Myeloperoxidase: Reviving an Old Ally for Immunomodulation in Heart Failure?

This article refers to ‘Inhibition of myeloperoxidase to treat left ventricular dysfunction in non-ischaemic cardiomyopathy’ by S. Geissen et al., published in Eur J Heart Fail 2024;26:2269-2281. Myeloperoxidase (MPO) is a member of the heme peroxidase superfamily and is primarily expressed in the granules of neutrophils, with smaller amounts present in monocytes, macrophages, and, to a lesser extent, endothelial cells. Its primary role is in host defense against microorganisms. Upon leucocyte activation, MPO it released and initiates a cascade of redox reactions, producing reactive species such as hypochlorous acid (HOCl). These reactive species can modify DNA, lipids, and lipoproteins and through posttranslational protein modification, they alter the function of signalling molecules and enzymes, potentially contributing to host tissue damage.1 Circulating MPO levels are elevated in inflammatory conditions and cardiovascular disease. Over the past decades, MPO has emerged as a biomarker of increased risk and poor outcome in various cardiovascular conditions, including atherosclerosis, acute coronary syndrome, myocardial infarction, hypertension and heart failure.1 Additionally, studies have implicated MPO in both the development and progression of cardiovascular disease.1 While MPO is perhaps best known for its interactions with lipids and its role in atherosclerosis, recent studies have provided mechanistic insights into its broader role beyond plaque formation. In 2002, Eiserich and colleagues demonstrated that MPO reduced nitric oxide (NO) bioavailability, impairing vascular relaxation in a mouse model of inflammation.2 More recently, MPO has been proposed as a mediator of cardiac fibrosis in atrial fibrillation, acting downstream of angiotensin II and upstream of matrix metalloproteinases.3 Pre-clinical studies using MPO knock-out models and MPO inhibitors have shown improvements in cardiac remodeling and function in myocardial infarction in mice,4, 5 as well as enhanced relaxation in hypertrophied human induced pluripotent stem cell-derived cardiomyocytes,6 supporting the mechanistic role of MPO in cardiomyopathy. These findings position MPO as a promising therapeutic target in cardiovascular diseases, including heart failure. Currently, MPO inhibition is being clinically explored primarily in patients with heart failure with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). Recently, Geissen et al.7 explored the role of MPO in a genetically induced non-ischaemic dilated cardiomyopathy (DCM) model. The authors elegantly show that MPO knock-out (MPO−/−) in muscle lim protein (Mlp)-deficient mice (Mlp−/−), or treatment of Mlp−/− mice with an MPO inhibitor, improved cardiac function via a heart-extrinsic mechanism by restoring endothelium-derived vasodilatation. Furthermore, MPO inhibition using AZD4831, following a protocol identical to that in the SATELLITE trial,8 improved left ventricular ejection fraction, increased 6-min walking distance, and lowered N-terminal pro-B-type natriuretic peptide levels in a small group of four patients with heart failure with (mildly) reduced ejection fraction (HFrEF/HFmrEF). Finally, proteomic changes observed in these patients upon MPO inhibition were linked to favourable changes in risk predictors of all-cause and cardiovascular mortality in the prospective MyoVasc cohort.9 Given that AZD4831 is currently in early clinical testing for treatment of HFpEF, these findings are significant, suggesting the potential to expand such efforts to patients with HFrEF. While this work by Geissen et al. represents a valuable and important contribution to the field, several unresolved questions remain, particularly given the inherent differences between mice and humans and the trial's small sample size of just four patients, which limits the generalizability of the findings. Although the Mlp−/− mouse model has been in use for over two decades, it remains incompletely characterized.10 Despite the fact it was originally described as a model of DCM, i.e. HFrEF, it has also been suggested that the model is driven by mechanisms related to diastolic dysfunction rather than systolic dysfunction.11 This raises the possibility that the model may share characteristics with HFpEF, rather than strictly reflecting non-ischaemic DCM as seen in humans. The lack of structural differences between Mlp−/−/MPO+/+ and Mlp−/−/MPO−/− mouse hearts, particularly regarding fibrosis, which is typically associated with inflammation and has been previously described in Mlp−/− hearts,10 further challenges the extrapolation of these findings to human DCM and HFrEF. Geissen et al. also did not observe immune cell migration, in particular neutrophils, into the myocardial tissue of Mlp−/− mice, despite elevated circulating neutrophils and cytokines. Recent studies have identified neutrophil extracellular traps (NETs) in endomyocardial biopsies of humans with DCM, correlating with lower ejection fraction and higher adverse event rates compared to DCM patients without NETs.12 Interestingly, MPO was found in purified NET components, and exposure of cardiomyocytes to purified NET components resulted in impaired mitochondrial respiration, potentially contributing to decreased systolic function in patients with DCM. These differences between the Mlp−/− mouse model and human DCM suggest the need for further investigation into the role of MPO in human non-ischaemic DCM. The case study presented by Geissen et al. involved AZD4831 treatment in four patients with heart failure, though two of the four patients completing the trial with 12 weeks of drug intake appeared closer to HFmrEF than HFrEF. Early this year, results from the double-blind, phase IIa SATELLITE trial were published,8 in which 41 patients with symptomatic heart failure and a left ventricular ejection fraction >40% were randomized to receive AZD4831 (5 mg once daily) or placebo for 90 days. AZD4831 was well tolerated (n = 27) and efficiently inhibited MPO activity, but none of the pre-specified clinical endpoints showed a clear improvement, except for a trend in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, which was slightly improved in the treatment arm. Plasma proteomic analyses indicated reduced inflammatory biomarker pathways linked to cardiovascular outcomes in patients treated with AZD4831,13 echoing findings from Geissen et al. However, the SATELLITE trial was terminated early due to the COVID-19 pandemic, unfortunately limiting interpretation of these data. The results of ENDEAVOR, a corresponding phase IIb/III trial,14 will soon be communicated, with primary endpoints including changes in the KCCQ overall summary score and 6-min walking distance. Immune- and redox-modulatory therapies for heart failure in humans have largely been unsuccessful, likely due to the complexity of immune regulation and the redox system, as well as the versatile, context-dependent roles of the targeted molecules.15, 16 Moreover, species-dependent differences may contribute to these failures, as many unsuccessful strategies were based on promising pre-clinical studies. Notably, while MPO deficiency aggravates atherosclerosis in mice,17 humans with MPO deficiency exhibit a lower prevalence of cardiovascular diseases, particularly coronary artery disease and myocardial infarction.18 Given the phenotypic differences between the Mlp−/− mouse and human DCM discussed above, there is hope that therapeutic targeting of MPO in humans may avoid the challenges faced by previous immunomodulatory and antioxidative therapies. In conclusion, the study by Geissen et al.7 provides a compelling rationale to expand the target population for MPO inhibition from HFpEF to HFrEF and non-ischaemic DCM (Figure 1). However, sufficiently powered clinical trials with morbidity and mortality endpoints will be crucial to establish clinical efficacy beyond afterload reduction and cardiac unloading. In the meantime, the forthcoming results from the ENDEAVOR trial in patients with HFmrEF and HFpEF are eagerly anticipated. Given the persistently high disease burden and mortality associated with heart failure, every ally – old or new – should be warmly welcomed. G.M.K. is supported by the Swiss National Science Foundation (No. 189877 and No. 219250) and the Swiss Heart Foundation (FF22101). F.M. is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219, Project-ID 322900939), and Deutsche Herzstiftung. Saarland University has received scientific support from Ablative Solutions, Medtronic and ReCor Medical. Conflict of interest: G.M.K. received consulting fees and speaker honoraria from Janssen-Cilag and PAGE Therapeutics, all paid to the institution and unrelated to this article. B.A. has nothing to disclose. Until May 2024, F.M. has received speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo.