Individualized Early Risk Assessment for Heart Diseases

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Total Enrollment

80 participants

Study Classification

OBSERVATIONAL

Study Start Date

2014-06-30

Study Completion Date

2019-06-30

Brief Summary

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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.

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Detailed Description

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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).

Conditions

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Cardiomyopathy, Hypertrophic Cardiomyopathy, Dilated

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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Control group

40 healthy volunteers will serve as control group. Skin biopsy, genotyping and disease phenotyping

Skin biopsy, genotyping and disease phenotyping

Intervention Type OTHER

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.

DCM patients

20 patients with dilated cardiomyopathy

Skin biopsy, genotyping and disease phenotyping

Intervention Type OTHER

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.

HCM patients

20 patients with hypertrophic cardiomyopathy

Skin biopsy, genotyping and disease phenotyping

Intervention Type OTHER

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.

Interventions

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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.

Intervention Type OTHER

Eligibility Criteria

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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