The immune system is intimately involved in the pathophysiology of heart failure. However, it is currently underused as a therapeutic target in the clinical setting. Moreover, the development of novel immunomodulatory therapies and their investigation for the treatment of patients with heart failure are hampered by the fact that currently used, evidence-based treatments for heart failure exert multiple immunomodulatory effects. In this Review, we discuss current knowledge on how evidence-based treatments for heart failure affect the immune system in addition to their primary mechanism of action, both to inform practising physicians about these pleiotropic actions and to create a framework for the development and application of future immunomodulatory therapies. We also delineate which subpopulations of patients with heart failure might benefit from immunomodulatory treatments. Furthermore, we summarize completed and ongoing clinical trials that assess immunomodulatory treatments in heart failure and present several therapeutic targets that could be investigated in the future. Lastly, we provide future directions to leverage the immunomodulatory potential of existing treatments and to foster the investigation of novel immunomodulatory therapeutics.
Immune activation is intimately involved in the pathophysiology of heart failure.
Immunomodulation is an underused therapeutic approach for the treatment of patients with heart failure.
All current evidence-based treatments for heart failure can modulate immune activation in diverse ways, which has important clinical and therapeutic implications.
The development of novel immunomodulatory interventions for the treatment of heart failure should take the immunomodulatory effects of existing treatments into account.
Future developments in immunomodulation for heart failure should investigate both the optimization of immunomodulatory effects of current treatments and the potential benefits that can be derived by novel treatments.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Savarese, G. & Lund, L. H. Global public health burden of heart failure. Card. Fail. Rev. 3, 7 (2017).
McDonagh, T. A. et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur. Heart J. 42, 3599–3726 (2021).
Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).
McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).
Van Linthout, S. & Tschöpe, C. The quest for antiinflammatory and immunomodulatory strategies in heart failure. Clin. Pharmacol. Ther. 106, 1198–1208 (2019).
Furtado, M. B. & Hasham, M. Properties and immune function of cardiac fibroblasts. Adv. Exp. Med. Biol. 1003, 35–70 (2017).
Van Linthout, S. & Tschöpe, C. Inflammation – cause or consequence of heart failure or both? Curr. Heart Fail. Rep. 14, 251–265 (2017).
Adamo, L., Rocha-Resende, C., Prabhu, S. D. & Mann, D. L. Reappraising the role of inflammation in heart failure. Nat. Rev. Cardiol. 17, 269–285 (2020).
Murphy, S. P., Kakkar, R., McCarthy, C. P. & Januzzi, J. L. Inflammation in heart failure: JACC state-of-the-art review. J. Am. Coll. Cardiol. 75, 1324–1340 (2020).
Gray, J. I. & Farber, D. L. Tissue-resident immune cells in humans. Annu. Rev. Immunol. 40, 195–220 (2022).
Grune, J. et al. Neutrophils incite and macrophages avert electrical storm after myocardial infarction. Nat. Cardiovasc. Res. 1, 649–664 (2022).
Nicolás-Ávila, J. A. et al. A network of macrophages supports mitochondrial homeostasis in the heart. Cell 183, 94–109.e23 (2020).
Li, D. & Wu, M. Pattern recognition receptors in health and diseases. Signal Transduct. Target. Ther. 6, 291 (2021).
Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).
Zheng, D., Liwinski, T. & Elinav, E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discov. 6, 36 (2020).
Tschöpe, C. et al. NOD2 (nucleotide-binding oligomerization domain 2) is a major pathogenic mediator of coxsackievirus B3-induced myocarditis. Circ. Heart Fail. 10, e003870 (2017).
Olsen, M. B. et al. Targeting the inflammasome in cardiovascular disease. JACC Basic. Transl. Sci. 7, 84–98 (2022).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Eiz-Vesper, B. & Schmetzer, H. M. Antigen-presenting cells: potential of proven und new players in immune therapies. Transfus. Med. Hemother. 47, 429–431 (2020).
Ngwenyama, N. et al. Antigen presentation by cardiac fibroblasts promotes cardiac dysfunction. Nat. Cardiovasc. Res. 1, 761–774 (2022).
Kumar, B. V., Connors, T. J. & Farber, D. L. Human t cell development, localization, and function throughout life. Immunity 48, 202–213 (2018).
Janeway, C. A., Travers, P., Walport, M. & Shlomchik, M. J. (eds) Immunobiology: the Immune System in Health and Disease 5th edn Ch. 7 (Garland, 2001).
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Varda-Bloom, N. et al. Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro. J. Mol. Cell. Cardiol. 32, 2141–2149 (2000).
Nevers, T. et al. Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure. Circ. Heart Fail. 8, 776–787 (2015).
Yndestad, A. et al. Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure. Cardiovasc. Res. 60, 141–146 (2003).
Bermea, K., Bhalodia, A., Huff, A., Rousseau, S. & Adamo, L. The role of B cells in cardiomyopathy and heart failure. Curr. Cardiol. Rep. 24, 935–946 (2022).
Moran, G. A. G. et al. in Autoimmunity From Bench to Bedside (eds Anaya, J. M., Shoenfeld, Y., Rojas-Villarraga, A., Levy, R. A. & Cervera, R.) 133–168 (El Rosario University Press, 2013).
Dong, C. Cytokine regulation and function in T cells. Annu. Rev. Immunol. 39, 51–76 (2021).
Schett, G., McInnes, I. B. & Neurath, M. F. Reframing immune-mediated inflammatory diseases through signature cytokine hubs. N. Engl. J. Med. 385, 628–639 (2021).
Altan-Bonnet, G. & Mukherjee, R. Cytokine-mediated communication: a quantitative appraisal of immune complexity. Nat. Rev. Immunol. 19, 205–217 (2019).
Hanna, A. & Frangogiannis, N. G. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc. Drugs Ther. 34, 849–863 (2020).
Bartekova, M., Radosinska, J., Jelemensky, M. & Dhalla, N. S. Role of cytokines and inflammation in heart function during health and disease. Heart Fail. Rev. 23, 733–758 (2018).
Shirazi, L. F., Bissett, J., Romeo, F. & Mehta, J. L. Role of inflammation in heart failure. Curr. Atheroscler. Rep. 19, 27 (2017).
Mann, D. L. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ. Res. 116, 1254–1268 (2015).
Nourshargh, S. & Alon, R. Leukocyte migration into inflamed tissues. Immunity 41, 694–707 (2014).
Cappenberg, A., Kardell, M. & Zarbock, A. Selectin‐mediated signaling—shedding light on the regulation of integrin activity in neutrophils. Cells 11, 1310 (2022).
Ivetic, A., Green, H. L. H. & Hart, S. J. L-selectin: a major regulator of leukocyte adhesion, migration and signaling. Front. Immunol. 10, 451997 (2019).
Sharma, D. & Farrar, J. D. Adrenergic regulation of immune cell function and inflammation. Semin. Immunopathol. 42, 709–717 (2020).
Devi, S. et al. Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Immunity 54, 1219–1230.e7 (2021).
Chhatar, S. & Lal, G. Role of adrenergic receptor signalling in neuroimmune communication. Curr. Res. Immunol. 2, 202–217 (2021).
Floras, J. S. & Ponikowski, P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur. Heart J. 36, 1974–1982 (2015).
Kaye, D. M. et al. Characterization of cardiac sympathetic nervous system and inflammatory activation in HFpEF patients. JACC Basic Transl. Sci. 7, 116–127 (2022).
Ohtsuka, T. et al. Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J. Am. Coll. Cardiol. 37, 412–417 (2001).
Mabuchi, N., Tsutamoto, T. & Kinoshita, M. Therapeutic use of dopamine and beta-blockers modulates plasma interleukin-6 levels in patients with congestive heart failure. J. Cardiovasc. Pharmacol. 36 (Suppl. 2), S87–S91 (2000).
Mayer, B. et al. Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels. Int. J. Cardiol. 103, 182–186 (2005).
von Haehling, S. et al. Leukocyte redistribution: effects of beta blockers in patients with chronic heart failure. PLoS ONE 4, e6411 (2009).
