We are IntechOpen, the world's leading publisher of Open Access books Built by scientists, for scientists

5,900+

Open access books available

144,000+

180M+

International authors and editors

Downloads

156 Countries delivered to Our authors are among the

Top 1% most cited scientists

Contributors from top 500 universities

Selection of our books indexed in the Book Citation Index in Web of Science™ Core Collection (BKCI)

### Interested in publishing with us? Contact book.department@intechopen.com

Numbers displayed above are based on latest data collected. For more information visit www.intechopen.com

## Meet the editor

Dr. Norihide Fukushima is a professor at Graduate School of Nursing, Senri Kinran University, Japan, a visiting director at the National Cerebral and Cardiovascular Center, Japan, and a recruit professor in the Department of Surgery, Graduate School of Medicine, Osaka University, Japan. After graduating from the Graduate School of Medicine, Osaka University, he finished clinical training in the 1st Department of Surgery,

Osaka University Hospital, and obtained his Ph.D. in Prolonged Cardiac Immersion storage in 1992. Dr. Fukushima worked at Loma Linda University, California, USA as a research and clinical fellow from 1991 to 1994. His team underwent the first heart transplantation in Japan in 1999. He and his colleagues made a revision to the Transplant Act in 2010 to increase deceased organ donation and heart transplantation in Japan.

### Contents




## Preface

Since the first heart transplantation was performed by Dr. Christiaan Barnard in South Africa in 1967 [1], there has been steady progress in terms of recipient selection, donor selection and management, surgical technique, preoperative management, immunosuppression regimens, and mechanical circulatory support during waiting for heart transplantation. The rapid progress in all these areas has been associated with steady improvement in outcomes before and after heart transplantation.

Until the early 1980s, even before cyclosporine became available, progress in the endomyocardial biopsy method and histological definition of acute cellular rejection as well as the addition of rabbit anti-thymocyte globulin to steroids and azathioprine as a method of immunosuppression increased post-heart transplant patient survival at one year to 65% [2].

Between 1981 and 1985, the use of cyclosporine reduced acute cellular rejection as well as lethal infection early after heart transplantation and patient survival rate at one year increased to more than 80%. This resulted in the widespread acceptance of heart transplantation in adults. However, acceptance of infantile heart transplantation was relatively slow in coming because there was no definition of brain death in children younger than 5 years of age until 1987 in the United States. After xenogeneic heart transplantation using a baboon heart was performed by Dr. Leonard L. Bailey in 1984 [3], the number of pediatric heart transplants slowly but steadily increased. In pediatric heart transplantation, we need to consider growth and development, the influence of steroids, non-compliance in adolescents, and the abilities of a transplanted heart to grow.

Medical therapy has improved the lives of most end-stage heart failure patients who will not receive heart transplants. The development of mechanical circulatory support also changed therapeutic strategies for Stage D heart failure patients. After the first total artificial heart as a bridge to transplant (BTT) was performed at the Texas Heart Institute in 1972 [4], the extracorporeal left ventricular assist device (LVAD) was introduced to BTT in 1978 and the Novacor LVAD (Baxter Health Corp., Oakland, CA) was first implanted at Stanford for BTT [5]. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study [6] revealed that implantable pulsatile LVAD had clinically meaningful survival benefits as well as improved the quality of life in Stage D heart failure patients in 1999, and thus destination therapy began worldwide. The development of continuous-flow LVAD further changed the feature of therapeutic strategies for Stage D heart failure patients. These LVADs had less morbidity such as pump thrombus and infection than pulsatile implantable LVAD. The CE Mark trial follow-up results of HeartMate 3 (Abbott, North Chicago, IL) implantation showed high patient survival rates of 98%, 92%, 81%, and 74% at 1 month, 6 months, 1 year, and 2 years post-implantation, respectively [7]. Temporary support with the Impella 5.0 (Abiomed, Danvers, MA) may allow for an effective bridge to decision

strategy for hemodynamic stabilization and multidisciplinary heart team assessment of critically ill patients with heart failure [8].

This book presents recent information in the field of heart transplantation. It includes thirteen chapters that address such topics as novel immunosuppression therapy and the role of transplant pharmacists, donor management and intervention for primary graft failure, mechanical circulatory, diagnostic modalities for cardiac allograft vasculopathy, surgical techniques, pediatric heart transplantation, and gene therapy. We hope that readers will find this book a useful resource because of its summarization of relevant details and issues that will facilitate the acquisition of emerging new information in each area of heart transplantation.

I would like to thank the contributors for their help in making this useful and interesting book.

> **Norihide Fukushima** Professor, Visiting Director at National Cerebral and Cardiovascular Center, Senri Kinran University Graduate School of Nursing Suita, Japan

#### **References**

[1] Cooper DK. Christiaan Barnard and his contributions to heart transplantation. Journal of Heart and Lung Transplantation. 2001;**20**(6):599-610

[2] Zhu Y, Lingala B, Baiocchi M, et al. The Stanford experience of heart transplantation over five decades. European Heart Journal. 2021;**42**(48):4934-4943

[3] Chinnock RE, Bailey LL. Heart transplantation for congenital heart disease in the first year of life. Current Cardiology Reviews. 2011;**7**(2):72-84

[4] Cooley DA. Heart substitution: transplantation and total artificial heart. The Texas Heart Institute experience. Artificial Organs. 1985;**9**(1):12-16

[5] Starnes VA, Oyer PE, Portner PM, et al. Isolated left ventricular assist as bridge to cardiac transplantation. Journal of Thoracic and Cardiovascular Surgery. 1988;**96**(1):62-71

[6] Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure. Annals of Thoracic Surgery. 1999;**67**(3):723-30

[7] Mehra MR, Naka Y, Uriel N, et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. New England Journal of Medicine. 2017;**376**:440-50

[8] Lima B, Kale P, Gonzalez-Stawinski GV, et al. Effectiveness and Safety of the Impella 5.0 as a Bridge to Cardiac Transplantation or Durable Left Ventricular Assist Device. American Journal of Cardiology. 2016 May 15;**117**(10):1622-1628

## Section 1 Donor Selection

#### **Chapter 1**

### Donor Assessment and Management for Heart Transplantation

*Norihide Fukushima*

#### **Abstract**

For many years, heart transplantation has been an established procedure for patients with end-stage heart failure using the so-called "Standard Criteria" for an optimal heart donor. However, annually listed patients for heart transplantation greatly increased worldwide, and the use of extended criteria donor hearts has been utilized as many as possible in many countries. In this chapter, firstly, pathophysiology of brain death is explained. Secondly, donor assessment and issues of extended criteria donors are introduced. Then, donor management to maximize the heart graft availability, and the Japanese donor assessment and evaluation system and its outcome are reviewed.

**Keywords:** heart transplantation, donor assessment, donor management, anti-diuretic hormone (ADH), denervation, brain death

#### **1. Introduction**

Heart transplantation (HTx) has been established as the definitive therapeutic strategy in end-stage organ failure patients and results in satisfying long-term results. However, this surgical therapy is extremely limited by severe donor organ shortages worldwide, especially in Japan [1]. Therefore, adequate, and optimal assessment and management for deceased organ donors are mandatory to increase heart graft availability [2].

As the revised Japanese Transplant Act was issued on 17th July 2010 and organs can be donated after brain death (BD) with their family's consent if he or she does not deny organ donation since this revision [1], BD organ donation increased from 13 cases in 2009 to 97 cases in 2019. However, the number of HTx was still extremely smaller than in other developed countries. The extraordinarily severe organ shortage and long waiting time for HTx had made Japanese transplant programs consider using extended criteria donor (ECD) hearts.

The most troublesome issue facing HTx is primary allograft dysfunction (PGD) [3, 4]. This complication is the leading cause of early post-HTx death in the world. The use of ECD hearts may increase the PGF rate. Therefore, it is essential to establish a special donor evaluation and management system to maximize donor heart utilization. Maximizing donor heart availability is also the last wish of donors and donor families. However, if a transplant recipient dies soon after HTx due to PGD, the donor family feels the loss of their lover again. Therefore, donor management strategies to

improve heart graft function and reduce early post-HTx mortality are very important for the donor family as well as for recipients [2–4].

Disease-transmitted disease (DTD) is also an inherent risk of heart transplantation as well as other solid organ transplantation [5]. The Ad Hoc Disease Transmission Advisory Committee (DTAC) reported that unanticipated DTD occurred only in 0.18% of recipients, with 0.23% of proven or probable DTD to at least one recipient. DTD was related to significant morbidity and mortality with about 33% of graft loss or recipient death. The recipient death in malignancy occurred significantly higher than that in infection. Therefore, the procurement transplant coordinator (PTC) should carefully listen to the clinical course, data, and history of medical staff and family to rule out these absolute contraindications prior to obtaining informed consent for organ donation from the relatives.

Full-scale donor management begins after the potential donor is sentenced brain dead and his or her family's consent to organ donation is obtained [2–4]. Basic therapeutic strategies for donor management consist of interventions for impaired heart and lung function to optimize the patient's hemodynamics, increase oxygen delivery to peripheral tissue, and finally improve the function of other organs, such as the liver and kidney. The hemodynamic targets are arterial blood pressure greater than 90 mmHg, central venous pressure (CVP) between 6 and 10 mmHg, urine output around 100 ml/h (0.3 to 3 ml/kg/h), and heart rate between 80 and 120/minutes. As there are only about 15 to 20 hours between the start of full-scale interventions for donor assessment and management and the start of organ retrieval surgery in Japan, we need to establish specific therapeutic strategies to optimize patient's hemodynamics and restore the function of damaged organs as many as possible in such short period [2], which are extremely different from those in standard intensive that usually take several days to accomplish. Moreover, the donor management physicians need to understand the pathological and physiological mechanisms and characteristics of brain death from the initiation to the completion period.

#### **2. Pathological and physiological mechanism and characteristics of brain death**

#### **2.1 Pathological and physiological changes from the initiation to completion of brain death**

Many investigators [3, 4] have reported that a short-lived catecholamine (CA) storm derived from acute intracranial hypertension caused systemic hypertension, acute left ventricular (LV) failure, and acute transient mitral valve regurgitation, leading to a rise in left atrial pressure in animal experiments. These events led to ischemic myocardial damage of LV associated with pulmonary edema. Histological examination of myocardial tissue exposed to CA storm shows widespread ischemic damage and necrosis in animal experiments. However, in the human clinical situation, a broad spectrum of adverse hemodynamic instability is observed and may depend on the speed of development of BD.

Soon after the initial surge of the CA storm, CA levels decreased to levels below the baseline and pituitary failure developed [6, 7]. In addition, the lung is also impaired by an acute systemic inflammatory response, neurogenic pulmonary edema, aspiration, hemopneumothorax, atelectasis, and later pneumonia.

#### **2.2 Absent or decreased secretion of anti-diuretic hormone (ADH) after brain death**

The anti-diuretic hormone (ADH) is principally produced by neurosecretory cells that have their cell bodies in the supra-optic and paraventricular nuclei of the hypothalamus, and the ADH storage vesicles are transported down the axon via the hypothalamic-hypophysial tract, released into a portal system in the posterior pituitary and finally enter the body's systemic circulation (**Figure 1**).

ADH is the primary hormone to maintain tonicity homeostasis by promoting water reabsorption in the kidneys and causing vasoconstriction. Briefly, ADH binds to the V receptor on the renal principal cells within the late distal tubule and collecting ducts and promotes reabsorption of water guided by the osmotic gradient established by sodium chloride and urea in the kidney. This action makes concentrated, or hyperosmotic, urine, and keeps our body to conserve water in times of dehydration or blood volume loss [8]. ADH also binds to V receptors on vascular smooth muscle and activates the G protein signaling cascade, which leads to a contraction of vascular smooth muscle leading to increases in total peripheral resistance and thus maintaining sufficient arterial blood pressure and tissue perfusion [8].

BD causes profound supraventricular and paraventricular hypothalamic nuclei ischemia and secondary loss of ADH secretion into the posterior lobe of the pituitary gland, which results in diabetes insipidus. As ADH is also secreted from peripheral tissues, undetectable levels of ADH have been noted in 75% of BD. As water reabsorption action of ADH is decreased, the kidneys cannot concentrate urine and make large amounts of dilute urine, which leads to hyponatremia associated with high serum osmolality and hypovolemia. As the vasoconstrictive effect of ADH is decreased, the vascular tone of systemic arteries is decreased and leads to hypovolemia. Therefore, the absence or decreased secretion of ADH after BD causes hemodynamic instability and compromised transplanted organ function.

Administration of ADH [9–11], in addition to treating diabetes insipidus by volume supply, reduces inotropic requirements and has been associated with improved heart graft function. Pure vasopressors, such ADH, are less likely to cause reduced tissue perfusion, metabolic acidosis, or pulmonary hypertension and may be more appropriate medicine than noradrenaline for vasoplegic shock syndrome, especially after BD

#### **2.3 Cessation of autonomic nerve regulations on circulation**

After BD, the brain-heart connections are definitively interrupted and autonomic cardiovascular regulation mainly thorough baroreflex is gone. Therefore, the hemodynamics of BD persons become unstable [4]. For example, a decrease in the blood return to the heart due to blood loss, hypovolemia, and putting pressure on the upper abdomen or postural change may rapidly cause low blood pressure in BD persons. After 20 to 30 seconds of the hypotension phase, the somatically induced adrenal sympathetic reflex responses result in an increase in adrenaline secretions from the adrenal medulla, which induces subsequent high blood pressure usually higher than 150 mmHg and tachycardia. In BD patients who are poorly controlled, arterial blood pressure and heart rate may go up and down. This phenomenon is often observed in hypovolemic patients derived from reduced ADH secretion due to BD. The subsequent increase in serum adrenaline decreases the myocardial density of beta-adrenergic receptors (BAR), which leads to PDG early post-HTx.

Disrupted brain-heart connections, so-called denervation, are also observed in HTx recipients. The authors [12] previously described that the heart graft could not augment cardiac performance rapidly in response to an acute decrease in the preload due to the cessation of autonomic nerve regulation on the graft. In normal individuals, if a preload of the heart rapidly decreases, autonomic sympathetic nerves are activated through vagal reflexes increasing heart rate and left ventricular contractility. Therefore, LV Emax after releasing occlusion of vena cava inferior (VCIO) is significantly higher than LV Emax during VCIO (**Figure 2A**). However, as the heart graft cannot autonomically increase heart rate or LV contractility soon after a rapid decrease in LV preload, LV Emax after releasing VCIO is not different from LV Emax during VCIO (**Figure 2B**). The heart graft performance may be augmented only after elevated serum adrenaline levels by secretion of adrenaline from the adrenal gland. Thus, the denervated heart, such as the heart graft as well as the heart of a BD person, cannot rapidly enhance its performance in response to a rapid decrease in the LV

#### **Figure 2.**

*Changes in left ventricular Emax during and after releasing vena cava inferior (VCI): A. Healthy individuals, B. Brain dead persons or heart transplant recipients.*

preload, such as sudden blood loss or a sudden decrease in cardiac return. Therefore, denervation also causes hemodynamic instability in a BD person.

#### **3. Donor assessment**

#### **3.1 Rule out of absolute contraindications for deceased donor eligibility**

Although absolute contraindications for deceased donor eligibility depend on the organ procurement organization (OPO), most OPO provided a list of absolute contraindications for donor eligibility (**Table 1**).

As mentioned above, DTD is an inherent risk of heart transplantation [5]. Although DTAC reported that unanticipated DTD occurred only in 0.23% of proven or probable DTD to at least one recipient, DTD was related to significant graft loss or recipient death. It is important for PTC to carefully get information associated with DTD to rule out these absolute contraindications for heart transplantation.

#### *3.1.1 Infection*

#### *3.1.1.1 Viral infection*

Almost all OPOs determine that a positive test for human immunodeficiency virus infection and acquired immunodeficiency syndrome is an absolute contraindication, and most OPOs determined that hepatitis B virus (HBV) surface antigen (HBsAg), human T cell lymphotropic virus types I and II and determined or suspected prionrelated disease are absolute contraindication.


