Abstract 4368108: The Human Heart Atlas: An Integrative High-Resolution Multi-Omics Pipeline to Discover Novel Therapeutic Targets in Heart Failure

Abstract

Research Question: Can an integrative, high-resolution multi-omics approach focused on the human myocardium identify potential therapeutic targets by mapping specific molecular and cellular changes across the progression of human heart failure? Background: Heart failure (HF) is a complex, heterogeneous condition influenced by genetic, environmental, and lifestyle factors. Traditional target identification approaches often focus on end-stage HF and animal models with limited clinical relevance. A patient-centric, multi-omics framework is needed to improve diagnostics and inform future therapies. A detailed understanding of disease trajectories from health to advanced HF, with tissue and cell-type specificity, enables the identification of both known and novel mechanisms, supporting precision medicine by targeting well-defined patient subgroups. Methods: At Evotec, we built a high-resolution, multi-omics human heart atlas to support data-driven target discovery by linking molecular signatures to cell type, tissue context, clinical data, and disease models. This atlas integrates >2 million cells from six public single-cell studies (>200 patients) and >50 proprietary spatial transcriptomes from human left ventricular myocardium across multiple cardiovascular indications andmore than clinical variables. Candidate targets are prioritized and semi-automatically ranked based on correlations with cardiac function, disease progression, known biomarkers, and molecular cohorts (e.g., Evotec’s Molecular Patient Cohort, UK Biobank). Results: Using our end-to-end target identification pipeline with a focus on acute myocardial infarction (AMI), we identified EGLN3 as a gene upregulated in cardiomyocytes located in the border zone of AMI samples. EGLN3 expression showed a strong correlation with markers of cardiac injury. Elevated EGLN3 protein expression was also confirmed in spatial proteomics data from AMI samples. Public mouse data further confirmed a peak in cardiomyocyte Egln3 expression approximately 24 hours after infarction. Conclusion: Hypoxia and cardiomyocyte apoptosis are key contributors to the pathophysiology of AMI. Using the Evotec Heart Atlas, EGLN3 was identified as a candidate therapeutic target. Its inhibition may offer cardioprotective benefits by sustaining HIF1A -driven adaptive responses. We will next assess its therapeutic potential in vitro using our proprietary iPSC-based platform.