The Role of Serum Monocytes and Tissue Macrophages in Driving Left Ventricular Systolic Dysfunction and Cardiac Inflammation Following Subarachnoid Hemorrhage

Abstract

Background: Neurocardiogenic injury is common after aneurysmal subarachnoid hemorrhage (aSAH) despite low prevalence of preexisting cardiac disease. Potential mechanisms include autonomic dysregulation due to excess catecholamines as well as systemic inflammation. Understanding how inflammation contributes to cardiac dysfunction may aid in identifying novel therapeutic strategies. Here, we investigated serum leukocytes as predictors of left ventricular systolic dysfunction in patients with aSAH. We also investigated increased cardiac macrophages in an animal model of SAH and whether immunomodulatory treatment could attenuate this inflammatory response.

Methods: We retrospectively analyzed 256 patients with aSAH admitted to University of Illinois Hospital between 2013 and 2019. Our inclusion criteria included patients with aSAH receiving an echocardiogram within 72 h of admission. Our primary outcome was echocardiographic evidence of systolic dysfunction. We performed multinomial regression and receiver operating curve analysis. We also used the endovascular perforation model of SAH in male Sprague-Dawley rats to assess for myocardial inflammation. Two days after surgery, hearts were collected and stained for the macrophage marker Iba-1. We compared the presence and morphology of macrophages in cardiac tissue isolated from SAH animals and sham controls treated with and without the immunomodulatory agent fingolimod.

Results: Of 256 patients with aSAH, 233 (91.0%) underwent echocardiography within 72 h of admission. Of 233, 81 (34.7%) had systolic dysfunction. Patients had baseline differences in the presence of hypertension, alcohol use, and admission Glasgow Coma Scale and Hunt-Hess score. On multivariable analysis, total leukocytes (odds ratio 1.312, p < 0.001), neutrophils (odds ratio 1.242, p = 0.012), and monocytes (odds ratio 6.112, p = 0.008) were independent predictors of reduced systolic function, whereas only monocytes (odds ratio 28.014, p = 0.030) predicted hyperdynamic function. Within the rodent heart, there were increased macrophages after SAH relative to controls, and this was attenuated by fingolimod treatment (p < 0.0001).

Conclusions: Increased serum leukocytes are associated with abnormal left ventricular systolic function following aSAH. The strongest independent predictor of both reduced and hyperdynamic systolic function was increased monocytes. Increased cardiac macrophages after experimental SAH can also be targeted by using immunomodulatory drugs.

Keywords: Animal model; Cardiac injury; Echocardiography; Fingolimod; Inflammation; Macrophage; Monocyte; Subarachnoid hemorrhage; Systolic function; White blood cell.