Introduction

The possibility of transplanting a human heart was first crystallized by the surgeon Dr. James Hardy in 1964 at the University of Mississippi . Dr. Hardy and his team made history by performing the first ever heart transplantation in a human patient using the heart of a chimpanzee. The work of Dr. Hardy and his colleagues paved the road to the first cardiac transplantation when the South African surgeon Dr. Christiaan Barnard stunned the world by performing the first human-donor-to-human recipient transplant in 1967 . However, it was not until the burgeoning field of transplant immunology developed that the critical importance of suppressing the recipient immune response was highlighted and the path to successful modern day heart transplantation was cleared . The introduction of the potent immunosuppressive drug cyclosporine cemented the clinical success of heart transplantation worldwide as the number of transplants dramatically rose in the 1980s. Currently, cardiac transplantation is widely accepted as the gold standard for the management of end-stage heart failure, comprising an overall 1-year and 5-year survival rate of 89% and 73%, respectively .

The most common conditions leading to transplantation are ischemic and idiopathic cardiomyopathies . Less common diagnoses include valvular heart disease, re-transplant, and congenital heart disease. Because of the limited availability of donor organs, numerous modalities have been developed to extend the life of patients awaiting organs. For heart transplants performed during the period spanning 2009–2013, 40% of recipients had received intravenous inotropic support and 49% had received mechanical circulatory support . In addition, cardiac resynchronization therapy (CRT) has been shown to reduce morbidity and mortality in patients with left ventricular systolic dysfunction, prolonged QRS duration, and New York Heart Association (NYHA) Class III or IV heart failure despite optimal pharmacologic therapy . Accordingly, end-stage heart failure patients presenting for heart transplantation are commonly managed with some form of CRT in combination with an implantable cardioverter-defibrillator option.

Recipient selection

Consensus guidelines for selection of patients for heart transplantation were published in 2006 and updated in 2016 ( Table 1 ) . Patients referred for transplant evaluation typically have NYHA Class III or IV heart failure despite optimal medical therapy . Surgical correction of coronary artery disease or valvular heart disease should be considered prior to listing, and patients with severe mitral regurgitation and low ejection fraction should be considered for mitral valve repair instead of transplantation. Although most candidates have severe LV systolic dysfunction, transplantation is occasionally indicated for refractory angina, unmanageable dysrhythmias, or diastolic heart failure.

Prognosis in patients with congestive heart failure (CHF) has been linked to functional capacity. Functional capacity can be assessed using exercise testing, and oxygen uptake (VO ₂ ) during maximal exercise is a useful method to determine functional capacity . In patients on a stable medical regimen, maximal VO ₂ < 10 mL/kg/min is associated with a poor prognosis. Patients with VO ₂ > 10 mL/kg/min have a better 1-year prognosis with medical therapy than transplantation.

Severe, irreversible pulmonary hypertension is a contraindication to transplant because of subsequent right ventricular failure in the transplanted heart ( Table 2 ). Right heart catheterization is performed to determine transpulmonary gradient (the difference between mean PA pressure and pulmonary capillary wedge pressure) and pulmonary arteriolar resistance. Transpulmonary gradient >12 mmHg indicates significant pathology. Pulmonary arteriolar resistance (the ratio of transpulmonary gradient to cardiac output, expressed as Wood units) > 2.5 also indicates a high risk of perioperative right ventricular (RV) failure. Patients with elevated transpulmonary gradient or pulmonary arteriolar resistance require a trial with nitroprusside, prostacyclin, dobutamine, or milrinone in an attempt to decrease pulmonary resistance. Patients unresponsive to these therapies are often considered at too high a risk for transplantation and may be candidates for ventricular assist device as definitive destination therapy.

Contraindications to cardiac transplantation include some significant non-cardiac diseases ( Table 3 ). Because immunosuppressive agents have renal and hepatic side effects, the presence of intrinsic renal or hepatic disease increases perioperative risk of organ dysfunction or failure . Some patients with multi-organ disease can be considered for combined heart-kidney or heart-liver transplantation. Patients with forced expiratory volume in 1 s (FEV ₁ ) <50% predicted, despite optimal management of CHF, are at increased risk for ventilatory failure and respiratory infections post-transplant. The presence of significant atherosclerosis is a contraindication because of the increased perioperative risk of atheroembolic complications ( Table 3 ).

Recipient selection

Consensus guidelines for selection of patients for heart transplantation were published in 2006 and updated in 2016 ( Table 1 ) . Patients referred for transplant evaluation typically have NYHA Class III or IV heart failure despite optimal medical therapy . Surgical correction of coronary artery disease or valvular heart disease should be considered prior to listing, and patients with severe mitral regurgitation and low ejection fraction should be considered for mitral valve repair instead of transplantation. Although most candidates have severe LV systolic dysfunction, transplantation is occasionally indicated for refractory angina, unmanageable dysrhythmias, or diastolic heart failure.

