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Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.
Thériault, S, Dina, C, Messika-Zeitoun, D, Le Scouarnec, S, Capoulade, R, Gaudreault, N, Rigade, S, Li, Z, Simonet, F, Lamontagne, M, et al
Circulation. Genomic and precision medicine. 2019;(10):e002617
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Abstract
BACKGROUND Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. METHODS A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. RESULTS In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. CONCLUSIONS Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
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Extracorporeal shock wave therapy, ultrasound-guided percutaneous lavage, corticosteroid injection and combined treatment for the treatment of rotator cuff calcific tendinopathy: a network meta-analysis of RCTs.
Arirachakaran, A, Boonard, M, Yamaphai, S, Prommahachai, A, Kesprayura, S, Kongtharvonskul, J
European journal of orthopaedic surgery & traumatology : orthopedie traumatologie. 2017;(3):381-390
Abstract
Treatment of calcific tendinitis using extracorporeal shock wave therapy (ESWT), ultrasound-guided percutaneous lavage (UGPL or barbotage), subacromial corticosteroid injection (SAI) and combined treatment is still controversial. This systematic review and meta-regression aimed to compare clinical outcomes between treatments. Relevant RCTs were identified using PubMed and Scopus search engines to date of September 23, 2015. Seven of 920 studies identified were eligible. Compared to the other treatments, the results of this study indicate that ESWT significantly improved CMS and VAS when compared to placebo. Barbotage plus ESWT significantly improved CMS, VAS and decreased size of calcium deposit when compared to ESWT, while barbotage plus SAI significantly improved CMS and decreased size of calcium deposit when compared to SAI. There have no different adverse effects of all treatment groups. Multiple active treatment comparisons indicated that barbotage plus SAI significantly improved VAS and size of calcium deposit when compared to other groups, while barbotage plus SAI improved CMS when compared to other groups. But there was no significant difference. The network meta-analysis suggested that combined US-guided needling and subacromial corticosteroid injection significantly decreased shoulder pain VAS, improved CMS score and decreased the size of calcium deposits, while also lowering risks of adverse event when compared to barbotage plus ESWT, ESWT and subacromial corticosteroid injection; therefore, the evidence points to UGPL as being the treatment of choice for nonsurgical options of treatment in calcific tendinitis of the shoulder. Level of evidence I.
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Prevalence and Prognostic Implications of Coronary Artery Calcification in Low-Risk Women: A Meta-analysis.
Kavousi, M, Desai, CS, Ayers, C, Blumenthal, RS, Budoff, MJ, Mahabadi, AA, Ikram, MA, van der Lugt, A, Hofman, A, Erbel, R, et al
JAMA. 2016;(20):2126-2134
Abstract
IMPORTANCE The role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear. OBJECTIVE To assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women. DESIGN, SETTING, AND PARTICIPANTS Women with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies. EXPOSURES CAC score by computed tomography. MAIN OUTCOMES AND MEASURES Main outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated. RESULTS Among 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC >0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction. CONCLUSIONS AND RELEVANCE Among women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy.
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Genetic associations with valvular calcification and aortic stenosis.
Thanassoulis, G, Campbell, CY, Owens, DS, Smith, JG, Smith, AV, Peloso, GM, Kerr, KF, Pechlivanis, S, Budoff, MJ, Harris, TB, et al
The New England journal of medicine. 2013;(6):503-12
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Abstract
BACKGROUND Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. METHODS We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. RESULTS One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. CONCLUSIONS Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
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Diagnostic performance of coronary CT angiography for stenosis detection according to calcium score: systematic review and meta-analysis.
den Dekker, MA, de Smet, K, de Bock, GH, Tio, RA, Oudkerk, M, Vliegenthart, R
European radiology. 2012;(12):2688-98
Abstract
OBJECTIVES A systematic review and meta-analysis to assess sensitivity and specificity of coronary CT angiography (CCTA) for significant stenosis at different degrees of coronary calcification. METHODS A literature search was performed including studies describing test characteristics of CCTA for significant stenosis, performed with at least 16-MDCT and according to calcium score (CS). Invasive coronary angiography was the reference standard. Pooled sensitivity and specificity of CCTA by CS categories and CT equipment were calculated. RESULTS Of 14,121 articles, 51 studies reported on the impact of calcium scoring on diagnostic performance of CCTA and could be included in the systematic review. Twenty-seven of these studies (5,203 participants) were suitable for meta-analysis. On a patient-basis, sensitivity of CCTA for significant stenosis was 95.8, 95.6, 97.6 and 99.0% for CS 0-100, 101-400, 401-1,000 and >1,000 respectively. Specificity was 91.2, 88.2, 50.6 and 84.0% respectively. Specificity of CCTA was significantly lower for CS 401-1,000 due to lack of patients without significant stenosis. Sensitivity and specificity of 16-MDCT were significantly lower compared to more modern CT systems. CONCLUSIONS Even in cases of severe coronary calcification, sensitivity and specificity of CCTA for significant stenosis are high. With 64-MDCT and newer CT systems, a CS cut-off for performing CCTA no longer seems indicated. KEY POINTS Decisions about performing coronary CT angiography (CCTA) sometimes depend on calcium scoring. CCTA is highly sensitive for coronary stenosis. With 16-MDCT, however, heavy calcification reduces specificity for significant stenosis. For 64-MDCT (and above), CCTA has high specificity, even with severe coronary calcification.
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Calcification of the abdominal aorta as an independent predictor of cardiovascular events: a meta-analysis.
Bastos Gonçalves, F, Voûte, MT, Hoeks, SE, Chonchol, MB, Boersma, EE, Stolker, RJ, Verhagen, HJ
Heart (British Cardiac Society). 2012;(13):988-94
Abstract
CONTEXT Abdominal aortic calcification (AAC) is a common finding in patients with atherosclerosis. OBJECTIVE The aim of this study was to demonstrate the incremental value of AAC in predicting long term cardiovascular (CV) outcome by conducting a meta-analysis of observational studies. DATA SOURCES MEDLINE and Cochrane databases. STUDY SELECTION Longitudinal studies with at least 2 years of follow-up, reporting the influence of AAC on CV outcome of general population patients. DATA EXTRACTION Four separate end points-coronary events, cerebrovascular events, all CV events and CV related death-were tested for their relationship with AAC at baseline, using weighted random effects meta-analysis. Heterogeneity was calculated using Q and I(2) statistic tests. Publication bias was assessed by funnel plot symmetry and trim and fill methods. The importance of calcium quantification was also explored (sensitivity analysis). RESULTS 10 studies were included. An increased relative risk (RR) was found for all end points: for coronary events (five studies, n=11250) 1.81 (95% CI 1.54 to 2.14); for cerebrovascular events (four studies, n=9736) 1.37 (1.22 to 3.54); for all CV events (four studies, n=4960) 1.64 (1.24 to 2.17); and for CV death (three studies, n=4986) 1.72 (1.03 to 2.86). Analysis of studies presenting results in categories (no/minimal, moderate and severe calcification) revealed a stepwise increase in the RR for all end points. Significant heterogeneity was found in the included studies. Sources of heterogeneity were identified in the publication date, duration of follow-up, and mean age and gender differences in the included patient cohorts. CONCLUSION Existing data suggest that AAC is a strong predictor of CV related events or death in the general population. The predictive impact is greater in more calcified aortas. The generalisability of the meta-analysis is limited by heterogeneity in the coronary events, all CV events and CV death end points.