UCL Institute of Cardiovascular Science
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Cardiovascular and thoracic surgery
Cardiovascular disease remains the leading cause of death in the developed world. Two common treatments for cardiac disease are cardiac valve replacement using chemically processed biological heart valves (BHV) from animal sources (cows, pigs) to treat valvular disease, and cardiac transplantation, a successful therapy for treating patients with end-stage organ failure. The durability of BHVs is limited by degenerative processes which lead to mechanical failure, calcification and stenosis. The benefits of cardiac transplantation are limited by a shortage of organs and the detrimental effects of chronic organ rejection. Increasingly there is recognition that human antibodies produced in response to BHV implantation or organ transplantation make a significant contribution to chronic BHV degeneration as well as to certain types of allograft rejection after transplantation. The role of antibody in inflammatory responses to biological devices and in organ rejection is the principal theme which underlies our research.
Key research activities
Heart valve disease occurs due to a birth defect, age related degenerative disease, and infections. About 500,000 surgeries to fix or replace heart valves are performed annually worldwide. Bioprosthetic heart valves are commonly produced from glutaraldehyde-fixed porcine aortic valves or sewn from fixed bovine pericardium. Such valves generally do not require anticoagulation, have a low level of thrombogenicity and are used principally in older patients as a durable therapy for heart valve disease. Over time biological heart valve degeneration occurs resulting in mechanical failure, calcification and stenosis requiring further surgery. Such degeneration is accelerated in younger patients. This process is due in part to immunological responses to the device. All patients produce a universal human preformed antibody which binds to a dominant carbohydrate antigen (alpha-Gal) present in animal tissues. Antibody to alpha-Gal is sufficient to accelerate calcification of glutaraldehyde-fixed tissues in experimental models. We use normal pig tissue and tissues from genetically modified pigs which do not produce the alpha-Gal antigen to determine the role of anti-Gal antibody in biological heart valve degradation.
Degeneration of biological heart valves occurs rapidly in younger patients. As a consequence, this group of patients is often treated with mechanical heart valves which require lifetime anticoagulation. We have defined an antibody (alpha-Gal) mediated inflammatory mechanism which enhances calcification. We have developed genetically modified sources of valves which do not make the Gal antigen (GTKO). Preclinical testing of fixed valves from GTKO sources will determine if this material can produce a biological heart valve with prolonged durability. Such valves would advance the standard of care as they would be expected to be more durable in older patients and could be used in younger patients currently treated with mechanical valves. This would eliminate the need for lifetime anticoagulation and the related risk of thromboembolic complications for these younger patients.
Experimental cardiac transplant models are used to elucidate the effects of ischemic injury and vascular antibody reactivity on cardiac gene expression, function and rejection. Genome wide expression studies are used to characterize changes in gene expression associated with ischemia reperfusion injury, as occurs during clinical cardiac transplantation, and with chronic vascular antibody deposition. These studies are used to define markers for better diagnosis of antibody mediated rejection and to gain insight into new therapeutic pharmacological or gene therapy treatments which minimize the effects of vascular antibody and enhance resistance to antibody mediated cardiac rejection.