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Biomedical subjects

R J Levy

Publications and source records attributed to R J Levy.

At least 109 records · Page 6Linked to original sources
PubMed1985

Inhibition by diphosphonate compounds of calcification of porcine bioprosthetic heart valve cusps implanted subcutaneously in rats.

Calcification limits the long-term success of heart valve bioprostheses fabricated from glutaraldehyde cross-linked porcine aortic valves. The pathophysiology of calcification of bioprostheses has been studied experimentally with subcutaneous implants of the valve cusps in rats; in this preparation, the accumulation of calcific deposits is biochemically and morphologically identical to that occurring in clinical specimens. The objective of the present study was to determine whether mineralization of bioprosthetic valve cusps (BC) subcutaneously implanted in 3-week-old male rats could be inhibited through the use of diphosphonate compounds. Ethanehydroxydiphosphonate (EHDP), administered by daily subcutaneous injection (25 mg/kg/24 hr) for 21 days inhibited calcification (BC Ca++ = 154.9 +/- 4.1), but caused somatic growth retardation and disruption of epiphyseal development. However, local administration of EHDP by osmotic pump (5 mg/kg/24 hr) implanted in direct contact with the cuspal tissue for 14 days prevented BC calcification (BC CA++ = 4.3 +/- 0.7) without adverse effects. Furthermore, EHDP given by osmotic pump had a prolonged effect on reducing calcification, as demonstrated by implants harvested 21 days (BC CA++ = 12.2 +/- 6.4) after the drug supply was exhausted. Finally, BC preincubated in aminopropanehydroxydiphosphonate for 24 hr before 21 day implantation underwent less calcification (CA++ = 24.2 +/- 7.4) than control valves (BC CA++ 126.6 +/- 7.5) with no adverse effects. We conclude that diphosphonates inhibit BC calcification, and that adverse effects of systemic therapy can be avoided by local administration.

Animals↗
PubMed1985

Onset and progression of experimental bioprosthetic heart valve calcification.

Calcification, the major cause of bioprosthetic heart valve failures, is a serious clinical problem with uncertain pathogenesis. The objectives of the present study were to define the progressive chemical and morphologic sequence of mineralization in glutaraldehyde-treated porcine aortic valve cusps implanted subcutaneously in rats and to compare the pathology and pathophysiology of calcification in subcutaneous implants with that of orthotopic valve replacements in calves. Cusps were implanted subcutaneously in 3-week-old rats for 24 hours to 18 weeks. Cuspal calcium was 114 +/- 18 micrograms/mg of dry weight (mean +/- SEM) at day 21 and 218 +/- 6 at day 56 of implantation and unchanged thereafter. The earliest mineral deposits, noted at 48 hours, were associated with devitalized porcine connective tissue cells, but by 7 days, mineral deposits also involved collagen bundles. Scanning electron microscopy with energy-dispersive x-ray analysis demonstrated predominant accumulation in the spongiosa with a spongiosa to fibrosa energy-dispersive x-ray analysis count ratio of calcium of 15 at 21 days. In stent-mounted glutaraldehyde-preserved porcine valves implanted in five calves as mitral replacements for 69 to 142 days, cuspal calcium was 86 micrograms/mg (mean) (range 47 to 128). Calf implants also had cell oriented and collagen calcification predominating in the valvar spongiosa. In both rat subcutaneous and calf mitral valve models, early diffuse calcific microcrystals evolved into confluent nodules that disrupted tissue architecture. It is concluded that calcification of glutaraldehyde-preserved porcine aortic valves implanted subcutaneously in rats begins within 48 hours, earliest deposits are localized to residual porcine connective tissue cells, but latter deposits also involve collagen fibrils, mineralization is most prominent in the spongiosa, the pathology of calcification in rat subcutaneous implants and calf mitral replacements is comparable, suggesting a common pathophysiology, and calcific nodule formation most likely initiates clinical features.

Animals↗
PubMed1985

Scanning electron microscopy methodology for study of the pathophysiology of calcification in bioprosthetic heart valves.

Scanning electron microscope (SEM) morphologic analysis combined with energy dispersive characteristic X-ray (EDX) microprobe analysis provides insight into the mechanisms associated with disease-related crystal formation in biological materials. SEM and EDX were employed in analyzing specimens which were embedded in standard fashion in glycolmethacrylate. The specimen surfaces under electron microscope investigation resulted from microtomy used in the preparation of reference light microscope histological sections; thus histology served as a direct reference for the SEM and EDX analyses. The particular application of these methods was in the study of bioprosthetic heart valve calcification, largely responsible for clinical failure of these heart valve substitutes. To simulate the clinically observed mineralization processes, glutaraldehyde-pretreated porcine heart valve leaflets were implanted subcutaneously in rats and subsequently removed at various time intervals from 1 to 56 days. Also, to address the hypothesis that the calcification process generates crystalline materials analogous to those in bone, EDX data obtained from pure hydroxyapatite were compared with the embedded tissue results. Further, EDX results were compared with data obtained by chemical analysis of the bulk specimens to assess the validity of the electron microscope technique.

