rpcardioRational Pharmacotherapy in CardiologyРациональная Фармакотерапия в Кардиологии1819-64462225-3653«SILICEA-POLIGRAF» LLC10.20996/1819-6446-2022-09-05rpcardio-2819Research ArticleORIGINAL STUDIESОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯNeuregulin-1β, Biomarkers of Inflammation and Myocardial Fibrosis in Heart Failure PatientsНейрегулин-1β, биомаркеры системного воспаления и миокардиального фиброза у больных с хронической сердечной недостаточностьюhttps://orcid.org/0000-0002-1574-3881ЖбановК. А.ZhbanovK. A.

 Жбанов Константин Александрович 

Москва

 Konstantin A. Zhbanov 

 Moscow 

https://orcid.org/0000-0003-4323-9671СалахееваЕ. Ю.SalakheevaE. Yu.

 Салахеева Екатерина Юрьевна 

Москва

 Ekaterina Yu. Salakheeva 

 Moscow 

https://orcid.org/0000-0002-8884-1087СоколоваИ. Я.SokolovaI. Ya.

 Соколова Ирина Яковлевна

Москва

 Irina Ya. Sokolova 

 Moscow 

https://orcid.org/0000-0002-2596-192XЖелезныхЕ. А.ZheleznykhE. A.

 Железных Елена Анатольевна

Москва

 Elena A. Zheleznykh 

 Moscow 

https://orcid.org/0000-0002-8547-8673ЗекцерВ. Ю.ZektserV. Yu.

 Зекцер Вита Юрьевна

Москва

 Vita Yu. Zektser 

 Moscow 

https://orcid.org/0000-0001-6675-7557ПриваловаЕ. В.PrivalovaE. V.

 Привалова Елена Витальевна

Москва

 Elena V. Privalova 

 Moscow 

https://orcid.org/0000-0002-3014-6129БеленковЮ. Н.BelenkovYu. N.

 Беленков Юрий Никитич 

Москва

 Yuri N. Belenkov 

 Moscow 

https://orcid.org/0000-0002-8220-0350ЩендрыгинаА. А.ShchendryginaA. A.

 Щендрыгина Анастасия Александровна

Москва

 Anastasia A. Shchendrygina 

 Moscow 

a.shchendrygina@gmail.comПервый Московский Государственный Медицинский Университет им. И.М. Сеченова (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202202112022185522529Copyright © Zhbanov K.A., Salakheeva E.Y., Sokolova I.Y., Zheleznykh E.A., Zektser V.Y., Privalova E.V., Belenkov Y.N., Shchendrygina A.A., 20222022Жбанов К.А., Салахеева Е.Ю., Соколова И.Я., Железных Е.А., Зекцер В.Ю., Привалова Е.В., Беленков Ю.Н., Щендрыгина А.А.Zhbanov K.A., Salakheeva E.Y., Sokolova I.Y., Zheleznykh E.A., Zektser V.Y., Privalova E.V., Belenkov Y.N., Shchendrygina A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpcardio.online/jour/article/view/2819

 Neuregulin-1β (NRG-1) is an emerging biomarker of heart failure (HF). The mechanisms of its action in HF patients are yet  to be investigated. Cardioprotective and anti-inflammatory  effects of NRG-1 have been reported.Aim. To assess NRG-1 levels in HF patients and investigate the association between NRG-1 and biomarkers of inflammation and myocardial fibrosis.Material and Methods. NRG-1, biomarkers of inflammation and fibrosis (hsCRP, IL-6, sVCAM-1, MMP-9, Galectin-3, ST2, TGF-β) were assessed in 47 patients with HF and preserved ejection fraction (HFpEF); 39 patients with HF and reduced ejection  (HFrEF) and 40 healthy participants. The associations between  NRG-1 and biomarkers of inflammation and fibrosis, as well as  the composite outcomes of cardiovascular death and HF  hospitalisations were assessed.Results. Median NRG-1 levels in HFpEF were 0.969 (0.348; 1.932) ng/ml, in HFrEF – 0.63 (0.348; 1.932), in healthy participants 0.379 (0.195; 0.861) ng/ml, and was significantly higher in HFpEF compared to healthy volunteers (р=0.004). There was no  difference in NRG-1 concentration between HFpEF and HFrEF. In  HF patients, all biomarkers of inflammation and fibrosis were  higher than in controls. ST2, IL-6 and TGF-β were significantly higher in HFrEF compared to HFpEF patients, while hsCRP,  sVCAM-1, MMP-9, and Galectin-3 levels were comparable. In  HFpEF, NRG-1 was associated with hsCRP (rs=0.378, p=0.023) and IL-6 (rs=0.378, p=0.014). Median follow-up time in patients with HFpEF and in patients was 312 (236; 388) days, in HFrEF – 147 (98; 237) days. In HFpEF, 2 patients died and 19 were  hospitalized due to HF. In HFrEF, 10 deaths and 19  hospitalizations were registered. Kaplan-Mayer analysis showed that HFpEF patients with increased NRG-1 and IL-6 had higher  levels of HF hospitalisation (log rank test, р=0.046 and р=0.012, respectively). In a multivariable cox proportional hazard model,  the association between the NRG-1 and outcomes remained significant after adjustment for age, gender and NTproBNP but diminished when hsCRP and IL-6 were included in the model.Conclusion. NGR-1 level significantly higher in HFpEF compared to healthy participants, and comparable with NRG-1 concentrations in HFrEF. In HFpEF, NRG-1 was associated with biomarkers of inflammation and fibrosis. The prognostic value of NRG-1 in HF requires further investigations. 

