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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - inHForm (Integrative omics of heart failure to inform discovery of novel drug targets and clinical biomarkers)

Teaser

Summary

Heart failure is a leading cause of morbidity and mortality in the aging European populations. This condition represents the end-stage of myocardial and valvular disease, arising from loss of viable or functional muscle cells in the heart. Therapy is complicated by the multitude of causes and comorbidities of heart failure. New therapeutic targets and clinical biomarkers to individually tailor therapy (â€˜precision medicineâ€™) are greatly needed. This research program aims to realize the promise of precision medicine for heart failure by application of an integrated proteomic, genomic and epidemiological approach.

Work performed

To date, the research group has established heritability of several subphenotypes in heart failure, supporting the hypothesis that systematic genetic studies may uncover molecular pathways underlying such subphenotypes. Genotyping has been completed in >40 000 subjects from two large population cohorts from Sweden, and initial genetic analyses of heart failure and related subphenotypes have been completed and implicated several new genetic loci. The research group has also contributed data and experience to large, international meta-analyses including multiple cohorts for certain phenotypes. Mechanisms linking such genetic loci to heart failure are being explored using an experimental pipeline which has been established in the laboratory of the principal investigator, and collection of human heart tissue is ongoing for this purpose. The research group has developed methods to improve resolution of transcriptional profiles of non-cardiomyocyte cells through single-cell sequencing of human heart tissue, which has previously not been possible. Large-scale proteomic characterization of plasma has also been undertaken in population-based cohorts and heart failure cases, and identified several promising proteins showing association with heart failure which are currently further explored in genetic and transcriptional analyses. The research group has developed an ultrasensitive assay to measure the gene product from one of the identified genetic loci in human plasma. One biomarker strongly associated with congestion and adverse prognosis has been brought forward for evaluation in clinical cohorts. Metabolomic analysis of heart failure in cohorts is ongoing.

Final results

These initial results provide highly novel insights into plasma proteome dynamics in the general population and in relation to heart failure, the genetic determinants of such plasma profiles and of heart failure, and on the cell type specific transcriptional regulation of the implicated genes. At completion of the project, additional well-powered discovery efforts for multiple heart failure related phenotypes will have been undertaken and the mechanisms and clinical utility of such markers will have been evaluated.