*positive test for HCV. HIV: human immunodeficiency virus.*

#### **Table 1.**

*Absolute contraindications for donor heart eligibility.*

Transplantation of donor hearts with anti-HBV core antibody (HBcAb) is associated with a small risk of virus transmission. In fact, Huprikar et al [13] reported that the risk of HBV transmission from HBcAb + HBsAg− donors are observed mainly in liver transplant recipients and that transmission is significantly lower in kidney transplant recipients and essentially negligible in thoracic transplant recipients. Even in liver transplantation, many investigators have reported that anti-hepatitis-B immunoglobulin (HBIg) or lamivudine can prevent HBV transmission by HBcAb + HBsAg− donors. In our institute, HBIg is routinely used in heart transplantation from anti-HBc + HBsAg− donors.

Most organs from donors with positive tests for hepatitis C virus (HCV) can be transplanted to a recipient with a positive test for HCV [5]. In the field of thoracic transplantation, transplantation of HCV + donor grafts to HCV + recipients is unacceptable, mainly because there are multiple strains of hepatitis C virus, and the presence of antiviral antibody in the recipient does not guarantee immediate immunity to HCV after heart transplantation.

#### *3.1.1.2 Other pathogen infection*

Regards bacterial or yeast infection, sepsis or infectious vegetation in the heart are contraindications for heart transplantation. Although the donor organ contamination (DOC) rate is high, infections due to DOC are rare after heart transplantation if adequate perioperative antibiotic prophylaxis and aseptic organ procurement are strictly performed [14]. The heart from a donor with positive blood culture without any signs of systemic infection can be transplanted if the proven bacteria are Grampositive cocci and sensitive to common antibiotics.

#### *3.1.2 Malignancies*

Of the 335 donors who transmitted proven or probable disease to at least one recipient being reported to UNOS from 2008 to 2017, 70 transmitted malignancies and kidney, lung, and liver cancers were the most common malignancies, with 18, 10, and 10 donors, respectively, transmitting to at least one recipient. Fifteen donors with potential donor disease transmission events involving breast cancer and 28 involving thyroid cancer were reported by either transplant centers or OPOs with no proven/probable transmissions.

Regards to central nervous system (CNS) tumors, Hynes et al. [15] analyzed a cohort of 58,314 adult thoracic organ recipients from the UNOS database and reported none of 337 recipients who received organs from the donor documented CNS tumor, developed CNS tumors at a median follow-up of 72 months and that Kaplan-Meier curves indicate no significant difference in the time to death between patients with and without receiving from the donor with CNS tumor.

Donors with past histories of certain types of cancers may be considered as donors, including certain types of primary CNS tumors. Desai et al. [16] reported that the use of organs from selected donors with a history of cancer had a potential overall benefit in survival. But a small, yet real, risk of cancer transmission is present, of which the recipient should be informed. Although the transmitted risk can be reduced by sophisticated evaluation, it cannot be no risk.

#### **3.2 Viability assessment of donor heart**

The real goal of donor heart assessment is not to evaluate the donor heart function just prior to the heart procurement but rather to predict the transplanted heart graft

performance after weaning from the cardiopulmonary bypass in the operating room and through the postoperative period. One also should consider the preexisting myocardial damage as well as myocardial damage due to BD-related stress.

#### *3.2.1 Assessment of Hemodynamics and Heart Function*

To accomplish optimal donor management, we need to obtain clinical information, such as the cause of BD, pathophysiological mechanism and findings of BD, past and family history, underlying disease, therapeutic interventions, especially inotrope dosage, ADH, thyroid hormone, and antibiotics, water and blood valance, and parameters of preload and afterload on the heart, such as systemic and pulmonary arterial pressure, CVP and pulmonary capillary wedge pressure, cardiac output, and/or mixed-venous oxygen saturation [2, 4].

Multicenter analysis (1719 consecutive primary HTx) reported that donor hearts requiring inotropic support of up to 6 mcg/kg/min of dopamine or dobutamine had satisfactory results [17]. Even if the donor experiences cardiopulmonary resuscitation (CPR) > 5 minutes, the donor heart might be acceptable to transplant, if optimal donor management stabilizes the donor's hemodynamics, improve left ventricular wall motion, and restore ischemic myocardial changes in ECG [2].

#### *3.2.2 Evaluation tools for donor heart viability*

#### *3.2.2.1 Chest X-ray*

As in usual clinical settings. cardiomegaly, chest trauma, or pleural effusions are checked by chest X-ray.

#### *3.2.2.2 Electrocardiogram (ECG)*

As most BD donors have some degree of myocardial damage caused by combined pre-underlying heart disease and BD events, ECG usually shows some degree of abnormality in ST segments and QRS waves. Sustained abnormalities in ST segments and QRS and multifocal ventricular ectopic beats under optimal donor management are considered high risks.

Even in an elderly donor with a history of cardiac arrest, the heart was acceptable for transplantation if hemodynamics becomes stable with a minimum dosage of inotrope administration and ischemic ECG changes disappear after optimal donor treatment.

#### *3.2.2.3 Echocardiography*

Echocardiography is the most reliable assessment tool to determine donor heart suitability. Echocardiography can evaluate cardiac valve function and myocardial hypertrophy as well as the existence of congenital malformations. Even if global and even regional ventricular dysfunction may be induced by the BD event, these wall motion abnormalities can be reversible within hours. Therefore, serial echocardiography should be done before a heart graft is abandoned to use due to myocardial dysfunction

In the presence of LV underfilling, LV seems to be hypertrophic or to have suitable LV systolic function. Therefore, circulatory blood volume should be estimated by central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), or the

size and respiratory movement of inferior vena cava (IVC), as well as the required dosage of inotropes prior to undergoing echocardiography to assess heart function.

#### *3.2.2.4 Coronary angiography*

As asymptomatic coronary atherosclerosis is found even in children and young people, coronary angiography, at least in donors >45 years or according to the donor risk factors, is routinely performed in western countries. However, it has not been elucidated which type or level of donor coronary atherosclerosis really impairs the post-transplant outcome, which suggested that angiography in donors <60 years might not be necessary. Of course, recent myocardial infarction especially during the completion of BD and diffuse coronary sclerosis are absolute contraindications for heart transplantation, but single stenosis with good myocardial performance in the responsible region is acceptable, especially if it can be treated by percutaneous cardiac intervention or concomitant bypass surgery during transplantation [18, 19].

#### *3.2.2.5 Chest computed tomography (CT)*

For several social reasons in Japan, we do not routinely perform coronary angiogram before procurement. Therefore, we often check for coronary artery calcification (CAC) on conventional chest computed tomography (CT) to estimate the risk of pre-existing coronary artery disease in the donor heart. But we previously reported that the pre-existing CAC in a donor heart is significantly associated with the maximum intimal thickness of the coronary artery greater than 0.5 mm after transplantation, but that it was not a significant predictor for cardiac events in the future, probably due to the higher use of everolimus in the CAC group posttransplant [20].

In the future, contrast CT scan, especially cardiac CT scan, might be useful to rule out coronary arterial disease in the donor heart.

#### **4. Extended donor criteria and how to decide the suitability of ECD hearts**

To expand the cardiac donor pool, ECD hearts should be used. In this section, extended donor criteria are shown and how to select and deal with ECD hearts are discussed (**Table 2**).

#### **4.1 Myocardial damage**

The donor myocardium is damaged to a greater or less extent, for many reasons, such as massive CA secretion at the BD completion, heart arrest, chest trauma, and the CPR maneuver.

As the brain-damaged patients are often maintained on the dry side to reduce brain edema, the heart appears to move with vigor due to reduced preload on the heart. To evaluate the precise cardiac systolic function, central venous pressure at the time of evaluation should be 8–10 mmHg. It is also important to adjust hemoglobin concentration, electrolyte balance, and acid-base equilibrium at that time. As Swan-Gatz catheterization or coronary angiography are not routinely able to perform in the procurement hospital in Japan for several social reasons, myocardial damage and underlying heart diseases are determined by hemodynamics, requirement doses of

1. Myocardial damage

	- •Correctable valvular dysfunction
	- •Correctable congenital heart anomaly
	- 55 years (especially without coronary angiography)
	- Bypassable one- or two-vessel coronary arterial disease
	- Undersizing or oversizing by more than 20% body weight
	- Female to male (especially undersized donor by more than 20% body weight)

#### **Table 2.**

*Extended criteria donor (ECD) for heart transplantation.*

inotropes and ADH administration, the LV wall motion and morphology by echocardiogram, and electrocardiogram (ECG) findings.

It is very important to evaluate donor cardiac function after treating diabetes insipidus, adjusting the tone of peripheral vessels, and recovering the affinity of the β-adrenergic receptor for adrenaline in the myocardium by administrating ADH via the central venous line and optimizing circulating blood volume [2].

The heart with a history of cardiac arrest with cardiopulmonary resuscitation can be transplanted if the cardiac function is recovered and the heart has no significant underlying disease or ischemic ECG changes [2, 21]. Recently, the ISHLT registry report 2020 also reported that recipients of donors who died from anoxia or head trauma had the highest 1-year survival (89.9%), whereas the lowest 1-year survival (84.1%) was seen in recipients of donors who died from cerebrovascular accident/stroke [22].

#### **4.2 High-dose requirement of inotrope administration**

Even hemodynamics or cardiac systolic function are well maintained, the myocardium is considered damaged if a high dose of inotrope administration is required to stabilize hemodynamics. Therefore, an assessment of LV function should be done after reducing dosages of inotropes as less as possible.

As high serum adrenaline concentration, as well as a high dose of intravenous adrenaline administration, has a significant relationship with a decrease in the myocardial density of β-adrenergic receptors [23, 24], the use of adrenaline should be used as less as possible. Less than 0.05 mcg/kg/min of adrenaline is acceptable. Regards to the dose of dopamine and others, the donor heart requiring greater than 15 mcg/kg/min of dopamine is considered ECD heart, especially with abnormal ECG and echocardiographic findings. Mostly, less than 15 mcg/kg/min of dopamine is acceptable.

#### **4.3 Underlying heart disease**

The hearts with the most valvular and congenital cardiac abnormalities are not eligible for transplantation. Therefore, pre-existing heart diseases should be carefully assessed by the echocardiogram and the chest CT scan before procurement surgery.

In donors with acceptable heart function, however, a simultaneous repair can be done on a donor heart with simple congenital heart disease (e.g., atrial septal defect, ventricular septal defect, or patent ductus arteriosus), mild or moderate valvular regurgitation in the mitral and/or tricuspid valve or normally functioning bicuspid aortic valve.

#### **4.4 LV hypertrophy**

As the hypertrophic myocardium is susceptible to ischemia-reperfusion injury, the hypertrophic heart with left ventricular wall thickness greater than 13 mm should be decided carefully to use. The hypertrophic heart with ECG criteria for LVH and total ischemic time (TIT) longer than 4 hours is inadvisable to transplant.

#### **4.5 Prolonged total ischemic time (TIT)**

It has been reported that prolonged total ischemic time (TIT) was a significant correlation with the early post-transplant death after HTx. The acceptable safe preservation time limit for HTx might be less than 4 hours. In fact, the report of the International Society for Heart and Lung Transplantation (ISHLT) showed that the relative risk of 1-year mortality was affected by TIT for longer than 6 hours [23]. However, pediatric hearts with TIT longer than 8 hours were reported to be safely transplanted [21].

To prolong the safe limit of preservation period in immerse heart preservation method, many studies were carried out. The author of the chapter reported that the modification of preservation solution and the application of terminal leukocytedepleted blood cardioplegia preserved good function of orthotopically transplanted cardiac grafts after 24-hour immersed preservation in the canines and goats [25].

#### **4.6 Elderly age**

As aging increases the risk to have the myocardial damage due to coronary arterial disease, left ventricular hypertrophy, and valvular disease, donors older than 50 years of age were generally considered to be ECD. In fact, older donor age is associated with decreased survival after heart transplantation, especially within the first month after transplantation [23]. Moreover, the relative risk of developing cardiac allograft vasculopathy within 8 years is also affected by donor age. Therefore, meticulous evaluation of coronary arteries with coronary angiography as well as left ventricular wall motion with echocardiography are essential to assess the heart of elderly persons.

Although coronary arterial interventions are applicable in the recipient after heart transplantation, several cases of simultaneous coronary arterial grafting have been reported to use the donor hearts with significant coronary artery disease [18, 19]. Overall graft patency at 2 years was reported to be 82%.

One may consider completion of BD as a certain kind of stress test on the myocardium such that if subsequent ECG or echocardiography is favorable, the chance of an elderly donor having significant CAD is probably low. This screening strategy without the use of coronary angiography is thought to make an efficient selection of elderly donor hearts for transplantation with a good outcome. But if the donor has left ventricular hypertrophy and/or significant ECG changes, the heart is not eligible for transplantation [2].

#### **4.7 Body size and gender**

Although a small donor size relative to the recipient may increase a survival risk post-transplantation, a normal-sized adult male is suitable for most recipients. Russo et al. [26] demonstrated that transplanting a female donor heart into a male recipient is associated with a significantly higher risk of PGD. On the other hand, the risk of CAV universally increased with increasing donor age [22]. However, recipients of male allografts had an increased risk of CAV development, regardless of the recipient's gender [22].

#### **5. Donor management**

To manage a donor optimally, hemodynamics, cardiac and respiratory function, infection, and other organ functions of the donor should be assessed precisely. As there are no specialized therapeutic strategies for liver or renal dysfunction during a short period of donor management usually less than 20 hours, cardiopulmonary management to improve organ perfusion and blood gas supply, and metabolic management are the main therapeutic strategies for ECD management.

#### **5.1 Circulatory management**

The repeated assessment and optimal management of donor left ventricular (LV) dysfunction offer a tremendous potential to increase cardiac donor utilization as a significant proportion of hearts are declined for reasons of "poor ventricular function." However, it has been reported that in younger donors, left ventricular dysfunction can completely recover to normal overtime prior to procurement in a donor and after transplantation in a recipient. Although echocardiography is a very effective tool to assess heart anatomy, especially valvular anomalies, the use of a single echo assessment of ventricular function is not recommended to decide the functional suitability of a donor heart graft.

The goals of hemodynamic management are to achieve normovolemia, minimize vasoconstrictors and vasodilators to keep a normal cardiac afterload and optimize cardiac output with minimal doses of inotropes, which increase myocardial oxygen demands, deplete high-energy phosphates and the density of BAR in the myocardium. The targets of hemodynamic parameters are systemic blood pressure > 90 mmHg, central venous pressure (CVP) 6 to 10 mmHg, urine output 100 ml/h (0.5 to 3 ml/kg/h), and heart rate 80 to 120/minutes with a minimum dosage of inotrope administration.

#### **5.2 Respiratory management**

The use of low-tidal-volume ventilation is recommended because a mechanical ventilator with high tidal volumes is potentially harmful and may exacerbate donor lung injury already damaged during the completion of BD. Recruitment maneuvers are an important component of donor optimization, especially when the oxygenation is subnormal and pulmonary abnormalities are visible on the chest x-ray. Repeated bronchoscopy (6 to 8 hours interval) is also important to improve donor lungs.

#### **5.3 Administration of ADH**

Administration of low-dose arginine vasopressin in conjunction with correction of hypovolemia due to diabetes insipidus reduces inotropic requirements and improves kidney, liver, and heart graft function, as shown previously [2]. As ADH increases both vascular tone and the affinity of BAR, ADH is effective even in patients with reduced urine output. ADH may stabilize hemodynamics, increase renal blood flow, and finally increase urine output.

Although desmopressin is mostly beneficial for the primary treatment of diabetes insipidus, it does not usually reduce inotrope requirements in organ donors [2]. Furthermore, desmopressin is reported to increase the incidence of thrombotic events.

ADH should be continuously given through a central venous line with a dose of 10–2o microU/Kg/h or 0.5–1 U/h. In case of hypotension, a loading bolus dose of ADH 0.5 to 1U is effective. If hemodynamics is stabilized by ADH administration, noradrenaline, and then adrenaline can be discontinued. If serum adrenaline level comes within a normal range, the heart rate is converged to an intrinsic heart rate between individuals of the same age, usually into a range of 90 to 120/minutes which is higher than the resting heart rate, because the autonomic regulation on the heart is gone in a BD patient. To optimize hemodynamics throughout procurement surgery, ADH should be continuously infused until the insertion of perfusion cannulas for all procured organs become ready and heparin is given [2].