Gage, J. R. et al. Beta blocker and angiotensin-converting enzyme inhibitor therapy is associated with decreased Th1/Th2 cytokine ratios and inflammatory cytokine production in patients with chronic heart failure. Neuroimmunomodulation 11, 173–180 (2004).
Grisanti, L. A. et al. Leukocyte-expressed β2-adrenergic receptors are essential for survival after acute myocardial injury. Circulation 134, 153–167 (2016).
Tanner, M. A., Maitz, C. A. & Grisanti, L. A. Immune cell b2-adrenergic receptors contribute to the development of heart failure. Am. J. Physiol. Heart Circ. Physiol. 321, H633–H649 (2021).
Grisanti, L. A. et al. Prior β-blocker treatment decreases leukocyte responsiveness to injury. JCI Insight 5, e99485 (2019).
Clemente-Moragón, A. et al. Metoprolol exerts a non-class effect against ischaemia-reperfusion injury by abrogating exacerbated inflammation. Eur. Heart J. 41, 4425–4440 (2020).
Poole-Wilson, P. A. et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 362, 7–13 (2003).
Baker, J. G. The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br. J. Pharmacol. 144, 317–322 (2005).
Yang, S. P. et al. Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity. Cardiovasc. Res. 59, 776–787 (2003).
Shaw, S. M. et al. The effect of beta-blockers on the adaptive immune system in chronic heart failure. Cardiovasc. Ther. 27, 181–186 (2009).
Wong, W. T. et al. Repositioning of the β-blocker carvedilol as a novel autophagy inducer that inhibits the NLRP3 inflammasome. Front. Immunol. 9, 1920 (2018).
Bernstein, K. E. et al. Angiotensin-converting enzyme in innate and adaptive immunity. Nat. Rev. Nephrol. 14, 325–336 (2018).
Danilov, S. M. et al. Angiotensin-converting enzyme (CD143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp. Hematol. 31, 1301–1309 (2003).
Viinikainen, A., Nyman, T., Fyhrquist, F. & Saijonmaa, O. Downregulation of angiotensin converting enzyme by TNF-α in differentiating human macrophages. Cytokine 18, 304–310 (2002).
Gullestad, L. et al. Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J. Am. Coll. Cardiol. 34, 2061–2067 (1999).
Schieffer, B. et al. Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J. Am. Coll. Cardiol. 44, 362–368 (2004).
Krysiak, R. & Okopień, B. Pleiotropic effects of angiotensin-converting enzyme inhibitors in normotensive patients with coronary artery disease. Pharmacol. Rep. 60, 514–523 (2008).
Krysiak, R. & Okopień, B. Lymphocyte-suppressing action of angiotensin-converting enzyme inhibitors in coronary artery disease patients with normal blood pressure. Pharmacol. Rep. 63, 1151–1161 (2011).
Largeau, B., Dupont, A. C., Guilloteau, D., Santiago-Ribeiro, M. J. & Arlicot, N. TSPO PET imaging: from microglial activation to peripheral sterile inflammatory diseases? Contrast Media Mol. Imaging 2017, 6592139 (2017).
Borchert, T. et al. Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation. Eur. J. Nucl. Med. Mol. Imaging 47, 1757–1768 (2020).
Leuschner, F. et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ. Res. 107, 1364–1373 (2010).
Rudi, W. S. et al. ACE inhibition modulates myeloid hematopoiesis after acute myocardial infarction and reduces cardiac and vascular inflammation in ischemic heart failure. Antioxid 10, 396 (2021).
Ma, Y. et al. ACE inhibitor suppresses cardiac remodeling after myocardial infarction by regulating dendritic cells and AT2 receptor-mediated mechanism in mice. Biomed. Pharmacother. 114, 108660 (2019).
Candido, R. et al. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E–deficient mice. Circulation 106, 246–253 (2002).
Yang, S. et al. TLR4-mediated anti-atherosclerosis mechanisms of angiotensin-converting enzyme inhibitor – fosinopril. Cell. Immunol. 285, 38–41 (2013).
Abd Alla, J. et al. Angiotensin-converting enzyme inhibition down-regulates the pro-atherogenic chemokine receptor 9 (CCR9)-chemokine ligand 25 (CCL25) axis. J. Biol. Chem. 285, 23496–23505 (2010).
Kranzhöfer, R. et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 19, 1623–1629 (1999).
Yakubova, A. et al. ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart. Sci. Rep. 8, 16169 (2018).
Garvin, A. M. et al. Transient ACE (Angiotensin-Converting Enzyme) inhibition suppresses future fibrogenic capacity and heterogeneity of cardiac fibroblast subpopulations. Hypertension 77, 904–918 (2021).
Zhang, Y. et al. Captopril attenuates TAC-induced heart failure via inhibiting Wnt3a/β-catenin and Jak2/Stat3 pathways. Biomed. Pharmacother. 113, 108780 (2019).
Chae, W. J. & Bothwell, A. L. M. Canonical and non-canonical wnt signaling in immune cells. Trends Immunol. 39, 830–847 (2018).
Hu, Q. et al. JAK/STAT pathway: extracellular signals, diseases, immunity, and therapeutic regimens. Front. Bioeng. Biotechnol. 11, 262 (2023).
Nataraj, C. et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest. 104, 1693–1701 (1999).
Silva-Filho, J. L. et al. AT1 receptor-mediated angiotensin II activation and chemotaxis of T lymphocytes. Mol. Immunol. 48, 1835–1843 (2011).
Schindler, R., Dinarello, C. A. & Koch, K. M. Angiotensin-converting-enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7, 526–533 (1995).
Constantinescu, C. S., Goodman, D. B. P. & Ventura, E. S. Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. Immunol. Lett. 62, 25–31 (1998).
Lapteva, N. et al. Activation and suppression of renin-angiotensin system in human dendritic cells. Biochem. Biophys. Res. Commun. 296, 194–200 (2002).
Dostal, D. E. & Baker, K. M. The cardiac renin-angiotensin system: conceptual, or a regulator of cardiac function? Circ. Res. 85, 643–650 (1999).
De Mello, W. C. & Danser, A. H. J. Angiotensin II and the heart. Hypertension 35, 1183–1188 (2000).
Kintscher, U. et al. Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes. Hypertension 37, 587–593 (2001).
Jurewicz, M. et al. Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation. J. Am. Soc. Nephrol. 18, 1093–1102 (2007).
Hoch, N. E. et al. Regulation of T-cell function by endogenously produced angiotensin II. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R208–R216 (2009).
Nahmod, K. A. et al. Control of dendritic cell differentiation by angiotensin II. FASEB J. 17, 491–493 (2003).
Tsutamoto, T. et al. Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor α, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure. J. Am. Coll. Cardiol. 35, 714–721 (2000).
Fliser, D., Buchholz, K. & Haller, H. Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation 110, 1103–1107 (2004).
Dandona, P. et al. Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-κB, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J. Clin. Endocrinol. Metab. 88, 4496–4501 (2003).
Maeda, A. et al. Immunosuppressive effect of angiotensin receptor blocker on stimulation of mice CTLs by angiotensin II. Int. Immunopharmacol. 9, 1183–1188 (2009).
Fernandez-Castelo, S. et al. Angiotensin II regulates interferon-γ production. J. Interferon Res. 7, 261–268 (1987).
Shao, J. et al. Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension 42, 31–38 (2003).
Dasu, M. R., Riosvelasco, A. C. & Jialal, I. Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo. Atherosclerosis 202, 76–83 (2009).
Pang, T. et al. Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes. J. Hypertens. 30, 87–96 (2012).
Espitia-Corredor, J. A. et al. Angiotensin II triggers NLRP3 inflammasome activation by a Ca2+ signaling-dependent pathway in rat cardiac fibroblast Ang-II by a Ca2+-dependent mechanism triggers NLRP3 inflammasome in CF. Inflammation 45, 2498–2512 (2022).
Chen, Y. et al. Cathepsin B-mediated NLRP3 inflammasome formation and activation in angiotensin II-induced hypertensive mice: role of macrophage digestion dysfunction. Cell. Physiol. Biochem. 50, 1585–1600 (2018).
Nahmod, K. et al. Impaired function of dendritic cells deficient in angiotensin II type 1 receptors. J. Pharmacol. Exp. Ther. 334, 854–862 (2010).
