
Gregory B. Lim
A new study indicates that proteins in the sarcomere complex are stochastically removed and degraded and are replaced by newly translated proteins. Sarcomere turnover occurs at a similar rate within cardiomyocytes and across the heart and slows with ageing.
{"title":"Cardiac sarcomere turnover by unidirectional replacement of proteins","authors":"Gregory B. Lim","doi":"10.1038/s41569-024-01065-3","DOIUrl":"10.1038/s41569-024-01065-3","url":null,"abstract":"A new study indicates that proteins in the sarcomere complex are stochastically removed and degraded and are replaced by newly translated proteins. Sarcomere turnover occurs at a similar rate within cardiomyocytes and across the heart and slows with ageing.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"21 9","pages":"600-600"},"PeriodicalIF":41.7,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748616","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 : 2024-07-19DOI: 10.1038/s41569-024-01047-5
Paul D. Morris, Ryan A. Anderton, Karina Marshall-Goebel, Joseph K. Britton, Stuart M. C. Lee, Nicolas P. Smith, Frans N. van de Vosse, Karen M. Ong, Tom A. Newman, Daniel J. Taylor, Tim Chico, Julian P. Gunn, Andrew J. Narracott, D. Rod Hose, Ian Halliday
For more than 60 years, humans have travelled into space. Until now, the majority of astronauts have been professional, government agency astronauts selected, in part, for their superlative physical fitness and the absence of disease. Commercial spaceflight is now becoming accessible to members of the public, many of whom would previously have been excluded owing to unsatisfactory fitness or the presence of cardiorespiratory diseases. While data exist on the effects of gravitational and acceleration (G) forces on human physiology, data on the effects of the aerospace environment in unselected members of the public, and particularly in those with clinically significant pathology, are limited. Although short in duration, these high acceleration forces can potentially either impair the experience or, more seriously, pose a risk to health in some individuals. Rather than expose individuals with existing pathology to G forces to collect data, computational modelling might be useful to predict the nature and severity of cardiovascular diseases that are of sufficient risk to restrict access, require modification, or suggest further investigation or training before flight. In this Review, we explore state-of-the-art, zero-dimensional, compartmentalized models of human cardiovascular pathophysiology that can be used to simulate the effects of acceleration forces, homeostatic regulation and ventilation–perfusion matching, using data generated by long-arm centrifuge facilities of the US National Aeronautics and Space Administration and the European Space Agency to risk stratify individuals and help to improve safety in commercial suborbital spaceflight. During commercial spaceflight, individuals who might have underlying cardiovascular disease will be exposed to increased gravitational and acceleration (G) forces. In this Review, Morris and colleagues explore the use of computational models to simulate the effects of G forces on human cardiovascular pathophysiology to risk-stratify individuals and help to improve safety in commercial suborbital spaceflight.
60 多年来，人类一直在太空中旅行。迄今为止，大多数宇航员都是政府机构的专业宇航员，他们之所以被选中，部分原因是他们具有超强的身体素质和没有疾病。现在，公众也可以参加商业航天飞行，其中许多人以前由于体能不佳或患有心肺疾病而被排除在外。虽然已有关于重力和加速度（G）对人体生理影响的数据，但关于航空航天环境对未经选择的公众，特别是对那些患有临床重大疾病的人的影响的数据却很有限。虽然持续时间很短，但这些高加速度力可能会损害某些人的体验，更严重的是会对其健康构成威胁。与其让已有病变的人暴露在 G 力下以收集数据，不如通过计算建模来预测心血管疾病的性质和严重程度，因为这些疾病的风险足以限制飞行、要求改装或建议在飞行前进行进一步的调查或培训。在这篇综述中，我们利用美国国家航空航天局和欧洲空间局的长臂离心机设施生成的数据，探讨了最先进的零维、分区人体心血管病理生理学模型，这些模型可用于模拟加速度力、稳态调节和通气-灌注匹配的影响，从而对个人进行风险分层，帮助提高商业亚轨道航天飞行的安全性。