Prognosis in patients with congestive heart failure (CHF) has been linked to functional capacity. Functional capacity can be assessed using exercise testing, and oxygen uptake (VO ₂ ) during maximal exercise is a useful method to determine functional capacity . In patients on a stable medical regimen, maximal VO ₂ < 10 mL/kg/min is associated with a poor prognosis. Patients with VO ₂ > 10 mL/kg/min have a better 1-year prognosis with medical therapy than transplantation.

Severe, irreversible pulmonary hypertension is a contraindication to transplant because of subsequent right ventricular failure in the transplanted heart ( Table 2 ). Right heart catheterization is performed to determine transpulmonary gradient (the difference between mean PA pressure and pulmonary capillary wedge pressure) and pulmonary arteriolar resistance. Transpulmonary gradient >12 mmHg indicates significant pathology. Pulmonary arteriolar resistance (the ratio of transpulmonary gradient to cardiac output, expressed as Wood units) > 2.5 also indicates a high risk of perioperative right ventricular (RV) failure. Patients with elevated transpulmonary gradient or pulmonary arteriolar resistance require a trial with nitroprusside, prostacyclin, dobutamine, or milrinone in an attempt to decrease pulmonary resistance. Patients unresponsive to these therapies are often considered at too high a risk for transplantation and may be candidates for ventricular assist device as definitive destination therapy.

Contraindications to cardiac transplantation include some significant non-cardiac diseases ( Table 3 ). Because immunosuppressive agents have renal and hepatic side effects, the presence of intrinsic renal or hepatic disease increases perioperative risk of organ dysfunction or failure . Some patients with multi-organ disease can be considered for combined heart-kidney or heart-liver transplantation. Patients with forced expiratory volume in 1 s (FEV ₁ ) <50% predicted, despite optimal management of CHF, are at increased risk for ventilatory failure and respiratory infections post-transplant. The presence of significant atherosclerosis is a contraindication because of the increased perioperative risk of atheroembolic complications ( Table 3 ).

Donor heart management and procurement

The physiological response of brain death is characterized by marked hemodynamic instability that results from a complex interplay between the autonomic and endocrine system . The initial response is predominated by a stage of catecholamine storm followed by marked depletion and profound hypotension. Brainstem infarction leads to uncontrolled hypothermia and exacerbation of vasodilation and hypotension . In addition, neuroendocrine failure has been reported in some donors resulting in depletion in the levels of circulating thyroid hormones, T ₃ and T ₄ , and cortisol and arginine vasopressin. Several studies have highlighted the favorable effects of thyroid, steroid, and arginine vasopressin resuscitation on myocardial performance in donors sustaining brain-stem infarction. Management of the donor heart may therefore require aggressive hemodynamic support in the form of careful fluid resuscitation, inotrope/vasopressor support, and hormone replacement to optimize cardiac function prior to harvest .

The procurement stage starts with a median sternotomy and a longitudinal incision through the pericardium in the donor . The donor heart is then closely examined for overall function and wall motion as well as evidence of cardiac injury or coronary artery disease. Following systemic heparinization, the heart is surgically explanted, and an inspection for a patent foramen ovale is performed; the latter is closed if present. At this time, interrogation of the valves for insufficiency is also undertaken prior to transporting the heart to the recipient site. Infusion of the donor heart with cold static preservation solution or conventional cardioplegia marks the final step of the procurement stage prior to transport. Preservation of the donor heart allows for an ischemic time of approximately 4–6 h .

Preparation of the recipient for cardiectomy and orthotropic heart transplantation begins with a conventional median sternotomy . The optimal timing coincides with the arrival of the donor heart. In the case of a redo sternotomy, extra preparation and time are required to facilitate quick access of the femoral vessels for immediate institution of cardiopulmonary bypass (CBP) as needed. Separation of the sternum is then achieved with an oscillating saw. After adequate hemostasis is attained, attention is given to opening of the pericardium. The recipient is heparinized in preparation for aortic and caval cannulation. If possible, distal aorta cannulation near the origin of the innominate artery is optimized. This is followed by bicaval cannulation of the superior and inferior venae cavae (SVC and IVC, respectively). After snaring both the SVC and IVC to optimize the surgical field, CBP is initiated with simultaneous cooling to ∼28 °C and application of the aortic cross clamp. Prior to isolating the great vessels, the pulmonary arterial catheter is withdrawn into the SVC to prevent inadvertent iatrogenic excision. The native aorta is transected just distal to the level of the aortic valve, and the pulmonary artery is similarly divided just distal to the pulmonic valve. The right and left atria are cut at their respective atrioventricular grooves, leaving an atrial cuff site for donor implantation .

Overview of heart transplantation procedure

The bicaval anastomotic technique described by Sievers et al. is currently the most commonly used method for orthotropic transplantation . The basic tenet of this technique is the preservation of an intact donor right atrium using individual anastomoses to the recipient venae cavae. This technique entails complete removal of the recipient right atrium at the junction of the SVC and IVC. The first step of the bicaval approach consists of the anastomosis of the donor and recipient left atrium. During the next stage, the anastomosis of the IVC and SVC is performed. Once the caval anastomoses are completed, anastomoses of the donor and recipient great vessels are usually undertaken, with the pulmonary arteries anastomosis followed by the aortic anastomosis. Once the great vessels’ anastomoses are completed, methylprednisolone is administered just prior to releasing the aortic cross-clamp. Deairing maneuvers are then performed with the aid of an ascending aorta vent in place. Alternatively, the IVC and SVC anastomoses can be performed on a perfused beating heart after the release of the aortic cross clamp, reducing the overall ischemic time. The potential advantage of the bicaval approach is that it preserves the right atrial morphology, sinus node, and tricuspid valve competency, yielding a reduction in atrial dysrhythmias, tricuspid regurgitation, and pacemaker requirement .

