An Open-Label, Exploratory Study of the Safety and Preliminary Efficacy of Danicamtiv in Stable Ambulatory Participants With Primary Dilated Cardiomyopathy Due to Either MYH7 or TTN Variants or Other Causalities

The purpose of this Phase 2a study is to establish safety and preliminary efficacy of treatment with danicamtiv in patients with primary dilated cardiomyopathy (DCM) due to MYH7 or TTN variants or other causalities.

开始日期2020-08-04

申办/合作机构

Bristol Myers Squibb Co.

NCT03860454 / RecruitingN/AIIT

The Deep Phenotype of Lamin A/C Cardiomyopathy - A Proof-of-principle Relax-omic Pipeline

This study seeks to discover clinically useful tests to improve the diagnosis of a rare and serious heart muscle disease caused by mutations in a gene called 'Lamin'.
Patients born with lamin gene mutations have apparently healthy hearts initially, they begin experiencing symptoms in their twenties or thirties, and by age 45 the majority have undergone a heart transplant, experienced a major cardiac complication, or have died. Sudden heart rhythm abnormalities are a major cause of sudden death so earlier diagnosis can save lives by enabling timely treatment or implantation of specialised pacemakers (defibrillators). In clinical practice, diagnosis of lamin heart disease currently relies on the genetic test. Very little is known about the detailed imaging features of the hearts of patients with lamin heart disease although advanced echocardiography and cardiac MRI now offer the opportunity to study the health of the heart without the need for radiation.

开始日期2019-03-07

申办/合作机构

University College London

NCT03049254 / RecruitingN/AIIT

Identification of Novel Genetic Variants and Biomarkers of Disease Progression in Arrhythmogenic Cardiomyopathy

Arrhythmogenic ventricular cardiomyopathy (AVC) is a genetic condition which affects the heart and can lead to heart failure and rhythm problems, of which, sudden cardiac arrest or death is the most tragic and dangerous. Diagnosis and screening of blood-relatives is very difficult as the disease process can be subtle, but sufficient enough, so that the first event is sudden death.
The Mayo Clinic AVC Registry is a collaboration between Mayo Clinic, Rochester, USA and Papworth Hospital, Cambridge University Hospitals, Cambridge, UK. The investigators aim to enroll patients with a history of AVC or sudden cardiac death which may be due to AVC, from the US and UK. Family members who are blood-relatives will also be invited, including those who do not have the condition. Data collected include symptoms, ECG, echocardiographic, MRI, Holter, loop recorder, biopsies, exercise stress testing, blood, buccal and saliva samples.
Objectives of the study:
Discover new genes or altered genes (variants) which cause AVC
Identify biomarkers which predict (2a) disease onset, (2b) disease progression, (2c) and the likelihood of arrhythmia (ventricular, supra-ventricular and atrial fibrillation)
Correlate genotype with phenotype in confirmed cases of AVC followed longitudinally using clinical, electrocardiographic and imaging data.
Characterize desmosomal changes in buccal mucosal cells with genotype and validate with gold-standard endomyocardial biopsies

开始日期2018-02-09

申办/合作机构

Mayo Clinic

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100 项与家族性扩张型心肌病相关的临床结果

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100 项与家族性扩张型心肌病相关的转化医学

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0 项与家族性扩张型心肌病相关的专利（医药）

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项与家族性扩张型心肌病相关的文献（医药）

2024-12-31·Scandinavian Cardiovascular Journal

Genetic analysis and family screening for dilated cardiomyopathy: a retrospective analysis of the stepwise pedigree approach

Article

作者: Andersson, Therese ; Ylipää, Josef

AIMSThis study aimed to assess the practicality of using a stepwise pedigree-based approach to differentiate between familial and sporadic Dilated Cardiomyopathy (DCM), while also considering timing of the genetic analysis. The analysis includes an examination of the extent to which complete family investigations were conducted in real-world scenarios as well as the length of the investigation.METHODSThe stepwise pedigree approach involved conducting a comprehensive family history spanning 3 to 4 generations, reviewing medical records of relatives, and conducting clinical screening using echocardiography and electrocardiogram on first-degree relatives. Familial DCM was diagnosed when at least 2 family members were found to have DCM, and genetic analysis was considered as an option. This study involved a manual review of all DCM investigations conducted at the Centre of Cardiovascular Genetics at Umeå University Hospital, where the stepwise pedigree approach has been employed since 2007.RESULTSThe investigation process had a mean duration of 643 days (95% CI 560.5-724.9). Of the investigations preformed, 94 (68%) were complete, 12 (9%) were ongoing, and 33 (24%) were prematurely terminated and thus incomplete. At the conclusion of the investigations, 55 cases (43%) were classified as familial DCM, 50 (39%) as sporadic DCM, and 22 (18%) remained unassessed due to incomplete pedigrees. Among the familial cases, genetic verification was achieved in 40%.CONCLUSIONThe stepwise pedigree approach is time consuming, and the investigations are often incomplete which may suggest that a more direct approach to genetic analysis, may be warranted.

