Dysfunctional HDL Diagnostic Metrics for Cardiovascular Disease Risk Stratification: Are we Ready to Implement in Clinics?

Epidemiological studies have revealed that patients with higher levels of high-density lipoprotein cholesterol (HDL-C) were more resistant to cardiovascular diseases (CVD), and yet targeting HDL for CVD prevention, risk assessment, and pharmacological management has not proven to be very effective. The mechanistic investigations have demonstrated that HDL exerts anti-atherogenic functions via mediating reverse cholesterol transport, antioxidant action, anti-inflammatory activity, and anti-thrombotic activity. Contrary to expectations, however, adverse cardiovascular events were reported in clinical trials of drugs that raised HDL levels. This has sparked a debate between HDL quantity and quality. Patients with atherosclerotic CVD are associated with dysfunctional HDL, and the degree of HDL dysfunction is correlated with the severity of the disease, independent of HDL-C levels. This growing body of evidence has underscored the need for integrating HDL functional assays in clinical practice for CVD risk management. Because HDL exerts diverse athero-protective functions, there is no single method for capturing HDL functionality. This review critically evaluates the various techniques currently being used for monitoring HDL functionality and discusses key structural changes in HDL indicative of dysfunctional HDL and the technical challenges that need to be addressed to enable the integration of HDL function-based metrics in clinical practice for CVD risk estimation and the development of newer therapies targeting HDL function.