Individualized Early Risk Assessment for Heart Diseases

Cardiomyopathy, Dilated Clinical Trial

— IndivuHeart  

Official title:

Individualized Early Risk Assessment for Heart Diseases

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02417311
• Other study ID #: 0174/134/2-1
• Status: Active, not recruiting
• Start date: June 2014
• Est. completion date: June 2019

Study information

• Verified date: April 2019
• Source: Universitätsklinikum Hamburg-Eppendorf
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Cardiomyopathy, Hypertrophic
• Heart Diseases
• Hypertrophy

Intervention

Other:
• Skin biopsy, genotyping and disease phenotyping
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.

Locations

Country	Name	City	State
Germany	Department of Experimental Pharmacology and Toxicology	Hamburg

Sponsors (1)

Lead Sponsor	Collaborator
Universitätsklinikum Hamburg-Eppendorf

Country where clinical trial is conducted

Germany, 

References & Publications (3)

Eschenhagen T, Fink C, Remmers U, Scholz H, Wattchow J, Weil J, Zimmermann W, Dohmen HH, Schäfer 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. — View Citation

Hansen A, Eder A, Bönstrup 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. Schwörer, Alexander [corrected to Schwoerer, Alexander P]. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	up to 60 month
Secondary	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.	up to 60 month
Secondary	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.	up to 60 month