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The interplay between mineral metabolism, vascular calcification and inflammation in Chronic Kidney Disease (CKD): challenging old concepts with new facts.
Viegas, C, Araújo, N, Marreiros, C, Simes, D
Aging. 2019;(12):4274-4299
Abstract
Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.
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Crowned dens syndrome: a neurologist's perspective.
Scheldeman, L, Van Hoydonck, M, Vanheste, R, Theys, T, Cypers, G
Acta neurologica Belgica. 2019;(4):561-565
Abstract
Crowned dens syndrome is an under-recognized entity that can mimic neurological disease, in particular meningitis or giant-cell arteritis. We present a 48-year-old woman presenting with an inflammatory meningitis-like syndrome with headache and neck stiffness. Lumbar puncture was normal and computed tomography (CT) of the atlantoaxial joint showed abnormal calcifications around the odontoid process, leading to a tentative diagnosis of crowned dens syndrome. In addition, signs of active inflammation in and around the dens were present on cervical MR imaging. Since CDS can mimic meningitis or giant-cell arteritis, neurologists should be aware of this entity. If CDS is suspected, the bone window on the head CT scan can lead to the diagnosis. On the other hand, asymptomatic periodontoid calcifications are common and should not preclude further investigations.
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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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Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism.
Iwase, T, Yoshida, M, Hashizume, Y, Yazawa, I, Takahashi, S, Ando, T, Ikeda, T, Nokura, K
Neuropathology : official journal of the Japanese Society of Neuropathology. 2019;(1):39-46
Abstract
We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth-Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.
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Leveraging the coronary calcium scan beyond the coronary calcium score.
Bos, D, Leening, MJG
European radiology. 2018;(7):3082-3087
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Abstract
UNLABELLED Non-contrast cardiac computed tomography in order to obtain the coronary artery calcium score has become an established diagnostic procedure in the clinical setting, and is commonly employed in clinical and population-based research. This state-of-the-art review paper highlights the potential gain in information that can be obtained from the non-contrast coronary calcium scans without any necessary modifications to the scan protocol. This includes markers of cardio-metabolic health, such as the amount of epicardial fat and liver fat, but also markers of general health including bone density and lung density. Finally, this paper addresses the importance of incidental findings and of radiation exposure accompanying imaging with non-contrast cardiac computed tomography. Despite the fact that coronary calcium scan protocols have been optimized for the visualization of coronary calcification in terms image quality and radiation exposure, it is important for radiologists, cardiologists and medical specialists in the field of preventive medicine to acknowledge that numerous additional markers of cardio-metabolic health and general health can be readily identified on a coronary calcium scan. KEY POINTS • The coronary artery calcium score substantially increased the use of cardiac CT. • Cardio-metabolic and general health markers may be derived without changes to the scan protocol. • Those include epicardial fat, aortic valve calcifications, liver fat, bone density, and lung density. • Clinicians must be aware of this potential additional yield from non-contrast cardiac CT.
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Radiological, Histological and Chemical Analysis of Breast Microcalcifications: Diagnostic Value and Biological Significance.
Bonfiglio, R, Scimeca, M, Toschi, N, Pistolese, CA, Giannini, E, Antonacci, C, Ciuffa, S, Tancredi, V, Tarantino, U, Albonici, L, et al
Journal of mammary gland biology and neoplasia. 2018;(1-2):89-99
Abstract
Classification of mammary microcalcifications is based on radiological and histological characteristics that are routinely evaluated during the diagnostic path for the identification of breast cancer, or in patients at risk of developing breast cancer. The main aim of this study was to explore the relationship between the imaging parameters most commonly used for the study of mammary microcalcifications and the corresponding histological and chemical properties. To this end, we matched the radiographic characteristics of microcalcifications to breast lesion type, histology of microcalcifications and elemental composition of microcalcifications as obtained by energy dispersive x ray (EDX)-microanalysis. In addition, we investigated the properties of breast cancer microenvironment, under the hypothesis that microcalcification formation could result from a mineralization process similar to that occurring during bone osteogenesis. In this context, breast lesions with and without microcalcifications were compared in terms of the expression of the main molecules detected during bone mineralization (BMP-2, BMP-4, PTX3, RANKL OPN and RUNX2). Our data indicate that microcalcifications classified by mammography as "casting type" are prevalently made of hydroxyapatite magnesium substituted and are associated with breast cancer types with the poorest prognosis. Moreover, breast cancer cells close to microcalcifications expressed higher levels of bone mineralization markers as compared to cells found in breast lesions without microcalcifications. Notably, breast lesions with microcalcifications were characterized by the presence of breast-osteoblast-like cells. In depth studies of microcalcifications characteristics could support a new interpretation about the genesis of ectopic calcification in mammary tissue. Candidating this phenomenon as an integral part of the tumorigenic process therefore has the potential to improve the clinical management of patients early during their diagnostic path.
