Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance

Abstract

Background: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk.

Results: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9.

Conclusions: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

Keywords: Beck Depression Inventory; Cardiovascular risk; Depression; Framingham risk score; Obesity; Proprotein Converatse Subtilisin/Kexin type 9.

Fig. 1

Distribution of fasting plasma concentrations of PCSK9 levels (ng/mL; panel a) and HOMA-IR (panel b) in 389 individuals. Data are presented as histograms and box-plots. PCSK9 is normally distributed, whereas HOMA-IR shows a skewed distribution. PCSK9 pro-protein convertase subtilisin/kexin type 9, HOMA-IR homeostasis model assessment of insulin resistance. Min minimun, Max maximum, SD standard deviation

Fig. 2

Scatterplots with regression line and confidence interval. Panel a—Association between severity of depression (BDI-II) and PCSK9. ∆ % represents the percentage increase in PCSK9 for one-unit increase in BDI-II score. Panel b–Association between PCSK9 and HOMA-IR on natural logarithmic scale, adjusted also for BDI-II. ∆ % represents the percentage increase in HOMA-IR for 100 ng/ml increase in PCSK9 concentration. Panel c—Association between severity of depression (BDI-II) and HOMA-IR on natural logarithmic scale. ∆ % represents the percentage increase in HOMA-IR for one-unit increase in BDI-II score. BDI Beck Depression Inventory, HOMA-IR homeostasis model assessment of insulin resistance, PCSK9 pro-protein convertase subtilisin/kexin type 9. Beta regression coefficients of panel a and b were used to estimate indirect effect of BDI-II on HOMA-IR

Fig. 3

Conceptual diagram of causal mediation analysis, that hypothesized mechanism linking BDI-II and HOMA-IR. The solid black arrow represents the effect of BDI-II on HOMA-IR levels that operates directly or through a pathway different from the mediator analyzed in the current study (PCSK9). The dotted black arrows represent the suggested alternative pathway, where an indirect effect of BDI-II on HOMA-IR is mediated by PCSK9 levels. The black thin arrows indicate increased levels of HOMA-IR. BDI Beck Depression Inventory, HOMA-IR homeostasis model assessment of insulin resistance, PCSK9 pro-protein convertase subtilisin kexin type 9