Animals↗
PubMed1984

Treatment of status epilepticus with lorazepam.

Twenty-one episodes of status epilepticus (SE) were each treated with 1 to 9 mg (mean, 4 mg) of intravenous lorazepam. All patients with generalized tonic-clonic ( GTC ) SE responded within 15 minutes. Nine (82%) of the 11 patients with episodes of partial SE with altered responsiveness responded poorly. Respiratory depression occurred in five instances (two requiring intubation) and was associated with transient loss of brain-stem reflexes, hypotension, and decorticate posturing in three cases. Generalized tonic-clonic SE was transformed into partial SE with altered responsiveness in three patients. In an additional four patients, marked lethargy developed. Lorazepam appears effective in controlling GTC SE but only occasionally effective in partial SE with altered responsiveness.

Adult↗
PubMed1984

A matter of ethics.

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Analysis of Variance↗
PubMed1984

Bioprosthetic heart valve failure: pathology and pathogenesis.

Bioprosthetic heart valves are widely used because of their low risk of thromboembolic complications. The major limitation to the long-term success of these prostheses is caused by degenerative processes leading to late primary valve failure, including calcification. Research into these processes has suggested potential approaches for inhibiting calcification and other degradative phenomena.

Aortic Valve↗
PubMed1983

Mechanism of calcification of porcine bioprosthetic aortic valve cusps: role of T-lymphocytes.

Calcification of glutaraldehyde-preserved porcine aortic valve bioprosthetic cusps limits their success as cardiac valve substitutes. Subcutaneous implants of porcine bioprostheses in rats and rabbits have provided a convenient experimental tool to study this calcification process. Previous clinical research has suggested that the host's immune response to the porcine xenograft tissue may contribute to the calcific degeneration. To investigate the possible contribution of the immune response, porcine bioprosthetic cusps implanted subcutaneously in congenitally athymic (nude) BALBc mice and normal controls were analyzed biochemically and histologically after retrieval at 21 days. Calcification was comparable in implants retrieved from athymic (calcium 95.5 +/- 24.5 micrograms/mg) and normal mice (calcium 102.3 +/- 4.66 micrograms/mg). Explants from nude mice demonstrated fewer adherent cells than those from normal animals, but the morphologic characteristics of the calcification were the same in both groups, with dystrophic mineralization of the spongiosa predominating. Thus, normal T-lymphocyte function is not necessary for porcine bioprosthetic calcification, and immunologic processes do not contribute to this process.

Animals↗
PubMed1983

The identification of the vitamin K-dependent bone protein osteocalcin as one of the gamma-carboxyglutamic acid containing proteins present in calcified atherosclerotic plaque and mineralized heart valves.

Calcium binding proteins containing gamma-carboxyglutamic acid (Gla) have previously been demonstrated to occur in calcified atherosclerotic plaque and calcified cardiac valves. Experiments were carried out to determine if one of the Gla-containing proteins in human cardiovascular calcifications is the vitamin K-dependent bone protein, osteocalcin. A radio-immunoassay for human osteocalcin was employed, and EDTA extractions of calcified atheromata, and aortic valves as well as relevant noncalcified material were analyzed. Tissue calcium levels were also determined, as were Gla levels as a measure of total vitamin K-dependent protein content. Osteocalcin was present at low levels in all calcified cardiovascular tissues (4.5-175.7 ng osteocalcin/mg protein) with trace levels or nondetectable amounts present in noncalcified tissue. Osteocalcin accounted for a small proportion of the total protein-bound Gla (0.01-0.05%). The relationship of osteocalcin to the other Gla-containing proteins of atherosclerotic plaque including atherocalcin, the principal extractable Gla-containing protein of calcified plaque, is discussed.

1-Carboxyglutamic Acid↗
PubMed1983

Porcine bioprosthetic valve calcification in bovine left ventricle-aorta shunts: studies of the deposition of vitamin K-dependent proteins.

Calcification of glutaraldehyde-preserved bioprosthetic cardiac valves represents a serious clinical problem. Previous work from this laboratory has established the presence in clinical bioprosthetic valve calcifications of vitamin K-dependent calcium-binding proteins, which contain the calcium-binding amino acid gamma-carboxyglutamic acid; no proteins containing gamma-carboxyglutamic acid are present in nonmineralized valves. The purpose of the present study was to examine a series of bovine circulatory bioprosthetic valve explants for calcification and proteins containing gamma-carboxyglutamic acid. Biochemical analyses of explanted bioprosthetic valves from calves demonstrated proteins with gamma-carboxyglutamic acid accumulating in calcified valves during both the onset and progression of valve calcification; calcium levels in the explanted calf bioprostheses were in the same range as those noted in clinical material. Accumulation of calcium and protein with gamma-carboxyglutamic acid occurred simultaneously and progressively, beginning 2 months after implantation. Small amounts of osteocalcin, the bone-derived protein containing gamma-carboxyglutamic acid, were present in both human and bovine bioprosthetic valve calcifications at comparable levels. No osteocalcin was detectable in non-mineralized valve tissue. Warfarin anticoagulant therapy did not prevent calcification or accumulation of protein with gamma-carboxyglutamic acid. It is concluded that proteins containing gamma-carboxyglutamic acid are involved in both the onset and progression of bioprosthetic valve calcification, and that conventional means of vitamin K antagonism do not alter this association or the course of bioprosthetic valve mineralization.

