Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom
{"title":"PRDM16缺失与性别依赖性心肌病和心脏死亡率相关：一项转化的多机构队列研究。","authors":"Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom","doi":"10.1161/CIRCGEN.122.003912","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor <i>PRDM16</i>. Early studies suggest that deletion of <i>PRDM16</i> may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of <i>PRDM16</i> loss is unknown.</p><p><strong>Methods: </strong>This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific <i>Prdm16</i> knockout mouse (<i>Prdm16</i> conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.</p><p><strong>Results: </strong>The retrospective cohort included 71 patients. Among individuals with <i>PRDM16</i> deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with <i>PRDM16</i> not deleted (<i>P</i>=0.1). In the combined retrospective and systematic review cohort (n=134), <i>PRDM16</i> deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, <i>P</i>=0.03). <i>PRDM16</i> deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (<i>P</i>=0.04). Among those <i>PRDM16</i> deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (<i>P</i>=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female <i>Prdm16</i> conditional knockout mice. Further, female <i>Prdm16</i> conditional knockout mice demonstrate significantly elevated risk of mortality (<i>P</i>=0.0003).</p><p><strong>Conclusions: </strong><i>PRDM16</i> deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. <i>Prdm16</i> conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with <i>PRDM16</i> deletion should be assessed for cardiac disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528350/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>PRDM16</i> Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.\",\"authors\":\"Ryan J Kramer, Amir Nima Fatahian, Alice Chan, Jeffery Mortenson, Jennifer Osher, Bo Sun, Lauren E Parker, Michael B Rosamilia, Kyra B Potter, Kaila Moore, Sage L Atkins, Jill A Rosenfeld, Alona Birjiniuk, Edward Jones, Taylor S Howard, Jeffrey J Kim, Daryl A Scott, Seema Lalani, Omid M T Rouzbehani, Samantha Kaplan, Marissa A Hathaway, Jennifer L Cohen, S Yukiko Asaki, Hugo R Martinez, Sihem Boudina, Andrew P Landstrom\",\"doi\":\"10.1161/CIRCGEN.122.003912\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor <i>PRDM16</i>. Early studies suggest that deletion of <i>PRDM16</i> may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of <i>PRDM16</i> loss is unknown.</p><p><strong>Methods: </strong>This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific <i>Prdm16</i> knockout mouse (<i>Prdm16</i> conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.</p><p><strong>Results: </strong>The retrospective cohort included 71 patients. Among individuals with <i>PRDM16</i> deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with <i>PRDM16</i> not deleted (<i>P</i>=0.1). In the combined retrospective and systematic review cohort (n=134), <i>PRDM16</i> deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, <i>P</i>=0.03). <i>PRDM16</i> deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (<i>P</i>=0.04). Among those <i>PRDM16</i> deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (<i>P</i>=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female <i>Prdm16</i> conditional knockout mice. Further, female <i>Prdm16</i> conditional knockout mice demonstrate significantly elevated risk of mortality (<i>P</i>=0.0003).</p><p><strong>Conclusions: </strong><i>PRDM16</i> deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. <i>Prdm16</i> conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with <i>PRDM16</i> deletion should be assessed for cardiac disease.</p>\",\"PeriodicalId\":10326,\"journal\":{\"name\":\"Circulation: Genomic and Precision Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2023-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528350/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Genomic and Precision Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGEN.122.003912\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/7/3 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Genomic and Precision Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCGEN.122.003912","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/7/3 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.
Background: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown.
Methods: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis.
Results: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003).
Conclusions: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.
期刊介绍：
Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations.
Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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