**4. Inclusion in heart transplant waiting list**

The decision of including a patient in the HTx waiting list is not easy and should be taken together by a medical and surgical team, in a case-by-case comprehensive evaluation. Only stage D HF patients without any other treatment option should be evaluated for HTx, because of the shortage of organs, the intrinsic risk of surgery, and the risk of rejection and complications due to immunosuppressant therapy. **Table 3** shows the indications for HTx.

Therefore, it is important to undergo an exhaustive study of the patient before listing for HTx, in order to exclude any significant risk factor that might compromise outcomes after HTx. Last but not least, the patient must be motivated, well informed and in an optimal psychological state to follow the intensive pharmacologic treatment that follows the HTx. **Table 4** shows recommended studies that should be done when evaluating candidacy for HTx.

To conclude, patients with LTVAD as BTC can be included in the waiting list once reversible PHT is confirmed by a right heart catheterization, and/or there is significant improvement in renal function (glomerular filtration rate [GFR] > 30 cc/min/1.73 m2 , especially if there is no evidence of intrinsic renal damage: absence of significant proteinuria without significant abnormalities in renal ultrasonography), and other parameters. In patients with concomitant treated malignant neoplasm, a thoughtful evaluation tackling life expectancy and relapse possibilities, together with an oncologist's evaluation should be performed before listing for HTx.

#### **Absolute Indications**

**1.**Hemodynamic compromise due to HF


#### **Relative Indications**


**4.1. Immune suitability evaluation**

• Clinical history and complete physical examination

• Blood Typing and Immune suitability study

• Assessment of severity of cardiac insufficiency

· General analysis with glycemia, lipid profile, renal function, hepatic profile, coagulation, thyroid hormones, natriuretic

· Lower extremity ankle/arm or Doppler echo index (if more than 50 years, diabetic, ischemic cardiomyopathy or clinical suspicion)

· Bone densitometry (if more than 50 years, woman or clinical

HLA: human leucocyte antigen and CT: computerized tomography.

• Size/weight/body mass index

· Panel-reactive antibody (PRA) · Flow cytometry (Luminex)

• Multiple organ function evaluation

· First-hour urinalysis with proteinuria

· Functional respiratory tests with arterial gases · Abdominal ultrasound or thoraco-abdominal CT scan · Doppler echo of supra-aortic trunks (if more than 50 years, diabetic, ischemic cardiomyopathy or clinical suspicion)

· ABO blood group · HLA typing

peptides

· Chest x-ray

suspicion)

· Electroencephalogram

Screening for humoral rejection is done through the panel-reactive antibody (PRA) test, which determines the presence of circulating anti-HLA antibodies. With this cytotoxic test, it is possible to estimate the sensitization of the recipient by the percentage of the serum reactivity that activates complement against a panel of the most common HLAs in the recipient's country. A PRA > 10% is considered positive and is a relative contraindication for HTx. In these cases, it is recommended to perform a prospective cross-match between the lymphocytes of the donor and recipient's serum before HTx. Currently, it is also possible to identify

**Table 4.** Recommended studies in the evaluation of candidates for HTx. Adapted from Mehra et al. [29].

• Infectious assessment

· Antibody hepatitis C virus · Antibody hepatitis A virus · Human immunodeficiency virus

· Herpes Simplex antibody · Cytomegalovirus antibody · Toxoplasma antibody · Epstein–Barr antibody · Varicella antibody

· Tuberculin or quantiferon test

· Fecal occult blood test × 3 · Colonoscopy (if >50 years old)

(men >50 years old) • Other evaluations · Social worker · Psychiatry

· Hepatitis B and A if it has not been done · Pneumococcal vaccine (every 5 years) • Study of hidden malignant neoplasm

· Mammography (if indicated or > 40 years) · Gynecological examination and vaginal cytology

· Specific prostate antigen and rectal examination

(if >18 years old and sexually active)

· Psychosocial and economic assessment

• Vaccination · Influenza (annual)

surface, anti-core

· Hepatitis B virus: surface antigen, antibody of

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· VDRL (venereal disease research laboratory)


#### **Insufficient indications**

**1.**Low left ventricular ejection fraction

**2.**History of NYHA functional class III or IV symptoms of HF

**3.**Peak VO2 greater than 15 mL per kg per minute (and greater than 55% predicted) without other indications

V02: Oxygen consumption; SHFM: Seattle Heart Failure Model; HFFS: Heart Failure Survival Score; NYHA: New York Heart Association.

