Genomics in Heart Transplants
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- This is an observational study: the protocol does not assign a study treatment.
- Who it may be relevant to
- Registry conditions: Heart Transplantation. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Germany
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
Unsure about the terms? Read our patient guide →
Official title
Long-read Genome Sequencing and Risk Stratification of Myocardial Ischemia in Patients With Heart Transplantation
Overview
A cross-sectional analysis of 200 heart transplant recipients, combining in-depth phenotyping and risk factor assessment (cardiac MRI, coronary angiogram with OCT, cardiorespiratory exercise tests, exogenic factors like nutrition, smoking, lipid profile) with short-read whole-genome sequencing to elucidate the interplay of established PRS from the literature and exogenic risk factors with respect to HTx outcomes will be carried out. Besides that, a long-read whole-genome sequencing of 100 newly transplanted recipients and their corresponding donors and extend latest bioinformatics methods developed by the study to analyze long-read data will be performed. This will enable a comprehensive and integrated analysis of structural variants, polygenic risk, high-penetrance variant genotypes, immunogenetic (major and minor histocompatibility), and individual lifestyle risk factors in a unique donor-recipient cohort, elucidating the extent of within-cohort variability and cross-correlations between the considered potential risk factors and an exploratory analysis of the utility of genetic risk scores in light of the study results will be carried out.
Detailed description
Background: Heart transplantation (HTx) is the treatment of choice for patients with end-stage heart failure who remain symptomatic despite optimal medical therapy. Even with best-practice follow-up care, one out of eight HTx patients eventually die of ischemic cardiomyopathy and recurrent acute myocardial infarction (AMI). Classical risk factors like the recipient indication for heart transplantation explain a fraction of adverse outcomes, but no conventional risk factor alone satisfactorily predicts the probability of cardiac allograft vasculopathy (CAV) or recurrent AMI in HTx patients; in addition, the underlying pathomechanisms are poorly understood.
Therefore, there is an urgent need for an improved understanding of the factors contributing to recurrent myocardial ischemia in HTx patients. Recent large-scale studies of the genetic architecture of coronary artery disease in the general population indicate that polygenic risk scores (PRS) explain more disease risk than any single non-genetic risk factor, but, due to a lack of longitudinal follow-up studies with deep phenotyping, PRS have not yet been widely adopted in clinical practice. Furthermore, current genetic studies are based on microarrays or short-read sequencing, severely limiting their ability to characterize the effect of complex or structural genetic variation, in the whole human genome as well as in key loci of potential importance for HTx outcomes, affecting, e.g., lipid metabolism (e.g. LPA) and immunogenetic compatibility (e.g. the major histocompatibility complex).
In summary, there is presently no study leveraging the improved ability to resolve human genomes with long-read sequencing technologies in a deeply phenotyped cohort for an improved understanding of recurring myocardial ischemia.
Study design and aims: In an innovative three-component study design, comprehensive phenotyping with the latest long-read sequencing technology and algorithmic advances in computational genomics to elucidate the interplay of genetic and non-genetic risk factors of myocardial ischemia in HTx patients at unprecedented resolution and pave the way towards detailed risk stratification and tailored treatment, will be combined
Significance and translational potential: By enabling the integrated analysis of structural variants, high-penetrance complex variants, and high-resolution immunogenetics, long-read sequencing will enable improved genetic models of the development of ischemia in HTx patients and contribute to an improved understanding of underlying pathomechanisms. Based on this, the investigators will be able to propose schemes to incorporate integrated risk scores in future clinical trials for personalized treatment stratification.
Primary outcome measures
- rate of Clinically significant ischemia [Time frame: 5 years]
Secondary outcome measures (6)
- cardiovascular death [Time frame: 5 years]
- myocardial infarction [Time frame: 5 years]
- Hospitalisation (w/o allograft rejection) [Time frame: 5 years]
- Cardiac allograft vasculopathy (macrocirculatory) [Time frame: 5 years]
- number of coronary microvascular dysfunction [Time frame: 5 years]
- number of coronary microvascular dysfunction [Time frame: 5 years]
Eligibility criteria
Inclusion criteria
- Patients > 18 years old undergoing heart transplantation in our centre
Exclusion criteria
- < 18 years
- incapable of giving consent
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Observational model
- Cohort
Study locations
Germany · 1 center
- University-Hospital Düsseldorf Division of Cardiology, Pulmonary Disease and Vascular Medi — Düsseldorf
Identifiers
NCT: NCT06012162 · Genomics in HTx