Barbara Radovani

Chronological age dominates cardiovascular (CVD) risk prediction, but glycan-based measures may better reflect biological ageing. In this secondary analysis of a six-month randomized controlled trial in Slovenia, we examined whether IgG glycosylation–derived biological age (GlycanAge) tracked short-term changes in estimated CVD risk. Adults without diagnosed CVD but with at least one risk factor (119 enrolled; 101 completed the final assessment) received digital risk visualization, continuous glucose monitoring, their combination, or usual care. SCORE2 showed small numerical changes in some intervention groups, but GlycanAge remained largely stable, with only modest and inconsistent change across groups, and no association between change in SCORE2 and change in the GlycanAge–chronological age gap was detectable. Over this short timeframe, GlycanAge did not behave as a surrogate of conventional risk modification; whether it instead reflects slower immune-inflammatory ageing processes complementary to established CVD risk algorithms will require longer studies to establish.

Background/Objective: Immunoglobulin G (IgG) N-glycosylation is an important regulator of immune function and systemic inflammation and has been associated with cardiometabolic diseases. However, little is known about how IgG glycosylation changes during the course of acute coronary syndrome (ACS) and whether these alterations relate to lipid-lowering response after the initiation of statin therapy. The primary aim of this study was to investigate IgG N-glycosylation following ACS and evaluate its association with response to atorvastatin therapy defined as baseline LDL cholesterol reduction of ≥50%. Methods: In this prospective cohort study, 79 statin-naïve patients hospitalized for the first episode of ACS and treated with atorvastatin 80 mg daily after percutaneous coronary intervention were followed longitudinally. Plasma samples were collected at admission (acute phase), discharge (subacute phase), and follow-up (chronic phase). A control group of 21 individuals received atorvastatin for primary prevention. IgG was isolated from plasma, and N-glycans were released, fluorescently labeled with 2-aminobenzamide, and analyzed using hydrophilic interaction-based ultra-high-performance liquid chromatography with fluorescence detection. Derived glycan traits were calculated, including agalactosylated (G0), monogalactosylated (G1), digalactosylated (G2), core fucosylated (F), bisected (B), and sialylated (S) glycans. Results: No significant differences in derived IgG glycan traits were observed between ACS patients and controls at baseline or follow-up. Within the ACS group, a longitudinal analysis revealed significant increases in G0 and F and a decrease in G2 between the acute and chronic phases. A total of 65% of patients achieved ≥50% reduction in LDL cholesterol (LDL-C), whereas only 22% reached the guideline-recommended LDL-C target of 3.9 mmol/L, those who failed to achieve ≥50% LDL-C reduction had significantly lower G0 and higher S across all time points. Conclusions: Specific glycan traits are associated with the degree of LDL-C reduction achieved during statin therapy, particularly in patients with high baseline LDL-C. These findings suggest that IgG glycosylation patterns may reflect biological phenotypes associated with differential lipid-lowering responsiveness after ACS.

Cardiovascular diseases (CVD) are the leading cause of death globally, with coronary artery disease (CAD) as the most prevalent single cause. While previous studies, including our own, have highlighted the role of immunoglobulin G (IgG) glycosylation in CAD, the present study uniquely investigates the total plasma protein N-glycome as a potential biomarker of CAD. In this cross-sectional study, we analyzed total plasma protein N-glycans from three independent study populations using ultra-high-performance liquid chromatography with fluorescence detection (HILIC-UHPLC-FLR). Meta-analysis revealed significant glycan alterations in individuals with coronary atherosclerosis compared to individuals without CAD. Specifically, highly branched, complex N-glycans (triantennary and sialylated glycans) were significantly increased in CAD+ cases (Effect = 0.193, SE = 0.0761, p_adj = 0.0358), while monogalactosylated (Effect = -0.2464, SE = 0.0768, p_adj = 0.00814) and core fucosylated glycans (Effect = -0.2025, SE = 0.0818, p_adj = 0.0358) were significantly decreased. These changes suggest an increased presence of acute-phase glycoproteins and systemic inflammation in CAD+ individuals. Our findings demonstrate that CAD-associated glycomic alterations are not confined to IgG but are present across the total plasma protein glycome, providing a broader molecular view of disease-associated glycosylation changes. Future studies should explore the integration of plasma glycan signatures with other inflammatory and metabolic markers to refine CAD risk stratification strategies.

The family of IgG Abs is a crucial component of adaptive immunity. Glycosylation of IgG maintains its structural integrity and modulates its effector functions. In this review, we discuss IgG glycosylation covering cell biological as well as therapeutic and disease-related aspects, focusing on the glycan structures in distinct IgG regions (Fab versus Fc). We also cover the impact of IgG glycosylation on disease modulation and therapeutic outcomes, alongside the potential for development of vaccines designed to induce Ag-specific IgG with glycoforms for optimal immune responses. Overall, we emphasize the significance of studying glycosylation to enhance our understanding of the dynamics and functional impacts of IgG glycosylation. These insights could be beneficial for advancing future research and clinical applications.

Immunoglobulin G (IgG) is the most abundant antibody in the blood and plays a critical role in host immune defense against infectious agents. Glycosylation is known to modulate the effector functions of IgG and is involved in disease development and progression. It is no surprise that the N-glycome of IgG from plasma has already been proposed as a biomarker for various physiological and pathological conditions. However, because saliva is easy to collect, it could be useful for exploring the functional role of salivary IgG N-glycosylation and its potential as a diagnostic biomarker. Therefore, in this study, we described a method for N-glycome analysis of IgG from saliva samples. Salivary IgG N-glycans were analyzed by ultra-high-performance liquid chromatography based on hydrophilic interactions with fluorescence detection (HILIC-UHPLC-FLR). In addition, we compared IgG N-glycan profiles from saliva with those from plasma, assessed the stability of salivary IgG N-glycan profiles under different storage conditions, and evaluated the effects of using a saliva preservation medium. This study provides an ultrasensitive UHPLC method for the analysis of total IgG N-glycosylation from saliva, gives insight into storage stability of salivary IgG, and highlights its (dis)advantages for further biomarker-related research. Graphical Abstract

Coronary artery disease (CAD) is the most common cardiovascular disease (CVD), and previous studies have shown a significant association between N-glycosylation, a highly regulated posttranslational modification, and the development of atherosclerotic plaques. Our aim was to determine whether the N-glycome of immunoglobulin G (IgG) is associated with CAD, as N-glycans are known to alter the effector functions of IgG, which may enhance the inflammatory response in CAD. Therefore, in this study, we isolated IgG from subjects with coronary atherosclerosis (CAD+) and from subjects with clean coronaries (CAD−). The purified IgGs were denatured and enzymatically deglycosylated, and the released and fluorescently labelled N-glycans were analysed by ultra-high performance liquid chromatography based on hydrophilic interactions with fluorescence detection (HILIC-UHPLC-FLR). Sex-stratified analysis of 316 CAD− and 156 CAD+ cases revealed differences in IgG N-glycome composition. The most notable differences were observed in women, where the presence of sialylated N-glycan structures was negatively associated with CAD. The obtained chromatograms provide insight into the IgG N-glycome composition in CAD as well as the biomarker potential of IgG N-glycans in CAD.