Reduced ADH secretion due to BD may increase urine output, serum sodium, and osmolality, as well as reduce serum potassium, which decreases circulatory blood volume and intracellular fluid and cause hepatic or renal dysfunction and arrhythmia. Therefore, ADH administration can restore these consequences and is considered a key medication for donor management. Adjusting serum sodium and potassium with 135–150 and 3.8–4.5 mEq/l, respectively, hematocrit greater than 30%, blood sugar with 120–180 mg/dl, and body temperature with 35.5–36.5°C, are also important for optimal donor management.

#### **6. Japanese strategies for donor evaluation and management**

#### **6.1 Medical consultant system in Japan**

Since BD organ transplantation was started on 28th February 1999 in Japan, every organ procurement team has taken its own staff physicians to the procurement hospital. They evaluated the donor heart function by performing echocardiography by themselves in ICU prior to procurement operation.

Since November 2002, special transplant management doctors (a medical consultant; MC), who used to be cardiac transplant surgeons and are currently cardiac transplant cardiologists, have been sent to the procurement hospital. They estimate donor heart function and determine whether the heart is useful for transplantation. They also intensively manage the donor by giving ADH as shown above, minimizing the dose of intravenous inotropes, and improving the donor organ function until the procurement heart team arrives at the procurement hospital.

*Donor Assessment and Management for Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.104504*

Management strategy of lungs has been modified after the 50th organ procurement from a BD donor in December 2006. After then, in addition to routine bronchial toileting and posture change, repeated broncho fiberscope and frequent bronchial toileting were performed, if there were symptoms and/or signs of atelectasis or pneumonia in the chest x-ray and CT chest scan, After changing the lung management strategy, not only lung availability but also patient survival rate after lung transplantation significantly increased [27]. Then, since 2011, lung transplant surgeons played a role in evaluating and managing lungs as lung MC [28].

#### **6.2 1st step donor evaluation**

PTC of Japan Organ Tx Network (JOT) is sent to a hospital if there is a potential BD organ donor. They evaluate the patient clinical course and check clinical records to rule out the absolute contraindications, shown above. They obtain informed consent for BD organ donation from his or her relatives. After then, two times of legal examination for BD is carried out.

#### **6.3 2nd step donor evaluation**

After completion of 1st legal examination for BD determination, MCs come to the hospital. They and JOT PTC obtain the donor's clinical data such as past history, family history, clinical course during the completion of BD and after BD, such as the history of cardiopulmonary resuscitation and pulmonary aspiration, medication given, such as inotropes, ADH and antibiotics, transfusion, blood examination, blood gas examination, hemodynamic parameters, ECG findings, and data of image examination such as the chest x-ray and the abdominal and chest CT scan. MCs also perform ultrasound examinations for heart and abdominal organs and broncho fiberscope. Rule out malignancies by findings of the CT scan and ultrasound examination and support of making donor evaluation sheets by JOT PTCs are is also an important job of MC.

After 2nd legal examination for BD determination, the patient has declared dead and donor evaluation sheets and images of sequential ECGs, chest x-rays, echocardiography, and chest CT scans are sent to the heart transplant centers of potential recipients using a mobile system, called a donor data delivery system (DDDS) established by JOT. Then transplant center decides whether the recipient undergo heart transplantation from this BD donor and the procurement team is sent to the hospital

According to their assessment of donor hemodynamics and respiration, MCs proposed individualized donor management strategies to physicians taking care of the donor in the procurement hospital.

#### **6.4 3rd step donor evaluation**

After arriving at the donor hospital, the procurement team also evaluates the donor heart function with echocardiography by themselves in ICU and determines whether the heart can be transplanted to their recipient. They send this information to their transplant team.

#### **6.5 Pre-procurement meeting and management of the procurement operation**

Before starting the procurement operation, all procurement surgeons, anesthesiologists, and operating room nurses gathered in the meeting room. They negotiated

on the types of organs procured, the organ transportation method, the method of each organ procurement (e.g., organ dissection/perfusion technique, incision lines, blood drainage technique, etc), what kinds of samples (e.g., blood, lymph nodes, and spleen) were needed, and how to manage the donor during operation. A heart procurement surgeon also supports anesthesiologists to stabilize the patient's hemodynamics throughout the procurement operation.

Skillful staff surgeons, not resident surgeons, harvests the donor heart. As it was reported that increased intraoperative colloid infusion was significantly associated with poor allograft function post-lung transplantation, maintenance of circulating blood volume and blood osmolality by infusing packed red blood cells and albumin during procurement operation are very important to improve lung graft function posttransplant. To achieve good organ perfusion with preservation solution, the dosage of inotropes should be kept to the minimum to dilate the procured organ vessels and ADH is continuously given until heparin sulfate (400 U/Kg) is given.

#### **6.6 Final donor evaluation**

After opening the chest, the procurement team will evaluate the heart by inspection and palpation to decide to use the heart. They also look out for unexpected malignancies in the pleural and abdominal cavities.

#### **7. Discussion**

For many years, heart transplantation has been an established treatment strategy for end-stage heart failure patients using the so-called "Standard Criteria" donor heart. However, over the past three decades, the number of annually listed patients for heart transplantation greatly increased worldwide, and the strict use of the "Standard Criteria" hearts has enhanced severe donor heart shortage, significantly prolonged waiting times and increased the death rate of listed patients prior to heart transplantation. Therefore, the use of ECD hearts has increased worldwide. However, even in 2020, only 3,658 hearts of 9,364 BD donors (39.1%) were transplanted in the USA. As only 760 BD donors have been available in Japan for more than 20 years until the end of 2020 because of the very strict Japanese Organ Transplant Act, only 297 donor hearts would have been transplanted if the rate of heart utilization from the BD donors in Japan is same as in the USA. These extraordinary pressures of donor heart shortage had made Japanese heart transplant programs use a much greater number of ECD donor hearts than in developed countries. Therefore, an original and sophisticated donor evaluation and management system have been established in Japan, such as MC and pre-procurement meetings and so on.

To elucidate the role of this Japanese donor evaluation and management system, consecutive 775 BD donors since the Act was issued until the end of August 2021 in Japan, were reviewed. A total of 611 hearts (78.8%) were transplanted, and organ transplanted per donor was 5.1 (3,985 organs from 775 donors). The number of heart donor ≥ 60 years of age was 63 (10.3%). In the heart donors who had information about the cause of death, the cause of BD was subarachnoid hemorrhage in 160, hypoxic brain damage in 126, other cerebrovascular disorders in 120, head trauma in 100, post-cardiopulmonary resuscitation in 29, and asphyxias in 23. Overall survival rates of cardiac recipients at 1 year, 5, 10, and 20 years were 93.3, 88.3, 79.1, and 75.3%, respectively. Patient survival at 10 years with donor aged 10–19 years, 20–29 years, 30–39 years, 40–49 years, 50–59 years, and 60–69 years were 100, 61.6, 95.5,

*Donor Assessment and Management for Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.104504*

#### **Figure 3.**

*Cumulative patient survival rate of heart transplant recipients by donor age group (up to August 31, 2021). yrs: years.*

#### **Figure 4.**

*Cumulative patient survival rate of heart transplant recipients by donor cause of death group (up to August 31, 2021). SAH: subarachnoid hemorrhage, Post-CPR: post-cardiopulmonary resuscitation.* 

88.4, 92.7, 85.9, and 89.3%, respectively (**Figure 3**). Patient survival at 10 years from a donor with subarachnoid hemorrhage, hypoxic brain damage, other cerebrovascular disorders, head trauma, post-cardiopulmonary resuscitation, and asphyxias were 87.7, 93,2 (at 8.6 years), 82.9, 88.3, 96.6, and 85.2%, respectively (**Figure 4**). These values were not significantly different.

#### **8. Conclusion**

As deceased organ donation has not increased compared to an increase in listed candidates for heart transplantation worldwide, extended criteria donor hearts have been used in many countries. However, in most countries, only 20–30% of donor hearts from BD donors have been used. Therefore, in Japan where donor shortage has been extremely sever than in other developed countries, special strategies for

maximizing heart availability should be established. By establishing the MC system in Japan, the availability of hearts has been very high (79%) and the patient survival rate at high (89% at 10 years). MC doctors may play a great role in increasing donor heart availability as well as in improving outcomes of cardiac recipients even from elderly donors or donors who died of post-resuscitation and anoxia in Japan. These strategies may be useful for maximizing heart transplant opportunities and improving posttransplant outcomes.

### **Author details**

Norihide Fukushima Department of Transplant Medicine, National Cerebral and Cardiovascular Center, Suita, Japan

\*Address all correspondence to: nori@ncvc.go.jp

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Fukushima N. Revised organ transplant act and transplant surgeons. Japan Medical Association Journal. 2011;**54**(6):387-391

[2] Fukushima N, Ono M, Nakatani T, et al. Strategies for maximizing heart and lung transplantation opportunities in Japan. Transplantation Proceedings. 2009;**41**(1):273-276

[3] Novitzky D, Cooper DK, Rosendale JD, Kauffman HM. Hormonal therapy of the brain-dead organ donor: Experimental and clinical studies. Transplantation. 2006;**82**(11):1396-1401

[4] Mascia L, Mastromauro I, Viverti S, et al. Management of optimize organ procurement in brain dead donors. Minerva Anesthesiol. 2009;**75**:125-133

[5] Kaul DR, Vece G, Blumberg E, et al. Ten years of donor-derived disease: A report of the disease transmission advisory committee. American Journal of Transplantation. 2021;**21**:689-702. DOI: 10.1111/ajt.16178

[6] Audibert G, Charpentier C, Sequim-Devaux C, et al. Improvement of donor myocardial function after treatment of autonomic strom during brain death. Transplantation. 2006;**82**:1031-1036

[7] Ryan JB, Hicks M, Cropper JR, et al. Functional evidence of reversible ischemic injury immediately after the sympathetic storm associated with experimental brain death. The Journal of Heart and Lung Trasnplantation. 2003;**22**:922-928

[8] Boone M, Deen PM. Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflügers Archives. 2008 Sep;**456**(6):1005-1024

[9] Pennefether SH, Bullock RE, Mantle D, Dark JH. Use of low dose arginine vasopressin to support braindead organ donors. Transplantation. 1995;**59**:58

[10] Kinoshita Y, Okamoto K, Yahata K, et al. Clinical and pathological changes of the heart in brain death maintained with vasopressin and epinephrine. Pathology, Research and Practice. 1990;**186**(1):173-179

[11] Iwai A, Sakano T, Uenishi M, et al. Effects of vasopressin and catecholamines on the maintena,nce of circulatory stability in braindead patients. Transplantation. 1989;**48**(4):613-617

[12] Fukushima N, Shirakura R, Nakata S, et al. Failure of rapid autonomic augmentation of cardiac performance in transplanted hearts. Transplantation Proceedings. 1998;**30**(7):3344-3346

[13] Huprikar S, Danziger-Isakov L, Ahn J, et al. Solid organ transplantation from hepatitis B virus-positive donors: Consensus guidelines for recipient management. American Journal of Transplantation. 2015;**15**(5):1162-1172. DOI: 10.1111/ajt.13187

[14] Ruiz I, Gavaldà J, Monforte V, Len O, Román A, et al. Donor-to-host transmission of bacterial and fungal infections in lung transplantation. American Journal of Transplantation. 2006;**6**:178-182

[15] Hynes CF, Ramakrishnan K, Alfares FA, et al. Risk of tumor transmission after thoracic allograft transplantation from adult donors with central nervous system neoplasm–A

UNOS database study. Clinical Transplantation. 2017;**31**(4):e12919. DOI: 10.1111/ctr.12919

[16] Desai R, Collett D, Watson CJE, Johnson P, Evans T, Neuberger J. Estimated risk of cancer transmission from organ donor to graft recipient in a national transplantation registry. BJS. 2014;**101**:768-774. DOI: 10.1002/bjs.946

[17] Grauhan O. Screening and assessment of the donor heart cardiopulmonary. Pathophysiology. 2011;**15**:191-197

[18] Laks H, Gates RN, Ardehali A, et al. Orthotopic heart transplantation and concurrent coronary bypass. The Journal of Heart and Lung Transplantation. 1993;**12**:810-815

[19] Marelli D, Laks H, Bresson S, et al. Results after transplantation using donor hearts with preexisting coronary artery disease. The Journal of Thoracic and Cardiovascular Surgery. 2003;**126**:821

[20] Kimura Y, Seguchi O, Iwasaki K, et al. Impact of coronary artery calcification in the donor heart on transmitted coronary artery disease in heart trnsplant recipients. Circulation Journal. 2018;**82**:3021-3028. DOI: 10.1253/circj.CJ-18-0107

[21] Bailey LL, Razzouk AJ, Hasaniya NW, Chinnock RE. Pediatric transplantation using hearts refused on the basis of donor quality. The Annals of Thoracic Surgery. 2009;**87**(6):1902-1908

[22] Khush KK, Potena L, Cherikh WS, et al. The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: 37th adult heart transplantation report—2020; focus on deceased donor characteristics.

The Journal of Heart and Lung Transplantation. 2020;**39**(10):1003-1015

[23] Sakagoshi N, Shirakura R, Nakano S, et al. Serial changes in myocardial betaadrenergic receptor after experimental brain death in dogs. The Journal of Heart and Lung Transplantation. 1992;**11**:1054-1058

[24] Fukushima N, Sakagoshi N, Ohtake S, et al. Effects of exogenous adrenaline on the number of the betaadrenergic receptors after brain death in humans. Transplantation Proceedings. 2002;**34**:2571-2574

[25] Fukushima N, Shirakura R, Nakata S, et al. Study of efficacies of leukocytedepleted terminal blood cardioplegia in 24-hour preserved hearts. The Annals of Thoracic Surgery. 1994;**58**(6):1651-1656

[26] Russo MJ, Iribarne A, Hong KN, et al. Factors associated with primary graft failure after heart transplantation. Transplantation. 2010;**90**(4):444-450

[27] Fukushima N, Ono M, Saito S, et al. Japanese strategies to maximize heart and lung availabilities: Experience from 100 consecutive brain-dead donors. Transplantation Proceedings. 2013;**45**:2871-2874

[28] Hoshikawa Y, Okada Y, Ashikari J, et al. Medical consultant system for improving lung transplantation opportunities and outcomes in Japan. Transplantation Proceedings. 2015;**47**:746-750

#### **Chapter 2**

## Primary Graft Dysfunction after Heart Transplantation

*Soo Yong Lee*

#### **Abstract**

The entire transplant journey that the donor heart experiences affect the donor heart function early after transplantation. The early graft dysfunction without discernible cause is primary graft dysfunction (PGD) and has been one of the critical complications and the cause of early mortality after orthotopic heart transplantation. Although, numerous researchers investigated the pathophysiology and the related biomarkers, the process is multifactorial and therefore no definite biomarker has been proposed. After the recent definition from the International Society of Heart and Lung Transplantation, the standard of management is still under investigation by each status. Here, the prevalence, pathophysiology, biomarkers, and recent progression of management of PGD will be reviewed.

**Keywords:** heart transplantation, primary graft dysfunction

#### **1. Introduction**

Heart transplantation (HTx) remains the most effective long-term treatment for eligible patients with advanced heart failure. Remarkable improvements in HTx outcomes over decades with advances in medicine and surgical techniques, Primary graft dysfunction (PGD) has been one of the critical complications after orthotopic heart transplantation and cause of early mortality [1, 2]. However, even the definition has formulated recently in 2014, by the International Society of Heart and Lung Transplantation (ISHLT) in the consensus statement and management guidelines are still absent [3]. The 30-day mortality of PGD had been reported with a wide range of 2.3-28.2% in the era before consensus definition. Although, applying new a definition, the early mortality with PGD patients showed no great difference, 6.06-18.4% [4–6].

