Heart Transplantation

Anatomy and Physiology

Thorough knowledge of the heart and the major vessels in the mediastinum is required to understand the transplant procedure. Historically, two types of transplant procedures have been described:

• Orthotopic heart transplant involving excision of the recipient's heart and implantation of a donor's heart in the chest of the recipient
• Heterotropic heart transplant in which the recipient's heart is not excised and the donor's heart is implanted into the recipient's chest

Indications

It is important to understand the indications of heart transplants for timely referral to the transplant list. A timely referral makes sure that the patient will be able to survive on inotropes or mechanical support until the time the heart is available. One thing to bear in mind before referring a patient is to make sure they do not have any contraindication to a heart transplant.[5][6][7]

Chronic Heart Failure

In outpatient settings, the following category of patients with chronic heart failure should be referred for a heart transplant:

• Patients on guideline-directed medical therapy (GDMT) who still have limiting symptoms on exertion. (New York heart association class 3 or 4 or American College of Cardiology stage D patients).
• Patients with frequent readmissions for heart failure exacerbation despite adherence to GDMT (two or more in 12 months).
• Worsening renal function attributed to the cardiorenal syndrome.
• Dose-limiting side effects like hypotension or contraindications like renal failure preventing the use of GDMT.
• Progressively worsening right ventricular function (cor pulmonale) or rising pulmonary artery pressure from left heart failure.
• Frequent episodes of ventricular arrhythmias despite optimal drug and electrophysiological therapy.
• Other features like anemia, weight loss, hyponatremia, or liver dysfunction that are attributable to heart failure.

Acute Heart Failure

In inpatient settings, patients that require urgent referral for cardiac transplant include:

• Refractory cardiogenic shock despite maximum dose inotropic treatment.
• Refractory cardiogenic shock despite percutaneous mechanical circulatory support.
• Refractory pulmonary edema not responding to diuretics and requiring ventilation and positive pulmonary pressure.
• Refractory ventricular arrhythmia not responding to medical therapy or electrophysiological procedures.

Contraindications

Unfortunately, many patients with advanced heart failure who meet the indications for a heart transplant may not be able to get it as they have one of the following contraindications:[8][9]

• Active infection: Acute infections should be treated first prior to consideration. Patients with well-controlled chronic infections like HIV, hepatitis C, and B with undetectable titers and no end-organ damage can be considered for a transplant.
• Chronic liver disease (cirrhosis)
• Advanced kidney disease (glomerular filtration rate of less than 30 ml/min/1.73m^2).
• Recent stroke or symptomatic, untreated peripheral vascular disease.
• Uncontrolled diabetes mellitus with end-organ damage.
• Active malignancy, in which case the discussion should involve oncologists in shared-decision, making to decide if a transplant is feasible or not.
• Severe lung disease with a forced expiratory volume (FEV1) and forced vital capacity (FVC) less than 50% predicted or evidence of parenchymal lung disease.
• Recent pulmonary embolism requiring anticoagulation (within the last 3 to 6 months).
• Severe pulmonary hypertension (PH) with pulmonary artery systolic pressure greater than 60 mmHg and pulmonary vascular resistance greater than 5 Wood units (if PH is refractory to medical therapy, then it is an absolute contraindication to heart transplant).
• Psychosocial factors including lack of social support, disabling psychiatric illness, non-compliance with previous medical management, active smoking or drug use, and not willing to quit.[10]
• Morbid obesity (body mass index greater than 35 kg/m^2).
• Multisystem disease requiring other transplant procedures (like renal, hepatic, or lung transplant).

Equipment

The key equipment needed is a well-preserved donor heart and an eligible recipient. Cardiopulmonary bypass is required during the procedure. Along with this, various other surgical instruments including but not limited to surgical blades and saw to open and dissect the chest, clamps to retract while dissecting, cannulas to engage the major vessels, and sutures to perform anastomosis as well as to close the chest post-procedure are needed.[11][12]

Personnel

The expertise involved include well trained cardiothoracic surgeon (helped by assistant surgeons) with the cardiac anesthesiologist as the procedure is performed under general anesthesia. For successful heart transplantation, a hospital needs to be equipped with a well-defined cardiac heart transplantation team, including:

• Cardiac surgeon
• Cardiac anesthesiologists
• Cardiologists
• Perfusionists
• Nursing team
• Staff coordinating organ transplantation with a well-equipped operating room and an intensive care unit.