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Aortic Calcification is Associated with Five-Year Decline in Handgrip Strength in Older Women.
Rodríguez, AJ, Lewis, JR, Scott, DS, Kiel, DP, Schousboe, JT, Ebeling, PR, Prince, RL
Calcified tissue international. 2018;(6):589-598
Abstract
The objective of the study was to determine the association between AAC and neuromuscular function over 5 years. Participants in this study were ambulant women over 70 years old residing in Perth, Western Australia who participated in the Calcium Intake Fracture Outcomes Study, a randomised controlled trial of calcium supplementation. 1046 women (mean age = 74.9 ± 2.6 years; BMI = 27.1 ± 4.4 kg/m2) were included. Lateral spine images captured during bone density testing were scored for AAC (AAC24; 0-24) at baseline. Severe AAC (AACsev) was defined using established cut points (AAC24 ≥ 6). At baseline and follow-up, isometric grip strength was assessed using a dynamometer. Mobility was assessed by the Timed-Up-and-Go (TUG) test. Using pre-defined criteria, muscle weakness was considered as grip strength < 22 kg and poor mobility defined as TUG > 10.2 s. A subset of women had appendicular lean mass (ALM) determined by dual-energy X-ray absorptiometry at baseline and follow-up (n = 261). AACsev was evident in 193 (18.5%) women. Average decline in grip strength after 5 years was greater in those with AACsev than those without (3.6 ± 3.7 vs. 2.9 ± 4.2 kg; p = 0.034). This remained significant after adjustment for age, treatment allocation, diabetes, smoking history, renal function, medical record-derived prevalent vascular disease, BMI and physical activity (β = - 0.184; 95% confidence interval: - 0.361, - 0.008; p = 0.040). AACsev was not associated with 5-year changes in TUG or ALM in univariable or multivariable analyses (all p > 0.05). In older women, severe aortic calcification was associated with greater 5-year decline in muscle strength, but not TUG or ALM. These findings support the concept that vascular disease may have an effect on the loss of muscular strength.
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Coronary artery calcifications and diastolic dysfunction versus visceral fat area in type 1 diabetes: VISCERA study.
De Block, CEM, Shivalkar, B, Goovaerts, W, Brits, T, Carpentier, K, Verrijken, A, Van Hoof, V, Parizel, PM, Vrints, C, Van Gaal, LF
Journal of diabetes and its complications. 2018;(3):271-278
Abstract
AIMS: Type 1 diabetic patients (T1DM) experience a higher cardiovascular disease and mortality risk than controls. We investigated whether visceral adipose tissue (VAT) contributes to coronary artery calcifications (CAC) and cardiac dysfunction in T1DM. METHODS A cross-sectional study of 118 T1DM patients without a history of cardiovascular disease (men/women: 68/50, age 46±12years, HbA1c 7.6±0.9%, BMI 25.8±4.1kg/m2) was conducted. CAC and VAT were measured using a CT scan. CAC was scored using the Agatston method. Cardiac functional abnormalities were assessed by echocardiography. RESULTS CAC scored ≥10 in 42% of patients. Systolic function was normal in all, but diastolic dysfunction was present in 75%. Forty-six percent had VAT≥100cm2. CAC score≥10 occurred more often in subjects with VAT≥100cm2 (54% vs 31%; p=0.01). Age (OR=1.10; p<0.0001), diabetes duration (OR=1.10; p=0.008), gender (OR=4.28; p=0.016), LDL-cholesterol (OR=1.03; p=0.009) and metabolic syndrome (OR=5.79; p=0.005) were independently associated with a CACS≥10. Subjects with CACS≥10 were more prone to have diastolic dysfunction (84 vs 54%; p=0.03). Factors independently associated with diastolic dysfunction were age (OR=1.11; p=0.002), waist circumference (OR=1.10; p=0.016) and VAT (OR=0.99; p=0.035). CONCLUSIONS Excess VAT in T1DM, present in 46%, is associated with diastolic dysfunction and CAC, present in respectively 75% and 42% of patients. Timely detection might improve future cardiovascular risk.
