Nonobstructive coronary artery disease as detected by 64-detector row cardiac computed tomographic angiography is associated with increased left ventricular mass.

BACKGROUND: Cardiac computed tomographic angiography (CCTA) permits simultaneous assessment of coronary artery disease (CAD) and left ventricular mass (LVM). While increased LVM predicts mortality and is associated with obstructive CAD, the relationship of LVM with non-obstructive CAD is unknown. METHODS: We evaluated 212 consecutive patients undergoing 64-detector row CCTA at 2 sites without evident cardiovascular disease or obstructive (≥70%) CAD by CCTA. LVM was measured by CCTA using Simpson's method of disks and indexed to body surface area (LVMI) and height to the allometric power of 2.7(LVM/ht2.7). CCTAs were evaluated by scoring a modified AHA 16-segment coronary artery model for none = 0 (0% stenosis), mild = 1 (1-49% stenosis) or moderate = 2 (50-69% stenosis). Overall CAD plaque burden was estimated by summing scores across all segments for a segment stenosis score (SSS, max = 32). RESULTS: The mean age was 53.3 ± 12.8 with 52% female, 48% hypertensive, and 7.4% diabetic. The mean LVM was 109 ± 32.5 g; 58.5% had any coronary artery plaque. In multivariable linear regression, SSS was significantly associated with increased LVM, LVMI and LVM/ht2.7. LVM increased by 2.0 g for every 1-point increase in SSS (95% CI 0.06-3.4, p = 0.006). Agatston scores provided no additional predictive value for increased LVM above and beyond SSS. CONCLUSION: Non-obstructive CAD visualized by CCTA is associated with increased LVM independent of effects of clinical risk factors and calcium scoring. Whether addition of LVM to stenosis assessment in patients undergoing CCTA enhances risk prediction of future CAD events warrants investigation.

Divergent members of a single autoreactive B cell clone retain specificity for apoptotic blebs.

Specificity for double-stranded DNA can arise due to somatic mutations within one of the branches of an autoreactive B cell clone. However, it is not known whether a different autospecificity predates anti-dsDNA and whether separate offshoots of an expanding B cell clone retain or evolve alternative specificities. We compared 3H9, an anti-dsDNA IgG, to 4H8 and 1A11, antibodies produced by hybridomas representing an alternative branch of the 3H9 B cell clone. All three IgG bound chromatin in ELISA and apoptotic cells in confocal microscopy, yet only 3H9 bound dsDNA, as measured by plasmon resonance. Moreover, we demonstrate that despite the unique specificity of 3H9 for dsDNA, all three clone members exhibited indistinguishable binding to chromatin. The binding to chromatin and apoptotic cells was unaffected by N-linked glycosylation in L chain CDR1, a modification that results from a replacement of serine 26 with asparagine in 4H8 and 1A11. These data provide the first evidence that specificity for nucleosome epitopes on apoptotic cells provides the initial positive stimulus for somatic variants that comprise a B cell clone, including those that subsequently acquire specificity for dsDNA. Conversely, selection of autoreactive B cells for binding to apoptotic cells leads to clonal expansion, antibody diversification, and the development of linked sets of anti-nuclear autoantibodies.

Atherosclerosis, antiphospholipid syndrome, and antiphospholipid antibodies.

In antiphospholipid syndrome (APS) patients, some antiphospholipid antibodies (APA) are directed against negatively-charged phospholipids, while other APA are specific for phospholipid-proteins such as beta2-glycoprotein I (beta2GPI). Increased levels of oxidized low density lipoproteins (oxLDL) are present in atherosclerosis patients and these patients develop anti-oxLDL antibodies. Several studies have reported cross-reactivities between APA and anti-oxLDL antibodies, and some authors have suggested that most APA are specific for oxidized forms of phospholipids. In contrast, other studies report that APA react with both reduced and oxidized cardiolipin. In this context, we have re-examined the literature surrounding antibodies found in atherosclerosis and the APS. We have also included results from a panel of anti-phospholipid monoclonal antibodies from W/B mice, an APS model, which indicates that these antibodies do not display any preference for oxidized epitopes on lipid molecules.

Antiphospholipid antibodies and atherosclerosis.

Antiphospholipid antibodies (APA) are present in a variety of autoimmune disorders, including systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Increasing evidence suggests that a subset of APA can also be detected in patients with atherosclerosis. In this review, we discuss the specificities of the autoantibodies that are present during both APS and atherosclerosis. A critical and unresolved question is whether these APA are specific for epitopes that result from lipid oxidation. Despite the fact that APA are present in patients with systemic autoimmunity and that they may participate in the pathogenesis of APS, recent studies have paradoxically proposed a beneficial role for some APA in atherosclerosis. We review the evidence that some APA specificities may be protective against plaque formation, and we discuss the putative mechanisms by which some APA could be useful in the prevention of atherosclerosis.

Reduction of atherosclerosis in low-density lipoprotein receptor-deficient mice by passive administration of antiphospholipid antibody.

OBJECTIVE: Patients with antiphospholipid syndrome (APS) are at a high risk of developing atherosclerotic complications. Conversely, individuals with primary atherosclerosis have an increased prevalence of antiphospholipid antibodies (aPL) and antibodies to oxidized low-density lipoproteins (ox-LDL). Several studies suggest that these two antibody populations may in fact overlap, although it is unclear how aPL contribute to pathogenesis. In this study, we characterized an IgG monoclonal aPL and assessed its ability to modulate atherosclerosis in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice. METHODS: The cardiolipin-reactive monoclonal antibody FB1 was obtained from an (NZW x BXSB)F(1) mouse, a strain with APS features that make it prone to fatal myocardial infarctions. Using an enzyme-linked immunosorbent assay, we investigated the binding of this antibody to phospholipid and LDL antigens. We also passively administered FB1 to atherosclerosis-prone mice to determine its effect on atherogenesis. RESULTS: In contrast to earlier studies of aPL that were specific for oxidized forms of LDL, FB1 cross-reacted with both native LDL and ox-LDL. In vivo, passive administration of FB1 significantly reduced plaque formation in atherosclerosis-prone LDLR(-/-) mice. CONCLUSION: These results indicate that some aPL may play a protective role in atherogenesis and suggest a novel approach to the prevention of atherosclerosis.