The spleen in ischaemic heart disease

Ischaemic heart disease is a consequence of coronary atherosclerosis, and atherosclerosis is a systemic inflammatory disease. The spleen releases various immune cells in temporally distinct patterns. Neutrophils, monocytes, macrophages, B cells and T cells execute innate and adaptive immune processes in the coronary atherosclerotic plaque and in the ischaemic myocardium. Prolonged inflammation contributes to ischaemic heart failure. The spleen is also a target of neuromodulation through vagal, sympathetic and sensory nerve activation. Efferent vagal activation and subsequent activation of the noradrenergic splenic nerve activate β₂-adrenergic receptors on splenic T cells, which release acetylcholine that ultimately results in attenuation of cytokine secretion from splenic macrophages. Coeliac vagal nerve activation increases splenic sympathetic nerve activity and drives the release of T cells, a process that depends on placental growth factor. Activation of the vagosplenic axis protects acutely from ischaemia–reperfusion injury during auricular tragus vagal stimulation and remote ischaemic conditioning. Splenectomy abrogates all these deleterious and beneficial actions on the cardiovascular system. The aggregate effect of splenectomy in humans is a long-term increase in mortality from ischaemic heart disease. The spleen has been appreciated as an important immune organ for inflammatory processes in atherosclerosis, myocardial infarction and heart failure, whereas its complex interaction with circulating blood factors and with the autonomic and somatic nervous systems, as well as its role in cardioprotection, have emerged only in the past decade. In this Review, we describe this newly identified cardioprotective function of the spleen and highlight the potential for translating the findings to patients with ischaemic heart disease.