Pub Date : 2024-12-04DOI: 10.1038/s44161-024-00577-y
Favour C. Onyeogaziri, Ross Smith, Maximiliano Arce, Hua Huang, Iza Erzar, Charlotte Rorsman, Matteo Malinverno, Fabrizio Orsenigo, Veronica Sundell, Dinesh Fernando, Geoffrey Daniel, Mika Niemelä, Aki Laakso, Behnam Rezai Jahromi, Anna-Karin Olsson, Peetra U. Magnusson
Cerebral cavernous malformation (CCM) is a neurovascular disease with symptoms such as strokes, hemorrhages and neurological deficits. With surgery being the only treatment strategy, understanding the molecular mechanisms of CCM is crucial in finding alternative therapeutic options for CCM. Neutrophil extracellular traps (NETs) were recently reported in CCM, and NETs were shown to have positive or negative effects in different disease contexts. In this study, we investigated the roles of NETs in CCM by pharmacologically inhibiting NET formation using Cl-amidine (a peptidyl arginine deiminase inhibitor). We show here that Cl-amidine treatment reduced lesion burden, coagulation and endothelial-to-mesenchymal transition. Furthermore, NETs promoted the activation of microglia and fibroblasts, leading to increased neuroinflammation and a chronic wound microenvironment in CCM. The inhibition of NET formation caused endothelial quiescence and promoted a healthier microenvironment. Our study suggests the inhibition of NETs as a potential therapeutic strategy in CCM. Onyeogaziri et al. show that the formation of neutrophil extracellular traps contributes to a chronic wound state in cerebral cavernous malformation, while inhibition of these traps with CI-amidine establishes a healthier microenvironment and promotes endothelial cell quiescence, suggesting use of CI-amidine as a potential therapeutic strategy.
{"title":"Pharmacological blocking of neutrophil extracellular traps attenuates immunothrombosis and neuroinflammation in cerebral cavernous malformation","authors":"Favour C. Onyeogaziri, Ross Smith, Maximiliano Arce, Hua Huang, Iza Erzar, Charlotte Rorsman, Matteo Malinverno, Fabrizio Orsenigo, Veronica Sundell, Dinesh Fernando, Geoffrey Daniel, Mika Niemelä, Aki Laakso, Behnam Rezai Jahromi, Anna-Karin Olsson, Peetra U. Magnusson","doi":"10.1038/s44161-024-00577-y","DOIUrl":"10.1038/s44161-024-00577-y","url":null,"abstract":"Cerebral cavernous malformation (CCM) is a neurovascular disease with symptoms such as strokes, hemorrhages and neurological deficits. With surgery being the only treatment strategy, understanding the molecular mechanisms of CCM is crucial in finding alternative therapeutic options for CCM. Neutrophil extracellular traps (NETs) were recently reported in CCM, and NETs were shown to have positive or negative effects in different disease contexts. In this study, we investigated the roles of NETs in CCM by pharmacologically inhibiting NET formation using Cl-amidine (a peptidyl arginine deiminase inhibitor). We show here that Cl-amidine treatment reduced lesion burden, coagulation and endothelial-to-mesenchymal transition. Furthermore, NETs promoted the activation of microglia and fibroblasts, leading to increased neuroinflammation and a chronic wound microenvironment in CCM. The inhibition of NET formation caused endothelial quiescence and promoted a healthier microenvironment. Our study suggests the inhibition of NETs as a potential therapeutic strategy in CCM. Onyeogaziri et al. show that the formation of neutrophil extracellular traps contributes to a chronic wound state in cerebral cavernous malformation, while inhibition of these traps with CI-amidine establishes a healthier microenvironment and promotes endothelial cell quiescence, suggesting use of CI-amidine as a potential therapeutic strategy.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1549-1567"},"PeriodicalIF":9.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00577-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-04DOI: 10.1038/s44161-024-00576-z
Leila Haghighat, Colette DeJong, John R. Teerlink
In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin–neprilysin inhibitors, sodium–glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment. Haghighat et al. provide an overview of the newest advances in heart failure drugs, describing their mechanisms of action and performance in recent clinical trials, and discuss the most promising future directions for the field.
