{"title":"NPPB在小儿扩张型心肌病心室辅助装置后恢复中的作用：单细胞多组学。","authors":"Yosuke Kugo, Takuji Kawamura, Akima Harada, Yuji Tominaga, Kenji Miki, Hidekazu Ishida, Takayoshi Ueno, Shigeru Miyagawa","doi":"10.1002/ehf2.15430","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>Paediatric heart transplantation requires lifelong immunosuppression, highlighting the need for recovery-oriented strategies. A subset of children with dilated cardiomyopathy (DCM) recovers left ventricular (LV) function after LV assist device (LVAD) implantation, allowing for device explantation. We aimed to identify factors associated with LV functional recovery using single-nucleus multiomics analysis of LV tissue collected at LVAD implantation.</p><p><strong>Methods: </strong>We included children with idiopathic DCM who underwent LVAD implantation between 2013 and 2023. Patients who achieved device explantation and medical stabilization were classified as the recovery group while those who required transplantation or died were classified as the non-recovery group. Single-nucleus RNA and ATAC sequencing were performed in six representative cases. Differential gene expression, chromatin accessibility and gene ontology (GO) enrichment analyses were conducted. Candidate markers were validated histologically and serologically in the full cohort.</p><p><strong>Results: </strong>Twenty-five cases were included (non-recovery, n = 15; recovery, n = 10). Age at LVAD implantation [median (range)] was 0.9 (0.1-4.6) versus 0.8 (0.3-5.6) years (P = 0.8), sex 27% versus 30% male (P > 0.9) and body weight 5.9 (3.8-14.0) versus 7.5 (5.0-26.0) kg (P = 0.049). LV ejection fraction at implantation was similar (24 (10-44) % vs. 15 (10-25) %, P = 0.2). RNA sequencing showed elevated NPPB, MYL7 and PCDH9 in recovery-group cardiomyocytes, with NPPB highest expression [baseMean = 16 305; log<sub>2</sub>Fold Change (FC) = 2.698; P < 0.001] and an accessible chromatin peak at its locus (log<sub>2</sub>FC = 1.17; P < 0.01). GO analysis indicated enrichment in apoptosis-related pathways (coefficient = 1.77, P = 0.023). Serum brain natriuretic peptide (BNP), the protein product of NPPB, was significantly higher in the recovery group at implantation [732 (372-4179) vs. 3048 (642-6032) pg/mL, P = 0.04] as was the proportion of non-apoptotic cardiomyocytes [0.21 (0.02-0.37) vs. 0.37 (0.19-0.48), P = 0.03].</p><p><strong>Conclusions: </strong>Elevated NPPB expression and BNP levels at LVAD implantation are associated with LV recovery in paediatric DCM. These findings support an anti-apoptotic role of BNP in successful bridge-to-recovery outcomes.</p>","PeriodicalId":11864,"journal":{"name":"ESC Heart Failure","volume":" ","pages":""},"PeriodicalIF":3.7000,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Role of NPPB for recovery post ventricular assist device in paediatric dilated cardiomyopathy: Single-cell multiomics.\",\"authors\":\"Yosuke Kugo, Takuji Kawamura, Akima Harada, Yuji Tominaga, Kenji Miki, Hidekazu Ishida, Takayoshi Ueno, Shigeru Miyagawa\",\"doi\":\"10.1002/ehf2.15430\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aims: </strong>Paediatric heart transplantation requires lifelong immunosuppression, highlighting the need for recovery-oriented strategies. A subset of children with dilated cardiomyopathy (DCM) recovers left ventricular (LV) function after LV assist device (LVAD) implantation, allowing for device explantation. We aimed to identify factors associated with LV functional recovery using single-nucleus multiomics analysis of LV tissue collected at LVAD implantation.</p><p><strong>Methods: </strong>We included children with idiopathic DCM who underwent LVAD implantation between 2013 and 2023. Patients who achieved device explantation and medical stabilization were classified as the recovery group while those who required transplantation or died were classified as the non-recovery group. Single-nucleus RNA and ATAC sequencing were performed in six representative cases. Differential gene expression, chromatin accessibility and gene ontology (GO) enrichment analyses were conducted. Candidate markers were validated histologically and serologically in the full cohort.</p><p><strong>Results: </strong>Twenty-five cases were included (non-recovery, n = 15; recovery, n = 10). Age at LVAD implantation [median (range)] was 0.9 (0.1-4.6) versus 0.8 (0.3-5.6) years (P = 0.8), sex 27% versus 30% male (P > 0.9) and body weight 5.9 (3.8-14.0) versus 7.5 (5.0-26.0) kg (P = 0.049). LV ejection fraction at implantation was similar (24 (10-44) % vs. 15 (10-25) %, P = 0.2). RNA sequencing showed elevated NPPB, MYL7 and PCDH9 in recovery-group cardiomyocytes, with NPPB highest expression [baseMean = 16 305; log<sub>2</sub>Fold Change (FC) = 2.698; P < 0.001] and an accessible chromatin peak at its locus (log<sub>2</sub>FC = 1.17; P < 0.01). GO analysis indicated enrichment in apoptosis-related pathways (coefficient = 1.77, P = 0.023). Serum brain natriuretic peptide (BNP), the protein product of NPPB, was significantly higher in the recovery group at implantation [732 (372-4179) vs. 3048 (642-6032) pg/mL, P = 0.04] as was the proportion of non-apoptotic cardiomyocytes [0.21 (0.02-0.37) vs. 0.37 (0.19-0.48), P = 0.03].