PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function

Abstract

Background and objectives: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of CKD patients are limited. Design, setting, participants, and measurements: The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5,138 Caucasians of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 mL/min/1.73 m2 or an eGFR>60 mL/min/1.73m2 in the presence of overt proteinuria (urine albumin-creatinine ratio >300mg/g or equivalent). Prevalent cardiovascular disease was defined as history of non-fatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute non-fatal myocardial infarction and non-fatal stroke. Results: Median PCSK9 concentration in the cohort was 285 ng/mL (interquartile range 231-346 ng/mL). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100 ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1,284) was 1.22-fold (95%CI 1.12-1.34, p<0.001) higher in a model with extended adjustment for major confounders. This association was stronger in non-statin than statin-users (p-value for interaction=0.009). During follow-up 474 individuals experienced a major adverse cardiovascular disease event and participants in PCSK9 quartiles 2 to 4 had a 32%-47% higher risk compared to quartile 1 (p<0.05). Subgroup analysis revealed this association was restricted to those participants who already had cardiovascular disease at baseline (all HR>1.75, p<0.05). In addition, PCSK9 showed a valuable gain in classification accuracy both for prevalent cardiovascular disease (NRI=0.27, 95%CI:0.20-0.33) and incident major adverse cardiovascular disease events during follow-up (NRI=0.10, 95%CI:0.008-0.21) when added to an extended adjustment model. Conclusions: Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria, but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors including LDL-cholesterol levels.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) as a marker of coronary lesion severity in stable coronary artery disease (CAD) patients

“…The patients also had high total cholesterol, low HDL, and high LDL (211.71 mg/dL, 38.57 mg/dL, and 134.29 mg/dL respectively). These results was in accordance with a previous study where in patients with the same population, abnormal total cholesterol, LDL, and HDL values were found [ 30 ].…”

Immune-Related Genes and Immune Cell Infiltration Characterize the Maturation Status of Arteriovenous Fistulas: An Integrative Bioinformatics Study and Experimental Validation Based on Transcriptome Sequencing

“…It may be a viable treatment option to use PCSK9 inhibitors, which have a cardiovascular protective effect, to promote VEGFA expression while mitigating the pro-inflammatory effects of high IL1B. 33,34 Further studies are needed to confirm the role of IL1B in the maturation of arteriovenous fistula.…”

Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

“…In a previous prospective study involving 5,138 individuals with chronic kidney disease, elevated levels of PCSK9 were shown to be associated with an increased risk of cardiovascular disease ( 123 ). Despite an increase in PCSK9 levels in cases of nephrotic syndrome, no association was found with the estimated glomerular filtration rate ( 124 ).…”