Organ System Crosstalk in Cardiometabolic Disease in the Age of Multimorbidity

Abstract

The close association among cardiovascular, metabolic, and kidney diseases suggests a common pathological basis and significant interaction among these diseases. Metabolic syndrome and cardiorenal syndrome are two examples that exemplify the interlinked development of disease or dysfunction in two or more organs. Recent studies have been sorting out the mechanisms responsible for the crosstalk among the organs comprising the cardiovascular, metabolic, and renal systems, including heart-kidney and adipose-liver signaling, among many others. However, it is also becoming clear that this crosstalk is not limited to just pairs of organs, and in addition to organ-organ crosstalk, there are also organ-system and organ-body interactions. For instance, heart failure broadly impacts various organs and systems, including the kidney, liver, lung, and nervous system. Conversely, systemic dysregulation of metabolism, immunity, and nervous system activity greatly affects heart failure development and prognosis. This is particularly noteworthy, as more and more patients present with two or more coexisting chronic diseases or conditions (multimorbidity) due in part to the aging of society. Advances in treatment also contribute to the increase in multimorbidity, as exemplified by cardiovascular disease in cancer survivors. To understand the mechanisms underlying the increasing burden of multimorbidity, it is vital to elucidate the multilevel crosstalk and communication within the body at the levels of organ systems, tissues, and cells. In this article, we focus on chronic inflammation as a key common pathological basis of cardiovascular and metabolic diseases, and discuss emerging mechanisms that drive chronic inflammation in the context of multimorbidity.

Keywords: cardiorenal syndrome; chronic inflammation; clonal hematopoiesis of indeterminate potential (CHIP); heart failure; metabolic syndrome; multimorbidity; organ crosstalk; somatic mutation.

Figure 1

Organ system crosstalk. The major organ systems discussed in this article are depicted schematically. Complex interactions among organs systems underlie the crosstalk between any two organs.

Figure 2

Immunometabolic organ crosstalk in obesity. Obesity induces chronic inflammation in visceral adipose tissue (17, 18). This inflammation increases the release of free fatty acids and some adipokines, which modulate the function of metabolic and endocrine organs and enhance inflammatory processes in those organs (19). Signals from the affected organs in turn affect metabolic and inflammatory signals and processes within the adipose tissue. Obesity may also directly activate or enhance inflammation. The central and autonomic nervous systems receive information from peripheral metabolic organs, and their output affects metabolism and inflammation in those organs (–23). Obesity also induces inflammation in some regions of the CNS, including the hypothalamus, which may alter its function (24). Although not depicted in the figure, the gut microbiome contributes to the organ network by supplying endotoxin and a variety of metabolites.

Figure 3

Brain-heart–kidney network in cardiac adaptation. Pressure overload on the left ventricle triggers a cardioprotective mechanism involving the brain, heart, and kidneys (51). Pressure overload activates sympathetic nerves to the kidneys. Within the kidneys, sympathetic nerves stimulate collecting duct epithelial cells, which activate cellular interactions leading to renal production of CSF2/GM-CSF. CSF2 is transferred to the heart via the circulation and activates cardiac tissue-resident Ly6C^lo macrophages. These activated Ly6C^lo macrophages then play a pivotal role in the adaptive response to the pressure overload. A key cardioprotective mediator produced by Ly6C^lo macrophages is amphiregulin (AREG).

Figure 4

Immunometabolic crosstalk at multiple levels. The crosstalk between immune and metabolic mechanisms operates at multiple levels in the body to maintain homeostasis. The intricate crosstalk also crucially contributes to the development of systemic, tissue, and cellular dysfunction and disease. One key pathological mechanism mediated by immunometabolic crosstalk is chronic inflammation. The interaction between immune and metabolic cells is exemplified here by interaction between a macrophage and an adipocyte (82).

Figure 5

Neuroimmune communication in inflammation. Afferent neurons monitor peripheral immune status by sensing PAMPs, such as LPS; DAMPs, such as ATP; and cytokines, such as TNF-α and IL-1β (84). Efferent nerves release neurotransmitters, such as noradrenaline and acetylcholine (ACh), which directly or indirectly activate a variety of immune cells, including macrophages, dendritic cells, and lymphocytes. Within the best-studied circuit of neuroimmune communication, the cholinergic anti-inflammatory pathway, inflammation in the periphery is detected by afferent vagal neurons. The information is processed in the brainstem, initiating the efferent arm of anti-inflammatory pathway. Within the spleen, noradrenaline released from efferent nerves activates β2-adrenergic receptors on choline acetyltransferase-expressing T cells. The affected T cells in turn release ACh, which suppresses TNF-α production in nicotinic α7-nicotinic receptor-expressing macrophages, in part by inhibiting NF-κB signaling (84, 86). Other stimuli that also activate the anti-inflammatory pathway includes PI3 kinase activation within inulin-expressing neurons (34).

Figure 6

Activation of age-associated chronic inflammation (inflammaging). A variety of local and systemic factors have been suggested to promote inflammation in the elderly.

Figure 7

Heart-cancer crosstalk. Clinical studies have revealed reciprocal associations between HF and cancer. Although the cardiotoxicity of cancer treatments is a key factor in the increased morbidity and mortality from HF among cancer patients, multiple other mechanisms, including direct organ crosstalk, also appear to be involved.