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PubMed1975

[The cardiovascular manifestations of Paget's disease].

After reviewing the old ideas (peripheral syndrome and cardiac insufficiency at high outputs) and more recent ideas (arterial and intracardiac vascular calcification), the authors report their experiences based on the study of the histories of 150 patients suffering from Paget's disease followed for several years. First they emphasize the frequent latency of cardiac manifestations looked for systematically by means of the electrocardiogram particularly during evolutive stages of the disease. Electrocardiographic disturbances were observed 91 times and included 43 cases of conduction disorders and 48 of repolarization disorders; their distribution was studied as a function of various inherent parameters, of the patient (age and sex) and of the disease (its evolutive character and its degree of diffusion). On the basis of the anti-arythmic power of calcitonin found during experiments and obtained excellent results three times. Finally the place of cardiovascular manifestations in the pathogenic hypotheses and nosology of Paget's disease is discussed.

Adult↗
PubMed2006

Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways.

Parathyroid hormone (PTH), the major systemic calcium-regulating hormone, has been linked to uremic vascular changes. Considering the possible deleterious action of PTH on vascular structures, it seemed logical to evaluate the impact of PTH on the receptor of advanced glycation end products (RAGE) and interleukin 6 (IL-6) mRNA and protein expression, taking into account that such parameters might be involved in the pathogenesis of vascular calcification, atherosclerosis, and/or arteriolosclerosis. Human umbilical vein cord endothelial cells (HUVEC) were stimulated for 24 h with 10(-12)-10(-10) mol/l PTH. The mRNA expression of RAGE and IL-6 was established by reverse transcriptase/PCR techniques. RAGE protein levels were determined by Western blot and IL-6 secretion was measured by ELISA. The pathways by which PTH may have an effect on HUVEC functions were evaluated. PTH (10(-11)-10(-10)mol/l) significantly increased RAGE mRNA and protein expression. PTH also significantly increased IL-6 mRNA expression without changes at protein levels. The addition of protein kinase (PKC or PKA) inhibitors or nitric oxide (NO) synthase inhibitors significantly reduced the RAGE and IL-6 mRNA expression and the RAGE protein expression. PTH stimulates the mRNA expressions of RAGE and IL-6 and the protein expression of RAGE. These stimulatory effects are probably through PKC and PKA pathways and are also NO dependent. Such data may explain the possible impact of PTH on the atherosclerotic and arteriosclerotic progression.

Atherosclerosis↗
PubMed2001

Determinants of arterial compliance in patients treated by hemodialysis.

BACKGROUND: Cardiovascular disease is the principal cause of morbidity and mortality among hemodialysis patients. Several studies have demonstrated the importance of a reduction in arterial compliance in the development of cardiovascular complications, reflecting the interaction of functional and structural alterations of the peripheral arterial system and left ventricle. The aim of the present study was to demonstrate that arterial compliance, evaluated by automated recording of the QKd interval, was lower in hemodialysis patients than in normal subjects. A secondary objective of the study was to assess the influence of several factors, including calcium-phosphorus parameters, on decreased arterial compliance in these patients. PATIENTS AND METHODS: Arterial compliance was evaluated in 24 chronic hemodialysis patients who had normal (n = 12) or high blood pressure (n = 12), using a method of measuring systolic wave velocity by automated recording of the QKd interval. This interval corresponds to the time (in ms) between the onset of the electrocardiogram QRS complex (Q) and the Korotkoff (K) sound at diastolic pressure (d) heard over the brachial artery during blood pressure measurement. The analysis was performed in comparison with reference values obtained in a population with normal renal function. The other parameters determined were: age, duration of chronic renal failure, duration of hemodialysis therapy, left ventricular mass, vascular calcification score, serum total and ionized calcium, phosphorus, parathyroid hormone, calcidiol, calcitriol, and blood concentration of hemoglobin. RESULTS: The arterial stiffness of all the patients was increased significantly (p < 0.001) compared to reference values obtained from subjects without renal failure, the average age, height, and blood pressure of whom were similar to those of the patients. Multivariate analysis demonstrated a positive relationship among the QKd interval, serum total calcium, and the duration of hemodialysis. This suggested that arterial wall elastic properties were dependent not only on hypertension and constraints of pressure, but that they were also influenced by calcium and phosphorus metabolism and the duration of renal substitution therapy. CONCLUSIONS: Arterial compliance, evaluated by the ambulatory method of QKd measurement, is reduced in chronic hemodialysis patients, and is inversely correlated with serum calcium concentration and dependent on the previous duration of hemodialysis therapy.

