MiR-9-5p Regulates Genes Linked to Cerebral Calcification in the Osteogenic Differentiation Model and Induces Generalized Alteration in the Ion Channels.

MicroRNA-9 (miR-9) modulates gene expression and demonstrates high structural conservation and wide expression in the central nervous system. Bioinformatics analysis predicts almost 100 ion channels, membrane transporters and receptors, including genes linked to primary familial brain calcification (PFBC), as possible miR-9-5p targets. PFBC is a neurodegenerative disorder, characterized by bilateral and symmetrical calcifications in the brain, associated with motor and behavioral disturbances. In this work, we seek to study the influence of miR-9-5p in regulating genes involved in PFBC, in an osteogenic differentiation model with SaOs-2 cells. During the induced calcification process, solute carrier family 20 member 2 (SLC20A2) and platelet-derived growth factor receptor beta (PDGFRB) were downregulated, while platelet-derived growth factor beta (PDGFB) showed no significant changes. Significantly decreased levels of SLC20A2 and PDGFRB were caused by the presence of miR-9-5p, while PDGFB showed no regulation. We confirmed the findings using an miR-9-5p inhibitor and also probed the cells in electrophysiological analysis to assess whether such microRNA might affect a broader range of ion channels, membrane transporters and receptors. Our electrophysiological data show that an increase of the miR-9-5p in SaOs-2 cells decreased the density and amplitude of the output ionic currents, indicating that it may influence the activity, and perhaps the expression, of some ionic channels. Additional investigations should determine whether such an effect is specific to miR-9-5p, and whether it could be used, together with the miR-9-5p inhibitor, as a therapeutic or diagnostic tool.

BMP-2 upregulates the AKT/mTOR pathway in breast cancer with microcalcification and indicates a poor prognosis.

BACKGROUND: As a reliable biomarker of breast cancer, breast microcalcification has been reported to be correlated with poor prognosis. Bone morphogenetic protein 2 (BMP-2) plays an important role in microcalcification of breast cancer. Studies in other tissues have shown an association between BMP-2 and AKT/mTOR pathway, while their relationship in breast cancer still remains largely undetermined. To clarify the relationship of these three factors, we collected patients of invasive breast cancer with/without microcalcification and immunohistochemical examination was performed. METHOD/PATIENTS: A total of 272 patients with primary invasive breast cancer were selected from the First Hospital of China Medical University from January 2010 to January 2012. Immunohistochemical examination of the BMP-2, p-AKT and p-mTOR was performed on 4-µm tissue microarray (TMA) sections. Then, we analyzed the relationship of BMP-2, p-AKT, and p-mTOR and their correlation with disease-free survival (DFS) in breast cancer with/without microcalcification. RESULTS: We found that breast cancer patients with microcalcification were correlated with HER-2 positive expression and poor prognosis. Immunohistochemical examination showed that the expressions of BMP-2 and p-mTOR were increased in breast cancer with microcalcification and the expressions of BMP-2, p-AKT, and p-mTOR were correlated with each other. Moreover, the high expressions of BMP-2, p-AKT, and p-mTOR were significantly correlated with poor prognosis. CONCLUSIONS: Based on the abovementioned findings, we hypothesized that the high expression of BMP-2 not only played a vital role in the formation of microcalcification, but also activated the AKT/mTOR pathway. Collectively, breast cancer patients with microcalcification were more likely to be resistant to targeted or endocrine therapy and be correlated with poor prognosis.

Calcitriol Reverses the Down-Regulation Pattern of Tuberous Sclerosis Complex Genes in an In Vitro Calcification Model.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with autosomal dominant inheritance, and most of the cases are related to loss of function of the TSC1 and TSC2 genes. TSC may occur with a wide range of clinical findings and skin, kidney, brain, and heart are the most commonly affected organs. Brain calcifications in TSC are also described and reported as diffuse and without pattern of symmetry or bilaterality. Recently, a new discovery opened the possibility of using vitamin D (VitD) for treating cerebral calcifications. Calcitriol, the active form of VitD, was able to reduce the calcification in an in vitro model, increasing expression of a gene related to primary familial brain calcification. We show that in the same experimental model, calcitriol was also able to restore and even increase expression of genes related to TSC. This article discusses the use of calcitriol supplementation in patients with TSC, which can be a very interesting strategy due to its low cost and because it is already used in various therapies.

