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The spleen in ischaemic heart disease

Nature Reviews Cardiology volume 22, pages 497–509 (2025)Cite this article

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Abstract

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.

Key points

  • The spleen is a central immune organ and provides an interface to the autonomic nervous system and the circulating blood.

  • Immune cells originating in the spleen contribute to atherosclerotic plaque inflammation and the inflammatory response to myocardial infarction.

  • Efferent vagal nerve activation induces the activation of splenic noradrenergic nerves that project onto splenic T cells, which then release acetylcholine to activate α7-nicotinic receptors on macrophages, resulting in decreased macrophage cytokine release.

  • Coeliac vagal nerve activation increases splenic sympathetic nerve activity and drives the release of T cells from the spleen, a process that is mediated by placental growth factor.

  • Activation of the vagosplenic axis is decisive for myocardial infarct size reduction by auricular tragus stimulation and remote ischaemic conditioning in rats, pigs and humans.

  • Splenectomy in humans is associated with increased mortality from ischaemic heart disease.

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Fig. 1: Spleen-derived immune cells in coronary atherosclerosis and reperfused acute myocardial infarction.
Fig. 2: Structure of the spleen.
Fig. 3: Splenic innervation and its activation during myocardial ischaemia–reperfusion and cardioprotection.
Fig. 4: Cardioprotection by vagosplenic axis activation.
Fig. 5: Interaction between the ischaemic–reperfused brain, the heart and the spleen in stroke.

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Acknowledgements

This article is dedicated to the memory of G.H.’s predecessor as chair of the Institute for Pathophysiology at the University of Essen Medical School, Werner Meesmann, who had been a scholar of Hermann Rein. We appreciate the assistance of E. A. Chowanietz in the collection of references and preliminary drafts for the figures. G.H. and P.K. were supported by the German Research Foundation (CRC 1116 B8, RTG 2989 P5), the European Union Cost Action CARDIOPROTECTION (CA 16225 and IGI 16225) and METAHEART (CA22169).

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  1. Institute for Pathophysiology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany

    Gerd Heusch & Petra Kleinbongard

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Heusch, G., Kleinbongard, P. The spleen in ischaemic heart disease. Nat Rev Cardiol 22, 497–509 (2025). https://doi.org/10.1038/s41569-024-01114-x

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