Cardiomyopathy, HypertrophicIndivuHeartNCT02417311
Individualized Early Risk Assessment for Heart Diseases
An observational study of Cardiomyopathy, Hypertrophic and Cardiomyopathy, Dilated, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Cardiomyopathy, Hypertrophic, Cardiomyopathy, Dilated
- What is being tested?
- Skin biopsy, genotyping and disease phenotyping
- How many people
- 80 participants
- Where
- 1 siteGermany
- Study dates
- Jun 2014to Jun 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Study population: 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).
Who may be able to join
- 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
Who cannot join
- Uncontrolled hypertension,
- coronary artery disease,
- persistent atrial fibrillation,
- enlisted for myectomy
Trial locations and contacts
1 site in 1 country.
Germany1 site
Department of Experimental Pharmacology and Toxicology
Hamburg, 20246
About this study
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.
Read the detailed description
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).
- Being tested
- Skin biopsy, genotyping and disease phenotyping
- Keywords
- Engineered Heart Tissue (EHT), human induced pluripotent stem cells (hiPSC)
- Medical subject headings
- Cardiomyopathy, Hypertrophic, Cardiomyopathy, Dilated
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Skin biopsy, genotyping and disease phenotypingOther
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.
| Study group | Role | What they receive |
|---|---|---|
| Control group | 40 healthy volunteers will serve as control group. Skin biopsy, genotyping and disease phenotyping Receives: Other: Skin biopsy, genotyping and disease phenotyping | |
| DCM patients | 20 patients with dilated cardiomyopathy Receives: Other: Skin biopsy, genotyping and disease phenotyping | |
| HCM patients | 20 patients with hypertrophic cardiomyopathy Receives: Other: Skin biopsy, genotyping and disease phenotyping |
What is being measured
The primary outcome is the main question the study is designed to answer.
generation of hiPSC-EHT and in vitro phenotyping
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.
Measured: up to 60 month
Secondary outcomes (2)
clinical phenotyping and disease progression
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.
Measured: up to 60 month
genotyping
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.
Measured: up to 60 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2015 (estimated)
- Study startJun 2014
- Primary completionJun 2019 (estimated)
- Study completionJun 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Cardiomyopathy, HypertrophicStudies of the same condition, open and under way.
- More trials run by Universitätsklinikum Hamburg-EppendorfThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitätsklinikum Hamburg-Eppendorf
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Eschenhagen, Prof.Dr.med., Principal investigator, Universitätsklinikum Hamburg-Eppendorf
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02417311
- Sponsor's protocol ID
- 0174/134/2-1
- Acronym
- IndivuHeart
- Status last verified
- Apr 2019
- First submitted
- 16 Mar 2015
- Last updated
- 29 Apr 2019
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 20448218Eschenhagen 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.
PubMed 9240969Takahashi 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.
PubMed 18035408Krause J, Nickel A, Madsen A, Aitken-Buck HM, Stoter AMS, Schrapers J, Ojeda F, Geiger K, Kern M, Kohlhaas M, Bertero E, Hofmockel P, Hubner F, Assum I, Heinig M, Muller C, Hansen A, Krause T, Park DD, Just S, Aissi D, Bornigen D, Lindner D, Friedrich N, Alhussini K, Bening C, Schnabel RB, Karakas M, Iacoviello L, Salomaa V, Linneberg A, Tunstall-Pedoe H, Kuulasmaa K, Kirchhof P, Blankenberg S, Christ T, Eschenhagen T, Lamberts RR, Maack C, Stenzig J, Zeller T. An arrhythmogenic metabolite in atrial fibrillation. J Transl Med. 2023 Aug 24;21(1):566. doi: 10.1186/s12967-023-04420-z.
PubMed 37620858Madsen 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.
PubMed 32885664
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Individualized Early Risk Assessment for Heart Diseases
- ClinicalTrials.gov ID
- NCT02417311
- Acronym / sponsor ID
- IndivuHeart / 0174/134/2-1
- Keywords
- Engineered Heart Tissue (EHT), human induced pluripotent stem cells (hiPSC)
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Universitätsklinikum Hamburg-EppendorfUniversity, hospital or other
- Study start
- Jun 2014
- Primary completion
- Jun 2019 (estimated)
- Study completion
- Jun 2019 (estimated)
- First posted
- 15 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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).
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control group | – | Other: Skin biopsy, genotyping and disease phenotyping40 healthy volunteers will serve as control group. Skin biopsy, genotyping and disease phenotyping |
| DCM patients | – | Other: Skin biopsy, genotyping and disease phenotyping20 patients with dilated cardiomyopathy |
| HCM patients | – | Other: Skin biopsy, genotyping and disease phenotyping20 patients with hypertrophic cardiomyopathy |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- 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).
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (4 listed)
- Uncontrolled hypertension,
- coronary artery disease,
- persistent atrial fibrillation,
- enlisted for myectomy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Skin biopsy, genotyping and disease phenotypingMajor 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. | Other | Control group, DCM patients, HCM patients |
Primary outcome
generation of hiPSC-EHT and in vitro phenotyping
Time frame: up to 60 month
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.
2 secondary outcomes
clinical phenotyping and disease progression
Time frame: up to 60 month
genotyping
Time frame: up to 60 month
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2019.
- Background: PubMed 20448218Hansen 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.
- Background: PubMed 9240969Eschenhagen 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.
- Background: PubMed 18035408Takahashi 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.
- Derived from this study: PubMed 37620858Krause J, Nickel A, Madsen A, Aitken-Buck HM, Stoter AMS, Schrapers J, Ojeda F, Geiger K, Kern M, Kohlhaas M, Bertero E, Hofmockel P, Hubner F, Assum I, Heinig M, Muller C, Hansen A, Krause T, Park DD, Just S, Aissi D, Bornigen D, Lindner D, Friedrich N, Alhussini K, Bening C, Schnabel RB, Karakas M, Iacoviello L, Salomaa V, Linneberg A, Tunstall-Pedoe H, Kuulasmaa K, Kirchhof P, Blankenberg S, Christ T, Eschenhagen T, Lamberts RR, Maack C, Stenzig J, Zeller T. An arrhythmogenic metabolite in atrial fibrillation. J Transl Med. 2023 Aug 24;21(1):566. doi: 10.1186/s12967-023-04420-z.
- Derived from this study: PubMed 32885664Madsen 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Eschenhagen, Prof.Dr.med. principal investigator
Universitätsklinikum Hamburg-Eppendorf
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cardiomyopathy, Hypertrophic and Cardiomyopathy, Dilated, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
generation of hiPSC-EHT and in vitro phenotyping (time frame: up to 60 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02417311, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Apr 2019.