Funding Acknowledgements Type of funding sources: None. Background Cancer patients undergoing heart-related complications result in high incidences of mortality. Nevertheless, it is still not fully understood whether localized tumors affect heart function prior to the onset of cachexia, hence, making the heart more vulnerable for functional abnormalities in later stages of the disease. In addition to analyse heart function, we focus on the expression BCL-2–associated athanogene 3 (BAG3), a co-chaperone protein and Hsp70, which are highly expressed in tumor but decrease in cardiomyocytes (CM) in heart failure (HF). Methods Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously into the right flank of 10-11 weeks old BALB/c male mice. Control mice were injected with vehicle (PBS; n=8). Cardiac function was assessed by echocardiography and invasive hemodynamic measurements 10 (early) and 20 (late) days after the injection, respectively. In addition, the expression of BAG3 and Hsp70 were determined by Western blot as well as the extend of cardiac fibrosis was determined by Masson-Goldner's trichrome staining. Results The tumor size was comparable between the two injected groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p<0.05, respectively), suggesting cachexia. Heart weight normalized to tibia length was not changed in the injected groups as compared to controls (day 20). However, left ventricular ejection fraction (LVEF) showed a tendency to decline in the early phase (p~0.08) in both injected group and it reached significance at late stage (p<0.05). Invasive hemodynamic assessment also confirmed the contractile dysfunction, resulting in a decrease in LV systolic pressure and increase of LV end-diastolic pressure (p<0.05, respectively). Importantly, these functional changes in the heart in tumor-bearing mice were associated with a marked reduction in both BAG3 and Hsp70 in the myocardium. Furthermore,  there was no sign of cardiac fibrosis in the injected groups. Discussion Our study shows for the first time that tumor rather than cancer cachexia plays a significant maladaptive role in the progression of cardiac dysfunction in a mouse model of C26 injection-induced cachexia. The progression of cardiac contractile dysfunction was associated with a decline in BAG3 and Hsp70 in tumor-bearing mice, suggesting changes of BAG3/Hsp 70 signalling may be a critical component as well as target.

Introduction: Cancer is independently associated with the alteration of cardiac function prior to cardiotoxic chemotherapy (CCT) exposure. Similar to cancer associated cachexia (CAC), the elevation and the deleterious role of IL-6 in plasma was associated with a reduced cardiac function in heart failure (HF) patients subpopulation. Cancer cells manipulate BCL-2-associated athanogene 3 (BAG3)-HSP70-regulated pathways in tumor cells, which is a key regulator of protein turnover and contractility in cardiomyocyte. Hypothesis: Here, we aimed to characterize the progression of cardiac dysfunction and the expression of BAG3 and HSP70 in tumor-bearing mice. Methods: Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously adult male BALB/c mice. Control mice were injected with PBS (n=13). Echocardiographic examinations and invasive hemodynamic measurements ( in vivo and ex vivo using isolated working hearts system) were performed at 10 (early) and 20 (late) days post injection, respectively. The expression of BAG3 and Hsp70 were determined by Western blot. Results: The tumor size was comparable between the cancer groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p<0.05, respectively), confirming cachectic condition. Echocardiography results show a tendency to decline of ejection fraction at the early phase (p~0.08 vs Control), and turned significance lower at late stage (p<0.05 vs Control) in tumor-bearing mice. In line with that, invasive hemodynamic and isolated working heart measurements confirmed LV systolic and diastolic dysfunction (late stage, p<0.05 vs Control, respectively). Interestingly, heart rate and aortic flow were predominantly declined in cachectic animals (p<0.05 vs Control). Importantly, cardiac dysfunction was associated with a significant reduction in both BAG3 and Hsp70 in the myocardium independently of cachexia. Conclusions: Cancer rather than CAC is a main driver for the development of cardiac contractile dysfunction prior to CCT exposure. In addition, our data suggest that targeting BAG3-Hsp70 complex in the cardiomyocytes may provide a novel strategy to improve the cancer associated cardiac dysfunction.