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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

The International Society for Heart and Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients

Published:December 20, 2022DOI:https://doi.org/10.1016/j.healun.2022.09.023

      ABBREVIATIONS:

      AAIR (atrium paced, atrium sensed inhibited rate modulation), ABOi (ABO incompatible), ACC (American College of Cardiology), ACEI (angiotensin converting enzyme inhibitor), ACR (acute cellular rejection), ACT (activated clotting time), ADA (American Diabetes Association), AHA (American Heart Association), AMR (antibody-mediated rejection), AP (aerosolized pentamidine), aPTT (activated partial thromboplastin time), ARB (angiotensin receptor blocker), ASD (atrial septal defect), ATG (anti-thymocyte globulin), AV (arteriovenous), AZA (azathioprine), BiV (biventricular), BMD (bone mass density), BNP (brain natriuretic peptide), BPAR (proven acute rejection), CAV (cardiac allograft vasculopathy), CBCR (center-based cardiac rehabilitation), CCB (calcium channel blocker), CCTA (Coronary computed tomography angiography), CEDIA (cloned enzyme donor immunoassay method), CHD (congenital heart disease), CI (cardiac index), CKD (chronic kidney disease), CO (cardiac output), CPB (cardiopulmonary bypass), c-PRA (calculated PRA), CMV (cytomegalovirus), CNI (calcineurin inhibitor), CRP (C-reactive protein), CS (corticosteroid), CT (computed tomography), CVP (central venous pressure), CYA (cyclosporine), CYP3A (cytochrome P-450 3A4), DDDR (dual-paced, dual-sensed, dual-response to sensing, rate modulation), DEXA (dual energy x-ray absorptiometry), DSA (donor specific antibody), ECG (electrocardiogram), ED (erectile dysfunction), ECMO (extracorporeal membrane oxygenation), EMB (endomyocardial biopsy), EMIT (enzyme multiplied immunoassay technique), ESC (European Society of Cardiology), EVL (everolimus), FFP (fresh frozen plasma), GEP (Gene Expression Profiling-Allomap), GFR (glomerular filtration rate), HBCR (Home-based cardiac rehabilitation), Hgb (hemoglobin), HIT (heparin-induced thrombocytopenia), HIV (Human Immunosdefiency virus), HLA (human leukocyte antigen), HPLC (high-performance liquid chromatography), HPV (human papillomavirus), HRS (Heart Rhythm Society), HSV (herpes simplex virus), HT (heart transplant), ICU (intensive care unit), Ig (immunoglobulin), IgG (immunoglobulin G), IH (Isohemagglutinin), INR (international normalized unit), IABP (intra-aortic balloon pump), ISHLT (International Society for Heart and Lung Transplantation), IUD (intrauterine device), IV (intravenous), IVUS (intravascular ultrasound), LV (left ventricle), LVAD (left ventricular assist device), LVEF (left ventricular ejection fraction), LVH (left ventricular hypertrophy), MAOI (monoamine oxidase inhibitors), MCS (mechanical circulatory support), MDRD equation (modified diet in renal disease equation), MFI (mean fluorescent intensity), MMF (mycophenolate mofetil), MPA (mycophenolic acid), mTOR (mammalian target of rapamycin), MVO2 (mixed venous oxygen), PAWP (pulmonary artery wedge pressure), PCC (prothrombin plasma concentrates), PFA-100 (platelets function assay 100), PGF (primary graft failure), PRA (panel reactive antibodies), PRES (posterior reversible leukoencephalopathy), PCSK9 (Proprotein convertase subtilisin-kexin type 9), PSI (proliferation signal inhibitor), PTLD (posttransplant lymphoproliferative disorder), PT (prothrombin time), PTT (partial thromboplastin time), PVR (pulmonary vascular resistance), RAP (right atrial pressure), rFVII (recombinant factor 7), RV (right ventricle), sCr (serum creatinine), SPECT (single-photon emission computed tomography), SRL (sirolimus), STI (sexually transmitted infection), SVT (sustained ventricular tachycardia), TAC (tacrolimus), TEE (transesophageal echocardiogram), TMP/SMZ (trimethoprim/sulfamethoxazole), TPG (Trans-Pulmonary Gradient), TTE (transthoracic echocardiogram), TV (tricuspid valve), VAD (ventricular assist device), VER (ventricular evoked responses), VT (ventricular tachycardia)

      Independent Expert Reviewers

      David Baran, Tiffany Buda, Adam Cochrane, Maria Crespo Leiro, Anne Dipchand, Brian Feingold, Kathleen Grady, Edward Horn, Maryl Johnson, Donna Mancini, Sean Pinney, Heather Ross, Kari Wujcik, Andreas Zuckermann(Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7a, Table 7b, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14)
      Table 1Hemodynamic profiles of pulmonary hypertension
      ClassificationMean pulmonary artery pressurePulmonary capillary wedge pressurePulmonary vascular resistance
      Isolated pre-capillary PH>20 mm Hg<15 mm Hg>3 WU
      Combined pre- and post-capillary PH>15 mm Hg>3 WU
      Isolated post-capillary PH>15 mm Hg<3 WU
      The 6th World Symposium on Pulmonary Hypertension defined three hemodynamic profiles of pulmonary hypertension (PH): isolated pre-capillary PH, combined. The pre- and post-capillary PH, and isolated post-capillary PH. WU, Wood units).
      • Tedford RJ
      • Beaty CA
      • Mathai SC
      • Kolb TM
      • Damico R
      • Hassoun PM
      • Leary PJ
      • Kass DA
      • Shah AS
      Prognostic value of the pre-transplant diastolic pulmonary artery pressure–to–pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.
      Table 2Predicted Heart Mass Calculator
      Predicted right ventricular mass(RVM)a×Age0.32×Height1.135×Weight0.315wherea=10.59forwomenand11.25formen
      Predicted left ventricular mass(LVM)a×Height0.54×Weight0.61wherea=6.82forwomenand8.25formen
      Predicted heart mass (PHM)RVM+LVM
      Body mass index (BMI)HeightWeight2
      Body surface area (BSA)a×Height0.725×Weight0.425wherea=0.007184
      Donor to recipient size matchSizemetricdonorSizemetricrecipient
      Table 3Recommendations for the Prevention of Cytomegalovirus in Heart Transplant Recipients
      GroupRecommendations
      D+/R-Ganciclovir 5mg/kg IV daily or valganciclovir 900mg po daily* for 3-6 months
      Preemptive therapy generally not preferred but is an alternate option
      Some HT centers will add CMV immune globulin for high-risk patients
      R+Ganciclovir 5mg/kg IV daily or valganciclovir 900mg po daily* for 3 months
      Preemptive therapy is an alternate to universal antiviral prophylaxis
      Table 4Recommended mTOR inhibitor & CNI target levels:
      Adults
      IS regimenEverolimus (ng/mL)Sirolimus (ng/mL)Cyclosporine (Time post-tx) (ng/mL)Tacrolimus (Time post-tx) (ng/mL)
      CNI + mTOR inhibitor3-84-1275-200 (3-6 months)

      50-100 (> 6 months)
      3-8 (> 6 months)
      CNI-free (e.g., mTOR + MMF)6-108-15
      Pediatrics*
      IS regimenEverolimus (ng/mL)Sirolimus (ng/mL)Cyclosporine (Time post-tx) (ng/mL)Tacrolimus (Time post-tx) (ng/mL)
      CNI + mTOR inhibitor3-64-7100-200 (3-6 months)

