Abstract 4248: Epithelial ovarian cancer causes cardiac dysfunction and myofilament dysregulation
Bibliographic record
Abstract
Abstract Introduction: The intersections between cancer and cardiovascular disease (CVD) have become increasingly relevant in the care of both patient populations. To date, the cardio-oncology field has largely focused on how cancer treatment influences long-term cardiac health. Indeed, many cancer therapeutics show various toxic effects to the cardiovascular system. However, studies have also shown cardiac deficits in therapy-naïve cancer patients. This suggests that these two disease states interact through similar signaling pathways, yet the mechanisms underlying cancer-induced cardiac dysfunction remain unknown. Thus, we investigated cardiac structure and function throughout the progression of epithelial ovarian cancer (EOC). Methods: We used an orthotopic, syngeneic mouse model of ovarian cancer. Briefly, transformed murine ovarian surface epithelial cells from C57BL/6 mice (ID8; 1.0 × 106), or saline for surgical controls, were injected under the ovarian bursa of syngeneic mice. In this model, 60 days after tumor induction, mice form large ovarian masses, numerous peritoneal lesions, and develop abdominal ascites - consistent with the clinical features of stage III (advanced) EOC. To determine whether cardiac abnormalities precede the presence of advanced disease, at 45 days post-tumor induction, mice were anesthetized, and left ventricular (LV) structure and function were assessed by echocardiography and invasive hemodynamics, respectively. Myofilament activity was measured with an actomyosin MgATPase assay and protein phosphorylation was determined by SDS-PAGE with Pro-Q Diamond phosphoprotein staining. Results: EOC mice showed systolic (i.e., reduced contraction rate) and diastolic dysfunction (i.e., reduced relaxation rate, elevated diastolic filling pressure), with no evidence of hypertrophy or atrophy (i.e., no change in LV wall thickness or dimension). While there were no observed differences in myofilament ATPase activity, phosphorylation of regulatory myosin light chain 2 (MYL2) and cardiac myosin binding protein C (cMyBP-C) decreased, and tropomyosin (Tpm) phosphorylation increased in EOC mice. Conclusion: Together, these data demonstrate that ovarian cancer impairs cardiac function and alters the regulation of myofilament proteins critical for contraction and relaxation. Interestingly, the observed dephosphorylation of MYL2 and cMyBP-C and hyperphosphorylation of Tpm are consistent with features of heart failure. The findings build upon our current understanding of the interactions between cancer and CVD and show that deficits in the heart precede the development of advanced malignancy. Future work further will investigate the tumor-heart axis to identify how tumor development disrupts normal cardiac physiology. Citation Format: Leslie M. Ogilvie, Madison Pereira, Kathy Matuszewska, Bridget Coyle-Asbil, Luca J. Delfinis, Shivam Gandhi, Keith R. Brunt, Christopher G. Perry, W. Glen Pyle, Jim Petrik, Jeremy A. Simpson. Epithelial ovarian cancer causes cardiac dysfunction and myofilament dysregulation. [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 4248.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".