Initially, a thoracotomy is performed once the graft is available in the operating room. The patient is set on bypass, and the aorta is clumped. Then, the superior vena cava is transected at the cavo–atrial junction, the great vessels are transected at the level of their valves, and the left atrium is transected by entering the roof of the left atrium, leaving the orifices of the pulmonary veins. In the next step, the graft is prepared. The large vessels are separated from each other, and the connection of the pulmonary artery to the left atrium is cut in the latter with an incision that joins the orifices of the pulmonary veins, creating an empty opening. The placement of the graft in the recipient can be performed in two ways:
Heterotopic HTx is used in pulmonary hypertension, in smaller grafts or those exposed to increased ischemic time, and in order to support circulation from the recipient’s native heart during severe graft rejection. First, the excess of the descending aorta is resected, and the right pulmonary veins are prepared together with the corresponding lung, while the left ones are prepared individually. Then, the left atrium is resected at the point of the pulmonary veins, and the superior and inferior vena cava are also resected. The heart is then rapidly decompressed with the left superior pulmonary vein, left atrium, and inferior vena cava incisions while the aorta is clubbed and cardioplegic fluid is infused.
In the recipient, we have superior and inferior vena cava and aorta cannulation. An anastomosis is performed on the part of the graft’s left sinus incision and the recipient’s left sinus incision. An end-to-side aorto-aortic anastomosis and an end-to-side donor pulmonary artery to the recipient’s right atrial wall are then performed. Finally, after superior and inferior vena cava anastomosis, air is removed with the patient in the Trendelenburg position.
4. Complications
4.1. Rejection
Rejection is a serious complication of transplantation. The clinical picture varies from asymptomatic with findings on endomyocardial biopsy to cardiogenic shock. Studies show that patients with microcirculatory resistance index [
65], donors with macrophages with activated C-C chemokine receptor 2 (CCR2) and myeloid differentiation primary response protein 88 (MYDD8) [
66], increased left ventricle posterior wall thickness (1 mm increases 66%) and increased left ventricle mass index (1 g/m
2, the chance increases 2.7%) [
66,
67], have an increased chance of rejection. Three types of rejection have been identified, which are described below.
-
Acute cellular rejection: This is the most frequent type of rejection. Pathophysiologically, the major and minor histocompatibility antigens are not uniformly expressed, with the result that they function as allografts and activate T-cytotoxic lymphocytes either indirectly or through antigen presentation. CD-4 and CD-8 positive T lymphocytes with high affinity to interleukin-2 receptors and increased intercellular adhesion molecules with high MHC-II expression on cardiac myocytes produce cytokines. This leads to the accumulation of inflammatory cells, such as macrophages and neutrophils, perivascularly inducing inflammation in the epicardial and endomyocardial arteries. Histopathologically, it is divided into three categories. The first is called low-grade, where inflammation is not observed in the myocardium. The second is the partial degree, where two or more foci are found in the myocardium. Finally, the third one, identified as high grade, shows multiple foci of damage with various types of inflammatory cells and necrotic elements.
-
Acute humoral rejection: This shows a more complicated clinical manifestation. It is believed that the production of antibodies against the major and minor histocompatibility complex system is induced due to previous exposure to allogens such as transfusion, transplantation, and long-term circulatory support devices. It is divided into five categories according to antibody-mediated rejection in histopathological and immunopathological studies. The first is pAMR 0 Negative for antibody-mediated rejection with negative histopathological and immunopathological studies. The second is called pAMR 1(H+), with the presence of histopathological findings such as activated immune cells, inflammation, necrosis, etc. The third is pAMR 1(I+) antibody-mediated rejection with immunopathological and not histopathological findings. Next is pAMR 2, combining histopathological and immunopathological findings. Last is pAMR 3, in which severe histopathology (hemorrhage, capillary fragmentation, inflammation, interstitial edema) and immunopathological markers are observed.
-
Hyperacute: This is created due to incompatibility with the ABO system, and its manifestations begin early with thrombosis of the vessels of the graft [
68].
The main categories of immunosuppressants are:
These are mainly used in the initial phase of immunosuppression and in acute rejection episodes. They enter the cell’s nucleus and modify the expression of many genes. At an immunological level, they increase the number but reduce the mobility of neutrophils while reducing the production of many factors that stimulate the inflammatory process. Due to their many side effects, their use is usually limited to the first six months after transplantation [
69], while their prolonged administration is associated with reduced survival [
70].
