PCSK9 Inhibitors May Harness Immune Mechanisms to Reduce Heart Disease Risks

PCSK9 inhibitors have been praised as a groundbreaking treatment that lowers high cholesterol to prevents cardiovascular disease.

A new study presented at the European Society of Cardiology Congress suggests that blocking PCSK9 may reduce atherosclerosis and heart disease by harnessing immune mechanisms that are unrelated to lowering cholesterol.

Atherosclerotic plaques contain both T cells and dendritic cells. Atherosclerosis is a chronic inflammatory condition, in which the immune cells may play a role in heart disease progression.

PCSK9 targets the LDL receptor for degradation, which is a mechanism used by PCSK9 inhibitors to lower LDL cholesterol levels. The goal of the new study was to assess how PCSK9 affects dendritic cell maturation and T cell activation by oxidized LDL, according to the authors.

In the study, the researchers isolated T cells from the carotid arteries of patients with atherosclerotic plaques who were undergoing a procedure to clear the plaque. T cells were also harvested from the peripheral blood of healthy control patients. Peripheral blood monocytes were then differentiated into dendritic cells.

The authors pretreated the dendritic cells with oxidized LDL and cultured with T cells from the plaques and blood. This allowed the researchers to examine the effects of PCSK9 inhibition on the immune cells, according to the study.

The investigators found that oxidized LDL promoted the maturation of dendritic cells, which facilitated the activation of T cells into helper T cells, according to the study.

Oxidized LDL was also found to induce PCKS9; however, its inhibition reversed the effects of the cholesterol on dendritic and T cells.

PCSK9 inhibition also diminished dendritic cell maturation and T cell activation, according to the study.

"We demonstrated for the first time that PCSK9 inhibition reversed the effects of oxidized [sic] LDL on immune activation,” said lead author Prof Johan Frostegård, MD, PhD. “This changed a pro-inflammatory profile into an anti-inflammatory state that is potentially anti-atherosclerotic."

These results suggest that PCSK9 inhibitors may provide patients with additional cardiovascular benefits than what is already known, according to the authors.

"Our study suggests that the benefits of PCSK9 inhibition extend beyond lowering LDL cholesterol,” Dr Frostegård said. “Here we show that PCSK9 inhibition has a novel immunological role in the maturation and activation of dendritic cells and T cells by oxidised [sic] LDL, a central player in atherosclerosis. This creates an anti-inflammatory state which may directly influence atherosclerosis and cardiovascular disease, independent of LDL-lowering."

While other lipid-lowering treatments also have anti-inflammatory effects, the pathways altered are different, suggesting different benefits, according to the study.

"Interestingly, statins also have anti-inflammatory and immune modulatory roles in addition to lipid lowering, although these are not exerted through the same mechanisms as those observed with PCSK9 inhibition," Dr Frostegård said.

To learn more about PCSK9 inhibitors and cardiovascular disease, visit the AJPB Insights page.