Adult↗
PubMed2006

Bone morphogenetic protein-induced MSX1 and MSX2 inhibit myocardin-dependent smooth muscle gene transcription.

During the onset and progression of atherosclerosis, the vascular smooth muscle cell (VSMC) phenotype changes from differentiated to dedifferentiated, and in some cases, this change is accompanied by osteogenic transition, resulting in vascular calcification. One characteristic of dedifferentiated VSMCs is the down-regulation of smooth muscle cell (SMC) marker gene expression. Bone morphogenetic proteins (BMPs), which are involved in the induction of osteogenic gene expression, are detected in calcified vasculature. In this study, we found that the BMP2-, BMP4-, and BMP6-induced expression of Msx transcription factors (Msx1 and Msx2) preceded the down-regulation of SMC marker expression in cultured differentiated VSMCs. Either Msx1 or Msx2 markedly reduced the myocardin-dependent promoter activities of SMC marker genes (SM22alpha and caldesmon). We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays. Our results showed that Msx1 or Msx2 formed a ternary complex with SRF and myocardin and inhibited the binding of SRF or SRF/myocardin to the CArG-box motif, resulting in inhibition of their transcription.

Amino Acid Sequence↗
PubMed2004

Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis.

BACKGROUND: Coronary artery calcification (CAC) is thought to be associated with greater cardiovascular mortality in patients with end-stage renal disease than in nonuremic persons. The purpose of the present study is to assess the effects of etidronate, a synthetic analogue of pyrophosphate, on progression of CAC score. METHODS: The extent of CAC was evaluated by using multidetector spiral computed tomography. Repeated CAC score estimation was possible in 35 patients (29 men, 6 women). Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Serum osteoprotegerin (OPG) was measured by using enzyme-linked immunoassay. Serum etidronate was measured by means of the gas spectrometry technique using deuterium-labeled etidronate as internal standard. RESULTS: Mean patient age was 63.2 +/- 8.2 (SD) years, and mean duration of dialysis therapy was 7.4 +/- 5.5 years. CAC score was estimated 3 times in each patient. After the second CAC score estimation, 35 patients were administered etidronate, 200 mg/d, for 14 days. This cycle was repeated 3 times every 90 days. CAC progression was significantly less pronounced during treatment with etidronate compared with the period before treatment was initiated. The median annualized absolute increase in calcified volume was 195.0 mm3 without treatment compared with -490.0 mm3 during treatment ( P < 0.01). Patients were divided into 2 groups based on changes in CAC score during etidronate treatment. Responders (n = 26) were patients whose CAC score decreased during therapy, and nonresponders (n = 9) were patients whose CAC score increased, even after etidronate therapy. Serum C-reactive protein values (0.18 +/- 0.13 mg/dL) in the responder group were greater than those (0.14 +/- 0.08 mg/dL) in the nonresponder group ( P = 0.013). Serum OPG levels decreased significantly during etidronate therapy (256.8 +/- 93.8 versus 245.0 +/- 83.0 pg/mL; P = 0.0161). Etidronate was well tolerated during the study. BMD values during etidronate therapy were not significantly changed from 0.941 +/- 0.125 to 0.968 +/- 0.246 g/cm2. CONCLUSION: Results of the present study suggest that the extent of CAC may be suppressed by etidronate in association with a reduction in chronic inflammatory responses. They also suggest that a decrease in serum OPG concentrations by means of etidronate may be associated with changes in vascular calcification in dialysis patients.

Aged↗
PubMed2005

Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease.

BACKGROUND: Patients with end-stage renal disease on maintenance dialysis therapy have a high prevalence of cardiovascular risk factors and cardiovascular disease (CVD). A similar finding is noted in patients with chronic kidney disease (CKD). The important contributors are premature and accelerated atherosclerosis and vascular calcification. We assessed the severity of arterial stiffness in 102 patients with CKD by using pulse wave velocity (PWV) and sought to identify associated risk factors. METHODS: PWV was measured by calculating the distance traveled by the flow wave and divided by the time delay. Correlations between PWV and traditional cardiovascular risk factors, estimated glomerular filtration rate (GFR) per 1.73 m2 , blood pressure (BP), and pulse pressure (PP) were analyzed. RESULTS: PWV values in patients with CKD stages 1 to 2 and the age-matched control group were similar. There was a significant trend for a stepwise increase in PWV corresponding to advance in CKD stage (P < 0.0001). Univariate linear regression analysis showed that age, prior CVD, diabetes, hypertension, any high risk, estimated GFR per 1.73 m2 , systolic BP, and PP correlated with PWV. In the multivariate model, decreased estimated GFR per 1.73 m2 and increased systolic BP were independently associated with increased PWV in patients with CKD (model R 2 = 0.539; P < 0.0001). CONCLUSION: This is the first study to show a greater PWV in patients with more advanced CKD from stages 1 to 5. Estimated GFR per 1.73 m2 and systolic BP were the major clinical determinants of arterial stiffness in patients with CKD independent of conventional risk factors for CVD.

