Pub Date : 2024-08-07DOI: 10.1038/s44161-024-00521-0
Endothelial-cell-specific inactivation of Lats2 or overexpression of YAP1, which are components of the Hippo pathway, induces myofibroblast formation. This leads to extensive fibrosis, osteosclerosis and impaired bone marrow function, and such changes are mediated by endothelial-to-mesenchymal transition. These findings offer insights into potential therapeutic strategies for myelofibrosis and osteosclerosis.
{"title":"Endothelial cells modulate bone marrow fibrosis","authors":"","doi":"10.1038/s44161-024-00521-0","DOIUrl":"10.1038/s44161-024-00521-0","url":null,"abstract":"Endothelial-cell-specific inactivation of Lats2 or overexpression of YAP1, which are components of the Hippo pathway, induces myofibroblast formation. This leads to extensive fibrosis, osteosclerosis and impaired bone marrow function, and such changes are mediated by endothelial-to-mesenchymal transition. These findings offer insights into potential therapeutic strategies for myelofibrosis and osteosclerosis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"895-896"},"PeriodicalIF":9.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980510","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 : 2024-07-31DOI: 10.1038/s44161-024-00511-2
Naman S. Shetty, Mokshad Gaonkar, Akhil Pampana, Nirav Patel, Peng Li, Garima Arora, Pankaj Arora
High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure1. However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0–7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62–3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63–10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers. Shetty et al. report that a favorable cardiovascular risk factor profile may partially offset the risk of heart failure and atrial fibrillation among carriers of high-proportion spliced-in titin truncating variants.
{"title":"Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure","authors":"Naman S. Shetty, Mokshad Gaonkar, Akhil Pampana, Nirav Patel, Peng Li, Garima Arora, Pankaj Arora","doi":"10.1038/s44161-024-00511-2","DOIUrl":"10.1038/s44161-024-00511-2","url":null,"abstract":"High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure1. However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0–7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62–3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63–10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers. Shetty et al. report that a favorable cardiovascular risk factor profile may partially offset the risk of heart failure and atrial fibrillation among carriers of high-proportion spliced-in titin truncating variants.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"899-906"},"PeriodicalIF":9.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980523","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 : 2024-07-29DOI: 10.1038/s44161-024-00508-x
Kishor K. Sivaraj, Paul-Georg Majev, Backialakshmi Dharmalingam, Silke Schröder, Bella Banjanin, Martin Stehling, Dagmar Zeuschner, Alfred Nordheim, Rebekka K. Schneider, Ralf H. Adams
Myelofibrosis and osteosclerosis are fibrotic diseases disrupting bone marrow function that occur in various leukemias but also in response to non-malignant alterations in hematopoietic cells. Here we show that endothelial cell–specific inactivation of the Lats2 gene, encoding Hippo kinase large tumor suppressor kinase 2, or overexpression of the downstream effector YAP1 induce myofibroblast formation and lead to extensive fibrosis and osteosclerosis, which impair bone marrow function and cause extramedullary hematopoiesis in the spleen. Mechanistically, loss of LATS2 induces endothelial-to-mesenchymal transition, resulting in increased expression of extracellular matrix and secreted signaling molecules. Changes in endothelial cells involve increased expression of serum response factor target genes, and, strikingly, major aspects of the LATS2 mutant phenotype are rescued by inactivation of the Srf gene. These findings identify the endothelium as a driver of bone marrow fibrosis, which improves understanding of myelofibrotic and osteosclerotic diseases, for which drug therapies are currently lacking. Sivaraj, Majev et al. demonstrate that the inactivation of Lats2 in endothelial cells triggers the upregulation of serum response factor and endothelial-to-mesenchymal transition, leading to myofibroblast formation, bone marrow fibrosis, osteosclerosis, impaired bone marrow function and extramedullary hematopoiesis.
