Multimorbidity is associated with myocardial DNA damage, nucleolar stress, dysregulated energy metabolism, and senescence in cardiovascular disease.

This study investigates why individuals with multimorbidity-two or more chronic conditions-are more prone to adverse outcomes after surgery. In our cohort, ninety-eight of 144 participants had multimorbidity. The myocardial transcriptome and metabolites involved in energy production were measured in 53 and 57 sequential participants, respectively. Untargeted analysis of the metabolome in blood and myocardium was performed in 30 sequential participants. Mitochondrial respiration in circulating mononuclear cells was measured in 70 participants. Results highlighted four main biological processes associated with multimorbidity: DNA damage with epigenetic changes, mitochondrial energy disruption, cellular aging (senescence) and innate immune response. Histone 2B, its ubiquitination enzymes and AKT3 were upregulated in the multimorbid group. Plasma senescence-associated proteins (IL-1β, GM-CSF) increased with more comorbidities. DNA damage and nucleolar instability were specifically apparent in multimorbid myocardium. We conclude that multimorbidity in cardiovascular patients accelerates biological aging, making them more vulnerable to metabolic stress.