Tag Archives: heart transplant

Pioneering non-beating heart transplant success – thanks to animal research!

Yesterday a team led by Consultant Surgeon Stephen Large at Papworth Hospital near Cambridge in the UK announced the successful transplant of a non-beating donor heart to heart failure patient Huseyin Ulucan, the first time such an operation has been performed in Europe.

Current practice is for donor hearts are obtained when the donor has been declared brain dead, but their heart is still beating, and the heart is then cooled and transferred to the recipient.  The technique used in Mr Ulucan’s operation involves re-starting the heart in the donor five minutes after death and perfusing it and other vital organs with blood and nutrients at body temperature using the Transmedics Organ Care System (OCS). In this case the donor heart was kept nourished and beating for three hours before being transplanted into Mr Ulucan. The main importance of the technique it that it has the potential to substantially increase the  number of donor hearts available for transplant, though it also enables the surgical team to assess the health of the donor heart more thoroughly.

Transmedics_OCS

The Transmedics Organ Care System.

 

The technique they used was developed by Cardiothoracic Transplant Registrar Simon Messer, who developed it with Consultant Surgeon Ayyaz Ali, and commented:

Using techniques developed to recover the abdominal organs in non-heart beating donors, we wanted to apply similar techniques to hearts from these donors.

“Until this point we were only able to transplant organs from DBD (Donation After Brain-stem Death) donors. However, research conducted at Papworth allowed us to develop a new technique not used anywhere else in the world to ensure the best possible outcome for our patients using hearts from non-heart beating donors.”

This approach, known as normothermic donor heart perfusion, is an example of a technique that is showing great promise in surgery, in 2013 we discussed how the normothermic transplantation technique using the OrganOx system – developed through research in pigs – had been used successfully in a liver transplant operation, and large scale clinical trials are now underway.

In a review entitled “Normothermic donor heart perfusion: current clinical experience and the future” published in 2014 (1) Simon Messer and colleagues highlights the role of research in animals including dogs, pigs and monkeys in demonstrating that Donation After Cardiac Death (DCD) heart transplantation is possible, and that normothermic donor heart perfusion improves the success rate.

DCD heart transplantation has been shown to be possible in animal models [32-34] and in humans [35, 36] provided that the warm ischaemic time could be kept below 30 min. However, we suspect that the only safe way to adopt DCD heart transplantation into routine clinical practice is by ex vivo functional and metabolic assessment following appropriate reconditioning. Normothermic blood perfusion has been shown to be superior to cold storage in preserving DCD hearts in dogs [37]. In the pig, reconditioned DCD hearts were shown to have comparable function to BSD donor hearts [38]. In an asphyxiation pig model, DCD hearts exposed to 30 min of warm ischaemia were evaluated on the OCS using lactate assessment. Four of seven transplanted DCD hearts were subsequently weaned off cardiopulmonary bypass on low dose inotrope [39].”

In a key paper published in 2013 (2) – reference 38 above – an Australian team assessed whether the Transmedics OCS system could be used to successfully transplant non-beating hearts in pigs, concluding that:

The Transmedics OCS provides an excellent platform to assess DCD heart recovery following warm ischemia. Using a clinically applicable model, we have shown that DCD hearts with WIT ≤30 mins appear to be a viable source of additional organs in cardiac transplantation and warrant human studies.”

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Results such as this led to Simon Messer and colleagues concluding in their 2014 review (1) that:

It is estimated that use of DCD hearts may increase the number of heart transplants by 11–15% [40]. We believe that functional assessment during ex situ normothermic donor heart perfusion must be made prior to transplantation in this setting. In Papworth Hospital, we are currently investigating whether DCD human hearts can be assessed on the OCS using pressure volume loop measurements.

In conclusion, cold ischaemic preservation for the donor heart has been universally adopted into clinical practice over the last 45 years. However, the diminishing pool of ideal donors coupled with the drive to further improve heart transplant outcomes mandate a rethink in this area. Normothermic donor heart perfusion is the logical next step and from the clinical experience to date, appears to hold promise.”

We congratulate Stephen Large, Simon Messer, Ayyaz Ali and colleagues at Papworth Hospital for taking this next important step successfully, and we wish Huseyin Ulucan a full recovery and long life.

Yesterday’s announcement was a reminder that more than 50 years after Norman Shumway’s pioneering heart transplants studies in dogs, animal research remains crucial to progress in this important field of medicine.

Paul Browne

1) Messer S1, Ardehali A, Tsui S.”Normothermic donor heart perfusion: current clinical experience and the future.” Transpl Int. 2014 May 23. doi: 10.1111/tri.12361. PubMed:24853906

2) Ali AA, White P, Xiang B, et al. “Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.” Am J Transplant 2011; 11: 1621. Link

 

To engineer a new heart, first you take a pig…

This week the prestigious science journal Nature carries two fascinating reports on the progress being made in the exciting field of tissue engineering that we recommend to our readers – both are open access so you don’t need a subscription to Nature to read them.