      60-120 (> 6 months)
      4-8 (> 6 months)
      CNI-free (e.g., mTOR + MMF)3-85-8
      *Aim for higher end of range when using mTOR to intensify immune suppression for CAV prevention in high-risk patients; aim for lower end of range when targeting reduced intensity immune suppression for PTLD, frequent infections, or renal failure.
      Table 5Drugs That Affect the Levels of Tacrolimus, Cyclosporine, Sirolimus, or Everolimus
      Decrease immunosuppression levelsIncrease immunosuppression levels
      Anti-epileptics

      Carbamazepine

      Fosphenytoin

      Phenobarbital

      Phenytoin
      Anti-fungals

      Clotrimazole

      Fluconazole

      Isavuconazole

      Itraconazole

      Ketoconazole

      Posaconazole

      Voriconazole
      Anti-microbials

      Caspofungin

      Nafcillin

      Rifabutin

      Rifampin

      Rifapentine
      Anti-microbials

      Clarithromycin

      Erythromycin

      Metronidazole and tinidazole
      Anti-retroviral therapy

      Efavirenz

      Etravirine

      Nevirapine
      Anti-retroviral therapy

      Protease inhibitors (general)

      Cobicistat

      Darunavir

      Fosamprenavir

      Indinavir

      Nelfinavir

      Ritonavir

      Saquinavir

      Tipranavir
      Antivirals

      Letermovir
      Monoclonal antibodies

      Tocilizumab
      Direct acting antivirals for Hepatitis C:

      Daclatasvir

      Glecaprevir-Pibrentasvir

      Grazoprevir-Elbasvir

      Ledipasvir-(Sofosbuvir)

      Velpatasvir-(Sofosbuvir)

      Voxilaprevir-Velpatasvir-(Sofosbuvir)
      Cardiovascular

      Bosentan
      Cardiovascular

      Amiodarone

      Diltiazem

      Verapamil
      Others

      Aprepitant

      Deferasirox

      Modafinil

      St. John's wort

      Thalidomide

      Ticlopidine
      Others

      Cimetidine

      Fluvoxamine

      Glipizide

      Glyburide

      Imatinib

      Nefazodone

      Rilonacept

      Theophylline

      Turmeric
      Nutraceuticals

      Bitter orange

      Grapefruit
      Table 6Significant Differences in Primary endpoints between Study Groups from Major Clinical Trials since 2010
      Author (year)StudyNo.Follow-upSurvivalRejectionCAV by IVUS
      Barten (2019)MANDELA:

      EVL/redCNI vs

      CNI-free
      1621 yearNSCNI-free

      = more rejection
      NS
      Potena (2018)EVERHEART:

      Immediate (≤144 h) (EVL-I) vs

      delayed (4-6 weeks post-HTx) (EVL-D) EVL initiation
      1816 monthsNSEVL-I

      = higher incidence

      BPAR ≥2R

      (but not SS)
      NS
      Arora (2015)

      Andreassen (2016)
      SCHEDULE:

      redCYA/EVL & CNI withdrawal at 7‐11 weeks vs

      CYA+ MMF
      1151-3 yearsNSEVL group

      = more rejection
      EVL group

      = less CAV
      Eisen (2013)CRAD 2310:

      redCyA/EVL 1.5mg vs

      redCyA/EVL 3mg (dc) vs

      CYA/MMF
      72112-24 monthsNSNo significant differences between groupsEVL/redCYA group

      = less CAV
      Table 7ASignificant Differences in Adverse Events from the Major Clinical Trials since 2010
      Author (year)StudyNo.Renal functionInfectionsCholesterol & triglyceridesHypertension
      Barten (2019)MANDELA:

      EVL/redCNI vs

      CNI-free
      162CNI‐free

      = better renal function
      CNI-free

      = less CMV

      (? SS, no p-value)
      -EVL/redCNI

      = more hypertension

      (? SS, no p-value)
      Potena (2018)EVERHEART:

      Immediate (≤144 h) (EVL-I) vs

      delayed (4-6 weeks post-HTx) (EVL-D) EVL initiation
      181comparable between both groupsEVL-I

      = lower risk CMV
      No significant differences between groupsNo significant differences between groups
      Arora (2015)

      Andreassen (2016)
      SCHEDULE:

      redCYA/EVL & CNI withdrawal at 7‐11 weeks

      vs CYA+ MMF
      115EVL

      = better renal function

      No significant differences between groupsNSNo significant differences between groups
      Eisen (2013)CRAD 2310:

      redCyA/EVL 1.5mg vs

      redCyA/EVL 3mg (dc)

      vs CYA/MMF
      721EVL/redCYA

      = inferior for renal function but comparable if predefined redCYA level achieved
      EVL/redCYA

      = less CMV
      EVL/redCYA

      = higher total cholesterol & HDL

      = higher LDL & TG at 1 year only
      No significant differences between groups
      Table 7BSignificant Differences in Adverse Events from the Major Clinical Trials since 2010
      Author (year)StudyNo.HematologicGI disordersOther
      Barten (2019)MANDELA:

      EVL/redCNI

      vs CNI-free
      162No significant differences between groupsEVL/redCNI

      = more diarrhoea & nausea

      (? SS, no p-value)
      -
      Potena (2018)EVERHEART:

      Immediate (≤144 h) (EVL-I) vs

      delayed (4-6 weeks post-HTx) (EVL-D) EVL initiation
      181No significant differences between groupsNSEVL-I

      = more pericardial effusion

      = more AEs

      = more discontinuations due to AEs & serious AEs

      EVL-I = 48% non-significant increase in the relative risk of incidence of the primary endpoint (postoperative wound healing delays, pericardial effusion, pleural effusion needing drainage and acute renal insufficiency events)
      Arora (2015)

      Andreassen (2016)
      SCHEDULE:

      redCYA/EVL & CNI withdrawal at 7‐11 weeks vs CYA+ MMF
      115No significant differences between groups-No significant differences between groups for surgical events or wound complications
      Eisen (2013)CRAD 2310:

      redCyA/EVL 1.5mg vs

      redCyA/EVL 3mg (dc)

      vs CYA/MMF
      721EVL/redCYA = more anemia-EVL 3mg/redCYA arm

      = enrolment dc due to higher early mortality

      EVL/redCYA

      = more pericardial effusion
      dc = discontinued; NS = not stated; SS = statistically significant; AE = adverse event
      Table 8Desensitization and AMR and Therapies
      • Sriwattanakomen R
      • Xu Q
      • Demehin M
      • Shullo MA
      • Mangiola M
      • Hickey GW
      • Sciortino CM
      • Horn ET
      • Keebler ME
      • Zeevi A.
      Impact of carfilzomib-based desensitization on heart transplantation of sensitized candidates.
      TherapyMechanism of ActionImmune EffectsMajor Adverse Effects
      AlemtuzumabCD52 monoclonal antibodyDepletes circulating lymphocytes, macrophages and monocytesLeukopenia, thrombocytopenia, infusion related reactions
      BortezomibProteasome inhibitorDepletes plasma cellsPeripheral neuropathy, thrombocytopenia, neutropenia
      CarfilzomibProteasome inhibitorDepletes plasma cellsAKI, thrombocytopenia, cardiotoxicity
      EculizumabComplement C5 inhibitorInhibits formation of terminal complement C5b-9Meningococcal infection (Vaccination recommended)
      Intravenous immunoglobulinImmunomodulatory effectsNeutralize circulating antibody, inhibit complement, inhibit B cellsInfusion-related reactions, hemolysis, interference with antibody assays
      PIasmapheresisExtracorporeal plasma antibody filtrationRemoves circulating immunoglobulinsAccess and line related complications, coagulopathy
      RituximabCD20 monoclonal antibodyDepletes circulating B cellsInfusion-related reactions
      SplenectomyRemoval of secondary lymphoid organRemoves major source of lymphocytesEncapsulated bacterial infections
      Table 9Examples of Therapies for Antibody-Mediated Rejection
      Therapeutic modalityDoseFrequencyDuration
      Plasmapheresis1-2 plasma exchangesDaily Every other day3-5 days

