DNA damage, nucleolar stress and dysregulated energy metabolism as mechanisms of multimorbidity in cardiovascular disease

Background People with two or more underlying chronic conditions (multimorbidity) are more susceptible to adverse events following surgery. This study used -omics methods to compare samples from people with or without multimorbidity in a cardiac surgery cohort. Methods and Results Measurements of the myocardial transcriptome and metabolites involved in energy production were performed 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 monocytes was measured in 63 participants. Ninety-eight of 144 participants (68%) had multimorbidity. Three major processes were affected by multimorbidity: innate immune response, DNA damage and associated epigenetic changes, and mitochondrial energy production. The innate immune response was upregulated in multimorbidity and most of the included comorbidities. The DNA damage, epigenetic changes, and aspects of mitochondrial function were specific for multimorbidity. Histone 2B, its ubiquitination enzymes and AKT3 were upregulated in the multimorbid group, supporting our hypothesis of senescence-like changes in multimorbidity. In addition, senescence-associated secretory phenotype analytes, IL-1β, its receptor, GM-CSF and fractalkine increased with the number of accumulating comorbidities. DNA damage was confirmed by independent immunohistochemistry experiments, which also identified nucleolar instability as more prominent in the multimorbid myocardium. Conclusions Multimorbidity in people with cardiovascular disease is characterized by biological aging processes that are known to increase susceptibility to metabolic stress. These present novel therapeutic targets for organ protection interventions.