Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification.

OBJECTIVE: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1ß (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1ß mRNA, and increased Rac1-dependent IL-1ß protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1ß expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2). CONCLUSIONS: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1ß signaling axis.

Impact of Slice Thickness on the Predictive Value of Lung Cancer Screening Computed Tomography in the Evaluation of Coronary Artery Calcification.

Background Image reconstruction thickness may impact quantitative coronary artery calcium scoring (CACS) from lung cancer screening computed tomography (LCSCT), limiting its application in practice. Methods and Results We evaluated Agatston-based quantitative CACS from 1.25-mm LCSCT and cardiac computed tomography for agreement in 87 patients. We then evaluated Agatston-based quantitative CACS from 1.25-, 2.5-, and 5.0-mm slice thickness LCSCT for agreement in 258 patients. Secondary analysis included the impact of slice thickness on predictive value of 4-year outcomes. Median age of patients who underwent 1.25-mm LCSCT and cardiac computed tomography was 63 years (interquartile interval, 57, 68). CACS from 1.25-mm LCSCT and cardiac computed tomography demonstrated a strong Pearson correlation, R=0.9770 (0.965, 0.985), with good agreement. The receiver operating characteristic curve areas under the curve for cardiac computed tomography and LCSCT were comparable at 0.8364 (0.6628, 1.01) and 0.8208 (0.6431, 0.9985), respectively ( P=0.733). Median age of patients who underwent LCSCT with 3 slice thicknesses was 66 years (interquartile interval, 63, 73). Compared with CACS from 1.25-mm scans, CACS from 2.5- and 5.0-mm scans demonstrated strong Pearson correlations, R=0.9949 (0.9935, 0.996) and R=0.9478 (0.9338, 0.959), respectively, though bias was largely negative for 5.0-mm scans. Receiver operating characteristic curve areas under the curve for 1.25-, 2.5-, and 5.0-mm scans were comparable at 0.7040 (0.6307, 0.7772), 0.7063 (0.6327, 0.7799), and 0.7194 (0.6407, 0.7887), respectively ( P=0.6487). When using individualized high-risk thresholds derived from respective receiver operating characteristic curves, all slice thicknesses demonstrated similar prognostic value. Conclusions Slice thickness is an important consideration when interpreting Agatston CACS from LCSCTs. Despite the absence of ECG gating, it appears reasonable to report CACS from either 1.25- or 2.5-mm slice thickness LCSCT to help stratify cardiovascular risk. Conversely, 5.0-mm scans largely underidentify calcium, limiting practical use within the established CACS values used to categorize cardiovascular risk.