Ji, Y., Liu, J., Wang, Z. & Liu, N. Angiotensin II induces inflammatory response partly via Toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell. Physiol. Biochem. 23, 265–276 (2009).
Meng, K. et al. Valsartan attenuates atherosclerosis via upregulating the Th2 immune response in prolonged angiotensin II-treated ApoE−/− mice. Mol. Med. 21, 143–153 (2015).
Marshall, T. G., Lee, R. E. & Marshall, F. E. Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor. Biol. Med. Model. 3, 1 (2006).
Delerive, P., Fruchart, J. C. & Staels, B. Peroxisome proliferator-activated receptors in inflammation control. J. Endocrinol. 169, 453–459 (2001).
Széles, L., Töröcsik, D. & Nagy, L. PPARγ in immunity and inflammation: cell types and diseases. Biochim. Biophys. Acta 1771, 1014–1030 (2007).
Villapol, S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell. Mol. Neurobiol. 38, 121–132 (2018).
Schupp, M., Janke, J., Clasen, R., Unger, T. & Kintscher, U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity. Circulation 109, 2054–2057 (2004).
Marketou, M. E. et al. Differential effect of telmisartan and amlodipine on monocyte chemoattractant protein-1 and peroxisome proliferator-activated receptor-gamma gene expression in peripheral monocytes in patients with essential hypertension. Am. J. Cardiol. 107, 59–63 (2011).
Ayoub, M. A. Angiotensin II type 1 receptor heterodimers in the kidney. Curr. Opin. Endocr. Metab. Res. 16, 96–101 (2021).
Urushihara, M. et al. Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis. Hypertension 57, 586–593 (2011).
Ayoub, M. A. et al. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease. PLoS ONE 10, e0119803 (2015).
Syrbe, U., Moebes, A., Scholze, J., Swidsinski, A. & Dörfel, Y. Effects of the angiotensin II type 1 receptor antagonist telmisartan on monocyte adhesion and activation in patients with essential hypertension. Hypertens. Res. 30, 521–528 (2007).
Iwata, A. et al. Do valsartan and losartan have the same effects in the treatment of coronary artery disease? Circ. J. 71, 32–38 (2007).
Connell, J. M. C. & Davies, E. The new biology of aldosterone. J. Endocrinol. 186, 1–20 (2005).
Ferreira, N. S., Tostes, R. C., Paradis, P. & Schiffrin, E. L. Aldosterone, inflammation, immune system, and hypertension. Am. J. Hypertension 34, 15–27 (2021).
Besedovsky, L., Born, J. & Lange, T. Blockade of mineralocorticoid receptors enhances naïve T-helper cell counts during early sleep in humans. Brain Behav. Immun. 26, 1116–1121 (2012).
Besedovsky, L., Linz, B., Born, J. & Lange, T. Mineralocorticoid receptor signaling reduces numbers of circulating human naïve T cells and increases their CD62L, CCR7, and CXCR4 expression. Eur. J. Immunol. 44, 1759–1769 (2014).
Tschöpe, C. et al. Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis. ESC Heart Fail. 7, 2838–2852 (2020).
Bendtzen, K. et al. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-α and interferon-γ and has potential in the treatment of arthritis. Clin. Exp. Immunol. 134, 151–158 (2003).
Salling Sønder, S. U., Mikkelsen, M., Rieneck, K., Hedegaard, C. J. & Bendtzen, K. Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction. Br. J. Pharmacol. 148, 46–53 (2006).
Hansen, P. R., Rieneck, K. & Bendtzen, K. Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. Immunol. Lett. 91, 87–91 (2004).
Duan, S. Z. & Mortensen, R. M. A new connection: myeloid mineralocorticoid receptor and cardiovascular disease. Am. Chin. J. Med. Sci. 3, 167 (2010).
Funder, J. W. RALES, EPHESUS and redox. J. Steroid Biochem. Mol. Biol. 93, 121–125 (2005).
Gomez-Sanchez, E. P. Third-generation mineralocorticoid receptor antagonists: why do we need a fourth? J. Cardiovasc. Pharmacol. 67, 26–38 (2016).
Usher, M. G. et al. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J. Clin. Invest. 120, 3350–3364 (2010).
Montes-Cobos, E. et al. Deletion of the mineralocorticoid receptor in myeloid cells attenuates central nervous system autoimmunity. Front. Immunol. 8, 1319 (2017).
De Marco, V. G. et al. Low-dose mineralocorticoid receptor blockade prevents western diet-induced arterial stiffening in female mice. Hypertension 66, 99–107 (2015).
Bostick, B. et al. Mineralocorticoid receptor blockade prevents western diet-induced diastolic dysfunction in female mice. Am. J. Physiol. Heart Circ. Physiol. 308, H1126–H1135 (2015).
Herrada, A. A. et al. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J. Immunol. 184, 191–202 (2010).
Amador, C. A. et al. Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes. Hypertension 63, 797–803 (2014).
Sun, X. N. et al. T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-gamma. Circ. Res. 120, 1584–1597 (2017).
Barbaro, N. R., Kirabo, A. & Harrison, D. G. A new role of Mister (MR) T in hypertension: mineralocorticoid receptor, immune system, and hypertension. Circ. Res. 120, 1527–1529 (2017).
Li, C. et al. Mineralocorticoid receptor deficiency in T cells attenuataces pressure overload-induced cardiac hypertrophy and dysfunction through modulating T-cell activation. Hypertension 70, 137–147 (2017).
Fraccarollo, D. et al. Macrophage mineralocorticoid receptor is a pleiotropic modulator of myocardial infarct healing. Hypertension 73, 102–111 (2019).
Lax, A. et al. Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction. JACC Heart Fail. 3, 50–58 (2015).
Grune, J. et al. Steroidal and nonsteroidal mineralocorticoid receptor antagonists cause differential cardiac gene expression in pressure overload-induced cardiac hypertrophy. J. Cardiovasc. Pharmacol. 67, 402–411 (2016).
Kuster, G. M. et al. Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. Circulation 111, 420–427 (2005).
Bender, S. B. et al. Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction. Hypertension 65, 1082–1088 (2015).
Kang, Y. M. et al. Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circ. Res. 99, 758–766 (2006).
Francis, J., Weiss, R. M., Johnson, A. K. & Felder, R. B. Central mineralocorticoid receptor blockade decreases plasma TNF-α after coronary artery ligation in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R325–R335 (2003).
Ibsen, D. B., Levitan, E. B., Åkesson, A., Gigante, B. & Wolk, A. The DASH diet is associated with a lower risk of heart failure: a cohort study. Eur. J. Prev. Cardiol. 29, 1114–1123 (2022).
Soltani, S., Chitsazi, M. J. & Salehi-Abargouei, A. The effect of dietary approaches to stop hypertension (DASH) on serum inflammatory markers: a systematic review and meta-analysis of randomized trials. Clin. Nutr. 37, 542–550 (2018).
Hernandez, A. L. et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J. Clin. Invest. 125, 4212–4222 (2015).
Jobin, K., Müller, D. N., Jantsch, J. & Kurts, C. Sodium and its manifold impact on our immune system. Trends Immunol. 42, 469–479 (2021).
Ezekowitz, J. A. et al. Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial. Lancet 399, 1391–1400 (2022).
Alnuwaysir, R. I. S., Hoes, M. F., van Veldhuisen, D. J., van der Meer, P. & Grote Beverborg, N. Iron deficiency in heart failure: mechanisms and pathophysiology. J. Clin. Med. 11, 125 (2022).
Prats, M. et al. Acute and sub-acute effect of ferric carboxymaltose on inflammation and adhesion molecules in patients with predialysis chronic renal failure. Nefrologia 33, 355–361 (2013).
Kassianides, X., Gordon, A., Sturmey, R. & Bhandari, S. The comparative effects of intravenous iron on oxidative stress and inflammation in patients with chronic kidney disease and iron deficiency: a randomized controlled pilot study. Kidney Res. Clin. Pract. 40, 89–98 (2021).