2024-10-01·Circulation: Genomic and Precision Medicine

How Normal Is Low-Normal Left Ventricular Ejection Fraction in Familial Dilated Cardiomyopathy?

Letter

作者: Rosa, Maraed ; Fatkin, Diane ; Wright, Leah ; Marwick, Tom ; McCall, Lauren ; Zentner, Dominica ; Lui, Elaine ; Peters, Stacey A. ; Fogarty, Samuel J. ; Joshi, Subodh B.

2024-09-01·European Heart Journal - Case Reports

Severe familial dilated cardiomyopathy in a young adult due to a rare LMNA mutation: a case report

Article

作者: Amer, Muhammad ; Elashery, Ahmad ; Annie, Frank H ; Rinehart, Sarah ; Belcher, Adam M

AbstractBackgroundFamilial dilated cardiomyopathy prognosis and disease progression vary greatly depending upon the type of genetic mutation. Family history and genetic testing are paramount in developing the best treatment plan for a patient. However, with rare or novel mutations, the significance may be unknown. Regarding this, the following case report highlights the importance of vigilance and suspicion when treating a patient with a variant of unknown significance. Additionally, it shows the importance of thoroughly investigating the family history of cardiovascular disease.Case summaryA 25-year-old Caucasian male was found to have a right bundle branch block and dilated cardiomyopathy upon presentation to the emergency department. Later testing showed that the dilated cardiomyopathy was due to an incredibly rare lamin A/C (LMNA) gene mutation, R349L. Despite treatment with a maximum-tolerable medication regimen and an automatic implantable cardioverter-defibrillator, the patient continued to decline and required a heart transplant.DiscussionThis case provides more information on the severity of this specific LMNA mutation that has only been documented once before. Of note, the time from the initial emergency department visit to the heart transplant was approximately 2 years. Given the patient’s young age and rapid disease progression, in addition to a strong family history of sudden cardiac death, the significance of this mutation should not be understated. The additional knowledge gained from this case report can be used to aid in timely interventions and prognosis evaluation.