{"title":"Endothelial LATS2 is a suppressor of bone marrow fibrosis","authors":"Kishor K. Sivaraj, Paul-Georg Majev, Backialakshmi Dharmalingam, Silke Schröder, Bella Banjanin, Martin Stehling, Dagmar Zeuschner, Alfred Nordheim, Rebekka K. Schneider, Ralf H. Adams","doi":"10.1038/s44161-024-00508-x","DOIUrl":"10.1038/s44161-024-00508-x","url":null,"abstract":"Myelofibrosis and osteosclerosis are fibrotic diseases disrupting bone marrow function that occur in various leukemias but also in response to non-malignant alterations in hematopoietic cells. Here we show that endothelial cell–specific inactivation of the Lats2 gene, encoding Hippo kinase large tumor suppressor kinase 2, or overexpression of the downstream effector YAP1 induce myofibroblast formation and lead to extensive fibrosis and osteosclerosis, which impair bone marrow function and cause extramedullary hematopoiesis in the spleen. Mechanistically, loss of LATS2 induces endothelial-to-mesenchymal transition, resulting in increased expression of extracellular matrix and secreted signaling molecules. Changes in endothelial cells involve increased expression of serum response factor target genes, and, strikingly, major aspects of the LATS2 mutant phenotype are rescued by inactivation of the Srf gene. These findings identify the endothelium as a driver of bone marrow fibrosis, which improves understanding of myelofibrotic and osteosclerotic diseases, for which drug therapies are currently lacking. Sivaraj, Majev et al. demonstrate that the inactivation of Lats2 in endothelial cells triggers the upregulation of serum response factor and endothelial-to-mesenchymal transition, leading to myofibroblast formation, bone marrow fibrosis, osteosclerosis, impaired bone marrow function and extramedullary hematopoiesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"951-969"},"PeriodicalIF":9.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00508-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980525","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 : 2024-07-25DOI: 10.1038/s44161-024-00516-x
Mariam Meddeb, Navid Koleini, Aleksandra Binek, Mohammad Keykhaei, Reyhane Darehgazani, Seoyoung Kwon, Celia Aboaf, Kenneth B. Margulies, Ken C. Bedi Jr, Mohamed Lehar, Kavita Sharma, Virginia S. Hahn, Jennifer E. Van Eyk, Cinthia I. Drachenberg, David A. Kass
Over half of patients with heart failure have a preserved ejection fraction (>50%, called HFpEF), a syndrome with substantial morbidity/mortality and few effective therapies1. Its dominant comorbidity is now obesity, which worsens disease and prognosis1–3. Myocardial data from patients with morbid obesity and HFpEF show depressed myocyte calcium-stimulated tension4 and disrupted gene expression of mitochondrial and lipid metabolic pathways5,6, abnormalities shared by human HF with a reduced EF but less so in HFpEF without severe obesity. The impact of severe obesity on human HFpEF myocardial ultrastructure remains unexplored. Here we assessed the myocardial ultrastructure in septal biopsies from patients with HFpEF using transmission electron microscopy. We observed sarcomere disruption and sarcolysis, mitochondrial swelling with cristae separation and dissolution and lipid droplet accumulation that was more prominent in the most obese patients with HFpEF and not dependent on comorbid diabetes. Myocardial proteomics revealed associated reduction in fatty acid uptake, processing and oxidation and mitochondrial respiration proteins, particularly in very obese patients with HFpEF. Although heart failure with preserved ejection fraction has a normal-looking contraction, under an electron microscope the muscle looks abnormal, with disrupted contracting proteins and mitochondria and excess fat, particularly in the most obese patients.
{"title":"Myocardial ultrastructure of human heart failure with preserved ejection fraction","authors":"Mariam Meddeb, Navid Koleini, Aleksandra Binek, Mohammad Keykhaei, Reyhane Darehgazani, Seoyoung Kwon, Celia Aboaf, Kenneth B. Margulies, Ken C. Bedi Jr, Mohamed Lehar, Kavita Sharma, Virginia S. Hahn, Jennifer E. Van Eyk, Cinthia I. Drachenberg, David A. Kass","doi":"10.1038/s44161-024-00516-x","DOIUrl":"10.1038/s44161-024-00516-x","url":null,"abstract":"Over half of patients with heart failure have a preserved ejection fraction (>50%, called HFpEF), a syndrome with substantial morbidity/mortality and few effective therapies1. Its dominant comorbidity is now obesity, which worsens disease and prognosis1–3. Myocardial data from patients with morbid obesity and HFpEF show depressed myocyte calcium-stimulated tension4 and disrupted gene expression of mitochondrial and lipid metabolic pathways5,6, abnormalities shared by human HF with a reduced EF but less so in HFpEF without severe obesity. The impact of severe obesity on human HFpEF myocardial ultrastructure remains unexplored. Here we assessed the myocardial ultrastructure in septal biopsies from patients with HFpEF using transmission electron microscopy. We observed sarcomere disruption and sarcolysis, mitochondrial swelling with cristae separation and dissolution and lipid droplet accumulation that was more prominent in the most obese patients with HFpEF and not dependent on comorbid diabetes. Myocardial proteomics revealed associated reduction in fatty acid uptake, processing and oxidation and mitochondrial respiration proteins, particularly in very obese patients with HFpEF. Although heart failure with preserved ejection fraction has a normal-looking contraction, under an electron microscope the muscle looks abnormal, with disrupted contracting proteins and mitochondria and excess fat, particularly in the most obese patients.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"907-914"},"PeriodicalIF":9.4,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141806363","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 : 2024-07-24DOI: 10.1038/s44161-024-00509-w
Joy Lincoln
The formation and remodeling of cardiac valves is a complex process that is crucial for normal development. A study now reveals a subpopulation of elastin-producing human valve interstitial cells that regulate fetal elastogenesis.
