Identification of Apolipoprotein E as a Potential Novel Mediator of Heart Failure with Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome where, despite having a normal left ventricular systolic function, patients present with symptoms of volume overload. Recent data have shown that HFpEF is associated with activation of the immune system. In a well-known rodent hypertensive model (DOCA-salt), we found expansion of macrophage populations with increased expression of Apolipoprotein E (APOE, FC = 1.45, p_adjusted = 9.19E-6). Using PrediXcan to model gene predicted expression, we found that, of the top 20 differentially expressed genes in cardiac macrophages after DOCA-salt treatment, APOE had the highest odds ratio (OR 1.85) for association with HFpEF development in BioVU, Vanderbilt DNA biobank. While non-human animals have one version of APOE, there are three common genetic variants of human APOE caused by 2 single nucleotide polymorphisms (SNPs) – APOE2, APOE3, and APOE4. There is increasing evidence that both murine Apoe and human APOE variants have pleiotropic effects on both adaptive and innate immune cells. The objective of this study is to evaluate whether APOE and its human polymorphisms play a causal role in the development of HFpEF. Hypothesis: We hypothesized that loss of APOE would impact the development of HFpEF in our murine model, and that the human genetic variants of APOE would differentially associate with risk for HFpEF. Methods: For mice studies, Apoe -/- mice underwent unilateral nephrectomy, implantation of a deoxycortisterone acetate (DOCA) pellet and had 1% NaCl in their drinking water for 3 weeks. Echocardiogram and exercise testing was performed pre- and post-DOCA-salt; blood pressure was measured by tail cuff weekly; left heart catheterization was performed prior to euthanasia, then organ weights were obtained post-mortem. For the human genetic experiments, patients (age > 40) in BioVU in which the APOE SNPs were genotyped underwent phenotyping for HFpEF using the eMERGE heart failure phenotyping algorithm. Patients without heart failure were classified as controls. Results: After the DOCA-salt protocol, Apoe-/- mice exhibit similar blood pressure and lung wet-to-dry ratio as wild type mice. However, they demonstrate worse diastolic function with higher tau on invasive hemodynamics (p=0.040), greater decline in exercise tolerance on treadmill testing (p=0.032) with more cardiac hypertrophy as measured by heart weight to tibia length ratio (p=0.032). In a logistic regression model incorporating age, sex, common co-morbidities associated with HFpEF, and the 10 principal components of ancestry, the APOE4 polymorphism is associated with protection from development of HFpEF in BioVU (OR 0.89, p=0.006). Conclusion: In a mouse model, we show that lack of APOE results in an exacerbated HFpEF phenotype; in parallel, we use genetic epidemiological approach to demonstrate that the common human genetic variants for APOE affects their risk for development of HFpEF. Together, this suggests that APOE is a potential mediator of HFpEF and may present a novel diagnostic and therapeutic target. This work is supported by the AHA (24CDA1278132 to JWW) and the NIH (R01HL159487 to ACD). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.