Individualized Early Risk Assessment for Heart Diseases (IndivuHeart)

General Information

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 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. and allow individualized drug testing (acute and chronic). 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 Sex/Gender Sexes Eligible for Study: All, 18 Years to 60 Years (Adult)
Clinical trials phase Other
Start date (estimated) 2014-06-01
End date (estimated) 2019-06-01
Clinical feature
Label hypertrophic cardiomyopathy
Description A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).; A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.

Administrative Information

NCT Number NCT02417311
Sponsor Protocol Number 0174/134/2-1
Regulatory body approval
Name Ethics commitee, University Medical Center Hamburg-Eppendorf
Approval number Az. PV4798 / 28.10.2014
Study sites
Public contact
First name Bärbel
Last name Ulmer
Street Martinistrasse 46
Postcode 20246
City Hamburg
Sponsors University Medical Center Hamburg-Eppendorf

Cell Line


Recruitment Status Completed
Comment recruitment status 60
Estimated number of participants 60
Contact institutions/departments