PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction

PCSK9 is a protein secreted into the circulation, mainly by the liver which interacts with low-density lipoprotein (LDL) homologous and non-homologous receptors thus promoting their intracellular degradation. On this premise, PCSK9 inhibitors have been developed to target circulating PCSK9, increase hepatic LDL receptor expression, reduce LDL-cholesterol plasma levels and improve ischaemic heart disease.

Of note, genetic PCSK9 deficiency results in increased risk of developing diabetes or ectopic fat accumulation pointing to a role of PCSK9 in controlling cellular and tissue lipid metabolism beyond liver. This was shown to be critical for pancreatic beta cell function and we aimed to investigate whether PCSK9 could play a role in other organs that rely on lipids such as the heart which largely uses aerobic metabolism for its energetic needs, with the majority of ATP being produced following fatty acid (FA) oxidation. Unlike the liver, the heart is not able to synthesize high amounts of FAs and, therefore, FA demand is primarily supported by the uptake from the circulation, where FAs are transported either as free FAs bound to albumin or as triglycerides in lipoproteins.

It is worth noting that cardiac lipid demand is a finely tuned process that balances lipid uptake and mitochondrial beta-oxidation to support cardiac metabolism with the need to prevent excessive lipid accumulation which on the contrary induces cardiomyocyte dysfunction.

Factors influencing lipoprotein receptor expression, such as PCSK9, could therefore impact heart metabolism. We therefore extensively profiled heart function and morphology in PCSK9 deficient experimental models (Pcsk9 KO) and observed that they presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with heart lipid accumulation.

A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice and highlighting a role for PCSK9 in heart biology beyond the modulation of this lipoprotein receptor.

In both human and mice, circulating PCSK9, which modulates LDL-R expression in the liver and is the target of monoclonal antibody, is largely contributed by the liver. Therefore, to separate the effect of circulating vs. locally produced PCSK9 on heart function, we profiled cardiac function and heart morphology in mice lacking PCSK9 production selectively in the liver (AlbCre+/Pcsk9^LoxP/LoxP mice) and therefore deficient for PCSK9 only in the circulation. In spite of a dramatic reduction in plasma cholesterol levels, heart morphology and function of these mice was not different from that of WT counterparts excluding a role for the deficiency of liver-produced (i.e. circulating) PCSK9 in the phenotype observed, rather pointing to locally produced PCSK9 deficiency as a driver of heart dysfunction.

Concordantly, human carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects.

In summary these findings highlight that PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF. Which are the translational implications of this observation? As PCSK9 inhibitors improve lipid metabolism by targeting circulating PCSK9, our finding supports the safety profile emerged so far with therapies targeting PCSK9, which are directed towards liver-derived circulating PCSK9.

While our findings excluded a role for circulating PCSK9 on the phenotype observed, a final confirmation for a selective role for PCSK9 in the heart should be determined in heart selective KO models. Similarly, the characterization of Pcsk9/CD36 DKO will be of help to investigate whether PCSK9 production following cardiac stress might represent a feedback mechanism contributing to maintain a proper balance between heart lipid uptake and lipid accumulation, thus limiting potential side effects of heart lipotoxicity.