Introduction: Cancer cachexia, characterized by the progressive loss of muscle mass (i.e., atrophy), has a significant impact on patient prognosis and quality of life. While skeletal muscle atrophy and weakness are well characterized in cancer patients, the progression of cancer-induced cardiac atrophy has received little attention. Preliminary work from our lab has shown that cardiac dysfunction, measured by invasive hemodynamic assessment, precedes the development of metastatic disease in a mouse model of epithelial ovarian cancer (EOC). Yet, the time course of changes in cardiac structure and function throughout the progression of ovarian cancer remain unknown. Thus, we non-invasively assessed changes in cardiac structure and function through the progression of EOC. Methods: To investigate the impact of advanced ovarian cancer on cardiac structure and function, we used an orthotopic, syngeneic mouse model of EOC. This model was generated by injecting transformed murine ovarian surface epithelial cells (ID8; 1.0 × 106) or saline (surgical sham) directly under the ovarian bursa of syngeneic mice. Echocardiography was used to assess changes in cardiac structure and function throughout the progression of EOC at days 45, 60, 75, and 90 post-tumor induction (PTI). Morphometric assessments at each timepoint were used to determine the presence of cardiac atrophy. Results: Echocardiography showed that EOC mice had preserved left ventricular (LV) function (i.e., ejection fraction) with no change in structural dimensions at days 45, 60 and 75 PTI. By day 90 PTI, LV wall thickness and end-systolic dimension decreased, suggesting evidence of cardiac atrophy. Consistent with echocardiographic data, morphometric assessment showed profound atrophy at 90 days PTI, but preserved cardiac mass at all other timepoints compared to shams. Conclusion: Together, this work demonstrates that when non-invasive techniques are used to measure changes in cardiac structure, atrophy is not evident until advanced stage ovarian cancer (i.e., 90 days PTI). Despite this, preliminary work from our lab has shown that cardiac dysfunction is present in EOC mice by 45 days PTI when assessed by invasive hemodynamics. Although echocardiography is a widely used technique for measuring indices of cardiac structure and function, our work demonstrates it lacks sensitivity to detect cardiac deficits until the overt stages of disease that accompany cancer cachexia. Thus, it is important to consider that subclinical cardiac dysfunction may exist in the early stages of cancer progression, however, these changes may go undetected unless more sensitive hemodynamic assessments are employed. Citation Format: Bridget Coyle-Asbil, Leslie M. Ogilvie, Madison Pereira, Kathy Matuszewska, Luca J. Delfinis, Shivam Gandhi, Keith R. Brunt, Christopher G. Perry, Jim Petrik, Jeremy A. Simpson. The progression of changes in cardiac structure and function in mice with epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 354.

<p>Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined if dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities. Male C57Bl/6N mice were fed an 8-week low-fat  diet (LFD), HFD, or HFD+Nitrate (4mM sodium nitrate). HFD-fed mice presented with pathological left ventricular (LV) hypertrophy, reduced stroke volume and increased end diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. </p>

<p>Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined if dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities. Male C57Bl/6N mice were fed an 8-week low-fat  diet (LFD), HFD, or HFD+Nitrate (4mM sodium nitrate). HFD-fed mice presented with pathological left ventricular (LV) hypertrophy, reduced stroke volume and increased end diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. </p>

<p>Impaired heart function can develop in diabetic individuals in the absence of coronary artery disease or hypertension, suggesting mechanisms beyond hypertension/increased afterload contribute to diabetic cardiomyopathy. Identifying therapeutic approaches that improve glycemia and prevent cardiovascular disease are clearly required for clinical management of diabetes-related comorbidities. Since intestinal bacteria are important for metabolism of nitrate, we examined if dietary nitrate and fecal microbial transplantation (FMT) from nitrate-fed mice could prevent high-fat diet (HFD)-induced cardiac abnormalities. Male C57Bl/6N mice were fed an 8-week low-fat  diet (LFD), HFD, or HFD+Nitrate (4mM sodium nitrate). HFD-fed mice presented with pathological left ventricular (LV) hypertrophy, reduced stroke volume and increased end diastolic pressure, in association with increased myocardial fibrosis, glucose intolerance, adipose inflammation, serum lipids, LV mitochondrial reactive oxygen species (ROS), and gut dysbiosis. In contrast, dietary nitrate attenuated these detriments. In HFD-fed mice, FMT from HFD+Nitrate donors did not influence serum nitrate, blood pressure, adipose inflammation, or myocardial fibrosis. However, microbiota from HFD+Nitrate mice decreased serum lipids, LV ROS, and similar to FMT from LFD donors, prevented glucose intolerance and cardiac morphology changes. Therefore, the cardioprotective effects of nitrate are not dependent on reducing blood pressure, but rather mitigating gut dysbiosis, highlighting a nitrate-gut-heart axis. </p>

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