Individualized Early Risk Assessment for Heart Diseases

NCT02417311 | Unknown

• 1 other identifier: 0174/134/2-1
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

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.

Conditions

Cardiomyopathy, Hypertrophic; Cardiomyopathy, Dilated

Keywords

Engineered Heart Tissue (EHT); human induced pluripotent stem cells (hiPSC)

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• clinical phenotyping and disease progression

  up to 60 month

• genotyping

  up to 60 month

Study Arms (3)

Control group

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

Other: Skin biopsy, genotyping and disease phenotyping

DCM patients

20 patients with dilated cardiomyopathy

Other: Skin biopsy, genotyping and disease phenotyping

HCM patients

20 patients with hypertrophic cardiomyopathy

Other: Skin biopsy, genotyping and disease phenotyping

Interventions

Skin biopsy, genotyping and disease phenotyping 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.

Control group; DCM patients; HCM patients

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• 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).

You may qualify if:

• 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

You may not qualify if:

• Uncontrolled hypertension,
• coronary artery disease,
• persistent atrial fibrillation,
• enlisted for myectomy

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead

Study Sites (1)

Department of Experimental Pharmacology and Toxicology

Hamburg, 20246, Germany

Location

Related Publications (5)

• 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.

  PMID: 20448218 BACKGROUND

• 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.

  PMID: 9240969 BACKGROUND

• 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.

  PMID: 18035408 BACKGROUND

• Krause 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.

  PMID: 37620858 DERIVED

• 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.

  PMID: 32885664 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Skin biopsy and blood

MeSH Terms

Conditions

Cardiomyopathy, Hypertrophic; Cardiomyopathy, Dilated

Interventions

Genotype

Condition Hierarchy (Ancestors)

Cardiomyopathies; Heart Diseases; Cardiovascular Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Aortic Valve Disease; Heart Valve Diseases; Cardiomegaly; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Genetic Phenomena

Study Officials

• Thomas Eschenhagen, Prof.Dr.med.

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2015
• First Posted: April 15, 2015
• Study Start: June 1, 2014
• Primary Completion: June 1, 2019
• Study Completion: June 1, 2019
• Last Updated: April 29, 2019

Record last verified: 2019-04

Locations

DE (1)