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

Abstract

Background Two-thirds of people over 65 have two or more underlying chronic conditions. Patients with multimorbidities are likely to classify as frail and have worse outcomes after cardiac surgery. We hypothesized that metabolite and transcript profiles could identify multimorbidity-specific mechanisms for clinical interventions. Methods and Results The multimorbidity was defined as two or more coexisting chronic conditions. Analysis of the metabolome was performed in 30 sequential patients. Measurements of transcriptome and metabolites involved in energy production were performed in 53 and 57 sequential patients, respectively. Mitochondrial function in circulating monocytes was performed in 63 sequential patients. Our analysis distinguished three major processes that are 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 suggesting senescence-like changes in gene expression. That was confirmed by the detection of senescence-associated secretory phenotype analytes, IL-1β, its receptor and fractalkine that 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. The nucleolar stress is potentially responsible for higher expression of ribosomal proteins and decreased mitochondrial function. Conclusions Our results suggest that accumulating comorbidities increase levels of innate immune response and lead to DNA damage, senescence-like changes in gene expression and consequently decreased mitochondrial function.

Immune system homeostasis in people with multiple long-term conditions determines susceptibility to organ injury and mortality following cardiac surgery

“…In previous work, we have shown that MLTC are associated with myocardial changes consistent with biological ageing including altered RNA processing, DNA damage, nucleolar stress, senescence, and dysregulated energy metabolism versus non-MLTC. (48) Biological ageing processes increase susceptibility to cellular stress in experimental models. (49,50) These results identify substantial baseline heterogeneity in cardiac surgery patients at baseline and suggest that a precision medicine approach to organ protection may be required to deliver clinical benefits.…”