- 2.
-
Calcineurins inhibitors
Cyclosporine and tacrolimus are the two drugs used in this class. Their action lies in inhibiting the synthesis of interleukins that activate T-lymphocytes, especially the helpers. A serious side effect is the worsening of kidney function [
68]. It has been found that the use of diltiazem helps to maintain cyclosporine levels with lower doses of administration, protecting kidney function [
71]. From studies, tacrolimus seems to be superior, especially in terms of side effects [
72].
- 3.
-
Anti-proliferative agents
This category includes azathioprine and mycophenolate. They are purine analogs where, through enzymes, they are converted into metabolites that mimic the action of purines by inhibiting DNA replication. In this way, they inhibit cell division and reduce the robustness of the immune system [
68]. These two drugs have a similar effect, with the second tending to replace the first in resistant rejection. It was shown that patients with thiopurine S-methyltransferase gene variants show a reduced benefit compared to the rest [
73].
- 4.
-
mTOR inhibitors
Medicines in this category are sirolimus and everolimus. Inhibition of the mTOR pathway results in the inhibition of several interleukins and reduces T lymphocyte replication, decreased worsening of graft vasculopathy, decreased likelihood of malignancy compared to mycophenolate [
74], and the possibility of de-escalation of ciclosporin dose with better results in terms of patient’s renal function outcome, according to the Madela study [
75]. Additionally, the combination with tacrolimus appeared to reduce the hypertrophy that can develop in the graft as well as the amount of fibrosis at 1 year [
76]. Conversely, an increase in the triglyceride levels of these patients has been observed, leading to the need for regular biochemical control of patients receiving the drug [
77].
- 5.
-
Induction Therapy
Induction therapy is used to introduce immunosuppression, avoid acute rejection, and maintain the other drugs at lower doses. It can also be given in case of relapse of graft rejection. The drug groups are as follows:
- -
-
Monoclonal anti-lymphocyte antibodies;
- -
-
Polyclonal anti-lymphocyte antibodies;
- -
-
Antibodies against cytokine receptors.
Treatment protocols usually include a steroid drug, a calcineurin inhibitor, and usually mycophenolate. Steroids, due to side effects, are discontinued within the first 6 months to 1 year in half of patients, with nearly 90% discontinued at 24 months [
78].
4.2. Graft Angiopathy
The most common cause of death after 1 year of transplantation is probably of an immunological origin (hypersensitivity reaction), where the T-helper cells are activated by antigens of the endothelial cells, promoting the production of pro-inflammatory substances, which leads to an attack on the smooth muscle fibers of the vessels causing their hyperplasia, resulting in the narrowing of the lumen. There is also evidence of the involvement of natural killer cells. Additional causes of graft vasculopathy include obesity, coronary artery disease, dyslipidemia, diabetes, donor age, male gender, brain-dead donors, increased graft ischemia time [
79], hypercholesterolemia [
80], increased end-diastolic diameter and decreased interleukin 33 (IL-33), as well as the increased suppression of tumorigenicity 2 (ST2) [
81]. Angina is rarely a symptom, as the grafts lack innervation (they are denervated upon removal from the donor) while suffering the same complications as classic coronary artery disease. Its diagnosis is a challenge, as coronary angiography essentially functions as an allography of the vessels, often underestimating the thickening of the vessel walls. A classification has been proposed by the International Society for Heart and Lung Transplantation (ISHLT) that classifies vasculopathy into three categories (
Table 3) [
82].
Table 3. ISHLT classification of vasculopathy.
The use of intravascular ultrasound (IVUS) significantly increases diagnostic accuracy, while stress echo seems to be gaining ground, as well. Immunosuppression has limited effects, with mycophenolate showing the best results. The gold standard method is still biopsy, which is performed at regular intervals up to 5 years after the transplant, as this specific complication lacks typical symptoms or may be asymptomatic for a long time without a specific widely accepted protocol. Efforts are being made through the use of magnetic resonance imaging (MRI) to avoid complications of the biopsy, which are still in the early stages [
83].
