Why don’t we use immunosuppressants for artificial heart valves?
Progressive heart valve failure leads to dreadful outcomes, including heart failure and death. Valve replacement surgery emerged in the 1950s and 1960s as a surgical remedy for calcified aortic stenosis and regurgitation. This began in 1952 when Charles Hufnagle was the first to implant a plastic ball valve into the descending thoracic aorta a 30-year-old woman who had experienced rheumatic fever with the resulting damage to her aortic valve. The valve utilized a metal cage that housed a silicone elastomer ball. Hufnagle’s valve afforded her years of additional life that her native valve would not have provided. In the years that followed many valves were placed in the descending aorta with damaged native valves remaining in place. Although the grafts did not prevent regurgitation from the upper areas more proximal, they did prevent regurgitation from the aorta distal to this point and could therefore reduce the overall strain on the left ventricle. It took another eight years Dwight Harken inserted the first artificial cardiac valve in this “native” aortic valve position.
These early devices required anticoagulation and therefore came with the attendant risks. Notably, in the 1950s and 1960s, vitamin K antagonists with higher INR goals were used, augmenting the bleeding risk that comes with these drugs. This fueled an increased interest in the use of bioprosthetic valves. Unfortunately, early experimental attempts at using homografts (i.e., valves taken from human cadavers) were discouraging. Then, in 1956, Gordon Murray inserted a human cadaver aortic valve in the descending aorta of a patient with marked aortic regurgitation and a dilated cardiomyopathy. While Murray had utilized the descending aorta as the implant site, subcoronary (i.e., orthotopic) insertion was the goal. Despite early setbacks, Donald Ross succeeded when he placed the first subcoronary aortic-valve replacement with a homograft at Guy’s Hospital in London on July 24, 1962. The patient was a 43-year-old man with a “rare combination of severe calcific aortic stenosis and an ostium secundum atrial septal defect.” “The patient remained at work as a security officer until four years and five months after the operation, when heart failure developed while he was walking up a hill; he died soon after. Reading through these early accounts provides a reminder of how pioneers must accept failure. Ross’s surgical mortality was 71% in his first 31 cases. For many, this would have prompted an abandonment of the procedure. Not for Ross and his team. They instead made changes in operative technique and saw the mortality drop to to 15% in the subsequent 60 cases.
The 1960s saw the emerging use of these homografts. But the success of these human valves and their advantages over plastic or mechanical led to the realization that limited availability would preclude their wide use; as with any human organ or tissue transplant, demand outstrips supply. There were also issues raised about size mismatch. These issues led surgeons and researchers to explore the use of heterografts (also known as xenografts) in which a non-human valve would be used. In 1965 Duran and Gunning demonstrated that freeze-dried pig aortic valves could be transplanted into the descending aorta of dogs. Just a few months later, on September 23, 1965, a team of French surgeons replaced the calcific aortic valve of a 48-year-old woman with a 2.7cm pig valve. The report of this case and 4 others was published in December 1965. Pig valves were chosen over primates or other closer relatives for two main reasons. One is that the supply of pig valves is far greater. Another explanation is that pig hearts are similar in size and shape to human valves, making them a suitable choice.
The transition from plastic or metal devices to biologic valves (either from humans or other animals) obviated the need for anticoagulation but raised the question of whether immunosuppression might be required. Initially, the possibility of an immune rejection to foreign valve tissue prompted Ross to use cortisone as an immunosuppressant. These initial homografts were considered homovital, having been procured from cadavers using aseptic technique and transplanted as soon as possible. The time and logistical constrictions present with harvesting and preserving viable homovital homografts led to the development of other storage methods. Ross’s team began to use a freeze-dying method and observed that this process left valves “demonstrably free from cell nuclei… they are, in effect, inert frameworks of elastic and collagen fibres.” After initial studies showed no evidence of immune rejection but high rates of fungal infection the use of steroids was abandoned. As Davies and Ross wrote in 1965, “unlike kidney or lung homografts, this procedure does not depend for success on tissue compatibility or the suppression of immune reactions.” In a 1968 follow-up of 91 cases, Ross noted that “we have found no evidence of immune rejection of the graft.”
Many reasons were offered for the relative paucity of immune rejection, particularly when compared with solid organs. These included the idea that the valves represent dead tissue, that their molecules are weak antigens, that valves have poor vascular supply, or reasons specific to the subcororary position (e.g., rapid blood flow).
One particularly intriguing hypothesis is that valves represent an area of immune privilege. This is an evolutionary adaptation that protects vital tissues from immune destruction. Tissues that the human species would not be able to survive and maintain without. Classic examples are the eyes, testes, and placenta. If we “allowed” our immune system to destroy these areas, our species would die off.
