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Pathogenetic mechanism of senile calcific aortic stenosis: the role of apoptosis.

OBJECTIVE: To investigate the pathogenetic mechanisms leading to the development of calcific degeneration of the aortic valve in the elderly patients with particular reference to the relationship between apoptosis and calcification in the aortic valve tissue. METHODS: High resolution scanning and transmission electron microscopic observations of the calcified aortic valves obtained during aortic valve replacement were carried out in 10 patients with senile calcific aortic stenosis. RESULTS: Various degrees of endothelial alterations from focal disruption of individual endothelial cells to extensive denudation of entire endothelium were observed particularly on the aortic side of the valve tissues. The apoptotic changes occurring in the nuclei of endothelial cells and fibroblasts were common findings in the calcified valve tissues. It was noteworthy that the severity of endothelial damage was closely related to apoptotic changes of the fibroblasts. Calcific deposits were frequently observed in association with the cellular fragments mainly derived from the apoptotic fibroblasts. CONCLUSIONS: Our results strongly indicate that apoptosis may play an important role in the alterations of endothelial integrity leading to the increased filtration of calcium into the deeper layer of the valve tissues. Then, the cellular degradation products and organelles extruded from the dead cells, mainly resulted from apoptosis provided the substrates for calcium binding with progressive development of calcification in the valve tissue. Although the role of apoptosis in contribution to the pathogenesis of senile calcific aortic stenosis is evident, further studies using modern molecular biotechnology are mandatory in order to clarify the mechanism for the initiation of apoptotic process in the endothelial cells and fibroblasts.

Aged↗

[Aortic calcification and matrix metalloproteinases].

OBJECTIVE: To study the relationship between arterial calcification and matrix metalloproteinases including MMP-1 and MMP-3. METHODS: 15 human aorta specimens from autopsies were stained with HE to identify calcification. Immunohistochemical method was used to determine the secretion of MMP-1 and MMP-3. RESULTS: Among the 15 aorta specimens, calcification was found in 10 and no calcification in the remaining 5. There was no significant difference in the percentage of MMP-1 positive cells between two groups, with 83.8% +/- 5.2% in calcified specimens vs 84.0% +/- 7.5% in non calcified ones. 9 of the 10 calcified aortas were positive for MMP-3 staining. Serial sections showed that the localization of positivity was in concordance with calcified regions. The 5 normal aortas were MMP-3 negative. The difference between the two groups was significant. CONCLUSION: MMP-3 secretion relates closely with arterial calcification. And MMP-3 may participate in calcium minerali-zation in arteries. MMP-1 has no relation with arterial calcification.

Aorta↗

[Prevalence of vertebral fractures and aortic calcifications in hemodialysis patients: comparison with a population of the same age and sex].

Dialysis patients have bone metabolic disorders and a higher prevalence of fractures, principally peripheral fractures. However, there are few studies focusing on the prevalence of vertebral fractures. Moreover, aortic calcifications are very common and are an independent predictive factor of vascular morbidity and mortality. The objective of this study was to assess the prevalence of vertebral fractures and vascular calcifications in haemodialysis (HD) patients (n = 99), in comparison with a random sample of general population of similar age and from the same geographical area (n = 624) and study their relationship with clinical, biochemical and therapeutical data. The prevalence of vertebral fractures in HD patients and general population was 19.1% and 24.1% respectively (non-significant statistical differences). In both, sexes, the presence of vertebral fractures was positively associated with age, mean maximum Ca, mean maximum CaxP. In women, time in HD was positively associated as well. On the other hand, the prevalence of aortic calcifications was much higher in HD patients (77.9% vs 37.5%, p < 0.001). HD was a risk factor for aortic calcification in women [OR = 7.7 (IC 95% = 2.6-22.9)] as in men [OR = 5 (IC 95% = 1.9-12.9)]. Severe vascular calcifications were more frequent in HD patients, it reached 57.4% compared with 17% of general population (p < 0.001). Both, in women (64.5% vs 13.3% p < 0.001) and in men (51.4% vs 20.9%), respectively (p < 0.001). In conclusion, the prevalence of vertebral fractures was similar in HD patients and in general population. Nevertheless, frequency and severity of aortic calcifications was higher in HD patients.

Aged↗

[Clinical significance of thyroid nodule calcification].

