Molecular biomarker profile of heart failure with mid-range and preserved ejection fraction in patients with type 2 diabetes

Aim. To study molecular biomarkers in patients with type 2 diabetes (T2D) in combination with heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) and compare the data obtained with clinical characteristics of myocardial remodeling.

Material and methods. The study included 42 patients with T2D (men — 53%, mean age — 60 years) with clinical manifestations of class II HF: 29 patients with HFpEF (group 1) and 13 patients with HFmrEF (group 2). The control group consisted of 13 healthy people, which were comparable in sex and age and had a normal body mass index (BMI). Patients received stable glucose-lowering and optimal drug therapy for HF for 3 months prior to enrollment in the study. Patients with HFpEF and HFmrEF were comparable in clinical and demographic parameters, had glycated hemoglobin (HbA ) of 8,5% and 8,8%, respectively (p>0,05), increased BMI or grade I-II obesity.

We studied following biomarkers: NT-proBNP, highly sensitive C-reactive protein (hsCRP), sST2, galectin-3, procollagen type I C-terminal propeptide (PICP), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1).

Results. Volumetric parameters of the left ventricle (LV),LV mass indexed to growth and NT-proBNP were higher in the group of HFpEF patients (p<0,05 for all). The concentrations of galectin-3, PICP were higher, and the MMP-9/TIMP-1 ratio decreased in patients with T2D compared with the control group (p<0,05 for all). PICP values were higher in patients with HFmrEF compared with patients with HFpEF (106,4 (85,4; 140,4) ng/ml vs 46,8 (12,6; 98,6 ng/ml), respectively, p=0,043). In patients with T2D and HF, a relationship was found between TIMP-1 andLV end-diastolic volume (r=-0,68; p=0,042).

Conclusion. Patients with HFmrEF and T2D have higherLV volume and mass, higher concentrations of NT-proBNP and PICP in comparison with patients with HFpEF. The direction of MMP-9/TIMP-1 changes may reflect a decrease in antifibrotic processes. Further prospective studies on large samples using a multiple biomarker model are required in T2D and various HF phenotypes.

1. Cosentino F. et al. ESC Scientific Document Group, 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J 2020; 41: 255

2. Johansson I., Dahlström U., Edner M. et al. Type 2 diabetes and heart failure: Characteristics and prognosis in preserved, mid-range and reduced ventricular function, Diabetes & Vascular Disease Research. 2018; 15(6): 494–503. doi: 10.1177/1479164118794619.

3. Paulus W., Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013; 62:263–71. doi: 10.1016/j.jacc.2013.02.092.

4. Takayuki Miki, Satoshi Yuda, Hidemichi Kouzu, Tetsuji Miura. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev.2013; 18:149–166 doi: 10.1007/s10741-012-9313-3

5. Ageev F.T., Ovchinnikov A.G. Heart failure with mid-range ejection fraction: are there clinical reasons in introduction of this new group as a distinct entity? Kardiologiia. 2018;58(S12):4–10

6. Sarhene M, Wang Y, Wei J, et al. Biomarkers in heart failure: the past, current and future. Heart Fail Rev. 2019;24(6):867‐903. doi:10.1007/s10741-019-09807-z

7. Ibrahim N., Januzzi J. Established and Emerging Roles of Biomarkers in Heart Failure. Circ Res. 2018;123(5):614‐629. doi:10.1161/CIRCRESAHA.118.312706

8. López B., González A., Díez J. Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation 2010;121:1645–1654. doi: 10.1161/CIRCULATIONAHA.109.912774

9. Levick S., Widiapradja A. The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function Int. J. Mol. Sci. 2020;21:970. doi:10.3390/ijms21030970

10. Belenkov Y.N., Privalova E.V., Iusupova A.O. et al. Markers of Vascular Wall Fibrosis Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinases-1 in Patients with Ischemic Heart Disease with and without Concomitant Type-2 Diabetes Mellitus. Kardiologiia. 2019;59(5):61–66.

11. Mueller C., McDonald K., de Boer R. et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations European Journal of Heart Failure. 2019; 21(7):15–731 doi:10.1002/ejhf.1494

12. Kenny H., Abel E. Heart Failure in Type 2 Diabetes Mellitus Impact of Glucose-Lowering Agents, Heart Failure Therapies, and Novel Therapeutic Strategies Circ Res. 2019;124:121-141 doi: 10.1161/CIRCRESAHA.118.311371.

