The role of pancreatic adenocarcinoma cancer-stromal interactions on cardiac structure and function

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival of <13% despite advances in therapy. Patients with PDAC also experience significantly lower cardiac-specific median survival compared to those with other GI cancers. While cancer cachexia impacts survival through skeletal muscle loss, the contribution of cardiac function to outcomes in PDAC is unknown. We aim to evaluate cardiac tissue structure and function in the most representative human preclinical model. This will provide insight into cardiac remodeling associated with PDAC and its clinical implication for possible interventions to improve overall survival. We implanted a PDAC patient-derived xenograft (PDX) into five NSG mice heterotopically and five NSG mice orthotopically, with five NSG mice receiving sham surgeries as controls. Tumor volumes were monitored weekly and once reaching 1.5cm, echocardiography and Millar catheterization were performed to assess cardiac structure and function between the three groups. Cardiac muscle, gastrocnemius muscle and tumors were collected for histologic and molecular analysis, including staining for structural assessment RNA sequencing to assess for changes associated with tumor burden, which is ongoing. An ANOVA and simple unpaired t-test were used with a significance value set at p < 0.05.Global longitudinal strain (GLS) measured by echocardiogram was within the normal values (-18 to -25%) across the groups, with no significant difference between the means of the sham (−20.3%), heterotopic (−21.2%), and orthotopic (−19.9%) groups. However, there is a slight trend showing a decline in GLS in the orthotopic group compared to the control group. The PV Loop data show a decline in left ventricular compliance (EDPVR) means in the heterotopic group (0.86) and orthotopic group (1.06) compared to the control group (0.22). The orthotopic group EDPVR mean is statistically different from the control group mean, with a simple unpaired t-test p-value of 0.02. The slight reduction in GLS observed in the orthotopic group relative to controls may indicate the presence of early systolic impairment in PDAC-bearing mice. Additionally, the results suggest that tumor burden is associated with impaired EDPVR, with the orthotopic group showing more stiffening as evidenced by a significantly elevated EDPVR when compared to the control group. This may indicate early diastolic dysfunction in the context of tumor related cardiac remodeling. We also anticipate that PDAC bearing mice will exhibit cardiac tissue remodeling, characterized by histological changes and transcriptional alterations linking cardiac decline and cancer progression. Recognizing early cardiac changes in patients with PDAC will help identify interventions that may ultimately improve treatment tolerance and clinical outcomes.