{"title":"Computational modelling of cardiovascular pathophysiology to risk stratify commercial spaceflight","authors":"Paul D. Morris, Ryan A. Anderton, Karina Marshall-Goebel, Joseph K. Britton, Stuart M. C. Lee, Nicolas P. Smith, Frans N. van de Vosse, Karen M. Ong, Tom A. Newman, Daniel J. Taylor, Tim Chico, Julian P. Gunn, Andrew J. Narracott, D. Rod Hose, Ian Halliday","doi":"10.1038/s41569-024-01047-5","DOIUrl":"10.1038/s41569-024-01047-5","url":null,"abstract":"For more than 60 years, humans have travelled into space. Until now, the majority of astronauts have been professional, government agency astronauts selected, in part, for their superlative physical fitness and the absence of disease. Commercial spaceflight is now becoming accessible to members of the public, many of whom would previously have been excluded owing to unsatisfactory fitness or the presence of cardiorespiratory diseases. While data exist on the effects of gravitational and acceleration (G) forces on human physiology, data on the effects of the aerospace environment in unselected members of the public, and particularly in those with clinically significant pathology, are limited. Although short in duration, these high acceleration forces can potentially either impair the experience or, more seriously, pose a risk to health in some individuals. Rather than expose individuals with existing pathology to G forces to collect data, computational modelling might be useful to predict the nature and severity of cardiovascular diseases that are of sufficient risk to restrict access, require modification, or suggest further investigation or training before flight. In this Review, we explore state-of-the-art, zero-dimensional, compartmentalized models of human cardiovascular pathophysiology that can be used to simulate the effects of acceleration forces, homeostatic regulation and ventilation–perfusion matching, using data generated by long-arm centrifuge facilities of the US National Aeronautics and Space Administration and the European Space Agency to risk stratify individuals and help to improve safety in commercial suborbital spaceflight. During commercial spaceflight, individuals who might have underlying cardiovascular disease will be exposed to increased gravitational and acceleration (G) forces. In this Review, Morris and colleagues explore the use of computational models to simulate the effects of G forces on human cardiovascular pathophysiology to risk-stratify individuals and help to improve safety in commercial suborbital spaceflight.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"21 10","pages":"667-681"},"PeriodicalIF":41.7,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727539","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 : 2024-07-19DOI: 10.1038/s41569-024-01063-5
Malcolm Irving
Contraction of the heart is driven by cyclical interactions between myosin and actin filaments powered by ATP hydrolysis. The modular structure of heart muscle and the organ-level synchrony of the heartbeat ensure tight reciprocal coupling between this myosin ATPase cycle and the macroscopic cardiac cycle. The myosin motors respond to the cyclical activation of the actin and myosin filaments to drive the pressure changes that control the inflow and outflow valves of the heart chambers. Opening and closing of the valves in turn switches the myosin motors between roughly isometric and roughly isotonic contraction modes. Peak filament stress in the heart is much smaller than in fully activated skeletal muscle, although the myosin filaments in the two muscle types have the same number of myosin motors. Calculations indicate that only ~5% of the myosin motors in the heart are needed to generate peak systolic pressure, although many more motors are needed to drive ejection. Tight regulation of the number of active motors is essential for the efficient functioning of the healthy heart — this control is commonly disrupted by gene variants associated with inherited heart disease, and its restoration might be a useful end point in the development of novel therapies. Contraction of the heart is driven by cyclical interactions between myosin and actin filaments driven by ATP hydrolysis. In this Review, Irving summarizes the basal cardiac cycle of the healthy human heart at the ventricular, cellular, sarcomeric, and molecular levels and the implications for the development of novel therapies for heart disease.
心脏的收缩是由肌球蛋白和肌动蛋白丝在 ATP 水解作用下的周期性相互作用驱动的。心肌的模块化结构和心脏搏动的器官级同步性确保了肌球蛋白 ATP 酶周期与宏观心脏周期之间紧密的相互耦合。肌球蛋白马达响应肌动蛋白丝和肌球蛋白丝的周期性激活，驱动压力变化，从而控制心腔的流入和流出瓣膜。瓣膜的打开和关闭反过来在大致等长和大致等张收缩模式之间切换肌球蛋白马达。尽管两种肌肉中的肌球蛋白丝具有相同数量的肌球蛋白马达，但心脏中肌球蛋白丝的峰值应力远小于完全激活的骨骼肌。计算表明，产生收缩压峰值只需要心脏中约 5% 的肌球蛋白马达，而驱动射血则需要更多的肌球蛋白马达。对活跃肌球蛋白马达数量的严格调控对健康心脏的高效运作至关重要--这种调控通常会被与遗传性心脏病相关的基因变异所破坏，恢复这种调控可能是开发新型疗法的一个有用终点。
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