Pub Date : 2025-09-05DOI: 10.1038/s41569-025-01205-3
Enzo R. Porrello, Chang Jie Mick Lee, Roger S. Y. Foo, David A. Elliott
A central paradigm in cardiac biology is the reactivation of the fetal gene programme in the adult heart in response to stress. This so-called ‘fetal gene hypothesis’ was first proposed almost 40 years ago following the observation that certain fetal contractile protein isoforms were re-expressed in hypertrophied ventricles in the rodent heart in response to haemodynamic overload. Consequently, this concept was broadly adopted, and activation of the fetal gene programme became synonymous in the literature with the cardiac stress response. Transcriptomic and epigenomic profiling studies from the past 20 years have revealed the extent to which the diseased heart redeploys fetal gene programmes in response to stress. In this Review, we describe the historical origins of the fetal gene hypothesis and re-evaluate the general principles of fetal gene regulation in heart development, disease and regeneration. In this Review, Porrello and colleagues describe the origins of the fetal gene hypothesis and discuss the evolution of this hypothesis by considering more recent evidence from genome-wide sequencing studies.
{"title":"Transcriptional regulation in heart development, disease and regeneration: reassessing the fetal gene hypothesis","authors":"Enzo R. Porrello, Chang Jie Mick Lee, Roger S. Y. Foo, David A. Elliott","doi":"10.1038/s41569-025-01205-3","DOIUrl":"10.1038/s41569-025-01205-3","url":null,"abstract":"A central paradigm in cardiac biology is the reactivation of the fetal gene programme in the adult heart in response to stress. This so-called ‘fetal gene hypothesis’ was first proposed almost 40 years ago following the observation that certain fetal contractile protein isoforms were re-expressed in hypertrophied ventricles in the rodent heart in response to haemodynamic overload. Consequently, this concept was broadly adopted, and activation of the fetal gene programme became synonymous in the literature with the cardiac stress response. Transcriptomic and epigenomic profiling studies from the past 20 years have revealed the extent to which the diseased heart redeploys fetal gene programmes in response to stress. In this Review, we describe the historical origins of the fetal gene hypothesis and re-evaluate the general principles of fetal gene regulation in heart development, disease and regeneration. In this Review, Porrello and colleagues describe the origins of the fetal gene hypothesis and discuss the evolution of this hypothesis by considering more recent evidence from genome-wide sequencing studies.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"23 3","pages":"183-196"},"PeriodicalIF":44.2,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995331","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 : 2025-09-02DOI: 10.1038/s41569-025-01208-0
Corey Giles, Peter J. Meikle
In this Tools of the Trade article, Giles and Meikle describe the development of the the Australian Cardiovascular disease Data Commons, which provides a comprehensive, secure, scalable and internationally integrated database containing pooled data from approximately 400,000 individuals in Australia.
{"title":"Building the Australian Cardiovascular disease Data Commons","authors":"Corey Giles, Peter J. Meikle","doi":"10.1038/s41569-025-01208-0","DOIUrl":"10.1038/s41569-025-01208-0","url":null,"abstract":"In this Tools of the Trade article, Giles and Meikle describe the development of the the Australian Cardiovascular disease Data Commons, which provides a comprehensive, secure, scalable and internationally integrated database containing pooled data from approximately 400,000 individuals in Australia.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 11","pages":"837-837"},"PeriodicalIF":44.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928250","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 : 2025-09-01DOI: 10.1038/s41569-025-01207-1
Karina Huynh
Investigators of a new study published in Cell have engineered a new peptide modulator that binds to sodium channels to inhibit the late sodium current, which was shown to reverse the effects of sodium channel dysfunction associated with cardiac arrhythmias and epilepsy.