To confirm the predictive value of calcifications in thyroid nodules as a risk factor for malignancy and to detect specific aspects for tumours, in a set of 175 patients--30 papillary carcinoma (PC) and 145 multinodular goiters (MNG) with dominant nodule--calcifications were detected by ultrasound scan. Calcifications were significantly more frequent in PC than in MNG (40% vs 20.7% p < 0.05) but their considered characteristics (size, number, position, location in the gland, sonographic features of the nodule) did not show any particular difference between PC and MNG. The frequency of calcifications in our series was higher in older patients (mean age 58.7 +/- 13.3 vs 51.1 +/- 12.7 in patients without calcifications, p < 0.001) and this could imply that their onset is time-dependent. Calcifications can be a useful indicator of enhanced risk, to be considered in the overall process of surgical decision making.

Adult↗

Clinical value of calcifications in thyroid carcinoma and multinodular goiter.

BACKGROUND: To confirm the predictive value of calcifications in thyroid nodules as a risk factor for malignancy and to detect aspects specific for tumours. MATERIALS AND METHODS: In a set of 196 patients (33 differentiated thyroid carcinoma, 9 follicular adenomas and 154 multinodular goiters with dominant nodule) calcifications were detected by ultrasound scan. RESULTS: Calcifications were significantly more frequent in differentiated thyroid carcinoma (DTC) than in benign diseases (DTC 39.4%, adenoma 11.1%, goiter 20.1%) but their considered characteristics (size, number, position, location in the gland, sonographic features of the nodule) did not show any particular difference between DTC and benign diseases. The frequency of calcifications in our series was higher in older patients (mean age 59.4 +/- 13.7 vs. 52.1 +/- 13.1 in patients without calcifications, p < 0.001) and this could imply that their onset is time-dependent. CONCLUSION: Calcifications can be a useful indicator of enhanced risk, to be considered in the overall diagnostic process.

Adenoma↗

[Significance of two-dimensional echocardiography in the diagnosis of mitral valve calcification--sensitivity and specificity].

The effect of two-dimensional echocardiography in assessment mitral valve calcifications was compared to computed tomography (CT) in 50 patients with pure rheumatic mitral stenosis (MS). Echocardiography revealed no mitral calcifications in 23 patients, respectively 46 per cent (grade 0). Twelve patients (24 per cent) had calcifications smaller than 2.5 mm (grade 1). Eleven (22 per cent) had moderate calcifications, smaller than one half of length of the anterior mitral leaflet (grade 2) and four (8 per cent) had calcifications larger than one half of the length of the anterior mitral leaflet (grade 3). The last two groups were thought to have clinically important calcifications. Specificity and sensitivity were examined in comparison to CT. By echocardiography, five (ten per cent) false positive findings were found in the group 2. There were neither false positive nor false negative findings in the last two group. The first group when compared with other three groups showed sensitivity of 100, specificity of 85, and predictive accuracy of 81 per cent. But the first two groups together compared with the last two groups showed sensitivity, specificity and predictive accuracy of 100 per cent.

Adult↗

Evaluation of mammographic calcification.

Breast calcifications can be classified into ductal, lobular, or miscellaneous types. Analysis is less difficult using this classification. Frequently, the characterization of miscellaneous types is straightforward. The analysis of ductal type and lobular type microcalcifications is more challenging. If they are scattered, the most important determination is whether or not there are casting calcifications present. If so, malignancy cannot be excluded. If clustered, then analysis of their form becomes critical. Teacup or pearl type calcifications are benign. Granular or casting calcifications are malignant. Mammographic calcifications that appear obviously malignant or highly suspicious for malignancy warrant biopsy whether or not a mass is clinically palpable. If calcifications are obviously benign, then routine follow-up at four to six month intervals if there is a high probability that they are benign. Otherwise, they are biopsied at the discretion of the clinician.

Breast Neoplasms↗

[Thyroid nodules with calcification and thyroid carcinoma].

OBJECTIVE: To investigate the significance of thyroid calcification for diagnosis of thyroid carcinoma. METHODS: Retrospective analysis of 817 thyroid nodules' pre-operative ultrasonic and postoperative pathologic results. RESULTS: Total ultrasonic thyroid calcification ratio was 18.1% (148/817). Total pathologic thyroid calcification ratio was 19.6% (160/817), which in benign samples was lower than that in malignant samples (13.1% vs 53.5%, P < 0.01). Micro-calcification ratio in benign samples was lower than that in malignant samples (2.9% vs 38.6%, P < 0.01). CONCLUSIONS: Thyroid nodules with calcification especially micro-calcification is considered to be the most specific sign of thyroid carcinoma, so the detection of it should be an important diagnostic criterion.

Adolescent↗

Calcification of allograft aortic wall in a rat subdermal model. Pathophysiology and inhibition by Al3+ and aminodiphosphonate preincubations.