#### **2. Primary graft dysfunction**

#### **2.1 Definition, prevalence, diagnosis**

#### *2.1.1 Definition*

PGD was defined as any graft dysfunction that occurs within 24 h after completion of transplant surgery (**Table 1**). This definition was established during the annual meeting of ISHLT in 2013. Primary means, not associated with a discernible cause, such as


*BiVAD, biventricular assist device; CI, cardiac index; ECMO, extracorporeal membrane oxygenation; IABP, intraaortic balloon pump; LVAD, left ventricular assist device; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RVAD, right ventricular assist device; TPG, transpulmonary pressure gradient. \* Inotrope score = dopamine (×1) + dobutamine (×1) + amrinone (×1) + milrinone (×15) + epinephrine (×100) + norepinephrine (×100) with each drug dosed in μg/kg/min.*

#### **Table 1.**

*Definition of severity scale for primary graft dysfunction [3].*

hyperacute rejection, pulmonary hypertension, or uncontrolled intraoperative bleeding requiring massive blood product transfusions and prolonged graft ischemic time [3, 7].

#### *2.1.2 Prevalence and outcomes*

Primary graft dysfunction develops fairly common after HTx. A report from two Italian center studies described a 518-patient cohort with a 14% prevalence of PGD and a mortality of 54% in patients with severe PGD [8]. In addition, a UK National study evaluated medical records, PGD developed in 163 among 450 adult heart transplant cohort, and the overall incidence of PGD was 36.2%. The distribution of PGD according to severity was 4, 72, 81 and 6 for mild, moderate, severe LV PGD, and RV. A recently published data from South Korea showed 6.7% (38/570) of incidence, most of them were moderate to severe state (34/38). The early mortality rate in patients with moderate to severe PGD-LV (20.6%) differed significantly from that in patients without PGD (0.6%; *P* < 0.001). From the landmark analysis, the authors showed the strong effect of moderate to severe PGD-LV on early death, and no significant difference in late survival rates (>3mo) in patients with or without moderate to severe PGD-LV.

The outcomes of a different cohort of 191 patients found worse 30-day mortality of 25% in moderate to severe PGD group, the survival curves diverged during the first 3 months following transplantation but went parallel after this initial postoperative period [9]. That means, PGD mainly affects the early deaths, not the late deaths.

The detailed incidence and outcomes of each study is summarized in **Table 2**.


**Table 2.**

*Incidences of PGD according to new ISHLT criteria showed in various reports.*

*Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

**23**

#### *2.1.3 Differential diagnosis with secondary graft dysfunction (SGD)*

When it comes to the first facing of PGD, a novice in HTx could have difficulties in differentiating PGD from SGD. SGD has discernible causes such as pulmonary hypertension, surgical complications, or hyperacute rejection [3]. A significant improvement in the pretransplant management of both donors and recipients could contribute to reducing the incidence of SGD over a decade, from10 to 5.6% [8], although there are some differences in the reported incidences [2, 8]. For SGD and PGD share some risk factors and could develop concurrently. Therefore, the patient's condition is unacceptable for the satisfactory evaluation for differential diagnosis, treatment targeting both SGD and PGD is warranted. Several diagnostic pearls and pitfalls are summarized in **Table 3**.

#### **2.2 Pathophysiology**

The entire transplant journey that the donor heart experiences including brain death, storage of the organ in a hypothermic environment, potential exposure to warm ischemia, and reperfusion could affect the allograft dysfunction [15]. The surge of catecholamines following brain injury leads to myocardial ischemia, calcium overload, and alteration in the sensitivity of myocytes to calcium. This is further aggravated by exogenous catecholamines following cardiopulmonary bypass and reperfusion [16, 17].

In addition, the ischemia-reperfusion injury (IRI) has been thought to play another major role in the development of PGD. Once the aortic cross-clamp is applied, cold cardioplegia is infused via the aortic root at approximately 4°C. The retrieval process is completed with the heart placed in a cold storage container. The cold storage induces hypothermic arrest of metabolism and maintains viability during this reduced metabolic state, therefore minimizing cellular swelling and reperfusion injury [18]. At these temperatures, and with limited oxygenation, the heart switches from aerobic to anaerobic metabolism. Generally in the hypothermic state (0–4°C), there is a 12-fold decrease in metabolic rate and reduces the accumulation of mitochondrial byproducts of metabolism such as oxygen-free radicals. However, the duration at which the hearts are kept in cold storage matters in the formation of these free radicals. Cellular swelling and lactic acidosis occur in prolonged cold storage, causing an elevation of intracellular H<sup>+</sup> ions [19]. Then, the Na<sup>+</sup> /H<sup>+</sup> exchanger is activated resulting in an increase in intracellular Na<sup>+</sup> which activates the Na<sup>+</sup> / Ca2+ exchanger. The final pathway is the accumulation of cytosolic Ca2+ [20]. After releasing cross-clamp, Ca2+ overload results in hypercontraction of the myocardium, and a marked rise in end-diastolic pressure with increased ventricular wall stiffness. A greater myofibrillar shortening and cytoskeletal damage occur compared to the ischemic phase [21]. In cellular studies, re-perfused infarcts consist almost exclusively of contraction band necrosis. This process, known as hypercontracturemediated sarcolemmal rupture (HMSR), impairs Na<sup>+</sup> /Ca2+ exchanger pumps, and finally increases Na<sup>+</sup> influx into cardiomyocytes via gap junctions and may propagate to adjacent cells [22]. Clinically, the prolonged cold ischemic time of more than 4 h was reported as one of the most important predictors of PGD [23, 24].

#### **2.3 Biomarkers**

Several biomarkers have been suggested as potential predictors of PGD, however, the guidelines are absent, and none are in routine use currently.


**Table 3.**

 *Brief characteristics of SGD for differential diagnosis with PGD.*

#### *Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

#### *2.3.1 Proinflammatory biomarkers in donors and recipients*

The pathophysiology of PGD itself is deeply connected with the inflammatory processes after IRI, the related markers were investigated. Tumor necrosis factor-α (TNF-α) is a representative pro-inflammatory biomarker produced by lymphocytes and macrophages [25]. Venkateswaran et al. highlighted poorer biventricular function in donors with elevated levels of TNF-α using serum immunoassays. In the study, the authors also showed higher baseline donor procalcitonin (PCT) levels were related to worse cardiac index and RV and LVEF and demonstrated PCT level of more than 2 ng/mL might be a tool for the usability of donor heart [26]. Wagner et al. also suggested a PCT level of 2 ng/mL as a cut-off value for increasing 30-day mortality and early graft dysfunction after transplantation [27].

Birks and colleagues noted an increased expression of TNF-α in unused donor hearts due to poor function and compared them with donors with good ventricular function (used donors) and patients with advanced heart failure (HF). They also noted IL-6 mRNA expression was 2.4-fold higher in the unused donor hearts than in those used for HTx [28]. This was accompanied by similar changes in the serum and suggests those could be potential biomarkers for PGD.

Hypoxia-inducible factor (HIF)-1 is activated by various growth factors, cytokines, and vascular hormones, which are essential mediators of IRI. HIF-1 is a heterodimeric α, β transcription factor, and potentiates tissue responses to hypoxia [29]. HIF-1 along with the early growth response factor facilitates the transcription of inflammatory cytokines. Aharinejad et al. performed a prospective analysis in 200 heart donors over 7 years and identified HIF-1 as an independent predictor of PGD [30]. They demonstrated a significant increase in HIF-1 levels especially 10 min after reperfusion and were correlated with higher incidences of PGD.

Recently, the pro-inflammatory tendency of recipients rather than donors has been actively focused by investigators. Giangreco et al. reported KLKB1, a serine protease that controls the activation of both inflammation and coagulation in what is known as the kallikrein-kinin system (KKS), as a potential predictor for PGD using gene set enrichment analysis (GSEA) [31]. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50%. In the inflammatory response, KLKB1 converts high molecular weight kininogen into bradykinin stimulating the release of nitric oxide and prostacyclin causing vasodilation and increased vascular permeability.

Truby et al. employed high-throughput proteomic profiling related to innate immune activation and inflammation in HTx recipients of pre-transplant serum from HTx recipients to identify relevant biomarkers [32]. Proteomic profiling revealed 9 out of 342 proteins showed statistical significance in the derivation set. When they were tested in the validation set, only CLEC4C (C-Type Lectin Domain Family 4 Member C, a protein marker of plasmacytoid dendritic cells (pDCs),) was significantly associated with PGD. The odd ratio (95% CI) for CLEC4C for PGD was 1.89 ([1.38, 2.64], *p* = 1.3 × 10–4) in sensitivity analysis combining the derivation and validation sets. Moreover, when the CLEC4C was added to the traditional risk stratification tool such as RADIAL score, they showed a better risk profile. The aforementioned studies identified not only the biomarkers but also the novel pathogenesis of PGD.

#### *2.3.2 Biomarkers for damaged heart*

The measurements of serum cardiac troponin I (cTnI) and cardiac troponin T (cTnT) have shown to be sensitive and specific markers of myocardial damage [33]. *Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

After SAH, sympathetic nervous system activation and release of norepinephrine from the myocardial sympathetic nerves could result in myocardial damage and troponin elevation [34]. Many systemic complications occur after brain death like myocardial dysfunction, neurogenic stunned myocardium, segmental wall motion abnormalities, stress cardiomyopathy, and these could affect the cardiac function after HTx. Deibert et al. assessed the clinical significance of elevated cTnI levels in patients with non-traumatic subarachnoid hemorrhage and found that an elevated cTnI (≥1.4 μg/l) was a good indicator of LV dysfunction in patients with subarachnoid hemorrhage [35]. However, the cardiac dysfunction in brain death donors was mostly reversible, and larger studies that investigated the association between donor serum troponin level and PGD showed no relevance [36, 37].

BNP and the BNP precursor N-terminal prohormone BNP (NT-proBNP) are released from myocardium in response to increased wall stress. These are the most useful markers utilized in the heart failure field, with significant predictive value on diagnosis and prognosis. The elevated levels of BNP have been identified in heart donors and high levels may distinguish those donors with severely impaired LV systolic function [38]. Elevated NT-proBNP levels (4125 pg/ml) have also been found to be a marker of poor hemodynamic function and echocardiographic data in potential donors after brain stem death [39].

#### *2.3.3 Other biomarkers*

Switch/sucrose non-fermentable, a matrix-associated, actin-dependent regulator of chromatin subfamily a-like 1(SMARCAL1) is an intracellular protein that acts as a DNA-dependent ATPase involved in transcription, DNA repair and chromatin dynamics [40]. In 2009, Ahrinejad et al. demonstrated in a cohort of 336 heart donors that SMARCAL1 levels were significant predictors of both short and long-term survival and PGD. Donor serum cutoff of ≥1.25 ng/ml showed 96% sensitivity and 88% specificity for predicting PGD, with corresponding positive predictive and negative predictive values of 83% and 97%, respectively [41]. It seemed SMARCAL1 could play as a potential biomarker before organ selection or donation, however, it has not been widely used in practice till recent days.

The potential biomarkers, related pathophysiology and clinical implications are summarized in **Table 4**.

#### **2.4 Clinically identified risk factors**

Numerous variables have been identified as risk factors for PGD. Broadly, they have been categorized in terms of donor, recipient, procurement, surgical procedural and post-operative factors (**Table 5**).

In general, PGD does not come from a single risk factor, rather from multiple or complex interplays of the risk factors. Therefore, a kind of scoring system for PGD would be reasonable to estimate the risk. In 2011, Segovia et al. suggested a risk scoring system called RADIAL for predicting PGD. 'RADIAL' represents 6 multivariate risk factors: Right atrial pressure ≥ 10 mm Hg, recipient Age ≥ 60 years, Diabetes mellitus, Inotrope dependence, Donor Age ≥ 30 years, Length of ischemic time ≥ 240. In a single-center cohort of 621 HTx recipients transplanted from 1984 to 2006, the percentages of PGD were 8.3%, 11.1%, 24% and, 44.4% in the score of 0–1, 2, 3, and ≥ 4 group. The validated score in an external multicenter cohort (698 HTx from 2006 to 2010) was acceptable for risk stratification [50, 52]. However, the transplanted patient


*BNP, brain natriuretic peptide, CLEC4C, C-Type Lectin Domain Family 4 Member C, HIF-1, hypoxia inducible factor-1, KLKB1, Kallikrein B1, PCT, procalcitonin, pDC, plasmacytoid dendritic cells, PGD, primary graft dysfunction, TNF-α, tumor necrosis factor.*

#### **Table 4.**

*Representative potential biomarkers, related pathophysiology and clinical implications.*

*Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*


#### **Table 5.**

*Known risk factors for the development of primary graft dysfunction.*

population bridged by LVAD was relatively low (16/621, 2.6%) in the study. In a recent single-center study, there was a trend toward increased PGD in pretransplant LVAD recipients (40.4% vs. 32.9%, *P* = 0.0555) [6]. The RADIAL score is the only validated scoring system for PGD thus far however, does not have a definitive role in donor selection or predicting PGD for its limited predictive power. The modifiable risk factors should be managed in every transplantation process. Female to male and undersized donors (≥30%) would have better been avoided. Possible infections should be controlled with antibiotics in both donor and recipient. Vasopressors such as vasopressin and terlipressin, are currently recommended as first-line treatment to reduce the noradrenaline requirement [53]. Insulin or thyroid hormone replacement would be helpful in some donors with hyperglycemia and hormone depletion [54, 55]. During procurement, the team should minimize allograft damage and try the best effort to

reduce the ischemic time. Especially, donors with hypertrophied hearts should be kept to a minimum cold ischemic time due to susceptibility to ischemic injury [2].

#### **2.5 Prevention**

Patients with significant coronary artery disease, and/or LV hypertrophy, above 55 years are generally classified as marginal donors [56]. To resolve the severe donor shortage problem, many transplant centers accept extended use of marginal donor hearts [56]. Some authors recommend avoiding marginal donor hearts to reduce the risk of PGD [15]. However, for the absolute shortage of donor supply, and the absence of a groundbreaking alternative, utilization of marginal donors would be inevitable. Therefore, making efforts to minimize PGD after utilizing marginal donors seems more rational than just declining them unconditionally.

Proper donor management (hormone therapy, lower inotropes), better matching of the donor to recipient, improved procurement techniques, better organ preservation (Oran Care System, different additives in solutions), gradual wean of inotropes, utilization of nitric oxide, making efforts to decrease ischemic time and transfusion by improving surgical techniques and thorough planning are suggested as prevention [3]. Among them, the ex-vivo perfusion modifies many variables arising in the course of procurement and delivery of allograft. Ex-vivo perfusion may avoid the limitation of cold storage by providing warm blood perfusion to the donor heart [57]. The Harefield Hospital team reported favorable results in their experience using marginal donors with mild LVH with normothermic ex vivo perfusion [58]. In the prospective, multicenter, randomized, clinical investigation of TransMedics Organ Care System (OCS) for Cardiac Use II trial, 130 patients were randomized to ex-vivo donor heart perfusion or standard cold storage and demonstrated no difference in 30-day patient and graft survival rates or serious adverse events.

The development of more effective donor management and donor heart preservation strategies may reduce the incidence of PGD. Each effort to reduce the risk of PGD could make better results when they gather.

#### **2.6 Management**

The current definition for PGD is including the treatment options for each status. By far the treatment of PGD is still primarily supportive care. PGD is initially managed by using inotropic support using catecholamines and phosphodiesterase inhibitors.

#### *2.6.1 Mild to moderate LV PGD*

Mild to moderate PGD cases could be treated medically first with inotropes, vasopressors, nitric oxide, and inhaled prostaglandins. If hemodynamics is not able to be improved to a level of adequate organ perfusion, mechanical support is implemented. IABPs may be a first-line device that gives counter pulsation that reduces afterload and improves coronary perfusion pressure, and it can be placed quickly at the bedside. However, it has limited utilization for partial hemodynamic support (maximum 30% increase in cardiac output) in severe graft dysfunction [15].

#### *2.6.2 Severe LV PGD*

In patients experiencing severe PGD early after transplantation, mechanical circulatory support other than IABP (by definition) is required to maintain adequate

#### *Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

end-organ perfusion. This involves veno-arterial extracorporeal membrane oxygenator (VA-ECMO) support or implantation of a temporary ventricular assist device (VAD) without oxygenators such as Centrimag (Thoratec Corporation, Pleasanton, CA), TandemHeart (Tandem Life, Pittsburgh, PA), or Impella (Abiomed, Danvers, MA). Choice of the device, the timing of insertion, device configuration, and management differ even among high-volume transplant centers [3].

