Ongoing Projects

The process of biomedical discovery has undergone a fundamental shift over the past 2 decades, facilitated by widespread accessibility and use of next-generation sequencing technologies. However, publications stemming from these ‘Omics-level analyses typically focus only a small fraction of “candidates,” leaving the remaining data largely unexplored and unshared. The current project exemplifies a global effort to reintegrate these published ‘Omics datasets into ongoing biomedical research. As a proof-of-concept, I am building a standardized, semi-automated pipeline for whole-tissue (“bulk”) RNA-sequencing analysis to permit cross-study comparisons. This core resource will become a tool for the analysis, visualization, and sharing of bulk RNA-Sequencing data by the cardiovascular science research community for the German Centre for Cardiovascular Research (DZHK): https://www.dzhk-omics.de

Precision-based molecular phenotyping of heart failure must overcome limited access to cardiac tissue. Although epigenetic alterations have been found to underlie pathological cardiac gene dysregulation, the clinical utility of myocardial epigenomics remains narrow owing to limited clinical access to tissue. Therefore, the current study determined whether patient plasma confers indirect phenotypic, transcriptional, and/or epigenetic alterations to ex vivocardiomyocytes that mirror the failing human myocardium. Neonatal rat ventricular myocytes (NRVMs) and single-origin human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and were treated with blood plasma samples from patients with dilated cardiomyopathy (DCM) and donor subjects lacking history of cardiovascular disease. Following plasma treatments, NRVMs and hiPSC-CMs underwent significant hypertrophy relative to non-failing controls, as determined via automated high-content screening. Array-based DNA methylation analysis of plasma-treated hiPSC-CMs and cardiac biopsies uncovered robust – and conserved – alterations in cardiac DNA methylation, from which 100 sites were validated using an independent cohort. Among the CpG sites identified, hypo-methylation of the ATG promoter was identified as a diagnostic marker of HF, wherein cg03800765 methylation (AUC = 0.986, P < 0.0001) was found to out-perform circulating NT-proBNP levels in differentiating heart failure. Taken together, these findings support a novel approach of indirect epigenetic testing in human HF.