{"title":"Synthetic ion channel modulator reverses sodium channel dysfunction linked to cardiac arrhythmias","authors":"Karina Huynh","doi":"10.1038/s41569-025-01207-1","DOIUrl":"10.1038/s41569-025-01207-1","url":null,"abstract":"Investigators of a new study published in Cell have engineered a new peptide modulator that binds to sodium channels to inhibit the late sodium current, which was shown to reverse the effects of sodium channel dysfunction associated with cardiac arrhythmias and epilepsy.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 11","pages":"839-839"},"PeriodicalIF":44.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144923936","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 : 2025-09-01DOI: 10.1038/s41569-025-01201-7
Andrew M. Glazer, Daniel R. Tabet, Victoria N. Parikh, Brett M. Kroncke, Atina G. Cote, Yuta Yamamoto, Qianru Wang, Ayesha Muhammad, Megan C. Lancaster, Matthew J. O’Neill, Jochen Weile, Tao Yang, Calum A. Macrae, Euan A. Ashley, Frederick P. Roth, Dan M. Roden
Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as ‘variants of uncertain significance’. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale. In this Review, Roden and co-workers describe how multiplexed assays of variant effects can be used for high-throughput functional assessment of nearly all coding variants in a target sequence to improve variant annotation for cardiovascular-related genes and to resolve the problem of classification as variants of uncertain significance. They also discuss how variant effect predictors can be integrated with multiplexed methods to inform cardiovascular genomic medicine.
{"title":"Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine","authors":"Andrew M. Glazer, Daniel R. Tabet, Victoria N. Parikh, Brett M. Kroncke, Atina G. Cote, Yuta Yamamoto, Qianru Wang, Ayesha Muhammad, Megan C. Lancaster, Matthew J. O’Neill, Jochen Weile, Tao Yang, Calum A. Macrae, Euan A. Ashley, Frederick P. Roth, Dan M. Roden","doi":"10.1038/s41569-025-01201-7","DOIUrl":"10.1038/s41569-025-01201-7","url":null,"abstract":"Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as ‘variants of uncertain significance’. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale. In this Review, Roden and co-workers describe how multiplexed assays of variant effects can be used for high-throughput functional assessment of nearly all coding variants in a target sequence to improve variant annotation for cardiovascular-related genes and to resolve the problem of classification as variants of uncertain significance. They also discuss how variant effect predictors can be integrated with multiplexed methods to inform cardiovascular genomic medicine.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"23 3","pages":"149-163"},"PeriodicalIF":44.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928599","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 : 2025-08-26DOI: 10.1038/s41569-025-01206-2
Lu Yang, Abha Shrestha
Lu Yang and Abha Shrestha revisit the first large-scale trial to investigate the effects of telemonitoring on heart failure outcomes and link the lessons learned from the trial to current digital health strategies and challenges.
Lu Yang和Abha Shrestha回顾了第一次大规模试验，以调查远程监测对心力衰竭结果的影响，并将从试验中吸取的经验教训与当前的数字健康战略和挑战联系起来。
{"title":"A deepening digital divide in cardiovascular disease management","authors":"Lu Yang, Abha Shrestha","doi":"10.1038/s41569-025-01206-2","DOIUrl":"10.1038/s41569-025-01206-2","url":null,"abstract":"Lu Yang and Abha Shrestha revisit the first large-scale trial to investigate the effects of telemonitoring on heart failure outcomes and link the lessons learned from the trial to current digital health strategies and challenges.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 12","pages":"918-918"},"PeriodicalIF":44.2,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899201","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 : 2025-08-15DOI: 10.1038/s41569-025-01202-6
Julia Grapsa
Difficulties, whether arising from work, academic or family environments, are a part of our life. A crucial part of our lives is our response to crisis and how we achieve resilience. In this sense, it is very important to try to turn negative experiences into positive — or at least constructive — experiences. In this Comment, I discuss how to achieve resilience in difficult times.
{"title":"Overcoming difficulties with resilience","authors":"Julia Grapsa","doi":"10.1038/s41569-025-01202-6","DOIUrl":"10.1038/s41569-025-01202-6","url":null,"abstract":"Difficulties, whether arising from work, academic or family environments, are a part of our life. A crucial part of our lives is our response to crisis and how we achieve resilience. In this sense, it is very important to try to turn negative experiences into positive — or at least constructive — experiences. In this Comment, I discuss how to achieve resilience in difficult times.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 11","pages":"833-834"},"PeriodicalIF":44.2,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851389","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}
Artificial intelligence (AI) technologies are revolutionizing cardiovascular health by analysing environmental factors at an unprecedented scale. Geospatial AI integrates vast datasets — from satellite imagery down to street-level views — to identify complex risk patterns, which enables personalized predictions and guides precision interventions to mitigate the environmental burden of disease.