      1-2 weeks
      3 times per week1-4 weeks
      Once weekly2-4 weeks
      IV

      immunoglobulin
      100 – 2000 mg/kgLow dose 1–3 times per week, often given after each plasmapheresis

      Immune modulating dose (2g/kg) after last plasmapheresis cycle q 4 weeks
      1-4 weeks
      Rituximab375 mg/m2Once weekly1-4 weeks
      IV Ig, intravenous immunoglobulin. [218]
      Table 10Recommended Nomenclature for Cardiac Allograft Vasculopathy
      ISHLT CAV0 (Not significant): No detectable angiographic lesion
      ISHLT CAV1 (Mild): Angiographic left main (LM) <50%, or primary vessel with maximum lesion of <70%, or any branch stenosis <70% (including diffuse narrowing) without allograft dysfunction
      ISHLT CAV2 (Moderate): Angiographic LM <50%; a single primary vessel ≥70%, or isolated branch stenosis ≥70% in branches of 2 systems, without allograft dysfunction
      ISHLT CAV3 (Severe): Angiographic LM ≥50%, or two or more primary vessels ≥70% stenosis, or isolated branch stenosis ≥70% in all 3 systems; or ISHLT CAV1 or CAV2 with allograft dysfunction (defined as LVEF ≤45% usually in the presence of regional wall motion abnormalities) or evidence of significant restrictive physiology (which is common but not specific; see text for definitions)
      Definitions
      a). A “Primary Vessel” denotes the proximal and Middle 33% of the left anterior descending artery, the left circumflex, the ramus and the dominant or co-dominant right coronary artery with the posterior descending and posterolateral branches.
      b). A “Secondary Branch Vessel” includes the distal 33% of the primary vessels or any segment within a large septal perforator, diagonals and obtuse marginal branches or any portion of a non-dominant right coronary artery.
      c). Restrictive cardiac allograft physiology is defined as symptomatic heart failure with echocardiographic E to A velocity ratio >2 (>1.5 in children), shortened isovolumetric relaxation time (<60 msec), shortened deceleration time (<150 msec), or restrictive hemodynamic values (Right Atrial Pressure >12mmHg, Pulmonary Capillary Wedge Pressure (PCWP) >25 mmHg (>15mmHg in children
      Modified PCWP threshold in children based on[273].
      ), Cardiac Index <2 l/min/m2)
      low asterisk Modified PCWP threshold in children based on
      • Kindel SJ
      • Law YM
      • Chin C
      • Burch M
      • Kirklin JK
      • Naftel DC
      • Pruitt E
      • Carboni MP
      • Arens A
      • Atz AM
      • Dreyer WJ
      • Mahle WT
      • Pahl E.
      Improved Detection of Cardiac Allograft Vasculopathy: A Multi-Institutional Analysis of Functional Parameters in Pediatric Heart Transplant Recipients.
      .
      Table 11Behavioral, Social, Medical, and Other Factors that Increase Risk for Recent HIV, HBV, or HCV Infection in Organ Donors
      Sex (i.e., any method of sexual contact, including vaginal, anal, and oral) with a person known or suspected to have HIV, HBV, or HCV infection
      Man who has had sex with another man
      Sex in exchange for money or drugs
      Sex with a person who had sex in exchange for money or drugs
      Drug injection for nonmedical reasons
      Sex with a person who injected drugs for nonmedical reasons
      Incarceration (confinement in jail, prison, or juvenile correction facility) for ≥72 consecutive hours
      Child breastfed by a mother with HIV infection
      Child born to a mother with HIV, HBV, or HCV infection
      Unknown medical or social history
      Table 12Sample
      The frequency of follow-up visits for HT recipients will depend on the time from HT and the post-operative clinical course. The frequency of follow-up should be increased if complications occur, particularly in patients with challenging medical or psychosocial conditions. In addition, in view of different local availabilities of newer noninvasive modalities (e.g., Gene Expression Profiling) and the lack of evidence about the optimal timing of echocardiographic studies in HT patients, it should be noted that the frequency of follow-up visits and schedule presented in the table serve merely as an example and should be tailored to each center. Furthermore, as noninvasive modalities improve, it is likely that the need for biopsies and serial conventional angiography will be reduced accordingly.
      : Follow-up visits and test schedule
      >52-51Year
      >60>24211815121110987654321Month
      242016121087654321Week
      ×××××××××××××××××××HT clinic visit
      ×××××××××××××××××××Lab tests[
      • Khan H
      • Kalogeropoulos AP
      • Georgiopoulou VV
      • Newman AB
      • Harris TB
      • Rodondi N
      • Bauer DC
      • Kritchevsky SB
      • Butler J
      Frailty and risk for heart failure in older adults: The health, aging, and body composition study.
      ]
      ××××××××××ECG
      ×××××××××××Echo
      ××××××××××××××B iopsy ²

      (Other non-invasive methods as appropriate)
      ×××××××Right heart study
      S tarting in the fifth year – to be done every other year alternating with coronary angiographyDobutamine echo/SPECT/CTA
      xx×xx×xx×xx×x××C MV DNA ³
      ×4×Coronary angiography
      ×××Urine 24h protein
      ×Malignancy screening 4
      ×××Chest X-ray
      ×××PSA
      xx××x×PRA (DSA)5
      ×××Bone density
      xxxxCPET
      x××××Skin-cancer screening clinic
      xxxxEndocrinology clinic
      xxxxDental exam
      low asterisk The frequency of follow-up visits for HT recipients will depend on the time from HT and the post-operative clinical course. The frequency of follow-up should be increased if complications occur, particularly in patients with challenging medical or psychosocial conditions. In addition, in view of different local availabilities of newer noninvasive modalities (e.g., Gene Expression Profiling) and the lack of evidence about the optimal timing of echocardiographic studies in HT patients, it should be noted that the frequency of follow-up visits and schedule presented in the table serve merely as an example and should be tailored to each center. Furthermore, as noninvasive modalities improve, it is likely that the need for biopsies and serial conventional angiography will be reduced accordingly.
      Table 13Special Anesthetic Considerationsfor Intercurrent Surgery in HT Recipients
      • Barbara DW
      • Christensen JM
      • Mauermann WJ
      • Dearani JA
      • Hyder JA.
      The Safety of Neuromuscular Blockade Reversal in Patients With Cardiac Transplantation.
      ,
      • De Jong FH
      • Mallios C
      • Jansen C
      • Scheck PAE
      • Lamberts SWJ.
      Etomidate Suppresses Adrenocortical Function by Inhibition of 1 lβ-Hydroxylation.
      ,
      • Gronwald C
      • Vowinkel T
      • Hahnenkamp K.
      Regional anesthetic procedures in immunosuppressed patients: risk of infection.
      ,
      • Koglin J
      • Gross T
      • Uberfuhr P
      • von Scheidt W.
      Time-dependent decrease of presynaptic inotropic supersensitivity: physiological evidence of sympathetic reinnervation after heart transplantation.
      ,
      • Sidi A
      • Kaplan RF
      • Davis RF.
      Prolonged neuromuscular blockade and ventilatory failure after renal transplantation and cyclosporine.
      Special consideration
      Single dose of etomidate, used during induction, has been shown to decrease serum concentration of cortisol for at least 24 hours. However, this has not been shown to be clinically relevant.
      Cyclosporine has been described as prolonging muscle relaxants; this effect has not been shown in patients on mycophenolate mofetil and tacrolimus.
      Although the apparent higher potential for infectious complications of spinal or epidural anesthesia, limited data have not demonstrated this occurrence for regional or neuraxial procedures
      Given the complete cardiac denervation, drugs that work on the autonomic nervous system have minimal effects on the transplanted heart.

