Individualized Early Risk Assessment for Heart Diseases (IndivuHeart)
2019年4月26日 更新者：Universitätsklinikum Hamburg-Eppendorf
Heart failure (HF) is the common end-stage of different medical conditions.
It is the only growing cardiovascular disease and its prognosis remains worse than that of many malignancies.
The lack of evidence-based treatment for patients with diastolic HF (HFpEF) exemplifies that the current "one for all" therapy has to be advanced by an individualized approach.
Inherited cardiomyopathies can serve as paradigmatic examples of different HF pathogenesis.
Both gain- and loss-of-function mutations of the same gene cause disease, calling for disease-specific agonism or antagonism of this gene´s function.
However, mutations alone do not predict the severity of cardiomyopathies nor therapy, because their impact on cardiac myocyte function is modified by numerous factors, including the genetic context.
Today, patient-specific cardiac myocytes can be evaluated by the induced pluripotent stem cell (hiPSC) technology.
Yet, unfolding the true potential of this technology requires robust, quantitative, high content assays.
The researchers' recently developed method to generate 3D-engineered heart tissue (EHT) from hiPSC provides an automated, high content analysis of heart muscle function and the response to stressors in the dish.
The aim of this project is to make the technology a clinically applicable test.
Major steps are (i) in depths clinical phenotyping and genotyping of patients with cardiomyopathies or HFpEF, (ii) follow-up of the clinical course, (iii) generation of hiPSC lines (40 patients, 40 healthy controls), and (iv) quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement.
The product of this study is an SOP-based assay with standard values for hiPSC-EHT function/stress responses from healthy volunteers and patients with different heart diseases.
The project could change clinical practice and be a step towards individualized risk prediction and therapy of HF.
調査の概要
詳細な説明
At present, heart function in patients can only be analysed by imaging methods or hemodynamic measurements. This has dramatically changed by the discovery that hiPSC can be generated from somatic cells (e.g. fibroblasts) by transduction of pluripotency genes. The investigators and others have shown that pluripotent stem cells can be efficiently differentiated into beating cardiac myocytes. This allows for the first time to study the function of cardiac myocytes from an individual patient. However, at present, only alterations were reproduced in hiPSC cells that were known previously and important limitations have to be resolved:
- Immaturity of hiPSC-derived cardiac myocytes
- Variability of hiPSC-generation, cardiac myocyte differentiation and experimental analyses
- No readout of contractile force, the parameter mostly affected in heart failure
- No modeling of hemodynamic stress in vitro
- No statistically valid correlation of hiPSC-cardiac myocyte function with clinical/genetic data
- Uncertainty as to standard values and adequate controls
- Unclear predictive value
The research challenge for the coming years is to resolve these shortcomings. IndivuHeart formulates a number of hypotheses and goals that are based on the researchers' longstanding expertise in tissue engineering and recent, still unpublished data on the pathophysiology of HCM and its modeling in EHT. The study will
- reveal standard values for hiPSC-EHT function in a statistically valid manner, both under basal and stress conditions,
- define a "cardiomyopathy phenotype" in vitro,
- allow new mechanistic insight into the pathogenesis of human HCM and DCM,
- uncover HCM-like abnormalities in HFpEF,
- allow individualized drug testing (acute and chronic).
研究の種類
観察的
入学 (予想される)
80
連絡先と場所
このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。
研究場所
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Hamburg、ドイツ、20246
- Department of Experimental Pharmacology and Toxicology
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参加基準
研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。
適格基準
就学可能な年齢
18年～60年 (大人)
健康ボランティアの受け入れ
はい
受講資格のある性別
全て
サンプリング方法
非確率サンプル
調査対象母集団
Recruitment of patients will be done by the Cardiomyopathy Outpatient Clinic which is led by Dr. M. Patten and Dr. J. Münch at the Department of Cardiology, University Heart Centre, UKE (Prof.
Blankenberg).
説明
Inclusion Criteria:
- HCM: ProBNP ≥ 300 ng/l; IVSd ≥ 20 mm; E/E´ ≥ 8, LVOT > 30 mmHg
- DCM: presence of signs and/or symptoms of HF (NYHA II-IV); ProBNP ≥ 300 ng/l; LV EF ≤ 40% for > 3 month
Exclusion Criteria:
- Uncontrolled hypertension,
- coronary artery disease,
- persistent atrial fibrillation,
- enlisted for myectomy
研究計画
このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。
研究はどのように設計されていますか？
デザインの詳細
コホートと介入
グループ/コホート |
介入・治療 |
|---|---|
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Control group
40 healthy volunteers will serve as control group.
Skin biopsy, genotyping and disease phenotyping
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Major steps of the project are (i) in depths clinical phenotyping and follow-up of the clinical course of probands (ii) genotyping of candidate genes involved in heart disease development and (iii) in vitro functional tests of engineered heart tissue (EHT), miniature beating heart muscles.
These EHTs are generated from hiPSC (human induced pluripotent stem cells) lines derived from skin biopsies of each participant.
