Genetic findings suggest it is time to rethink how we treat heart failure
There are an estimated 23 million people with heart failure worldwide. Diseases of the heart muscle that make it difficult for the heart to pump blood to the rest of the body – such as dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) – can result in heart failure. However, current treatments are often inadequate since they do not take these distinct conditions into account. Systematically identifying molecules and pathways involved in heart failure could lay the foundation for more effective treatments. To make this possible, an international team of researchers used single-nucleus RNA sequencing (snRNAseq) to gain insight into the specific changes that occur in different cell types and cell states. Supported in part by the EU-funded CodingHeart project, their research resulted in some surprising findings. Although some genetic signatures are shared by healthy and diseased hearts, others are distinct. This points to new candidate targets for therapy and suggests that personalised treatment could lead to better patient care. The study has been published in the journal ‘Science’. “Our findings hold enormous potential for rethinking how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that may alter how the heart functions,” states the study’s corresponding author Dr Christine E. Seidman in an article posted on ‘Newswise’. Dr Seidman is the Thomas W. Smith Professor of Medicine at Harvard Medical School and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital.
Genotyping is important
“This is fundamental research, but it identifies targets that can be experimentally pursued to propel future therapeutics,” Dr Seidman goes on to say. “Our findings also point to the importance of genotyping — not only does genotyping empower research but it can also lead to better, personalized treatment for patients.” The research team analysed tissue samples from 18 healthy donors and 61 heart failure patients with DCM, ACM or an unknown cardiomyopathy disease. Using snRNAseq, they studied the genetic readouts of individual cells to identify cellular and molecular changes in each distinct cell type. Of the estimated 881 000 nuclei isolated from healthy and diseased hearts, the scientists identified 10 major cell types and 71 distinct transcriptional states. In DCM and ACM tissues, cardiomyocytes – the cells that make the heart contract, helping it to pump blood to the rest of the body – were significantly depleted, while endothelial and immune cells were increased. Additionally, while connective tissue in diseased hearts was thicker and had more scarring, unexpectedly, fibroblasts – the cells that contribute to the formation of connective tissue – did not increase. Instead, they showed altered transcriptional states. Further analyses of hearts with mutations in certain disease genes, including DCM genes LMNA and TTN and ACM gene PKP2, identified molecular and cellular differences as well as multiple shared transcriptional changes. The team also made use of machine learning approaches to investigate cell and genotype patterns in the data. Thanks to the remarkably high level of prediction of genotypes achieved for each cardiac sample, they were therefore able to confirm that genotypes activate very specific heart failure pathways. CodingHeart (Novel Coding Factors in Heart Disease) is hosted by the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany. The project ends in December 2023. For more information, please see: CodingHeart project
Keywords
CodingHeart, heart, heart failure, cell, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, gene, single-nucleus RNA sequencing