1-Carboxyglutamic Acid↗
PubMed1983

Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats.

Bioprosthetic cardiac valve calcification is a frequent complication after long-term valve replacement. In this study the authors sought to examine the biologic determinants of this type of dystrophic calcification using subcutaneous implants of glutaraldehyde-preserved porcine aortic valve leaflets (GPVs) in rats. GPVs and clinical valvular bioprostheses were prepared identically. Retrieved implants were examined for calcification and the deposition of osteocalcin (OC), a vitamin K-dependent, bone-derived protein, that is found in other dystrophic and ectopic calcifications. GPVs implanted in 3-week-old rats calcified progressively (GPV Ca2+, 122.9 +/- 6.0 micrograms/mg) after 21 days, with mineral deposition occurring in a morphologic pattern comparable to that noted in clinical retrievals. Calcified GPVs accumulated osteocalcin (OC, 183.4 +/- 19.4 ng/mg); Nonpreserved porcine aortic leaflet implants did not calcify (Ca2+ + 5.6 +/- 1.0 micrograms/mg). Millipore diffusion chamber (0.45-mu pore size enclosed GPV implants accumulated calcium and adsorbed osteocalcin despite the absence of attached host cells. GPVs implanted for 21 days in 8-month-old rats calcified less (GPV Ca2+, 22.4 +/- 5.0 micrograms/mg) than did GPVs implanted in 3-week-old rats (see above). High-dose warfarin therapy (80 mg/kg) did not alter GPV calcification (GPV Ca2+, 39.6 +/- 2.9 micrograms/mg) in 72-hour subcutaneous implants in 3-week-old male rats, compared with control rats (GPV Ca2+, 40.8 +/- 4.8 micrograms/mg).

Age Factors↗
PubMed1982

Calcifications of cardiac valve bioprostheses. Biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system.

To study the process of calcification in bioprosthesis, 108 glutaraldehyde-treated porcine aortic valve leaflets were implanted subcutaneously in rabbits and removed 1 day to 6 months later; morphologic findings were correlated with biochemically determined levels of calcium (Ca++) and gamma-carboxyglutamic acid (Gla), a vitamin K-dependent Ca++-binding amino acid known to be present in a variety of tissues with pathological calcification. Gla and Ca++ levels began to increase about 2 months after implantation and increased progressively with time. Ca/Gla molar ratios were comparable to those in leaflets of bioprostheses explanted from patients, 22 to 64 months after implantation. Morphologically evident calcification began at the same time that Gla and Ca++ increases were detected biochemically and also increased in severity with time. Electron microscopy showed that calcification primarily involved the surface of collagen fibrils and the interfibrillar spaces. The biochemical and morphological findings in this experimental system are similar to those described in calcified porcine bioprosthetic valve leaflets removed from patients, but occurred much more rapidly. As with pathological calcification of other tissues, progressive calcification was accompanied by increased Gla levels, suggesting that Gla plays a role in the calcification of the leaflets. This model allows rapid comparative evaluation of large numbers of valve leaflets maintained under similar host conditions.

1-Carboxyglutamic Acid↗
PubMed1980

Vitamin K-dependent calcium binding proteins in aortic valve calcification.

The pathogenesis of valvar calcification, which complicates the course of cardiac valve disease and also affects tissue valve prostheses, is incompletely understood. The present work explores the possible role of the vitamin K-dependent, calcium-binding amino acid, gamma-carboxyglutamic acid (Gla) in valve mineralization. Gla is normally found in the vitamin K-dependent clotting factor proteins, and is also present in unique calcium binding proteins in bone, kidney, and lung. Unique Gla-containing proteins have also been isolated from pathologic calcifications including calcium containing renal stones and calcified atherosclerotic plaque. Calcified valves including specimens with calcific aortic stenosis, calcified porcine xenograft valves, and a calcified aortic homograft valve were analyzed for Gla content, complete amino acid analysis, and tissue calcium and phosphorus levels. Normal porcine valves contained protein-bound Gla (2.0-10.6 Gla/10(4) amino acids): no Gla was present in normal valve leaflets. Furthermore, Gla levels paralleled tissue calcium content in the calcified valves. In addition, complete amino acid analysis indicated a decline in valvar collagen content plus increased acidic proteins in conjunction with valvar calcification and the presence of Gla-containing proteins. These results suggest that calcific valvar disease may result in part from vitamin K-dependent processes.

1-Carboxyglutamic Acid↗