PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Genomic and Precision Medicine Pub Date : 2023-08-01 Epub Date: 2023-07-03 DOI:10.1161/CIRCGEN.122.003912

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

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引用次数: 0

Abstract

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.

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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。

背景：1p36缺失综合征可使儿童易患心肌病。缺失断点是可变的，并且可以删除转录因子PRDM16。早期研究表明，在1p36缺失的患者中，PRDM16的缺失可能是心肌病的基础；然而，PRDM16缺失对预后的影响尚不清楚。方法：该回顾性队列包括来自4家医院的1p36缺失综合征受试者。分析了心肌病的患病率和免于死亡、心脏移植或心室辅助装置。导出了一个系统回顾队列进行进一步分析。产生心脏特异性Prdm16敲除小鼠（Prdm16条件敲除）。超声心动图分别在4个月和6至7个月时进行。在7个月时进行组织学染色和qPCR以评估纤维化。结果：回顾性队列包括71例患者。在PRDM16缺失的个体中，34.5%的个体发展为心肌病，而PRDM16未缺失的个体为7.7%（P=0.01）。在回顾性和系统性联合回顾队列（n=134）中，PRDM16删除相关的心肌病风险被概括且显著（29.1%对10.8%，P=0.03），或心室辅助装置（P=0.04）。在PRDM16缺失的小鼠中，34.5%的雌性小鼠患上了心肌病，而雄性小鼠的发病率为16.7%（P=0.02）。我们发现，在雌性PRDM16条件敲除小鼠中，收缩功能障碍和纤维化的发生率和严重程度存在性别特异性差异。此外，雌性Prdm16条件性敲除小鼠的死亡率显著升高（P=0.0003）。结论：Prdm16缺失与心肌病和心脏死亡率显著增加有关。Prdm16条件敲除小鼠以性别偏见的方式发展为心肌病。PRDM16缺失的患者应进行心脏病评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

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.