WITHDRAWN: Executive Summary - The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients

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 Classification Mean pulmonary artery pressure Pulmonary capillary wedge pressure Pulmonary 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). [22] 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. The Journal of Heart and Lung Transplantation. 2014; 33: 289-297 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Open table in a new tab Table 2Predicted Heart Mass Calculator Predicted right ventricular mass(RVM) a × Ag e − 0.32 × Heigh t 1.135 × Weigh t 0.315 where a = 10.59 for women and 11.25 for men Predicted left ventricular mass(LVM) a × Heigh t 0.54 × Weigh t 0.61 where a = 6.82 for women and 8.25 for men Predicted heart mass (PHM) RVM + LVM Body mass index (BMI) Height Weigh t 2 Body surface area (BSA) a × Heigh t 0.725 × Weigh t 0.425 where a = 0.007184 Donor to recipient size match Size metri c donor Size metri c recipient Open table in a new tab Table 3Recommendations for the Prevention of Cytomegalovirus in Heart Transplant Recipients Group Recommendations 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 Open table in a new tab Table 4Recommended mTOR inhibitor & CNI target levels: Adults IS regimen Everolimus (ng/mL) Sirolimus (ng/mL) Cyclosporine (Time post-tx) (ng/mL) Tacrolimus (Time post-tx) (ng/mL) CNI + mTOR inhibitor 3-8 4-12 75-200 (3-6 months)50-100 (> 6 months) 3-8 (> 6 months) CNI-free (e.g., mTOR + MMF) 6-10 8-15 Pediatrics* IS regimen Everolimus (ng/mL) Sirolimus (ng/mL) Cyclosporine (Time post-tx) (ng/mL) Tacrolimus (Time post-tx) (ng/mL) CNI + mTOR inhibitor 3-6 4-7 100-200 (3-6 months)60-120 (> 6 months) 4-8 (> 6 months) CNI-free (e.g., mTOR + MMF) 3-8 5-8 *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. Open table in a new tab Table 5Drugs That Affect the Levels of Tacrolimus, Cyclosporine, Sirolimus, or Everolimus Decrease immunosuppression levels Increase immunosuppression levels Anti-epilepticsCarbamazepineFosphenytoinPhenobarbitalPhenytoin Anti-fungalsClotrimazoleFluconazoleIsavuconazoleItraconazoleKetoconazolePosaconazoleVoriconazole Anti-microbialsCaspofunginNafcillinRifabutinRifampinRifapentine Anti-microbialsClarithromycinErythromycinMetronidazole and tinidazole Anti-retroviral therapyEfavirenzEtravirineNevirapine Anti-retroviral therapyProtease inhibitors (general)CobicistatDarunavirFosamprenavirIndinavirNelfinavirRitonavirSaquinavirTipranavir AntiviralsLetermovir Monoclonal antibodiesTocilizumab Direct acting antivirals for Hepatitis C:DaclatasvirGlecaprevir-PibrentasvirGrazoprevir-ElbasvirLedipasvir-(Sofosbuvir)Velpatasvir-(Sofosbuvir)Voxilaprevir-Velpatasvir-(Sofosbuvir) CardiovascularBosentan CardiovascularAmiodaroneDiltiazemVerapamil OthersAprepitantDeferasiroxModafinilSt. John's wortThalidomideTiclopidine OthersCimetidineFluvoxamineGlipizideGlyburideImatinibNefazodoneRilonaceptTheophyllineTurmeric NutraceuticalsBitter orangeGrapefruit Open table in a new tab Table 6Significant Differences in Primary endpoints between Study Groups from Major Clinical Trials since 2010 Author (year) Study No. Follow-up Survival Rejection CAV by IVUS Barten (2019) MANDELA:EVL/redCNI vsCNI-free 162 1 year NS CNI-free= more rejection NS Potena (2018) EVERHEART:Immediate (≤144 h) (EVL-I) vsdelayed (4-6 weeks post-HTx) (EVL-D) EVL initiation 181 6 months NS EVL-I= higher incidenceBPAR ≥2R(but not SS) NS Arora (2015)Andreassen (2016) SCHEDULE:redCYA/EVL & CNI withdrawal at 7‐11 weeks vsCYA+ MMF 115 1-3 years NS EVL group= more rejection EVL group= less CAV Eisen (2013) CRAD 2310:redCyA/EVL 1.5mg vsredCyA/EVL 3mg (dc) vsCYA/MMF 721 12-24 months NS No significant differences between groups EVL/redCYA group= less CAV Open table in a new tab Table 7ASignificant Differences in Adverse Events from the Major Clinical Trials since 2010 Author (year) Study No. Renal function Infections Cholesterol & triglycerides Hypertension Barten (2019) MANDELA:EVL/redCNI vsCNI-free 162 CNI‐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) vsdelayed (4-6 weeks post-HTx) (EVL-D) EVL initiation 181 comparable between both groups EVL-I= lower risk CMV No significant differences between groups No significant differences between groups Arora (2015)Andreassen (2016) SCHEDULE:redCYA/EVL & CNI withdrawal at 7‐11 weeksvs CYA+ MMF 115 EVL= better renal function No significant differences between groups NS No significant differences between groups Eisen (2013) CRAD 