An international study led by a Tel Aviv University (TAU) researcher describes a novel technology that can assist many patients who are implanted with bioprosthetic heart valves. By genetically engineering the biological component in the valve, it is possible to avoid immunological attack and calcification risk, offering next-generation durable bioprosthetic heart valves.

Dr. Vered Padler-Karavani of TAU’s  Shmunis School of Biomedicine and Cancer Research led the study, a project of the EU-funded TRANSLINK consortium consisting of 14 members from Europe, United States, and Canada. The results were published in the journal Nature Medicine.

Many heart patients implanted with such bioprosthetic valves (made from bovine, porcine, or equine tissue) are forced to replace them ten years later due to calcification of valve tissue. “Since bioprosthetic heart valves are made of animal tissues, we hypothesized they contain foreign non-human sugars (Neu5Gc and alpha-Gal) that are attacked by the human immune system, which then mediate the calcification that lead to structural valve deterioration,” Dr. Padler-Karavani says. “Indeed, in our research we proved that this was the reason and even suggested an implementable solution.

“We discovered that all bioprosthetic heart valve patients developed an immune response against the foreign sugars in the valves. We could clearly see an increase in antibody responses against these sugars in implanted patients as early as one month after implantation, some lasting even two years later. We also found that some of the patients showed signs of calcification as early as two years post implantation.”

The researchers examined about 5,000 blood samples from about 1,700 individuals, covering almost 15 years since the valves’ implantation.

Anu Paul of Dr. Padler-Karavani’s lab demonstrated that the foreign sugars and the antibodies attacking them were found on calcified bioprosthetic heart valves explanted from patients some 10 years after implantation. Additionally, the dietary non-human sugar Neu5Gc and the antibodies against it were also found on explanted calcified native valves (the original malfunctioning human valves that needed to be replaced with a bioprosthesis).

Because this sugar is not produced in the human body, it most likely accumulates on these valves from diet rich in red meat and dairy products, where it is abundant. Therefore, it is possible that red meat diet mediates the initial need for valve replacement. The researchers also confirmed in a human-like animal model that antibodies against the foreign sugars indeed mediate calcification of tissues used for production of bioprosthetic heart valves.

Furthermore, the option to employ genetic engineering to resolve the problem was examined. For this purpose, the consortium created genetically modified pigs that do not express the sugars that are foreign to humans. The researchers found that, in a human-like animal model, engineered tissue lacking the foreign sugars exhibited significantly less calcification even in the presence of antibodies against the sugars, increasing the durability of bioprosthetic heart valves made of such tissues.

“This study marks breakthrough technology in the field of bioprosthetic heart valves and provides deep understanding of the mechanisms leading to structural valve deterioration,” Dr. Padler-Karavani concludes. “These findings can lead to a dramatic improvement in the quality of life of many heart patients. In the future it may also be possible to devise a modified diet to reduce the risk or to actually produce biological valves from the tissues of engineered animals that do not contain the sugars at all.”

The TRANSLINK consortium management team included Rafael Mañez, Jean-Christian Roussel, Jean-Paul Soulillou, and Emanuele Cozzi (the coordinator). Thomas Senage and Thierry Le Tourneau from France led investigation of the clinical arm of the study. At Dr. Padler-Karavani’s lab, the study was led by Anu Paul, currently a postdoctoral fellow at Harvard University, along with Salam Bashir and other researchers and students.