4.3. Primary Graft Failure
Primary graft failure is the leading cause of death in the 1st month after transplantation. It affects the left and/or right ventricle, with ultrasound findings and hemodynamics ranging from mild manifestations to hemodynamic instability requiring inotropes and mechanical circulatory support. Pathophysiologically, the involvement of several mechanisms is thought to contribute. Initially, a serious role is played by the ischemia time of the graft. Despite being immersed in ice-cold solutions, the graft suffers ischemia with disruption of the Na
+/K
+ pump function, resulting in the diversion of metabolism to anaerobic and, at the same time, the appearance of cell swelling. On the other hand, reperfusion of the graft after transplantation leads to the release of free radicals with further deterioration of cellular homeostasis. In addition, the brain death of the donor plays an important role. Due to the increased catecholaminergic activity of the donor, desensitization of β-receptors is caused, while an overload of the cell with Ca
++ is created, thus contributing to the appearance of myocardial stunning [
84].
There are several predisposing factors responsible for this particular complication reflected in the RADIAL score, and they are right atrial pressure > 20 mmHg, donor age > 30 years, recipient age > 60 years, graft ischemia time > 4 h. Others are pre-operative LVAD use, female gender [
85,
86], obesity [
87], and diabetes [
88]. When donor risk factors are categorized, they are brain death, use of intravenous inotropes, age, and dysfunction of another donor graft. Contributors include age, fibroin use, mechanical ventilation, circulatory support devices, pulmonary hypertension, obesity, and diabetes. Finally, regarding the procedure, the ischemia time, donor–recipient mismatch, and transplantation from a female donor to a male recipient have been implicated [
84]. The ISHLT has set certain criteria for grading the severity of this particular complication (
Table 4).
Table 4. ISHLT criteria for grading the severity of primary graft failure.
Early right ventricular failure is a serious complication of transplantation. To be diagnosed, acute right heart failure must occur in the absence of pulmonary hypertension, myocardial damage, and graft rejection. The pathophysiological mechanism is similar to that of the left ventricle described above. It usually appears immediately, in the first 24 h after the operation, but can also occur later, with the peak on the 3rd postoperative day, and usually lasts a week. Patients with severe disease also have an increased chance of dialysis. Treatment ranges from inotropic support to mechanical circulatory support [
89]. It has been found that filling pressures in the right ventricles usually show normal values at 3–6 months after transplantation, and improvement in their function is expected in the 1st year after the operation [
90]. Finally, the measurement of pulmonary arterial elastance shows a strong correlation between mortality in 1 year and the possibility of developing right heart failure, and some authors recommend its regular measurement in transplant patients [
91].
Treatment is mainly focused on supporting the graft until it regenerates. Often, there is a need for the use of inotropic drugs, and sometimes, there is also a need for the use of circulation support devices. From studies it has been observed that the use of VA-ECMO is a very good choice. It also appears that the shorter use of ECMO seems to have more benefit in early survival while showing better results than LVAD [
92].
4.4. Infections
Infections are a common complication of transplantation due to the immunosuppression administered. The most common infection is CMV, followed by EBV, herpes, the adenovirus that causes severe morbidity and mortality with many myocardial complications [
93], and bacterial infections. Protozoa and fungi follow these. The most common Gram-negative bacterial infections are extended-spectrum beta-lactamase (ESBL)
Escherichia coli and
Klebsiella pneumoniae,
Pseudomonas aeruginosa, and carbapenem-resistant
Klebsiella pneumoniae, while the most common Gram-positive one is
Staphylococcus. Studies have shown that transplant patients with bacterial infections had an increased one-year mortality [
94].
4.5. Neoplasms
Neoplasms are an important cause of late mortality after HTx. The most likely explanation is the need for immunosuppression, which makes the patient more vulnerable to the carcinogenesis that certain viruses such as EBV, human herpesvirus 8, human papillomavirus, and hepatitis B, C can cause. It is estimated that >10% of transplanted adults will develop malignancy within 5 years [
95]. Skin cancers and some rare neoplasms show the greatest increase [
96]. Increased risk factors are male sex, old age, white race, and increased duration of administration of intense immunosuppressive therapy [
97]. Studies have shown that switching from calcineurin inhibitors to mTOR reduces the chance of cancer [
98,
99].
4.6. Retransplantations
A small number of patients will be retransplanted. This mainly occurs in young patients between 19 and 40 years old who experience severe graft failure due to rejection, graft vasculopathy, and primary graft failure. They are usually patients with a severe clinical picture with an unmet need to support circulation with vasoconstrictor drugs or devices and hemodialysis. Survival rates are poor. Risk factors for survival are the use of LVAD, older age, increased ischemic time, and primary graft failure. For now, due to the international shortage of grafts, this specific procedure is limited to selected cases [
100,
101].