Social defeat stress exacerbates atopic dermatitis through downregulation of DNA methyltransferase 1 and upregulation of C-C motif chemokine receptor 7 in skin dendritic cells.

DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.

MicroRNA-766-3p Contributes to Anti-Inflammatory Responses through the Indirect Inhibition of NF-κB Signaling.

MicroRNA (miRNA) is small RNA of 20 to 22 nucleotides in length and is stably present in plasma. Regulating the expression of miRNA taken into cells has been suggested as a general therapeutic approach. We identified the novel anti-inflammatory miRNA hsa-miR-766-3p and investigated its biological function in human rheumatoid arthritis (RA) fibroblast-like synoviocyte MH7A cells. To verify the function of the miRNA present in the plasma of RA patients, we performed a comprehensive analysis of the miRNA expression during abatacept treatment and identified eight miRNAs with significantly altered expression levels. Among these eight miRNAs, miR-766-3p was found to have a clear function. The expression of inflammatory genes in response to inflammatory stimuli was suppressed in MH7A transduced with miR-766-3p. We showed that miR-766-3p indirectly reduced the activation of NF-κB and clarified that this mechanism was partially involved in the reduction of the mineralocorticoid receptor expression. In addition, the inflammatory responses were suppressed in other types of cells. These results indicate the novel function of miR-766-3p, findings that may aid in the development of therapies to suppress inflammation, not only in RA but also in other diseases.

Connective Tissue Growth Factor Neutralization Aggravates the Psoriasis Skin Lesion: The Analysis of Psoriasis Model Mice and Patients.

BACKGROUND: Connective tissue growth factor (CTGF) is a multifunctional cellular protein and playing a role as a central mediator in tissue remodeling and fibrosis. The physiological function of CTGF in psoriasis is unknown. OBJECTIVE: The purpose of this study was to investigate the function of CTGF in psoriasis using the established imiquimod (IMQ)-induced psoriasis murine model and psoriasis patients. METHODS: Anti-CTGF monoclonal antibody was applied to IMQ induced psoriasis mice and those skin were clinically, pathologically and immunologically analyzed. Additionally, CTGF expression was analyzes using skin samples and plasma from psoriasis patients. RESULTS: CTGF expression was observed in the dermis from both IMQ-induced psoriatic mice and psoriasis patients. CTGF inhibition using an anti-CTGF antibody slightly worsened IMQ-induced dermatitis. In addition, the increase of CTGF showed tendency to suppress the psoriatic dermatitis through inhibition of suprabasal cells proliferation and macrophage infiltration in the skin. CTGF was also detected significantly higher in plasma from psoriasis patients comparing with healthy control. CONCLUSION: Our findings suggest that CTGF could contribute to the healing rather than the worsening of psoriasis skin lesions.

Circulating plasma microRNA profiling in patients with polymyositis/dermatomyositis before and after treatment: miRNA may be associated with polymyositis/dermatomyositis.

BACKGROUND: MicroRNAs (miRNAs) are involved in the regulation of key biological processes and have been implicated in various diseases, including autoimmune disorders. The pathogenesis of polymyositis (PM) and dermatomyositis (DM) is considered to be mediated by autoimmune reactions. To determine miRNA role in the development and progression of PM and DM, we performed plasma miRNA profiling in PM/DM patients before and after treatment. METHODS: Total RNA was isolated from plasma of 10 patients before and after treatment with prednisolone, or, in case of prednisolone resistance or complications, with the combination of calcineurin inhibitors (cyclosporine or tacrolims) and/or pulse intravenous cyclophosphamide. The expression of miRNAs was determined using miRNA microarray and validated by qRT-PCR. RESULTS: More differentially expressed miRNAs were found in plasma of DM patients compared to PM patients before and after treatment, and their profiles were different. Among the differentially expressed plasma miRNA identified by microarray, the levels of hsa-miR-4442 were confirmed by qRT-PCR to be significantly decreased by treatment. In addition, plasma hsa-miR-4442 content in active PM/DM significantly exceeded that in other active autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as in healthy individuals. The level of plasma hsa-miR-4442 was positively correlated with Skeletal Disease Activity in MITAX (Myositis Intention to Treat Activity Index). CONCLUSION: This is the first report describing plasma miRNA expression profiles in PM/DM patients. The present data suggest that plasma levels of miRNAs may be associated with polymyositis/dermatomyositis and hsa-miR-4442 could be used as a biomarker for PM/DM diagnosis and/or disease activity.

JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation.

BACKGROUND: We previously reported that JAK-STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. Here, we evaluated the efficacy of the JAK inhibitor tofacitinib (TOFA) for controlling IFN signalling via the JAK-STAT pathway and as a therapeutic for SLE. RESULTS: We treated NZB/NZW F1 mice with TOFA and assessed alterations in their disease, pathological, and immunological conditions. Gene-expression results obtained from CD4+ T cells (SLE mice) and CD3+ T cells (human SLE patients) were measured by DNA microarray and qRT-PCR. TOFA treatment resulted in reduced levels of anti-dsDNA antibodies, decreased proteinuria, and amelioration of nephritis as compared with those observed in control animals. Moreover, we observed the rebalance in the populations of naïve CD4+ T cells and effector/memory cells in TOFA-treated mice; however, treatment with a combination of TOFA and dexamethasone (DEXA) elicited a stronger inhibitory effect toward the effector/memory cells than did TOFA or DEXA monotherapy. We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4+ from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3+ T cells from human patients following immunosuppressant therapy including steroid, respectively. CONCLUSION: Modulation of type I IFN signalling via JAK-STAT inhibition may exert a beneficial effect in SLE patients, and our results suggest that TOFA could be utilised for the development of new SLE-specific therapeutic strategies.

Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis.

We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study.

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

Identifying Small Coronary Calcification in Non-Contrast 0.5-mm Slice Reconstruction to Diagnose Coronary Artery Disease in Patients with a Conventional Zero Coronary Artery Calcium Score.

AIMS: In a new-generation computed tomography (CT) scanner, coronary artery calcium (CAC) scores were measured using 3.0-mm slice reconstruction images originally acquired with 0.5 mm thickness scans in a single beat. This study investigated the usefulness of thin-slice (0.5 mm) reconstruction for identifying small calcifications in coronary arteries and evaluated the association with coronary plaques and stenosis compared to conventional 3.0-mm reconstruction images. METHODS: We evaluated 132 patients with zero CAC scores in conventional 3.0-mm Agatston method using a 320-slice CT. Then, 0.5-mm slice reconstruction was performed to identify small calcifications. The presence of stenosis and coronary plaques was assessed using coronary CT angiography. RESULTS: In total, 22 small calcifications were identified in 18 patients. There were 28 (21%) patients with any (≥ 25%) stenosis (34 lesions). Forty-seven coronary plaques were found in 33 patients (25%), including 7 calcified plaques in 7 patients (5%), 34 noncalcified plaques in 27 patients (20%), and 6 partially calcified plaques in 5 patients (4%). Patients with small calcifications had a significantly higher prevalence of noncalcified or partially calcified plaques (83% vs 14%; p＜0.001) and obstructive stenosis (33% vs 5.2%; p＜0.001) compared to those without small calcifications. The addition of small calcifications to the coronary risk factors when diagnosing stenosis significantly improved the diagnostic value. CONCLUSION: Small calcifications detected by thin-slice 0.5-mm reconstruction are useful for distinguishing coronary atherosclerotic lesions in patients with zero CAC scores from conventional CT reconstruction.

Data set for volumetric and pathological findings of epicardial adipose tissue.

This article contains the data regarding clinically-assessed visceral adipose tissue (VAT) area and epicardial adipose tissue (EAT) volume on computed tomography (CT) images and EAT pathology, represented by inflammation and neoangiogenesis, complementing the data reported by Kitagawa et al. [1]. In 45 patients scheduled for cardiac surgery, we studied CT images obtained prior to surgery and the numbers of CD68+ individual macrophages and CD31+ neovessels in EAT samples subsequently obtained during surgery. The data revealed a moderate correlation between VAT area and EAT volume, and a strong correlation between EAT macrophage infiltration and neoangiogenesis.

The relationship between inflammation and neoangiogenesis of epicardial adipose tissue and coronary atherosclerosis based on computed tomography analysis.

