Mechanistic investigation of maladaptive metabo-energetics remodelling in the development of multimorbid cardiovascular disease

Multimorbid cardiovascular disease (CVD) refers to the co-occurrence of conditions like hypertension, coronary artery disease, diabetes, and heart failure (HF). These complications are intricately tied to maladaptive metabo-energetics remodelling, particularly the interplay between biological fuel substrates utilisation and disease progression presents a potential avenue for innovative therapeutic strategies. This proposal will generate data to develop larger key grants, provide advanced data analysis training in R programming for proteomics, develop leadership skills, and bolster industrial collaborations to develop sustained track record for independence and establish a research programme in cellular energetics and multiple long-term conditions. Pilot studies by the applicant using proteomics, in a well-established HF cohort, revealed that differentially expressed proteins in blood were linked with key metabolic pathways. Metabolic remodelling in HF revealed impaired fatty acid and glucose oxidation, compensated by increased glycolysis with distinct key hub proteins amenable to novel therapies. This proposal will apply integrated multiomics to mechanistically investigate metabolic pathways, mitochondrial health, and epigenetic regulatory enzymes in well-established pre-HF and developed-HF cohorts. Understanding disease progression will enable targeting of key regulatory enzymes as markers for novel therapeutic interventions. The results will support future work that examines the role of maladaptive metabo-energetics remodelling in multimorbid CVD development.