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Biochemical aspects of gender differences in response to cardiac resynchronization therapy

Enina T. N., Kuznetsov V. A., Soldatova A. M., Petelina T. I., Krinochkin D. V., Rychkov A. Yu., Nochrina O. Yu.
"Tyumen Cardiology Science Center", Branch of the Federal State Budgetary Science Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences", Melnikayte 111, Tyumen 625026

Keywords: cardiac resynchronization therapy, gender differences, cytokines, NT-proBNP, galectin-3, matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1 and -4

DOI: 10.18087/rhj.2017.2.2323

Background. Cardiac resynchronization therapy (CRT) is known to be more effective for women than for men. However, gender specificity of this difference is understudied. Aim. To study gender-related differences in CRT effectiveness and to evaluate the effect of CRT on processes of immune inflammation and myocardial fibrosis in patients with chronic heart failure (CHF). Materials and methods. The best response to CRT at the mid-term of 15.0 [7.0; 26.0] months was evaluated in 77 patients (mean age, 55.9±8.2) with ischemic (65 %) and non-ischemic CHF. Patients were divided into two groups – group 1 (n=61; 79%), men and group 2 (n=16; 21%), women. Plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukins (IL) -1β, -6, and -10, tumor necrosis factor α (TNF-α), С-reactive protein (CRP), galectin-3 (Gal-3), matrix metalloproteinase 9 (ММР-9), tissue inhibitors of metalloproteinases 1 and 4 (TIMP-1, TIMP-4), and MMP-9/TIMP-1 and MMP-9/TIMP-4 ratios were measured. Based on time-related changes in left ventricular end-systolic volume (LVESV) patients were defined as non-responders (<15% decrease in LVESV), responders (15–29% decrease in LVESV), and super-responders (>30% decrease in LVESV). Results. In group 2, there was a higher incidence of full left bundle branch block (81.3% vs. 47.5%, р=0.016); a greater number of super-responders (62.5 vs. 32.8%); and smaller numbers of non-responders (18.8 vs. 36.1%) and responders (18.8 vs. 31.1%) (р=0.03). In both groups, decreases in IL-6 (р<0.05), TNF-α (р<0.001; р<0.05), NT-proBNP (р=0.001; р<0.05), and Gal-3 (р<0.05) were observed. However, their changes were more pronounced in group 2; IL-6 was decreased by 44.4% vs. 23.5% (р=0.029), TNF-α – by 41.4% vs. 30.9%, NT-proBNP – by 73.3% vs. 46% (р=0.002), and Gal-3 – by 82.3% vs. 64.9%. Reduced levels of IL-10 (р<0.05), MMP-9 (р<0.05), and MMP-9/TIMP-4 (р<0.05) were also observed in group 1. Opposite changes in TIMP-1 were observed in the groups; a tendency to decrease in TIMP-1 in group 1 (p=0.054) and an increase in TIMP-1 in group 2 (р<0.05). Conclusion. The best response to CRT was associated with female gender, probably due to greater decreases in neurohormonal activation, immune inflammation, and myocardial fibrosis. Possibly, CRT influences the condition of extracellular cardiac matrix by reducing immune inflammation. Opposite changes in TIMP-1 in the groups may indicate gender-related peculiarities in the activity of the system of matrix metalloproteinases and their tissue inhibitors.
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Enina T. N., Kuznetsov V. A., Soldatova A. M., Petelina T. I., Krinochkin D. V., Rychkov A. Yu. et al. Biochemical aspects of gender differences in response to cardiac resynchronization therapy. Russian Heart Journal. 2017;16 (2):103–109

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