Calcification and Oxidative Modifications Are Associated With Progressive Bioprosthetic Heart Valve Dysfunction.

BACKGROUND: Bioprosthetic heart valves (BHVs), fabricated from glutaraldehyde-pretreated bovine pericardium or porcine aortic valves, are widely used for the surgical or interventional treatment of heart valve disease. Reoperation becomes increasingly necessary over time because of BHV dysfunction. METHODS AND RESULTS: Forty-seven explanted BHV aortic valve replacements were retrieved at reoperation for clinically severe BHV dysfunction over the period 2010-2016. Clinical explant analyses of BHV leaflets for calcium (atomic absorption spectroscopy) and oxidized amino acids, per mass spectroscopy, were primary end points. Comorbidities for earlier BHV explant included diabetes mellitus and coronary artery bypass grafting. Mean calcium levels in BHV leaflets were significantly increased compared with unimplanted BHV (P<0.001); however, time to reoperation did not differ comparing calcified and noncalcified BHV. BHV dityrosine, an oxidized amino acid cross-link, was significantly increased in the explants (227.55±33.27 µmol/mol [dityrosine/tyrosine]) but was undetectable in unimplanted leaflets (P<0.001). BHV regional analyses revealed that dityrosine, ranging from 57.5 to 227.8 µmol/mol (dityrosine/tyrosine), was detectable only in the midleaflet samples, indicating the site-specific nature of dityrosine formation. 3-Chlorotyrosine, an oxidized amino acid formed by myeloperoxidase-catalyzed chlorinating oxidants, correlated with BHV calcium content in leaflet explant analyses from coronary artery bypass graft patients (r=0.62, P=0.01) but was not significantly correlated with calcification in non-coronary artery bypass graft explanted BHV. CONCLUSIONS: Both increased BHV leaflet calcium levels and elevated oxidized amino acids were associated with bioprosthesis dysfunction necessitating reoperation; however, BHV calcium levels were not a determinant of implant duration, indicating a potentially important role for oxidized amino acid formation in BHV dysfunction.

Association between a healthy cardiovascular risk factor profile and coronary artery calcium score: Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Our goal was to evaluate cross-sectionally the association between ideal risk factor (IRF) profile and the presence and severity of subclinical atherosclerosis measured as coronary artery calcium (CAC) in the Brazilian Longitudinal Study of Adult Health. METHODS: We included 4,077 participants with no prior history of cardiovascular disease aged 35 to 74 years who underwent CAC measurement. The 2010 Task Force of the American Heart Association cutoffs were used to define the ideal level of smoking, physical activity, diet, blood pressure, glucose/cholesterol levels, and body mass index. RESULTS: Participants were categorized according the number of IRF: 0 to 1 (n = 1,025, 25.1%), 2 (n = 1,200, 29.4%), 3 to 4 (n = 1,551, 38.1%), or 5 to 7 (n = 301, 7.4%). Compared to individuals with 0 to 1 IRF, the odds ratio of participants with 2 IRFs presenting with CAC >0 (compared to 0), ≥100 (compared to <100), and ≥400 (compared to <400) was 0.75 (95% CI 0.62-0.91), 0.64 (0.49-0.84), and 0.75 (0.49-1.15), respectively. Similarly, the odds ratios of CACs >0, ≥100, and ≥400 in individuals with 3 to 4 IRFs were 0.59 (95% CI 0.48-0.71), 0.46 (0.34-0.62), and 0.50 (0.30-0.83), respectively, and, for individuals with 5 to 7 IRFs, were 0.36 (95% CI 0.24-0.56), 0.22 (0.09-0.55), and 0.20 (0.03-1.45), respectively. CONCLUSIONS: Subjects with an IRF profile have lower CAC when compared to subjects with fewer controlled risk factors. However, even among individuals with 5 to 7 IRFs, it is possible to find a CAC higher than zero reflecting that measures of IRF do not fully account for all factors that resulted in coronary artery disease.

