Conference Coverage

Low HDL Cholesterol Linked to Higher Risk of HFpEF in Middle Age

Kate Young

Key Highlights

  • Middle-aged adults with low HDL-C (<5 0 mg/dL) had a 33% higher risk of developing HFpEF over 20 years.
  • The association persisted across sexes and after adjusting for comorbidities and lipid profiles.
  • Findings suggest incorporating HDL-C into heart failure risk prediction models.

New data presented at the American Heart Association (AHA) Scientific Sessions reveal that low high-density lipoprotein cholesterol (HDL-C) levels in middle-aged adults are independently associated with an increased long-term risk of developing heart failure with preserved ejection fraction (HFpEF). The study, conducted by researchers at West Virginia University, analyzed two decades of electronic health record data to clarify HDL-C’s role in HFpEF pathogenesis.

Study Findings

Investigators, led by Zulkifl Ishaq Jafary, MD, and colleagues performed a retrospective cohort analysis using the TriNetX global network of de-identified electronic health records. Adults aged around 49 years who had HDL-C levels recorded between January 2005 and April 2006 were included, provided they had no baseline ischemic heart disease (IHD) or heart failure (HF).

After propensity score matching for demographics, comorbidities, and lipid profiles, 224,412 individuals were analyzed (112,206 in each HDL-C group: < 50 mg/dL vs. 50–80 mg/dL). Over 20 years, those with low HDL-C had a significantly higher incidence of HFpEF (hazard ratio [HR], 1.33; 95% CI, 1.29–1.38; P < .01). Kaplan–Meier curves showed early divergence that widened over time, suggesting a sustained impact of HDL-C on HF risk.

Subgroup analyses showed consistency across sex: males (HR, 1.29; 95% CI, 1.23–1.36) and females (HR, 1.35; 95% CI, 1.29–1.41) both demonstrated higher HFpEF risk with low HDL-C. Patients with lower HDL-C also displayed a more atherogenic lipid pattern, including elevated triglycerides and reduced LDL-C and total cholesterol.

Clinical Implications

These results highlight HDL-C as a potential biomarker for identifying individuals at risk of developing HFpEF—an increasingly prevalent condition that accounts for more than half of all heart failure cases. While HDL-C has long been associated with vascular protection and endothelial health, this study indicates that lower HDL-C levels in middle age are independently linked to higher long-term HFpEF risk.

The findings also align with the study’s background discussion, which notes emerging interest in HDL particle number and functionality as additional markers of cardiovascular risk. Incorporating HDL-C into existing heart failure risk models may enhance early identification of at-risk individuals and guide preventive strategies.

Expert Commentary

“Low HDL-C in middle-aged adults was associated with a higher long-term HFpEF risk, regardless of sex or baseline cardiovascular comorbidities,” Dr Zulkifl Ishaq Jafary and colleagues concluded. “This independent relationship suggests HDL-C may reflect vascular and myocardial vulnerability beyond traditional risk factors.”

The study provides evidence that HDL-C plays a role in HFpEF development over the long term. Integrating HDL-C into preventive cardiology assessments may enhance early detection and improve management strategies for patients at risk of heart failure with preserved ejection fraction.

Reference
Jafary ZI, Rana S, Murshid A, Watson H, Alruwaili W. Association of high-density lipoprotein cholesterol in middle-aged adults and development of heart failure with preserved ejection fraction later in life. Presented at: American Heart Association Scientific Sessions; November 8, 2025; Chicago, IL.