Association between self-replicating calcifying nanoparticles and aortic stenosis: a possible link to valve calcification
Miguel-Angel Bratos-PerezPedro L. SánchezSusana García de CruzEduardo VillacortaIgor F. PalaciosJosé M. Fernández‐FernándezSalvatore Di StefanoAntonio Orduña‐DomingoYolanda CarrascalP. MotaCándido Martín‐LuengoJavier BermejoJosé Alberto San RománA Rodríguez‐TorresFrancisco Fernández‐Avilés
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Abstract:
Among various hypotheses proposed for pathological tissue calcification, recent evidence supports the possibility that self-replicating calcifying nanoparticles (CNPs) can contribute to such calcification. These CNPs have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. We evaluated calcific aortic valves for the presence of CNP. Calcific aortic valves were obtained from 75 patients undergoing surgical valve replacement. The control group was formed by eight aortic valves corresponding to patients with heart transplants. In the microbiology laboratory, valves were screened for CNP using a 4–6 weeks specific culture method. The culture for CNP was positive in 48 of the 75 valves with aortic stenosis (64.0%) in comparison with zero of eight (0%) for the control group (P = 0.0005). The observation of cultures by way of scanning electron microscopy highlighted the resemblance in size and morphology of CNP. Self-replicating calcific nanometer-scale particles, similar to those described as CNP from other calcific human tissues, can be cultured and visualized from calcific human aortic valves. This finding raises the question as to whether CNP contribute to the pathogenesis of the disease or whether they are only innocent bystanders.Keywords:
Pathogenesis
Objective
To analyze the clinical features of juvenile dermatomyositis (JDM) combined with soft-tissue calcification.
Methods
Forty-seven patients with JDM combined with soft-tissue calcification (soft-tissue calcification group) were retrospectively analyzed, and they were contrasted with 89 patients with non-calcification (non-calcification group).
Results
The rates of Gotton signe, muscle contracture and joint dysfunction in soft-tissue calcification group were significantly higher than those in non-calcification group: 87.23% (41/47) vs. 43.82% (39/89) and 68.09% (32/47) vs. 21.35% (19/89), and there were statistical differences (P<0.05). The dosage of glucocorticoid (conversion of prednisone measuring more than 1.5 mg/kg), rate of using immunodepressant, level of creatine kinase in soft-tissue calcification group were significantly lower than those in non-calcification group: 17.02% (8/47) vs. 68.54% (61/89), 25.53% (12/47) vs. 88.76% (79/89), (566.45±240.41) U/L vs. (1 680.12±656.50) U/L, and there were statistical differences (P<0.05).
Conclusions
The patients with JDM combined with Gotton signe are more prone to soft-tissue calcification. The rate of muscle contracture and joint dysfunction in soft-tissue calcification patients is significantly higher than that in non-calcification patients. For the patients whose creatine kinase are not obviously elevated, they are more prone to soft-tissue calcification. Early active application of glucocorticoid and immunodepressant therapy can reduce or prevent the occurrence or development of late calcium deposition.
Key words:
Dermatomyositis; Retrospective studies; Solt-tissue calcification
Juvenile Dermatomyositis
Creatine kinase
Dystrophic calcification
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Among various hypotheses proposed for pathological tissue calcification, recent evidence supports the possibility that self-replicating calcifying nanoparticles (CNPs) can contribute to such calcification. These CNPs have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. We evaluated calcific aortic valves for the presence of CNP. Calcific aortic valves were obtained from 75 patients undergoing surgical valve replacement. The control group was formed by eight aortic valves corresponding to patients with heart transplants. In the microbiology laboratory, valves were screened for CNP using a 4–6 weeks specific culture method. The culture for CNP was positive in 48 of the 75 valves with aortic stenosis (64.0%) in comparison with zero of eight (0%) for the control group (P = 0.0005). The observation of cultures by way of scanning electron microscopy highlighted the resemblance in size and morphology of CNP. Self-replicating calcific nanometer-scale particles, similar to those described as CNP from other calcific human tissues, can be cultured and visualized from calcific human aortic valves. This finding raises the question as to whether CNP contribute to the pathogenesis of the disease or whether they are only innocent bystanders.