项与家族性扩张型心肌病相关的新闻（医药）

2023-11-03

·药智网

《问心》收官，扩心病治疗药物有哪些？

最近收官的高口碑医疗剧《问心》，让扩心病（全称扩张型心肌病）进入大众视野，也使人们更加关注心脏健康。那么，扩张型心肌病到底是什么？临床上又是如何治疗的呢？注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。01扩心病定义及分类扩张型心肌病（Dilated cardiomyopathy，DCM）是一种以心室扩大和心肌收缩功能降低为特征的异质性心肌病，同时排除缺血性心脏病、高血压心脏病、心脏瓣膜病等，是引起心力衰竭（心衰）、心律失常和猝死的常见疾病之一[1]。根据病因和诱因不同，扩张型心肌病可分为原发性和继发性两种。其中，原发性扩张型心肌病包括家族性扩张型心肌病（Familial Dilated cardiomyopathy，FDCM）、获得性扩张型心肌病和特发性扩张型心肌病；继发性扩张型心肌病指全身性系统性疾病累及心肌，心肌病变仅是系统性疾病的一部分。扩张型心肌病的具体分类、特征及常见病因如下表所示。表1 扩张型心肌病的分类数据来源：参考文献2，药智咨询整理02扩心病如何诊断？DCM病因诊断的生物标记物包括遗传标记物（TTN、LMNA、MYH7、MYH6、TNNT2等）和免疫标记物（抗心肌抗体、AHA）。DCM的临床诊断标准为具有心室扩大和心肌收缩功能降低的客观证据：①左心室舒张末内径（LVEDd）＞5.0 cm（女性）和LVEDd＞5.5 cm（男性）（或大于年龄和体表面积预测值的117%，即预测值的2倍SD+5%）；②左室射血分数（LVEF）＜45%（Simpsons法），左室短轴缩短率（LVFS）＜25%；③发病时除外高血压、心脏瓣膜病、先天性心脏病或缺血性心脏病。DCM的影像学检查包括超声心动图（UCG）检查、心脏磁共振（CMR）检查、胸部X线检查、心电检查、冠状动脉造影检查、心脏放射性核素扫描（ECT）检查及心内膜心肌活检。表2 扩张型心肌病影像学检查汇总数据来源：参考文献1，药智咨询整理根据《中国扩张型心肌病诊断和治疗指南》（2018），DCM的诊断流程可汇总如下图。图1 扩张型心肌病诊断流程图图片来源：参考文献203扩心病治疗药物分析DCM的防治宗旨是阻止基础病因介导心肌损害，有效控制心衰和心律失常，预防猝死和栓塞，提高患者的生活质量及生存率。国内多中心临床试验资料将DCM分为3期，即早期阶段（NYHA心功能Ⅰ级）、中期阶段（心功能Ⅱ-Ⅲ级）和晚期阶段（心功能Ⅳ级），DCM初次诊断时患者的心功能状态各异，DCM的早期诊断和治疗可明显改善患者预后。对于心衰的治疗针对早期阶段、中期阶段和晚期阶段。（注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。）在早期阶段，针对DCM病因治疗，针对心室重构进行早期药物干预，包括β受体阻滞剂和血管紧张素转换酶抑制剂（ACEI）/血管紧张素受体拮抗剂（ARB），可减少心肌损伤和延缓病变发展，显著改善成年人心衰患者和DCM患者的预后。在中期阶段，采用三大类神经激素拮抗剂：β受体阻滞剂和血管紧张素转换酶抑制剂（ACEI）/血管紧张素受体拮抗剂（ARB）/血管紧张素受体-脑啡肽酶抑制剂（ARNI）、醛固酮受体拮抗剂（MRA）治疗被证实能够降低心衰患者的患病率和死亡率。三大类神经激素拮抗剂常用药物如下表所示。表3 心衰中期阶段治疗所用三大类神经激素拮抗剂常用药物数据来源：参考文献1，药智咨询整理在晚期阶段，经过利尿剂、ACEI/ARB/ARNI、β受体阻滞剂、螺内酯、地高辛等药物治疗后心衰症状仍然不能缓解的患者，可考虑静脉滴注正性肌力药物（如多巴胺、多巴酚丁胺、米力农等）和血管扩张剂（如硝酸甘油、硝普钠、萘西立肽等）作为姑息疗法短期治疗以缓解症状。药物仍未能改善症状者，可以进行超滤治疗、左室机械辅助装置或心脏移植等非药物治疗。室性心律失常和猝死是DCM的常见临床表现，预防猝死主要是控制诱发室性心律失常的可逆性因素：①纠正心衰，降低室壁张力；②纠正低钾低镁；③改善神经激素机能紊乱，选用ACEI和β受体阻滞剂；④避免药物因素如洋地黄、利尿剂的毒副作用。栓塞是DCM常见的并发症，对于已经有附壁血栓形成和血栓栓塞并发症发生的患者必须接受长期抗凝治疗。此外，DCM患者，尤其是免疫性DCM患者还可选择免疫学治疗。04结语通过本文简单的概述，相信大家对于扩张型心肌病的基本情况都有了一定的了解。希望大家可以在了解相关疾病的同时，更加关注自身的心脏健康问题。注：本文仅作信息交流之目的，文中观点不代表药智网立场，也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。参考文献[1]中华医学会心血管病学分会,中国心肌炎心肌病协作组.中国扩张型心肌病诊断和治疗指南[J].临床心血管病杂志,2018,34(5):421-434.[2]复旦大学附属中山医院心内科心肌病联盟中心.扩张型心肌病的诊断治疗流程及质量控制[J].中国分子心脏病学杂志,2023,23(2):5233-5238.声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八斤转载开白 | 马老师 18996384680（同微信）阅读原文，是昨天最受欢迎的文章哦

