HEART TRANSPLANTATION-II

PRACTICED & PROPOSED METHODS OF EXTENDING THE TRANSPLANT DONOR POOL & OTHER NEW DEVELOPMENTS

For a conventional heart transplant to happen, there has to be a donor with a functionally acceptable heart. The team leader has to decide whether to proceed with the transplant.  The ejection fraction, a measure of the heart's contractile force, the myocardial and wall thicknesses, the cavity dimensions, and the absence of regional wall motion abnormalities anywhere are all critically evaluated, especially by echocardiography. So, for a transplant to happen, a brain-dead donor,  an acceptably healthy heart, a similar blood group, and reasonable tissue matching between donor and recipient.

There is always a mismatch between recipients and donors. There has to be an appropriate brain-dead donor for a heart to be available. Even being the vice-president of the USA at that time, Dick Cheney, had to wait with a circulatory assist device for 20 months for an appropriate donor heart. Since 2011, efforts have been made to expand the donor pool and modify surgical techniques to achieve similar results. The various techniques and the rationale behind each method are summarised as follows:-

A. Donation After Circulatory Death (DCD): 

Basically, there is a basic difference between donation after brain death and donation after cardiorespiratory death. In a brain-dead subject, the beating heart maintains the circulation to the other vital organs adequately for a period until catecholamine storm and other events start happening and cause eventual deterioration of the heart itself. In contrast, in cardiorespiratory death, there is no flow of oxygenated blood or nutrients, and cellular death is rapid. The longer the circulatory absence, the greater the warm ischemia and the more consequential anaerobic energy production at the cellular level. So an effort at reanimation has to be fast as well. Immediate Heparinisation keeps the blood liquid and limits further embolic injury. It must be remembered that not all organs can be restored to a satisfactory level of transplantable function, and warm ischemic time varies among organs. As of now, efforts are focused only on the organs needed for life-saving measures. Also, the time of death, the circumstances, and the time elapsed before the dead body is brought before a reanimation clinician are important in making decisions. The modified Maastricht classification (and yearly updates) and the guidelines there govern the procedural protocols to be followed in donation after circulatory death (DCD).  The classification is divided into uncontrolled (unexpected arrest) and controlled (planned withdrawal) categories. The original classification was in 1995 (Koostra and colleagues, at Maastricht), with further modifications and inclusion of criteria in Madrid, 2011 (adjustments to categories I & II), Paris, 2013 (inclusion of category V).

The Modified Maastricht Classification

Category	Type	Description	Location & Sub-categories
I	Uncontrolled	Dead on arrival at the hospital	Ia: Out-of-hospital Ib: In-hospital
II	Uncontrolled	Death following unsuccessful resuscitation	IIa: Out-of-hospital IIb: In-hospital
III	Controlled	Awaiting cardiac death after planned withdrawal of life-sustaining treatment (WLST)	N/A
IV V	Controlled Controlled	Unexpected cardiac arrest in a patient already diagnosed as brain dead Euthanasia - practised only in limited countries like Belgium and the Netherlands.

Currently, the organs of interest in DCD are the —

ORGANS WARM ISCHEMIC TIME

Liver < 30 mins,

Kidneys 20–30 min is generally acceptable, Lungs approximately 60 - 90 mins,

Pancreas 30 mins or less,

Heart           30 mins or less.

The warm ischemic time (WIT) is important in transplant surgery, and it has been shown that reduced organ temperature lowers the basal metabolic rate (BMR). Cold ischemia added to the period of warm ischemia considerably extends the safe period for implantation, and the surgeon can unhurriedly proceed with uniform and equidistant, leakproof, everting stitches without compromising the cavities. 

The currently known methods of organ revival after cardiorespiratory death are : 

1. Normothermic regional perfusion (NRP) – this is in-situ, after a mandatory wait for 2 to 5 mins after death, institution of any form of extracorporeal membrane oxygenation.

2. The ex-situ version is also called the normothermic machine perfusion (NMP). Here, the organ of interest is brought out of the body before being connected to some sort of perfusion device.

3. Sequential perfusion (NRP + NMP)

All the methods are in practice and used as the situation demands.

DCD allows a 15-20% increase in the donor pool.

B. Partial Heart Transplant:

Some congenital hearts, especially in the pediatric age group, cannot be repaired properly, and a full transplant is needed as a remedy. In some cases, homograft valves can be implanted, avoiding a conventional heart transplant. If myocardial viability is acceptable, only the diseased valve-bearing portion is to be replaced. Appropriately sized homografts should be available, and ABO blood group matching lowers the rejection probability.  Also, the dose of immunosuppressants is reduced, the implants grow, and the procedure appears less menacing. Possibly, the greatest advantage is freedom from reoperations and messy replacement of the degenerated previous homograft, and non-requirement of daily anticoagulants. Thus, this process differs from routine homograft valve replacement in adults, and because it has some similarities to heart transplantation, the procedure is termed partial heart transplantation.