{"title":"New and future heart failure drugs","authors":"Leila Haghighat, Colette DeJong, John R. Teerlink","doi":"10.1038/s44161-024-00576-z","DOIUrl":"10.1038/s44161-024-00576-z","url":null,"abstract":"In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin–neprilysin inhibitors, sodium–glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment. Haghighat et al. provide an overview of the newest advances in heart failure drugs, describing their mechanisms of action and performance in recent clinical trials, and discuss the most promising future directions for the field.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1389-1407"},"PeriodicalIF":9.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781822","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 : 2024-11-29DOI: 10.1038/s44161-024-00563-4
José Gabriel Barcia Durán, Dayasagar Das, Michael Gildea, Letizia Amadori, Morgane Gourvest, Ravneet Kaur, Natalia Eberhardt, Panagiotis Smyrnis, Burak Cilhoroz, Swathy Sajja, Karishma Rahman, Dawn M. Fernandez, Peter Faries, Navneet Narula, Rami Vanguri, Ira J. Goldberg, Edward A. Fisher, Jeffrey S. Berger, Kathryn J. Moore, Chiara Giannarelli
Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors. Barcia Durán, Dayasagar, et al. map the expression of immune checkpoints in human atherosclerosis and examine the influence of lipid-lowering treatments and type 2 diabetes to understand how immune checkpoint inhibitors worsen cardiovascular risk in survivors of cancer.
{"title":"Immune checkpoint landscape of human atherosclerosis and influence of cardiometabolic factors","authors":"José Gabriel Barcia Durán, Dayasagar Das, Michael Gildea, Letizia Amadori, Morgane Gourvest, Ravneet Kaur, Natalia Eberhardt, Panagiotis Smyrnis, Burak Cilhoroz, Swathy Sajja, Karishma Rahman, Dawn M. Fernandez, Peter Faries, Navneet Narula, Rami Vanguri, Ira J. Goldberg, Edward A. Fisher, Jeffrey S. Berger, Kathryn J. Moore, Chiara Giannarelli","doi":"10.1038/s44161-024-00563-4","DOIUrl":"10.1038/s44161-024-00563-4","url":null,"abstract":"Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors. Barcia Durán, Dayasagar, et al. map the expression of immune checkpoints in human atherosclerosis and examine the influence of lipid-lowering treatments and type 2 diabetes to understand how immune checkpoint inhibitors worsen cardiovascular risk in survivors of cancer.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1482-1502"},"PeriodicalIF":9.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00563-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-29DOI: 10.1038/s44161-024-00571-4
Jesse W. Williams, Esther Lutgens
Researchers map the expression of immune checkpoints and cell interactions within human atherosclerotic plaques, and the influence of relevant comorbidities such as dyslipidemia and diabetes. The findings shed light on the potential mechanisms behind the increased risk of cardiovascular events after treatment with immune checkpoint inhibitors.
{"title":"Unrestrained cancer immunity ignites atherosclerosis","authors":"Jesse W. Williams, Esther Lutgens","doi":"10.1038/s44161-024-00571-4","DOIUrl":"10.1038/s44161-024-00571-4","url":null,"abstract":"Researchers map the expression of immune checkpoints and cell interactions within human atherosclerotic plaques, and the influence of relevant comorbidities such as dyslipidemia and diabetes. The findings shed light on the potential mechanisms behind the increased risk of cardiovascular events after treatment with immune checkpoint inhibitors.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1380-1382"},"PeriodicalIF":9.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755948","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 : 2024-11-27DOI: 10.1038/s44161-024-00580-3
Alexandre Gallerand, Jichang Han, Stoyan Ivanov, Gwendalyn J. Randolph
The past 15 years have witnessed a leap in understanding the life cycle, gene expression profiles, origins and functions of mouse macrophages in many tissues, including macrophages of the artery wall and heart that have critical roles in cardiovascular health. Here, we review the phenotypical and functional diversity of macrophage populations in multiple organs and discuss the roles that proliferation, survival, and recruitment and replenishment from monocytes have in maintaining macrophages in homeostasis and inflammatory states such as atherosclerosis and myocardial infarction. We also introduce emerging data that better characterize the life cycle and phenotypic profiles of human macrophages. We discuss the similarities and differences between murine and human macrophages, raising the possibility that tissue-resident macrophages in humans may rely more on bone marrow-derived monocytes than in mouse. Gallerand et al. review the main human and murine macrophage populations, highlighting their phenotypic and functional diversity and how they contribute to cardiovascular health by regulating the inflammatory response.