Kassianides, X., Allgar, V., Macdougall, I. C., Kalra, P. A. & Bhandari, S. Analysis of oxidative stress, inflammation and endothelial function following intravenous iron in chronic kidney disease in the Iron and Heart Trial. Sci. Rep. 12, 6853 (2022).
Fell, L. H. et al. Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells. Nephrol. Dial. Transplant. 31, 1835–1845 (2016).
Fell, L. H. et al. Distinct immunologic effects of different intravenous iron preparations on monocytes. Nephrol. Dial. Transplant. 29, 809–822 (2014).
Toblli, J. E., Cao, G., Giani, J. F., Dominici, F. P. & Angerosa, M. Markers of oxidative/nitrosative stress and inflammation in lung tissue of rats exposed to different intravenous iron compounds. Drug. Des. Devel. Ther. 11, 2251–2263 (2017).
Iwamoto, I., Kimura, A., Ochiai, K., Tomioka, H. & Yoshida, S. Distribution of neutral endopeptidase activity in human blood leukocytes. J. Leukoc. Biol. 49, 116–125 (1991).
Shipp, M. A., Stefano, G. B., Switzer, S. N., Griffin, J. D. & Reinherz, E. L. CD10 (CALLA)/neutral endopeptidase 24.11 modulates inflammatory peptide-induced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation. Blood 78, 1834–1841 (1991).
Saeland, S. et al. Distribution of surface-membrane molecules on bone marrow and cord blood CD34+ hematopoietic cells. Exp. Hematol. 20, 24–33 (1992).
Young, H. E. et al. Human pluripotent and progenitor cells display cell surface cluster differentiation markers CD10, CD13, CD56, and MHC class-I. Exp. Biol. Med. 221, 63–72 (1999).
Knox, J. J., Cosma, G. L., Betts, M. R. & McLane, L. M. Characterization of T-bet and Eomes in peripheral human immune cells. Front. Immunol. 5, 217 (2014).
Cutrona, G. et al. Expression of CD10 by human T cells that undergo apoptosis both in vitro and in vivo. Blood 94, 3067–3076 (1999).
Morabito, F. et al. Expression of CD10 by B-chronic lymphocytic leukemia cells undergoing apoptosis in vivo and in vitro. Haematologica 88, 864–873 (2003).
Mishra, D., Singh, S. & Narayan, G. Role of B cell development marker CD10 in cancer progression and prognosis. Mol. Biol. Int. 2016, 4328697 (2016).
Maguer-Satta, V., Besançon, R. & Bachelard-Cascales, E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. Stem Cell 29, 389–396 (2011).
Lu, B. et al. Neutral endopeptidase modulation of septic shock. J. Exp. Med. 181, 2271–2275 (1995).
Stefano, G. B., Paemen, L. R. & Hughes, T. K. Autoimmunoregulation: differential modulation of CD10/neutral endopeptidase 24.11 by tumor necrosis factor and neuropeptides. J. Neuroimmunol. 41, 9–14 (1992).
Pierart, M. E., Najdovski, T., Appelboom, T. E. & Deschodt-Lanckman, M. M. Effect of human endopeptidase 24.11 (‘enkephalinase’) on IL-1-induced thymocyte proliferation activity. J. Immunol. 140, 3808–3811 (1988).
Delikat, S. E., Galvani, D. W. & Zuzel, M. A function of CD10 on bone marrow stroma. Br. J. Haematol. 87, 655–657 (1994).
Shipp, M. A. et al. Downregulation of enkephalin-mediated inflammatory responses by CDl0/neutral endopeptidase 24.11. Nature 347, 394–396 (1990).
Painter, R. G. et al. Function of neutral endopeptidase on the cell membrane of human neutrophils. J. Biol. Chem. 263, 9456–9461 (1988).
McCormack, R. T., Nelson, R. D. & LeBien, T. W. Structure/function studies of the common acute lymphoblastic leukemia antigen (CALLA/CD10) expressed on human neutrophils. J. Immunol. 137, 1075–1082 (1986).
Connelly, J. C., Chambless, R., Holiday, D., Chittenden, K. & Johnson, A. R. Up-regulation of neutral endopeptidase (CALLA) in human neutrophils by granulocyte-macrophage colony-stimulating factor. J. Leukoc. Biol. 53, 685–690 (1993).
Salzer, U. et al. Susceptibility to infections and adaptive immunity in adults with heart failure. Esc. Hear. Fail. 9, 1195–1205 (2022).
Ishii, M. et al. Cardioprotective effects of LCZ696 (sacubitril/valsartan) after experimental acute myocardial infarction. JACC Basic Transl. Sci. 2, 655–668 (2017).
Matsumura, T. et al. Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity. J. Clin. Invest. 97, 2192–2203 (1996).
Pfeffer, M. A. et al. Receptor–neprilysin inhibition in acute myocardial infarction. N. Engl. J. Med. 385, 1845–1855 (2021).
Palaniyappan, A., Uwiera, R. R. E., Idikio, H. & Jugdutt, B. I. Comparison of vasopeptidase inhibitor omapatrilat and angiotensin receptor blocker candesartan on extracellular matrix, myeloperoxidase, cytokines, and ventricular remodeling during healing after reperfused myocardial infarction. Mol. Cell. Biochem. 321, 9–22 (2009).
Palaniyappan, A. et al. Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction. Mol. Cell. Biochem. 376, 175–188 (2013).
Raj, P. et al. Comparative and combinatorial effects of resveratrol and sacubitril/valsartan alongside valsartan on cardiac remodeling and dysfunction in mi-induced rats. Molecules 26, 5006 (2021).
Mann, D. L. et al. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA Cardiol. 7, 17–25 (2022).
Vasquez, N., Carter, S. & Grodin, J. L. Angiotensin receptor–neprilysin inhibitors and the natriuretic peptide axis. Curr. Heart Fail. Rep. 17, 67–76 (2020).
Mtairag, E. M. et al. Pharmacological potentiation of natriuretic peptide limits polymorphonuclear neutrophil–vascular cell interactions. Arterioscler. Thromb. Vasc. Biol. 22, 1824–1831 (2002).
Garlichs, C. D., Zhang, H., Schmeißer, A. & Daniel, W. G. Priming of superoxide anion in polymorphonuclear neutrophils by brain natriuretic peptide. Life Sci. 65, 1027–1033 (1999).
Biselli, R., Farrace, S., De Simone, C. & Fattorossi, A. Potentiation of human polymorphonuclear leukocyte activation by atrial natriuretic peptide. Inhibitory effect of carnitine congeners. Inflammation 20, 33–42 (1996).
Wiedermann, C. J., Niedermuhlbichler, M. & Braunsteiner, H. Priming of polymorphonuclear neutrophils by atrial natriuretic peptide in vitro. J. Clin. Invest. 89, 1580–1586 (1992).
De Vito, P. Atrial natriuretic peptide: an old hormone or a new cytokine? Peptides 58, 108–116 (2014).
Vollmar, A. M. The role of atrial natriuretic peptide in the immune system. Peptides 26, 1086–1094 (2005).
Ogawa, T. & de Bold, A. J. Brain natriuretic peptide production and secretion in inflammation. J. Transplant. 2012, 962347 (2012).
Pavo, I. J. et al. Heart failure with reduced ejection fraction is characterized by systemic NEP downregulation. JACC Basic Transl. Sci. 5, 715–726 (2020).
Prausmüller, S. et al. Relevance of neutrophil neprilysin in heart failure. Cells 10, 2922 (2021).
Marini, O. et al. Mature CD10+ and immature CD10− neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood 129, 1343–1356 (2017).
Vodovar, N. et al. Elevated plasma B-type natriuretic peptide concentrations directly inhibit circulating neprilysin activity in heart failure. JACC Heart Fail. 3, 629–636 (2015).
Vaduganathan, M. et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet 400, 757–767 (2022).
Sano, R., Shinozaki, Y. & Ohta, T. Sodium–glucose cotransporters: functional properties and pharmaceutical potential. J. Diabetes Investig. 11, 770–782 (2020).
Maldonado-Cervantes, M. I. et al. Autocrine modulation of glucose transporter SGLT2 by IL-6 and TNF-α in LLC-PK1 cells. J. Physiol. Biochem. 68, 411–420 (2012).