Adult↗
PubMed2000

Rhabdomyolysis as the presenting manifestation of calciphylaxis.

A 43-year-old woman was admitted with progressive leg pains and weakness and was found to have rhabdomyolysis. Prior to this admission the patient had hypercalcemia, but this returned to normal following treatment with calcitonin. During the hospitalization, she developed the syndrome of calciphylaxis consisting of necrotic skin and muscle associated with vascular calcification. This is the first case report of rhabdomyolysis caused by calciphylaxis in a patient without chronic renal failure.

Adult↗
PubMed2006

Transcriptional co-repressors of Runx2.

Runx2 is an essential transcription factor for skeletal mineralization because it stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones. Runx2 is also expressed during mouse embryo development in nascent mammary gland epithelium. Recent evidence implicates deregulation of Runx2 as a contributing factor in breast cancer-induced osteolysis and invasion, as well as in ectopic vascular calcification. Like other Runt domain proteins, Runx2 is a context-dependent transcriptional activator and repressor of genes that regulate cellular proliferation and differentiation. Proteins that temporally and spatially associate with Runx2 dictate these opposing transcriptional activities. Recent studies have identified several co-repressor proteins that bind to Runx2 to regulate gene expression. These co-factors include histone deacetylases (HDACs), transducin-like enhancer of split (TLE) proteins, mSin3a, and yes-associated protein (YAP). These proteins do not bind DNA themselves and appear to act by preventing Runx2 from binding DNA, altering chromatin structure, and/or by possibly blocking co-activator complexes. The nuclear localization of several of these factors is regulated by extracellular signaling events. Understanding the mechanisms whereby co-repressor proteins affect Runx2 activity during normal cellular development and tumor progression will identify new therapeutic targets for skeletal disorders such as osteoporosis and for bone metastatic cancers.

Animals↗
PubMed1988

Paleoradiologic evaluation of the Egyptian royal mummies.

We examined radiographs of 12 Egyptian royal mummies obtained by two of the authors (W.R. and J.E.H.) and never before published. These radiographs demonstrate findings not previously described in Egyptian mummies, including congenital lunate-triquetral fusion and destructive skeletal lesions not explainable on the basis of vandalism by tomb robbers. Antemortem fractures, degenerative joint disease, and arterial vascular calcification were also seen. In 11 of the 12 cases, there was chondrocalcinosis of intervertebral discs or menisci, probably an artifact of embalming. Visceral packing and skeletal deformity due to wrapping were observed, as well. Radiology provides important paleopathologic and archeologic information for the accurate, comprehensive study of Egyptian mummies.

Bone Diseases↗
PubMed1978

Specificity of computed tomography in the diagnosis of supratentorial neoplasms. Consideration of metastases and meningiomas.

A previously unsuspected linear relationship between the initial density and the amount of uptake of various tumors is described. As a rule, initially radiodense neoplasms enhance less than radiolucent neoplasms. For a given amount of enhancement, meningiomas are initially more radiodense than metastases; also, breast metastases are more radiodense than lung metastases. The density versus uptake curve tends to show certain specificity for a given type of neoplasm. Absolute differentiation of histologic types is still not possible on the basis of these curves. The correlation, however, is interesting and seems to be related to the amount of damage to the blood-brain barrier and the degree of calcification, vascularity, and cellularity of the various tumors. With improved precision of scanners the specificity of the CT image may be improved.

Brain Neoplasms↗
PubMed1998

Hypercalcemia associated with dysgerminoma: case report and imaging findings.

Hypercalcemia associated with malignancy is rare in children. We report a case of hypercalcemia associated with ovarian dysgerminoma in a 13-year-old girl with renal medullary calcinosis and vascular calcifications. To our knowledge this is the first report of the imaging findings in this condition and only the fourth case report of hypercalcemia associated with dysgerminoma.

Adolescent↗
PubMed2004

Multislice spiral CT angiography in peripheral arterial occlusive disease: a valuable tool in detecting significant arterial lumen narrowing?

