Impact of Myeloperoxidase Inhibition on Right Ventricular Remodeling in Heart Failure with reduced Ejection Fraction: An Echocardiographic Substudy of the Randomized, Double-Blind MYSTERY-HF Trial

S. Macherey-Meyer (Köln)¹, A. Polzin (Düsseldorf)², A. Costard-Jäckle (Bad Oeynhausen)³, C. Morbach (Würzburg)⁴, B. Haring (Homburg/Saar)⁵, H. Lapp (Bad Berka)⁶, V. ten Cate (Mainz)⁷, A. Gieswinkel (Mainz)⁷, J. Weliwitage (Köln)⁸, M. Hellmich (Köln)⁹, E. Michaëlsson (Gothenburg)¹⁰, K. Nelander (Gothenburg )¹¹, N. Ens-Jäger (Marburg)¹², S. Rosenkranz (Köln)¹³, S. Geißen (Köln)¹, N. Frey (Heidelberg)¹⁴, C. Schulze (Jena)¹⁵, M. Aurell (Gothenburg)¹⁶, M. Böhm (Homburg/Saar)⁵, S. Frantz (Würzburg)¹⁷, M. Kelm (Düsseldorf)², V. Rudolph (Bad Oeynhausen)¹⁸, S. Shah (Chicago)¹⁹, P. S. Wild (Mainz)⁷, S. Baldus (Köln)¹, S. Braumann (Köln)^13
1Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland; ²Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; ³Herz- und Diabeteszentrum NRW Klinik für Thorax- und Kardiovaskularchirurgie Bad Oeynhausen, Deutschland; ⁴Universitätsklinikum Würzburg Medizinische Klinik I, Kardiologie Würzburg, Deutschland; ⁵Universitätsklinikum des Saarlandes Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin Homburg/Saar, Deutschland; ⁶Zentralklinik Bad Berka GmbH Klinik für Kardiologie und Internistische Intensivmedizin Bad Berka, Deutschland; ⁷Universitätsmedizin der Johannes Gutenberg-Universität Mainz Präventive Kardiologie und Medizinische Prävention Mainz, Deutschland; ⁸Universität zu Köln Institut für Medizinische Statistik und Bioinformatik Köln, Deutschland; ⁹Universitätsklinikum Köln Institut für Med. Statistik, Informatik und Epidemiologie Köln, Deutschland; ¹⁰Translational and Clinical Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Schweden; ¹¹Biometrics, Late-stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Gothenburg , Schweden; ¹²Philipps-Universität Marburg Coordinating Center for Clinical Trials Marburg, Deutschland; ¹³Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; ¹⁴Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; ¹⁵Universitätsklinikum Jena Klinik für Innere Medizin I - Kardiologie, Angiologie, Internistische Intensivmedizin Jena, Deutschland; ¹⁶Translational and Clinical Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Schweden; ¹⁷Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik I Würzburg, Deutschland; ¹⁸Herz- und Diabeteszentrum NRW Allgemeine und Interventionelle Kardiologie/Angiologie Bad Oeynhausen, Deutschland; ¹⁹Northwestern Memorial Hospital Institute for Augmented Intelligence in Medicine - Center for Deep Phenotyping and Precision Therapeutics Chicago, USA

Background:
Heart failure with reduced ejection fraction (HFrEF) is characterized by systemic inflammation, endothelial dysfunction, and vascular remodeling, which extend beyond the left ventricle and also affect right ventricular (RV) structure and function. Myeloperoxidase (MPO), a neutrophil-derived enzyme has been implicated in adverse cardiac remodeling. Preclinical data demonstrated MPO inhibition to be a potential therapeutic strategy in chronic HFrEF. However, results from the randomized MYSTERY-HF trial revealed no impact of MPO-inhibition with mitiperstat on HFrEF surrogate endpoints NT-proBNP, 6MWD and KCCQ-TSS or left ventricular remodelling. Preclinical data from pulmonary hypertension models suggest a potential role of MPO inhibition in modulating RV remodelling, yet its clinical relevance in chronic HFrEF remains unclear.
Objective:
To evaluate the effect of MPO inhibition with mitiperstat on RV remodeling in patients with chronic HFrEF compared to placebo.
Methods:
MYSTERY-HF (EudraCT 2022-003797-23) was a multicenter, randomized, double-blind, placebo-controlled trial investigating mitiperstat in chronic symptomatic HFrEF. Patients were randomized to mitiperstat or placebo for 12 weeks. In this post-hoc substudy, patients with complete echocardiographic data at baseline and end-of-treatment (EoT) were included. Artificial-intelligence-assisted echocardiographic analysis quantified RV volumes, systolic function, and right-heart pressures. Group differences in mean change from baseline to EoT were assessed using the two-sided paired Student’s t-test.
Results:
Among 136 randomized patients, 119 (mitiperstat = 59, placebo = 60) met echocardiographic criteria for inclusion. Baseline characteristics were balanced between groups. The median age was 68.0 years (mitiperstat) and 67.4 years (placebo). Female patients comprised 13.6% and 14.9% of each group, respectively. At baseline, 53% of patients in the mitiperstat group were classified as NYHA II and 47% as NYHA III; corresponding rates for placebo were 58.2% and 41.8%.
Over 12 weeks, no significant between-group differences were observed in RV function, volumes, or right-heart pressures (Table). Specifically, no differences were detected in RV end-diastolic volume (Δ 4.9 mL, p = 0.12), fractional area change (Δ –0.6%, p = 0.80), TAPSE (Δ 0.22 mm, p = 0.80), or free-wall longitudinal strain (Δ –0.28%, p = 0.82). Pulmonary artery systolic pressure did not differ between groups (Δ –3.36 mmHg, p = 0.42).
Conclusion:
In this substudy of the randomized controlled MYSTERY HF trial MPO inhibition with mitiperstat did not induce reverse RV remodeling in HFrEF over a 12-week treatment period. These findings suggest that short-term MPO inhibition does not modulate RV structure or afterload. Longer-term studies are warranted to determine whether sustained MPO inhibition might favourably influence right-heart adaptation and clinical outcomes in chronic heart failure.