      Indirect-acting sympathomimetics such as ephedrine are therefore not very effective for treating hypotension and maintaining cardiac output; and ketamine may not display hemodynamic stability in heart transplant patients in extremis.

      Direct-acting sympathetic agents, like norepinephrine, epinephrine, isoproterenol, and dopamine, are effective, although the beta-adrenergic inotropic effects are attenuated early after HT.

      Phosphodiesterases have been shown to increase inotropy in the transplanted heart. The alpha-adrenergic response of phenylephrine is effective, but the reflex bradycardia is absent.
      The indirect acting anticholinergics (atropine, glycopyrrolate) and anticholinesterases (neostigmine, edrophonium) have no effect on the heart rate of the cardiac allograft, and the safety of neuromuscular reversal has been demonstrated in a large-scale study with no instances of severe bradycardia or cardiac arrest.

      The direct neuromuscular blockade Sugammadex, which directly inhibits neuromuscular blocking agents, is devoid of any direct cholinergic effects, and is a reasonable alternative in HT recipients.
      Table 14Sample Procedures for Pathological examination of the explanted hearts
      • Leone O
      • Angelini A
      • Bruneval P
      • Potena L.
      Appropriated photographic documentation of the intact and the sectioned hearts should be performed

      Preferably before fixation in 10% formalin, sampling of fresh myocardium from the four cavities taking multiple small fragments to be frozen for genetic and molecular analysis, and to be fixed in Karnovsky/glutaraldehyde for electron microscopy for diagnostic and for research purposes.

      Gross examination before sectioning according to standard protocols, which take into consideration the different types of pathologies, which have led to transplant.

      Sectioning according to the different types of pathologies:

      - for cardiomyopathies, ischemic heart disease, and valve diseases transverse cut from apex to the base of the heart.

      - for congenital heart disease the transverse cut is not recommended but use the sequential segmental approach

      5) Histological sampling of the entire circumferential midventricular transverse cut and of the coronary arteries for multiple appropriate staining including immunohistochemistry

      6) In case of mechanical assistance device implantation prior to transplant it would be important to evaluate grossly the device before removing it. In case of interventional procedures, both percutaneous and surgical, on the coronary arteries and on the valves particular care should be adopted for stents, valve, and vascular prosthesis with specific technique.
      The International Society for Heart and Lung Transplantion (ISHLT) Guidelines for the Care of Heart Transplant Recipients were originally published in 2010. These guidelines provided the first comprehensive guideline for the care of Heart Transplant patients. A great deal has changed in the years after this initial unprecedented document. The ISHLT has made the commitment to convene experts in all areas of heart transplantation to develop a focused update to the original practice guidelines. Writers and Chairs were charged with reviewing the existing guidelines and where signifigant new literature exists, updating those original recommendations. Additionally, they were charged to add specific new areas of focus that were undeveloped, undiscovered, or unsupported at the time of the original publication. After a vast effort involving 39 writers from 11 countries worldwide, the “ISHLT Guidelines for the Care of Heart Transplant Recipients” has now been completed and the Executive Summary of these guidelines is the subject of this article.
      The document results from the work of 4 Task Force groups each co-chaired by a pediatric heart transplant clincian who had the specific mandate to highlight issues unique to the pediatric heart transplant population and to ensure their adequate representation.
      • Task Force 1 addresses the peri-operative care of heart transplant recipients, including:
        • Pre-Transplant Optimization
        • Surgical Issues Impacting Care in the Immediate Post-operative Period
        • Considerations in Patients Bridged with Mechanical Circulatory Support
        • Early Post-Operative Care of the Heart Transplant Recipient
        • Evaluation of Allosensitization, Approaches to Sensitized Heart Transplant Recipients, and Hyperacute and Delayed Antibody-Mediated Rejection
        • Management of ABO “Incompatible” Heart Transplant Recipients
        • Coagulopathies in Heart Transplant Surgery
        • Documentation and Communication with the Multidisciplinary Team
        • Use of Extracorporeal Membrane Oxygenation for the Management of Primary Graft
      • Task Force 2 discusses the Immunosuppression and Rejection including:
        • Rejection Surveillance
        • Monitoring of Immunosuppressive Drug Levels
        • Principles of Immunosuppression and Recommended Regimens
        • Treatment of Acute Cellular Rejection
        • Treatment of Hyperacute and Antibody-Mediated Rejection
        • Management of Late Acute Rejection
      • Task Force 3 addresses the Long-term Care of Heart Transplant Recipients; Management of Complications including:
        • Minimization of Immunosuppression
        • Management of Neurologic Complications After Heart Transplantation
        • Cardiac Allograft Vasculopathy
        • Malignancy After Heart Transplantation
        • Chronic Kidney Disease After Heart Transplantation
        • Management of Cardiovascular Risk After Heart Transplantation
        • Other Complications of Chronic Immunosuppression
        • Arrhythmias
        • Anticoagulation after Heart Transplant
        • Monitoring Recipients of Organs from Donors at Higher Risk of Infectious Diseases
        • Graft Failure & Considerations for Cardiac Retransplantation
      • Taskforce 4 covers the Long-term Care of Heart Transplant Recipients: Prevention and Prophylaxis including:
        • Frequency of Routine Tests and Clinic Visits in Heart Transplant Recipients
        • Prophylaxis for Corticosteroid-Induced Bone Disease
        • Exercise, Nutrition and Physical Rehabilitation After Heart Transplantation
        • Management of Intercurrent Surgery in Heart Transplant Recipients
        • Reproductive Health After Heart Transplantation
        • Psychosocial and Psychologic Issues Particularly Related to Adherence to Medical Therapy in Heart Transplant Recipients
        • Substance Use & Abuse
        • Endocarditis Prophylaxis After Heart Transplantation
        • Return to Work or School and Occupational Restrictions After Heart Transplantation
        • Return to Operating a Vehicle After Heart Transplantation
        • Family Screening
        • Management of the Transition from Pediatric to Adult Care After Heart Transplantation
        • Principles of Shared Care After Heart Transplantation
        • Travelling After Heart Transplant
        • Emerging Pathogens, Epidemics and Pandemic Considerations for Heart Transplant Recipients
      International Society for Heart and Lung Transplantation Standards and Guidelines Committee Grading Criteria
      Tabled 1
      Class IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective
      Class IIConflicting evidence and/or divergence of opinion about the usefulness/efficacy of the treatment or procedure
      Class IIaWeight of evidence/opinion is in favor of usefulness/efficacy
      Class IIbUsefulness/efficacy is less well established by evidence/opinion
      Class IIIEvidence or general agreement that the treatment or procedure is not useful or effective and in some cases may be harmful
      Level of evidence AData derived from multiple randomized clinical trials or meta-analyses
      Level of evidence BData derived from a single randomized clinical trial or large non-randomized studies
      Level of evidence CConsensus of opinion of the experts and/or small studies, retrospective studies, registries