The aim of this study was to evaluate the potential of multislice CT angiography (CTA) in detecting hemodynamically significant (> or =70%) lesions of lower extremity inflow and runoff arteries. Fifty patients (42 men, 8 women; mean age 68 years) with peripheral arterial occlusive disease underwent multislice spiral CTA and digital subtraction angiography (DSA) from the infrarenal aorta to the supramalleolar region. CT parameters were 4x2.5-mm collimation, 15-mm table increment/rotation (pitch 6), and 1.25-mm reconstruction increment. Semitransparent volume rendering technique (STVR) images with semitransparent display of the arterial lumen (opacity: 50%) and vascular calcifications (opacity: 20%), as well as maximum intensity projection (MIP), and MIP together with axial CT studies were independently reviewed for hemodynamically significant lesions (> or =70% cross-sectional area reduction). DSA was the standard of reference. In 46 patients, 260 lesions were found (95 stenoses, 165 occlusions). For detecting > or =70% lesions in all vessel regions, sensitivity and specificity were 84% and 78% (STVR), 89% and 74% (MIP), and 92% and 83% (MIP+axial CT), respectively, with a significantly lower sensitivity of STVR ( p<0.05) and a significantly lower specificity of MIP studies ( p<0.01). Sensitivity and specificity were, respectively, 81% and 93% (STVR), 88% and 75% (MIP). and 92% and 95% (MIP+axial CT) at aortoiliac arteries, 92% and 73% (STVR), 95% and 70% (MIP) and 98% and 70% (MIP+axial CT) at femoropopliteal arteries, as well as 82% and 64% (STVR), 86% and 74% (MIP), and 90% and 74% (MIP+axial CT) at infrapopliteal arteries. Specificity of MIP-CTA was significantly lower in the aortoiliac region ( p<0.01), whereas STVR revealed significantly lower specificity at infrapopliteal arteries ( p<0.05). In the infrapopliteal region, the particular CTA imaging modalities led to misinterpretation regarding stenoses and occlusions in 39-45 cases, whereas only 0-6 significant aortoiliac and femoropopliteal lesions were misinterpreted. Multislice CTA is helpful in detecting hemodynamically significant lesions in peripheral arterial occlusive disease. Since axial CT studies yielded the most correct results, they should always be reviewed additionally. In the infrapopliteal region, exact lesion assessment remains problematic due to small vessel diameters.

Aged↗
PubMed1999

Acute arterial occlusion associated with total knee arthroplasty.

Acute arterial occlusion is a rare but limb-threatening complication in total knee arthroplasty. Most of the previously reported cases of this complication required surgical intervention. This report illustrates an unusual case of this complication that was managed conservatively with an acceptable outcome. The case is also indicative of the etiology and the optimal prevention of this complication. In a patient with advanced arteriosclerosis, as indicated by vascular calcification around the knee or in the abdomen, knee arthroplasty should be performed without a tourniquet, and intra-operative manipulation should be done cautiously because of the potential for intimal disruption.

Acute Disease↗
PubMed2004

New Vitamin D analogues for osteodystrophy in chronic kidney disease.

Vitamin D therapy for patients with chronic kidney disease has until recently comprised alfacalcidol or calcitriol, both of which effectively attenuate secondary hyperparathyroidism and the target organ consequences thereof. Unfortunately, both these agents also have significant calcaemic and phosphataemic actions leading to frequent episodes of hypercalcaemia, hyperphosphataemia and an increase in the CaxP product. It is likely that these in turn have adverse effects on cardiovascular and survival outcomes by promoting soft tissue and vascular calcification. These drawbacks have fuelled a search for vitamin D compounds with a wider therapeutic window. Experimentally, some of these have exhibited remarkable dissociation between their ability to suppress parathyroid hormone (PTH) and concomitant calcaemic actions. In the case of 22-oxacalcitriol, the calcaemic potency relative to parathyroid suppression is 100th of that of calcitriol. 22-oxacalcitriol, with paricalcitol and doxercalciferol, are now widely used. Clinical studies of these agents, while confirming efficacy that is at least as good as alfacalcidol/calcitriol, have not consistently shown benefit in head to head comparison. Experience with these agents in the paediatric arena is very limited. One placebo-controlled study has now been completed in children-paricalcitol appeared effective and well tolerated. Calcimimetics, which simultaneously lower PTH, calcium and the CaxP product are about to enter the clinical arena-early studies in adults look promising, although they will need careful evaluation in children. These two therapies are likely to be additive and will probably complement one another effectively.

Child↗
PubMed2005

Are new vitamin D analogues in renal bone disease superior to calcitriol?