{"title":"Mouse and human macrophages and their roles in cardiovascular health and disease","authors":"Alexandre Gallerand, Jichang Han, Stoyan Ivanov, Gwendalyn J. Randolph","doi":"10.1038/s44161-024-00580-3","DOIUrl":"10.1038/s44161-024-00580-3","url":null,"abstract":"The past 15 years have witnessed a leap in understanding the life cycle, gene expression profiles, origins and functions of mouse macrophages in many tissues, including macrophages of the artery wall and heart that have critical roles in cardiovascular health. Here, we review the phenotypical and functional diversity of macrophage populations in multiple organs and discuss the roles that proliferation, survival, and recruitment and replenishment from monocytes have in maintaining macrophages in homeostasis and inflammatory states such as atherosclerosis and myocardial infarction. We also introduce emerging data that better characterize the life cycle and phenotypic profiles of human macrophages. We discuss the similarities and differences between murine and human macrophages, raising the possibility that tissue-resident macrophages in humans may rely more on bone marrow-derived monocytes than in mouse. Gallerand et al. review the main human and murine macrophage populations, highlighting their phenotypic and functional diversity and how they contribute to cardiovascular health by regulating the inflammatory response.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1424-1437"},"PeriodicalIF":9.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741713","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}
After birth, the heart undergoes a shift in energy metabolism and cytoarchitecture to enhance efficient energy production and cardiac contraction, which is essential for postnatal development and growth. However, the precise mechanisms regulating this process remain elusive. Here we show that the RNA modification enzyme Mettl1 is a critical regulator of postnatal metabolic reprogramming and cardiomyocyte maturation in mice, primarily through its influence on the translation of the rate-limiting ketogenesis enzyme Hmgcs2. Our findings reveal that ketogenesis is vital for the postnatal transition of fuel from glucose to fatty acids in cardiomyocytes, achieved by modulating tricarboxylic acid cycle–related enzymatic activity via lysine β-hydroxybutyrylation protein modification. Loss of Mettl1 results in aberrant metabolic reprogramming and cardiomyocyte immaturity, leading to heart failure, although some clinical features can be rescued by β-hydroxybutyrate supplementation. Our study provides mechanistic insights into how Mettl1 regulates metabolic reprogramming in neonatal cardiomyocytes and highlights the importance of ketogenesis in cardiomyocyte maturation. Du et al. elucidate the mechanism by which Mettl1, a tRNA m7G methyltransferase, regulates cardiomyocyte maturation by influencing the translation of the rate-limiting ketogenesis enzyme Hmgcs2, thereby impacting cardiomyocyte fuel utilization.
{"title":"The tRNA methyltransferase Mettl1 governs ketogenesis through translational regulation and drives metabolic reprogramming in cardiomyocyte maturation","authors":"Tailai Du, Yanchuang Han, Hui Han, Ting Xu, Youchen Yan, Jialing Wu, Yan Li, Chen Liu, Xinxue Liao, Yugang Dong, Demeng Chen, Jingsong Ou, Shuibin Lin, Zhan-Peng Huang","doi":"10.1038/s44161-024-00565-2","DOIUrl":"10.1038/s44161-024-00565-2","url":null,"abstract":"After birth, the heart undergoes a shift in energy metabolism and cytoarchitecture to enhance efficient energy production and cardiac contraction, which is essential for postnatal development and growth. However, the precise mechanisms regulating this process remain elusive. Here we show that the RNA modification enzyme Mettl1 is a critical regulator of postnatal metabolic reprogramming and cardiomyocyte maturation in mice, primarily through its influence on the translation of the rate-limiting ketogenesis enzyme Hmgcs2. Our findings reveal that ketogenesis is vital for the postnatal transition of fuel from glucose to fatty acids in cardiomyocytes, achieved by modulating tricarboxylic acid cycle–related enzymatic activity via lysine β-hydroxybutyrylation protein modification. Loss of Mettl1 results in aberrant metabolic reprogramming and cardiomyocyte immaturity, leading to heart failure, although some clinical features can be rescued by β-hydroxybutyrate supplementation. Our study provides mechanistic insights into how Mettl1 regulates metabolic reprogramming in neonatal cardiomyocytes and highlights the importance of ketogenesis in cardiomyocyte maturation. Du et al. elucidate the mechanism by which Mettl1, a tRNA m7G methyltransferase, regulates cardiomyocyte maturation by influencing the translation of the rate-limiting ketogenesis enzyme Hmgcs2, thereby impacting cardiomyocyte fuel utilization.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1438-1453"},"PeriodicalIF":9.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717934","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 : 2024-11-25DOI: 10.1038/s44161-024-00572-3
Pilar Ruiz-Lozano, Mark Mercola
The maturation of postnatal cardiomyocytes is vital for the heart to sustain pump activity through adulthood. The methyltransferase METTL1 drives cardiomyocyte maturation during the first week of postnatal life in the mouse by enhancing ketogenesis and fatty acid oxidation.