Insulin Resistance in Adipose Tissue but Not in Liver Is Associated with Aortic Valve Calcification.

Background. Insulin resistance is involved in the pathogenesis of cardiovascular disease, but its relationship with cardiovascular calcification has yielded conflicting results. The purpose of the present study was to investigate the role of hepatic and adipose tissue insulin resistance on the presence of coronary artery (CAC > 0) and aortic valve calcification (AVC > 0). Methods. In 1201 subjects (52% women, 53.6 ± 9.3 years old) without familiar and personal history of coronary heart disease, CAC and AVC were assessed by multidetector-computed tomography. Cardiovascular risk factors were documented and lipid profile, inflammation markers, glucose, insulin, and free fatty acids were measured. Hepatic insulin resistance (HOMA-IR) and adipose tissue insulin resistance (Adipo-IR) indices were calculated. Results. There was a significant relationship between HOMA-IR and Adipo-IR indices (r = 0.758, p < 0.001). Participants in the highest quartiles of HOMA-IR and Adipo-IR indices had a more adverse cardiovascular profile and higher prevalence of CAC > 0 and AVC > 0. After full adjustment, subjects in the highest quartile of Adipo-IR index had higher odds of AVC > 0 (OR: 2.40; 95% CI: 1.30-4.43), as compared to those in the lowest quartile. Conclusions. Adipo-IR was independently associated with AVC > 0. This suggests that abnormal adipose tissue function favors insulin resistance that may promote the development and progression of AVC.

Association of thoracic aorta calcium and non cardiac vascular events in cardiac disease-free individuals.

OBJECTIVE: Thoracic aorta calcium (TAC) is measurable on the same computed tomography (CT) scan as coronary artery calcium (CAC) but has still unclear clinical value. We assessed TAC and CAC relations with non-cardiac vascular events history in a cohort of subjects at risk for cardiovascular disease. METHODS: We analyzed retrospectively 1000 consecutive subjects having undergone CAC detection by non-contrast multi-slice CT with measurement field longer than usual in order to measure total TAC including aortic arch calcium. We also determined partial TAC restricted to ascending and descending thoracic aorta sites by removing arch calcium from total TAC. Calcium deposits were measured with a custom made software using Agatston score. RESULTS: Compared with the rest of the cohort, the 30 subjects with non-cardiac vascular event history had higher median values [95% CI] of total TAC (282 [28-1809] vs 39 [0-333], p < 0.01) and partial TAC (4 [0-284] vs 0 [0-5], p < 0.01) but no different value of CAC (73 [0-284] vs 16 [0-148]). Odds ratio [95% CI] of having non-cardiac vascular event per 1-SD increase in log-transformed calcium value was significant for total TAC but not for CAC, if total TAC and CAC were entered separately (1.56 [1.12-2.24], p < 0.01 and 1.13 [0.86-1.50], respectively) or together (1.57 [1.10-2.32], p < 0.01 and 0.98 [0.73-1.32], respectively) in the logistic adjusted model. CONCLUSION: TAC assessment simultaneous with CAC detection provides complementary information on the extra coronary component of cardiovascular risk beyond CAC's coronary risk prediction. Further studies are required to prospectively confirm this result.

Oxalate induces breast cancer.

