Inhibition of myeloperoxidase to treat left ventricular dysfunction in non-ischaemic cardiomyopathy

IF 16.9 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

European Journal of Heart Failure Pub Date : 2024-08-30 DOI:10.1002/ejhf.3435

Simon Geissen, Simon Braumann, Joana Adler, Felix Sebastian Nettersheim, Dennis Mehrkens, Alexander Hof, Henning Guthoff, Philipp von Stein, Sven Witkowski, Norbert Gerdes, Frederik Tellkamp, Marcus Krüger, Lea Isermann, Aleksandra Trifunovic, Alexander C. Bunck, Martin Mollenhauer, Holger Winkels, Matti Adam, Anna Klinke, Gregor Buch, Vincent ten Cate, Martin Hellmich, Malte Kelm, Volker Rudolph, Philipp S. Wild, Stephan Rosenkranz, Stephan Baldus

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Abstract

Aims

Non-ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti-inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro-fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.

Methods and results

Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long-term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow-up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo^−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo^−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6-min walking distance. MPO inhibitor-related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.

Conclusions

Myeloperoxidase predicts long-term outcome in HFrEF and its inhibition elicits systemic anti-inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.

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抑制髓过氧化物酶治疗非缺血性心肌病的左心室功能障碍

目的非缺血性心肌病（NICMP）是一种终末于收缩性心力衰竭（射血分数降低性心力衰竭[HFrEF]）的不治之症，会导致免疫激活，但迄今为止，抗炎治疗策略未能改变这种疾病的病程。髓过氧化物酶（MPO）是中性粒细胞中的主要酶，具有细胞毒性、促纤维化和一氧化氮氧化作用。抑制 MPO 是否能改善 NICMP 的表型仍是一个未知数。方法和结果MPO 的诊断信息来自于一个大型人类心血管健康队列（n = 3289）的蛋白质组数据。在 NICMP 的小鼠模型中，我们研究了 MPO 在这种疾病中的作用机制。在一个病例系列中，我们还对 NICMP 患者的 MPO 抑制剂进行了评估。MPO增高的患者长期死亡率较高，心力衰竭恶化，当随访期间MPO增高时，预后受损。输注 MPO 会降低 NICMP 小鼠的左心室射血分数（LVEF），而基因消融或抑制 MPO 会降低全身血管阻力（SVR，NICMP 为 9.4 ± 0.7 mmHg*min/ml vs. NICMP 为 6.7 ± 0.8 mmHg*min/ml vs. NICMP 为 6.7 ± 0.8 mmHg*min/ml vs. NICMP 为 6.7 ± 0.8 mmHg*min/ml ）。8 mmHg*min/ml，n = 8，p = 0.006，数据以均值±均值标准误差表示），并改善左心室功能（NICMP 的 LVEF 为 30.3 ± 2.2% vs. NICMP/Mpo-/- 小鼠的 40.7 ± 1.1%，n = 16，p < 0.0001）。四名被诊断为 NICMP 并接受 MPO 抑制剂治疗 12 周的患者显示 LVEF 增加，钠尿肽下降，6 分钟步行距离改善。与上述心血管健康队列蛋白质组的变化相比，NICMP 患者蛋白质组中 MPO 抑制剂相关的变化预示着死亡率的降低。MPO抑制作为一种新型的、补充性的治疗策略，值得进一步评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Heart Failure 医学-心血管系统

CiteScore

27.30

自引率

11.50%

发文量

365

审稿时长

1 months

期刊介绍： European Journal of Heart Failure is an international journal dedicated to advancing knowledge in the field of heart failure management. The journal publishes reviews and editorials aimed at improving understanding, prevention, investigation, and treatment of heart failure. It covers various disciplines such as molecular and cellular biology, pathology, physiology, electrophysiology, pharmacology, clinical sciences, social sciences, and population sciences. The journal welcomes submissions of manuscripts on basic, clinical, and population sciences, as well as original contributions on nursing, care of the elderly, primary care, health economics, and other related specialist fields. It is published monthly and has a readership that includes cardiologists, emergency room physicians, intensivists, internists, general physicians, cardiac nurses, diabetologists, epidemiologists, basic scientists focusing on cardiovascular research, and those working in rehabilitation. The journal is abstracted and indexed in various databases such as Academic Search, Embase, MEDLINE/PubMed, and Science Citation Index.