New heart failure drug shows promiseHigher circulating apolipoprotein A (ApoE) concentrations appear to increase the risk for incidence major adverse cardiovascular events (MACE), ischaemic heart disease (IHD), and heart failure, suggests a study.
“This risk is independent of cholesterol and inflammatory pathways but is attenuated by the triglyceride level, potentially signalling the residual risk of cardiovascular disease (CVD),” said the investigators, who used electronic health records from a multispecialty outpatient population in Shenzhen, China, to identify adults with serum ApoE measured and had no prior IHD, stroke, or HF (n=14,852).
Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 percent confidence intervals (CIs) for outcomes (ie, MACE, IHD, HF, and stroke).
Overall, 491 MACE, 515 IHD, 293 stroke, and 181 HF incident events occurred over a median follow-up of 4 years. [Am J Med 2026;139:1348-1356.e6]
Elevated ApoE concentrations showed a significant association with higher risks of incident MACE (HR per 1 mg/dL increment, 1.09, 95 percent CI, 1.04‒1.15), IHD (HR, 1.07, 95 percent CI, 1.02‒1.13), and HF (HR, 1.14, 95 percent CI, 1.07‒1.22), but not stroke (HR, 1.03, 95 percent CI, 0.96‒1.11).
Although these associations existed irrespective of low-density lipoprotein cholesterol (LDL-C), small and dense (sd)LDL-C, high-density lipoprotein cholesterol (HDL-C), and neutrophil-to-lymphocyte ratio (NLR), they were attenuated after adjustments for triglycerides. Notably, individuals with elevated ApoE and triglycerides were at disproportionately increased risk of cardiovascular events.
“Concurrent elevation in ApoE and triglycerides may represent a high-risk clinical phenotype, suggesting the joint assessment of ApoE and triglycerides may improve risk stratification for hypertriglyceridaemic individuals,” the investigators said.
Atherogenic potential
These findings suggest that the atherogenic potential of elevated ApoE concentration might interact with triglyceride concentrations. ApoE, a core surface protein, exists on triglyceride-rich lipoproteins (TRL) particles, acting as a ligand and determining the clearance of TRL/remnants from the circulation in the liver. [Biochemistry (Mosc) 2004;69:720-737; Neurobiol Dis 2014;72:3-12]
“[W]e observed that the positive association between elevated ApoE and increased IHD risk was largely attenuated by the TRLs/remnant pathways, proxied by triglyceride concentration, but not by metabolism pathways related to HDL-C, LDL-C, sdLDL-C, which is a downstream consequence of delayed TRL clearance, and the inflammatory marker of NLR,” the investigators said. [Front Cardiovasc Med 2022;8:804214; Eur Heart J 2011;32:1345-1361]
In earlier studies, triglycerides also attenuated the association between ApoE and CVD in the Danish population. [Atherosclerosis 2016;246:63-70]
Overall, elevated serum ApoE may serve as a functional surrogate for an increased burden of atherogenic TRL/remnants and is indicative of the residual risk of CVD beyond the classical cholesterol pathway, according to the investigators.
“Notably, our joint-effects and stratified analyses indicate a potential synergistic interplay between ApoE concentration and TG levels,” they said. “From a clinical perspective, our findings expand the understanding of the clinical utility of ApoE and suggest that circulating ApoE concentration could serve as a risk-stratifier when interpreted in the context of a patient's triglyceride status.”
A component of TRLs, ApoE serves as a key modulator in lipid transport and metabolism. [Circ Res 2016;118:547-563; Int J Mol Sci 2018;19:3479; Annu Rev Genom Hum Genet 2000;1:507-537]