      Task Force 1: Peri-operative Care of the Heart Transplant Recipient

      Chair: Kumud Dhital
      Co-Chair: Estela Azeka
      Contributing Writers: Monica Colvin, Eugene DePasquale, Marta Farrero, Luis García-Guereta, Gina Jamero, Kiran Khush, Stephanie Pouch, Jacob Lavee, CJ Michaud, Jignesh Patel

      Topic 1: Pre-Transplant Optimization

      Frailty Assessment

      There is an important interplay between frailty and heart failure (HF). Frailty is an independent predictor for the development of HF.[
      • Khan H
      • Kalogeropoulos AP
      • Georgiopoulou VV
      • Newman AB
      • Harris TB
      • Rodondi N
      • Bauer DC
      • Kritchevsky SB
      • Butler J
      Frailty and risk for heart failure in older adults: The health, aging, and body composition study.
      ] However, frailty is also associated with increased mortality and morbidity in the elderly and general HF population. The prevalence of frailty is high in advanced HF patients, accounting for over 30% amongst those referred for advanced HF therapies, including heart transplantation (HT). It is an independent prognostic factor for morbidity and mortality, especially in patients with lower peak oxygen consumption (VO2).[
      • Moayedi Y
      • Duero Posada JG
      • Foroutan F
      • Goldraich LA
      • Alba AC
      • MacIver J
      • Ross HJ
      The prognostic significance of frailty compared to peak oxygen consumption and B-type natriuretic peptide in patients with advanced heart failure.
      ]A variety of methods have been utilized to assess frailty in HF with increasing support for its value in assessing HT patients. Currently, the modified Fried frailty criteria with five physical domains (fatigue, hand grip strength, gait speed, unintended weight loss and physical activity) and additional cognitive assessment (Montreal Cognitive Assessment [MoCA] tool) appears to be a reasonable resource for HT candidates.[
      • Jha SR
      • Hannu MK
      • Chang S
      • Montgomery E
      • Harkess M
      • Wilhelm K
      • Hayward CS
      • Jabbour A
      • Spratt PM
      • Newton P
      • Davidson PM
      • Macdonald PS.
      The Prevalence and Prognostic Significance of Frailty in Patients With Advanced Heart Failure Referred for Heart Transplantation.
      ] While frailty is associated with increased morbidity and mortality in patients undergoing ventricular assist device (VAD) implantation and HT, it is also largely reversible following these procedures.[
      • Jha SR
      • Hannu MK
      • Chang S
      • Montgomery E
      • Harkess M
      • Wilhelm K
      • Hayward CS
      • Jabbour A
      • Spratt PM
      • Newton P
      • Davidson PM
      • Macdonald PS.
      The Prevalence and Prognostic Significance of Frailty in Patients With Advanced Heart Failure Referred for Heart Transplantation.
      ,
      • Chung CJ
      • Wu C
      • Jones M
      • Kato TS
      • Dam TT
      • Givens RC
      • Templeton DL
      • Maurer MS
      • Naka Y
      • Takayama H
      • Mancini DM
      • Schulze PC.
      Reduced Handgrip Strength as a Marker of Frailty Predicts Clinical Outcomes in Patients With Heart Failure Undergoing Ventricular Assist Device Placement.
      ,
      • Macdonald PS
      • Gorrie N
      • Brennan X
      • Aili SR
      • De Silva R
      • Jha SR
      • Fritis-Lamora R
      • Montgomery E
      • Wilhelm K
      • Pierce R
      • Lam F
      • Schnegg B
      • Hayward C
      • Jabbour A
      • Kotlyar E
      • Muthiah K
      • Keogh AM
      • Granger E
      • Connellan M
      • Watson A
      • Iyer A
      • Jansz PC
      The impact of frailty on mortality after heart transplantation.
      ]

