Cardiac Extracellular Vesicles Mediate The Neoplastic Properties Of Heart Failure

Background: Heart failure (HF) is associated with an increased incidence of cancer independently of shared risk factors. The mechanism behind this link is complex and not entirely clear. We aimed to test the hypothesis that cardiac extracellular vesicles (cEVs) contribute to the link between HF and cancer. Methods & Results: We used a mouse model of heterotopic lung cancer and post-myocardial infarction (MI) HF. To determine the role of cEVs in tumor growth, we focused on cardiac mesenchymal stromal cells (cMSCs) derived EVs, isolated by size exclusion chromatography. cMSCs after MI secreted twice more EVs, characterized with unique proteome, compared to cMSCs from sham-MI ( Fig A, B ). cMSC-EVs from HF harbored more tumor trophic cytokines and microRNA (miR), such as Periostin, Osteopontin, IL-6, TNFα, miR 221, and miR 21. Next, lung cancer cells were inoculated into mice. While HF accelerated tumor growth, EV depletion by GW4869 attenuated this effect. We found that labeled cMSC-EVs targeted lung cancer tumors, and adoptive transfer of cMSC-EVs from failing hearts accelerated tumor growth with and without systemic EV depletion ( Fig C, D ). Finally, we found that spironolactone, a renin-angiotensin-aldosterone inhibitor, mitigated the neoplastic effects of HF, attenuated tumor growth ( Fig E ), and reduced the secretion of cMSC-EVs by 26%. Conclusions: Our results provide new insight into the link between heart failure and cancer. We show, for the first time, that cardiac extracellular vesicles promote tumor growth independently of other secreted factors. Moreover, spironolactone reduces the number of cardiac extracellular vesicles and the neoplastic effects of heart failure.