BACKGROUND: Microcalcifications can be the early and only presenting sign of breast cancer. One shared characteristic of breast cancer is the appearance of mammographic mammary microcalcifications that can routinely be used to detect breast cancer in its initial stages, which is of key importance due to the possibility that early detection allows the application of more conservative therapies for a better patient outcome. The mechanism by which mammary microcalcifications are formed is still largely unknown but breast cancers presenting microcalcifications are more often associated with a poorer prognosis. METHODS: We combined Capillary Electrochromatography, histology, and gene expression (qRT-PCR) to analyze patient-matched normal breast tissue vs. breast tumor. Potential carcinogenicity of oxalate was tested by its inoculation into mice. All data were subjected to statistical analysis. RESULTS: To study the biological significance of oxalates within the breast tumor microenvironment, we measured oxalate concentration in both human breast tumor tissues and adjoining non-pathological breast tissues. We found that all tested breast tumor tissues contain a higher concentration of oxalates than their counterpart non-pathological breast tissue. Moreover, it was established that oxalate induces proliferation of breast cells and stimulates the expression of a pro-tumorigenic gene c-fos. Furthermore, oxalate generates highly malignant and undifferentiated tumors when it was injected into the mammary fatpad in female mice, but not when injected into their back, indicating that oxalate does not induce cancer formation in all types of tissues. Moreover, neither human kidney-epithelial cells nor mouse fibroblast cells proliferate when are treated with oxalate. CONCLUSIONS: We found that the chronic exposure of breast epithelial cells to oxalate promotes the transformation of breast cells from normal to tumor cells, inducing the expression of a proto-oncogen as c-fos and proliferation in breast cancer cells. Furthermore, oxalate has a carcinogenic effect when injected into the mammary fatpad in mice, generating highly malignant and undifferentiated tumors with the characteristics of fibrosarcomas of the breast. As oxalates seem to promote these differences, it is expected that a significant reduction in the incidence of breast cancer tumors could be reached if it were possible to control oxalate production or its carcinogenic activity.

Expression of claudin, paxillin and FRA-1 in non-nodular breast lesions in association with microcalcifications.

CONTEXT AND OBJECTIVE: The possible role of adhesion molecules in early breast carcinogenesis has been shown in the literature. We aimed to analyze early adhesion imbalances in non-nodular breast lesions and their association with precursor lesions, in order to ascertain whether these alterations exist and contribute towards early carcinogenesis. DESIGN AND SETTING: Retrospective cross-sectional study based on medical records at a private radiological clinic in São Paulo, Brazil. METHODS: We retrospectively reviewed the medical records of all consecutive women attended between August 2006 and July 2007 who presented mammographic evidence of breast microcalcifications classified as Breast Imaging Reporting and Data System Atlas (BI-RADS) type 4. These women underwent stereotaxic biopsy. Clinical, radiological and pathological data were collected, and immunohistochemical assays searched for claudin, paxillin, FRA-1 and HER-2. RESULTS: Over this period, 127 patients were evaluated. Previous BI-RADS diagnoses showed that 69 cases were in category 4A, 47 in 4B and 11 in 4C. Morphological assessment showed benign entities in 86.5%. Most of the benign lesions showed preserved claudin expression, associated with paxillin (P < 0.001). Paxillin and HER-2 expressions were correlated. FRA-1 expression was also strongly associated with HER-2 expression (P < 0.001). CONCLUSIONS: Although already present in smaller amounts, imbalance of adhesion molecules is not necessarily prevalent in non-nodular breast lesions. Since FRA-1 expression reached statistically significant correlations with radiological and morphological diagnoses and HER-2 status, it may have a predictive role in this setting.

Analysis of gene expression pattern and neuroanatomical correlates for SLC20A2 (PiT-2) shows a molecular network with potential impact in idiopathic basal ganglia calcification ("Fahr's disease").

Familial idiopathic basal ganglia calcification (FIBGC), also known as "Fahr's disease," is a neuropsychiatric disorder with motor and cognitive symptoms. It is characterized pathologically by bilateral calcification most commonly in the basal ganglia and also in other brain regions such as the thalamus and cerebellum. A recent report by Wang et al. (2012) discovered multiple families with FIBGC carrying mutations in the SLC20A2 gene, encoding the inorganic phosphate transporter PiT-2, which segregated in an autosomal dominant pattern. To understand further the role of SLC20A2 in FIBGC brain pathology, here we described the gene expression pattern across the whole brain for SLC20A2, using the Allen Institute Human Brain Atlas database. Microarray analysis provided evidence that the neuroanatomical pattern of expression for SLC20A2 is highest in the regions most commonly affected in FIBGC. Neuroanatomical regions that demonstrated high correlation or anti-correlation with SLC20A2 expression also showed a molecular network with potential to explain the limited neuroanatomical distribution of calcifications in IBGC. Lastly, these co-expression networks suggest additional further candidate genes for FIBGC.