Matthews, V. B. et al. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J. Hypertens. 35, 2059–2068 (2017).
Katsurada, K., Nandi, S. S., Sharma, N. M. & Patel, K. P. Enhanced expression and function of renal SGLT2 (sodium-glucose cotransporter 2) in heart failure: role of renal nerves. Circ. Heart Fail. 14, e008365 (2021).
Byrne, N. J. et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ. Heart Fail. 13, e006277 (2020).
Ye, Y., Bajaj, M., Yang, H. C., Perez-Polo, J. R. & Birnbaum, Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc. Drugs Ther. 31, 119–132 (2017).
Kolijn, D. et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovasc. Res. 117, 495–507 (2021).
Koyani, C. N. et al. Empagliflozin protects heart from inflammation and energy depletion via AMPK activation. Pharmacol. Res. 158, 104870 (2020).
Lee, T. M., Chang, N. C. & Lin, S. Z. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic. Biol. Med. 104, 298–310 (2017).
Sundararaman, A., Amirtham, U. & Rangarajan, A. Calcium-oxidant signaling network regulates AMP-activated protein kinase (AMPK) activation upon matrix deprivation. J. Biol. Chem. 291, 14410–14429 (2016).
Auciello, F. R., Ross, F. A., Ikematsu, N. & Hardie, D. G. Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP. FEBS Lett. 588, 3361–3366 (2014).
Murakami, T. et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl Acad. Sci. USA 109, 11282–11287 (2012).
Abais, J. M., Xia, M., Zhang, Y., Boini, K. M. & Li, P. L. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid. Redox Signal. 22, 1111–1129 (2015).
Xu, C. et al. Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells. Biochem. Pharmacol. 152, 45–59 (2018).
Lin, F. et al. Canagliflozin alleviates LPS-induced acute lung injury by modulating alveolar macrophage polarization. Int. Immunopharmacol. 88, 106969 (2020).
Lee, N. et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J. Immunol. Res. 2021, 9944880 (2021).
Zhang, H. & Liu, Z. Effects of dapagliflozin in combination with metoprolol sustained-release tablets on prognosis and cardiac function in patients with acute myocardial infarction after PCI. Comput. Math. Methods Med. 2022, 106969 (2022).
Xu, Y. et al. Bone marrow-derived naïve B lymphocytes improve heart function after myocardial infarction: a novel cardioprotective mechanism for empagliflozin. Basic Res. Cardiol. 117, 47 (2022).
Paolisso, P. et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc. Diabetol. 21, 77 (2022).
Kim, S. R. et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat. Commun. 11, 2127 (2020).
Borzouei, S., Moghimi, H., Zamani, A. & Behzad, M. Changes in T helper cell-related factors in patients with type 2 diabetes mellitus after empagliflozin therapy. Hum. Immunol. 82, 422–428 (2021).
Borghi, C., Palazzuoli, A., Landolfo, M. & Cosentino, E. Hyperuricemia: a novel old disorder—relationship and potential mechanisms in heart failure. Heart Fail. Rev. 25, 43–51 (2020).
Doehner, W. et al. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial. Eur. Heart J. 43, 3435–3446 (2022).
Ito, H. et al. Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS ONE 6, e27817 (2011).
Riehle, C. & Abel, E. D. Insulin signaling and heart failure. Circ. Res. 118, 1151–1169 (2016).
Vaziri, N. D., Pahl, M. V., Crum, A. & Norris, K. Effect of uremia on structure and function of immune system. J. Ren. Nutr. 22, 149–156 (2012).
La Grotta, R. et al. Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin. Cell. Mol. Life Sci. 79, 273 (2022).
Cowie, M. R. & Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol. 17, 761–772 (2020).
Hattori, Y. Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization. Heart Fail. Rev. 25, 403–408 (2020).
Yaribeygi, H., Sathyapalan, T., Maleki, M., Jamialahmadi, T. & Sahebkar, A. Molecular mechanisms by which SGLT2 inhibitors can induce insulin sensitivity in diabetic milieu: a mechanistic review. Life Sci. 240, 117090 (2020).
Mancini, S. J. et al. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci. Rep. 8, 5276 (2018).
Hu, Z., Cano, I. & D’Amore, P. A. Update on the role of the endothelial glycocalyx in angiogenesis and vascular inflammation. Front. Cell Dev. Biol. 9, 734276 (2021).
Campeau, M. A. & Leask, R. L. Empagliflozin mitigates endothelial inflammation and attenuates endoplasmic reticulum stress signaling caused by sustained glycocalyx disruption. Sci. Rep. 12, 12681 (2022).
Cooper, S., Teoh, H., Campeau, M. A., Verma, S. & Leask, R. L. Empagliflozin restores the integrity of the endothelial glycocalyx in vitro. Mol. Cell. Biochem. 459, 121–130 (2019).
Sukhanov, S. et al. The SGLT2 inhibitor empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/caspase-1-dependent IL-1β and IL-18 secretion. Cell. Signal. 77, 109825 (2021).
Nasiri-Ansari, N. et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc. Diabetol. 17, 106 (2018).
Fu, J. et al. Empagliflozin inhibits macrophage inflammation through AMPK signaling pathway and plays an anti-atherosclerosis role. Int. J. Cardiol. 367, 56–62 (2022).
Kiuchi, S. et al. Long-term use of ipragliflozin improved cardiac sympathetic nerve activity in a patient with heart failure: a case report. Drug. Discov. Ther. 12, 51–54 (2018).
Hamaoka, T. et al. Different responses of muscle sympathetic nerve activity to dapagliflozin between patients with type 2 diabetes with and without heart failure. J. Am. Heart Assoc. 10, 22637 (2021).
Herat, L. Y. et al. SGLT2 inhibitor–induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl. Sci. 5, 169–179 (2020).
Wang, F. Z. et al. The cardioprotective effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in rats with isoproterenol-induced cardiomyopathy. Am. J. Transl. Res. 13, 10950–10961 (2021).
Lymperopoulos, A., Borges, J. I., Cora, N. & Sizova, A. Sympatholytic mechanisms for the beneficial cardiovascular effects of SGLT2 inhibitors: a research hypothesis for dapagliflozin’s effects in the adrenal gland. Int. J. Mol. Sci. 22, 7684 (2021).
Lymperopoulos, A. et al. Downregulates adrenal G protein-coupled receptor-kinase-2 to exert sympatholysis in heart failure. Circulation 146, A11977 (2022).
Chait, A. & den Hartigh, L. J. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front. Cardiovasc. Med. 7, 22 (2020).
Alzaim, I. et al. Adipose tissue immunomodulation: a novel therapeutic approach in cardiovascular and metabolic diseases. Front. Cardiovasc. Med. 7, 277 (2020).
Díaz-Rodríguez, E. et al. Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovasc. Res. 114, 336–346 (2018).
Carlos, G. S. et al. Benefits of the Sglt2 inhibitor empagliflozin on epicardial adipose tissue in non-diabetic Hfref. Circulation 146, A15407 (2022).
Rafeh, R., Viveiros, A., Oudit, G. Y. & El-Yazbi, A. F. Targeting perivascular and epicardial adipose tissue inflammation: therapeutic opportunities for cardiovascular disease. Clin. Sci. 134, 827–851 (2020).
Gislason, G. H. et al. Persistent use of evidence-based pharmacotherapy in heart failure is associated with improved outcomes. Circulation 116, 737–744 (2007).
Kolandaivelu, K., Leiden, B. B., O’Gara, P. T. & Bhatt, D. L. Non-adherence to cardiovascular medications. Eur. Heart J. 35, 3267–3276 (2014).
Jarjour, M. et al. Care gaps in adherence to heart failure guidelines: clinical inertia or physiological limitations? JACC Heart Fail. 8, 725–738 (2020).
Savarese, G. et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur. J. Heart Fail. 23, 1499–1511 (2021).
Jonsson Holmdahl, A. et al. Motives, frequency, predictors and outcomes of MRA discontinuation in a real-world heart failure population. Open Heart 9, e002022 (2022).
