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 5.5years 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.
Highlights
Efforts to improve the predictive capacity of existing cardiovascular risk-scoring models have been intense and have included the study of both novel blood and imaging biomarkers (Hoefer et al, 2015)
A previous study found that serum IgG but not IgM was associated with a higher risk of myocardial infarction in dyslipidemic patients (Kovanen et al, 1998), whilst another failed to show any association between IgG or IgM and risk of myocardial infarction in a general population (Muscari et al, 1995)
In the Bruneck study, IgG antibodies against copper-oxidized low-density lipoprotein (LDL) were associated with higher risk of CV events, whilst IgM antibodies were associated with lower risk (Rosenfeld et al, 1990; Tsimikas et al, 2012)
Summary
Efforts to improve the predictive capacity of existing cardiovascular risk-scoring models have been intense and have included the study of both novel blood and imaging biomarkers (Hoefer et al, 2015). The roles of specific antibodies as biomarkers in atherosclerosis have been more extensively studied These include antibodies directed against epitopes induced by oxidative modifications of low-density lipoprotein (LDL), in particular antibodies reacting with phosphorylcholine or adducted malondialdehyde (MDA), as well as many less well-defined epitopes (Leibundgut et al, 2013; Tsiantoulas et al, 2014). In the Bruneck study, IgG antibodies against copper-oxidized LDL (heavily-oxidized LDL that includes MDA-LDL epitopes) were associated with higher risk of CV events, whilst IgM antibodies were associated with lower risk (Rosenfeld et al, 1990; Tsimikas et al, 2012). The EPIC Norfolk study implicated IgG and IgM anti-MDA-LDL antibodies as possible modifiers of the risk associated with oxidative biomarkers, rather than independent predictors of coronary artery disease events (Ravandi et al, 2011). A study from Sweden has reported that individuals with low levels of antibodies against MDA-adducted LDL peptides are associated with significantly higher coronary acute event rate (Bjorkbacka et al, 2016)
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