 Нейрегулин-1β является потенциальным биомаркером хронической сердечной недостаточности (ХСН), механизмы действия которого у больных ХСН до конца не изучены. В ранее выполненных исследованиях описаны  кардиопротективные и противовоспалительные эффекты нейрегулина-1β.Цель. Определить концентрацию нейрегулина-1β у больных ХСН и изучить ассоциацию нейрегулина-1β с маркерами системного воспаления и миокардиального фиброза, а также с клиническим исходами.Материалы и методы. В наблюдательное проспективное исследование было включено 86 пациентов с ХСН: c сохраненной фракцией выброса (СНсФВ; n=47) и низкой  фракцией выброса (СНнФВ; n=39). Группу здоровых  добровольцев (ЗД) составили 40 человек. Всем участникам  определялись уровни нейрегулина-1β, биомаркеров  системного воспаления [высокочувствительный С-реактивный белок (вчСРБ), интерлейкин-6 (ИЛ-6), sVCAM-1, ST2] и фиброза (MMP-9, Галектин-3, ТГФ-β). Пациенты с ХСН наблюдались в течение 2 лет. Регистрировались сердечно-сосудистая смертность и госпитализации по поводу  декомпенсации ХСН. Результаты. В группах СНсФВ, СНнФВ и ЗД медиана концентрации нейрегулина-1β составила 0,969 (0,348; 1,932) нг/мл, 0,63 (0,348; 1,932) нг/мл и 0,379 (0,195; 0,861) нг/мл соответственно. В группе СНсФВ уровень нейрегулина-1β был значимо выше по сравнению с группой ЗД (р=0,004) и не отличался от такового в группе СНнФВ. У больных ХСН концентрации всех исследуемых биомаркеров системного воспаления (ИЛ-6, sVCAM-1, ТГФ-β и ST2) были значимо  выше, чем у ЗД. Концентрации ST-2, ТГФ-β и ИЛ-6 были  выше у пациентов с СНнФВ, чем у СНсФВ. Уровни вчСРБ, sVCAM-1, MMP-9 и Галектина-3 между группами пациентов с ХСН не различались. У пациентов с СНсФВ уровень нейрегулина-1β значимо ассоциировался с маркерами системного воспаления: вчСРБ (rs=0,378, p=0,023), ИЛ-6 (rs=0,378, p=0,014) и фиброза: ТГФ-β (rs=0,603, p=0,001). Анализ Каплана-Майера показал, что у пациентов с СНсФВ, но не СНнФВ, имеющих повышенные уровни нейрегулина-1β и ИЛ-6, частота госпитализаций по поводу декомпенсации ХСН была выше, чем у больных с низкими уровнями биомаркеров (logrank test, р=0,046 и р=0,012 соответственно). Многофакторный анализ показал, что ассоциация нейрегулина-1β с исходами оставалась значимой при включении в модель факторов пол, возраст, NTproBNP.Заключение. У больных СНсФВ концентрация  нейрегулина-1β выше, чем у здоровых добровольцев, и  сопоставима с таковой в группе СНнФВ. Высокие уровни нейрегулина-1β ассоциируются с маркерами системного  воспаления и фиброза у больных СНсФВ. Дальнейшие  исследования необходимы для оценки прогностической  значимости нейрегулина-1β при СНсФВ. 

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The authors declare that there are no conflicts of interest present.