Preparation

After confirmation of a potentially suitable donor, a shaved, washed (4% chlorhexidine) and the fasting patient is taken to the operation room in coordination with the donor heart's availability. This is done in coordination with the transplant registry that selects the appropriate donor heart after matching. General anesthesia is not induced to the recipient until the donor heart acceptability is confirmed. After confirming availability, the recipient's heart should be removed before the donor's heart is available to reduce ischemia time. Once the recipient's chest is opened, the heart and surrounding anatomy are dissected and prepared to go on cardiopulmonary bypass. The donor heart retrieval is timed to prevent ischemia time. The whole surgery is carried under general anesthesia using cardiopulmonary bypass, transesophageal echocardiography, and multiple monitoring techniques including but not limited to the Swan-Ganz catheter.

Technique or Treatment

For the two different types of implantation procedures the general procedural technique is as follows:[12][13]

Orthotopic Heart Transplantation

This is a much more commonly utilized procedure. The recipient's heart is excised except for the cuffs of the right and left atria. The donor's heart is transplanted by anastomosing the donor, and recipient right atrium to right atrial cuff left atrium to left atrial cuff, aorta, and pulmonary artery (PA). This is followed by a bicaval technique whereby the recipient's right atrium is fully excised, and the recipient's vena cava is anastomosed to the donor's right atrium. 

Heterotopic Heart Transplantation

This is rare, and only a handful of procedures have been performed worldwide. The recipient's heart is not excised, and the donor's heart is transplanted into the patient's thoracic cavity. Anastomosis is made between the donor and recipient atria. The donor aorta is anastomosed to the recipient aorta, and the donor PA is anastomosed to the recipient PA.

A detailed description of the orthotopic heart transplant is described below.

Recipient Heart Excision

Excision begins with opening the chest with sternotomy and pericardiotomy. Aorta and pulmonary veins are separated, and superior and inferior vena cavae are mobilized and secured with tapes. Heparinization is initiated, and the aortic cannula is inserted into the aorta after appropriate activated coagulation time (ACT) is achieved. Superior vena cava (SVC) is cannulated with right-angled cannula located proximal to tape snare well above the cavo-atrial junction. Inferior vena cava (IVC) is cannulated with a straight cannula via purse-string above the diaphragm reflection. 

With the donor heart 10 to 15 minutes from arrival, cardiopulmonary bypass is started at a temperature of 32 degrees celsius (hypothermia). The left atrium is excised at the junction of the right superior pulmonary vein, which decompresses the left heart. This incision is extended in both directions. The SVC is divided into the cavo-atrial junction. The right atrium is excised above the IVC tape snare leaving behind the right atrial cuff. Both aorta and then pulmonary artery are excised just above the valves. This leaves a good length of the distal vessel. In the end, the incision of the left atrium is extended medially and downwards into the appendage hence excising it. Both atrial incisions are joined, which forms a large cuff made of four pulmonary veins, and the heart is excised.

The Donor's Heart

Donor heart excision begins with joining pulmonary veins and then trimming the left atrial cuff, so it corresponds to that of the recipient. The mitral valve is inspected and the foramen ovale to determine if it is patent or closed. The great vessels, including the aorta and pulmonary artery, are excised.

Reperfusion and Completion

The great vessels are unclamped, hence reperfusing the heart. The heart is reperfused for at least 30 minutes as the rewarming process continues. De-airing is also performed to decompress the ventricles. The patient is slowly weaned off the bypass. Once off bypass, mediastinal drains (two) are placed, and protamine administered to reverse heparin. The chest is closed in a standard fashion.

Careful monitoring and post-operative care and instructions to minimize post-operative wound infections are required. In general, a re-visit to a cardiothoracic surgeon for suture and drain removal in four to six weeks is required.[14]

Complications

Post-transplant complications are broadly divided into early and late complications.[15][16]

Early Complications

They occur in the immediate postoperative period within days of transplantation.

Primary Graft Dysfunction (PGD)

Primary graft dysfunction (PGD) is defined as the failure of graft function within the first 24 hours after transplantation in the absence of hyperacute rejection, pulmonary hypertension, or known surgical complications such as bleeding or tamponade. The International Society of Heart and Lung Transplant (ISHLT) reported the PGD incidence to be 33% in all cardiac transplant procedures. In some case series, patients with severe PGD, have shown to have a survival of 44% at one year.[17]

Rejection

Rejection occurs as a result of interaction between the recipient's immune system and the allograft. It may be categorized by the type of immune response (cell-mediated vs. antibody-mediated) and by severity (ranging from mild rejection without allograft dysfunction to severe rejection with hemodynamic compromise). The incidence of rejection requiring augmentation of immunosuppression has fallen from 23.5% (2004–2006) with contemporary rates approximately 13% (2010–2014) between discharge from hospital and one year. Surveillance endomyocardial biopsies (generally 10 to 12 in the first year) are performed to look for evidence of rejection. Grading is standardized according to the 2005 revised ISHLT nomenclature, which includes the use of immunohistochemistry.

