The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure

Current heart failure (HF) treatments target 2 main pathways, the renin-angiotensinaldosterone system and the sympathetic nervous system. The disease continues to have high morbidity/mortality and high health care costs, however and new approaches are required. Atherosclerosis progression is one potential pathway, but treatment with statins has not shown clear benefits. One interesting target for treatment of atherosclerosis is proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds to low density lipoprotein receptor (LDLR) on hepatocytes and enhances its degradation, resulting in reduced LDL-cholesterol clearance. Inhibition of PCSK9 can reduce atherosclerotic disease and cardiovascular events.

This study aimed to see if the PCSK9/LDLR axis is involved in and could be a therapeutic target for HF, using the large multinational BIOSAT-CHF prospective cohort. 2, 174 patients were included (mean age 68), with a median follow up time of 21 months. Two endpoints were examined; 1) all-cause mortality 2) a composite measurement of death or unscheduled hospitalization for HF. PCSK9 and LDLR levels were measured using the Olink CVD III panel. Multivariate analysis (standard BIOSAT-CHF risk score, LDLR and statin treatment) showed positive linear association between PCSK9 and mortality risk (p = 0.02), while a similar analysis showed a negative linear association of LDLR and mortality (p = 0.025). PCSK9, LDLR and statin treatment added value in performance over the standard BIOSTAT risk score. Similarly for the composite endpoint, PCSK9 showed a positive linear association with risk (p = 0.011). For this endpoint, however, LDLR only showed a borderline negative association with risk (p = 0.087).

This study is therefore the first to show that the PCSK9/LDLR axis is associated with poor outcome in HF patients. The two proteins exhibit linear risk associations that work in opposite directions, which is entirely logical in the context of their biological relationship. The authors conclude that the finding that PCSK9 predicts risk in HF could be the basis for further prospective studies designed to inhibit PCSK9 activity.

Note: In the study limitations section, they state “the assay used to measure PCSK9 and LDLR was designed for research only, and its use cannot be recommended in clinical practice”. They do qualify this, however, by saying “both exposures were measured with state-of-the-art proteomics technology, currently available and well validated”