The antitumor functions of trastuzumab are associated with its ability to modulate signaling through the HER-2/neu receptor as well as initiate antibody-dependent cell-mediated cytotoxicity (ADCC) . Recent studies suggest that trastuzumab disrupts HER2/HER3 interactions, leading to downregulation of AKT signaling, which results in decreased cell proliferation [16–18]. At any stage, the use of trastuzumab reduces recurrence by about 50% and increases overall survival by about 30% [19–21] and reduction in the risk for death by about 44% (P < .0001, hazard ratio [HR] = 0.56) .
In approximately 4% of patients with trastuzumab therapy are associated with severe congestive heart failure, and most of the cardiac toxicity seen with treatment is limited to asymptomatic decreases in the left ventricular ejection fraction (LVEF); however .
In the present study, we tested the hypotheses that TLR4 mediates mononuclear infiltration and chemokine expression that response to underlying trastuzumab treatment. We found that TLR4-competent mice treated with trastuzumab display severe systolic and diastolic LV dysfunction, resulting in impaired cardiac output as measured by the assessment of pressure - volume loops, while in TLR4-/- cardiac output was improved as a result of enhanced systolic and diastolic performance, and reduced mononuclear infiltration with significantly lower levels of TNF-α, MCP-1 and ICAM-1. These result of correspond to myocardium injury after global ischemia and reperfusion led to TNF- expression and other cytokines , and is under the control by myocardial TLR4 , TNF- may serve as an intermediate in TLR4-mediated myocardial, including IL-8 and MCP-1. In myocardiac regional ischemia and reperfusion (I/R) demonstrate a critical role of TLR4 in myocardial chemokines response .
The John Cha  and his group studies show that the TLR4 signaling is involved in the myocardial inflammatory response after global ischemia/reperfusion and that TLR4 signaling contributes to cardiac dysfunction after global ischemia/reperfusion through its influence on myocardial production of TNF-α and IL-1 peptides. The Kaczorowski and colleagues  in which their data demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation.
In our earlier study we found that the Myocardial injury after global cold ischemia and perfusion was evaluated by serum cardiac troponin-I (cTn-I) as cardiac marker injury that was decreased levels in HeJ, p < 0.05 vs. TLR4 competent (HeN) [29, 30] also we found the same sequel in the present study the serum levels of cTn-I in the HeJ mutant (TLR4-/-) was reduced.
According to our knowlage no study was done that link between the TLR4 and trastuzumab treatment, so our data demonstrate for the first time a relevant role of TLR4 in the development myocardial injury following used trastuzumab under experimental conditions. Further studies using therapeutic interventions such as pharmacological TLR4 inhibition are required.