      Nutritional Assessment and Rehabilitation

      Prevalence of malnutrition in the heart failure population is high and represents an independent predictor of poor outcome and mortality.[
      • Aggarwal A
      • Kumar A
      • Gregory MP
      • Blair C
      • Pauwaa S
      • Tatooles AJ
      • Pappas PS
      • Bhat G.
      Nutrition Assessment in Advanced Heart Failure Patients Evaluated for Ventricular Assist Devices or Cardiac Transplantation.
      ] Pre transplant body mass index (BMI) is a factor that has been shown to correlate with survival post heart transplant. A United Network for Organ Sharing (UNOS) registry study showed the relationship between BMI and post-transplant survival to be U-shaped, with transplant candidates who were underweight (BMI <18.5 kg/m2) and candidates who were obese (BMI > 35 kg/m2) having significantly decreased survival from year 1 to 5.[
      • Russo MJ
      • Hong KN
      • Davies RR
      • Chen JM
      • Mancini DM
      • Oz MC
      • Rose EA
      • Gelijns A
      • Naka Y.
      The effect of body mass index on survival following heart transplantation: do outcomes support consensus guidelines?.
      ] It is important to note, however, that in regards to nutritional screening and assessment of patients with heart failure, the accuracy of any single nutritional indicator may be compromised by many confounding factors, especially be edema. Edema is caused by fluid retention in addition to inflammatory responses, induced by cytoprotective responses to cellular damage caused by under perfusion of peripheral tissues. Both fluid retention and the inflammatory response affect anthropometric measures such as BMI, triceps skinfold measurement and mid-arm circumference, as well as serum markers, such as albumin and prealbumin. Given secondary confounding factors, multidimensional tools should be used to assess nutrition status.[
      • Aggarwal A
      • Kumar A
      • Gregory MP
      • Blair C
      • Pauwaa S
      • Tatooles AJ
      • Pappas PS
      • Bhat G.
      Nutrition Assessment in Advanced Heart Failure Patients Evaluated for Ventricular Assist Devices or Cardiac Transplantation.
      ,
      • Barge-Caballero E
      • García-López F
      • Marzoa-Rivas R
      • Barge-Caballero G
      • Couto-Mallón D
      • Paniagua-Martín MJ
      • Solla-Buceta M
      • Velasco-Sierra C
      • Pita-Gutiérrez F
      • Herrera-Noreña JM
      • Cuenca-Castillo JJ
      • Vázquez-Rodríguez JM
      • Crespo-Leiro MG
      Prognostic Value of the Nutritional Risk Index in Heart Transplant Recipients.
      ,
      • Lin H
      • Zhang H
      • Lin Z
      • Li X
      • Kong X
      • Sun G.
      Review of nutritional screening and assessment tools and clinical outcomes in heart failure.
      ] Based on a systematic review of literature, the most commonly used tools that provide scores that were independent prognostic factors for mortality risk in heart failure patients, were the Mini Nutrinritional Assessment, MNA-short form, Nutritional Risk Index, and Geriatric Nutritional Risk Index.[
      • Lin H
      • Zhang H
      • Lin Z
      • Li X
      • Kong X
      • Sun G.
      Review of nutritional screening and assessment tools and clinical outcomes in heart failure.
      ]
      Preliminary studies regarding prehabilitation, exercise, and nutrition interventions prior to surgery have shown promising results with improved outcomes post-surgery.[
      • West MA
      • Wischmeyer PE
      • Grocott MPW.
      Prehabilitation and Nutritional Support to Improve Perioperative Outcomes.
      ] Interventions may include strategies to: 1) improve appetite, such as appetite stimulating agents, including megestrol acetate and anabolic steroids; 2) augment caloric intake, including oral food supplements, or with enteral feedings via nasogastric feeding tube, or percutaneous endoscopic gastrostomy; and 3) directly provide micronutrients, carbohydrates and proteins, such as total parental nutrition.[
      • Russo MJ
      • Hong KN
      • Davies RR
      • Chen JM
      • Mancini DM
      • Oz MC
      • Rose EA
      • Gelijns A
      • Naka Y.
      The effect of body mass index on survival following heart transplantation: do outcomes support consensus guidelines?.
      ] Lastly, post-transplant patients are at high risk for osteopenia and osteoporosis, largely due to use of glucocorticoids and calcineurin inhibitors. Transplant candidates should therefore be evaluated for bone disease by bone marrow density (BMD) and parameters of bone and mineral metabolism, so that appropriate therapies, such as vitamin D supplementation and bisphosphonates, can be initiated to minimize patient's risk for osteopenia following transplant.[
      • Kulak CA
      • Borba VZ
      • Kulak Jr, J
      • Custodio MR
      Osteoporosis after transplantation.
      ,
      • Rahman A
      • Jafry S
      • Jeejeebhoy K
      • Nagpal AD
      • Pisani B
      • Agarwala R.
      Malnutrition and Cachexia in Heart Failure.
      ]
      Cardiac rehabilitation has been shown to improve functional capacity and decrease hospital readmissions in HF patients, and is currently recommended by guidelines.[
      • Piepoli MF
      • Conraads V
      • Corra U
      • Dickstein K
      • Francis DP
      • Jaarsma T
      • McMurray J
      • Pieske B
      • Piotrowicz E
      • Schmid JP
      • Anker SD
      • Solal AC
      • Filippatos GS
      • Hoes AW
      • Gielen S
      • Giannuzzi P
      • Ponikowski PP.
      Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation.
      ,
      • Ponikowski P
      • Voors AA
      • Anker SD
      • Bueno H
      • Cleland JGF
      • Coats AJS
      • Falk V
      • Gonzalez-Juanatey JR
      • Harjola VP
      • Jankowska EA
      • Jessup M
      • Linde C
      • Nihoyannopoulos P
      • Parissis JT
      • Pieske B
      • Riley JP
      • Rosano GMC
      • Ruilope LM
      • Ruschitzka F
      • Rutten FH
      van der Meer P and Group ESCSD
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ] Pre habilitation has been shown to decrease post-operative complication after cardiovascular or abdominal surgery.[
      • Barberan-Garcia A
      • Ubre M
      • Roca J
      • Lacy AM
      • Burgos F
      • Risco R
      • Momblan D
      • Balust J
      • Blanco I
      • Martinez-Palli G.
      Personalised Prehabilitation in High-risk Patients Undergoing Elective Major Abdominal Surgery: A Randomized Blinded Controlled Trial.
      ,
      • Drudi LM
      • Tat J
      • Ades M
      • Mata J
      • Landry T
      • MacKenzie KS
      • Steinmetz OK
      • Gill HL.
      Preoperative Exercise Rehabilitation in Cardiac and Vascular Interventions.
      ] Physical activity was related to increased event-free survival on the HT waiting list[
      • Spaderna H
      • Vogele C
      • Barten MJ
      • Smits JMA
      • Bunyamin V
      • Weidner G.
      Physical activity and depression predict event-free survival in heart transplant candidates.
      ] and better functional capacity and health-related quality of life in heart failure, heart transplant or left ventricular assist device (LVAD) patients.[
      • Karapolat H
      • Engin C
      • Eroglu M
      • Yagdi T
      • Zoghi M
      • Nalbantgil S
      • Durmaz B
      • Kirazli Y
      • Ozbaran M.
      Efficacy of the cardiac rehabilitation program in patients with end-stage heart failure, heart transplant patients, and left ventricular assist device recipients.
      ]

      Psychosocial and Behavioral Optimization

      Pre-transplant psychosocial factors, including patients’ history of medical adherence, mental health, substance use, and social support, can predict outcomes following heart transplantation. Certain factors, such as noncompliance to medical regimen, smoking and alcohol abuse, psychiatric conditions such as depression, and minimal or no social support, have been shown to lead to behaviors of continued or relapse of nonadherence to medical regimen, relapse of substance use, poor self-care, and poor coping. These behaviors lead to poor health-related quality of life with increased morbidity and mortality post-transplant. To maximize outcomes, efforts should be made, prior to transplant, to optimize factors that are modifiable, based on pre-transplant psychosocial evaluation. Interventions may include support groups for substance use, ongoing counseling or therapy, optimization of medical therapy for psychiatric illnesses, and utilization of community resources.[
      • Dew MA
      • DiMartini AF
      • Dobbels F
      • Grady KL
      • Jowsey-Gregoire SG
      • Kaan A
      • Kendall K
      • Young Q-R
      • Abbey SE
      • Butt Z
      • Crone CC
      • De Geest S
      • Doligalski CT
      • Kugler C
      • McDonald L
      • Ohler L
      • Painter L
      • Petty MG
      • Robson D
      • Schlöglhofer T
      • Schneekloth TD
      • Singer JP
      • Smith PJ
      • Spaderna H
      • Teuteberg JJ
      • Yusen RD
      • Zimbrean PC.
      The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support.
      ]