{"title":"Elastin-producing valve interstitial cells stretch our understanding of cardiac valve remodeling","authors":"Joy Lincoln","doi":"10.1038/s44161-024-00509-w","DOIUrl":"10.1038/s44161-024-00509-w","url":null,"abstract":"The formation and remodeling of cardiac valves is a complex process that is crucial for normal development. A study now reveals a subpopulation of elastin-producing human valve interstitial cells that regulate fetal elastogenesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"888-889"},"PeriodicalIF":9.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141809340","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 : 2024-07-24DOI: 10.1038/s44161-024-00510-3
Ziyi Liu, Yu Liu, Zhiyun Yu, Cheng Tan, Nicole Pek, Anna O’Donnell, Angeline Wu, Ian Glass, David S. Winlaw, Minzhe Guo, Jason R. Spence, Ya-Wen Chen, Katherine E. Yutzey, Yifei Miao, Mingxia Gu
Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE)+, elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell–cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1–NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling. Z. Liu, Y. Liu and Z. Yu et al. discovered a subtype of valve interstitial cells underneath the valve endothelial cells sensing unidirectional flow. These cells express high levels of APOE, which is responsible for JAG1–NOTCH2-mediated fetal elastogenesis.
{"title":"APOE–NOTCH axis governs elastogenesis during human cardiac valve remodeling","authors":"Ziyi Liu, Yu Liu, Zhiyun Yu, Cheng Tan, Nicole Pek, Anna O’Donnell, Angeline Wu, Ian Glass, David S. Winlaw, Minzhe Guo, Jason R. Spence, Ya-Wen Chen, Katherine E. Yutzey, Yifei Miao, Mingxia Gu","doi":"10.1038/s44161-024-00510-3","DOIUrl":"10.1038/s44161-024-00510-3","url":null,"abstract":"Valve remodeling is a process involving extracellular matrix organization and elongation of valve leaflets. Here, through single-cell RNA sequencing of human fetal valves, we identified an elastin-producing valve interstitial cell (VIC) subtype (apolipoprotein E (APOE)+, elastin-VICs) spatially located underneath valve endothelial cells (VECs) sensing unidirectional flow. APOE knockdown in fetal VICs resulted in profound elastogenesis defects. In valves with pulmonary stenosis (PS), we observed elastin fragmentation and decreased expression of APOE along with other genes regulating elastogenesis. Cell–cell interaction analysis revealed that jagged 1 (JAG1) from unidirectional VECs activates elastogenesis in elastin-VICs through NOTCH2. Similar observations were made in VICs cocultured with VECs under unidirectional flow. Notably, a drastic reduction of JAG1–NOTCH2 was also observed in PS valves. Lastly, we found that APOE controls JAG1-induced NOTCH activation and elastogenesis in VICs through the extracellular signal-regulated kinase pathway. Our study suggests important roles of both APOE and NOTCH in regulating elastogenesis during human valve remodeling. Z. Liu, Y. Liu and Z. Yu et al. discovered a subtype of valve interstitial cells underneath the valve endothelial cells sensing unidirectional flow. These cells express high levels of APOE, which is responsible for JAG1–NOTCH2-mediated fetal elastogenesis.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"933-950"},"PeriodicalIF":9.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980504","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 : 2024-07-23DOI: 10.1038/s44161-024-00503-2
Farid Moussavi-Harami, Michael Regnier
Aficamten, a small-molecule myosin inhibitor, binds to the catalytic domain of cardiac myosin and reduces contraction by stabilizing the initial weak interaction between myosin and actin.
{"title":"Aficamten reduces cardiac contractility by modifying the actomyosin interaction","authors":"Farid Moussavi-Harami, Michael Regnier","doi":"10.1038/s44161-024-00503-2","DOIUrl":"10.1038/s44161-024-00503-2","url":null,"abstract":"Aficamten, a small-molecule myosin inhibitor, binds to the catalytic domain of cardiac myosin and reduces contraction by stabilizing the initial weak interaction between myosin and actin.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"893-894"},"PeriodicalIF":9.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141812296","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 : 2024-07-23DOI: 10.1038/s44161-024-00505-0
James J. Hartman, Darren T. Hwee, Julien Robert-Paganin, Chihyuan Chuang, Eva R. Chin, Samantha Edell, Ken H. Lee, Roshni Madhvani, Preeti Paliwal, Julien Pernier, Saswata Sankar Sarkar, Julia Schaletzky, Kristine Schauer, Khanha D. Taheri, Jingying Wang, Eddie Wehri, Yangsong Wu, Anne Houdusse, Bradley P. Morgan, Fady I. Malik
Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM. Hartman et al. use mouse models of cardiac function to show that aficamten decreases the availability of myosin heads for contraction during systole, attenuating a primary driver of hypertrophic cardiomyopathy pathophysiology.
{"title":"Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy","authors":"James J. Hartman, Darren T. Hwee, Julien Robert-Paganin, Chihyuan Chuang, Eva R. Chin, Samantha Edell, Ken H. Lee, Roshni Madhvani, Preeti Paliwal, Julien Pernier, Saswata Sankar Sarkar, Julia Schaletzky, Kristine Schauer, Khanha D. Taheri, Jingying Wang, Eddie Wehri, Yangsong Wu, Anne Houdusse, Bradley P. Morgan, Fady I. Malik","doi":"10.1038/s44161-024-00505-0","DOIUrl":"10.1038/s44161-024-00505-0","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM. Hartman et al. use mouse models of cardiac function to show that aficamten decreases the availability of myosin heads for contraction during systole, attenuating a primary driver of hypertrophic cardiomyopathy pathophysiology.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"1003-1016"},"PeriodicalIF":9.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00505-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141814245","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}
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