Pathogenesis
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The purpose of this study was to characterize the onset and progression of mineralization in porcine bioprosthetic valves implanted in sheep and to test the hypothesis that such valves simulate calcification that is observed clinically and in other experimental models. Hancock I porcine aortic bioprosthetic valves (Medtronic Heart Valve Division, Irvine, Calif.) were implanted as orthotopic mitral valve replacements in juvenile sheep, retrieved after 1 to 124 days, and analyzed as follows: gross inspection, radiography, light, transmission, and surface scanning electron microscopy, and calcium analysis by absorption spectroscopy. Mineralization increased with increasing time after implantation in both valve cusps and adjacent aortic wall. Mean cuspal calcification was 80 micrograms/mg in valves removed after 3 to 4 months. Nevertheless, considerable variability among valves was apparent in the level of calcification noted at specific time intervals. Virtually all aspects of the morphologic characteristics were identical to those previously noted for clinical explants and experimental specimens, both subcutaneous and circulatory. In particular, ultrastructural examination revealed that the earliest calcific deposits were associated with devitalized cuspal connective tissue cells and their fragments. Collagen calcification was sparse. Both surface scanning and transmission electron microscopy indicated a lack of endothelial or blood-derived cells on the valves at all sampling times. We conclude that porcine bioprosthetic valves implanted as mitral valves in sheep provide a useful calcification model, simulating morphologic and pathobiologic events that occur clinically and in noncirculatory models. However, sufficient specimen replicates must be done to overcome variability in calcification among valves and sampling sites.
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Aortic valve calcification that is visualized on chest radiographs is considered a marker for clinically significant aortic stenosis, but the clinical importance of this finding on CT is unknown. Accordingly, we studied the prevalence and clinical relevance of aortic valve calcification found incidentally on CT scans of the chest. After comparing computer records of chest CTs and echocardiograms, we identified 109 patients who underwent both studies during a 2-year period. Two thoracic radiologists reviewed the CT scans to identify and quantify aortic valve calcification. The quantity of aortic valve calcification was graded on a scale of 1 to 3, with grade 3 indicating the most severe calcification. The prevalence of calcification was correlated with patient age and sex. The findings on CT were correlated with hemodynamic data from echocardiography. At echocardiography, a peak aortic valve gradient of greater than 25 mm Hg was defined as abnormal. Aortic valve calcification was noted on CT scans in 33 (30%) of the 109 patients. Aortic valve calcification shown by CT was significantly more common in patients more than 65 years old (p < .01). Five (15%) of 33 patients with aortic valve calcification shown by CT had abnormal aortic valve gradients at echocardiography. In contrast, none of 76 patients without aortic valve calcification shown by CT had abnormal aortic valve gradients (p < .01). All five patients with abnormal aortic valve gradients had moderate quantities of aortic valve calcification seen on CT scans. Two of the five were younger than 55 years old. Aortic valve calcification is a common finding on CT scans and is usually clinically insignificant. Nevertheless, some patients with aortic valve calcification on CT have aortic stenosis, particularly those younger than 55 years old and those with moderately dense aortic valve calcification shown by CT. These patients may benefit from hemodynamic assessment of the aortic valve by echocardiography.
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Calcification of bioprosthetic heart valves fabricated from glutaraldehyde (GA)-pretreated heterograft tissue is frequently responsible for the clinical failure of these devices. Stentless bioprostheses fabricated from GA-fixed porcine aortic valves pose an important challenge in this regard, as pathologic calcification can affect not only the bioprosthetic cusps, but also the aortic wall segment.A synergistic approach was used to prevent bioprosthetic cusp and aortic wall calcification. Ethanol pretreatment of bioprosthetic heart valves was shown to inhibit cuspal calcification due to multiple mechanisms, including alterations of collagen structure and lipid extraction. AlCl3 pretreatment of bioprostheses to prevent calcification was also investigated; this alters elastin structure, inhibits alkaline phosphatase, and complexes with phosphoesters, thereby inhibiting aortic wall mineralization.Experimental data from rat subdermal implants and sheep mitral replacements showed successful synergism with co-pretreatment of porcine aortic valve bioprostheses with ethanol and AlCl3. Significant inhibition of both cusp and aortic wall calcification was achieved by differential pretreatments that restrict AlCl3 to only the aortic wall, and not the cusp, accompanied by ethanol cuspal exposure. Sequential exposure of bioprostheses, first to AlCl3 and then to ethanol, led to unexpectedly severe cuspal calcification.Differential pretreatment of stentless bioprostheses with ethanol and AlCl3 can effectively inhibit both cuspal and aortic wall calcification.
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We fabricated PDMS microfluidics with an internal collagen hydrogel to develop a bench-top model of calcific aortic valve disease.
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REPORTS of metastatic calcification in the skin are uncommon, even though it was described by Jadassohn1 as long ago as 1910. Metastatic calcification is seen in diseases associated with chronically elevated blood calcium and phosphorus levels. In contrast, dystrophic calcification occurs in diseases associated with local tissue injury, in which serum calcium and phosphorus levels remain normal.2 Recently, Selye3 described an experimental form of soft-tissue calcification called "calciphylaxis." This form of calcification occurred in rats when acute calcium mobilization, which of itself would not induce metastatic calcification, was followed by an injury or challenge, which also of itself would not . . .
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