Long-term statin therapy is associated with severe coronary artery calcification.

BACKGROUND: Atherosclerosis and consequent risk of cardiovascular events or mortality can be accurately assessed by quantifying coronary artery calcium score (CACS) derived from computed tomography. HMG-CoA-reductase inhibitors (statins) are the primary pharmacotherapy used to reduce cardiovascular events, yet there is growing data that support statin use may increase coronary calcification. We set out to determine the likelihood of severe CACS in the context of chronic statin therapy. METHODS: We established a retrospective, case-control study of 1,181 U.S. veterans without coronary artery disease (CAD) from a single site, the Providence VA Medical Center. Duration of statin therapy for primary prevention was divided into 5-year categorical increments. The primary outcome was CACS derived from low-dose lung cancer screening computed tomography (LCSCT), stratified by CACs severity (none = 0; mild = 1-99; moderate = 100-399; and severe ≥400 AU). Statin duration of zero served as the referent control. Ordinal logistic regression analysis determined the association between duration of statin use and CACS categories. Proportional odds assumption was tested using likelihood ratio test. Atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index, and CKD (glomerular filtration rate of <60 ml/min/1.73 m2) were included in the adjustment models. RESULTS: The mean age of the study population was 64.7±7.2 years, and 706 (60%) patients were prescribed a statin at baseline. Duration of statin therapy was associated with greater odds of having increased CACS (>0-5 years, OR: 1.71 [CI: 1.34-2.18], p<0.001; >5-10 years, OR: 2.80 [CI: 2.01-3.90], p<0.001; >10 years, OR: 5.30 [CI: 3.23-8.70], p<0.001), and the relationship between statin duration and CACS remained significant after multivariate adjustment (>0-5 years, OR: 1.49 [CI: 1.16-1.92], p = 0.002; >5-10 years, OR: 2.38 [CI: 1.7-3.35], p<0.001; >10 years, OR: 4.48 [CI: 2.7-7.43], p<0.001). CONCLUSIONS: Long-term use of statins is associated with increased likelihood of severe CACS in patients with significant smoking history. The use of CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.

Aortic Valve Calcification Is Associated with Future Cognitive Impairment.

BACKGROUND: While an association between atherosclerosis and dementia has been identified, few studies have assessed the longitudinal relationship between aortic valve calcification (AVC) and cognitive impairment (CI). OBJECTIVE: We sought to determine whether AVC derived from lung cancer screening CT (LCSCT) was associated with CI in a moderate-to-high atherosclerotic risk cohort. METHODS: This was a single site, retrospective analysis of 1401 U.S. veterans (65 years [IQI: 61, 68] years; 97%male) who underwent quantification of AVC from LCSCT indicated for smoking history. The primary outcome was new diagnosis of CI identified by objective testing (Mini-Mental Status Exam or Montreal Cognitive Assessment) or by ICD coding. Time-to-event analysis was carried out using AVC as a continuous variable. RESULTS: Over 5 years, 110 patients (8%) were diagnosed with CI. AVC was associated with new diagnosis of CI using 3 Models for adjustment: 1) age (HR: 1.104; CI: 1.023-1.191; p = 0.011); 2) Model 1 plus hypertension, hyperlipidemia, diabetes, CKD stage 3 or higher (glomerular filtration rate < 60 mL/min) and CAD (HR: 1.097; CI: 1.014-1.186; p = 0.020); and 3) Model 2 plus CVA (HR: 1.094; CI: 1.011-1.182; p = 0.024). Sensitivity analysis demonstrated that the association between AVC and new diagnosis of CI remained significant upon exclusion of severe AVC (HR: 1.100 [1.013-1.194]; p = 0.023). Subgroup analysis demonstrated that this association remained significant when including education in the multivariate analysis (HR: 1.127 [1.030-1.233]; p = 0.009). CONCLUSION: This is the first study demonstrating that among mostly male individuals who underwent LCSCT, quantified aortic valve calcification is associated with new diagnosis of CI.

Aortic valve calcification predicts all-cause mortality independent of coronary calcification and severe stenosis.

BACKGROUND AND AIMS: Calcific aortic valve disease is highly prevalent in patients with significant smoking history and is a marker of atherosclerosis. The aim of this study was to define the prognostic value of aortic valve calcification (AVC) derived from low dose, lung cancer screening computed tomography (LCSCT) for all-cause mortality in this higher risk population. METHODS: This is a single site, retrospective analysis of 1529 moderate-to-high atherosclerotic cardiovascular risk U.S. veterans (65 years [IQI: 61, 68] years; 96% male), who underwent clinically indicated LCSCT. CTs were scored for aortic valve calcification (AVC) and coronary artery calcification (CAC). The primary endpoint was all-cause mortality and secondary endpoints were nonfatal myocardial infarction (MI) and nonfatal cerebrovascular accident (CVA). RESULTS: Over 4-year follow-up, 227 patients (15%) died, 112 patients (7%) had nonfatal MI, and 52 patients (3%) had nonfatal CVA. AVC was predictive of all-cause mortality (HR per 100: 1.041 [1.030-1.052], p < 0.001), and this association remained significant after multivariate adjustment for traditional atherosclerotic risk factors, including CAC (1.021 [1.007-1.036], p = 0.003). After excluding patients with severe aortic stenosis (AS) or severe AVC (≥1274 AU in women and ≥2065 AU in men), in a subset of 765 patients who had echocardiograms, this association remained significant after multivariate analysis (HR per 100: 1.052 [1.010-1.095], p = 0.014). Despite controlling for CAC in the models, AVC was still associated with MI (HR per 100: 1.021 [1.004-1.039], p = 0.017) and with CVA (HR per 100: 1.027 [1.002-1.051], p = 0.032). CONCLUSIONS: Scoring AVC derived from LCSCT is predictive of mortality, nonfatal MI, and nonfatal CVA in patients at known risk for cardiovascular disease, independent of coronary calcification or severe aortic valve stenosis.

Takotsubo cardiomyopathy and acute manic attack.

Takotsubo cardiomyopathy predominantly occurs in women, with a high incidence in patients with psychiatric diseases. We present a 64-year-old white woman with an acute manic episode complicated by rhabdomyolysis and takotsubo cardiomyopathy.

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.