**Table 3.** Heart transplant indications (Source Kirklin JK et al. and Hunt S et al. [46, 19]).


stage D HF patients without any other treatment option should be evaluated for HTx, because of the shortage of organs, the intrinsic risk of surgery, and the risk of rejection and complica-

Therefore, it is important to undergo an exhaustive study of the patient before listing for HTx, in order to exclude any significant risk factor that might compromise outcomes after HTx. Last but not least, the patient must be motivated, well informed and in an optimal psychological state to follow the intensive pharmacologic treatment that follows the HTx. **Table 4** shows

To conclude, patients with LTVAD as BTC can be included in the waiting list once reversible PHT is confirmed by a right heart catheterization, and/or there is significant improvement

no evidence of intrinsic renal damage: absence of significant proteinuria without significant abnormalities in renal ultrasonography), and other parameters. In patients with concomitant treated malignant neoplasm, a thoughtful evaluation tackling life expectancy and relapse possibilities, together with an oncologist's evaluation should be performed before listing for HTx.

**2.**Peak VO2 less than 14 mL per kg per minute with achievement of anaerobic metabolism or less than 12 mL per kg

**3.**Severe symptoms of ischemia that consistently limit routine activity and are not amenable to coronary artery bypass

**1.**In the presence of sub-maximal cardiopulmonary exercise test (RER˂1.05), ventilation equivalent of carbon dioxide

**2.**Use of prognostic scores in conjunction with cardiopulmonary exercise stress test. A 1-year estimated survival cal-

**4.**Recurrent instability of fluid balance/renal function not due to patient noncompliance with medical regimen

**3.**Peak VO2 greater than 15 mL per kg per minute (and greater than 55% predicted) without other indications

V02: Oxygen consumption; SHFM: Seattle Heart Failure Model; HFFS: Heart Failure Survival Score; NYHA: New York

, especially if there is

tions due to immunosuppressant therapy. **Table 3** shows the indications for HTx.

recommended studies that should be done when evaluating candidacy for HTx.

in renal function (glomerular filtration rate [GFR] > 30 cc/min/1.73 m2

**·** Documented dependence on IV inotropic support to maintain adequate organ perfusion

**4.**Recurrent symptomatic ventricular arrhythmias refractory to all therapeutic modalities

culated by the SHFM less than 80% and a HFSS in high/medium risk range

**Table 3.** Heart transplant indications (Source Kirklin JK et al. and Hunt S et al. [46, 19]).

**3.**Recurrent unstable ischemia not amenable to other intervention

**2.**History of NYHA functional class III or IV symptoms of HF

**Absolute Indications**

20 Heart Transplantation

**Relative Indications**

(VE/VCO2) slope > 35

**Insufficient indications**

Heart Association.

**1.**Low left ventricular ejection fraction

**1.**Hemodynamic compromise due to HF

per minute with the use of β-blockers

surgery or percutaneous coronary intervention

**·** Refractory cardiogenic shock


· General analysis with glycemia, lipid profile, renal function, hepatic profile, coagulation, thyroid hormones, natriuretic peptides


· Doppler echo of supra-aortic trunks (if more than 50 years, diabetic, ischemic cardiomyopathy or clinical suspicion)

· Lower extremity ankle/arm or Doppler echo index (if more than 50 years, diabetic, ischemic cardiomyopathy or clinical suspicion)

· Electroencephalogram

· Bone densitometry (if more than 50 years, woman or clinical suspicion)

• Infectious assessment

· Hepatitis B virus: surface antigen, antibody of surface, anti-core


· Gynecological examination and vaginal cytology (if >18 years old and sexually active)

· Specific prostate antigen and rectal examination (men >50 years old)


HLA: human leucocyte antigen and CT: computerized tomography.