Infection

The use of immunosuppression inevitably increases the risk of infection. The risk of death due to infection is greatest in the first year post-transplant when maximum immunosuppression is being used. Patients should be vaccinated for influenza and pneumococcal infections. Live vaccines are contraindicated. Routine prophylaxis for pneumocystis jerovecii, cytomegalovirus, candida, and in some cases, herpes is given to these patients.  

Delayed Complications

They occur late in the transplantation period after months or years of transplant. 

Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is a process that leads to the narrowing or occlusion of the coronary arteries of the allograft. CAV is a significant cause of death late post-transplant, and its incidence increases with the time elapsed since transplant. It is a combined immunological and non-immunological insult. Intimal hyperproliferation due to smooth muscle cell hyperplasia and accumulation of lipids and inflammatory cells is the hallmark of the pathology of a biopsy specimen. Both epicardial and endocardial vessels are involved. Most patients may not have any symptoms and may be detected on routine biopsy surveillance. Some patients may have angina or heart failure symptoms at presentation. Due to the diffuse nature of the disease, outcomes of revascularization are not good. Post-transplant use of statins and rapamycin, when given early in the post-transplant period, may delay the development of CAV. Common risk factors for developing CAV can include immune-mediated (mismatch between donor and recipient including HLA and DR) and non-immune mediated (increased age, recipient coronary artery disease, or risk factors like smoking, hypertension, hyperlipidemia, and obesity). This vasculopathy can present as heart failure and needs to be monitored using regular echocardiographic examinations and hemodynamic measurements.[18][19]

Malignancy

New onset of solid malignancies occurs in around 10% of transplant patients after 1 to 5 years of transplant. 

Immunosuppression Related Side Effects

Human papillomavirus (HPV) related squamous cell cancer is the most common malignancy reported. Avoiding sun exposure is recommended in these patients. Ebstein-Barr virus-related post-transplantation lymphoproliferative (PTLD) is also common in these patients from immunosuppression. Other toxicities related to tacrolimus or sirolimus use include renal disease, diabetes, hyperlipidemia, and metabolic derangements (hypoglycemia and hyperglycemia).[20]

Clinical Significance

Heart transplant rates have been growing exponentially. There are more people on the waiting list now than is the organ availability. Proper selection of the recipient, improved organ preservation techniques, timely referral for the eligible patients, careful surveillance and immunosuppression, and monitoring for any complication with prompt management can overall improve the outcomes and survival post-transplant.[21]

Enhancing Healthcare Team Outcomes

The management of advanced heart failure, whether acute or chronic, is challenging and complex. With improved surgical and organ preservation strategies, a heart transplant is an option for eligible patients. To derive good outcomes, the goals and objectives of the heart transplantation have to be defined prior to taking the patient to surgery. In some cases, chronic infections, cirrhosis, and chronic kidney diseases, as well as psychosocial factors, may preclude cardiac transplants. Proper screening is thus required for proper patient selection. As with any other complex procedure, the preoperative workup must be thorough, and the patient should be seen by a pulmonologist and cardiologist to optimize lung and cardiac function. Due to the potential of complications from immunosuppression and the procedure itself, routine surveillance and biopsies are recommended.[22]

To improve outcomes, the ISHLT working in collaboration with ACC/AHA/HFSA and ESC has issued indications for a heart transplant in both acute and chronic heart failure patients. For optimum results, patients with any contraindications to heart transplants should be excluded from the list and managed medically and on mechanical support.

In addition to complications of the surgery, both early and late complications can complicate heart transplants. Hence careful supervision is needed in the immediate post-operative period as well as years after transplant. An integrated interprofessional team with a cardiologist, cardiothoracic surgeon, trained nursing staff, and pharmacist well trained with titration and side effects of immunosuppressants can greatly improve heart transplantation outcomes. The role of a primary care physician in follow-up is also crucial; thus, further emphasizing the need for an interprofessional approach to the management of heart transplant patients. The need for meticulous planning and discussion with other professionals involved in the management of the patient is highly recommended to lower the morbidity and improve post-transplant outcomes.[23][24]