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

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

Our final objective is to produce a new more durable bioprosthetic heart valve. Heart valve disease occurs due to birth defect, infection and age related degeneration. About 500,000 operations to fix or replace heart valves are performed annually worldwide. There are two types of replacement valves, mechanical heart valves (MHVs) which require lifetime anticoagulation and bioprosthetic heart valves (BHVs) made from biological tissues, typically human or porcine heart valve leaflets or animal pericardium. BHVs are preferred in older patients where they are more durable. Patients under 60 generally receive MHVs due to more rapid age-dependent BHV calcification and degeneration. Significant efforts have been devoted to develop calcification resistant BHVs which could be used in younger patients without chronic anticoagulation.
BHV calcification is attributed to mechanical stress, passive calcium binding to phospholipids, and immune injury. Current anti-calcification treatments rely on phospholipid depletion. These processes are effective in animal models but have not improved BHV durability or permitted their routine use in younger patients. We have identified an antibody-mediated inflammatory process involving the dominant xenogeneic antigen galactose alpha 1,3 galactose (Gal) binding to universally present human anti-Gal antibody which enhances calcification of fixed Gal-positive (WT), but not Gal-free bioprosthetic materials. Growing evidence indicates that this antibody mediated inflammatory mechanism may significantly contribute to age-dependent calcification. Genetically modified pigs which do not make the Gal antigen (GTKO) are a potential new source for BHVs which resists anti-Gal induced calcification and may be more durable in younger patients. This study is designed to produce prototype BHVs made from WT and GTKO porcine pericardium and determine by in vitro testing their equivalence. This is an essential first step in commercial GTKO BHV development.

There are two main beneficiaries of this technology, patients affected by heart valve disease and manufacturers of replacement heart valves. Approximately 250,000 heart valve replacement operations are performed annually worldwide. The Society of Thoracic Surgeons National Database for aortic valve replacement (AVR) in North America shows an increase in the use of BHVs compared to MHVs. In 1997 43% of patients undergoing AVRs received BHVs which increased to 78% by 2006. The Society for Cardiothoracic Surgery in Great Britain and Ireland database shows a similar trend which extends even to patients under age 55 where BHV usage increased from 18 to 25% between 2004 and 2009. [3, 4] This shift represents the growing favour by patients and physicians for BHVs. Because of rheumatic heart disease (RHD), patients in developing nations likely represent an even larger more significantly affected end user patient population. The WHO estimates 15.6 million cases of RHD occur worldwide with an estimated 230,000 deaths annually. In developing countries these patients are often subject to suboptimal valve repair as the facilities to manage MHV anticoagulation are frequently not available.
Manufacturers of clinical heart valves (5 - 7 major corporations) are a second end user.
Successful demonstration in this proposal of equivalency between WT and GTKO BHVs is expected to enhance interest in this technology from industry manufacturers. Clinical development of a GTKO BHV is expected to broaden the patient population and improve the quality of life of recipients who receive this improved therapy.