OBJECTIVE: Previous studies indicate that epicardial adipose tissue (EAT) biologically contributes to the progression of coronary atherosclerosis. We evaluated the relationship between EAT pathology, represented by inflammation and neoangiogenesis, and coronary atherosclerosis on computed tomography (CT) images. METHODS: We performed CT examination in 45 patients scheduled for cardiac surgery (coronary artery bypass graft [CABG], n = 21; non-CABG, n = 24) to assess visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and presence of non-calcified coronary plaque (NCP) on CT angiography. Each patient was assessed with the numbers of CD68(+) individual macrophages and CD31(+) neovessels in six random high-power fields (400×) of EAT samples subsequently obtained during cardiac surgery. RESULTS: In three groups based on CCS (mild, 0-100; moderate, 101-400; severe, >400), the moderate group had the most extensive macrophage infiltration (p = 0.0025) and neoangiogenesis (p = 0.0036) in EAT. The patients with NCP had more extensive macrophage infiltration (p = 0.010) and neoangiogenesis (p = 0.0043) in EAT than those without. On multivariate analysis adjusted for age, sex, CABG versus. non-CABG, VAT area, and EAT volume, moderate CCS and the presence of NCP showed significant correlations with increased macrophage infiltration (ß = 0.65; p < 0.0001, and ß = 0.49; p = 0.0089, respectively) and neoangiogenesis (ß = 0.55; p = 0.0011, and ß = 0.53; p = 0.012, respectively) in EAT. CONCLUSION: Inflammation and neoangiogenesis in EAT independently correlate with moderate coronary calcification and presence of NCP, suggesting that these two factors may have a role in promoting coronary atherosclerosis.

Immunoregulatory role of IL-35 in T cells of patients with rheumatoid arthritis.

OBJECTIVE: IL-35 is the most recently identified member of the IL-12 family. It consists of EBV-induced gene 3 (EBI3) and IL-12α chain p35. We investigated whether IL-35 enhances the in vitro immunosuppressive function of peripheral blood isolated from patients with RA. METHODS: Peripheral blood was harvested from 17 active and 10 inactive RA patients and IL-35 concentrations were quantified using an ELISA. An expression vector containing IL-35 with a FLAG tag at the carboxyl-terminus was constructed by covalently linking EBI3 and IL-12α (p35). The function of IL-35 was then evaluated in a suppression assay using T cells isolated from human RA patients with CD2, CD3 and CD28 antibodies. RESULTS: Serum IL-35 levels and the number of Treg were decreased significantly in patients with active RA. There was a significant correlation between serum IL-35 and the 28-joint DAS with ESR (DAS28-ESR) in patients with active RA. IL-35 treatment enhanced the regulatory function, suppressing the levels of inflammatory cytokines such as IL-17 and IFN-γ and the cellular growth of effector T cells stimulated by conjugation with CD2, CD3 and CD28. CONCLUSION: These data revealed that IL-35 might suppress T cell activation during the peripheral immune responses of RA. Therefore our data suggest that IL-35 might have multiple therapeutic targets.

Association of epicardial and abdominal visceral adipose tissue with coronary atherosclerosis in patients with a coronary artery calcium score of zero.

BACKGROUND: We sought to examine whether epicardial and abdominal visceral adipose tissue distribution is associated with coronary atherosclerosis in patients with a coronary artery calcium (CAC) score of zero, assessed by coronary computed tomography angiography (CCTA). METHODS AND RESULTS: We studied 352 patients with suspected coronary artery disease (mean age 61±11 years, 57% male) with a CAC score of zero who had undergone CCTA. Non-calcified coronary plaques (NCPs) were detected in 102 patients (29%); those causing ≥50% stenosis were found in 15 patients (4%). Patients were divided into 4 groups on the basis of CT-based epicardial adipose tissue (EAT) volume and abdominal visceral adipose tissue (VAT) area using the sex-specific median value. Multivariate analysis showed that the adjusted odds ratios for the presence of NCPs in the high VAT area/low EAT volume group, and the high VAT area/high EAT volume group were 2.80 (95% confidence interval [95% CI]: 1.25-6.35, P=0.01) and 2.68 (95% CI: 1.36-5.45, P=0.004), respectively. Interestingly, the low VAT area/high EAT volume group showed an equivalent adjusted odds ratio of 3.02 (95% CI: 1.33-6.90, P=0.008). CONCLUSIONS: EAT volume is eligible as a marker to be evaluated in addition to VAT area in patients with a CAC score of zero.

Second-to-fourth Digit Ratio in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) occurs predominantly in women, and sex hormones play an important role in SLE. Variation in the second-to-fourth digit ratio (2D4D ratio) is attributed to sex hormone exposure. Therefore, we evaluated the relationship between sex hormones and SLE by measuring 2D4D ratios. METHODS: We measured 2D4D ratios in 100 patients with SLE and 200 normal healthy controls (NHC). RESULTS: Patients with SLE had a lower 2D4D ratio than NHC. CONCLUSION: Our study suggests that patients with SLE have experienced high prenatal testosterone and low prenatal estrogen. To our knowledge, this is the first study evaluating the association between 2D4D ratio and SLE.

Prognostic value of coronary artery calcium and epicardial adipose tissue assessed by non-contrast cardiac computed tomography.

OBJECTIVE: Epicardial adipose tissue (EAT) accumulation is believed to be associated with development of coronary atherosclerosis. We investigated whether EAT volume as assessed by computed tomography (CT) has value in prediction of future cardiac events. METHODS: We studied 722 patients without proven coronary artery disease (CAD) who underwent non-contrast cardiac CT. EAT volume and coronary artery calcium (CAC) score were measured simultaneously. Patients were followed as to the occurrence of coronary events (cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, and late coronary revascularization≥3 months after CT examination). RESULTS: During a 3.7±1.7 years follow-up period, 37 coronary events were documented. Annual event rates increased across CAC score categories (0.3%, 1.0%, 2.4%, and 4.3%, in 0, 1-99, 100-399, and ≥400, respectively, p<0.001); these were significantly higher in the higher EAT volume group (>median; 107.2 mL, 0.7% vs., 2.1%, adjusted hazard ratio; 2.65, p=0.0090). Cox-proportional hazard analysis demonstrated that a combination of CAC score≥100 and high EAT volume had a significantly higher event rate than CAC score<100 and low EAT volume group (adjusted hazard ratio 11.6, p<0.0001). Using Cox regression models, incremental prognostic values were identified by adding high EAT volume to clinical risks plus CAC score≥100 (global χ2, 6.7; p=0.059). CONCLUSION: We suggest that high EAT volume may be an independent predictor of future coronary events and increases predictive values of CAC score in patients without proven CAD.

Incremental prognostic value of cardiac computed tomography angiography in asymptomatic aortic stenosis: significance of aortic valve calcium score.

BACKGROUND: Cardiac computed tomography angiography (CCTA) provides the simultaneous evaluation of the aortic valve, myocardium, and coronary arteries. In particular, aortic valve calcium score (AVCS) can be accurately measured on the same scanning sequence used to measure coronary artery calcification, with no additional cost or radiation exposure. We sought to evaluate the prognostic value of CCTA measures, including AVCS, in asymptomatic aortic stenosis (AS). METHODS AND RESULTS: Sixty-four initially asymptomatic patients with AS with a normal ejection fraction were prospectively enrolled and followed for median 29 (IQR=18-50) months. During follow-up, 27 (42%) patients experienced cardiac events, including five cardiac deaths, eleven aortic valve replacements. Multivariate Cox proportional hazards analysis identified three CCTA measures as significant predictors of cardiac events: aortic valve area (per 0.1cm(2) decrease; hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.05-1.34); multi-vessel obstructive coronary artery disease (HR: 2.84, 95% CI: 1.10-7.32); and AVCS (per 100; HR: 1.09, 95% CI: 1.04-1.15). Kaplan-Meier analysis showed that patients with AVCS greater than or equal to the median value of 723 had significantly worse outcomes than those with AVCS less than 723 (p<0.0001). The C-statistic value for cardiac events substantially increased when these CCTA measures were added to clinical characteristics plus echocardiographic peak transaortic velocity (0.913 vs. 0.702, p<0.001). CONCLUSIONS: In patients with asymptomatic AS, CCTA measures of valve area, coronary stenosis, and calcification severity provide independent and incremental prognostic value after accounting for the echocardiographic severity of stenosis.

Association between serum levels of n-3 polyunsaturated fatty acids and coronary plaque detected by coronary computed tomography angiography in patients receiving statin therapy.

