Development of a Gal-free Calcification Resistant Porcine Pericardial Heart Valve.

心脏中有瓣膜，它们的作用是控制血液的正常流动。这些瓣膜可能由于出生缺陷、年老或反复感染风湿热而受损。如果不治疗，这是一个威胁生命的情况。每年大约有50万例手术用于修复或更换心脏瓣膜。置换瓣膜是由塑料和金属制成的机械瓣膜，或由通常从猪或牛获得的非活体组织制成的生物瓣膜。患者和医生更喜欢生物心脏瓣膜（BHV），因为它们在老年患者（最常见的群体）中工作时间较长，并且不需要每天使用必须与机械瓣膜一起使用的血液稀释剂。在年轻人（30 - 50岁）和儿童中，BHV通常在5年内迅速磨损。这些BHV失败是因为它们积累了骨样钙沉积物，这削弱了瓣膜，导致撕裂，或阻塞血流，因为它们阻塞了瓣膜的开口。长期以来，科学家和商业瓣膜公司一直在寻求生产不会钙化的BHV，因为这些BHV可以用于年轻患者，而不需要血液稀释剂。到目前为止，已经开发的钙化阻断治疗在动物试验中能够大大减少瓣膜钙化，但无法阻止钙化或扩大BHV在年轻成人中的使用。我们已经确定了一种免疫驱动的炎症，它会加速生物心脏瓣膜材料的钙化。这种炎症是人类独有的，因为他们的免疫系统的一部分与一种称为Gal的物质反应，这种物质不是由人产生的，而是通常在动物中产生并存在于BHV上。为了阻止这种免疫炎症，我们对猪进行了基因改造，使它们不再产生半乳糖，并表明这种不含半乳糖的组织钙化率降低。这些Gal基因敲除的猪是健康和正常的。本课题旨在比较由正常猪组织制成的BHVs与由无半乳糖组织制成的BHVs的力学功能。成功地进行了这些英国标准所要求的测试，是制造一种新的抗钙化的BHV的第一步，可能对年轻患者有用

There are valves in the heart which work to control the normal flow of blood. These valves may be damaged because of birth defects, old age, or after repeated infection with rheumatic fever. If left untreated this is a life threatening condition. There are about 500,000 surgeries to repair or replace heart valves each year. Replacement valves are either mechanical, made of plastic and metal, or biological, made of non-living tissue generally obtained from pigs or cows. Patients and doctors prefer biological heart valves (BHVs) because they work for a long time in older patients, the most frequent group, and do not require daily use of blood thinners which must be used with mechanical valves. In younger adults (30 - 50 years) and in children BHVs wear out rapidly, often within 5 years. These BHVs fail because they build up bone-like deposits of calcium which weaken the valve, leading to tears, or obstruct blood flow because they block the opening of the valve. Scientist and commercial valve companies have long sought to produce BHVs which do not calcify because these could be used in younger patients without the need for blood thinners. So far the calcification blocking treatments which have been developed have been able to greatly reduce valve calcification, when they are tested in animals, but have not been able stop calcification or broaden the use of BHV in younger adults. We have identified an immune driven inflammation which accelerates calcification of biological heart valve materials. This inflammation is unique to humans because a portion of their immune system reacts with a substance, called Gal, not made by people but commonly made in animals and present on the BHV. To block this immune inflammation we have genetically altered pigs so they no longer make Gal and have shown that this Gal-free tissue has a reduced rate of calcification. These Gal knockout pigs are healthy and normal. This project is designed to compare the mechanical function of BHVs made from normal pig tissue with the function of BHVs made from Gal-free tissue. Successfully performing these test which are required by British standards, is the first forward to making a new BHV which resists calcification and may be useful in younger patients