Jacob Kuempel

Background: Heart failure affects over 23 million people globally and is the leading cause of mortality worldwide.¹ Heart failure with reduced ejection fraction (HFrEF) has the worst prognosis of the 3 clinical subtypes of heart failure and accounts for ~50% of all heart failure cases.¹ Increasing global incidence of heart failure and frequent discontinuation of effective medications due to hypotension in HFrEF suggest that novel therapeutic strategies are desperately needed.² Immune system dysfunction and elevated cytokine levels are frequently observed in HFrEF patients, and infiltration of bone marrow-derived immune cells into the myocardium has been shown to correlate with adverse left ventricular (LV) remodeling and dysfunction, the cardinal features of HFrEF.³ However, there are no currently no reliable therapeutic interventions that target the immune system in HFrEF patients. Unlike bone marrow-derived immune cells, resident cardiac macrophages can prevent maladaptive LV remodeling and dysfunction during HFrEF^4-8. However, molecular mechanisms underlying this phenomenon are not well understood.

Objective: To investigate potential molecular mechanisms underlying the beneficial role of resident cardiac macrophages in HFrEF.

Search Methods: An online search in the PubMed database was conducted from 2017 to 2023 using the following keywords: “heart failure”, “resident immune cell”, “macrophage”, and “immune system”.

Results: Resident cardiac macrophages proliferate locally within the myocardium as an acute response to pressure overload induced by transverse aortic constriction (TAC) in mice.⁴ Pharmacological depletion of these macrophages resulted in complete loss of adaptive LV remodeling and earlier-onset HFrEF after TAC.⁴ Kruppel-like factor 4 (Klf4) promotes resident cardiac macrophage proliferation, and genetic deletion of Klf4 in myeloid cells disrupted resident macrophage proliferation and caused earlier-onset HFrEF after TAC.⁴ Pharmacological depletion of KLF4 increased cardiac macrophage polarization to the M1 proinflammatory phenotype and caused LV dysfunction, and KLF4 overexpression rescued the M1 macrophage polarization.⁵ Additionally, renal sympathetic nerve activation and subsequent production of colony-stimulating factor 2 (CSF2) by renal endothelial cells promote resident cardiac macrophage proliferation after pressure overload.⁶ Disruption of this multi-organ system signaling pathway inhibited resident cardiac macrophage proliferation and caused earlier-onset HFrEF after TAC.⁶ Furthermore, preferential depletion of resident cardiac macrophages resulted in increased fibrosis and reduced angiogenesis after TAC.⁷ Depletion of the CCR2- subpopulation of resident cardiac macrophages also caused increased non-resident monocyte infiltration into the myocardium after ischemia-reperfusion injury.⁸ Interestingly, anti-inflammatory therapy with canakinumab reduced adverse cardiovascular outcomes in human patients with previous myocardial infarction and resultant chronic inflammation.⁹

Conclusion: Resident and non-resident cardiac immune cells have vastly different implications on the pathogenesis of HFrEF. Resident cardiac macrophages inhibit infiltration of non-resident monocytes, prevent fibrosis, stimulate myocardial angiogenesis, and ultimately promote adaptive cardiac remodeling in HFrEF. Anti-inflammatory therapy had recent success in clinical trials for cardiovascular disease patients, and activating resident cardiac macrophages and their downstream signaling could have similar therapeutic efficacy for HFrEF patients. The resident cardiac macrophage population is regulated by a multi-organ system signaling network that converges on macrophage KLF4 and presents several novel therapeutic targets for HFrEF.

Works Cited:

1. Murphy SP, Ibrahim NE, Januzzi JL, Jr. Heart Failure With Reduced Ejection Fraction: A Review. JAMA. Aug 4 2020;324(5):488-504. doi:10.1001/jama.2020.10262
2. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association. Circulation. 2023;147(8):e93-e621. doi:doi:10.1161/CIR.0000000000001123
3. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol. May 2020;17(5):269-285. doi:10.1038/s41569-019-0315-x
4. Liao X, Shen Y, Zhang R, et al. Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy. Proc Natl Acad Sci U S A. May 15 2018;115(20):E4661-E4669. doi:10.1073/pnas.1720065115
5. Xia W, Zou C, Chen H, Xie C, Hou M. Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling. Cell Death & Disease. 2020/07/24 2020;11(7):575. doi:10.1038/s41419-020-02778-2
6. Fujiu K, Shibata M, Nakayama Y, et al. A heart–brain–kidney network controls adaptation to cardiac stress through tissue macrophage activation. Nature Medicine. 2017/05/01 2017;23(5):611-622. doi:10.1038/nm.4326
7. Revelo XS, Parthiban P, Chen C, et al. Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis. Circ Res. Dec 3 2021;129(12):1086-1101. doi:10.1161/CIRCRESAHA.121.319737
8. Bajpai G, Bredemeyer A, Li W, et al. Tissue Resident CCR2- and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury. Circ Res. Jan 18 2019;124(2):263-278. doi:10.1161/CIRCRESAHA.118.314028
9. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. New England Journal of Medicine. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914