13. Jonathan M. et al. Cardiac Steatosis in Diabetes MellitusA 1H-Magnetic Resonance Spectroscopy Study Circulation.2007;116(10):1170-1175. doi: 10.1161/CIRCULATIONAHA.106.645614

14. Marwick T. et al. Recommendations on the Use of Echocardiography in Adult Hypertension: A Report from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE) Journal of the American Society of Echocardiography. 2015; 28(7):727-754. doi:10.1016/j.echo.2015.05.002.

15. Saikhan L, Hughes D, Chung W, et al. Left atrial function in heart failure with mid-range ejection fraction differs from that of heart failure with preserved ejection fraction: a 2D speckle-tracking echocardiographic study. European Heart Journal - Cardiovascular Imaging. 2019;20(3): 279–290. doi: 10.1093/ehjci/jey171

16. Carolyn S.P. Lam and Scott D. Solomon The middle child in heart failure: heart failure with mid-range ejection fraction (40–50%) European Journal of Heart Failure.2014; (16):1049–1055 doi:10.1002/ejhf.159.

17. Prastaro M., Paolillo S., Savarese G. N-terminal pro-b-type natriuretic peptide and left atrial function in patients with congestive heart failure and severely reduced ejection fraction European Journal of Echocardiography. 2011;(12):506–513. doi:10.1093/ejechocard/jer070

18. Moliner P., Lupón J., Barallat J. et al. Bio-profiling and bio-prognostication of chronic heart failure with mid-range ejection fraction. International Journal of Cardiology. 2018; (257):188–192. doi: 10.1016/j.ijcard.2018.01.119

19. Tromp J., Khan M., Mentz R. et al. Biomarker Profiles of Acute Heart Failure Patients With a Mid-Range Ejection Fraction. 2017;5(7):507‐517. doi:10.1016/j.jchf.2017.04.007;

20. Chionel O. et al. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry European Journal of Heart Failure. 2017;(19):1574–1585. doi:10.1002/ejhf.813.

21. Berezin A. Prognostication of clinical outcomes in diabetes mellitus: Emerging role of cardiac biomarkers Diabetes & Metabolic Syndrome: Clinical Research & Reviews Volume. 2019;13(2):995-1003. doi:10.1016/j.dsx.2019.01.018

22. Song, Y., Li F., Xu Y. et al. Prognostic value of sST2 in patients with heart failure with reduced, mid-range and preserved ejection fraction. Int. J. Cardiol. 2020;(304):95–100. doi:10.1016/j.ijcard.2020.01.039

23. de Boer R.,van Veldhuisen D.,Gansevoort R. et al. The fibrosis marker galectin-3 and outcome in the general population. J Intern Med. 2012;(272):55–64. doi: 10.1111/j.1365-2796.2011.02476.x

24. Alonso et al. Impact of diabetes on the predictive value of heart failure biomarkers Cardiovasc Diabetol. 2016;15:151. DOI 10.1186/s12933-016-0470-x.

25. Xiang et al. Efficacy and Safety of Spironolactone in the Heart Failure With Mid-Range Ejection Fraction and Heart Failure With Preserved Ejection Fraction: A Meta-Analysis of Randomized Clinical Trials Medicine. 2019;(98):13 doi: 10.1097/MD.0000000000014967.

26. Karetnikova V., Kashtalap V., Kosareva S. et al. Myocardial fibrosis: Current aspects of the problem. Therapeutic archive. 2017;01:88-93. doi: 10.17116/terarkh201789188-93

27. Zaitsev V.V., Gurshchenkov A.V., Mitrofanova L.B. et al. Clinical significance of different assesment methods of myocardial fibrosis in patients with hypertrophic cardiomyopathy.. Kardiologiia. 2020;60(3):44-50. (In Russ.) doi: 10.18087/cardio.2020.3.n561

28. Morishita T. et al. Association between matrix metalloproteinase-9 and worsening heart failure events in patients with chronic heart failure. ESC Heart Failure 2017;4: 321–330. DOI: 10.1002/ehf2.12137

29. Berg G., Barchuk М., Miksztowicz V. Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling. Cells. 2019; 8(2): 158. doi: 10.3390/cells8020158

30. Lewandowski K., Banach E., Bieńkiewicz M. et al. Matrix metalloproteinases in type 2 diabetes and non-diabetic controls: effects of short-term and chronic hyperglycaemia Arch Med Sci. 2011; 7(2): 294-303. DOI: 10.5114/aoms.2011.22081.

31. Ceron C., Luizon M. Plasma matrix metalloproteinases in coronary artery disease patients. European Journal of Clinical Investigation. 2016;46(1):104–5. DOI: 10.1111/eci.12537