Seferović, P. M. et al. Navigating between Scylla and Charybdis: challenges and strategies for implementing guideline-directed medical therapy in heart failure with reduced ejection fraction. Eur. J. Heart Fail. 23, 1999–2007 (2021).
Aboumsallem, J. P. et al. Multi-omics analyses identify molecular signatures with prognostic values in different heart failure aetiologies. J. Mol. Cell. Cardiol. 175, 13–28 (2023).
Ridker, P. M. et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 2060–2069 (2021).
Buckley, L. F. et al. Potential role for interleukin-1 in the cardio-renal syndrome. Eur. J. Heart Fail. 21, 385–386 (2019).
Li, K. et al. Interleukin-6 stimulates epithelial sodium channels in mouse cortical collecting duct cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R590–R595 (2010).
Svensson, E. C. et al. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial. JAMA Cardiol. 7, 521–528 (2022).
Díaz, M. L. et al. The characterization of cardiac explants reveals unique fibrosis patterns and a predominance of CD8+ T cell subpopulations in patients with chronic chagas cardiomyopathy. Pathogens 11, 1402 (2022).
Bian, R. T., Wang, Z. T. & Li, W. Y. Immunoadsorption treatment for dilated cardiomyopathy: a PRISMA-compliant systematic review and meta-analysis. Medicine 100, E26475 (2021).
Tschöpe, C. et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat. Rev. Cardiol. 18, 169–193 (2021).
Murray, E. C. et al. Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective. Cardiovasc. Res. 117, 2589–2609 (2021).
Mann, D. L. et al. targeted anticytokine therapy in patients with chronic heart failure: results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).
Chung, E. S., Packer, M., Lo, K. H., Fasanmade, A. A. & Willerson, J. T. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trail. Circulation 107, 3133–3140 (2003).
Givertz, M. M. et al. Effects of xanthine oxidase inhibition in hyperuricemic heart failure patients: the xanthine oxidase inhibition for hyperuricemic heart failure patients (EXACT-HF) study. Circulation 131, 1763–1771 (2015).
Hare, J. M. et al. Impact of oxypurinol in patients with symptomatic heart failure. results of the OPT-CHF study. J. Am. Coll. Cardiol. 51, 2301–2309 (2008).
Kjekshus, J. et al. Rosuvastatin in older patients with systolic heart failure. N. Engl. J. Med. 357, 2248–2261 (2007).
GISSI-HF investigators et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 372, 1231–1239 (2008).
Gong, K. et al. The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic heart failure. Am. Heart J. 151, 62–68 (2006).
Gullestad, L. et al. Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study. Circulation 112, 3408–3414 (2005).
Moreira, D. M., Vieira, J. L. & Mascia Gottschall, C. A. The effects of METhotrexate therapy on the physical capacity of patients with ISchemic Heart failure: a randomized double-blind, placebo-controlled trial (METIS Trial). J. Card. Fail. 15, 828–834 (2009).
Orea-Tejeda, A. et al. Effects of thalidomide treatment in heart failure patients. Cardiology 108, 237–242 (2007).
Torre-Amione, G. et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet 371, 228–236 (2008).
Deftereos, S. et al. Anti-inflammatory treatment with colchicine instable chronic heart failure. A prospective, randomized study. JACC Heart Fail. 2, 131–137 (2014).
Tardif, J.-C. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381, 2497–2505 (2019).
Granger, C. B. et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation 108, 1184–1190 (2003).
Mahaffey, K. W. et al. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 108, 1176–1183 (2003).
Armstrong, P. W. et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 297, 43–51 (2007).
Piot, C. et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N. Engl. J. Med. 359, 473–481 (2008).
Ghaffari, S., Kazemi, B., Toluey, M. & Sepehrvand, N. The effect of prethrombolytic cyclosporine-a injection on clinical outcome of acute anterior ST-elevation myocardial infarction. Cardiovasc. Ther. 31, e34–e39 (2013).
Cung, T.-T. et al. Cyclosporine before PCI in patients with acute myocardial infarction. N. Engl. J. Med. 373, 1021–1031 (2015).
Ottani, F. et al. Cyclosporine a in reperfused myocardial infarction the multicenter, controlled, open-label CYCLE trial. J. Am. Coll. Cardiol. 67, 365–374 (2016).
Liu, C. & Liu, K. Cardiac outcome prevention effectiveness of glucocorticoids in acute decompensated heart failure: COPE-ADHF study. J. Cardiovasc. Pharmacol. 63, 333–338 (2014).
Liu, C. et al. Potent potentiating diuretic effects of prednisone in congestive heart failure. J. Cardiovasc. Pharmacol. 48, 173–176 (2006).
Liu, C. et al. Prednisone in uric acid lowering in symptomatic heart failure patients with hyperuricemia (PUSH-PATH) study. Can. J. Cardiol. 29, 1048–1054 (2013).
Liu, C. & Liu, K. Systemic corticosteroid use in heart failure: let evidence reveal the truth. JACC Heart Fail. 8, 153 (2020).
Sliwa, K., Skudicky, D., Candy, G., Wisenbaugh, T. & Sareli, P. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 351, 1091–1093 (1998).
Skudicky, D., Sliwa, K., Bergemann, A., Candy, G. & Sareli, P. Reduction in Fas/APO-1 plasma concentrations correlates with improvement in left ventricular function in patients with idiopathic dilated cardiomyopathy treated with pentoxifylline. Heart 84, 438–439 (2000).
Skudicky, D., Bergemann, A., Sliwa, K., Candy, G. & Sareli, P. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol: results of a randomized study. Circulation 103, 1083–1088 (2001).
Sliwa, K. et al. Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am. J. Cardiol. 90, 1118–1122 (2002).
Sliwa, K. et al. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 109, 750–755 (2004).
Champion, S. et al. Pentoxifylline in heart failure: a meta-analysis of clinical trials. Cardiovasc. Ther. 32, 159–162 (2014).
Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).
Patel, B. et al. CCR2+ monocyte-derived infiltrating macrophages are required for adverse cardiac remodeling during pressure overload. JACC Basic Transl. Sci. 3, 230–244 (2018).
Fei, L., Ren, X., Yu, H. & Zhan, Y. Targeting the CCL2/CCR2 axis in cancer immunotherapy: one stone, three birds? Front. Immunol. 12, 4657 (2021).
Hiraiwa, H., Okumura, T. & Murohara, T. The cardiosplenic axis: the prognostic role of the spleen in heart failure. Heart Fail. Rev. 27, 2005–2015 (2022).
Tynan, A., Brines, M. & Chavan, S. S. Control of inflammation using non-invasive neuromodulation: past, present and promise. Int. Immunol. 34, 119–128 (2022).
Gold, M. R. et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J. Am. Coll. Cardiol. 68, 149–158 (2016).
Stavrakis, S. et al. Neuromodulation of inflammation to treat heart failure with preserved ejection fraction: a pilot randomized clinical trial. J. Am. Heart Assoc. 11, 23582 (2022).
Zahid, A., Li, B., Kombe, A. J. K., Jin, T. & Tao, J. Pharmacological inhibitors of the NLRP3 inflammasome. Front. Immunol. 10, 2538 (2019).
Toldo, S. & Abbate, A. The NLRP3 inflammasome in acute myocardial infarction. Nat. Rev. Cardiol. 15, 203–214 (2018).
Cao, D. & Yi et al. A small molecule inhibitor of caspase-1 inhibits NLRP3 inflammasome activation and pyroptosis to alleviate gouty inflammation. Immunol. Lett. 244, 28–39 (2022).
Van Hout, G. P. J. et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur. Heart J. 38, 828–836 (2017).
Gao, R. F. et al. The covalent NLRP3-inflammasome inhibitor Oridonin relieves myocardial infarction induced myocardial fibrosis and cardiac remodeling in mice. Int. Immunopharmacol. 90, 107133 (2021).
Pappritz, K. et al. Colchicine prevents disease progression in viral myocarditis via modulating the NLRP3 inflammasome in the cardiosplenic axis. ESC Heart Fail. 9, 925–941 (2022).
Tardif, J. C. et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir. Med. 9, 924–932 (2021).