The idea that valves may be a site of immune privilege was first offered by Mohri et al who wrote in 1967 “the reason for the delayed or absent rejection of the homologous aortic valve, especially the fresh viable valve, remains obscure. An explanation may rest with the low antigenicity of the homologous aortic valve or the ‘privileged site’ of the subcoronary position.” After studying fresh canine aortic valve allografts they found no microscopic evidence of rejection and concluded that the low antigenicity of the homologous aortic valve may indicate “a possible privileged site of the subcoronary position.”
More recent observations support this idea. Mitchell et al examined homograft hearts after death or retransplantation. Even in those who died from rejection, the aortic valves were spared without apparent immunologic injury.
Although immune privilege may explain the lack of immune response to homografts, it doesn’t offer an explanation for the paucity of rejection to xenografts. It is worth noting that xenotransplantation is riddled with failure, particularly when immunosuppression is not used. The primary basis of hyperacute rejection to xenografts is the immune response to galactose-α-1,3-galactose, also known as α-gal. We talked about α-gal and xenotransplantation in episode 70 when we covered meat allergies and cardiac xenotransplants from pigs. Most non-primates contain α-gal on their organ epithelium, but that humans lack this carbohydrate. As a result, α-gal is perceived as a foreign antigen by our immune system. Given this, one might expect a reaction to α-gal leading to hyperacute rejection of valve xenografts.
But, right from the first xenograft surgeries in the 1960s, immunosuppression wasn’t used and hyperacute rejection did not occur. However, there were high rates of valve failure. They just weren’t only acute failures. With these early surgeries, at one year, just 45-50% were well functioning. Explanted valves showed features indicating an immune response to the xenograft tissue.
A solution to this problem was offered by glutaraldehyde. This organic compound generates cross-links with amino groups of lysine or other amino acids resulting in “fixation” of the tissue. This reduces the antigenicity of the valves. After glutaraldehyde was added to the conditioning regimen, the rates of valve success at 1 year increased to 82%. Glutaraldehyde is one reason we don’t use immunosuppression after xenograft insertion: many antigens are masked by its cross-linking.
Although glutaraldehyde cross-links amino acids it has no effect on carbohydrates like α-gal. And there is evidence of an immune response to α-gal after valve replacement. This was suggested by a 2011 study by Bloch et al. It showed a sizable anti-α-gal antibody response even after glutaraldehyde treatment. This indicates that glutaraldehyde treatment does not eliminate the immune response to this antigen.
This means we have two discordant findings. The first is that glutaraldehyde does not eliminate the main antigen in acute rejection. The second is that patients receiving glutaraldehyde-fixed bioprosthetic xenografts don’t experience hyperacute rejection. The explanation for these findings comes from the observation of valve structure. Here it isn’t about immune privilege but instead about the amount of α-gal in different tissues. A clue comes from a 2000 study by Chen et al. They transplanted whole pig hearts into baboons. Although the hearts were acutely rejected within hours after implantation, the aortic and pulmonary valves were entirely spared. This and a follow-up study showed that although pig valve endothelium expresses α-gal, they do so much less intensely than aortic or vein endothelial cells. Less α-gal may mean a lesser immune reaction.
This does not mean that α-gal doesn’t matter when it comes to valves. Some have suggested that it is a factor in the slower degeneration we have seen from the first valve xenograft replacements in the 1960s and continue to see today. And given that bioprosthetic xenografts do elicit an immune reaction that likely contributes to this degeneration, some have wondered whether we ought to administer immunosuppression.
There is even evidence that those who experience meat allergy after tick bites that sensitize them to α-gal also have issues with valve replacements. There are emerging case reports showing that those with α-gal allergy experience accelerated valve degeneration. For example, one patient underwent bioprosthetic aortic valve replacement in 2004. This valve worked great through 2011. Then, in 2012, he developed urticaria six hours after eating steak, followed by similar episodes. In 2014, he developed shortness of breath and an echocardiogram showed severe aortic insufficiency and prosthetic valve deterioration. Labs were consistent with alpha-gal allergy. When they replaced the degenerated valve they found no evidence of endocarditis but the prosthetic valve leaflets were mostly destroyed. So α-gal allergy may not just reflect intolerance to red meat but could have broader implications as well.
Take Home Points
- Heart valves, particularly the aortic valve, may be tissue sites of immune privilege.
- Before placement, bioprosthetic valve fixation with glutaraldehyde reduces the antigenicity of the graft.
- α-gal is not affected by glutaraldehyde; it therefore contributes to valve degeneration.
- Valve tissue may have less α-gal leading to a lessened risk of acute rejection.
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Credits & Citation
◾️Episode and shot notes written by Tony Breu
◾️Audio edited by Clair Morgan of nodderly.com
Breu AC, Abrams HR, Cooper AZ. Valve Privilege. The Curious Clinicians Podcast. October 4, 2023.
Image credit: https://pubmed.ncbi.nlm.nih.gov/31972604/
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