{"title":"tRNA methylation drives early postnatal cardiomyocyte maturation","authors":"Pilar Ruiz-Lozano, Mark Mercola","doi":"10.1038/s44161-024-00572-3","DOIUrl":"10.1038/s44161-024-00572-3","url":null,"abstract":"The maturation of postnatal cardiomyocytes is vital for the heart to sustain pump activity through adulthood. The methyltransferase METTL1 drives cardiomyocyte maturation during the first week of postnatal life in the mouse by enhancing ketogenesis and fatty acid oxidation.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1375-1376"},"PeriodicalIF":9.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717936","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 : 2024-11-21DOI: 10.1038/s44161-024-00567-0
Art Schuermans, Ashley B. Pournamdari, Jiwoo Lee, Rohan Bhukar, Shriienidhie Ganesh, Nicholas Darosa, Aeron M. Small, Zhi Yu, Whitney Hornsby, Satoshi Koyama, Charles Kooperberg, Alexander P. Reiner, James L. Januzzi Jr., Michael C. Honigberg, Pradeep Natarajan
Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein–disease associations—including 441 proteins—at Bonferroni-adjusted P < 8.6 × 10−6. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein–disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases. Schuermans et al. identify a causal relationship between the circulating proteins spondin-1 and atrial fibrillation and SPINT1 and coronary artery disease and show that adding proteomic data improves clinical risk factor-based cardiovascular risk prediction.
{"title":"Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction","authors":"Art Schuermans, Ashley B. Pournamdari, Jiwoo Lee, Rohan Bhukar, Shriienidhie Ganesh, Nicholas Darosa, Aeron M. Small, Zhi Yu, Whitney Hornsby, Satoshi Koyama, Charles Kooperberg, Alexander P. Reiner, James L. Januzzi Jr., Michael C. Honigberg, Pradeep Natarajan","doi":"10.1038/s44161-024-00567-0","DOIUrl":"10.1038/s44161-024-00567-0","url":null,"abstract":"Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein–disease associations—including 441 proteins—at Bonferroni-adjusted P < 8.6 × 10−6. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein–disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases. Schuermans et al. identify a causal relationship between the circulating proteins spondin-1 and atrial fibrillation and SPINT1 and coronary artery disease and show that adding proteomic data improves clinical risk factor-based cardiovascular risk prediction.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1516-1530"},"PeriodicalIF":9.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00567-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1038/s44161-024-00564-3
Kathryn A. McGurk, Mengyun Qiao, Sean L. Zheng, Arunashis Sau, Albert Henry, Antonio Luiz P. Ribeiro, Antônio H. Ribeiro, Fu Siong Ng, R. Thomas Lumbers, Wenjia Bai, James S. Ware, Declan P. O’Regan
Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. Here we report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and ventricular development. Genome-wide association studies identified 68 loci in pathways that regulate sarcomeric function, differentiation of the conduction system and cell fate determination. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease expression. The inner surface of the heart has a meshwork of muscles called trabeculae. McGurk et al. report the genetic regulation of these complex structures across common and rare variants, revealing pathways implicated in heart development and cell fate.
