Immune Response Mediates Cardiac Dysfunction after Traumatic Brain Injury

Abstract

Cardiovascular complications are common after traumatic brain injury (TBI) and are associated with increased morbidity and mortality. In this study, we investigated the possible role of the immune system in mediating cardiac dysfunction post-TBI in mice. Adult male C57BL/6J mice were subjected to a TBI model of controlled cortical impact (CCI) with or without splenectomy (n = 20/group). Splenectomy was performed immediately prior to induction of TBI. Cardiac function was measured using echocardiography prior to and after TBI. Neurological and cognitive functional tests and flow cytometry and immunostaining were performed. TBI mice exhibited significant cardiac dysfunction identified by decreased left ventricular ejection fraction and fractional shortening at 3 and 30 days post-TBI. In addition, these mice exhibited significantly increased cardiomyocyte apoptosis, inflammation, and oxidative stress at 3 and 30 days post-TBI, as well as cardiac hypertrophy and fibrosis and ventricular dilatation at 30 days after TBI. TBI mice subjected to splenectomy showed significantly improved cardiac function, and decreased cardiac fibrosis, oxidative stress, cardiomyocyte apoptosis, and infiltration of immune cells and inflammatory factor expression in the heart compared with TBI control mice. TBI mice exhibited severe neurological and cognitive function deficits. However, splenectomy did not improve neurological and cognitive functional outcome after TBI compared with the TBI control group. TBI induces immune cell infiltration and inflammatory factor expression in the heart as well as cardiac dysfunction. Splenectomy decreases heart inflammation and improves cardiac function after TBI. Immune response may contribute to TBI-induced cardiac dysfunction.

Intracerebral Hemorrhage Induces Cardiac Dysfunction in Mice Without Primary Cardiac Disease

“…ICAM-1 and MCP-1 can be induced by the pro-inflammation molecules interleukin-1 (IL-1) and TNF. Our pre-clinical studies also found that ischemic stroke and TBI in mice significantly increase serum and heart ICAM-1 and MCP-1 expression as well as induce heart deficits ( 5 , 10 ). In the present study, we found that ICH significantly increases ICAM-1, MCP-1 and IL-1 expression in the heart and serum as well as increases inflammatory cells (leukocyte and macrophage) infiltration into the heart after ICH.…”

“…Mortality rates associated with ICH are as high as 35–52% within the first 30 days after ICH and approximately 42–65% over the first year following ICH ( 1 ). Cardiac dysfunction occurs commonly in patients and experimental animals with stroke and traumatic brain injury (TBI) ( 3 – 5 ). Cardiovascular complications in ICH patients are closely related with early mortality and poor outcome after ICH ( 6 ).…”

“…Another study reported that roughly 2% of ICH patients with or without coronary artery disease before ICH attacked developed acute myocardial infarction and these patients experienced increased risk of heart failure which were associated with increased mortality and extended hospital stays ( 8 ). Previous pre-clinical studies in mice have shown that ischemic stroke and TBI induce cardiac dysfunction characterized by significantly decreased (LVEF), cardiomyocyte hypertrophy, interstitial fibrosis, cardiac inflammatory responses, and cardiomyocyte death ( 5 , 9 , 10 ). However, whether ICH induces acute and chronic or progressive cardiac dysfunction in the absence of primary cardiac disease and mechanisms underlying of ICH induced cardiac dysfunction remain poorly understood.…”

Approaches to Monitor Circuit Disruption after Traumatic Brain Injury: Frontiers in Preclinical Research

“…Mild TBI enhances liver inflammatory markers by altering the redox homeostasis and given their wide implications for their interaction between brain and body, leakage of pro-inflammatory factors through the disrupted BBB can exacerbate brain injury pathology [242][243][244]. TBI can promote cardiovascular risk factors through increase in expression of pro-inflammatory chemokines and apoptosis [245,246]. The spleen is an important lymphoid organ innervated by sympathetic nerve fibers that are in contact with splenic immune cells to create a neuroimmune link [247].…”

Making sense of gut feelings in the traumatic brain injury pathogenesis

“…In agreement with this idea, mice subjected to splenectomy after controlled cortical impact (CCI) showed significantly improved cardiac function, and decreased cardiac fibrosis, oxidative stress, cardiomyocyte apoptosis, and decreased infiltration of immune cells and inflammatory factors to the heart. (Zhao et al, 2019). Considering that systemic inflammatory response syndrome in TBI patients is associated with systolic cardiac dysfunction (Deepika et al, 2018) (Hasen et al, 2019), it is plausible that a paroxysmal sympathetic hyperactivity followed by immune response after brain injury may play a vital role in mediating brain-heart interaction.…”