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Observational and Genetic Associations of Resting Heart Rate With Aortic Valve Calcium.
Whelton, SP, Mauer, AC, Pencina, KM, Massaro, JM, D'Agostino, RB, Fox, CS, Hoffmann, U, Michos, ED, Peloso, GM, Dufresne, L, et al
The American journal of cardiology. 2018;(10):1246-1252
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Abstract
It is unknown if lifelong exposure to increased hemodynamic stress from an elevated resting heart rate (HR) may contribute to aortic valve calcium (AVC). We performed multivariate regression analyses using data from 1,266 Framingham Heart Study (FHS) Offspring cohort participants and 6,764 Multi-Ethnic Study of Atherosclerosis (MESA) participants. We constructed a genetic risk score (GRS) for HR using summary-level data in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AVC Consortium to investigate if there was evidence in favor of a causal relation. AVC was present in 39% of FHS Offspring cohort participants and in 13% of MESA cohort participants. In multivariate adjusted models, participants in the highest resting HR quartiles had significantly greater prevalence of AVC, with a prevalence ratio of 1.19 (95% confidence interval [CI] 0.99 to 1.44) for the FHS Offspring cohort and 1.32 (95% CI 1.12 to 1.63) for the MESA cohort, compared with those in the lowest quartile. There was a similar increase in the prevalence of AVC per standard deviation increase in resting HR in both FHS Offspring (prevalence ratio 1.08, 95% CI 1.01 to 1.15) and MESA (1.10, 95% CI 1.03 to 1.17). In contrast with these observational findings, a HR associated GRS was not significantly associated with AVC. Although our observational analysis indicates that a higher resting HR is associated with AVC, our genetic results do not support a causal relation. Unmeasured environmental and/or lifestyle factors associated with both increased resting HR and AVC that are not fully explained by covariates in our observational models may account for the association between resting HR and AVC.
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Association between common bile duct diameter and abdominal aorta calcium score.
Moharamzad, Y, Abbasi, S, Sanei Taheri, M, Faghihi Langroudi, T
Abdominal radiology (New York). 2018;(8):2097-2102
Abstract
BACKGROUND AND OBJECTIVE There is evidence of association between aging and increase in the normal upper limit of the common bile duct (CBD) diameter. As aging is a documented risk factor for atherosclerosis, and the possible effect that atherosclerosis can have on the CBD diameter via affecting its smooth muscle contractility and blood flow, we decided to determine the association between CBD diameter and atherosclerosis in the abdominal aorta (AA). METHODS A total of 99 asymptomatic patients (53 males and 46 females; age range of 18-88 years) without history of cholecystectomy who underwent abdominal contrast-enhanced CT scan were included. The CBD diameter was measured. The atherosclerosis of AA was quantified by Agatston score. RESULTS Mean (± SD) CBD diameter was 6.14 (± 1.95) mm; range = 2.4-12.7 mm. Agatston score was 0 in 59 patients. In the remaining 40 patients, median (interquartile range, IQR) Agatston score was 497.5 (2026.3). Mean (± SD) CBD diameter in patients with Agatston score > 0 was 7.39 (± 2.07) mm compared to 5.29 (± 1.32) mm in patients without calcification plaque (P < 0.001). A moderate correlation was seen between CBD diameter and Agatston score (ρ = 0.43; P = 0.005). CONCLUSION Although the exact cause of increased CBD diameter with advancing age is not understood, a general atherosclerotic process which occurs with aging may affect smooth muscle of the CBD. Whether an upper limit for normal CBD should be defined or not when evaluating dilated CBD for patients with subclinical or clinical atherosclerosis needs further studies.