Abstract 1270: Toll-Like Receptor 4 Mediates Maladaptive Left Ventricular Remodeling Following Experimental Myocardial Infarction in Mice
Introduction Left ventricular (LV) remodeling leads to congestive heart failure and is a main determinant of morbidity and mortality following myocardial infarction (MI). Therapeutic options to prevent LV remodeling are limited, which necessitates the exploration of alternative therapeutic targets. Toll-like receptors (TLRs) serve as pattern-recognition receptors within the innate immune system. Activation of TLR4 results in an inflammatory response and is involved in extracellular matrix degradation, both key processes of LV remodeling following MI.
Methods and Results To establish the role of TLR4 in post infarct LV remodeling, MI was induced in wild type BALB/c mice and TLR4 defective C3H-Tlr4LPS-d mice. Without affecting infarct size, TLR4 defectiveness reduced the extent of LV remodeling (end-diastolic volume: 103.7 ± 6.8 μl vs. 128.5 ± 5.7 μl; p=0.032) and preserved systolic function (ejection fraction: 28.2 ± 3.1 % vs. 16.6 ± 1.3 %; p=0.007) twenty-eight days following MI as assessed by magnetic resonance imaging. In the non-infarcted myocardium, fibrosis (1.90 ± 0.04 vs. 2.08 ± 0.05 grayvalue/μm2; p=0.013) and hypertrophy (538 ± 26 vs. 729 ± 27 μm2/cardiomyocyte; p<0.001) were reduced in C3H-Tlr4LPS-d mice. In the infarcted area of C3H-Tlr4LPS-d mice, collagen density was increased (7.78 ± 1.03 vs. 4.67 ± 0.30 grayvalue/μm2; p=0.013), which was accompanied by less macrophages (13.0 ± 3.2 vs. 25.1 ± 3.9 macrophages/mm2; p=0.029), reduced inflammatory cytokine expression (TNF-alpha, IL-1a, IL2, IL-4, IL-5, IL-6, IFN-gamma) and reduced MMP2 (4684 ± 515 vs. 7573 ± 611; p=0.002) and MMP9 activity (76.0 ± 14.3 vs. 168.0 ± 36.2; p=0.027).
Conclusion These data provide direct evidence for a causal role of TLR4 in post infarct maladaptive LV remodeling, probably via inflammatory cytokine production and matrix degradation. TLR4 may therefore constitute a novel target in the prevention of cardiac remodeling.