{"title":"Emerging AI tools for geospatially resolved cardiovascular risk","authors":"Zhuo Chen, Jean Eudes Dazard, Salil Deo, Sadeer Al-Kindi, Sanjay Rajagopalan","doi":"10.1038/s41569-025-01204-4","DOIUrl":"10.1038/s41569-025-01204-4","url":null,"abstract":"Artificial intelligence (AI) technologies are revolutionizing cardiovascular health by analysing environmental factors at an unprecedented scale. Geospatial AI integrates vast datasets — from satellite imagery down to street-level views — to identify complex risk patterns, which enables personalized predictions and guides precision interventions to mitigate the environmental burden of disease.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 10","pages":"697-699"},"PeriodicalIF":44.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850847","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 : 2025-08-14DOI: 10.1038/s41569-025-01192-5
Anna F. Dominiczak, Christian Delles
The latest developments in the field of hypertension have led to a better understanding of the pathophysiology of hypertension as well as to new pharmacological and device-based therapies and a wealth of clinical guidelines on prevention, diagnosis and treatment. To truly tackle the global epidemic of hypertension, we need a combination of pragmatic approaches and novel precision-medicine-based concepts.
{"title":"Hypertension in 2025: are we ready for bold precision public health approaches worldwide?","authors":"Anna F. Dominiczak, Christian Delles","doi":"10.1038/s41569-025-01192-5","DOIUrl":"10.1038/s41569-025-01192-5","url":null,"abstract":"The latest developments in the field of hypertension have led to a better understanding of the pathophysiology of hypertension as well as to new pharmacological and device-based therapies and a wealth of clinical guidelines on prevention, diagnosis and treatment. To truly tackle the global epidemic of hypertension, we need a combination of pragmatic approaches and novel precision-medicine-based concepts.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 9","pages":"607-608"},"PeriodicalIF":44.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840038","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 : 2025-08-13DOI: 10.1038/s41569-025-01203-5
Rukshan Ahamed Mohamed Rafeek, Natkunam Ketheesan
In this Tools of the Trade article, Rukshan Ahamed Mohamed Rafeek and Natkunam Ketheesan describe the utility of the Lewis rat autoimmune valvulitis model in assessing potential therapeutic applications for rheumatic heart disease.
{"title":"A transformative preclinical model of rheumatic heart disease","authors":"Rukshan Ahamed Mohamed Rafeek, Natkunam Ketheesan","doi":"10.1038/s41569-025-01203-5","DOIUrl":"10.1038/s41569-025-01203-5","url":null,"abstract":"In this Tools of the Trade article, Rukshan Ahamed Mohamed Rafeek and Natkunam Ketheesan describe the utility of the Lewis rat autoimmune valvulitis model in assessing potential therapeutic applications for rheumatic heart disease.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 10","pages":"700-700"},"PeriodicalIF":44.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840043","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 : 2025-08-05DOI: 10.1038/s41569-025-01200-8
Karina Huynh
According to a study published in Nature, the gut microbial metabolite imidazole propionate can induce atherosclerosis in atheroprone mice, further highlighting the role of microbiome-informed precision medicine to treat cardiovascular disease.
{"title":"The gut metabolite imidazole propionate is a potential biomarker of and therapeutic target for atherosclerosis","authors":"Karina Huynh","doi":"10.1038/s41569-025-01200-8","DOIUrl":"10.1038/s41569-025-01200-8","url":null,"abstract":"According to a study published in Nature, the gut microbial metabolite imidazole propionate can induce atherosclerosis in atheroprone mice, further highlighting the role of microbiome-informed precision medicine to treat cardiovascular disease.","PeriodicalId":18976,"journal":{"name":"Nature Reviews Cardiology","volume":"22 10","pages":"701-701"},"PeriodicalIF":44.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778511","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}
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