Does low HDL cholesterol increase cardiovascular risk?

Low high-density lipoprotein cholesterol (HDL-C) is a well-established marker for cardiovascular disease (CVD), particularly in older adults. For a 74-year-old male, maintaining adequate HDL levels is a significant factor in vascular health and long-term prognosis.

Clinical association with cardiovascular risk

Epidemiological data consistently demonstrate that low HDL-C levels significantly elevate the risk of major cardiovascular events and all-cause mortality. In elderly cohorts, individuals in the lowest HDL-C quartile (typically <1.1 mmol/L) have shown hazard ratios (HR) as high as 3.2 for ischemic heart disease compared to those with higher levels. In older men specifically, levels below 40 mg/dL correlate with a poor prognosis. While clinical focus has shifted from HDL-C as a direct therapeutic target to its role as a global risk marker, its predictive value remains high. Notably, some research suggests a U-shaped relationship where extremely high HDL-C may also be associated with increased risk, though low levels remain a primary concern for atherosclerosis progression.

Mechanistic pathways

The protective role of HDL is driven by its function in reverse cholesterol transport (RCT) and pleiotropic vascular maintenance:

• Reverse Cholesterol Transport: HDL initiates cholesterol removal from the arterial wall via the ABCA1 transporter, which facilitates cholesterol efflux from macrophage foam cells to lipid-free apolipoprotein A-I (apoA-I). These particles then mature and transport the cholesterol to the liver for biliary excretion.
• Anti-inflammatory and Anti-oxidative Actions: HDL carries the enzyme Paraoxonase 1 (PON1), which protects against LDL oxidation by hydrolyzing pro-inflammatory oxidized phospholipids. This action reduces the expression of adhesion molecules like VCAM-1 on the endothelium, effectively dampening vascular inflammation and preventing plaque destabilization.

Bottom line

• Low HDL-C levels are strongly linked to increased cardiovascular risk due to impaired cholesterol removal and the loss of enzymatic vascular protection, making HDL quality and efflux capacity essential markers of arterial health.