Immune/Inflammatory Response Contributes To Intracerebral Hemorrhage Induced Cardiac Dysfunction

Background and Objective:Spontaneous,non-traumatic intracerebral hemorrhage(ICH)is a life threatening stroke subtype and a major cause of high mortality and morbidity in the world.Cardiovascular complications in ICH patients are common and closely related with early mortality and poor outcome after ICH.Peripheral immune system and systemic oxidative stress are activated after ICH.Immune responses and oxidative stress are involved in the pathological cascade leading to cardiac muscle dysfunction and heart failure.Cardiac damage may occur after stroke in the absence of primary cardiac diseases.In this study,we investigate whether ICH induces cardiac dysfunction in the absence of primary cardiac disease and evaluate the role of the immune/inflammatory-response in mediating ICH induced cardiac dysfunction in mice.Methods:To investigate whether ICH induces cardiac dysfunction in the absence of primary cardiac disease.Adult male C57BL/6J mice were subjected to ICH by blood injection or sham control without blood injection.To identify whether immune/inflammatory-response plays an important role in mediating ICH induced cardiac dysfunction in mice,splenectomy was performed immediately after ICH.The experimental groups include:1)sham control;2)ICH group;3)Splenectomy with ICH;4)Splenectomy alone(n=8/group).Cardiac function was measured respectively by echocardiography at 7 and 28 days after ICH.Neurological(mNSS test and foot-fault test)and cognitive functional tests(odor test and novel objective recognition test)were employed.Flow cytometry,Western-blot and immunostaining were performed to explore the machanism of ICH induced cardiac dysfunction.Results:Compared to sham control mice,ICH mice exhibit significantly(p<0.05):1)increased neurological and cognitive deficits,and increased cardiac dysfunction identified by decreased cardiac contractile function measured by left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS)at 7 and 28days after ICH.2)increased cardiomyocyte apoptosis,cardiac hypertrophy and fibrosis at 28 days after ICH;3)increased inflammatory factors and oxidative stress in systemic and heart tissue and increased inflammatory cellinfiltration into the heart(macrophages:CD45~+/CD11b~+/F480~+and neutrophil:CD45~+/CD11b~+/Ly6G~+)at 7days post-ICH.Compared to ICH control mice,ICH with splenectomy mice exhibited significantly(p<0.05):1)improved neurological and cognitive functional outcome as well as attenuated cardiac dysfunction with increased LVEF and LVFS;2)decreased cardiac fibrosis and hypertrophy in the heart;3)decreased infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart.Compared to sham control mice,splenectomy alone did not induce cardiac dysfunction at 7days or 28 days after surgery.Conclusions:Our study demonstrates that ICH induces cardiac dysfunction in the absence of primary cardiac diseases and inflammatory cell infiltration into heart.Splenectomy not only reduces ICH induced neurological and cognitive functional deficits,but also has a protective effect on heart of mice with ICH by inhibiting infiltration of immune cells and inflammatory factor expression in the heart,hence leading to alleviating cardiac function deflects and cardiac remodeling.Immune/inflammatory response,as evidenced by the effects of splenectomy in conjunction with ICH,may contribute to brain-heart adverse interaction after ICH.