Christoffer Frisk: Exploring Heart Failure Through Bioinformatics: A Transcriptomic Analysis of Cardiac and Adipose Tissues

Abstract

Heart failure, characterised by either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction, involves complex and diverse pathophysiological mechanisms, making it a challenging field of research. Despite extensive studies, much remains to be learned about its underlying mechanisms and early diagnostic markers—particularly for HFpEF, as evidenced by the lack of effective treatment options.

This thesis aims to explore the transcriptomic profiles of cardiac and adipose tissues in patients with different HF phenotypes, investigating differential gene expression, associated regulatory pathways, and correlation networks. Additionally, the work examines the expression of specific genes involved in iron metabolism under conditions of iron deficiency in myocardial and skeletal muscle tissues.

Using high-throughput RNA sequencing, gene expression was analyzed in left and right ventricular biopsies from patients undergoing coronary artery bypass grafting, with or without diagnostic signs of HF. Gene expression and network analysis techniques were employed to identify distinct gene expression patterns and potential regulatory mechanisms in epicardial adipose tissue.

The studies revealed significant differences in gene expression related to myocardial contraction, energy supply, remodeling, and fibrosis between HFpEF and normal physiology, as well as distinct profiles between HFpEF and HFrEF. Moreover, genes involved in heart muscle movement and energy production were less active in the left ventricle of HFpEF, particularly those facilitating contraction and relaxation of the heart muscle. This reduced activity potentially explains the stiffness and impaired relaxation characteristic of HFpEF. Additionally, genes influencing the heart's structural integrity, especially those involved in collagen production, showed changes that suggest alterations beyond simple stiffening in the heart’s structure. The analysis of adipose tissues identified unique gene expression clusters correlating with echocardiographic HF characteristics. These findings reveal the pathophysiological discrepancies and shared mechanisms across HF subtypes, offering a richer understanding of the disease's transcriptomic basis.

By demonstrating the distinct transcriptomic signatures associated with HFpEF and HFrEF, this thesis builds on our understanding of heart failure's complex biology. Further research is needed to explore the therapeutic potential of the identified targets and to validate these findings in a larger, but also a more diverse patient cohort.