Nidorf, S. M., Eikelboom, J. W., Budgeon, C. A. & Thompson, P. L. Low-dose colchicine for secondary prevention of cardiovascular disease. J. Am. Coll. Cardiol. 61, 404–410 (2013).
Deftereos, S. G. et al. Colchicine in cardiovascular disease: in-depth review. Circulation 145, 61–78 (2022).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04705987 (2021).
Chia, Y. C. et al. Interleukin 6 and development of heart failure with preserved ejection fraction in the general population. J. Am. Heart Assoc. 10, e018549 (2021).
Markousis-Mavrogenis, G. et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur. J. Heart Fail. 21, 965–973 (2019).
Markousis-Mavrogenis, G. et al. The additive prognostic value of serial plasma interleukin-6 levels over changes in brain natriuretic peptide in patients with acute heart failure. J. Card. Fail. 27, 808–811 (2021).
Szekely, Y. & Arbel, Y. A review of interleukin-1 in heart disease: where do we stand today? Cardiol. Ther. 7, 25–44 (2018).
Toldo, S. et al. Interleukin-1β blockade improves left ventricular systolic/diastolic function and restores contractility reserve in severe ischemic cardiomyopathy in the mouse. J. Cardiovasc. Pharmacol. 64, 1–6 (2014).
van Tassell, B. W. et al. Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PLoS ONE 7, e33438 (2012).
Van Tassell, B. W. et al. Interleukin-1 blockade in recently decompensated systolic heart failure: results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ. Heart Fail. 10, e004373 (2017).
Van Tassell, B. W. et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ. Heart Fail. 11, e005036 (2018).
Van Tassell, B. W. et al. Interleukin-1 blockade in acute decompensated heart failure: a randomized, double-blinded, placebo-controlled pilot study. J. Cardiovasc. Pharmacol. 67, 544–551 (2016).
Abbate, A. et al. Interleukin-1 blockade with anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials. Eur. Hear. J. Cardiovasc. Pharmacother. 8, 503–510 (2022).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 139, 1289–1299 (2019).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03797001 (2023).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05177822 (2023).
Finkel, M. S. et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257, 387–389 (1992).
Yu, X. W., Kennedy, R. H. & Liu, S. J. JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes. J. Biol. Chem. 278, 16304–16309 (2003).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05636176 (2023).
Commins, S., Steinke, J. W. & Borish, L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J. Allergy Clin. Immunol. 121, 1108–1111 (2008).
Verma, S. K. et al. Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-κB. Circulation 126, 418–429 (2012).
Stafford, N. et al. Signaling via the interleukin-10 receptor attenuates cardiac hypertrophy in mice during pressure overload, but not isoproterenol infusion. Front. Pharmacol. 11, 1742 (2020).
Jung, M. et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res. Cardiol. 112, 33 (2017).
Domínguez Rodríguez, A., Abreu González, P., García González, M. J. & Ferrer Hita, J. Association between serum interleukin 10 level and development of heart failure in acute myocardial infarction patients treated by primary angioplasty. Rev. Esp. Cardiol. 58, 626–630 (2005).
Dhingra, S., Sharma, A. K., Arora, R. C., Slezak, J. & Singal, P. K. IL-10 attenuates TNF-α-induced NFκB pathway activation and cardiomyocyte apoptosis. Cardiovasc. Res. 82, 59–66 (2009).
Lancellotti, P. & Oury, C. IL-10 targets myofibroblasts and dampens cardiac fibrosis. J. Public Health Emerg. 1, 83 (2017).
Buscarlet, M. et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753–762 (2017).
Sano, S. et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. J. Am. Coll. Cardiol. 71, 875–886 (2018).
Abplanalp, W. T. et al. Clonal hematopoiesis-driver DNMT3A mutations alter immune cells in heart failure. Circ. Res. 128, 216–228 (2021).
Cremer, S. et al. Interaction of inherited genetic variants in the NLRP3 inflammasome/IL-6 pathway with acquired clonal hematopoiesis to modulate mortality risk in patients with HFrEF. Eur. Heart J. 43, ehac544.832 (2022).
Markousis-Mavrogenis, G. et al. Multimarker profiling identifies protective and harmful immune processes in heart failure: findings from BIOSTAT-CHF. Cardiovasc. Res. 118, 1964–1977 (2022).
Kallikourdis, M. et al. T cell costimulation blockade blunts pressure overload-induced heart failure. Nat. Commun. 8, 14680 (2017).
Martini, E. et al. T cell costimulation blockade blunts age-related heart failure. Circ. Res. 127, 1115–1117 (2020).
Rahmati, Z. et al. Association of levels of interleukin 17 and T-helper 17 count with symptom severity and etiology of chronic heart failure: a case-control study. Croat. Med. J. 59, 139–148 (2018).
Li, X. F., Pan, D., Zhang, W. L., Zhou, J. & Liang, J. J. Association of NT-proBNP and interleukin-17 levels with heart failure in elderly patients. Genet. Mol. Res. 15, gmr.15028014 (2016).
Zhang, Y. et al. Ablation of interleukin-17 alleviated cardiac interstitial fibrosis and improved cardiac function via inhibiting long non-coding RNA-AK081284 in diabetic mice. J. Mol. Cell. Cardiol. 115, 64–72 (2018).
Zhou, S. F. et al. IL-17A promotes ventricular remodeling after myocardial infarction. J. Mol. Med. 92, 1105–1116 (2014).
Xue, G. L. et al. Interleukin-17 upregulation participates in the pathogenesis of heart failure in mice via NF-κB-dependent suppression of SERCA2a and Cav1.2 expression. Acta Pharmacol. Sin. 42, 1780–1789 (2021).
Zhu, D. et al. Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 28, 965–973 (2022).
Kishore, M. et al. Regulatory T cell migration is dependent on glucokinase-mediated glycolysis. Immunity 47, 875–889.e10 (2017).
Yang, Y. et al. The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death Dis. 7, e2234 (2016).
Liu, L. et al. Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction. J. Cell. Mol. Med. 19, 2728–2740 (2015).
Boyd, J. H., Mathur, S., Wang, Y., Bateman, R. M. & Walley, K. R. Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-κB dependent inflammatory response. Cardiovasc. Res. 72, 384–393 (2006).
Riad, A. et al. Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice. Eur. J. Heart Fail. 10, 233–243 (2008).
Riad, A. et al. Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J. Immunol. 180, 6954–6961 (2008).
Ehrentraut, H. et al. The Toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy. Eur. J. Heart Fail. 13, 602–610 (2011).
Ling, S. & Xu, J.-W. NETosis as a pathogenic factor for heart failure. Oxid. Med. Cell. Longev. 2021, 6687096 (2021).
Martinod, K. et al. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214, 439–458 (2017).
Eiserich, J. P. et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296, 2391–2394 (2002).
Vasilyev, N. et al. Myeloperoxidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 112, 2812–2820 (2005).
Tang, W. H. W. et al. Prognostic value and echocardiographic determinants of plasma myeloperoxidase levels in chronic heart failure. J. Am. Coll. Cardiol. 49, 2364–2370 (2007).
Chamardani, T. M. & Amiritavassoli, S. Inhibition of NETosis for treatment purposes: friend or foe? Mol. Cell. Biochem. 477, 673–688 (2022).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04986202 (2023).
Meier, L. A. & Binstadt, B. A. The contribution of autoantibodies to inflammatory cardiovascular pathology. Front. Immunol. 9, 352216 (2018).
Harding, D. et al. Dilated cardiomyopathy and chronic cardiac inflammation: pathogenesis, diagnosis and therapy. J. Intern. Med. 293, 23–47 (2023).
Felix, S. B. et al. Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study. J. Am. Coll. Cardiol. 35, 1590–1598 (2000).
Müller, J. et al. Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 101, 385–391 (2000).
Tschöpe, C. et al. Targeting CD20+ B-lymphocytes in inflammatory dilated cardiomyopathy with rituximab improves clinical course: a case series. Eur. Heart J. Case Rep. 3, ytz131 (2019).
Iacobellis, G. Epicardial fat: a new cardiovascular therapeutic target. Curr. Opin. Pharmacol. 27, 13–18 (2016).
