Abnormal cardiac metabolism affects accelerated cardiac fibrosis and dysfunction in ACTCE99K induced HCM

Thesis

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder, with both monogenic and polygenic forms, affecting approximately 1 in 500 individuals. While its morbidity and mortality rates are lower than those of many other cardiovascular diseases (CVDs), patients with HCM often experience a poor quality of life and unfavourable clinical prognosis. To date, over 1000 genetic mutations have been identified as potential etiological factors for HCM. HCM patients typically present diastolic dysfunction, and abnormal systolic dysfunction has also been reported. Despite recent advances in mechanical interventions and pharmacotherapies, treatment options remain limited. Disease-causing mutations are most frequently found in genes encoding cardiac contractile proteins, particularly MYH7 and MYBPC3 (thick filament components), but also occur in thin filament protein genes such as ACTC, which encodes alpha-cardiac actin. Functional studies on HCM-linked contractile protein mutations indicate that they initially induce a hypercontractile state. This altered contractility is postulated to disrupt Ca2+ handling - potentially triggering Ca2+ dependent hypertrophic signalling- and impair cardiac energetics. However, the precise secondary mechanism through which these initial changes lead to remodelling and fibrosis remain elusive.

This study employed a previously characterized ACTCE99K mouse model, which recapitulates the human E99K missense mutation in alpha-cardiac actin known to cause HCM and apical hypertrophy. This model exhibited severe cardiac fibrosis (CF) and contractile dysfunction at an early stage. Pronounced cardiac hypertrophy, particularly in the apical region, was observed alongside increased fibrotic accumulation. Cardiac contractile function was significantly impaired from 10 weeks of age, as evidenced by a reduced ejection fraction. Mechanistically, transcriptomic analysis revealed aberrant expression of genes involved in cardiac energetics. Pathways related to cardiac metabolism were significantly downregulated, with both glycometabolism and fatty acid metabolism found to be attenuated. Furthermore, mitochondrial metabolism and calcium homeostasis were disrupted in ACTCE99K hearts. These findings suggest that abnormal cardiac metabolism contributes to the accelerated cardiac fibrosis and dysfunction in ACTCE99K-induced HCM. The ACTCE99K mutation induces early cardiac hypertrophy accompanied by accelerated fibrosis, with mitochondrial metabolic abnormalities and calcium dysregulation likely playing key roles in pathogenesis. This work validates the ACTCE99K HCM model as a robust platform for detailed molecular investigation of HCM mechanisms.

Authors: Huang, A

• DOI: 10.5287/ora-x55gyrpwv
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: cardiac metabolism; ACTC; HCM; cardiac fibrosis
• Subjects: Medicine; Biology