Expression of claudin, paxillin and FRA-1 in non-nodular breast lesions in association with microcalcifications / Expressão de claudina, paxilina e FRA-1 em lesões mamárias não nodulares associadas a microcalcificações

CONTEXT AND OBJECTIVE The possible role of adhesion molecules in early breast carcinogenesis has been shown in the literature. We aimed to analyze early adhesion imbalances in non-nodular breast lesions and their association with precursor lesions, in order to ascertain whether these alterations exist and contribute towards early carcinogenesis. DESIGN AND SETTING Retrospective cross-sectional study based on medical records at a private radiological clinic in São Paulo, Brazil. METHODS We retrospectively reviewed the medical records of all consecutive women attended between August 2006 and July 2007 who presented mammographic evidence of breast microcalcifications classified as Breast Imaging Reporting and Data System Atlas (BI-RADS) type 4. These women underwent stereotaxic biopsy. Clinical, radiological and pathological data were collected, and immunohistochemical assays searched for claudin, paxillin, FRA-1 and HER-2. RESULTS Over this period, 127 patients were evaluated. Previous BI-RADS diagnoses showed that 69 cases were in category 4A, 47 in 4B and 11 in 4C. Morphological assessment showed benign entities in 86.5%. Most of the benign lesions showed preserved claudin expression, associated with paxillin (P < 0.001). Paxillin and HER-2 expressions were correlated. FRA-1 expression was also strongly associated with HER-2 expression (P < 0.001). CONCLUSIONS Although already present in smaller amounts, imbalance of adhesion molecules is not necessarily prevalent in non-nodular breast lesions. Since FRA-1 expression reached statistically significant correlations with radiological and morphological diagnoses and HER-2 status, it may have a predictive role in this setting. .

CONTEXTO E OBJETIVO A literatura tem mostrado a importância de moléculas de adesão na carcinogênese precoce de mama. Objetivamos analisar desequilíbrios precoces de adesão em lesões não nodulares da mama e associação com lesões precursoras, a fim de verificar se essas alterações existem e contribuem com a carcinogênese. TIPO DE ESTUDO E LOCAL Estudo retrospectivo baseado em prontuários médicos, numa clínica radiológica privada em São Paulo, Brasil. MÉTODOS Revisamos retrospectivamente prontuários de todas as mulheres consecutivamente atendidas com evidência mamográfica de microcalcificações mamárias, classificadas como tipo 4 do Breast Imaging Reporting and Data System Atlas (BI-RADS) entre agosto de 2006 e julho de 2007. Elas foram submetidas a biópsia estereotáxica. Dados clínicos, radiológicos e histopatológicos foram coletados e ensaios de imunoistoquímica procuraram por claudina, paxilina, HER-2 e FRA-1. RESULTADOS No período, 127 pacientes foram avaliadas. Diagnósticos de BI-RADS anteriores tinham 69 casos na categoria 4A, 47 em 4B, e 11 em 4C. A avaliação morfológica mostrou entidades benignas em 86,5%. A maioria das lesões benignas mostrou expressão preservada de claudina, associada a paxilina (P < 0,001). Expressões de paxilina e HER-2 foram correlacionadas. Expressão de FRA-1 associou-se à de HER-2 (P < 0,001). CONCLUSÕES Embora já presente em menor quantidade, o desequilíbrio de moléculas de adesão não é necessariamente prevalente em lesões mamárias nodulares e talvez a expressão de FRA-1 possa ter um papel preditivo neste cenário, uma vez que atingiu correlações ...

Homocysteine is related to aortic mineralization in patients with ischemic heart disease.

