Mechanisms of Post-critical Illness Cardiovascular Disease

Abstract

Prolonged critical care stays commonly follow trauma, severe burn injury, sepsis, ARDS, and complications of major surgery. Although patients leave critical care following homeostatic recovery, significant additional diseases affect these patients during and beyond the convalescent phase. New cardiovascular and renal disease is commonly seen and roughly one third of all deaths in the year following discharge from critical care may come from this cluster of diseases. During prolonged critical care stays, the immunometabolic, inflammatory and neurohumoral response to severe illness in conjunction with resuscitative treatments primes the immune system and parenchymal tissues to develop a long-lived pro-inflammatory and immunosenescent state. This state is perpetuated by persistent Toll-like receptor signaling, free radical mediated isolevuglandin protein adduct formation and presentation by antigen presenting cells, abnormal circulating HDL and LDL isoforms, redox and metabolite mediated epigenetic reprogramming of the innate immune arm (trained immunity), and the development of immunosenescence through T-cell exhaustion/anergy through epigenetic modification of the T-cell genome. Under this state, tissue remodeling in the vascular, cardiac, and renal parenchymal beds occurs through the activation of pro-fibrotic cellular signaling pathways, causing vascular dysfunction and atherosclerosis, adverse cardiac remodeling and dysfunction, and proteinuria and accelerated chronic kidney disease.

Keywords: CKD; atherosclerosis; chronicity; critical illness; heart failure; immune aging; inflammation; insulin resistance.

Figure 1

Immunometabolic determination of immune cell polarization. A complex set of metabolic changes occur under cell stress, involving upregulation of GLUT1 transporters, upregulation of cholesterol biosynthesis, decrease in mitochondrial oxidative phosphorylation (causing increased succinate formation), and upregulation of glycolytic enzyme activity. Cellular redox status (reflected in NAD⁺/NADH⁺ ratio) is consequently altered. These changes determine future immune cell behavior through alterations in epigenetic imprinting (EI), but also determine current immune cell cytokine responses via HIF-1α. The involvement of mitochondria (center in picture) is fundamental to this process; alterations in fusion/fission status under the control of mTOR, PGC1α, and Drp1 control immune cell functional state and might also directly contribute to organ dysfunction (not shown).

Figure 2

Outline of how acute inflammation leads to chronicity affecting the cardiovascular and renal systems. Areas in green are triggered during the onset of acute inflammation whereas areas in gold become apparent during survivorship. The white area between acute and chronic phases represents the cellular processes precipitated (de novo disease) or accelerated (disease already exists) by acute inflammation; these processes continue during survivorship because antigen presentation and deleterious immune infiltrates have become established. Note that none of the mechanisms in the white area are reliant on traditional risk factors of hypertension, dyslipidaemia, obesity, and diabetes for triggering the chronic diseases in gold. Nevertheless, the recently elucidated inflammatory and immune mechanisms underlying vascular dysfunction, hypertension, and atherosclerosis are central to triggering these chronic diseases. What is not specifically highlighted is the legacy effect of epigenetic reprogramming (trained immunity) due to the effects of altered cellular redox status and accelerated glycolysis on macrophages, monocytes, and T-cells.