The Role of HDL-C Levels in Cardioprotection: 5 Things to Know

High-density lipoprotein cholesterol (HDL-C), the "good cholesterol," transports cholesterol from the arteries to the liver for elimination. Previous studies have demonstrated an association between higher HDL-C and lower cardiovascular (CV) risk. Epidemiologic studies reported CV disease (CVD) reductions of around 2%-3% for every unit rise in HDL-C level. However, a recently published prospective, multicenter, cohort study found that very high levels of HDL-C (> 80 mg/dL [> 2.069 mmol/L]) were associated with adverse outcomes in patients with coronary heart disease (CHD), suggesting that hyperalphalipoproteinemia (HALP) can negatively affect CV mortality.

Here are five things about the role of HDL-C and the potential negative impact of HALP on CV health.

1. HDL-C is essential for lipid homeostasis.

HDL-C comprises various particles that differ in size, density, electrophoretic mobility, and apolipoprotein (Apo) content. ApoA-I and ApoA-II, the two major HDL-C apolipoproteins, are essential for normal HDL-C biosynthesis. ApoA-I constitutes about 70% of HDL-C protein while ApoA-II constitutes about 20%. The multiple proteins and lipids that comprise HDL-C not only assist in lipid metabolism but also play a role in acute-phase response, complement regulation, and proteinase inhibition. HDL-C plays an integral role in reverse cholesterol transport by removing excess cholesterol from peripheral vessels and transporting it back to the liver for elimination. It also has important anti-inflammatory, cytoprotective, antithrombotic, and antioxidative functions, inhibits the expression of adhesion molecules in endothelial cells, and increases the production of the atheroprotective signaling molecule nitric oxide.

2. Several factors can impair HDL-C functionality.

In addition to ApoA-I and ApoA-II, HDL-C comprises several other proteins, including ApoC-III, ApoC-II, ApoC-I, ApoL, APOE, lecithin-cholesterol acyltransferase, Apo-J, platelet-activating factor acetylhydrolase, and serum paraoxonase-1. An acute-phase response (eg, to infection, inflammation, trauma) can alter plasma proteins in HDL-C, converting HDL-C from an anti-inflammatory to a proinflammatory particle. A study on human smooth muscle and aortic endothelial cells found that HDL-C levels of patients before cardiac surgery inhibited the low-density lipoprotein (LDL)-induced increase in monocyte transmigration. However, HDL-C levels obtained 2-3 days after surgery did not inhibit monocyte transmigration but rather increased it up to 1.8-fold. Further, glycation and protein carbamylation may impair HDL-C function and reduce its antiatherogenic effects.

Ethnicity and dietary patterns can also affect HDL-C functionality. For example, a study by Woudberg and colleagues found higher HDL-C antioxidant functionality and increased protection against CHD — irrespective of lower circulating HDL-C levels and higher obesity — in Black South African women as compared with White women. Regarding dietary habits, saturated fat intake has been shown to reduce the anti-inflammatory properties of HDL-C and impair arterial endothelial function.

3. Understanding HDL-C levels can be effective in assessment of CVD risk.

Most studies have shown that reducing LDL-C with statin monotherapy and/or with ezetimibe can lower the number of CV events and that HDL-C plays an important, beneficial role in CV morbidity and mortality. A study by Ko and associates reported increased risk for death in patients with low HDL-C (< 40 mg/dL [< 1.0344 mmol/L] in men and < 50 mg/dL [< 1.293 mmol/L] in women) or very high HDL-C levels (> 80-90 mg/dL [> 2.069-2.3274 mmol/L]) compared with patients with moderate HDL-C levels. While other studies showed that HDL-C levels higher than around 60 mg/dL (1.5516 mmol/L) did not further improve CVD prognosis, other trials, including EPIC and IDEAL, found that while low HDL-C is a predictor of increased CVD risk, very high HDL-C may also lead to adverse outcomes.

4. Several factors are associated with high HDL-C levels.

Factors contributing to HALP include genetic mutations in cholesteryl ester transfer protein (CETP), hepatic lipase, endothelial lipase, and scavenger receptor class B type I (SR-B1). Cholesteryl ester transfer protein is associated with the transportation of triglyceride from very low-density lipoproteins (VLDLs)/chylomicrons to HDL-C and (LDL-C along with cholesteryl esters from HDL-C to VLDLs/chylomicrons. In Japan, which has the highest prevalence of primary HALP, studies found CETP deficiency of around 60% and 31% among patients with high and very high levels of HDL-C, respectively.

Some clinical trials over the past few decades have focused on deficiency in hepatic lipase, a heparan-sulfate proteoglycan-bound lipolytic enzyme associated with HDL-C and triglyceride metabolism that can increase HDL-C size and affect HDL-C function in the reverse cholesterol transport process, in turn increasing the risk for premature CVD. Endothelial lipase is mainly associated with HDL-C phospholipid hydrolysis and can negatively affect HDL-C metabolism. In addition, studies show that SR-B1, a receptor for HDL-C that regulates the uptake of cholesterol esters by HDL-C, increased atherosclerosis and plasma HDL-C levels and impaired liver cholesterol transfer in SR-B1 knockout mice.

5. The focus of lipid studies has shifted to further evaluate the CV risks associated with very high HDL-C.

Very high HDL-C levels may result in abnormally large dysfunctional HDL-C particles that have the potential to become trapped in the arterial intima, promoting deposition of cholesterol and increasing CVD risk. More studies need to be carried out to confirm such findings. Some clinical trials over the past few decades have focused on targeting HDL-C to reduce CVD risk. These studies mostly used niacin, statins, fibrates, and other drugs to increase HDL-C levels. Most of these clinical trials (HATS, AIM-HIGH, ARBITER-2, HPS2-THRIVE, CLAS, and CDP) found that increasing HDL-C had no significant impact on CV events or outcomes, although studies on naturally occurring high HDL-C are yet to be done. A few trials that evaluate cardioprotection based on improving HDL-C functions or increasing specific HDL-C subclasses are underway. Targeting HDL-C function and quality can be an effective strategy to understand mechanisms related to CV protection, which in turn can lead to the development of newer therapies to prevent CVD.

Follow Medscape on Facebook, X (formerly known as Twitter), Instagram, and YouTube

© 2023 American College of Cardiology & Medscape

Cite this: The Role of HDL-C Levels in Cardioprotection: 5 Things to Know - Medscape - Dec 11, 2023.