Investigating pathology associated with cardiac hypertrophy at the single-cell level

Abstract

Cardiac hypertrophy (CH) is the heart’s response to sustained increased workload, marked by myocardial expansion to preserve output. However, under pathological stimuli—such as hypertension, valvular disease, or diabetes—CH becomes maladaptive, leading to structural and functional abnormalities, heart failure, and associated morbidity and mortality. These stimuli trigger complex cardiac remodelling involving both muscle and non-muscle cells, primarily driven by changes in gene expression. Investigating these changes can shed light on the molecular mechanisms driving pathological CH.

This PhD thesis aimed to characterise dysregulated gene expression in distinct cardiac cell types during pathological CH using single-cell RNA-sequencing. The study used samples from three established mouse models of CH, two of which included 5-Azacitidine treatment groups, an anti-hypertrophic medication. All major cardiac cell types were implicated in remodelling and pro-hypertrophic signalling. Importantly, 19 genes were consistently dysregulated across all models, suggesting a common link to CH regardless of the pathological stimulus. These candidate genes are novel or poorly characterised in the context of pathological CH.

After devising a bioinformatic technique to systematically assess conservation in mouse-human cardiac gene expression, dysregulated expression was characterised at the single-cell level in human heart samples from hypertensive disease patients. This represents a novel study of human HTD, identifying prominent changes in gene expression and possible alterations in cardiac tissue composition in HTD, a condition which is responsible for most cases of pathological CH in humans. Of the 19 candidate genes implicated in CH via mouse models, 15 were also dysregulated in human HTD versus normal heart. These 15 genes (ADAMTS4, ADAMTS9, AKAP12, B2M, B4GALT5, CMSS1, DENND4A, EMP1, FOSL2, JUN, KLF2, NFKBIZ, PDE4B, UBASH3B, and ZBTB16) are hypothesised to include key drivers of cardiac hypertrophy under pathological stimulus, a characterisation which is either novel or under-appreciated for each of the 15 candidates.

Thesis is embargoed until 31 July 2030.

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	British Heart Foundation
Supervisor	David Simpson (Supervisor) & Chris Watson (Supervisor)