BACKGROUND: Intensive lipid-lowering therapy with statins reduces cardiovascular events, but residual cardiovascular risks remain. Intake of n-3 polyunsaturated fatty acids (PUFAs) has been associated with cardiovascular events. We examined the relationships between serum n-3 PUFAs and coronary atherosclerotic findings on computed tomography angiography (CTA) in patients undergoing statin treatment. METHODS AND RESULTS: We enrolled 172 subjects (mean age: 68.2 years; 64% men) prior to statin treatment for 6 months. Serum PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid, were measured. When the patients were divided into 2 groups according to the median EPA level (61.3 µg/ml), the low-EPA group showed higher incidences of 3-vessel plaque involvement (62% vs. 43%, P=0.015), noncalcified plaques (NCPs) (74% vs. 52%, P=0.0016), extensive NCPs (≥ 2 segments) (56% vs. 34%, P=0.0036), and high-risk plaques (minimum CT density <39 HU and remodeling index >1.05) (43% vs. 22%, P=0.0034). Multivariate analyses revealed that low EPA levels were an independent factor for these coronary plaque findings. The DHA levels were not independently associated with these findings. CONCLUSIONS: Low serum EPA level, but not serum DHA, is associated with the presence and extent of NCPs and high-risk plaques detected by coronary CTA in patients undergoing lipid-lowering therapy with statins.

Noncalcified atherosclerotic lesions with vulnerable characteristics detected by coronary CT angiography and future coronary events.

BACKGROUND: The ability of coronary CT angiography (CTA) findings such as plaque characteristics to predict future coronary events remains controversial. OBJECTIVE: We investigated whether noncalcified atherosclerotic lesions (NCALs) detected by coronary CTA were predictive of future coronary events. METHODS: A total of 511 patients who underwent coronary CTA were followed for cardiovascular events over a period of 3.3 ± 1.2 years. The primary end point was defined as hard events, including cardiac death, nonfatal myocardial infarction, or unstable angina that required urgent hospitalization. Early elective coronary revascularizations (n = 58) were excluded. The relationship between features of NCALs and outcomes is described. RESULTS: A total of 15 hard events (2 cardiac deaths, 7 myocardial infarctions, 6 cases of unstable angina that required urgent hospitalization) were documented in the remaining 453 patients with modest risks during a follow-up period of 3.3 ± 1.2 years. For these hard events, a univariate Cox proportional hazard model showed that the hazard ratio for the presence of >50% stenosis was 7.27 (95% CI, 2.62-21.7; P = .0002). Although the presence of NCAL by itself was not statistically significant, NCALs with low attenuation and positive remodeling (low-attenuation plaque [LAP] and positive remodeling [PR]; plaque CT number ≤ 34 HU and remodeling index ≥ 1.20) showed an adjusted hazard ratio of 11.2 (95% CI, 3.71-36.7; P < .0001). With C-statistics analysis, when both LAP and PR and >50% stenosis were added, the C-statistic was significantly improved compared with the basal model adjusted for age, sex, and log2 (Agatston score +1) (0.900 vs 0.704; P = .0018). CONCLUSIONS: Identification of NCALs with LAP and PR characteristics by coronary CTA provides additional prognostic information to coronary stenosis for the prediction of future coronary events.

Association between heart calcification assessed by echocardiography and future cardiovascular disease mortality and morbidity.

BACKGROUND: Echocardiography can detect calcium deposits in heart valves and aortic root, but the relationship of echocardiographic heart calcification such as aortic valve calcification (AVC), mitral annular calcification (MAC), and aortic root calcification (ARC) with future cardiovascular disease (CVD) mortality and morbidity is not fully elucidated. METHODS: We analyzed data from 943 patients with suspected coronary heart disease (mean age, 65.7 years; 36% female). Echocardiographic total heart calcification (THC) score was determined by summing up the AVC, MAC, and ARC variables; THC-0 (N = 397), THC-1 (N = 236), THC-2 (N = 224), and THC-3 (N = 86). Subjects were followed for mean 2.9 years to assess the risk of death from CVD causes. Cardiovascular morbidity was defined as new episodes of non-fatal myocardial infarction, congestive heart failure, stroke, and surgical treatment of vascular disease. RESULTS: There were 43 CVD deaths and a total of 160 CVD events. Kaplan-Meier curves showed a graded CVD mortality and morbidity across increasing THC score values. With full adjustment, Cox regression hazard ratios (95% confidence intervals) for CVD mortality and morbidity, using no calcification as reference, for THC-1, THC-2, and THC-3 were 2.21 (1.31-3.74), 2.59 (1.53-4.39) and 4.14 (2.30-7.47), respectively. When THC score was added to models with CVD risk factors, C-statistics were significantly larger for CVD mortality (p = 0.048) and for CVD mortality and morbidity (p = 0.004). CONCLUSIONS: THC score, the sum of the amounts of AVC, MAC, and ARC present as estimated by echocardiography, has an independent and incremental prognostic value in a high-risk population.