High Serum Immunoglobulin G and M Levels Predict Freedom From Adverse Cardiovascular Events in Hypertension: A Nested Case-Control Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

Abstract

AimsWe aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination.Methods and ResultsThe Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5 years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80 [95% confidence interval, CI 0.72,0.89], p < 0.0001; IgM 0.83[0.75,0.93], p = 0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p < 0.0001, IgM OR 0.81 (0.71,0.93); p = 0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification (17.6% and 7.5% respectively) as well as in the integrated discrimination index.ConclusionHigh total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

“…In contrast to their role in mouse studies,28, 33 CD43 + B cells, suggested to resemble B1 cells in mice,15 did not associate with protection against secondary events in our study. Contrasting results have been reported for the association of serum IgM levels with primary cardiovascular events 51, 52, 53. In our study, patients with high numbers of unswitched memory cells expressed more IgM on their cell surface, suggesting an increased production and release of IgM antibodies.…”

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

“…High levels of IgM-type antibodies to MDA and phosphorylcholine reduce the risk for cardiovascular disease, [5][6][7] although not in all studies. 8,9 In contrast, IgG antibodies of similar specificity can in some cases be positively associated with disease 10 but more commonly show no association. 5,8,9 Recently, total serum IgG and IgM, in addition to oxLDL-specific, was associated with reduced risk of cardiovascular events.…”

“…8,9 In contrast, IgG antibodies of similar specificity can in some cases be positively associated with disease 10 but more commonly show no association. 5,8,9 Recently, total serum IgG and IgM, in addition to oxLDL-specific, was associated with reduced risk of cardiovascular events. 9 In mice, many studies suggest IgM antibodies provide an important atheroprotective layer.…”

“…5,8,9 Recently, total serum IgG and IgM, in addition to oxLDL-specific, was associated with reduced risk of cardiovascular events. 9 In mice, many studies suggest IgM antibodies provide an important atheroprotective layer. [11][12][13][14][15] The specific effect of deleting IgM antibodies (rather than B cells in general) was first addressed by Lewis et al 16 Mice lacking soluble IgM (but not B cell surface IgM or other isotypes of antibodies) have increased atherosclerosis.…”

Increased Plasma IgE Accelerate Atherosclerosis in Secreted IgM Deficiency

“…Indeed, both total IgM and MDA-LDL-specific IgM are inversely associated with cardiovascular disease complications in individuals of the AngloScandinavian Cardiac Outcomes Trial. 29 Interestingly, recent work indicates that IgE promote lupus like autoimmunity in mice 30 and that the presence of autoreactive IgE positively associates with disease activity in systemic lupus erythematosus (SLE) patients. 31 Notably, lupus-prone mice lacking sIgM develop enhanced autoimmune pathology compared with their controls.…”