The incidence differs from report to report, a significant proportion of PGDs develop as biventricular involvement. Therefore, when it comes to severe PGD, MCS that supports both ventricles could be a better choice than a single ventricular support system. Takeda et al. demonstrated improved outcomes with the use of ECMO compared with temporary surgically implanted VAD for severe PGD with retrospective analysis of data collected in Columbia University Medical Center [59].

In general, it is thought that ECMO leads to better results when applied in early cardiogenic shock before multi-organ failure progresses. The forementioned institution adopted an aggressive ECMO approach for patients with evidence of severe PGD in 2015. VA-ECMO support was initiated early in the assessment of graft dysfunction in the immediate perioperative period, often during or immediately after weaning from cardiopulmonary bypass. In-hospital mortality improved from 28% (conservative) to 5% (prompt, *P* = 0.083). Post-transplant survival at 1 year was 67% in the conservative ECMO cohort and 90% in the prompt ECMO cohort (*P* = 0.117). Although, there was no statistical difference in survival rate for 3 yrs., they concluded that a possible mortality reduction in the prompt ECMO after severe PGD could be expected [60]. Regardless of modality, early intervention and short-term mechanical support seem to be associated with improved survival in severe LV PGD.

#### *2.6.3 RV PGD*

Currently, available treatment options for postoperative RV failure are optimization of acid-base status, fluid management, intravenous inotropes and vasodilators, and right-sided mechanical support. Inhaled vasodilators are often preferred because of their more direct effect on the pulmonary vasculature [61]. However, treatment options tend to be dependent on physicians or institutional preferences due to the lack of guidelines. Pulmonary vasodilators have been indicated only for the mild form of PGD-RV, with mechanical circulatory support indicated at an early stage for signs of severe PGD-RV [3].

#### **3. Conclusions**

PGD is the leading cause of early morbidity following heart transplantation. It is thought to be multifactorial in origin and several risk factors implicated. Researchers for potential biomarkers have been reporting novel predictors and are still ongoing. Prevention with adjusting modifiable risk factors is needed. Treatment options remain supportive with no definitive pharmacological agents identified yet, however, in terms of severe PGDs, timely mechanical circulatory support could reverse the fatal clinical outcome.

#### **Acknowledgements**

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1F1A106657312).

### **Author details**

#### Soo Yong Lee

Division of Cardiology, Department of Internal Medicine and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University School of Medicine, Pusan National University Yangsan Hospital, South Korea

\*Address all correspondence to: shonge0906@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Iyer A, Kumarasinghe G, Hicks M, Watson A, Gao L, Doyle A, et al. Primary graft failure after heart transplantation. Journal of Transplantation. 2011;**2011**: 175768

[2] Singh SSA, Dalzell JR, Berry C, Al-Attar N. Primary graft dysfunction after heart transplantation: A thorn amongst the roses. Heart Failure Reviews. 2019;**24**(5):805-820

[3] Kobashigawa J, Zuckermann A, Macdonald P, Leprince P, Esmailian F, Luu M, et al. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. The Journal of Heart and Lung Transplantation. 2014;**33**(4):327-340

[4] Rhee Y, Kim HJ, Kim JJ, Kim MS, Lee SE, Yun TJ, et al. Primary graft dysfunction after isolated heart transplantation-incidence, risk factors, and clinical implications based on a single-center experience. Circulation Journal. 2021;**85**(9):1451-1459

[5] Avtaar Singh SS, Banner NR, Rushton S, Simon AR, Berry C, Al-Attar N. ISHLT primary graft dysfunction incidence, risk factors, and outcome: A UK National Study. Transplantation. 2019;**103**(2):336-343

[6] Nicoara A, Ruffin D, Cooter M, Patel CB, Thompson A, Schroder JN, et al. Primary graft dysfunction after heart transplantation: Incidence, trends, and associated risk factors. American Journal of Transplantation. 2018;**18**(6):1461-1470

[7] Kim IC, Youn JC, Kobashigawa JA. The past, present and future of heart transplantation. Korean Circulation Journal. 2018;**48**(7):565-590

[8] Sabatino M, Vitale G, Manfredini V, Masetti M, Borgese L, Maria Raffa G, et al. Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: Epidemiology, risk factors, and outcomes. The Journal of Heart and Lung Transplantation. 2017;**36**(11):1217-1225

[9] Squiers JJ, Saracino G, Chamogeorgakis T, MacHannaford JC, Rafael AE, Gonzalez-Stawinski GV, et al. Application of the International Society for Heart and Lung Transplantation (ISHLT) criteria for primary graft dysfunction after cardiac transplantation: Outcomes from a high-volume centredagger. European Journal of Cardio-Thoracic Surgery. 2017;**51**(2):263-270

[10] Dronavalli VB, Rogers CA, Banner NR. Primary cardiac allograft dysfunctionvalidation of a clinical definition. Transplantation. 2015;**99**(9):1919-1925

[11] Foroutan F, Alba AC, Stein M, Krakovsky J, Chien KGW, Chih S, et al. Validation of the International Society for Heart and Lung Transplantation primary graft dysfunction instrument in heart transplantation. The Journal of Heart and Lung Transplantation. 2019;**38**(3):260-266

[12] Gorlitzer M, Ankersmit J, Fiegl N, Meinhart J, Lanzenberger M, Unal K, et al. Is the transpulmonary pressure gradient a predictor for mortality after orthotopic cardiac transplantation? Transplant International. 2005;**18**(4):390-395

[13] Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, et al. Pretransplantation risk factors for death after heart

transplantation: A multiinstitutional study. The transplant cardiologists research database group. The Journal of Heart and Lung Transplantation. 1993;**12**(4):549-562

[14] Murali S, Kormos RL, Uretsky BF, Schechter D, Reddy PS, Denys BG, et al. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: The Pittsburgh experience. American Heart Journal. 1993;**126**(4):896-904

[15] Subramani S, Aldrich A, Dwarakanath S, Sugawara A, Hanada S. Early graft dysfunction following heart transplant: Prevention and management. Seminars in Cardiothoracic and Vascular Anesthesia. 2020;**24**(1):24-33

[16] Pratschke J, Wilhelm MJ, Kusaka M, Basker M, Cooper DK, Hancock WW, et al. Brain death and its influence on donor organ quality and outcome after transplantation. Transplantation. 1999;**67**(3):343-348

[17] D'Amico TA, Meyers CH, Koutlas TC, Peterseim DS, Sabiston DC Jr, Van Trigt P, et al. Desensitization of myocardial beta-adrenergic receptors and deterioration of left ventricular function after brain death. The Journal of Thoracic and Cardiovascular Surgery. 1995;**110**(3):746-751

[18] Schipper DA, Marsh KM, Ferng AS, Duncker DJ, Laman JD, Khalpey Z. The critical role of bioenergetics in donor cardiac allograft preservation. Journal of Cardiovascular Translational Research. 2016;**9**(3):176-183

[19] Anaya-Prado R, Delgado-Vazquez JA. Scientific basis of organ preservation. Current Opinion in Organ Transplantation. 2008;**13**(2):129-134

[20] Karmazyn M, Gan XT, Humphreys RA, Yoshida H, Kusumoto K. The myocardial Na(+)-H(+) exchange: Structure, regulation, and its role in heart disease. Circulation Research. 1999;**85**(9):777-786

[21] Piper HM, Abdallah Y, Schafer C. The first minutes of reperfusion: A window of opportunity for cardioprotection. Cardiovascular Research. 2004;**61**(3): 365-371

[22] Garcia-Dorado D, Rodriguez-Sinovas A, Ruiz-Meana M. Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion. Cardiovascular Research. 2004;**61**(3):386-401

[23] Russo MJ, Iribarne A, Hong KN, Ramlawi B, Chen JM, Takayama H, et al. Factors associated with primary graft failure after heart transplantation. Transplantation. 2010;**90**(4):444-450

[24] Jahania MS, Sanchez JA, Narayan P, Lasley RD, Mentzer RM Jr. Heart preservation for transplantation: Principles and strategies. The Annals of Thoracic Surgery. 1999;**68**(5):1983-1987

[25] Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell. 2001;**104**(4):487-501

[26] Venkateswaran RV, Dronavalli V, Lambert PA, Steeds RP, Wilson IC, Thompson RD, et al. The proinflammatory environment in potential heart and lung donors: Prevalence and impact of donor management and hormonal therapy. Transplantation. 2009;**88**(4):582-588

[27] Wagner FD, Jonitz B, Potapov EV, Qedra N, Wegscheider K, Abraham K, et al. Procalcitonin, a donor-specific predictor of early graft failure-related mortality after heart transplantation. Circulation. 2001;**104**(12 Suppl 1): I192-I196

*Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

[28] Birks EJ, Burton PB, Owen V, Mullen AJ, Hunt D, Banner NR, et al. Elevated tumor necrosis factor-alpha and interleukin-6 in myocardium and serum of malfunctioning donor hearts. Circulation. 2000;**102**(19 Suppl. 3):III352-III358

[29] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxiainducible factor 1. The Journal of Biological Chemistry. 1996;**271**(30):17771-17778

[30] Aharinejad S, Schafer R, Krenn K, Zuckermann A, Schneider B, Neumann F, et al. Donor myocardial HIF-1alpha is an independent predictor of cardiac allograft dysfunction: A 7-year prospective, exploratory study. American Journal of Transplantation. 2007;**7**(8):2012-2019

[31] Giangreco NP, Lebreton G, Restaino S, Jane Farr M, Zorn E, Colombo PC, et al. Plasma kallikrein predicts primary graft dysfunction after heart transplant. The Journal of Heart and Lung Transplantation. 2021;**40**(10):1199-1211

[32] Truby LK, Kwee LC, Agarwal R, Grass E, DeVore AD, Patel CB, et al. Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation. The Journal of Heart and Lung Transplantation. 2021;**40**(12):1589-1598

[33] Sharma S, Jackson PG, Makan J. Cardiac troponins. Journal of Clinical Pathology. 2004;**57**(10):1025-1026

[34] Zahid T, Eskander N, Emamy M, Ryad R, Jahan N. Cardiac troponin elevation and outcome in subarachnoid hemorrhage. Cureus. 2020;**12**(8):e9792

[35] Deibert E, Barzilai B, Braverman AC, Edwards DF, Aiyagari V, Dacey R, et al.

Clinical significance of elevated troponin I levels in patients with nontraumatic subarachnoid hemorrhage. Journal of Neurosurgery. 2003;**98**(4):741-746

[36] Khush KK, Menza RL, Babcock WD, Zaroff JG. Donor cardiac troponin I levels do not predict recipient survival after cardiac transplantation. The Journal of Heart and Lung Transplantation. 2007;**26**(10):1048-1053

[37] Madan S, Saeed O, Shin J, Sims D, Goldstein D, Pina I, et al. Donor troponin and survival after cardiac transplantation: An analysis of the United Network of Organ Sharing Registry. Circulation: Heart Failure. 2016;**9**(6):e002909

[38] Nicolas-Robin A, Salvi N, Medimagh S, Amour J, Le Manach Y, Coriat P, et al. Combined measurements of N-terminal pro-brain natriuretic peptide and cardiac troponins in potential organ donors. Intensive Care Medicine. 2007;**33**(6):986-992

[39] Dronavalli VB, Ranasinghe AM, Venkateswaran RJ, James SR, McCabe CJ, Wilson IC, et al. N-terminal pro-braintype natriuretic peptide: A biochemical surrogate of cardiac function in the potential heart donor. European Journal of Cardio-Thoracic Surgery. 2010;**38**(2):181-186

[40] Dronavalli VB, Banner NR, Bonser RS. Assessment of the potential heart donor: A role for biomarkers? Journal of the American College of Cardiology. 2010;**56**(5):352-361

[41] Aharinejad S, Andrukhova O, Gmeiner M, Thomas A, Aliabadi A, Zuckermann A, et al. Donor serum SMARCAL1 concentrations predict primary graft dysfunction in cardiac transplantation. Circulation. 2009;**120**(11 Suppl):S198-S205

[42] Plenz G, Eschert H, Erren M, Wichter T, Bohm M, Flesch M, et al. The interleukin-6/interleukin-6-receptor system is activated in donor hearts. Journal of the American College of Cardiology. 2002;**39**(9):1508-1512

[43] Potapov EV, Wagner FD, Loebe M, Ivanitskaia EA, Muller C, Sodian R, et al. Elevated donor cardiac troponin T and procalcitonin indicate two independent mechanisms of early graft failure after heart transplantation. International Journal of Cardiology. 2003;**92**(2-3):163-167

[44] Riou B, Dreux S, Roche S, Arthaud M, Goarin JP, Leger P, et al. Circulating cardiac troponin T in potential heart transplant donors. Circulation. 1995;**92**(3):409-414

[45] Vorlat A, Conraads VM, Jorens PG, Aerts S, Van Gorp S, Vermeulen T, et al. Donor B-type natriuretic peptide predicts early cardiac performance after heart transplantation. The Journal of Heart and Lung Transplantation. 2012;**31**(6):579-584

[46] Russo MJ, Chen JM, Sorabella RA, Martens TP, Garrido M, Davies RR, et al. The effect of ischemic time on survival after heart transplantation varies by donor age: An analysis of the United Network for Organ Sharing database. The Journal of Thoracic and Cardiovascular Surgery. 2007;**133**(2):554-559

[47] Marasco SF, Esmore DS, Negri J, Rowland M, Newcomb A, Rosenfeldt FL, et al. Early institution of mechanical support improves outcomes in primary cardiac allograft failure. The Journal of Heart and Lung Transplantation. 2005;**24**(12):2037-2042

[48] D'Alessandro C, Golmard JL, Barreda E, Laali M, Makris R, Luyt CE, et al. Predictive risk factors for primary graft failure requiring temporary

extra-corporeal membrane oxygenation support after cardiac transplantation in adults. European Journal of Cardio-Thoracic Surgery. 2011;**40**(4):962-969

[49] Stehlik J, Edwards LB, Kucheryavaya AY, Aurora P, Christie JD, Kirk R, et al. The registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult heart transplant report--2010. The Journal of Heart and Lung Transplantation. 2010;**29**(10):1089-1103

[50] Segovia J, Cosio MD, Barcelo JM, Bueno MG, Pavia PG, Burgos R, et al. RADIAL: A novel primary graft failure risk score in heart transplantation. The Journal of Heart and Lung Transplantation. 2011;**30**(6):644-651

[51] Wright M, Takeda K, Mauro C, Jennings D, Kurlansky P, Han J, et al. Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation. The Journal of Heart and Lung Transplantation. 2017;**36**(11):1226-1233

[52] Cosio Carmena MD, Gomez Bueno M, Almenar L, Delgado JF, Arizon JM, Gonzalez Vilchez F, et al. Primary graft failure after heart transplantation: Characteristics in a contemporary cohort and performance of the RADIAL risk score. The Journal of Heart and Lung Transplantation. 2013;**32**(12):1187-1195

[53] McKeown DW, Bonser RS, Kellum JA. Management of the heartbeating braindead organ donor. British Journal of Anaesthesia. 2012;**108**(Suppl. 1):i96-i107

[54] Novitzky D, Mi Z, Collins JF, Cooper DK. Increased procurement of thoracic donor organs after thyroid hormone therapy. Seminars in Thoracic and Cardiovascular Surgery. 2015;**27**(2):123-132

*Primary Graft Dysfunction after Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102506*

[55] Wood KE, Becker BN, McCartney JG, D'Alessandro AM, Coursin DB. Care of the potential organ donor. The New England Journal of Medicine. 2004;**351**(26):2730-2739

[56] Khush KK. Donor selection in the modern era. Annals of Cardiothoracic Surgery. 2018;**7**(1):126-134

[57] DePasquale EC, Ardehali A. Primary graft dysfunction in heart transplantation. Current Opinion in Organ Transplantation. 2018;**23**(3):286-294

[58] Garcia Saez D, Zych B, Sabashnikov A, Bowles CT, De Robertis F, Mohite PN, et al. Evaluation of the organ care system in heart transplantation with an adverse donor/ recipient profile. The Annals of Thoracic Surgery. 2014;**98**(6):2099-2105. discussion 105-6

[59] Takeda K, Li B, Garan AR, Topkara VK, Han J, Colombo PC, et al. Improved outcomes from extracorporeal membrane oxygenation versus ventricular assist device temporary support of primary graft dysfunction in heart transplant. The Journal of Heart and Lung Transplantation. 2017;**36**(6):650-656

[60] DeRoo SC, Takayama H, Nemeth S, Garan AR, Kurlansky P, Restaino S, et al. Extracorporeal membrane oxygenation for primary graft dysfunction after heart transplant. The Journal of Thoracic and Cardiovascular Surgery. 2019;**158**(6):1576-1584 e3

[61] Khan TA, Schnickel G, Ross D, Bastani S, Laks H, Esmailian F, et al. A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. The Journal of Thoracic and Cardiovascular Surgery. 2009;**138**(6):1417-1424

#### **Chapter 3**

## Hepatic and Endocrine Aspects of Heart Transplantation

*Andrea Székely, András Szabó and Balázs Szécsi*

#### **Abstract**

End-organ dysfunction is a progression that can often develop in patients with end-stage heart failure. Hepatic abnormalities in advanced systolic heart failure may affect several aspects of the liver function. Hepatic function is dependent on age, nutrition, previous hepatic diseases, and drugs. The hepatic dysfunction can have metabolic, synthetic, and vascular consequences, which strongly influence the short- and long-term results of the transplantation. In this chapter, the diagnostic and treatment modalities of the transplanted patient will be discussed. On the other hand, endocrine abnormalities, particularly thyroid dysfunction, are also frequently detected in patients on the waiting list. Endocrine supplementation during donor management after brain death is crucial. Inappropriate management of central diabetes insipidus, hyperglycemia, or adrenal insufficiency can lead to circulatory failure and graft dysfunction during procurement. Thyroid dysfunction in donors and recipients is conversely discussed.

