Abstract Body: Background There is currently no therapy targeting cancer-related cardiomyopathy and treatment of heart failure in the oncological setting is nonspecific. Moreover, cancer is often assocaited with cachexia and the pathophysiology of cancer-cachexia induced cardiac (dys)functions are not fully known.
MethodsColon-26 adenocarcinoma (C26; n=30) or shIL-6 (C26 shIL-6; n=30) cells were inoculated subcutaneously into the flank of syngeneic adult male BALB/cmice, meanwhile control mice were injected with PBS (n=25). Twenty days after the cells injection, cardiac function was assessed using transthoracic echocardiography, ex vivo isolated working heart methods. In addition, intracellular Ca²⁺ transient and force-calcium relationships were assessed in isolated single ventricular cardiomyocytes (CMs). Cardiac inflammation, metabolism and fibrosis were also assessed.
Results
Despite that tumor size was comparable between the cancer groups, C26 group showed a loss of subcutaneous fat and skeletal muscle confirming a cachectic phenotype in association with an elevation of serum IL-6 levels. Tumor-bearing mice groups show a tendecy towards to both LV systolic and diastolic dysfunction. Sarcomere dysfunction, including significantly reduced maximum calcium-activated tension (Tmax) and increased calcium sensitivity (decreased EC₅₀) was found in skinned cardiomyocyte preparation from both tumor-bearing mice in compared to controls (p<0.05, respectively). Intracellular Ca²⁺ transient was exclusively increased in CM isolated from cachectic mice, suggesting the SERCA2 upregulation. Infiltration of macrophage or T-cells, nor interstital fibrosis were difference. β-myosin heavy chain expression is upregulated in a cell autonomous fashion in C26 mice. Comprehensive energetic and metabolims analysis showed shift to a profound glucose metabolsim and reduction in fatty acid oxidation in LV samples. This was futher proven in h9c2 cells were incubated with C26 or shIL6 cell culture medium.
Discussion
Our results suggest that LV dysfunction in cancer mice is associated with sarcomere dysfunction while additional abnormal intracellular Ca²⁺ handling is solely present in mice with cachectic phenotype. These functional alterations are independent from changes in myocardial fibrosis and inflammation but may rely on the cardiac metabolism alterations. These data provide new insights into how cancer and cancer-cachexia impacts the cardiac performance even prior to cancer therapy treatments.