PATHOGENESIS AND PREVENTION OF VALVE CALCIFICATION

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Dystrophic calcification is the most common cause of failure to bioprosthestic valves. The pathogenesis of this complication is not clearly known and there are no effective and clinically safe preventive measures to mitigate or inhibit calcification. The mechanism of calcification of bioprosthetic valves and its prevention will be the subject of this proposed study. One particular calcium entry blocker, Diltiazem, is proposed to be tested in prevention of calcification in orthotopically implanted bioprosthetic valves in calves. From our results with valve tissue implantations in a rat model together with reported effectiveness of Diltiazem in prevention of calcification in atherosclerosis, we hypothesize that (1) a calcium entry blocker reacts with the plasma membrane components of dead cells as well as viable excitatory cells, and (2) a calcium entry blocker prevents dystrophic calcification which occurs in the plasma membrane components of dead cells and their subcellular components. The specific aims of this project are: (1) to investigate in vitro the effects of a calcium entry blocker on the calcium and phosphorus uptake process by degraded cells and extracellular matrix proteins. The evaluation will rely heavily on quantitative electron probe X-ray microanalysis to elucidate these crucial steps in dystrophic calcification; (2) To investigate in vivo effects of a calcium entry blocker on valve calcification using rat subcutaneous implantation to obtain a dose-response relationship, and in eventual orthotopic valve replacement in calves. The importance of glutaraldehyde as an accelerator in bioprosthetic valve calcification is still controversial. Since both glutaraldehyde-treated and non-treated materials are used in this program, a role of glutaraldehyde in calcification will also be investigated in both in vitro and in vivo experiments. Calcium entry blockers have not been investigated for prevention purposes of prosthetic valve calcification. From the results of our preliminary studies we anticipate that a calcium entry blocker will also suppress calcification of orthotopically implanted bioprosthetic valves. If this is proved to be true, in preventing calcification o cardiovascular implants, calcium entry blockers would be the drug of choice, which can be administered safely for a long term without significant side effects.