PCSK9: Associated with cardiac diseases and their risk factors?

PCSK9 plays a critical role in cholesterol metabolism via the PCSK9–LDLR axis. Liver-derived, circulating PCSK9 has become a novel drug target in lipid-lowering therapy. Accumulative evidence supports the possible association between PCSK9 and cardiac diseases and their risk factors. PCSK9 exerts various effects in the heart independently of LDL-cholesterol regulation. Acute myocardial infarction (AMI) induces local and systemic inflammation and reactive oxygen species generation, resulting in increased PCSK9 expression in hepatocytes and cardiomyocytes. PCSK9 upregulation promotes excessive autophagy and apoptosis in cardiomyocytes, thereby contributing to cardiac insufficiency. PCSK9 might also participate in the pathophysiology of heart failure by regulating fatty acid metabolism and cardiomyocyte contractility. It also promotes platelet activation and coagulation in patients with atrial fibrillation. PCSK9 is an independent predictor of aortic valve calcification and accelerates calcific aortic valve disease by regulating lipoprotein(a) catabolism. Accordingly, the use of PCSK9 inhibitors significantly reduced infarct sizes and arrhythmia and improves cardiac contractile function in a rat model of AMI. Circulating PCSK9 levels are positively correlated with age, diabetes mellitus, obesity, and hypertension. Here, we reviewed recent clinical and experimental studies exploring the association between PCSK9, cardiac diseases, and their related risk factors and aiming to identify possible underlying mechanisms.