D’Marco, L. et al. SGLT2i and GLP-1RA in cardiometabolic and renal diseases: from glycemic control to adipose tissue inflammation and senescence. J. Diabetes Res. 2021, 9032378 (2021).
Bendotti, G. et al. The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol. Res. 182, 106320 (2022).
Huixing, L., Di, F. & Daoquan, P. Effect of glucagon-like peptide-1 receptor agonists on prognosis of heart failure and cardiac function: a systematic review and meta-analysis of randomized controlled trials. Clin. Ther. 45, 17–30 (2023).
Withaar, C. et al. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction. Cardiovasc. Res. 117, 2108–2124 (2021).
Belli, M. et al. Treatment of HFpEF beyond the SGLT2-Is: does the addition of GLP-1 RA improve cardiometabolic risk and outcomes in diabetic patients? Int. J. Mol. Sci. 23, 14598 (2022).
Casas, R. et al. Long-term immunomodulatory effects of a mediterranean diet in adults at high risk of cardiovascular disease in the PREvención con DIeta MEDiterránea (PREDIMED) randomized controlled trial. J. Nutr. 146, 1684–1693 (2016).
Casas, R. et al. Anti-inflammatory effects of the mediterranean diet in the early and late stages of atheroma plaque development. Mediators Inflamm. 2017, 3674390 (2017).
Marcelino, G. et al. Effects of olive oil and its minor components on cardiovascular diseases, inflammation, and gut microbiota. Nutrients 11, 1826 (2019).
Xiao, Y. et al. Effects of nut consumption on selected inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Nutrition 54, 129–143 (2018).
Hosseini, B. et al. Effects of fruit and vegetable consumption on inflammatory biomarkers and immune cell populations: a systematic literature review and meta-analysis. Am. J. Clin. Nutr. 108, 136–155 (2018).
Milesi, G., Rangan, A. & Grafenauer, S. Whole grain consumption and inflammatory markers: a systematic literature review of randomized control trials. Nutrients 14, 374 (2022).
Xu, Y. et al. Whole grain diet reduces systemic inflammation: a meta-analysis of 9 randomized trials. Medicine 97, e12995 (2018).
Iwaniak, A., Minkiewicz, P. & Darewicz, M. Food-originating ACE inhibitors, including antihypertensive peptides, as preventive food components in blood pressure reduction. Compr. Rev. food Sci. food Saf. 13, 114–134 (2014).
Chen, J., Jayachandran, M., Bai, W. & Xu, B. A critical review on the health benefits of fish consumption and its bioactive constituents. Food Chem. 369, 130874 (2022).
Moradi-Marjaneh, R., Paseban, M. & Sahebkar, A. Natural products with SGLT2 inhibitory activity: possibilities of application for the treatment of diabetes. Phytother. Res. 33, 2518–2530 (2019).
Hsieh, M. S., How, C. K., Hsieh, V. C. R. & Chen, P. C. Preadmission antihypertensive drug use and sepsis outcome: impact of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Shock 53, 407–415 (2020).
Wu, M. Z. et al. Risk of sepsis and pneumonia in patients initiated on SGLT2 inhibitors and DPP-4 inhibitors. Diabetes Metab. 48, 101367 (2022).
Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).
Wouda, R. D. et al. Sex-specific associations between potassium intake, blood pressure, and cardiovascular outcomes: the EPIC-Norfolk study. Eur. Heart J. 43, 2867–2875 (2022).
Neal, B. et al. Effect of salt substitution on cardiovascular events and death. N. Engl. J. Med. 385, 1067–1077 (2021).
Bomer, N. et al. Micronutrient deficiencies in heart failure: mitochondrial dysfunction as a common pathophysiological mechanism? J. Intern. Med. 291, 713–731 (2022).
Hoffmann, P. R. & Berry, M. J. The influence of selenium on immune responses. Mol. Nutr. Food Res. 52, 1273–1280 (2008).
Hoffmann, F. W. et al. Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols. J. Nutr. 140, 1155–1161 (2010).
Hu, Y. et al. Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto’s thyroiditis: a prospective randomized-controlled trial. Clin. Transl. Sci. 14, 1390–1402 (2021).
Gammoh, N. Z. & Rink, L. Zinc in infection and inflammation. Nutrients 9, 624 (2017).
Jafari, A., Noormohammadi, Z., Askari, M. & Daneshzad, E. Zinc supplementation and immune factors in adults: a systematic review and meta-analysis of randomized clinical trials. Crit. Rev. Food Sci. Nutr. 62, 3023–3041 (2022).
Nielsen, F. H. Magnesium deficiency and increased inflammation: current perspectives. J. Inflamm. Res. 11, 25–34 (2018).
Talebi, S., Miraghajani, M., Hosseini, R. & Mohammadi, H. The effect of oral magnesium supplementation on inflammatory biomarkers in adults: a comprehensive systematic review and dose-response meta-analysis of randomized clinical trials. Biol. Trace Elem. Res. 200, 1538–1550 (2022).
Veronese, N., Pizzol, D., Smith, L., Dominguez, L. J. & Barbagallo, M. Effect of magnesium supplementation on inflammatory parameters: a meta-analysis of randomized controlled trials. Nutrients 14, 679 (2022).
Chen, W. et al. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat. Rev. Cardiol. 19, 228–249 (2022).
McNamara, D. M. et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 103, 2254–2259 (2001).
Gullestad, L. et al. Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure. Circulation 103, 220–225 (2001).
Latham, R. D., Mulrow, J. P., Virmani, R., Robinowitz, M. & Moody, J. M. Recently diagnosed idiopathic dilated cardiomyopathy: incidence of myocarditis and efficacy of prednisone therapy. Am. Heart J. 117, 876–882 (1989).
Parrillo, J. E. et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N. Engl. J. Med. 321, 1061–1068 (1989).
Wojnicz, R. et al. Randomized, placebo- controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 104, 39–45 (2001).
Bahrmann, P., Hengst, U. M., Richartz, B. M. & Figulla, H. R. Pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy: effects on left-ventricular function, inflammatory cytokines and symptoms. Eur. J. Heart Fail. 6, 195–201 (2004).
Deswal, A. et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 99, 3224–3226 (1999).
Bozkurt, B. et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 103, 1044–1047 (2001).
Staudt, A. et al. Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution. Circulation 103, 2681–2686 (2001).
Pokrovsky, S. N. et al. Ig apheresis for the treatment of severe DCM patients. Atheroscler. Suppl. 14, 213–218 (2013).
Yoshikawa, T. et al. Immunoadsorption therapy for dilated cardiomyopathy using tryptophan column—a prospective, multicenter, randomized, within-patient and parallel-group comparative study to evaluate efficacy and safety. J. Clin. Apher. 31, 535–544 (2016).
Zannad, F. et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural cardiac therapy for heart failure (NECTAR-HF) randomized controlled trial. Eur. Heart J. 36, 425–433 (2015).
Testa, L. et al. Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients. J. Thorac. Cardiovasc. Surg. 136, 884–893 (2008).
Yingzhong, C., Lin, C. & Chunbin, W. Clinical effects of cyclosporine A on reperfusion injury in myocardial infarction: a meta-analysis of randomized controlled trials. Springerplus 5, 1117 (2016).
Sant’Anna, L. B. et al. Vagal neuromodulation in chronic heart failure with reduced ejection fraction: a systematic review and meta-analysis. Front. Cardiovasc. Med. 8, 1466 (2021).
Wang, X. et al. SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism. Heart Fail. Rev. 27, 961–980 (2022).
A.A.V. received consultancy fees and/or research grants from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cytokinetics, Merck, Novo Nordisk, Novartis and Roche Diagnostics. P.v.d.M. received consultancy fees and/or grants from Novartis, Corvidia, Singulex, Servier, Vifor Pharma, AstraZeneca, Pfizer and Ionis. The other authors declare no competing interests related to this manuscript.
Peer review information
Nature Reviews Cardiology thanks Antonio Abbate, Pilar Alcaide, Douglas Mann and Sophie Van Linthout for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Markousis-Mavrogenis, G., Baumhove, L., Al-Mubarak, A.A. et al. Immunomodulation and immunopharmacology in heart failure. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00919-6