Scientific achievements usually raise big new questions, and the remarkable surgery that took place on January 7, when Maryland resident David Bennett was transplanted with a genetically modified heart from a pig, has been no different.
The 57-year-old with end-stage heart failure had been repeatedly turned down for a standard transplant and was judged a poor candidate for a ventricular assist device. Now his new heart is beating soundly and apparently accepted by his immune system as Bennett, his physicians at the University of Maryland where the procedure took place, and indeed the world set out on a journey with far more unknowns than knowns.
“I think even just a couple of years ago, people felt that xenotransplantation for the heart and other organs was still a long way off. And it seems like it’s started to move very quickly,” Larry A. Allen, MD, MHS, University of Colorado School of Medicine, Aurora, told theheart.org | Medscape Cardiology.
Demand for donor hearts far outstrips supply, and despite advances in the development of ventricular assist pumps and artificial hearts, “there are still significant limitations to them in terms of clotting, stroke, and infection. We’ve seen the use of those devices plateau,” Allen said. “So, the concept of a nonhuman source of organs is exciting and very much in need, if people can get it to work.”
“I really credit the surgeons at the University of Maryland for courageous clinical work and a brilliant scientific innovation. But it’s always in the implementation that we have to hold our breath,” Clyde W. Yancy, MD, MSc, Northwestern University, Chicago, said in an interview.Heart xenotransplantation is an old idea that “has never before been successful,” he said. And standard heart transplantation has set a high bar, with a 1-year survival of about 90% and low 1-year risk for rejection. Whether the new procedure can meet that standard is unknown, as is its potential for complications, such as chronic rejection or cancers due to long-term immunosuppression. Those are “major questions requiring more time and careful follow-up.”
“Still a Nascent Technology”
“This is an exciting and courageous step forward in heart transplantation, and kudos to the team at the University of Maryland,” said Mandeep R. Mehra, MD, Brigham and Woman’s Hospital, Boston. But “there are many challenges here.”
The procedure’s 10 gene modifications were reportedly aimed at preventing hyperacute rejection of the heart and its excessive growth after transplantation, and making the organ less immunogenic, Mehra told theheart.org | Medscape Cardiology. But even if those goals are met, could the same changes potentially impede the heart’s adaptation to human physiology, such as during ambulation or stress?
That kind of adaptation may become important. For example, Mehra observed, normally a pig heart “provides flow in a four-footed configuration, and pig temperature is inherently higher than humans by several degrees, so it will be functioning in a relatively hypothermic environment.”
Transplantation remains the gold standard for patients with advanced heart failure despite modern medical and device therapy, Allen agreed. But “if we can raise pig hearts that provide the organ, and it can be implanted with a surgery that’s been done for 50 years, and rejection can be managed with gene editing and tailored immunosuppression, then it’s not hard to think about this very rapidly replacing a lot of what we do in the advanced heart failure and transplantation world.”
Certainly, it would be a major advance if the gene editing technique successfully improves the heart’s immunologic compatibility, Yancy noted. But do we have enough genomic knowledge to select gene deletions and insertions in the safest way for a successful outcome? “We have to appreciate that this is still a nascent technology, and we should be careful that there might be consequences that we haven’t anticipated.”
For example, he said, the xenotransplantation and gene-modifying techniques should be explored in a range of patients, including older and younger people, women and men, and people of different ethnicities and races.
“There may be some differences based on ancestry, based on gender, based on aging, that will influence the way in which these engineered donor hearts are experienced clinically,” Yancy said.
The xenotransplantation technique’s potential impact on health equity should also be considered, as it “almost assuredly will be a very expensive technology that will be utilized in a very select population,” he noted. “We need to have a really wide lens to think about all of the potential ramifications.”
“This Field Needs to Evolve”
Mehra also flagged the procedure’s potential cost should it become mainstream. Perhaps that would promote dialogue on how to primarily use it “after legitimately exhausting all available options, such as total artificial heart support.”
It might also teach the field to take greater advantage of the many donated hearts discarded as suboptimal. “The general usage rate for offered organs is around a third,” despite opportunities to expand use of those that are “less than perfect,” Mehra said. “I think that the field will grow with the community focusing on reduced discards of current available heart organs, and not necessarily grow because of the availability of ‘xeno-organs’.”
“This field needs to evolve because we’re actively transplanting patients today. But in my mind, the real future is to have such a sufficient understanding of the biology of left ventricular dysfunction that transplantation is a rare event,” Yancy proposed.
“I’m not certain that heart transplantation per se is the endgame. I think the avoidance of transplantation is the real end game,” he said. “This may be controversial, but my vision of the future is not one where we have a supply of animals that we can use for transplantation. My vision of the future is that heart transplantation becomes obsolete.”