HDL Antioxidant Function Diminished in Patients with HFpEF, Study Finds

Credit: Fotolia

Elevated levels of oxidized high-density lipoprotein (HDL) were associated with heart failure with preserved ejection fraction (HFpEF) in a new analysis, suggesting the presence of reduced HDL antioxidant function in this population.¹

This cross-sectional observational study assessed the antioxidant function of HDL in more than 350 patients with suspected heart failure, with HFpEF assessment conducted according to the current Heart Failure Society of America (HFSA) clinical guidelines.²

“Our results consistently show that increased HDLox levels are associated with HFpEF in both univariate and multivariate analyses,” wrote the investigative team, led by Benjamin Sasko, department of cardiology, Medical School Theodor Fontane, University Medical Center Brandenburg an Der Have. “Therefore, our main finding is that reduced antioxidant HDL function is present in HFpEF.”

Guidelines designate HFpEF by clinical signs of HF, irrespective of a normal left ventricular ejection fraction (LVEF) of ≥50%. More than half of all HF cases are considered HFpEF, driven by an abnormal ventricular filling from impaired relaxation due to increased myocardial stiffness. Ventricular-arterial uncoupling stemming from this increased myocardial stiffness results in increased LV filling pressure.³

HDL-cholesterol (HDL-C) has not previously been considered in guidelines as a contributor to HF rates, with very low and high levels of high-density HDL-C traditionally a lower indicator of cardiovascular disease (CVD). Sasko and colleagues suggested HDL function, rather than absolute HDL-C levels, could be a more accurate predictor of CVD risk, with prior research tying HDL function to an inverse association with CVD.³

Across this cross-sectional study, Sasko and colleagues evaluated HDL’s antioxidant function in a population with confirmed HFpEF, hypothesizing a reduced antioxidant function linked to the presence of HFpEF. A population of 366 consecutive patients presenting with symptoms of HF, including dyspnea, orthopnea, and fatigue, at a single center in Germany underwent assessment between 2019 and 2021.¹

Two cohorts were built based on the assessment: patients with HFpEF determined by LVEF ≥50%, echographic evidence of cardiac functional and structural alterations, and increased NT-proBNP levels (n = 88) and patients without HF, defined by LVEF ≥50% with normal range NT-proBNP levels (n = 180). Individuals with an LVEF < 50% (n = 98) were excluded from the study.

The study used a validated cell-free biochemical assay to determine reduced HDL antioxidant function as determined by increased HDL-lipid peroxide content (HDLox), normalized by HDLC levels, and the mean value of a pooled serum control from healthy participants (nHDLox).

Patients with HF were older than patients without HF (P <.001), with a higher proportion of females (P = .002) and more frequently dealing with diabetes (P = .002), atrial fibrillation (P <.001), and impaired renal function (P <.001). Investigators identified no differences in LV function between patients with HFpEF and those without HF.

Upon analysis, those with HFpEF had 15% higher mean relative levels of nHDLox than those patients without HF. A multivariate model analysis, adjusted for age, sex, and estimated glomerular filtration rate (eGFR), found nHDLox remained a significant risk factor for HFpEF (odds ratio [OR], 2.03; 95% CI, 1.19–3.45; P <.01).

Further multivariate analysis, adjusted for diabetes, hypertension, atrial fibrillation (AF), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP), and coronary artery disease (CAD), revealed nHDLox remained an independent predictor for HFpEF (P <.05). An increase in 1-SD in nHDLox was linked to a 67% elevated risk for HFpEF, compared with patients without heart failure (OR, 1.67; 95% CI, 1.07–2.6; P = .02).

Based on these data, Sasko and colleagues called for further studies to focus on the mechanistic impact of HDLox on the cardiomyocyte and endothelial function.¹

“It is plausible to hypothesize that the oxidation of HDL significantly contributes to the development of HFpEF and improving HDL function is a promising target for early heart failure treatment,” Sasko and colleagues added.¹ “However, further studies are needed, focusing on the mechanistic impact of HDL-lipid peroxide content on the cardiomyocyte and endothelial function.”

References

1. _{Sasko, B., Kelesidis, T., Kostin, S. et al. Reduced antioxidant high-density lipoprotein function in heart failure with preserved ejection fraction. Clin Res Cardiol (2025). https://doi.org/10.1007/s00392-024-02583-3}
2. _{Bozkurt B, Coats AJ, Tsutsui H, et al. Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. Published online March 1, 2021. doi:10.1016/j.cardfail.2021.01.022}
3. _{Mody P, Joshi PH, Khera A, Ayers CR, Rohatgi A. Beyond Coronary Calcification, Family History, and C-Reactive Protein: Cholesterol Efflux Capacity and Cardiovascular Risk Prediction. J Am Coll Cardiol. 2016;67(21):2480-2487. doi:10.1016/j.jacc.2016.03.538}