In the classic biatrial approach described by Shumway et al. , donor implantation begins with the left atrial anastomosis followed by suturing of the right atrial cuff. The donor and recipient pulmonary artery is then sewn end to end. The final step of the implantation ends with the aortic anastomosis. The classic biatrial approach remains a formidable option because of its simplicity and efficiency. However, its main drawback centers on the enlarged atrial cavities that are created between the recipient and donor atria, leading to increased incidence of tricuspid and mitral regurgitation, atrial arrhythmias, and abnormal atrial transport function .

Left ventricular assist devices

A significant number of patients presenting for heart transplantation are supported by a mechanical assist device, and with a limited amount of available organs, the number of patients assisted or bridged by mechanical support may continue to rise . Optimal intraoperative management of the left ventricular assist device (LVAD) patient presenting for transplantation consists of balancing the pump flow of the device and unloading the left ventricle. The flow of the LVAD is primarily dependent on the volume of blood (preload) delivered from the right heart and the systemic vascular resistance (afterload). The LVAD flow may be adjusted by the pump speed of the device in revolutions per minute in relation to the blood delivered from the right heart. If an increase in LVAD speed is not matched by right ventricular output, the left ventricle will collapse, resulting in diminished LVAD flow and distal aortic hypotension. Similarly, a decrease in LVAD flow despite adequate pump speed can result in the event of afterload mismatch arising from excessive aortic hypertension. During the prebypass period, it is prudent to tailor the LVAD pump speed in relation to right ventricular output to optimize LVAD flow while maintaining normal ventricular dimensions. This can be achieved with the guidance of live intraoperative echocardiography, ensuring that the position of the interventricular septum is neutral, and by close examination of right ventricular performance .

Anesthetic preparation

Heart transplantation often occurs on an emergency basis. As minimization of the ischemic time to 4–6 h is crucial in maximizing the chance of graft survival, the efficient preoperative evaluation and preparation of the recipient is critical. During the entire process, it is of paramount importance that both the donor and recipient teams stay in close communication to minimize ischemic times . There are many factors that need to be considered during the preparation of the recipient and donor: distance and time necessary to transport the donor heart, history of previous sternotomy, possibility of difficult airway, challenging central venous access, and patients requiring mechanical circulatory support. All these factors can increase the time required to adequately prepare the recipient and potentially prolong the ischemic time. Ideally, the recipient is on CBP in preparation for native heart explantation when the donor heart arrives in the operating room.

Preoperative evaluation of the patient presenting for heart transplantation is similar to that in other cardiac surgical procedures. A few elements of the preoperative evaluation are worth highlighting. It may be prudent to pay particular attention to a history of malignant arrhythmias and the presence of an implanted antiarrhythmic device. In such cases, implantable devices will require interrogation and reprogramming to prevent inadvertent discharge during surgical electrocautery. Additionally, it is imperative to determine if the patient is taking any agent that may interfere with the coagulation cascade such as warfarin, aspirin, clopidogrel, or any of the new direct oral anticoagulants (DOACs) that inhibit thrombin or activated factor X. In the case of an elevated international normalized ratio (INR) due to warfarin, reversal with prothrombin complex concentrates such as Kcentra (CSL Behring) may be necessary prior to surgical incision . Typical dosing guidelines for INR values between 2 and 4 initially start at 25 units/kg. If the INR is greater than 4 at the time of surgery, a dose of 35 units/kg may be considered . Similarly, preparation of fresh frozen plasma, cryoprecipitate, and platelets may be required if there is a history of platelet inhibition or the presence of thrombin or activated factor X inhibitor. Preparation of antifibrinolytic agents such as aminocaproic acid or tranexamic acid may prove useful to increase clot stability. Identifying patients with full stomach status is important to minimize aspiration risk.

Many patients presenting for transplantation require pharmacological or mechanical hemodynamic support. Preparation of vasopressors such as vasopressin, phenylephrine, or norepinephrine may be prudent, especially in light of a history of consumption of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB), or other risk factors for vasoplegia . Inotropes such as dobutamine, epinephrine, or milrinone should be readily available before induction. Recipients of new hearts often have residual pulmonary hypertension, rendering the donor heart suddenly challenged with a much higher pulmonary vascular resistance (PVR) than its native circulation. This may result in right-sided afterload mismatch as the newly transplanted heart struggles to cope with higher pulmonary pressures. The use of selective pulmonary vasodilators such as inhaled nitric oxide (iNO) may prove to be the determining factor between a failing and successful donor heart in the face of pulmonary hypertension .