{"title":"Genetic and phenotypic architecture of human myocardial trabeculation","authors":"Kathryn A. McGurk, Mengyun Qiao, Sean L. Zheng, Arunashis Sau, Albert Henry, Antonio Luiz P. Ribeiro, Antônio H. Ribeiro, Fu Siong Ng, R. Thomas Lumbers, Wenjia Bai, James S. Ware, Declan P. O’Regan","doi":"10.1038/s44161-024-00564-3","DOIUrl":"10.1038/s44161-024-00564-3","url":null,"abstract":"Cardiac trabeculae form a network of muscular strands that line the inner surfaces of the heart. Their development depends on multiscale morphogenetic processes and, while highly conserved across vertebrate evolution, their role in the pathophysiology of the mature heart is not fully understood. Here we report variant associations across the allele frequency spectrum for trabecular morphology in 47,803 participants of the UK Biobank using fractal dimension analysis of cardiac imaging. We identified an association between trabeculation and rare variants in 56 genes that regulate myocardial contractility and ventricular development. Genome-wide association studies identified 68 loci in pathways that regulate sarcomeric function, differentiation of the conduction system and cell fate determination. We found that trabeculation-associated variants were modifiers of cardiomyopathy phenotypes with opposing effects in hypertrophic and dilated cardiomyopathy. Together, these data provide insights into mechanisms that regulate trabecular development and plasticity, and identify a potential role in modifying monogenic disease expression. The inner surface of the heart has a meshwork of muscles called trabeculae. McGurk et al. report the genetic regulation of these complex structures across common and rare variants, revealing pathways implicated in heart development and cell fate.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1503-1515"},"PeriodicalIF":9.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00564-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1038/s44161-024-00562-5
Emily E. Bramel, Wendy A. Espinoza Camejo, Tyler J. Creamer, Leda Restrepo, Muzna Saqib, Rustam Bagirzadeh, Anthony Zeng, Jacob T. Mitchell, Genevieve L. Stein-O’Brien, Albert J. Pedroza, Michael P. Fischbein, Harry C. Dietz, Elena Gallo MacFarlane
Loeys–Dietz syndrome (LDS) is a connective tissue disorder caused by mutations that decrease transforming growth factor-β signaling. LDS-causing mutations increase the risk of aneurysm throughout the arterial tree, yet the aortic root is a site of heightened susceptibility. Here we investigate the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1M318R/+ LDS mice by single-cell transcriptomics to identify molecular determinants of this vulnerability. Reduced expression of components of the extracellular matrix–receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human single-cell RNA sequencing dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired transforming growth factor-β signaling. Bramel et al. identify a population of GATA4+ vascular smooth muscle cells enriched in the human and mouse aortic root that is intrinsically more susceptible to Loeys–Dietz-syndrome-causing mutations and demonstrate that postnatal deletion of Gata4 in vascular smooth muscle cells reduces aortic root dilation in a mouse model of Loeys–Dietz syndrome.
{"title":"Intrinsic GATA4 expression sensitizes the aortic root to dilation in a Loeys–Dietz syndrome mouse model","authors":"Emily E. Bramel, Wendy A. Espinoza Camejo, Tyler J. Creamer, Leda Restrepo, Muzna Saqib, Rustam Bagirzadeh, Anthony Zeng, Jacob T. Mitchell, Genevieve L. Stein-O’Brien, Albert J. Pedroza, Michael P. Fischbein, Harry C. Dietz, Elena Gallo MacFarlane","doi":"10.1038/s44161-024-00562-5","DOIUrl":"10.1038/s44161-024-00562-5","url":null,"abstract":"Loeys–Dietz syndrome (LDS) is a connective tissue disorder caused by mutations that decrease transforming growth factor-β signaling. LDS-causing mutations increase the risk of aneurysm throughout the arterial tree, yet the aortic root is a site of heightened susceptibility. Here we investigate the heterogeneity of vascular smooth muscle cells (VSMCs) in the aorta of Tgfbr1M318R/+ LDS mice by single-cell transcriptomics to identify molecular determinants of this vulnerability. Reduced expression of components of the extracellular matrix–receptor apparatus and upregulation of stress and inflammatory pathways were observed in all LDS VSMCs. However, regardless of genotype, a subset of Gata4-expressing VSMCs predominantly located in the aortic root intrinsically displayed a less differentiated, proinflammatory profile. A similar population was also identified among aortic VSMCs in a human single-cell RNA sequencing dataset. Postnatal VSMC-specific Gata4 deletion reduced aortic root dilation in LDS mice, suggesting that this factor sensitizes the aortic root to the effects of impaired transforming growth factor-β signaling. Bramel et al. identify a population of GATA4+ vascular smooth muscle cells enriched in the human and mouse aortic root that is intrinsically more susceptible to Loeys–Dietz-syndrome-causing mutations and demonstrate that postnatal deletion of Gata4 in vascular smooth muscle cells reduces aortic root dilation in a mouse model of Loeys–Dietz syndrome.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 12","pages":"1468-1481"},"PeriodicalIF":9.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00562-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：