      Hemodynamic Optimization

      The presence of pre-transplant pulmonary hypertension (PH) in heart organ recipients increases the risk of post-transplant PH and deterioration in right ventricular function in the donor heart. Large registry studies show pre-transplant PH is associated with significantly worse short-term survival post HT compared to patients without pre-transplant PH.[
      • Crawford TC
      • Leary PJ
      • Fraser CD
      • Suarez-Pierre A
      • Magruder JT
      • Baumgartner WA
      • Zehr KJ
      • Whitman GJ
      • Masri SC
      • Sheikh F
      • De Marco T
      • Maron BA
      • Sharma K
      • Gilotra NA
      • Russell SD
      • Houston BA
      • Ramu B
      • Tedford RJ.
      Impact of the New Pulmonary Hypertension Definition on Heart Transplant Outcomes.
      ,
      • Yost G
      • Gregory M
      • Bhat G
      Short-Form Nutrition Assessment in Patients With Advanced Heart Failure Evaluated for Ventricular Assist Device Placement or Cardiac Transplantation.
      ] However, assessment of isolated pulmonary hypertension, related to left ventricular failure and reversibility following transplant, remains challenging. In 2018, the 6th World Health Symposium on Pulmonary Hypertension developed two main changes in the definition and classification of PH.[
      • Tedford RJ
      • Beaty CA
      • Mathai SC
      • Kolb TM
      • Damico R
      • Hassoun PM
      • Leary PJ
      • Kass DA
      • Shah AS
      Prognostic value of the pre-transplant diastolic pulmonary artery pressure–to–pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.
      ] First, PH is defined by a mean PAP (mPAP) greater than 20mmHg (previously greater than 25mmHg). The lower parameter reflects recent studies suggesting that individuals with mPAP 21-24mmHg are at increased risk of poor outcomes and tend to progress to “overt PH” (mPAP 25 or greater) more often than patients with lower mPAP(20mmHg or less).[
      • Condon DF
      • Nickel NP
      • Anderson R
      • Mirza S
      • de Jesus
      • Perez VA.
      The 6th World Symposium on Pulmonary Hypertension: what's old is new.
      ,
      • Tsukashita M
      • Takayama H
      • Takeda K
      • Han J
      • Colombo PC
      • Yuzefpolskaya M
      • Topkara VK
      • Garan AR
      • Mancini DM
      • Kurlansky PA
      • Naka Y.
      Effect of pulmonary vascular resistance before left ventricular assist device implantation on short- and long-term post-transplant survival.
      ] In addition, PH was further subclassified by pulmonary vascular resistance (PVR) to help stratify pre-capillary PH (as seen in PAH), and isolated post-capillary PH (IpcPH, related to left ventricle (LV) dysfunction, as well as combined pre- and post- capillary PH (CpcPH) (Table 1). While subcategorization and method of detecting CpcPH remains controversial, current evidence suggests that CpcPH is a distinct entity from PAH or IpcPH and carries a different prognosis both before and after HT.[
      • Tedford RJ
      • Beaty CA
      • Mathai SC
      • Kolb TM
      • Damico R
      • Hassoun PM
      • Leary PJ
      • Kass DA
      • Shah AS
      Prognostic value of the pre-transplant diastolic pulmonary artery pressure–to–pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension.
      ,
      • Vakil K
      • Duval S
      • Sharma A
      • Adabag S
      • Abidi KS
      • Taimeh Z
      • Colvin-Adams M.
      Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: A UNOS registry analysis.
      ]
      Right heart catheterization should be performed on all adult candidates in preparation for listing, and periodically when patients are listed.[
      • Mehra MR
      • Canter CE
      • Hannan MM
      • Semigran MJ
      • Uber PA
      • Baran DA
      • Danziger-Isakov L
      • Kirklin JK
      • Kirk R
      • Kushwaha SS
      • Lund LH
      • Potena L
      • Ross HJ
      • Taylor DO
      • Verschuuren EAM
      • Zuckermann A.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update.
      ] Strategies to assess and optimize elevated pulmonary artery (PA) pressures should be utilized to determine reversibility in order to prevent right ventricular failure post-transplant (Figure 1). Medical therapies include diuretics, inotropes, and vasoactive agents, both inhaled (i.e., nitric oxide and prostacyclins), and intravenous (i.e., nitroglycerin and nitroprusside). Phosphodiesterase-3 (PDE-3) inhibitors (i.e., milrinone) have shown immediate hemodynamic effects, however, with no long-term effects on clinical outcomes in PH due to LV failure. Other therapies typically used for WHO Group 1 PH (pulmonary arterial hypertension) have been utilized for WHO group 2 PH (due to LV failure) with varying results. PDE-5 inhibitors (i.e., sildenafil) has demonstrated some beneficial effects. Additionally, endothelin receptor antagonists (ERAs) such as bosentan and tezosentan have shown some improvement in hemodynamics in pre-clinical and small studies albeit with adverse effects, including hepatic dysfunction. Newer ERAs, such as macetentan, without adverse effects on hepatic function are currently being studied. Finally, PH refractory to medical therapy has been effectively treated with mechanical circulatory support, such as LVADs, with improvement in PH and successful bridging to transplant.[
      • Koulova A
      • Gass AL
      • Patibandla S
      • Gupta CA
      • Aronow WS
      • Lanier GM
      Management of pulmonary hypertension from left heart disease in candidates for orthotopic heart transplantation.
      ]
      Figure 1:
      Figure 1Established effects of some targeted interventions. Blue bars symbolize depleting or reducing effect. Anti-CD20 antibodies show strong effect on naïve, effector, and memory B cells but no effect on plasma cells, which are not expressing CD20. Proteasome inhibitors show strong effect on PC and moderate effect on memory B cells. Anti-CD19 cells target PC but are currently not available as an effective clinical therapeutic for transplant. Effect of all of these therapies on LLPC is unclear but appears to be limited. (IL: interleukin, LLPC: long lives plasma cell, PC: plasma cell)

      Consideration of mechanical circulatory support (MCS) for Bridging to Transplant

      Patients with HF refractory to optimal medical therapy, with hemodynamic instability and/or progressive end organ dysfunction, should be considered for short-term and/or long-term MCS. MCS therapy should be directed by the trajectory of HF progression and clinical status.[
      • den Uil CA
      • Akin S
      • Jewbali LS
      • dos Reis Miranda D
      • Brugts JJ
      • Constantinescu AA
      • Kappetein AP
      • Caliskan K
      Short-term mechanical circulatory support as a bridge to durable left ventricular assist device implantation in refractory cardiogenic shock: a systematic review and meta-analysis.
      ,
      • Feldman D
      • Pamboukian SV
      • Teuteberg JJ
      • Birks E
      • Lietz K
      • Moore SA
      • Morgan JA
      • Arabia F
      • Bauman ME
      • Buchholz HW
      • Deng M
      • Dickstein ML
      • El-Banayosy A
      • Elliot T
      • Goldstein DJ
      • Grady KL
      • Jones K
      • Hryniewicz K
      • John R
      • Kaan A
      • Kusne S
      • Loebe M
      • Massicotte MP
      • Moazami N
      • Mohacsi P
      • Mooney M
      • Nelson T
      • Pagani F
      • Perry W
      • Potapov EV
      • Eduardo Rame J
      • Russell SD
      • Sorensen EN
      • Sun B
      • Strueber M
      • Mangi AA
      • Petty MG
      • Rogers J
      International Society for H and Lung T. The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary.
      ,
      • Nagpal AD
      • Singal RK
      • Arora RC
      • Lamarche Y.
      Temporary Mechanical Circulatory Support in Cardiac Critical Care: A State of the Art Review and Algorithm for Device Selection.
      ,
      • Peura JL
      • Colvin-Adams M
      • Francis GS
      • Grady KL
      • Hoffman TM
      • Jessup M
      • John R
      • Kiernan MS
      • Mitchell JE
      • O'Connell JB
      • Pagani FD
      • Petty M
      • Ravichandran P
      • Rogers JG
      • Semigran MJ
      • Toole JM.
      Recommendations for the Use of Mechanical Circulatory Support: Device Strategies and Patient Selection: A Scientific Statement From the American Heart Association.
      ,
      • Potapov EV
      • Antonides C
      • Crespo-Leiro MG
      • Combes A
      • Färber G
      • Hannan MM
      • Kukucka M
      • de Jonge N
      • Loforte A
      • Lund LH
      • Mohacsi P
      • Morshuis M
      • Netuka I
      • Özbaran M
      • Pappalardo F
      • Scandroglio AM
      • Schweiger M
      • Tsui S
      • Zimpfer D
      • Gustafsson F.
      2019 EACTS Expert Consensus on long-term mechanical circulatory support.
      ,
      • Rihal CS
      • Naidu SS
      • Givertz MM
      • Szeto WY
      • Burke JA
      • Kapur NK
      • Kern M
      • Garratt KN
      • Goldstein JA
      • Dimas V
      • Tu T
      Society for Cardiovascular A, Interventions, Heart Failure Society of A, Society of Thoracic S, American Heart A and American College of C. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care: Endorsed by the American Heart Assocation, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d'intervention.
      ,
      • Sánchez-Enrique C
      • Jorde UP
      • González-Costello J
      Heart Transplant and Mechanical Circulatory Support in Patients With Advanced Heart Failure.
      ]