Aortic allograft conduits and valves frequently undergo calcific degeneration. To study this problem, a rat subdermal model of nonvalved aortic wall allograft calcification was characterized, and experimental studies were carried out to test the hypothesis that aortic allograft preincubation in either amino-propanehydroxydiphosphonate (APDP) or AlCl3 would inhibit calcification in a rat subdermal model. Fresh thoracic aortas were harvested under sterile conditions from male Sprague-Dawley rats (350-400 g). APDP aortas were preincubated immediately in either 4 x 10(-3) mol/l, 4 x 10(-4) mol/l, or 4 x 10(-5) mol/l [14C] APDP (37 degrees C, pH 7.4) and controls were incubated in 0.05 mol/l HEPES buffer (pH 7.4, 37 degrees C, 30 min). Al3+ aortas were preincubated in either 10(-1) mol/l, 10(-2) mol/l, or 10(-3) mol/l AlCl3. Pretreated aortas were next implanted subdermally in weanling rats (3-week-old, male, Sprague-Dawley, 50-60 g) and retrieved after 21 days. Control explants retrieved at intervals up to 21 days demonstrated progressive calcification with bulk aortic allograft Ca2+ levels increasing from a preimplant value of 0.8 +/- 0.1 micrograms/mg to 129.8 +/- 12.9 micrograms/mg by 21 days. Light microscopy revealed that much of the calcium deposition was associated with elastin. Calcification was significantly inhibited in the 4 x 10(-3) mol/l and 4 x 10(-4) mol/l APDP preincubated groups was observed (Ca2+ = 0.70 +/- 0.15 micrograms/mg, 36.6 +/- 19.8 micrograms/mg, respectively versus 117.2 +/- 24.3 micrograms/mg, control). Inhibition of calcification in the groups preincubated in the two most concentrated AlCl3 solutions (Ca2+ = 13.9 +/- 4.9 micrograms/mg [10(-2) mol/l AlCl3], 36.6 +/- 7.1 micrograms/mg [10(-3) mol/l AlCl3], 171.0 +/- 13.2 micrograms/mg [control]) was also demonstrated. No adverse effects of either pretreatment, APDP, or AlCl3 were noted on bone or overall somatic growth.

Aluminum↗

ADAPT-treated porcine valve tissue (cusp and wall) versus Medtronic Freestyle and Prima Plus: crosslink stability and calcification behavior in the subcutaneous rat model.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the crosslink stability and calcification behavior of porcine tissue (cusp and wall), treated with a new antimineralization process (ADAPT) with that of commercially prepared Freestyle and Prima Plus bioprosthetic tissues. METHODS: Porcine aortic roots were divided into two groups: (i) tissue zero pressure-fixed with 0.625% glutaraldehyde (GA) for seven days and stored in 0.25% GA (as control); and (ii) tissue exposed to the ADAPT process for four days and stored in 0.25% buffered GA. These groups were compared with Freestyle and Prima Plus tissues (cusp and wall). Crosslink stability was assessed by shrinkage temperature and resistance to pronase degradation. Calcification behavior was assessed histologically (Von Kossa staining) and by atomic absorption spectrophotometry of explanted tissue after eight weeks. in a subcutaneous rat model. RESULTS: Crosslink stability and calcification potential of ADAPT-treated porcine valve cusps were comparable to those of Freestyle and Prima Plus cusps (p = NS). ADAPT-treated porcine wall tissue showed improved crosslink stability (p <0.05) and significantly (p <0.001) reduced calcification (-95.95%) compared to control (-0.00%), Freestyle (-47.87%) and Prima Plus (-51.95%) tissues. CONCLUSION: The ADAPT process is effective in reducing calcification in both porcine cusp and wall tissues in a subcutaneous rat model, and further suggest that enhanced crosslinking plays an important role in minimizing aortic wall calcification.

Animals↗

Calcium oxalate in breast lesions biopsied for calcification detected in screening mammography: incidence and clinical significance.

Two types of calcification have been reported in breast tissue: one appears as dark-blue deposits in routine histologic tissue sections and has been found to be composed mostly of calcium phosphate (CaP); the other is colorless and represents calcium oxalate (CaOx). CaP has been well characterized, but little is known about CaOx. The presence of CaOx was evaluated in 91 breast lesions (71 retrospective and 20 prospective cases) biopsied for the presence of calcification in screening mammography. CaOx was found in 36 cases (39%). CaOx is usually not clearly visible in routine histologic sections. CaOx is found as refractile, strongly birefringent crystals with characteristic morphology. CaOx was present only within benign lesions which frequently showed apocrine metaplasia. However, the breast tissue away from the areas with CaOx displayed a morphologic spectrum roughly similar to that in cases with CaP only. CaOx was clinically significant, i.e., actually represented the mammographic calcification, for which the biopsy was performed in 12% (11/91) of all cases studied and in 31% (11/36) of cases in which CaOx was found. In the cases where CaOx was not considered clinically significant, it was either not radiographically visible or, if visible, did not definitely represent the mammographic calcification for which the biopsy was performed. Since CaOx in breast biopsies is often clinically significant, and since CaOx is not clearly visible in routine sections, examination under polarized light is suggested for all breast biopsies removed for mammographic calcification, particularly when CaP deposits corresponding to the mammographic calcification are not apparent.

