Abstract 11453: Plasma Levels of Tnf-α and Il-6 Are Associated With Diastolic Heart Failure Through Downregulation of Sarcoplasmic Reticulum Ca2+ Atpase
Background: Previous experiments from animal models found that active proinflammatory process might be associated with cardiac diastolic dysfunction. We investigated the detailed mechanism in cellular level and in diastolic heart failure (DHF) patients.
Methods: A total of 140 patients with a diagnosis of DHF confirmed by echocardiography and 70 matched controls were recruited. Soluble plasma levels of tissue necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured in all subjects and the association between cytokines levels and diastolic function parameters were calculated. An ≈1.75-kb promoter region of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene was then cloned to the pGL3 luciferase vector. The direct effects of TNF-α and IL-6 on the SERCA2 gene expression and diastolic calcium re-uptake in HL-1 cardiomyocytes were examined by promoter activity assay, quantitative real-time reverse transcription polymerase chain reaction for SERCA2 messenger ribonucleic acid (mRNA) amounts, and diastolic calcium decay.
Results: Patients with DHF presented significantly higher TNF-α and IL-6 levels than the controls. Significant correlations (all P < 0.05) were found for TNF-α and E/Em (r = −0.78), E/A (r= -0.67); IL-6 and E/Em (r= -0.65), E/A (r= -0.53). In addition, both TNF-α and IL-6 downregulated the promoter activity of the 1754-bp promoter -receptor construct of the SERCA2 gene. The levels of SERCA2 mRNA were also decreased after 24 hours after either TNF-α or IL-6 were treated. Accordingly, we also found increasing time constant of diastolic calcium transient decay (Figure).
Conclusions: Through downregulation of SERCA2 gene, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium re-uptake. Our study offered the evidence to apply novel therapies for DHF patients aim at limiting the inflammatory reactions.
- © 2010 by American Heart Association, Inc.