The impact of genotype on the cellular architecture of dilated and arrhythmogenic cardiomyopathies
Creators
- 1. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany
Description
Heart failure is a clinical syndrom and leading cause of death worldwide, caused by functional and structural abnormalities of the heart. Dilated Cardiomyopathy, defined by a left ventricular enlargement, and arrhythmogenic cardiomyopathy, defined by a right ventricular dysfunction, are leading causes of heart failure. Despite previous efforts to characterise molecular changes in the failing heart, little is known on cell-type specific abundance and expression changes under pathological conditions, and how individual cell-types interact during heart failure and cardiac remodelling. To address this question, a protocol for the isolation of intact nuclei was firstly established to perform robust single-nucleus RNA sequencing in the heart. Next, the cell-type composition of the healthy adult human heart was characterised. Here my focus was on the fibroblast nieche by characterising fibroblast states, their composition and their atria- and ventricle specific expression patterns. Cell type and state annotation was then used to characterize the transcriptome of roughly 900,000 nuclei from 61 failing, non-ischemic human hearts with distinct pathogenic variants in DCM and ACM genes or idiopathic disease and compared those to 18 healthy donor hearts. This dataset revealed distinct responses of the right and left ventricle with differently regulated genes and pathways, and compositional changes across cell types and states. To independently confirm genotype-specific responses, machine learning approaches were applied, predicting genotype subgroups with high accuracy. Taken together, the findings published in this thesis upends the prevalent dogma that heart failure results in a final common pathway. This repository contains supplementary tables of this thesis. The results generated during this project were previously published in https://www.science.org/doi/10.1126/science.abo1984.
Files
T10_LV_Myeloids_Cell_States.zip
Files
(7.6 MB)
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