**Keywords:** hepatic dysfunction, heart transplant, MELD score, thyroid function, donor management, endocrine dysfunction

#### **1. Introduction**

The increased need for transplantation cannot be met because of the shortage of the available grafts. In the last decades, the number of heart transplantation has not increased. As a consequence, the patients will be longer on the waiting list, becoming older and having more severe end organ dysfunction, or even they lose their candidacy for transplantation because of the irreversible hepatic or liver failure. Bridging techniques, such as temporary extracorporeal circulation or implantable mechanical assist devices, may improve and reverse the end-organ failure and transplantation can be done. The physician of the transplantation team must be familiar with the diagnosis and possible treatment of these organ dysfunctions. Recently, recognition and extended investigation of the end-stage heart-failure-related hepatic failure have been highlighted, since the liver dysfunction can worsen in the posttransplantation period through hypoxic hepatitis or by the immunsuppressive medications, which should be taken lifelong.

Besides the liver, another important system, the endocrine hormones, must be strictly followed in the perioperative period. End-stage heart failure can cause thyroid dysfunction, and it can lead to circulatory failure or hemodynamic instability. Amiodarone, a frequently applied antiarrhythmic drug, can cause severe hypo- or hyperthyreosis. In the postoperative period, the physicians must distinguish the nonthyroidal illness syndrome from the chronic illness-related thyroid dysfunction. Endocrine replacement must be also initiated during the donor procurement to decrease the graft loss or the graft dysfunction in the posttransplant period.

In this chapter, we aimed to describe briefly the basic liver function, the diagnostic modalities in the preoperative evaluation, and the special considerations related to transplantation care. The endocrine part will overview the thyroid dysfunction, the treatment of central diabetes insipidus, and the posttransplantation endocrine management.

#### **2. Hepatic aspects of heart transplantation**

#### **2.1 Basic anatomy and physiology of the liver**

The human liver is wedge-shaped with two lobes, and it weighs cca 1.5 kg [1, 2]. The hepatic artery via the celiac trunk and the portal vein are the main blood supply of the liver. The liver receives approximately one-fourth of the cardiac output, which secures one-third of the blood supply, and the rest will be supplied by the portal system. These blood vessels divide into small capillaries, called hepatic sinusoids, which then build the lobules. Lobules are the functional units of the liver. Each lobule is made up of hepatocytes. The lobules are held together by fibroelastic connective tissue that extends from a fibrous capsule covering the entire liver [3]. The function of the liver is very complex and diversified. Liver has excretion function, including synthesis and excretion of biliary acids. Furthermore, liver also plays a key role in endocrine homeostasis in the metabolism of various hormones. To understand the potential perioperative issues, it is necessary to review the complex role of the liver in the human body. Oxidative capacity decreases with the age and congestive disorders, which may cause delayed drug metabolism [4].

#### **2.2 Congestive heart-failure-related hepatic dysfunction**

Heart failure with reduced ejection fraction can alter many pathways in the liver. As a forward failure due to (the) low cardiac output syndrome, reduced systolic function leads to hypoperfusion, while backward failure caused by biventricular or isolated right ventricular dysfunction will result in venous congestion. As a response for the constantly elevated high pressure in the inferior caval and hepatic veins, the perivenular space of the lobule will be dilated, and fibrotic transformation will be initiated. As the congestive state persists, perivenular-perivenular bridging develops, which has less effect on centrally located portal tracks. This pattern is the reverse lobulation. As the circulatory failure progresses, the portal part also undergoes fibrotic transformation and complete congestive hepatopathy may develop. The collagen is deposited in the subendothelial region and in the Disse space. The elevated right ventricular pressure can now affect the portal circulation, causing cirrhotic portal hypertension. The well-known symptoms of cirrhosis, such as ascites and development of the varices of esophageal veins, are often present. Laboratory parameters remain unchanged or minimally elevated in the early phase of the congestion. Only elevation of aspartate aminotransferase (AST) and alanine transaminase (ALT) may be abnormal, an increase in bilirubin or obstructive enzyme

(alkaline phosphatase, ALP) levels is frequently seen. Highly elevated transaminase levels and increased bilirubin levels are more common in advanced or end-stage liver failure, usually associated with acute on chronic heart failure.

#### **2.3 Preoperative evaluation algorithms**

Routine laboratory tests, including hepatic function tests, are good but rough indicators of hepatic dysfunction in the pre-transplant period. It should be stressed that normal transaminase and serum bilirubin levels are not suitable for early detection of hepatic problems. As shown in the scores presented, elevated serum bilirubin levels and spontaneous prolonged coagulation are strong predictors of a negative outcome. Nonalcoholic fatty liver disease is a sign that the congestion has reached a distinct stage caused by heart failure with or without reduced ejection fraction. Transient elastography is a good and reliable method to measure fibrotic transformation of the liver. In the decompensated period of advanced heart failure, fibroelastography shows higher than real fibrotic results.

Liver biopsy is the most accurate way to assess fibrotic transformation of liver tissue. In some advanced cases, a liver biopsy can be used to rule out candidates for a heart transplantation or to determine the need for combined heart and liver transplantation [4]. Existing gallstone should be removed before surgery as it is potential infectious focus.

#### **2.4 Laboratory tests**

The classic laboratory tests for estimating hepatic function are serum bilirubin, transaminases (ALT, AST), alkaline phosphatase, lactate dehydrogenase, total serum protein and albumin, serum bilirubin, and coagulation parameters, especially prothrombin time. Most patients with advanced heart failure were found to have moderately elevated levels of transaminase in random blood samples. Chronic anticoagulation can influence the prothrombin levels and must be considered in the calculation of model for end-stage liver disease (MELD) scores.

In acute hypoxic hepatitis, transaminases (AST, ALT) can rise more than 100-fold above normal ranges. This increase reflects the severity of centrolobular hepatic necrosis. Peak transaminase is usually expected within 12–24 hours, and normalization take 2 weeks with treatment. Abnormalities in alkaline phosphates and serum bilirubin levels are less common. Prolonged prothrombin time has important prognostic value. Thrombocytopenia, if present, occurs simultaneously with prolonged prothrombin time. Renal failure is often associated with global hypoperfusion.

#### **2.5 Hepatic vein flow Doppler measurement**

Nowadays, hepatic vein flow measurement using duplex Doppler technic is an arising increasingly common method of assessing changes caused in heart failure. It may also be useful and feasible for noninvasive hemodynamic monitoring in acute conditions. Accurate interpretation of spectral Doppler tracing from hepatic veins is valuable, because they reflect important cardiac and hepatic physiology. There are usually four phases: A, S, V, and D; the S and D waves indicate the antegrade flow toward the heart. In hepatic and cardiac disease, these normal waves may be absent, indicating non-physiological flow in the hepatic circulation. In addition, transient patient factors, such as phase of the respiratory cycle, may can affect the appearance of the spectral trace. Knowledge of the normal and abnormal spectral Doppler waveforms of the hepatic veins and the corresponding physiology and pathophysiology provide valuable insights. Systematic analysis of the direction, regularity, and phasing of the spectral trace and the ratio of S- and D-wave amplitudes allows in most cases a correct differential diagnosis [5].

Under abnormal conditions, the normal triphasic pattern is altered, and the original waves may not exist or be distinguishable. The biphasic pattern may indicate severe tricuspid valve regurgitation and/or acute right ventricular overload. Normally, the hepatic vein spectrum shows the normal S-wave to D-wave ratio, where the S-wave is larger than the D-wave. According to Scheinfeld, there are three types of right-sided heart failure. (According to its classification, in mild tricuspid regurgitation, the relationship between the S-wave and the D-wave changes, with the S-wave being smaller than the D-wave.) Type 1 tricuspid regurgitation is classified as a change in the relationship between the S-wave and the D-wave, with the S-wave being smaller than the D-wave. However, there is still antegrade flow during the ventricular systole. In type 2 tricuspid regurgitation, there is no systolic flow during the ventricular systole. In type 3 tricuspid regurgitation, there is retrograde flow during the ventricular systole [5].

In the early state of fibrotic hepatic transformation or nonalcoholic fatty liver disease (NAFLD). the hepatic vein waveform may be remarkably damped due to stiffness of hepatic tissue and vessel walls. Flow pattern changes, such as monophasicity or blunt waveform, are also often observed in these conditions. Hepatic vein flow patterns also suitable for follow-up of the right ventricular function, the severity of tricuspidal regurgitation, and the venous congestion during the perioperative period. On the pictures 1 and 2, hepatic vein flow patterns are shown (**Figure 1**).

#### **2.6 Transient elastography**

Transient elastography (TE) is a noninvasive, simple, fast, and highly accurate clinical examination method. During TE, a special probe is used to measure the liver stiffness, which correlates well with the fibrotic hepatic remodeling [6]. However, the test has high reliability and may overestimate the level of liver fibrosis depending on the severity of decompensation. Thus, the examination should be planned in an elective setting with relatively well-compensated patient [7, 8].

In the literature reports could be seen with examination of the relationship between chronic coronary syndrome and nonalcoholic fatty liver disease (NAFLD). Reports have appeared in the literature examining the association between chronic coronary syndrome and nonalcoholic fatty liver disease (NAFLD). These findings are noteworthy because the liver structure transformation begins before the presence of a notable reduction in global cardiac function or congestive right heart failure [9].

#### **2.7 Risk stratification system**

Precise multidisciplinary risk assessment in the pre-transplant period is a key factor. The possible contraindicating coexisting diseases and states should be ruled out. The risk estimation can be helpful in planning, preparing, and managing the intraoperative and postoperative period. For preoperative hepatic dysfunction, two scores are mostly used. The Child-Pugh score is a traditional risk estimation method. *Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

**Figure 1.** *Hepativ vein flow pattern.*

The Child-Pugh score was based on serum bilirubin and albumin levels, international normalized ratio (INR), and the presence of ascites and encephalopathy. While the Child-Pugh score is useful for risk stratification in the clinical practice, MELD score(s) are more feasible for patients admitted to intensive care unit (ICU) due to their better prognostic value and lower negative likelihood ratio [10].

#### *2.7.1 Model for end-stage liver disease (MELD) score*

MELD score was originally developed to predict mortality in patients with hepatopathy and/or cirrhosis after porto-jugular shunt placement. The baseline MELD score gives an estimate of 3-month mortality as a function of the need for dialysis, INR, serum bilirubin, and creatinine (**Table 1**) [11].

(1)

The MELD score has several modifications according to the patients' comorbidities. MELD XI score excludes INR from the equation. MELD XI is promoted for use in patients receiving anticoagulant therapy. Frequent anticoagulant therapy in end-stage heart failure emphasizes the INR-independent MELD score.

Since UNOS (United Network for Organ Sharing) started using the MELD score, its importance for estimating the risk of liver complications and mortality before heart transplantation is unquestioned. Use of Na-corrected or XI (INR excluded) MELD scores in patients with end-stage heart failure in the pre-transplant period is the basics for liver failure risk estimation [12].


#### **Table 1.**

*The components of updated MELD score (used for 12 years and older patients after 2016).*

#### **3. Perioperative considerations**

#### **3.1 Synthetic dysfunctions in perioperative period**

Decreased serum albumin levels are present in 30–50% of patients, but the serum level is usually not less than 25 g/L. Low albumin levels do not correlate with hepatic injury, but are associated with nutritional impairment and protein wasting. The serum albumin level is an independent risk factor for mortality after heart transplantation [13]. Multiple studies suggest that serum albumin level under 35 g/L is related with worse mortality. Intravenous albumin substitution was not proven useful in the perioperative period.

Mild increase of the prothrombin time (PT) indicates a secondary impairment of the coagulation factor synthesis. In case of portal hypertension, the protein content of the ascites is usually more than 25 g/L and the ratio higher than 1:1 (serum albumin to ascites albumin). Some studies have reported a significant relationship between central venous pressure, low cardiac index, and elevated total bilirubin, AST, or ALT levels [14]. Increased transaminase levels correlate with the severity of hepatocellular injury caused by hypoperfusion. Increased direct bilirubin and ALP with ALT/ALP levels are markers of cholestatic injury and increased venous congestion. Increased bilirubin levels have been reported to be associated with high inotropic requirement, low cardiac output states, early readmission, in patients with advanced heart failure [15].

#### **3.2 Hepatic dysfunction in patients during mechanical circulatory support (MCS)**

End-stage heart failure patients with significantly impaired end-organ dysfunction often need a bridging method to become candidates for heart transplantation. For these patients, more frequent use of various mechanical circulatory supports may be a solution. However, even short to medium periods of support for planned pathophysiological changes caused by devices should be of concern. Short-term devices (veno-arterial extracorporeal membrane oxygenation, VA-ECMO) and various mid-term ventricular assist devices, such as left ventricular assist device (LVAD) or biventrular assist devices (BIVAD), also have a major impact on complex physiological processes. In case of LVAD implantation—similar than in heart transplantation cases—the low serum albumin level (≤35 g/L) is related to worse survival (**Figures 2** and **3**) [16].

*Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

#### **Figure 2.**

*Normalization of hepatic vein flow pattern in a patient with end-stage heart failure on BiVAD treatment for 85 days. The flow pattern is normal with minimal retrograde flow in venticular systole.*

#### **Figure 3.**

*Hepatic vein flow in a patient with end-stage heart failure treated with implantable LVAD for 22 days. Regarding grade 3 tricuspidal regurgitation, prominent V wave could be seen. Often the A, S, and V waves are fusional and indicate severe retrograde flow during the global systole.*

#### **3.3 Lactic acidosis, decreased lactate clearance**

The liver is 60% responsible for the elimination of lactate via the Cori cycle, (lactate is therefore a glycogen precursor molecule). Renal lactate excretion is meaningful as serum lactate levels above 6–8 mM. In cirrhosis patients, lactate clearance is decreased, which can lead to type B lactic acidosis caused by reduced activity of lactate dehydrogenase. A parallel problem is the dysregulated carbohydrate balance. Without a well-functioning hepatic enzyme system, accumulated substrate levels slowly return to normal.

#### **3.4 Coagulation disorders**

In intraoperative settings, hepatic impairment is often associated with hemostatic disorders. The liver plays a crucial role in hemostasis through the synthesis of procoagulants, anticoagulants, and components of the fibrinolytic system, as well as the clearance of activated clotting factors. In hepatic dysfunction, these synthetic functions are insufficient, and hemostatic changes within and between procoagulant, anticoagulant, and fibrinolytic systems result in a new balance, defined as a rebalanced hemostatic state. This conception is defined as a) dysfunction in thrombin generation/disturbance in thrombus production and b) instability in the face of relatively small disturbances that commonly lead to a disruption of the balance between bleeding or thrombotic events [17].