The first is a feature article by Brenden Maher entitled “Tissue engineering: How to build a heart” which focuses on the research being done by Doris Taylor  at the Texas heart Institute and  Harald Ott at Massachusetts General Hospital in Boston. He also discusses research being done on other tissues, including several that we have discussed on this blog, such as relatively simple tissues like bladders and blood vessels which are already being trialed in patients, and more complex tissues such as lungs that require more laboratory research before they can move to the clinic. Brenden Maher’s article, and the accompanying video and podcast, are an excellent overview of this exciting field.  It’s an overview that highlights the key contribution of animal research, not just the provision of the raw material, the decellularized pig heart scaffolds upon which new organs can be built and the stem cells used to seed these scaffolds, but also the evaluation and continuing refinement of the artificial organs and tissues produced.

The second article “Miniature human liver grown in mice” by Monya Baker provides another example of how the field of tissue engineering is progressing. There have been several previous attempts to create artificial liver tissue in the laboratory, but this is the first time that an engineered liver has been produced that is vascularized and when transplanted into a mouse model of liver failure was able to connect with the mouse blood vessels and function as a liver.

Like the heart grown by Harald Ott, the artificial liver buds were produced by Takanori Takebe and colleagues were created using induced pluripotent stem cells (iPS cells), but rather than using a scaffold they found – after hundreds of experiments – that if they mixed iPS cell derived liver precursor cells with other stem cells that develop into tissues such as blood vessels, and got the ratios of cells and conditions just right they would self-organize and develop into a functioning liver bud.  It’s an example of why scientists need be able to use a wide variety of approaches in tissue engineering, the technique that works best for the heart may not be best for the liver, while another technique again might work best for the trachea.

Studies in mice were key to the assessment of engineered mini-livers

Studies in mice were key to the assessment of engineered mini-livers

This artificial liver bud holds great promise for use in transplant operations, though before that becomes a reality the liver buds will need to be studied for longer times in mice to ensure that they continue to function over extended periods and do not develop abnormalities such as cancer, and the technique needs to be improved in order to produce the far larger amounts of liver tissue required for human transplants. In the shorter term the liver buds may have a role in preclinical screening of new drugs, as the initial studies in mice reported by Takanori Takebe and colleagues (1) demonstrated that when the mice were given a range of small molecules – including two drugs they are metabolized differently by human and mouse livers –  they produced a metabolic profile that closely resembled that of an adult human liver. It is also likely that this liver bud technology, or a derivation more suitable for high-throughput screening, will be used to screen chemicals in vitro, reducing the number that need to be evaluated in live animals later.

It’s a great window on an exciting area of 21st century medicine, one that we will all be hearing about a lot over the coming years.

Speaking of Research

1) Takanori Takebe et al. “Vascularized and functional human liver from an iPSC-derived organ bud transplant” Nature (2013) doi:10.1038/nature12271

The new face of transplant surgery, thanks to animal research

Yesterday the University of Maryland Medical Center (UMM) announced most extensive full face transplant completed to date, including both jaws, teeth, and tongue. In a marathon 36-hour operation the surgical team led by Professor Eduardo Rodriguez were able to transplant a face of an anonymous donor onto their patient Richard Lee Norris, who had been injured in a gun accident 15 years ago.  The operation was the culmination of years of clinical and animal research undertaken at UMM under the leadership of Professor Stephen Bartlett, and funded by the Department of Defense and  Office of Naval Research due to its potential to help war veterans who have received serious facial injuries.

This successful operation, termed a vascularized composite allograft, was made possible not only by the selflessness of the family of the anonymous donor, but also by the years of animal research undertaken by Professors Rodriguez and Bartlett and colleagues. For example, a key factor in the success of this operation was that they transplanted high amounts of vascularized bone marrow (VBM), which came inside the transplanted jaw, a technique that was developed by the team after observing that tissue rejection following composite tissue allotransplantation in a cynomolgus monkeys was greatly reduced when VBM was included in the transplant. This discovery will also help to reduce the amount of immunosuppression that Mr. Norris and future patients require following facial transplants.

Of course this is far from the first contribution that animal research has made to transplant surgery, from the development of the techniques of kidney transplant through research in dogs by Joseph Murray and colleagues, to the careful experiments in dogs conducted by Norman Schumway and Richard Lower that led to the first successful heart transplants, to the studies in mice and rats that identified the immunosuppressive properties of the drug cyclosporin that transformed the transplantation field in the 1980’s, animal research has made a crucial contribution to this field. Indeed, in his 1990 Nobel Lecture Edward Donnall Thomas stressed the importance of animal research to his Nobel prize winning discoveries concerning bone marrow transplantation.

Finally, it should be noted that marrow grafting could not have reached clinical application without animal research, first in inbred rodents and then in outbred species, particularly the dog.”

Animal research continues to make key contributions to transplant science, and we have had several opportunities to discuss its role in the development of lab-engineered tissues for transplant, such as the artificial bladder, on this blog.

Yesterday’s news from the University of Maryland is another reminder that animal research is still crucial to advances in transplant surgery. It is also worth remembering that when animal rights groups attack animal research conducted by the Department of Defense, it is work such as that which led to yesterday’s breakthrough that they are attacking.

Paul Browne