AHA会议

2022-12-01

·生物谷

Science子刊：碱基编辑，挽救致命心脏病并延长寿命

这些发现证明了对突变基因的精确修正是治疗基因突变导致的扩张型心肌病（DCM）的有潜力的方法。扩张型心肌病（DCM）是一种以心脏增大伴随收缩功能障碍和心源性猝死为特征的严重心脏病，扩张性心肌病是人类心力衰竭最常见的原因之一，患病率约为1/250。 RBM20基因突变，是心肌病的常见原因，占家族性扩张型心肌病（DCM）患者的2-6%。在年轻时进行心脏移植是目前唯一有效的治疗方法。而基于CRISPR的基因编辑疗法，例如碱基编辑（Base Editing）和先导编辑（Prime Editing），能够精确且永久性修正基因突变，这为治愈这种家族性心肌病带来可能，但仍需要改进其编辑效率，并避免脱靶效应。近日，德州大学西南医学中心的研究人员在 Science 子刊 Science Translational Medicine 发表了题为：Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy 的研究论文。该研究在iPSC中验证了碱基编辑和先导编辑在修正RBM20基因突变的效果，并进一步在RBM20基因突变的扩张型心肌病（DCM）小鼠模型中证实了腺嘌呤碱基编辑器（ABE）能够有效修正基因突变，恢复其心脏功能并延长寿命。首先，研究团队使用腺嘌呤碱基编辑器（ABE）对诱导多能干细胞（iPSC）中 RBM20 R634Q 突变的精确修正（A-to-G编辑效率高达92%）。虽然ABE对 RBM20 R634Q 突变的编辑效率很高，但由于编辑窗口有限，某些位点附近缺少合适的PAM序列，因此无法修正所有的RBM20突变。因此，研究团队还使用先导编辑（PE）对iPSC中的 RBM20 R636S 突变进行了精确修正（A-to-C编辑效率达40%）。为了评估腺嘌呤碱基编辑器（ABE）用于体内治疗扩张型心肌病（DCM）的潜力，研究团队进一步构建了 RBM20 R636Q 突变小鼠模型，由于人类和小鼠的 RBM20 蛋白的氨基酸数量差异，RBM20 R636Q 突变小鼠模型与人类的 RBM20 R634Q 突变相对应，其能够模拟人类扩张型心肌病（DCM）的表型。纯合子（R636Q/R636Q）小鼠表现出严重的心脏功能障碍、心力衰竭和过早死亡。研究团队使用腺相关病毒9型（AAV9）分别递送基于SpCas9突变体SpCas9-VRQR的腺嘌呤碱基编辑器ABEmax-VRQR-SpCas9，以及靶向 RBM20 R636Q 突变位点的gRNA，通过超声心动图评估显示，治疗后的小鼠恢复了心脏功能并延长了寿命。进一步RNA转录组测序分析显示，腺嘌呤碱基编辑器（ABE）挽救了纯合子R636Q/R636Q小鼠的心脏转录谱，恢复了正常基因表达。这些发现证明了对突变基因的精确修正是治疗基因突变导致的扩张型心肌病（DCM）的有潜力的方法。

基因疗法

2022-10-31

·PRNewswire

Deerfield Management and BioSymetrics partner to discover and develop novel therapeutics

Collaboration to advance cardiology and neurology targets using phenomics and genomic data to improve human health NEW YORK , Oct. 31, 2022 /PRNewswire/ -- Deerfield Management, a healthcare investment firm, and BioSymetrics, a phenomics-driven drug discovery company, today announced a five-year joint venture to accelerate the advancement of new therapeutics, with an initial focus on cardiovascular and neurological diseases. The collaboration will identify new drug discovery programs that combine BioSymetrics' AI-powered target discovery and validation platform with Deerfield's drug discovery and commercial modeling capabilities. "BioSymetrics' platform creates proprietary and highly valuable insights into biology that can help identify novel therapeutics," said James Flynn, Managing Partner, Deerfield Management and Cure Founder. "Our collaboration focuses on complex conditions in cardiovascular and neurological disease where BioSymetrics' data and analytical capabilities can be particularly important. We are excited about the breakthroughs possible through this partnership." BioSymetrics takes a phenomics-driven approach to advancing drug discovery. The company's target discovery platform uses machine learning to connect clinical and experimental data – including patient data from millions of electronic medical records, genomics, and experimental data captured in zebrafish models using proprietary computer vision – to identify high-confidence targets for drug discovery. Targets discovered using BioSymetrics' platform are grounded in human genetic evidence, giving them twice the likelihood of clinical success as demonstrated in the seminal paper by Matt Nelson, VP Genetics & Genomics at Deerfield Management. BioSymetrics is advancing programs in cardiometabolic, neurological, and rare diseases, including familial dilated cardiomyopathy, atherosclerosis, and epilepsy. "Deerfield shares our philosophy of using human genetic evidence and rapid in vivo validation in target discovery," said Anthony Iacovone, Co-founder and CEO. "For a prolific target discovery platform like ours, Deerfield's strengths in drug discovery and healthcare expertise ensure that together we can aim to focus on the programs with the highest probability of success and drive forward the best science. We are enthusiastic to begin this effort and work together with Deerfield in translating complex clinical and experimental biology into actionable therapeutic development programs." Under the terms of the agreement, Deerfield and BioSymetrics will identify therapeutic targets using BioSymetrics' platform and database. Deerfield will provide target product profiles and due diligence support, commercial modeling services, and drug development plans and infrastructure for projects that the parties decide to advance. About Deerfield Management Deerfield Management is an investment management firm committed to advancing healthcare through investment, information and philanthropy. The Firm works across the healthcare ecosystem to connect people, capital, ideas and technology in bold, collaborative and inclusive ways. For more information, please visit . About BioSymetrics BioSymetrics is a phenomics-driven drug discovery company with a vision to translate data into discoveries. BioSymetrics integrates clinical and experimental data, using machine learning, to translate human disease biology and advance precision medicines. For more information, please visit or follow us on LinkedIn. SOURCE Deerfield Management