Adult↗

[Genetic basis of arterial calcification for diabetes mellitus].

Frequency of arterial calcification is high in diabetic patients, particularly in those with end-stage renal disease. A familial syndrome of aortic calcification, difference in the prevalence of arterial calcification among different races and different strains of mice suggest the contribution of genetic factor to arterial calcification. Among candidate genes, a common polymorphism in the promoter of Matrix matalloproteinase 3 gene (MMP3) has been reported to be associated with arterial calcification. Elucidation of genetic basis of arterial calcification will contribute to develop effective methods for prediction, prevention and intervention of this complication.

English Abstract↗

[Degenerative calcification of mitral and aortic valves].

The heart of the elderly is characterized by increased occurrence of characteristic calcifications on mitral and aortic valves. These valves have been found calcified in persons older than 70 years at about equal frequency, in nearly 50% of these individuals simultaneously. A calcified mitral ring was more common in females of all age classes, aortic calcifications showed a less marked difference for gender. Only the most severe calcifications of the mitral ring have hemodynamic consequences. The clinical significance of these calcifications lie in their propensity for bacterial colonisation. The risk for infective endocarditis rises tenfold. Aortic valves, calcified by degenerative processes, lead to more pronounced alterations of hemodynamics. In nearly one half of the patients this type of calcification results in stenosis with corresponding left ventricular hypertrophy. Since coronary arteriosclerosis has a similar age distribution the risk for ischemic heart disease is increased. Early and particularly frequent calcifications of the aortic valve develop in patients with bicuspid valves. Risk for infective endocarditis is also raised by a factor of ten in patients with calcified aortic valve.

Aged↗

Calcification of human valve interstitial cells is dependent on alkaline phosphatase activity.

BACKGROUND AND AIM OF THE STUDY: The calcification of heart valves is associated with valve degeneration and failure, but the mechanisms involved are poorly understood. The presence of lamellar bone has been demonstrated in calcified aortic valves. Since osseous calcification is closely associated with alkaline phosphatase (ALP) activity, it was hypothesized that ALP activity might be implicated in the calcification of isolated leaflet interstitial cells (ICs). METHODS: Human valve leaflet ICs were isolated from transplant-explanted hearts at the time of transplantation (n = 12). RESULTS: Isolated leaflet ICs expressed the fibroblast-specific antigen (100% of cells) and smooth muscle (SM) alpha-actin (70-80% of cells), but osteoblastic markers were not expressed. Cultured ICs did not calcify spontaneously, however when the growth medium was supplemented with beta-glycerophosphate (an organic phosphate) it induced the formation of calcified nodules that expressed osteonectin and ALP, but not SM alpha-actin. Beta-glycerophosphate-induced calcification of ICs showed a time-dependent effect on the calcium content of treated cells over a 14-day period. ALP activity was considerably increased in beta-glycerophosphate-treated ICs, and this correlated with the calcium content (r = 0.5: p = 0.01). Levamisol (an ALP inhibitor) inhibited the beta-glycerophosphate-induced calcification process, as well as the expression of osteoblastic differentiation markers. CONCLUSION: Isolated and cultured leaflet ICs did not calcify spontaneously, though organic phosphate induced the formation of calcified nodules that expressed osteoblastic markers. The calcification of isolated ICs was seen to be dependent on ALP activity.

Actins↗

[Development and factors related to the appearance of diaphragmatic pleural calcifications--follow up study of employees in an asbestos plant].

Seventy-eight subjects who had continuously worked for more than 25 years until 1985 in an asbestos plant were investigated for diaphragmatic pleural lesions (mainly calcifications) on chest roentgenograms. Diaphragmatic pleural lesions were found in 21 cases (32 sites). Among these cases, calcifications were found in 18 cases (26 sites) and bilateral calcifications in 8 cases. In retrospective observation, 19 sites initially showed diaphragmatic protuberant shadows, and of these, 13 sites subsequently showed calcification in the same positions. The duration between first exposure and appearance of calcification ranged from 15 years to 31 years. The duration of exposure was significantly correlated to the appearance of diaphragmatic pleural calcification, whereas age, smoking habit, and exposure level showed no significant correlation.