The most sensitive laboratory parameters are prothrombin time (PT) and partial thromboplastin time (PTT), which are sensitive to reduced levels of procoagulants but not to anticoagulants; this has led to the erroneous assumption in the past that patients with liver disease are auto-anticoagulated and are protected against thrombosis. Nevertheless, PT and INR are not reliable risk factors for bleeding after surgery or invasive procedures [17, 18].

Under VA-ECMO support, patients with preexisting hepatic dysfunction have increased morbidity and mortality, with obviously serious implications for the planning and further bridging [19]. According to the current recommendations for the implantable LVAD devices, the candidacy for implantation must fulfill strong criteria in their hepatic function. Mid-term and especially long-term LVADs are associated with serious side effects by altering the molecular mass spectrum of von Willebrand factor (vWf). A kind of degradation (more precisely multimerization into smaller molecules) of von Willebrand factor caused by shear stress associated with mechanical circulatory devices can lead to device specific coagulopathy and unexpected and defective angiogenesis—smaller multimers of vWf may act as vascular endothelial growth factor. The clinical context is often driven by unexplained bleeding from interstitial angiodysplasias. The acquired von Willebrand factor dysfunction type of hemostatic dysfunction is diagnosed mostly by viscoelastic tests [20].

Furthermore, coagulopathy based on hepatic dysfunction is often accompanied by thrombocytopenia. Platelet function seems to be normal in patients with cirrhosis, but intrinsic dysfunction has not yet been confirmed [21].

#### **4. Immunosuppressive therapy and the liver**

A major function of the liver is drug metabolism. Drugs given in the perioperative period, lifelong immunosuppressive therapy often interact with the liver. In the

#### *Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

perioperative period, special attention should be paid to hepatic function problems caused by immunosuppressive therapy. The impaired liver condition before surgery makes these interactions more complex and difficult.

In heart transplant patients, the drugs that induce immunosuppression are mostly antithymocyte globulin (ATG). ATG is safe to use in liver failure; however, some case reports have reported extremely elevated transaminase levels within a few hours of infusion. Liver damage associated with ATG therapy is usually mild and asymptomatic, self-limited [22].

Calcineurin inhibitors are metabolized by the liver's P450 enzyme system (CYP 3A4). The most commonly used calcineurin inhibitors are cyclosporin and tacrolimus. Initiation of cyclosporine therapy may sometimes be associated with a slight increase in serum bilirubin levels, often without a considerable increase in serum ALT or alkaline phosphatase. Tacrolimus therapy is associated with a mild to moderate increase in serum aminotransferase levels in 5–10% of patients. Rises in serum aminotransferase levels are usually mild, asymptomatic, and self-limiting, but occasionally persistent and may require a dose modification. Tacrolimus has also been implicated in the development of cholestatic hepatitis, but clinically apparent liver damage is rare [22].

Corticosteroids are the basis of the immunosuppressive therapy, particularly in the early period and in case of rejection. Corticosteroids also have major effects on the liver, particularly when given in long term and in higher doses. Glucocorticoid usage may result in liver enlargement, steatosis, or glycogenosis. Hepatomegaly and moderate elevation of serum aminotransferase levels are common in glycogenosis. There is little or no change in alkaline phosphatase and serum bilirubin levels. Furthermore, steroids can aggravate nonalcoholic fatty liver disease. Long-term therapy can also worsen chronic viral hepatitis. Thus, hepatic complications of corticosteroids are mostly associated with high intravenous dosing and usually represent the worsening or triggering of an underlying liver disease, and rarely are the result of drug


#### **Table 2.**

*The preoperative examination modalities, their focus and optimal timing before the heart transplantation.*

hepatotoxicity. High doses of intravenous corticosteroids, such as those used in antirejection shot therapy, are rarely associated with fatal acute liver injury [22].

Among antiproliferative agents, azathioprine and mycophenolate-mofetil (MMF) are commonly used in heart transplant patients. Azathioprine has a worse side effect profile, including severe hepatic problems, so MMF is usually preferred. In mild cases, azathioprine has been associated with a transient and asymptomatic rise in serum aminotransferase levels, which is associated with acute cholestatic damage in the first year after initiation of therapy. Chronic damage to the liver characterized by peliosis hepatis, veno-occlusive disease or nodular regeneration is typical with long-term use. Hepatocellular carcinomas have also been reported with long-term azathioprine use. In contrast, MMF use is safe, with side effects mostly nausea and digestive problems that respond well to dose reduction (**Table 2**) [22].

#### **5. Thyroid function and transplantation**

Nonthyroidal illness (NTI) is a syndrome that is observed in critically ill patients. As the name suggests, it is not a primary endocrine disease, but a result of severe systemic stress. Many conditions can lead to a generalized stress, such as severe infection, sepsis, prolonged starvation, bone marrow transplantation, extensive myocardial infarction, end-stage heart failure, heart transplantation, or any potentially life-threatening condition [23]. As for the changes in hormone levels, plasma T3 levels decrease, followed by a decrease in plasma T4 levels, while rT3 levels show an increasing trend. This is due to both altered protein binding and altered deiodinase enzyme activity. However, in the vast majority of cases, plasma TSH levels remain unchanged or decrease slightly [24]. In the international literature, several synonyms for nonthyroidal illness are common, such as euthyroid sick syndrome or low T3 syndrome (**Table 3**) [23].

The course of nonthyroidal illness can be divided into two basic phases, an acute phase and a chronic phase. The first acute phase is observed during a sudden change in critical condition. The main laboratory parameters in the acute phase are characterized by decreased peripheral free T3 levels and elevated rT3 concentrations. This is due to mechanisms such as reduced binding of plasma proteins to thyroid hormones and altered activity of certain deiodinase enzymes (D1, D3). In fact, the acute phase of NTI is an adaptive response to a reduced nutrient supply to the body due to a critical condition. Consequently, this phase of NTI, whose primary purpose is to reduce the catabolism of the body, has a positive effect on the body [24]. Other research has also observed that during starvation, the catabolism of peripheral skeletal muscle slows down as T3 levels decrease, while thyroid hormone administration increases its breakdown again [25, 26]. However, some research is in stark contrast to this view, as there is no correlation between a decrease in T3 levels during starvation and a concomitant decrease in peripheral skeletal muscle breakdown [27].

In the event that the acute phase is prolonged, the adaptive response that initially seems beneficial is replaced by a phase that is already less beneficial to the body. This is the chronic phase of NTI. In terms of thyroid laboratory parameters, not only the T3 but also the T4 levels start to decrease, while the plasma TSH levels fall below the lower limit of the normal range [24]. According to one study, these changes are due to a decrease in hypothalamic TRH secretion for an as yet unknown reason. This is because the research team found an association between TRH gene expression and plasma T3 and TSH levels [28]. During the chronic phase, adaptive mechanisms are developed in the peripherical located tissues to maximize the utilization of reduced thyroid hormones: increased


#### **Table 3.**

*Hormonal changes in NTI.*

transcription and activity of the D2 enzyme, increased localization of certain transporters, and increased activity of active isoforms of TRs' expression [24].

A clear, definite pathomechanism for the nonthyroidal illness syndrome has not been established. Samples of muscle and liver tissue from several patients who died in intensive care units (ICU) were collected. Biopsies from liver and muscle tissue from died patients were found to be increased in the expression of type 3 deiodinase enzymes and decreased in the expression of type 1 deiodinase enzymes. Blood collected from died patients showed decreased total T3, T4, TSH levels, while rT3 levels were higher than normal. In this study, a correlation was found that the plasma T3/ rT3 ratio was positively correlated with the expression of type 1 deiodinase enzyme [29]. rT3 level, T3/rT3 ratio and D3 enzyme expression measured on the very first day of ICU admission may have prognostic value for mortality [30].

In the chronic phase of NTI, decreased TRH gene expression may be strongly influenced by increased D2 enzyme activity mediated by inflammatory mediators, transcription factor NFκB (nuclear factor κB), and corticosterone [31, 32]. Certain drugs, such as dopamine can keep plasma T3, T4, and TSH levels, are low [33]. The role of different drugs in the suppression of the hypothalamic–pituitary-thyroid axis is conversely discussed [34, 35]. This association could not be demonstrated by another study group that used dopexamine and dobutamine simultaneously in high-risk surgical patients (**Figure 4**) [35].

#### **5.1 Amiodarone**

Amiodarone is a commonly used antiarrhythmic drug in patients with end-stage heart failure. Moreover, antiarrhythmic treatment of atrial or ventricular arrhythmias with amiodarone is an effective and widely known phenomenon in clinical practice. Amiodarone maintains normal sinus rhythm in patients with atrial fibrillation (AF)

**Figure 4.**

*Regulation of hypothalamic–pituitary-thyroid axis.*

and also reduces the recurrence rate of ventricular tachycardia. Amiodarone remains the preferred treatment, particularly for patients awaiting heart transplantation (HTX). Due to its slow distribution in body's tissue, amiodarone may take several months to reach steady-state tissue concentrations and to exert a sufficient antiarrhythmic effect. In addition, the registered half-life of amiodarone is highly variable. Because of this phenomenon, the administration of amiodarone before transplantation has been controversially discussed in the literature, and different results have been reported for morbidity and mortality after heart transplantation [36, 37].

The administration of this antiarrhythmic medication may increase the probability of one-year mortality, graft failure, transplantation, and permanent pacemaker implantation [38]. Amiodarone-induced hypothyroidism (AIH) and amiodarone-induced thyrotoxicosis (AIT) can also occur during chronic administration. In addition, there is a mixed/indefinite form to which both pathogenic mechanisms mentioned above contribute. Type 1 AIT develops in patients with preexisting thyroid disorders, while type 2 AIT occurs in substantially normal thyroid gland. On the one hand, the rate of serious adverse cardiovascular events was three times higher in AIT compared with euthyroid patients [39]. On the other side, several studies demonstrated the safety of amiodarone in end-stage heart failure and in early postoperative atrial fibrillation [36, 37].

#### **6. Donor management**

Endocrine dysfunction is common in severe brain injury. Traumatic brain injury is usually associated with increased intracranial pressure, which can be followed by a brainstem herniation, resulting in brainstem infarction [40]. Ischemic lesions can cause dysfunction in the hypothalamic–pituitary axis. One of the most frequent

#### *Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

complications is the posterior pituitary deficiency, characterized by central diabetes insipidus (CDI). Arginine vasopressin (AVP) deficiency can cause inadequate diuresis with hypovolemia, hyperosmolality, and hypernatremia [41]. Anterior pituitary gland dysfunction has also been detected with hypothyroidism and hypocortisolemia. Lack of these hormones may lead to hemodynamic instability, with reduced myocardial function, hypovolemia, inadequate stress response, increased proinflammatory condition. Each of them can impair graft function [42, 43]. Endogenous catecholamine release is enhanced in both neurological death and acute critical illness. Although it causes increased systemic vascular resistance, cardiac output is compromised by myocardial suppression induced by neurological death and by a reduced thyroid hormone release due to pituitary gland deficiency. Therefore, a theoretical advantage exists for exogenous thyroid hormone supplementation [44].

#### **6.1 Arginine-vasopressin**

Arginine-vasopressin should be considered if hypotension persists despite adequate volume resuscitation or if central diabetes insipidus (CDI) occurs. Damage of the posterior lobe of the pituitary gland, hypothalamic paraventricular nuclei, and supraoptic nuclei results in undetectable or low levels of AVP. The deficiency of AVP can lead to inadequate diuresis and is associated with hyperosmolality, hypovolemia, and hypernatremia, which is consistent with DI. In addition, even in patients who do not meet the criteria for DI, baroreflex-mediated secretion of AVP can be impaired in response to decreased hypotension and decreased circulatory volume. Appropriate therapy with early intervention can restore hemodynamic stability and prevent end-organ damage. A recent analysis of the OPTN database has shown that the administration of AVP in organ donors is independently associated with an increased rate of organ recovery. The study did not recommend indications for AVP use (such as DI and hypotension). Prolonged hypernatremia (Na+ > 155 mmol/L) due to untreated DI has been associated with postoperative graft dysfunction in several retrospective studies and one prospective study; however, this association was not generally reported. Maintaining normal sodium levels remains a reasonable goal of the appropriate treatment. Hypernatremia, excessive diuresis, and volume depletion can occur for reasons other than DI (e.g., osmotic diuresis due to hyperglycemia or mannitol administration) and should be investigated [45]. Treatment of AVP deficiency could be considered if hypotension persists despite adequate resuscitation or in the presence of DI, which is likely to occur if one or more of the following criteria are identified, unless there is another cause of the disorder: polyuria (urinary output>3–4 l/d or 2.5–3.0 ml/kg/h); normal or increased serum motility; inadequately diluted urine (specific gravity <1.005, urinary osmolality <200 mOsm/kg H2O); hypernatremia (Na+ > 145 mmol/L) [45].

#### **6.2 The use of corticosteroids**

The use of corticosteroids can reduce the inflammation caused by brain death and modulating immune functions can improve the quality of donor organs (e.g., lungs) and posttransplant graft function. Corticosteroid administration for brain-dead organ donors is highly recommended for two reasons. The first reason is the treatment of hypothalamic–pituitary–adrenal (HPA) axis failure, which could potentially lead to hemodynamic instability. However, like the axis of the thyroid gland, the HPA axis is generally not deficient after brain death. Additionally, in observational studies, the donor's hemodynamic instability was not associated with hypocortisolemia or lack of adrenal corticotropin sensitivity. Nevertheless, corticosteroids may improve hemodynamics through their vasopressor effects. The second possible reason for the administration of corticosteroids is reduced inflammation, which can have a negative effect on graft function. Observational studies highlight the increased organ procurement and improved graft and survival of the recipient by administration of corticosteroids. However, good-quality RCT evidence is lacking. With high heterogeneity of the study design and concomitant therapies, as well as poor quality, most RCTs rule out a strong conclusion. Several studies analyzed the effect of high-dose methylprednisolone. Theoretically, corticosteroid-induced hyperglycemia may outweigh all possible benefits. Recently, lower doses of hydrocortisone have been studied. Improved blood glucose was improved by a small observational study control by such strategy without any benefit on patient-centered outcomes. In summary, the indications of corticosteroid use in possible organ donors remain controversial, but can be considered in hemodynamic instability. It is important that it could be administered only after sampling for tissue typing, as it can reduce the expression of human leukocyte antigen [43]. Administration of high-dose corticosteroids (methylprednisone 1000 mg IV, 15 mg/kg IV, or 250 mg IV bolus followed by an infusion at a rate of 100 mg/h) reduces the potential adverse effects of the inflammatory cascade on donor organ function after brain death. Ideally, it should be administered after taking blood for tissue typing as it is able to suppress human leukocyte antigen expression [45].

#### **6.3 The use of thyroid hormone**

Changes in the axis of the thyroid are common after brain death, and levels of biologically active T3 are generally low. However, several studies with brain-dead organ donors have shown that the majority of patients have maintained pituitary function with normal or elevated thyroid-stimulating hormone levels due to internal carotid supply. T4 levels generally remain in the normal range and inactive reverse T3 levels are normal or elevated. This constellation points to non-thyroid disease rather than central hypothyroidism in the presence of thyroid gland with increased peripheral inactivation of thyroid hormone, as is the case in patients in the general intensive care unit. Because prolonged and severe hypothyroidism can lead to myocardial dysfunction, low T3 levels are thought to induce hemodynamic instability in the potential donor.

The changes in the neuroendocrine axes have a biphasic manner. During the acute phase of critical illness, it seems to be evolutionarily selective and is likely to be beneficial for survival. Therefore, exogenous intervention may not be required at this stage of critical illness. If these profound changes last longer, a maladaptive phase begins. Although treatment with exogenous active hormones in the chronic phase seems to be a reasonable option, experimental studies have highlighted the difficulties of optimal dosing and posology [46]. In addition, a large study has highlighted the fact that thyroid hormone supplementation may be associated with an increased risk of early graft loss (EGL) and early graft dysfunction (EGD) [47, 48]. However, reliable data have shown that thyroid hormone supplementation in combination with methylprednisolone may reduce the likelihood of developing of primer graft dysfunction (PGD). In addition, thyroxine administration may also have a beneficial effect on long-term survival after HTX [49].