UNLABELLED: Homocysteine is implicated as an early atherosclerotic promoter, which enhances the smooth muscle cell proliferation and produces free radicals that induce cellular damage. These factors must have a role in the progression of atherosclerosis that subsequently leads to vascular mineralization. AIM: Identify a correlation between the plasma concentration of total homocysteine and the amount of minerals that accumulate in the aorta of patients with atherosclerosis. METHODS: We performed a cross-sectional study in 13 patients with three-vessel coronary artery disease, undergoing coronary artery bypass surgery. Aortic and mammary artery specimens were analyzed using a scanning electron microscope with an energy dispersive X-ray spectrometer. The homocysteine was determined using an immunonephelometry method. RESULTS: The amount of minerals in the aorta was greater (300 ± 181.6 particles per 500 µm2 than that in the mammary artery (64 ± 45 particles per 500 µm2 (p < 0.01). The average tHcy was 9.5 ± 2.3 µmol/L. The Spearman's rank correlation coefficient was positive between tHcy, and aortic iron (p < 0.05). CONCLUSIONS: Our study demonstrates that the aorta is dramatically affected by mineralization compared to the mammary artery. In addition, a direct correlation was identified between the levels of tHcy and the iron particles in the aortic wall.

Skeletonized coronary arteries: pathophysiological and clinical aspects of vascular calcification.

The role of calcification in coronary artery disease is gaining importance, both in research studies and in clinical application. Calcified plaque has long been considered to be the most important atherosclerotic plaque within the arterial tree and frequently presents a challenge for percutaneous intervention. Current investigations have shown that plaque calcification has a dynamic course that is closely related to the magnitude of vascular inflammation. Numerous inflammatory factors synthesized during the early stages of atherosclerosis induce the expression and activation of osteoblast-like cells localized in the arterial wall that produce calcium. There is no doubt that the role of these factors in calcification associated with coronary artery disease could be a crucial strategic point in prevention and treatment. A number of diagnostic imaging methods have been developed in recent years, but their performance needs to be improved. In this context, we undertook an update on coronary calcification, focusing on physiopathology, clinical implications, and imaging techniques.

Alterações do metabolismo do cálcio, ferro, zinco e cobre / Changes in the metabolism of calcium, iron, zinc and copper

Os minerais são imprescindíveis na dieta de todos os seres humanos, mas em excesso podem provocar doenças

Phosphorus overload and PTH induce aortic expression of Runx2 in experimental uraemia.

BACKGROUND: Vascular calcification (VC) is commonly seen in patients with chronic kidney disease (CKD). Elevated levels of phosphate and parathormone (PTH) are considered nontraditional risk factors for VC. It has been shown that, in vitro, phosphate transforms vascular smooth muscle cells (VSMCs) into calcifying cells, evidenced by upregulated expression of runt-related transcription factor 2 (Runx2), whereas PTH is protective against VC. In addition, Runx2 has been detected in calcified arteries of CKD patients. However, the in vivo effect of phosphate and PTH on Runx2 expression remains unknown. METHODS: Wistar rats were submitted to parathyroidectomy, 5/6 nephrectomy (Nx) and continuous infusion of 1-34 rat PTH (at physiological or supraphysiological rates) or were sham-operated. Diets varied only in phosphate content, which was low (0.2%) or high (1.2%). Biochemical, histological, immunohistochemistry and immunofluorescence analyses were performed. RESULTS: Nephrectomized animals receiving high-PTH infusion presented VC, regardless of the phosphate intake level. However, phosphate overload and normal PTH infusion induced phenotypic changes in VSMCs, as evidenced by upregulated aortic expression of Runx2. High-PTH infusion promoted histological changes in the expression of osteoprotegerin and type I collagen in calcified arteries. CONCLUSIONS: Phosphate, by itself is a potential pathogenic factor for VC. It is of note that phosphate overload, even without VC, was associated with overexpression of Runx2 in VSMCs. The mineral imbalance often seen in patients with CKD should be corrected.

O hiperparatireoidismo secundário e a doença cardiovascular na doença renal crônica / Secondary hyperparathyroidism and cardiovascular disease in chronic kidney disease

Os pacientes portadores de doença renal crônica (DRC) apresentam elevado risco de complicações cardiovasculares (DCV). Esta associação foi primeiramente reconhecida nos pacientes em diálise, nos quais a incidência de morte por DCV é elevada. Nesses pacientes, fatores de risco nãotradicionais aliam-se aos tradicionais na promoção da DCV. Os distúrbios do metabolismo mineral são fatores de risco modificáveis, relacionados com calcificação vascular, mortalidade geral e cardiovascular. O mecanismo da calcificação vascular consiste em um processo ativo de precipitação de cálcio e fósforo e na presença de um desequilíbrio entre fatores estimuladores e inibidores da calcificação. A associação quer da remodelação óssea quer dosníveis séricos do PTH com a calcificação vascular não é clara. O efeito do PTH sobre o sistema cardiovascular não é explicado somente pela potencialização dos estados de hipercalcemia e hiperfosfatemia, ele atua na remodelação cardíaca e, portanto, sobre a morfologia e a função deste órgão.São necessários mais estudos para compreender o mecanismo fisiopatológico da DCV nos pacientes com DRC.