Adult↗

Effectiveness of radial shock-wave therapy for calcific tendinitis of the shoulder: single-blind, randomized clinical study.

BACKGROUND AND PURPOSE: Radial shock-wave therapy (RSWT) is a pneumatically generated, low- to medium-energy type of shock-wave therapy. This single-blind, randomized, "less active similar therapy"-controlled study was performed to evaluate the effectiveness of RSWT for the management of calcific tendinitis of the shoulder. SUBJECTS: Ninety patients with radiographically verified calcific tendinitis of the shoulder were tested. METHODS: Subjects were randomly assigned to either a treatment group (n=45) or a control group (n=45). Pain and functional level were evaluated before and after treatment and at a 6-month follow-up. Radiographic modifications in calcifications were evaluated before and after treatment. RESULTS: The treatment group displayed improvement in all of the parameters analyzed after treatment and at the 6-month follow-up. Calcifications disappeared completely in 86.6% of the subjects in the treatment group and partially in 13.4% of subjects; only 8.8% of the subjects in the control group displayed partially reduced calcifications, and none displayed a total disappearance. DISCUSSION AND CONCLUSION: The results suggest that the use of RSWT for the management of calcific tendinitis of the shoulder is safe and effective, leading to a significant reduction in pain and improvement of shoulder function after 4 weeks, without adverse effects.

Adult↗

Lower serum calcium levels are associated with greater calcium hydroxyapatite deposition in native aortic valves of male patients with severe calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the relationship between serum calcium levels and the degree of calcification found in stenotic aortic valves. METHODS: Using atomic absorption spectroscopy, the hydroxyapatite content of 228 excised human stenotic aortic valves was determined and expressed as a percentage of valve mass. Left heart catheterization preceded valve replacement. In addition, serum levels of calcium and creatinine were determined before native calcific aortic valve excision. RESULTS: Valves from male patients contained more hydroxyapatite than those of female patients (26 +/- 9 versus 22 +/- 9 mass%; p < 0.001). Patients presenting with lower serum calcium levels showed a slight trend towards higher levels of valve calcification (r = -0.15, p = 0.026), but this association appeared only within the subgroup of male patients. Male patients with lowest serum calcium levels displayed greatest valvular hydroxyapatite deposition (1st calcium tertiary: 29.5 +/- 8.9 mass% versus 2nd calcium tertiary 26.4 +/- 7.8 mass% versus 3rd calcium tertiary 21.4 +/- 8.9 mass%; n = 122; p = 0.001; r = -0.25; p = 0.006). This association was even more distinct in male patients with normal serum creatinine levels. Furthermore, serum calcium was inversely and significantly associated with serum C-reactive protein in male patients (r = - 0.34; p < 0.001). CONCLUSION: Serum calcium levels appear to be inversely related to valve calcification in patients with severe calcific aortic stenosis (AS). This finding indicates the importance of systemic calcium metabolism in calcific AS, independent of manifest disorders of calcium metabolism or renal function. Interestingly, this association was evident only in male patients, suggesting a gender-dependent pathogenesis.

Aged↗

[Analysis of some risk factors of coronary artery calcification in peritoneal dialysis patients].

Cardiovascular disease (CVD) is a major cause of death in peritoneal dialysed patients (PD-pts). Coronary artery calcification (CAC) is likely to affect the development of CVD. Purpose of our study was to evaluate coronary artery calcification and risk factors of this calcification in PD-pts. We studied 62 patients (38 F, 24 M) undergoing peritoneal dialysis (PD). Coronary calcification was examined by ECG-gated multidetector CT (Light Speed Ultra) using Agatson (AG) and volumetric (V) methods. Patients were divided into 3 groups depending on mean value of estimated CAC: group A-no calcification, group B-CAC maximal value 400 mm3, group C-CAC value more than 400 mm3. As risk factors of CAC were evaluated: patients age, sex, dialysis duration, serum concentration of Ca, P, homocysteine CRP and fibrinogen, as well as, CaxP product, intact PTH; presence of diabetes or hypertension. Coronary artery calcification was detected in 68% of patients. In the whole observed population positive correlation between CAC determined by AG and V methods and CRP (r = 0.36, p < 0.05) as well as patients age (r = 0.5, p < 0.01) was observed. There was also positive correlation between CAC and fibrinogen concentration (AG CAC r = 0.58, p < 0.05; V CAC r = 0.72, p < 0.05). When compared group C with the groups A and B cardiovascular complications were in this group more frequent than in the last two: 4 patients from group C died because of cardiovascular complications.

Adult↗