However, it remains unclear whether non-thyroid disease following cerebral death should be treated. An extensive observational study that included data from 63,593 brain-dead organ donors independently linked thyroid hormone replacement to an increased number of procured organs. The apparent benefits of thyroid hormone

*Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

replacement were not confirmed by another RCT. However, the relatively low number of patients with hemodynamic stability in RCTs can preclude a conclusion in this subset of patients. Consensus guidelines have suggested that thyroid hormone replacement should be considered in hemodynamically unstable donors. Both T4 and T3 substitutions have been used for this purpose, although T4 is increasingly degraded to inactive reverse T3(46). One commonly utilized protocol is the following: T4 IV administration with a 20 μg bolus, followed by an infusion at 10 μg/h, or administer T3 IV with a 4.0 μg bolus, followed by an infusion at 3 μg/h [45].

Although target glucose levels for intensive insulin therapy in critically ill patients are still a matter of debate, hyperglycemic organ donors should be treated in the same way as other critically ill patients [45].

#### **7. Hormone replacement therapy in recipients during transplantation**

Although donor organ replacement therapies are still a matter of debate, there are some reliable data on HRT for cardiac recipients [50]. The use of triiodothyronine (T3) and thyroxine (T4) should be considered in patients with hemodynamic instability or potential cardiac donors with reduced ejection fraction [45]. The perioperative l-thyroxine treatment supplementation of cardiac recipients revealed that thyroid hormone administration initiated preoperatively was associated with a significantly

#### **Figure 5.**

*Kaplan–Meier curve. Survival function according to the initiation of l-thyroxine supplementation in recipients. Preoperatively initiated supplementation was associated with significantly better survival function than no or postoperatively initiated supplementation.*

better survival than either no thyroid hormone substitution or postoperative thyroid hormone substitution [50]. According to our institutional practice, thyroid hormone levels should be measured before the transplantation and thereafter weekly. While T3 levels are usually low and considered as a consequence of a natural response for huge stress, T4 levels should be closely monitored and values lower than the normal range must be treated. TSH levels in the perioperative period have also become interest of recent research (**Figure 5**).

#### **8. Conclusions**

Detection of hepatic dysfunction during preoperative evaluation, even in subclinical form, is the cornerstone of postoperative mortality estimation. As discussed above, hepatic dysfunction can affect both the intraoperative and postoperative period. In early-stage liver fibrosis, higher transaminase levels after surgery were associated with worse survival [51]. Moderate and elevated MELD XI scores predict increased short- and mid-term mortality after heart transplantation [52]. A remarkable increased MELD XI score is also associated with higher rates of postoperative stroke, need of dialysis, infection, and rejection [53].

Hepatic vein flow patterns are an intensively researched topic. Results suggest that pathological changes in flow patterns, such as damped, reduced, and reversed flow, may be an early predictor of hepatic tissue fibrotic transformation. Therefore, it can be an important marker of adverse outcome after adult heart transplantation. Moreover, hepatic vein congestion signs seem to be not only the marker of the right heart failure but can also estimate the severity of the abdominal venous insufficiency. After a successful heart transplantation [or LVAD implantation], congestive problems no longer exist as they did before the operation. In a manner, hepatic functions may improve. MELD scores are usually improving during the first postoperative year. In the vast majority of cases, normalization occurs within the first two months [54]. However, our findings indicated that a rise in the transaminase levels after transplantation was associated with higher risk of two-year mortality [19]. Hypoxic hepatitis in the early perioperative period must be followed, as it can worsen survival.

Endocrine abnormalities can develop during end-stage heart failure, and it should be monitored to detect early the chronic phase of the maladaptive response, which requires thyroid hormone substitution. Certain hormone replacements during donor procurement, such as treatment of central diabetes insipidus with arginine-vasopressin, are well established. In the current guidelines, use of thyroid hormones has been debated. After transplantation, the steroids can cause impaired glucose tolerance or diabetes. Thyroid hormone levels should be regularly checked.

#### **Acknowledgements**

We would like to thank you Veronika Rajki RN, PhD, for English editing.

#### **Conflict of interest**

The authors declare no conflict of interest related to this chapter.

*Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

#### **Abbreviations**


#### **Author details**

Andrea Székely1 \*, András Szabó1 and Balázs Szécsi2

1 Department of Anesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary

2 Doctoral School of Theoretical and Translational Medicine, Semmelweis University, Budapest, Hungary

\*Address all correspondence to: andi\_szekely@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Molina DK, DiMaio VJM. Normal organ weights in women: Part II— The brain, lungs, liver, spleen, and kidneys. The American Journal of Forensic Medicine and Pathology. 2015;**36**(3):182-187

[2] Molina DK, DiMaio VJM. Normal organ weights in men: Part II—The brain, lungs, liver, spleen, and kidneys. The American Journal of Forensic Medicine and Pathology. 2012;**33**(4):368-372

[3] Yen T-C, Chen Y-S, King K-L, Yeh S-H, Wei Y-H. Liver mitochondrial respiratory functions decline with age. Biochemical and Biophysical Research Communications. 1989;**165**(3): 994-1003

[4] Louie CY, Pham MX, Daugherty TJ, Kambham N, Higgins JPT. The liver in heart failure: A biopsy and explant series of the histopathologic and laboratory findings with a particular focus on precardiac transplant evaluation. Modern Pathology. 2015;**28**(7):932-943

[5] Scheinfeld MH, Bilali A, Koenigsberg M. Understanding the spectral Doppler waveform of the hepatic veins in health and disease. Radiographics. 2009;**29**(7):2081-2098

[6] Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut. 2007;**56**(7):968-973

[7] Castéra L, Foucher J, Bernard PH, Carvalho F, Allaix D, Merrouche W, et al. Pitfalls of liver stiffness measurement: A 5-year prospective study of 13,369 examinations. Hepatology. 2010;**51**(3):828-835

[8] Castera L, Forns X, Alberti A. Noninvasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology. 2008;**48**(5):835-847

[9] Friedrich-Rust M, Schoelzel F, Maier S, Seeger F, Rey J, Fichtlscherer S, et al. Severity of coronary artery disease is associated with non-alcoholic fatty liver dis-ease: A single-blinded prospective mono-center study. PLoS One. 2017;**12**(10):e0186720

[10] Peng Y, Qi X, Guo X. Child-Pugh versus MELD score for the assessment of prognosis in liver cirrhosis: A systematic review and Meta-analysis of observational studies. Medicine. 2016;**95**(8):e2877

[11] Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;**33**(2):464-470

[12] Kim MS, Kato TS, Farr M, Wu C, Givens RC, Collado E, et al. Hepatic dysfunction in ambulatory patients with heart failure: Application of the MELD scoring system for outcome prediction. Journal of the American College of Cardiology. 2013;**61**(22):2253-2261

[13] Kato TS, Cheema FH, Yang J, Kawano Y, Takayama H, Naka Y, et al. Preoperative serum albumin levels predict 1-year postoperative survival of patients undergoing heart transplantation. Circulation. Heart Failure. 2013;**6**(4):785-791

[14] Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation. 1989;**80**(2): 299-305

[15] Maleki M, Vakilian F, Amin A. Liver diseases in heart failure. Heart Asia. 2011;**3**(1):143-149

[16] Kato TS, Kitada S, Yang J, Wu C, Takayama H, Naka Y, et al. Relation of preoperative serum albumin levels to survival in patients undergoing left ventricular assist device implantation. The American Journal of Cardiology. 2013;**112**(9):1484-1488

[17] Caldwell S, Intagliata N. Dismantling the myth of "autoanticoagulation" in cirrhosis: An old dogma dies hard. Hepatology. 2012;**55**(5):1634-1637

[18] Tripodi A, Primignani M, Mannucci PM, Caldwell SH. Changing concepts of cirrhotic coagulopathy. The American Journal of Gastroenterology. 2017;**112**(2):274-281

[19] Nagy Á, Holndonner-Kirst E, Eke C, Kertai MD, Fazekas L, Benke K, et al. Model for end-stage liver disease scores in veno-arterial extracorporeal membrane oxygenation. The International Journal of Artificial Organs. 2020;**43**(10):684-691

[20] Nascimbene A, Neelamegham S, Frazier OH, Moake JL, Dong JF. Acquired von Willebrand syndrome associated with left ventricular assist device. Blood. 2016;**127**(25):3133-3141

[21] Lisman T, Porte RJ. Platelet function in patients with cirrhosis. Journal of Hepatology. 2012;**56**(4):993-994

[22] Hoofnagle JH, Serrano J, Knoben JE, Navarro VJ. LiverTox: A website on druginduced liver injury. Hepatology. 2013;**57**:873-874. DOI: 10.1002/HEP.26175 [23] De Groot LJ. Dangerous dogmas in medicine: The nonthyroidal illness syndrome. The Journal of Clinical Endocrinology and Metabolism. 1999;**84**(1):151-164

[24] Van den Berghe G. Non-thyroidal illness in the ICU: A syndrome with different faces. Thyroid. 2014;**24**(10):1456-1465

[25] Burman KD, Wartofsky L, Dinterman RE, Kesler P, Wannemacher RWJ. The effect of T3 and reverse T3 administration on muscle protein catabolism during fasting as measured by 3-methylhistidine excretion. Metabolism. 1979;**28**(8): 805-813

[26] Gardner DF, Kaplan MM, Stanley CA, Utiger RD. Effect of triiodothyronine replacement on the metabolic and pituitary responses to starvation. The New England Journal of Medicine. 1979;**300**(11): 579-584

[27] Byerley LO, Heber D. Metabolic effects of triiodothyronine replacement during fasting in obese subjects. The Journal of Clinical Endocrinology and Metabolism. 1996;**81**(3):968-976

[28] Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. The Journal of Clinical Endocrinology and Metabolism. 1997;**82**(12):4032-4036

[29] Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. The Journal of Clinical Endocrinology and Metabolism. 2003; **88**(7):3202-3211

*Hepatic and Endocrine Aspects of Heart Transplantation DOI: http://dx.doi.org/10.5772/intechopen.102418*

[30] Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3′,5′-triiodothyronine (rT3) and 3,5,3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. The Journal of Clinical Endocrinology and Metabolism. 2005;**90**(8):4559-4565

[31] de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. The Journal of Endocrinology. 2015;**225**(3):R67-R81

[32] de Vries EM, Kwakkel J, Eggels L, Kalsbeek A, Barrett P, Fliers E, et al. NFkappaB signaling is essential for the lipopolysaccharide-induced increase of type 2 deiodinase in tanycytes. Endocrinology. 2014;**155**(5): 2000-2008

[33] Van den Berghe G, de Zegher F, Lauwers P. Dopamine and the sick euthyroid syndrome in critical illness. Clinical Endocrinology. 1994;**41**(6):731-737

[34] Lee E, Chen P, Rao H, Lee J, Burmeister LA. Effect of acute high dose dobutamine administration on serum thyrotrophin (TSH). Clinical Endocrinology. 1999;**50**(4):487-492

[35] Schilling T, Gründling M, Strang C, Möritz K-U, Siegmund W, Hachenberg T. Effects of dopexamine, dobutamine or dopamine on prolactin and thyreotropin serum concentrations in high-risk surgical patients. Intensive Care Medicine. 2004;**30**:1127-1133

[36] Rivinius R, Helmschrott M, Ruhparwar A, Schmack B, Erbel C, Gleissner CA, et al. Long-term use of amiodarone before heart transplantation significantly reduces early posttransplant atrial fibrillation and is not associated with increased mortality after heart transplantation. Drug Design, Development and Therapy. 2016;**10**:677

[37] Rivinius R, Helmschrott M, Ruhparwar A, Darche FF, Thomas D, Bruckner T, et al. Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation. Drug Design, Development and Therapy. 2017;**11**:1827

[38] Cooper LB, Mentz RJ, Edwards LB, Wilk AR, Rogers JG, Patel CB, et al. Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality. The Journal of Heart and Lung Transplantation. 2017;**36**(2):202-210

[39] Jabrocka-Hybel A, Bednarczuk T, Bartalena L, Pach D, Ruchała M, Kamiński G, et al. Amiodarone and the thyroid. Endokrynologia Polska. 2015;**66**(2):176-196

[40] Smith M. Physiologic changes during brain stem death - Lessons for management of the organ donor. Journal of Heart and Lung Transplantation. 2004;**23**(9):217-222

[41] Loh JA, Verbalis JG. Disorders of water and salt metabolism associated with pituitary disease. Endocrinology and Metabolism Clinics of North America. 2008;**37**:213-234

[42] Dimopoulou I, Tsagarakis S, Anthi A, Milou E, Ilias I, Stavrakaki K, et al. High prevalence of decreased cortisol reserve in brain-dead potential organ donors. Critical Care Medicine. 2003;**31**(4):1113-1117

[43] Meyfroidt G, Gunst J, Martin-Loeches I, Smith M, Robba C, Taccone FS, et al. Management of the brain-dead donor in the ICU: General and specific therapy to improve transplantable organ quality. Intensive Care Medicine. 2019;**45**:343-353

[44] Ball IM, Hornby L, Rochwerg B, Weiss MJ, Gillrie C, Chassé M, et al. Management of the neurologically deceased organ donor: A Canadian clinical practice guideline. CMAJ. 2020;**192**(14):E361-E369

[45] Kotloff RM, Blosser S, Fulda GJ, Malinoski D, Ahya VN, Angel L, et al. Management of the potential organ donor in the ICU: Society of Critical Care Medicine/American College of Chest Physicians/Association of Organ Procurement Organizations Consensus Statement. Critical Care Medicine. 2015;**43**(6):1291-1325

[46] Teblick A, Langouche L, Van den Berghe G. Anterior pituitary function in critical illness. Endocrine Connections. 2019;**8**(8):R131-R143

[47] Peled Y, Ram E, Klempfner R, Lavee J, Cherikh WS, Stehlik J. Donor thyroid hormone therapy and heart transplantation outcomes: ISHLT transplant registry analysis. The Journal of Heart and Lung Transplantation. 2020;**39**(10):1070-1078

[48] Lander MM. Thyroid hormone in cardiac transplantation: Cat chasing its tail? Journal of Heart and Lung Transplantation. 2020;**39**:1079-1080

[49] Nagy Á, Szécsi B, Eke C, Szabó A, Mihály S, Fazekas L, et al. Endocrine management and hormone replacement therapy in cardiac donor management: A retrospective observational study. Transplantation Proceedings. 2021;**53**(10):2807-2815

[50] Holndonner–Kirst E, Nagy A, Czobor NR, Fazekas L, Dohan O, Kertai MD, et al. The impact of

l-thyroxine treatment of donors and recipients on postoperative outcomes after heart transplantation. Journal of Cardiothoracic and Vascular Anesthesia. 2019;**33**(6):1629-1635

[51] Holndonner-Kirst E, Nagy A, Czobor NR, Fazekas L, Lex DJ, Sax B, et al. Higher transaminase levels in the postoperative period after Orthotopic heart transplantation are associated with worse survival. Journal of Cardiothoracic and Vascular Anesthesia. 2018;**32**(4):1711-1718

[52] Grimm JC, Shah AS, Magruder JT, Kilic A, Valero V 3rd, Dungan SP, et al. MELD-XI score predicts early mortality in patients after heart transplantation. The Annals of Thoracic Surgery. 2015;**100**(5):1737-1743

[53] Deo SV, Al-Kindi SG, Altarabsheh SE, Hang D, Kumar S, Ginwalla MB, et al. Model for end-stage liver disease excluding international normalized ratio (MELD-XI) score predicts heart transplant outcomes: Evidence from the registry of the united network for organ sharing. The Journal of Heart and Lung Transplantation. 2016;**35**(2):222-227

[54] Chokshi A, Cheema FH, Schaefle KJ, Jiang J, Collado E, Shahzad K, et al. Hepatic dysfunction and survival after orthotopic heart transplantation: Application of the MELD scoring system for outcome prediction. The Journal of Heart and Lung Transplantation. 2012;**31**(6):591-600

### Section 2
