Handling hearts: improving heart preservation in transplants

heartThe problems associated with preserving hearts during transplants are well known. Alongside the anticipated problems of graft rejection, there is the logistical issue of transporting the living heart from the donor to the recipient.

Transporting the heart to the donor means cutting off its oxygen supply and mechanism of waste removal (i.e. the blood vessel system that supplies nutrient rich blood and washes away metabolites). Often, the heart must be kept without oxygen for a sustained period of time, and for this reason, transplantation often leads to ‘ischemic-reperfusion injury’ (IRI).

IRI consists of two phases – the ischemic phase and the reperfusion phase.

The ischemic phase happens because the hearts oxygen supply is cut off during the transplant. The lack of oxygen means that the cardiac myocytes switch their metabolism from aerobic to anaerobic. As a result of this, the tissue begins producing excess hydrogen ions and lactate, which contribute to the increase in acidity of the tissue. The anaerobic metabolism produces metabolites (i.e. adenosine and xanthine) and harmful reactive oxygen species that damage cells [2]. The cardiac muscle cells and endothelial cells are both damaged as a result of the ischemia and anaerobic respiration.

The reperfusion phase happens once the heart has begun to receive oxygen and nutrients again. The supply of oxygen through blood, whist allowing the heart tissue to produce energy aerobically, also means that the waste products produced in the ischemic phase can cause damage to the cell membranes. This causes oedema as excess fluid enters the cells and inflammation of the heart tissue, further damaging it [1].

IRI can often compromise donor hearts and so it is extremely important to reduce the severity of IRI.

The most well known method to reduce IRI is ‘cold static storage’ [1]. In short, this means stopping the heart beating and then “cooling to reduce metabolism” [2]. This reduces the increase the acidity the heart would experience if it were at a higher temperature, helping to maintain it at a suitable standard for donation. The main issue with this however is that metabolism continues – so although the severity of IRI decreases, it is still a key issue.

Two other methods that have been tested in clinical trials to see whether the severity of IRI can be further reduced are hypothermic continuous myocardial perfusion and normothermic continuous myocardial perfusion.

Continuous myocardial perfusion means that the heart muscle is continuously ‘perfused’ and other nutrients via blood or another solution. The principle of this is that the supply of oxygen and removal of metabolites can continue whilst the heart is being transported from donor to recipient [1]. This helps to reduce the impact that IRI has on the donor heart as aerobic metabolism can continue.

The main difference between hypothermic and normothermic continuous myocardial perfusion is the temperature at which they occur. Hypothermic continuous myocardial perfusion happens at ‘4-10°C’ [1], whilst normothermic continuous myocardial perfusion happens at ’35-37°C’ [1].

Currently, only normothermic continuous myocardial perfusion is used for cardiac transplants. The method is truly remarkable in that it not only maintains sufficient perfusion; it also keeps the heart beating during transport. This means the heart only goes without oxygen twice (at first once the heart is retrieved and prior to transplanting it into the recipient) [1].

Normothermic CMP is also preferable to cold static storage as it allows the transplant surgeons to “assess the heart prior to decision to implant” [1]. This is becoming even more important today as “marginal organs are increasingly being used as the gap between the numbers listed for transplant and available organs widens” [1]. This means organs from higher risk donors are used to attempt to buy more time for those on the waiting list. In cases where organs from higher risk donors are used, assessing the organs functionality prior to transplanting it is extremely important. For this reason, the use of normothermic continuous myocardial perfusion is advantageous.

The only machine capable of this is the organ care system from Transmedics, Inc.

Whilst there are still of number of questions surrounding the method (i.e. the optimal concentrations of molecules in the perfusate [1]) and practical issues such as the cost of the machine (i.e. £30,000 for one single use machine or £180,000 for a reusable one [2]) this looks to be a suitable way to maintain the integrity of donor hearts (and other organs) in transplants. For example, some studies have shown that the mean preservation time increased from 195 minutes to 324 minutes when the machine was used [1].

However, in terms of the impact the machine has on the success of the transplant, studies are varied. Some studies show the impact the machine has on graft survival and the probability of rejection does not appear to differ between the use of the organ care system or the cold static storage. This along with the cost brings into question the machines applicability in the NHS (especially in its current state of chronic underfunding – but that’s a story for another day).

The area of continuous myocardial perfusion is developing as more clinical trials take place, so we should definitely keep a look out for future research!

Hello everyone, I hope you enjoyed my first article! I am a new member of the TMS team, so I would appreciate any feedback you have – whether this be on the topic or my writing style! I hope you enjoyed reading this and I look forward to bringing you another article in a couple of weeks.

 

Sincerely, Catherine.

 

References, full papers and further reading:

[1] Continuous donor perfusion for heart preservation

http://www.sciencedirect.com/science/article/pii/S1058981317300930

[2] NICE guidelines on the use of the organ care system

https://www.nice.org.uk/advice/mib86/chapter/the-technology

Organ care system from Transmedics, Inc.

http://www.transmedics.com/wt/page/organ_care

Image credits: The Independent

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