Associations of cartilage intermediate layer protein 1 and hypoxia-inducible factor-1-alpha with transthoracic echocardiography results in patients with heart failure with preserved ejection fraction

Aim. To evaluate the relationship of serum concentrations of myocardial remodeling and cellular hypoxia biomarkers cartilage intermediate layer protein 1 (CILP-1) and hypoxia-inducible factor-1-alpha (HIF-1α) with paraclinical parameters in patients with heart failure with preserved ejection fraction (HFpEF) and in the control group.

Material and methods. The study included 47 patients diagnosed with HFpEF, aged from 47 to 79 years, who were treated from May 2018 to December 2019 in the hospital of the National Medical Research Center for Therapy and Preventive Medicine. The control group consisted of 32 people without a diagnosis of HFpEF, matched by sex and age. All participants underwent transthoracic echocardiography with assessment of diastolic function. Serum concentrations of CILP-1 and HIF-1α were determined by enzyme immunoassay using standardized test systems (RayBio and Clone-Cloud, USA).

Results. In patients with HFpEF, the median serum concentrations of CILP-1 (3,24 ng/ml) and HIF-1α (14,3 pg/ml) were not significantly different from the values obtained in the control group (3,6 ng/ml and 7,5 pg/ml, respectively). Significant correlations of CILP-1 with echocardiographic indicators of the left ventricular interstitial fibrosis severity were revealed, while echocardiographic markers of HFpEF positively correlated with the HIF-1α level.

Conclusion. Although the serum concentrations of CILP-1 and HIF-1α do not differ depending on HFpEF presence, it demonstrates an association with a number of echocardiographic parameters both in subgroups of patients with HFpEF and in subgroups of controls with different body mass index.

1. Polyakov DS, Fomin IV, Belenkov YuN, et al. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiologiia. 2021;61(4):4-14. (In Russ.) doi:10.18087/cardio.2021.4.n1628.

2. Ivanova AA, Dzhioeva ON, Lavrenova EA, et al. Diagnostic challenges of heart failure with preserved ejection fraction: focus on echocardiography. Cardiovascular Therapy and Prevention. 2023;22(5):3565. (In Russ.) doi:10.15829/1728-8800-2023-3565.

3. Anker SD, Butler J, Filippatos G, et al. EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-61. doi:10.1056/NEJMoa2107038.

4. Solomon SD, McMurray JJV, Claggett B, et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-98. doi:10.1056/NEJMoa2206286.

5. Nikiforova TA, Shchekochikhin DIu, Lomonosova AA, et al. Biomarkers role in the first decompensation of chronic heart failure with preserved left ventricular ejection fraction: 2-year follow-up. Russian Journal of Cardiology and Cardiovascular Surgery. 2017;10(6):46-51. (In Russ.) doi:10.17116/kardio201710646-51.

6. Badianyama M, Mpanya D, Adamu U, et al. New Biomarkers and Their Potential Role in Heart Failure Treatment Optimisation-An African Perspective. J Cardiovasc Dev Dis. 2022;9(10):335. doi:10.3390/jcdd9100335.

7. Bayes-Genis A, Aimo A, Jhund P, et al. Biomarkers in heart failure clinical trials. A review from the Biomarkers Working Group of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2022;24(10):1767-77. doi:10.1002/ejhf.2675.

8. Regan JA, Truby LK, Tahir UA, et al. Protein biomarkers of cardiac remodeling and inflammation associated with HFpEF and incident events. Sci Rep. 2022;12(1):20072. doi:10.1038/s41598-022-24226-1.

9. Zeng H, Chen JX. Microvascular Rarefaction and Heart Failure With Preserved Ejection Fraction. Front Cardiovasc Med. 2019;6:15. doi:10.3389/fcvm.2019.00015.

10. Weidenhammer A, Prausmüller S, Partsch C, et al. CILP-1 Is a Biomarker for Backward Failure and Right Ventricular Dysfunction in HFrEF. Cells. 2023;12(24):2832. doi:10.3390/cells12242832.

11. Van Nieuwenhoven FA, Munts C, Op't Veld RC, et al. Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling. Sci Rep. 2017;7:16042. doi:10.1038/s41598-017-16201-y.

12. Wang C, Jian W, Luo Q, et al. Prognostic value of cartilage intermediate layer protein 1 in chronic heart failure. ESC Heart Fail. 2022;9(1):345-52. doi:10.1002/ehf2.13746.

13. Lee CC, Wu CY, Yang HY. Discoveries of how cells sense oxygen win the 2019 Nobel Prize in Physiology or medicine. Biomed J. 2020;43(5):434-7. doi:10.1016/j.bj.2020.05.019.

14. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13(2): 167-71. doi:10.1016/s0955-0674(00)00194-0.

15. Warbrick I, Rabkin SW. Hypoxia-inducible factor 1-alpha (HIF-1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction. Obes Rev. 2019;20(5):701-12. doi:10.1111/obr.12828.

16. Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297-317. doi:10.1093/eurheartj/ehz641.

17. Bachmann JC, Baumgart SJ, Uryga AK, et al. Fibrotic Signaling in Cardiac Fibroblasts and Vascular Smooth Muscle Cells: The Dual Roles of Fibrosis in HFpEF and CAD. Cells. 2022;11(10):1657. doi:10.3390/cells11101657.

18. Ma J, Chen Q, Ma S. Left atrial fibrosis in atrial fibrillation: Mechanisms, clinical evaluation and management. J Cell Mol Med. 2021;25(6):2764-75. doi:10.1111/jcmm.16350.

19. Borisov AA, Gvozdeva AD, Ageev FT. Heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus: pathophysiology and treatment options. Medical Herald of the South of Russia. 2021;12(2):6-15. (In Russ.) doi:10.21886/2219-8075-2021-12-2-6-15.

20. Тadic M, Cuspidi C.Obesity and heart failure with preserved ejection fraction: a paradox or something else? Heart Fail Rev. 2019;24(3):379-85. doi:10.1007/s10741-018-09766-x.

21. Tabucanon T, Wilcox J, Tang WHW. Does Weight Loss Improve Clinical Outcomes in Overweight and Obese Patients with Heart Failure? Curr Diab Rep. 2020;20(12):75. doi:10.1007/s11892-020-01367-z.