C. Use of repaired hearts as a harvest.

Simple defects and short coronary lesions having minimal myocardial effects can be operatively corrected, and the heart harvested for donation. Alternatively, surgical correction can be performed on the heart already harvested before implantation. This effectively extends the donor pool.

D. Increasing the age limit.

International guidelines, reports, and statements from transplant registries cite 50 years of age as the optimal limit for heart harvest. However, the ever-expanding recipient registry and uncertainties with the brain-dead donors have led to a huge mismatch. This has made transplant surgeons around the world look at other avenues – stretching the upper age limit to 65 years in case of echocardiographically assessed healthy hearts.

E. The ‘Domino’ situation.

The ‘Domino’ heart of an irreversible pulmonary hypertension patient can be used as a donor heart with certain advantages, viz.,

• Considered more suitable for recipients with a high pulmonary vascular pressure, as the heart is already accustomed to a situation of high pulmonary vascular resistance.

• The short-term survival (actuarial) is better than the implantation of normally selected donor organs.

• The ejection fraction of the implanted heart averages around 70% that happens to be more than usual.

• It is an interesting observational fact that the incidence of atherosclerotic obstructive lesions in these hearts is low.    

However, a risk of early acute right ventricular failure is present. It needs aggressive management. Incidents of arrhythmia may be worrying at times.  A late right ventricular preponderance may complicate matters as a reminder of failure in the process of reverse remodelling that is usual in these implanted hearts.

F. Heart transplantation in an ABO-incompatible situation

The immune system is immature in the newborn. Advantage is taken of this period, and infants and newborns with congenital complex heart defects have little chance of improvement, both in the quality of life and prognosis. As of now, such transplantations are practised in this age group only.

These are the current accepted methods of increasing the donor pool in heart transplantation. Of late, study groups are focused on two aspects of human heart transplantation, and they are ---

1. ways to make transplantation safe when the ischemic time is prolonged, and

2. transplantation of the heart from other mammalian species.

The following paragraphs give examples of the methods:-

A. ORGAN CARE SYSTEM (Heart-in-a-box)

A new way to shorten ischemic time is the Heart-in-a-box technique. Developed in Australia and marketed by Transmedics as the 'Organ Care System', the technology has several advantages. This device keeps a donor heart beating outside the human body by pumping warm, oxygenated blood and nutrients through it. It can also reanimate a heart from a dead donor if brought within the stipulated time. Visual assessment of contractility is possible because the box containing the beating heart is transparent. The whole contraption is provided with instruments and analysers, allowing a functional assessment as well.

B. XENOTRANSPLANTATION

An alternative approach to heart transplantation in end-stage heart failure is xenotransplantation with a specially treated 'pig' heart. Xenotransplantation has the potential to do away with the long waiting list and the uncertainty of getting an immunomatched brain-dead donor. Pigs are chosen as the animal model because their circulatory pattern comes closest to humans and because of the positive track record of the Porcine bioprosthetic valve.   Genetically remodelled pigs bred and reared by single or double Gal genes knocked out, Somatic Cell Nuclear Transfer (SCNT), adding human complement regulatory proteins (e.g., hDAF), and knocking out other carbohydrate genes like Neu5Gc and SDa to create "triple knockout" (TKO) pigs, etc. These methods are supposed to suppress the immune responses common in humans.

The concept of xenotransplantation is not new. Experience with primate hearts, baboons and chimpanzees, naturally, was tried as 98% of the genetic material is similar. The "Baby Fae" affair, where a baboon heart was implanted in a newborn with hypoplastic left heart syndrome, Oct'-Nov' 1984, was infamous. and even caused artists in pop culture to make references in their creations. This was the first recorded attempt at xenotransplantation where the recipient was human. The incident helped tighten and modify the already stringent rules governing transplantation.

In India, in 1997, Prof. Dhaniram Baruah created notoriety by transplanting a pig heart in one of his patients. The patient died after 20 days, with acute rejection being the main cause. Prof. Baruah's feat did not get any recognition because of a satisfactory explanation for the reason of transplantation or any clue to the immunomodulatory methods used. Later, it was also revealed that the centre, where the event occurred, did not even have the necessary government Licences or permits for transplantation surgery.

Xenotransplantation with genetic engineering is the way to go forward in heart transplant studies now. Pigs are specially bred and genetically engineered so that their immune systems are sufficiently suppressed or modified. Hearts harvested from such pigs have a greater chance of acceptance when implanted in human subjects.

The researchers at the University of Maryland are pursuing this approach, and in 2023, the surgeons at the Medical Centre implanted two pig hearts in two terminally ill patients on compassionate grounds. Both patients ultimately succumbed to humoral rejection, and the longest survivor lived 40 days.

Xenotransplantation with appropriate genetic engineering may be an answer to the problem of the donor-recipient mismatch and the uncertainty of getting a brain-dead donor in time. However, further consideration is needed, especially in immune rejection and the eradication of zoonosis.