Adverse cardiovascular events are frequent complications of renal disease. This association was initially reported in end-stage renal disease patients inwhom cardiovascular death has a high frequency. In dialysis patients, non-traditional risk factors may act in concert with the traditional ones to the development of cardiovascular disease (CVD). Disorders of mineral metabolism are potentially modifiable and have been linked with cardiovascular outcomes indialysis population. Mechanisms involved in vascular calcification in CKD include active precipitation of calcium and phosphorus in the presence of markedly elevated extracellular concentrations, effect of calcification inducers or deficiency of inhibitors. The relationship between bone turnover and intact PTH concentration with vascular calcification were inconclusive. The adverse cardiovascular outcome in patients with high PTH concentrations is presumably not only explained by the association between PTH and high serum calcium and phosphorus concentrations. It also reflects direct adverse effects of PTH oncardiac function and morphology. The intrinsic effects of CKD on CVD risk profile are still unknown.

Bone metabolism and vascular calcification.

Osteoporosis and atherosclerosis are chronic degenerative diseases which have been considered to be independent and whose common characteristic is increasing incidence with age. At present, growing evidence indicates the existence of a correlation between cardiovascular disease and osteoporosis, irrespective of age. The morbidity and mortality of osteoporosis is mainly related to the occurrence of fractures. Atherosclerosis shows a high rate of morbidity and especially mortality because of its clinical repercussions such as angina pectoris, acute myocardial infarction, stroke, and peripheral vascular insufficiency. Atherosclerotic disease is characterized by the accumulation of lipid material in the arterial wall resulting from autoimmune and inflammatory mechanisms. More than 90% of these fatty plaques undergo calcification. The correlation between osteoporosis and atherosclerosis is being established by studies of the underlying physiopathological mechanisms, which seem to coincide in many biochemical pathways, and of the risk factors for vascular disease, which have also been associated with a higher incidence of low-bone mineral density. In addition, there is evidence indicating an action of antiresorptive drugs on the reduction of cardiovascular risks and the effect of statins, antihypertensives and insulin on bone mass increase. The mechanism of arterial calcification resembles the process of osteogenesis, involving various cells, proteins and cytokines that lead to tissue mineralization. The authors review the factors responsible for atherosclerotic disease that correlate with low-bone mineral density.

Vascular calcification: contribution of parathyroid hormone in renal failure.

Hyperphosphatemia is a driving force in the pathogenesis of vascular calcification (VC) and secondary hyperparathyroidism associated with renal failure. To test for the possible contribution of parathyroid hormone (PTH) to cardiovascular calcification, we removed the parathyroid glands from rats but infused synthetic hormone at a supraphysiologic rate. All rats were pair-fed low, normal, or high phosphorus diets and subjected to a sham or 5/6 nephrectomy (remnant kidney). Control rats were given a normal diet and underwent both sham parathyroidectomy and 5/6 nephrectomy. Heart weight/body weight ratios and serum creatinine levels were higher in remnant kidney rats than in the sham-operated rats. Remnant kidney rats on the high phosphorus diet and PTH replacement developed hyperphosphatemia and hypocalcemia along with low bone trabecular volume. Remnant kidney rats on the low phosphorus diet or intact kidney rats on a normal phosphorus diet, each with hormone replacement, developed hypercalcemia. All rats on PTH replacement developed intense aortic medial calcification, and some animals presented coronary calcification. We suggest that high PTH levels induce high bone turnover and medial calcification resembling Mömckeberg's sclerosis independent of uremia. This model may be useful in defining mechanisms underlying VC.