Contribution of TNF-R1 to reduced exercise capacity in hypertensive heart disease. Mediating role of left atrial mechanical function reserve

Abstract

Abstract Background Tumor necrosis factor alpha (TNF-alpha) plays a relevant pathophysiological role in cardiovascular disorders, including hypertensive heart disease (HHD) – a clinical condition frequently contributing to the development of heart failure with preserved ejection fraction (HFpEF). TNF receptor 1 (TNF-R1) has been found to mediate proinflammatory and proapoptotic effects of TNF-alpha, and its soluble circulating form proved to be effective in predicting incident HF. Existing evidence indicates the association between TNF pathways activation and cardiac dysfunction, but exact mechanisms mediating this link are unclear. Objectives We sought to investigate the association of TNF-R1 with exercise capacity, and left ventricular (LV) and left atrial (LA) function reserve in asymptomatic patients with HHD. Methods We enrolled 80 (55±12 yo) patients with HHD and normal exercise tolerance (stage A and B HF). Echocardiography (including LA and LV strain assessment) was performed at rest and immediately post exercise test. Blood samples for TNF-R1 were drawn in fasting conditions. Exercise reserve of cardiac function parameters was calculated by subtracting resting value from exercise value. Results The study population was categorized into 2 subsets using a median value of exercise capacity (9.2 METs). Patients with higher exercise capacity were characterized by lower TNF-R1 concentrations and higher LA reservoir and LA contractile strain reserves (Table). No significant intergroup differences were found for exercise reserves in LV ejection fraction (LVEF), LV global longitudinal strain and diastolic parameters (e’ and E/e’). TNF-R1 significantly correlated with peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) reserves (r=-0.27; p<0.02 and r=-0.24; p<0.04, respectively), but not with LVEF, global longitudinal strain (GLS), e’ and E/e’ reserves. Regression-based mediation analysis revealed that the relationships between TNF-R1 and exercise capacity were mediated by PALS and PACS reserve, as evidenced by the reduction in variance of exercise capacity (METs) explained by TNF-R1 after the inclusion of PALS and PACS reserve to the models (decrease in beta coefficient from -0.24 to -0.19 for PALS, and to -0.20 for PACS, Figure). Conclusions In patients with HHD, higher TNF-R1 is associated with lower exercise capacity, and this relationship may be mediated by lower LA strain reserve. This finding may contribute to elucidating the mechanisms behind the involvement of the left atrium in HF progression.Mediation analysis