Individualized Early Risk Assessment for Heart Diseases (IndivuHeart)
2019년 4월 26일 업데이트: 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.
연구 개요
상세 설명
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).
연구 유형
관찰
등록 (예상)
80
연락처 및 위치
이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.
연구 장소
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Hamburg, 독일, 20246
- Department of Experimental Pharmacology and Toxicology
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참여기준
연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.
자격 기준
공부할 수 있는 나이
18년 (성인)
건강한 자원 봉사자를 받아들입니다
예
연구 대상 성별
모두
샘플링 방법
비확률 샘플
연구 인구
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).
설명
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
공부 계획
이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.
연구는 어떻게 설계됩니까?
디자인 세부사항
코호트 및 개입
그룹/코호트 |
개입 / 치료 |
|---|---|
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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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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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generation of hiPSC-EHT and in vitro phenotyping
기간: 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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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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clinical phenotyping and disease progression
기간: 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
기간: 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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공동 작업자 및 조사자
여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.
수사관
- 수석 연구원: Thomas Eschenhagen, Prof.Dr.med., Universitatsklinikum Hamburg-Eppendorf
간행물 및 유용한 링크
연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.
일반 간행물
- 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.
연구 기록 날짜
이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.
연구 주요 날짜
연구 시작
2014년 6월 1일
기본 완료 (예상)
2019년 6월 1일
연구 완료 (예상)
2019년 6월 1일
연구 등록 날짜
최초 제출
2015년 3월 16일
QC 기준을 충족하는 최초 제출
2015년 4월 10일
처음 게시됨 (추정)
2015년 4월 15일
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
2019년 4월 29일
QC 기준을 충족하는 마지막 업데이트 제출
2019년 4월 26일
마지막으로 확인됨
2019년 4월 1일
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- 0174/134/2-1
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