Apolipoprotein M in Right Heart Failure

Background: Right heart failure (RHF) leads to an elevation in central venous pressure and causes hepatic congestion. Apolipoprotein M (ApoM), a hepatocyte-derived lipocalin bound to high-density lipoprotein, transports sphingosine-1-phosphate (S1P), which maintains vascular integrity and modulates inflammation. Although low ApoM predicts adverse outcomes in heart failure (HF), its role in RHF is unclear. We sought to investigate the impact of RHF on circulating ApoM, its prognostic value in RHF mortality, and its functional role in the cardio-hepatic axis. Methods: Patients undergoing right heart catheterization were classified as normal, HF, or RHF. Serum ApoM and S1P were measured by ELISA. Survival was analyzed using Kaplan-Meier and Cox proportional hazards models. Meanwhile, ApoM Tg or WT mice were subjected to pulmonary artery banding (PAB) to induce right ventricular (RV) dysfunction or partial inferior vena cava ligation (pIVCL) to cause hepatic congestion. Cardiac and hepatic pathology were assessed by tissue imaging and molecular analyses. Results: ApoM levels were lowest in RHF patients and inversely correlated with inflammatory markers. Each 0.01 μM increase in ApoM was associated with a 6% lower risk of mortality. PAB induced RV dysfunction and reduced serum ApoM in wild-type mice, while ApoM Tg mice showed less severe RV remodeling and improved hepatic congestion. In contrast, ApoM Tg mice subjected to pIVCL showed no significant improvement in liver pathology. Conclusion: In patients with RHF and mice with RV dysfunction, circulating ApoM was reduced. Lower ApoM was independently associated with worse outcomes. Restoring ApoM expression primarily protects the heart and subsequently alleviates liver congestion, underscoring its distinct protective role in the heart-liver axis. Further investigation of the ApoM axis in RHF is warranted.