Clinical trial NCT02417311: Individualized Early Risk Assessment for Heart Diseases
Official title: Individualized Early Risk Assessment for Heart Diseases
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Cardiomyopathy, Hypertrophic
Cardiomyopathy, Dilated
Keywords: Engineered Heart Tissue (EHT)
human induced pluripotent stem cells (hiPSC)
Lead sponsor: Universitätsklinikum Hamburg-Eppendorf
Sponsor class: OTHER
First posted: 2015-04-15
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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).

Brief 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: generation of hiPSC-EHT and in vitro phenotyping
timeFrame: up to 60 month
Secondary outcomes:
measure: clinical phenotyping and disease progression
timeFrame: up to 60 month
measure: genotyping
timeFrame: up to 60 month
Other outcomes:
Locations:
city: Hamburg
country: Germany
facility: Department of Experimental Pharmacology and Toxicology
Study officials:
affiliation: Universitätsklinikum Hamburg-Eppendorf
name: Thomas Eschenhagen, Prof.Dr.med.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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. doi: 10.1016/j.cell.2007.11.019.
citation: 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.