      Impact of Pediatric Risk Models on Wait-list Management

      Selection of pediatric recipients is a multifactorial process including specific considerations of factors that will directly impact posttransplant outcome. Furthermore, the spectrum of advanced therapies as well as donor polices, public initiatives and published studies have significantly changed approaches in the management and care of this special population. Candidate selection and waitlist removal are a multidisciplinary process that balances the risks and benefits for the transplant procedure.[
      • Chen CK
      • Manlhiot C
      • Mital S
      • Schwartz SM
      • Van Arsdell GS
      • Caldarone C
      • McCrindle BW
      • Dipchand AI
      Prelisting predictions of early postoperative survival in infant heart transplantation using classification and regression tree analysis.
      ,
      • Peng D
      • Schumacher K.
      Risk factors for early and late mortality in pediatric heart transplantation.
      ]
      Pediatric risk factor models have been studied in early and late mortality.[
      • Chen CK
      • Manlhiot C
      • Mital S
      • Schwartz SM
      • Van Arsdell GS
      • Caldarone C
      • McCrindle BW
      • Dipchand AI
      Prelisting predictions of early postoperative survival in infant heart transplantation using classification and regression tree analysis.
      ] Risk factors for early mortality include: recipient variables such as diagnosis, age, gender, sensitization, pulmonary vascular resistance, non-cardiac end organ status, mechanical ventilation, extracorporeal membrane oxygenation, VADs; donor-related factors including ischemic time, donor graft function, cause of death. Small center volume has been described as a potential variable for increased post-transplant mortality. A model for in-hospital mortality after pediatric transplantation has been studied using variables available in Organ Procurement Transplantation Network (OPTN) which includes hemodynamic support; Extracorporeal Membrane Oxygenation (ECMO), VAD, ventilator and medical therapy, cardiac diagnosis, renal dysfunction, and serum total bilirubin. This model has C-statistics of 0.75 and 0.81.[
      • Almond CS
      • Gauvreau K
      • Canter CE
      • Rajagopal SK
      • Piercey GE
      • Singh TP.
      A Risk-Prediction Model for In-Hospital Mortality After Heart Transplantation in US Children: Risk Prediction in Pediatric Heart Transplant.
      ] The risk factor model using donor variables on 1-year or late mortality post-transplant has been studied using the OPTN registry[
      • Zafar F
      • Jaquiss RD
      • Almond CS
      • Lorts A
      • Chin C
      • Rizwan R
      • Bryant R
      • Tweddell JS
      • Morales DLS.
      Pediatric Heart Donor Assessment Tool (PH-DAT): A novel donor risk scoring system to predict 1-year mortality in pediatric heart transplantation.
      ] including ischemic time, stroke as the cause of death, donor-to recipient height ratio, donor left ventricular ejection fraction, and donor glomerular filtration rate. This model can be useful when assessing acceptability of a prospective organ in a recipient. Therefore, risk factors models can provide an impact on wait list management after acknowledgement of unmeasured and confounding factors.

      Nutritional Assessment, Nutritional Rehabilitation and Nutritional Interventions in the Pediatric Population

      Nutritional status in most pediatric chronic conditions is a major determinant of childhood well-being. Chronic HF in children is a major cause of malnutrition.[
      • Godown J
      • Friedland-Little JM
      • Gajarski RJ
      • Yu S
      • Donohue JE
      • Schumacher KR.
      Abnormal nutrition affects waitlist mortality in infants awaiting heart transplant.
      ,
      • Heuschkel RB
      • Gottrand F
      • Devarajan K
      • Poole H
      • Callan J
      • Dias JA
      • Karkelis S
      • Papadopoulou A
      • Husby S
      • Ruemmele F
      • Schäppi MG
      • Wilschanski M
      • Lionetti P
      • Orel R
      • Tovar J
      • Thapar N
      • Vandenplas Y.
      ESPGHAN Position Paper on Management of Percutaneous Endoscopic Gastrostomy in Children and Adolescents.
      ,
      • Kirk R
      • Dipchand AI
      • Rosenthal DN
      • Addonizio L
      • Burch M
      • Chrisant M
      • Dubin A
      • Everitt M
      • Gajarski R
      • Mertens L
      • Miyamoto S
      • Morales D
      • Pahl E
      • Shaddy R
      • Towbin J
      • Weintraub R.
      The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary.
      ,
      • Schwarz SM
      • Gewitz MH
      • See CC
      • Berezin S
      • Glassman MS
      • Medow CM
      • Fish BC
      • Newman LJ.
      Enteral nutrition in infants with congenital heart disease and growth failure.
      ,
      • Spillane NT
      • Kashyap S
      • Bateman D
      • Weindler M
      • Krishnamurthy G.
      Comparison of Feeding Strategies for Infants With Hypoplastic Left Heart Syndrome: A Randomized Controlled Trial.
      ] Malnutrition is an imbalance of nutrients between intake and nutritional requirements. The body is unable to meet metabolic demands in the setting of cardiac dysfunction. The pathophysiology of heart failure involves activation of compensatory pathways, pro-inflammatory cytokines, neurohormonal abnormalities, increased metabolic demands, reduced intake, and malabsorption.[
      • Lewis KD
      • Conway J
      • Cunningham C
      • Larsen BMK.
      Optimizing Nutrition in Pediatric Heart Failure: The Crisis Is Over and Now It's Time to Feed.
      ] These mechanisms lead to starvation, malabsorption nutritional loss and hypermetabolism which result in malnutrition and suboptimal growth. Therefore, it is recommended that nutritional status should be addressed by history, and nutritional and physical assessment. The basic tools for initial evaluation include a history of energy, protein and fluid intake, weight, length, head circumference measurements on sex- and age- specific growth curves[
      • Lewis KD
      • Conway J
      • Cunningham C
      • Larsen BMK.
      Optimizing Nutrition in Pediatric Heart Failure: The Crisis Is Over and Now It's Time to Feed.
      , ] (weight for age, length for age, body mass index) on which individual patient's values can be plotted and detection of growth velocity deviation. Nutritional support includes hypercaloric feeds, oral supplements, and enteral and parenteral nutrition. Enteral nutrition is required when oral intake is insufficient. Conditions such as severe cord dysfunction, dysphagia, or oral aversion can interfere with adequate oral intake. Nasojejunal tube feeds may be used when nasogastric tube feeds are not tolerated. Nutritional support via gastrostomy can be effective at reversing malnutrition, in maintaining nutritional status, and may be indicated in children requiring prolonged enteral tube feeding. Multidisciplinary discussions surrounding the risk of surgical intervention and anesthesia are required in these cases.

      Consideration of Bridge to Transplant with MCS in Pediatric Recipients

      The use of VADs in pediatric patients for the treatment of advanced HF has increased significantly in the past decade and has supplanted ECMO as the most common form of MCS as a bridge to HT. The percentage of children with MCS as a bridge to transplantation has increased from 25% in 2010 to 36% in 2019. The majority of MCS implants in the pediatric population are INTERMACS profiles 1 or 2 with significantly decreased waitlist mortality. However, the ISHLT registry data demonstrates no survival difference between children with or without VAD support, except for worse outcomes in those bridged with ECMO.[
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      Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) Report: Preimplant Characteristics and Outcomes.
      ,
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      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-second pediatric heart transplantation report –2019; Focus theme: Donor and recipient size match.
      ,
      • Yarlagadda VV
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      Temporary Circulatory Support in U.S. Children Awaiting Heart Transplantation.
      ]

      Pre-Transplant Vaccinations in Adult & Pediatric Candidates for Heart Transplantation

      There are limited data specifically addressing vaccination of adults and children with advanced HF in the pre-transplant setting.[
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