</p><p><strong>Conclusions: </strong>Elevated NPPB expression and BNP levels at LVAD implantation are associated with LV recovery in paediatric DCM. These findings support an anti-apoptotic role of BNP in successful bridge-to-recovery outcomes.</p>\",\"PeriodicalId\":11864,\"journal\":{\"name\":\"ESC Heart Failure\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-10-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ESC Heart Failure\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ehf2.15430\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ESC Heart Failure","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ehf2.15430","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
摘要
目的：儿童心脏移植需要终身免疫抑制，强调需要以恢复为导向的策略。一部分患有扩张型心肌病（DCM）的儿童在左室辅助装置（LVAD）植入后恢复左室（LV）功能，允许设备外植。我们的目的是通过对LVAD植入时收集的左室组织进行单核多组学分析，确定与左室功能恢复相关的因素。方法：我们纳入了2013年至2023年间接受LVAD植入的特发性DCM儿童。将器械移植成功且医疗稳定的患者归为康复组，将需要移植或死亡的患者归为非康复组。对6例代表性病例进行了单核RNA和ATAC测序。进行了差异基因表达、染色质可及性和基因本体（GO）富集分析。候选标记物在整个队列中进行组织学和血清学验证。结果：共纳入25例（未痊愈15例，痊愈10例）。LVAD植入年龄[中位（范围）]为0.9（0.1-4.6）岁vs 0.8（0.3-5.6）岁（P = 0.8），性别27% vs 30%男性（P > 0.9），体重5.9 (3.8-14.0)vs 7.5 (5.0-26.0) kg （P = 0.049）。植入时左室射血分数相似(24 （10-44)% vs 15 (10-25) %, P = 0.2）。RNA测序结果显示，恢复组心肌细胞NPPB、MYL7、PCDH9表达升高，其中NPPB表达最高[baseMean = 16 305；log2Fold Change (FC) = 2.698；p 2fc = 1.17；结论：LVAD植入时NPPB表达和BNP水平升高与儿童DCM的LV恢复有关。这些发现支持BNP在成功的桥接恢复结果中的抗凋亡作用。
Role of NPPB for recovery post ventricular assist device in paediatric dilated cardiomyopathy: Single-cell multiomics.
Aims: Paediatric heart transplantation requires lifelong immunosuppression, highlighting the need for recovery-oriented strategies. A subset of children with dilated cardiomyopathy (DCM) recovers left ventricular (LV) function after LV assist device (LVAD) implantation, allowing for device explantation. We aimed to identify factors associated with LV functional recovery using single-nucleus multiomics analysis of LV tissue collected at LVAD implantation.
Methods: We included children with idiopathic DCM who underwent LVAD implantation between 2013 and 2023. Patients who achieved device explantation and medical stabilization were classified as the recovery group while those who required transplantation or died were classified as the non-recovery group. Single-nucleus RNA and ATAC sequencing were performed in six representative cases. Differential gene expression, chromatin accessibility and gene ontology (GO) enrichment analyses were conducted. Candidate markers were validated histologically and serologically in the full cohort.
Results: Twenty-five cases were included (non-recovery, n = 15; recovery, n = 10). Age at LVAD implantation [median (range)] was 0.9 (0.1-4.6) versus 0.8 (0.3-5.6) years (P = 0.8), sex 27% versus 30% male (P > 0.9) and body weight 5.9 (3.8-14.0) versus 7.5 (5.0-26.0) kg (P = 0.049). LV ejection fraction at implantation was similar (24 (10-44) % vs. 15 (10-25) %, P = 0.2). RNA sequencing showed elevated NPPB, MYL7 and PCDH9 in recovery-group cardiomyocytes, with NPPB highest expression [baseMean = 16 305; log2Fold Change (FC) = 2.698; P < 0.001] and an accessible chromatin peak at its locus (log2FC = 1.17; P < 0.01). GO analysis indicated enrichment in apoptosis-related pathways (coefficient = 1.77, P = 0.023). Serum brain natriuretic peptide (BNP), the protein product of NPPB, was significantly higher in the recovery group at implantation [732 (372-4179) vs. 3048 (642-6032) pg/mL, P = 0.04] as was the proportion of non-apoptotic cardiomyocytes [0.21 (0.02-0.37) vs. 0.37 (0.19-0.48), P = 0.03].
Conclusions: Elevated NPPB expression and BNP levels at LVAD implantation are associated with LV recovery in paediatric DCM. These findings support an anti-apoptotic role of BNP in successful bridge-to-recovery outcomes.
期刊介绍：
ESC Heart Failure is the open access journal of the Heart Failure Association of the European Society of Cardiology dedicated to the advancement of knowledge in the field of heart failure. The journal aims to improve the understanding, prevention, investigation and treatment of heart failure. Molecular and cellular biology, pathology, physiology, electrophysiology, pharmacology, as well as the clinical, social and population sciences all form part of the discipline that is heart failure. Accordingly, submission of manuscripts on basic, translational, clinical and population sciences is invited. Original contributions on nursing, care of the elderly, primary care, health economics and other specialist fields related to heart failure are also welcome, as are case reports that highlight interesting aspects of heart failure care and treatment.
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