**Table 4.** Recommended studies in the evaluation of candidates for HTx. Adapted from Mehra et al. [29].

#### **4.1. Immune suitability evaluation**

Screening for humoral rejection is done through the panel-reactive antibody (PRA) test, which determines the presence of circulating anti-HLA antibodies. With this cytotoxic test, it is possible to estimate the sensitization of the recipient by the percentage of the serum reactivity that activates complement against a panel of the most common HLAs in the recipient's country. A PRA > 10% is considered positive and is a relative contraindication for HTx. In these cases, it is recommended to perform a prospective cross-match between the lymphocytes of the donor and recipient's serum before HTx. Currently, it is also possible to identify and quantify the amount of antibodies against surface HLA antigens using a flow cytometry immunofluorescence technique. This method (Luminex) is much more sensitive than the PRA and allows a better assessment of the risk of positive cross-reactivity at the time of HTx and eventual humoral rejection.

Finally, vaccination against hepatitis A and B viruses is also recommended if not previously given, as well as vaccination against Pneumococcus (every 5 years), Influenza (annual) and

Absolute contraindications for HTx are progressively diminishing because of the improved treatment strategies both for comorbidities and immunosuppressive therapies after HTx, so nowadays it is preferable to talk about risk factors that increase post-HTx morbidity and mortality than contraindications. According to the latest recommendations from the ISHLT [19] the most important HTx risk factors are classified in **Table 5**. Nonetheless, it is important to

• Patients with age > 70 years could be considered for HTx based on individual evaluation. It is important to take into consideration that this population has lower rates of rejection but

have more difficulty in finding an adequate donor. Besides, there is some evidence that this

• Poorly controlled diabetes (glycosylated hemoglobin [HbA1c] >7.5% or 58 mmol/mol) with end-organ damage (other than non-proliferative retinopathy) is a relative contraindication

sidered a relative contraindication for HTx alone, although the combination of heart and

• Clinically severe symptomatic cerebrovascular disease could be considered a contraindication for HTx based on the existence of a study that shows how these patients have an increased risk of stroke and functional decline as an independent variable after transplantation [49]. Peripheral vascular disease that limits rehabilitation without possibility of re-

• Frailty defined as a clinically identifiable disorder of amplified vulnerability of age-related decline in reserve and function across multiple physiologic systems brought on with minor stressors [50] should be assessed before HTx, the presence of three of five possible symptoms, including unintentional weight loss of 5 kg within the past year, muscle loss, fatigue,

• Psychosocial evaluation previous to HTx is important in order to make sure that the patient is going to be able to accomplish an optimal care after transplantation. Absence of this con-

slow walking speed and low levels of physical activity define a fragile patient.

group of patients have an increase in post-operative morbidity and mortality.

• Presence of irreversible renal dysfunction with GFR <30 cc/min/1.73 m2

to be included in the waiting list, because patients with BMI > 35 kg/m2

should wait until they achieve a

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should be con-

*Haemophilus influenzae* before the HTx [29].

**6. Risk factors and contraindications**

higher mortality than younger patients.

kidney transplant could be considered.

vascularization continues to be a contraindication.

dition is considered a relative contraindication.

• Patients with a body mass index (BMI) > 35 kg/m2

especially consider the following:

BMI ≤ 35 kg/m2

for HTx.

Patients can be sensitized after pregnancies, blood transfusions, after previous transplantation or after the implant of a ventricular assist device, although sometimes there is no obvious sensitizer event, and it is thought to be due to cross-reactivity between bacterial or viral epitopes and HLAs. In case that the recipient has a ventricular assist device, it is recommended to repeat the PRA and flow cytometry every 2–3 months. If blood transfusions are required, the PRA and flow cytometry should be repeated 2 weeks after the transfusion and each month during 6 months [29].

The presence of anti-HLA antibodies with high levels of median fluorescent intensity or MFI (units used to quantify antibodies), usually over 3000–5000, depending on the immunology laboratory, is considered potentially cytotoxic. By this technique it is also possible to obtain a calculated PRA (cPRA), which gives the percentage of unacceptable HLAs in the donor population. For example, if the cPRA is 80%, it means that only 20% of all possible donors in this specific population will be compatible with the receptor. Although the cPRA cut-points are not clearly established, some authors consider an absolute contraindication if cPRA is above 50–70%, and thus recommend a desensitization therapy before HTx [47]. In these cases it is also necessary to perform a virtual cross-match at the time of HTx, consisting of the evaluation of anti-HLA receptor antibodies titters relative to the donor HLA. If the virtual cross-match is positive, the risk of hyperacute rejection is very high and the donor organ must not be accepted.