Progression of chronic kidney disease is associated with an early reduction in serum calcitriol levels; thus, therapy with calcitriol should be initiated early in the course of chronic kidney disease to prevent the development of secondary hyperparathyroidism. Initial studies demonstrated a potential role of calcitriol in the prevention of growth retardation in children with chronic kidney disease prior to dialysis. But the optimal parathyroid hormone (PTH) levels that will maximize growth response during calcitriol treatment remain to be defined. Therapy with calcitriol has been shown to control the biochemical and skeletal manifestations of secondary hyperparathyroidism, but patients developed hypercalcemia, hyperphosphatemia and adynamic osteodystrophy. Thus, new vitamin D analogues with a lower hypercalcemic response have been developed. Although comparative studies are lacking, current evidence indicates that these new active vitamin D sterols (19-nor-paracalcitol and doxercalciferol) adequately control secondary hyperparathyroidism with minimal changes in serum calcium and phosphorus levels during treatment with calcium-containing binders. The long-term effect of such therapies on the skeleton and the process of vascular calcifications remain to be evaluated.

Calcitriol↗
PubMed2005

Chronic kidney disease and inflammation in pediatric patients: from bench to playground.

Signs of an activated immune system can be observed already in the early stages of chronic kidney disease (CKD). Markers of a chronically activated immune system are closely linked to several complications of CKD, such as accelerated atherosclerosis, vascular calcification, insulin resistance, increased muscle catabolism, loss of appetite, bone remodeling, and increased peritoneal permeability. Interestingly, all the aforementioned pathological states resemble a state of accelerated ageing and are strongly associated with increased morbidity and mortality in CKD patients. In recent studies, signs of inflammation have been shown as predictors for mortality in dialysis patients, and the role of inflammation as a risk factor for complications of CKD in children has emerged. Although preliminary findings suggest that inflammation is highly prevalent in the pediatric population with CKD, information related pathogenic links and to clinical outcomes is lacking. For the future, it is crucial for investigations to address the mechanisms and complications of inflammation that are manifested in pediatric patients with CKD in all stages. Since early identification and intervention may generate the most efficient strategies for prevention and treatment of cardiovascular disease in CKD patients, the pediatric population deserves special attention in future studies. In this review, we discuss the mechanisms involved in the inflammatory activation and the main causes and consequences of the inflammatory state observed in the CKD patient, with special emphasis on the pediatric population.

Aging↗
PubMed2005

Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines.

Childhood renal osteodystrophy (ROD) is the consequence of disturbances of the calcium-regulating hormones vitamin D and parathyroid hormone (PTH) as well as of the somatotroph hormone axis associated with local modulation of bone and growth cartilage function. The resulting growth retardation and the potentially rapid onset of ROD in children are different from ROD in adults. The biochemical changes of ROD as well as its prevention and treatment affect calcium and phosphorus homeostasis and are directly associated with the development of cardiovascular disease in pediatric renal patients. The aims of the clinical and biochemical surveillance of pediatric patients with CRF or on dialysis are prevention of hyperphosphatemia, avoidance of hypercalcemia and keeping the calcium phosphorus product below 5 mmol(2)/l(2). The PTH levels should be within the normal range in chronic renal failure (CRF) and up to 2-3 times the upper limit of normal levels in dialysed children. Prevention of ROD is expected to result in improved growth and less vascular calcification.

Algorithms↗
PubMed2006

Bone mineral density in children with chronic renal failure.

Bone mineral density (BMD) is important in children and adolescents because of its relationship to long-term skeletal health, and because, in adults with chronic renal failure (CRF), a relationship between low BMD and vascular calcification has been suggested. To investigate the relationship between BMD and manipulable factors that might affect it, i.e. plasma calcium, phosphate and parathyroid hormone (PTH), 64 patients with a median glomerular filtration rate (GFR) of 31 (range 7-60) ml min(-1) 1.73 m(-2) and median age of 10.0 (4.1-16.9) years were followed over 1.3 (0.7-1.7) years at an average of 5 (3-14) clinic visits. At one visit, BMD of the lumbar spine was measured by dual energy X-ray absorptiometry. The mean BMD Z-score was normal (=0.0). Overall mean calcium, phosphate and PTH levels were in their respective normal ranges. The majority of the patients (72%) were treated with calcium carbonate, mean dose 65 mg kg(-1) day(-1); prescription was positively related to serum calcium levels and calcium-phosphate product (P=0.012 and P<0.01 respectively). Almost all patients (98%) were treated with alfacalcidol, mean dose 12 ng kg(-1) day(-1); prescription was not related to investigated factors. Patients grew well; there was no change in height standard deviation score (DeltaHtSDS=0.0). Normal BMD Z-score for age and sex can be achieved in children with CRF managed with the aim of maintaining normal PTH levels by dietary phosphate restriction, calcium-based phosphate binders and small doses of alfacalcidol. Further investigation of the underlying bone by the use of biopsy and histomorphometry is required to determine actual bone health.

Absorptiometry, Photon↗