Abstract 10625: Inflammatory Cytokines Modulate Left Ventricular Diastolic Function Through Downregulation of Sarcoplasmic Reticulum calcium Atpase
Background The inflammatory process is associated with cardiac diastolic dysfunction. We evaluated the mechanism from cellular models to patients with high inflammation status.
Materials and Method An ≈1.75-kb promoter region of SERCA2 gene was cloned to pGL3 luciferase vector. The direct effects of cytokines on SERCA2 gene expression in HL-1 cardiomyocytes were examined by promoter activity assay, followed by western analysis, RT-PCR and also diastolic calcium decay. We further evaluated the mechanisms in 2 study groups. 101 continuous ambulatory peritoneal dialysis (CAPD) patients along with 120 controls (group 1) and 102 otherwise-healthy obese adults (group 2) were enrolled. The participants were classified as having LV diastolic dysfunction by echocardiography. In group 1, the correlation of cytokines and diastolic dysfunction were compared between CAPD patients and controls. Multivariate regression analysis was made to distinguish the interaction between cytokines and CAPD for LV diastolic dysfunction. In group 2, all participants received computerized tomography to determine central obesity. The relationship between inflammation, visceral adipose tissue (VAT) and diastolic dysfunction were evaluated by multivariate regression analysis and path analysis.
Results Inflammatory cytokines decreased the promoter activity of the 1754-bp promoter -receptor construct of the SERCA2 gene. The levels of SERCA2 protein and mRNA also changed after treatment of cytokines. In study group 1, the interaction of CAPD and inflammation significantly contributed to the development of LV diastolic dysfunction (CAPD*TNF-α: OR: 1.45, 95% CI: 1.13 - 1.79, P=0.004). In study group 2, the relationship between VAT and LV diastolic dysfunction became insignificant when CRP was introduced into the model, although CRP itself was significantly associated with LV diastolic dysfunction (OR: 1.32, 95% CI: 1.01∼1.72, p=0.04).
Conclusions Inflammatory cytokines may cause diastolic dysfunction through downregulation of SERCA2 gene. Higher amounts of VAT were associated with low-grade inflammation and may lead to LV diastolic dysfunction. In CAPD patients, a synergistic effect between CAPD and inflammation would further aggravate LV diastolic dysfunction.
- © 2011 by American Heart Association, Inc.