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DCM patients
20 patients with dilated cardiomyopathy
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Major steps of the project are (i) in depths clinical phenotyping and follow-up of the clinical course of probands (ii) genotyping of candidate genes involved in heart disease development and (iii) in vitro functional tests of engineered heart tissue (EHT), miniature beating heart muscles.
These EHTs are generated from hiPSC (human induced pluripotent stem cells) lines derived from skin biopsies of each participant.
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HCM patients
20 patients with hypertrophic cardiomyopathy
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Major steps of the project are (i) in depths clinical phenotyping and follow-up of the clinical course of probands (ii) genotyping of candidate genes involved in heart disease development and (iii) in vitro functional tests of engineered heart tissue (EHT), miniature beating heart muscles.
These EHTs are generated from hiPSC (human induced pluripotent stem cells) lines derived from skin biopsies of each participant.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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generation of hiPSC-EHT and in vitro phenotyping
時間枠：up to 60 month
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After generation of proband-specific 3D-engineered heart tissue (EHT) from hiPSC we will make a quantitative assessment of hiPSC-EHT function under basal conditions and in response to pro-arrhythmic or cardio-active drugs and chronic afterload enhancement.
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up to 60 month
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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clinical phenotyping and disease progression
時間枠：up to 60 month
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All 40 patients will be subjected to (i) high-end echocardiography including tissue Doppler and speckle tracking technology, (ii) MRI, (iii) spiroergometry and (iv) 24 h-holter ECG monitoring.
Key parameters are guideline-recommended indices of systolic (e.g.
fractional shortening, ejection fraction) and diastolic heart function (e.g.
left atrial size, E/A, E'/A' and E/E´ratios), outflow tract gradient and cardiac remodeling (gadolinium late enhancement).
The latter will be only done in HCM/DCM for ethical reasons.
Technical analyses will be made at study entry and after 4 years, clinical examinations once a year (Cardiomyopathy Outpatient Clinic).
Patients and their treating physicians will be prompted to report any clinical event during the course of the study.
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up to 60 month
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genotyping
時間枠：up to 60 month
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The genetic part of this project does not focus on the detection of new HCM/DCM disease genes, but on comprehensively determining the molecular basis of cardiomyopathy in the included patients. DNA samples will first be subjected to sequencing of a panel of about 120 cardiomyopathy-related candidate genes, which detects approximately 75% of all disease-causing mutations. The rest will be analysed by whole genome sequencing. The resulting sequence data will be processed using CASAVA, followed by subsequent analyses using the GATK software package provided through the Broad Institute (Boston, USA) and the commercial software CLC-BIO. |
up to 60 month
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協力者と研究者
ここでは、この調査に関係する人々や組織を見つけることができます。
捜査官
- 主任研究者：Thomas Eschenhagen, Prof.Dr.med.、Universitätsklinikum Hamburg-Eppendorf
出版物と役立つリンク
研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。
一般刊行物
- Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007 Nov 30;131(5):861-72. doi: 10.1016/j.cell.2007.11.019.
- Hansen A, Eder A, Bonstrup M, Flato M, Mewe M, Schaaf S, Aksehirlioglu B, Schwoerer AP, Uebeler J, Eschenhagen T. Development of a drug screening platform based on engineered heart tissue. Circ Res. 2010 Jul 9;107(1):35-44. doi: 10.1161/CIRCRESAHA.109.211458. Epub 2010 May 6. Erratum In: Circ Res. 2011 Nov 11;109(11):e54. Schworer, Alexander [corrected to Schwoerer, Alexander P].
- Eschenhagen T, Fink C, Remmers U, Scholz H, Wattchow J, Weil J, Zimmermann W, Dohmen HH, Schafer H, Bishopric N, Wakatsuki T, Elson EL. Three-dimensional reconstitution of embryonic cardiomyocytes in a collagen matrix: a new heart muscle model system. FASEB J. 1997 Jul;11(8):683-94. doi: 10.1096/fasebj.11.8.9240969.
- Madsen A, Hoppner G, Krause J, Hirt MN, Laufer SD, Schweizer M, Tan WLW, Mosqueira D, Anene-Nzelu CG, Lim I, Foo RSY, Hansen A, Eschenhagen T, Stenzig J. An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility. Circulation. 2020 Oct 20;142(16):1562-1578. doi: 10.1161/CIRCULATIONAHA.119.044444. Epub 2020 Sep 4. Erratum In: Circulation. 2021 Apr 13;143(15):e830.
研究記録日
これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。
主要日程の研究
研究開始
2014年6月1日
一次修了 (予想される)
2019年6月1日
研究の完了 (予想される)
2019年6月1日
試験登録日
最初に提出
2015年3月16日
QC基準を満たした最初の提出物
2015年4月10日
最初の投稿 (見積もり)
2015年4月15日
学習記録の更新
投稿された最後の更新 (実際)
2019年4月29日
QC基準を満たした最後の更新が送信されました
2019年4月26日
最終確認日
2019年4月1日
詳しくは
本研究に関する用語
その他の研究ID番号
- 0174/134/2-1
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