2310:redCyA/EVL 1.5mg vsredCyA/EVL 3mg (dc)vs CYA/MMF 721 EVL/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 Open table in a new tab Table 7BSignificant Differences in Adverse Events from the Major Clinical Trials since 2010 Author (year) Study No. Hematologic GI disorders Other Barten (2019) MANDELA:EVL/redCNIvs CNI-free 162 No significant differences between groups EVL/redCNI= more diarrhoea & nausea(? SS, no p-value) - Potena (2018) EVERHEART:Immediate (≤144 h) (EVL-I) vsdelayed (4-6 weeks post-HTx) (EVL-D) EVL initiation 181 No significant differences between groups NS EVL-I= more pericardial effusion= more AEs= more discontinuations due to AEs & serious AEsEVL-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 115 No significant differences between groups - No significant differences between groups for surgical events or wound complications Eisen (2013) CRAD 2310:redCyA/EVL 1.5mg vsredCyA/EVL 3mg (dc)vs CYA/MMF 721 EVL/redCYA = more anemia - EVL 3mg/redCYA arm= enrolment dc due to higher early mortalityEVL/redCYA= more pericardial effusion dc = discontinued; NS = not stated; SS = statistically significant; AE = adverse event Open table in a new tab Table 8Desensitization and AMR and Therapies [400] 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. J Heart Lung Transplant. 2021; 40: 595-603 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Therapy Mechanism of Action Immune Effects Major Adverse Effects Alemtuzumab CD52 monoclonal antibody Depletes circulating lymphocytes, macrophages and monocytes Leukopenia, thrombocytopenia, infusion related reactions Bortezomib Proteasome inhibitor Depletes plasma cells Peripheral neuropathy, thrombocytopenia, neutropenia Carfilzomib Proteasome inhibitor Depletes plasma cells AKI, thrombocytopenia, cardiotoxicity Eculizumab Complement C5 inhibitor Inhibits formation of terminal complement C5b-9 Meningococcal infection (Vaccination recommended) Intravenous immunoglobulin Immunomodulatory effects Neutralize circulating antibody, inhibit complement, inhibit B cells Infusion-related reactions, hemolysis, interference with antibody assays PIasmapheresis Extracorporeal plasma antibody filtration Removes circulating immunoglobulins Access and line related complications, coagulopathy Rituximab CD20 monoclonal antibody Depletes circulating B cells Infusion-related reactions Splenectomy Removal of secondary lymphoid organ Removes major source of lymphocytes Encapsulated bacterial infections Open table in a new tab Table 9Examples of Therapies for Antibody-Mediated Rejection Therapeutic modality Dose Frequency Duration Plasmapheresis 1-2 plasma exchanges Daily Every other day 3-5 days1-2 weeks 3 times per week 1-4 weeks Once weekly 2-4 weeks IVimmunoglobulin 100 – 2000 mg/kg Low dose 1–3 times per week, often given after each plasmapheresisImmune modulating dose (2g/kg) after last plasmapheresis cycle q 4 weeks 1-4 weeks Rituximab 375 mg/m2 Once weekly 1-4 weeks IV Ig, intravenous immunoglobulin. [218] Open table in a new tab 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) Modified PCWP threshold in children based on [273] 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. J Am Coll Cardiol. 2015; 66: 547-557 Crossref PubMed Google Scholar . Open table in a new tab 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 Open table in a new tab 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 >5 2-5 1 Year >60 >24 21 18 15 12 11 10 9 8 7 6 5 4 3 2 1 Month 24 20 16 12 10 8 7 6 5 4 3 2 1 Week × × × × × × × × × × × × × × × × × × × HT clinic visit × × × × × × × × × × × × × × × × × × × Lab tests[ [1] 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. American Heart Journal. 2013; 166: 887-894 Crossref PubMed Scopus (0) Google Scholar ] × × × × × × × × × × 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 angiography Dobutamine echo/SPECT/CTA x x × x x × x x × x x × x × × C MV DNA ³ ×4 × Coronary angiography × × × Urine 24h protein × Malignancy screening 4 × × × Chest X-ray × × × PSA x x × × x × PRA (DSA)5 × × × Bone density x x x x CPET x × × × × Skin-cancer screening clinic x x x x Endocrinology clinic x x x x Dental exam 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. Open table in a new tab Table 13Special Anesthetic Considerationsfor Intercurrent Surgery in HT Recipients 833 Barbara DW Christensen JM Mauermann WJ Dearani JA Hyder JA. The Safety of Neuromuscular Blockade Reversal in Patients With Cardiac Transplantation. Transplantation. 2016; 100: 2723-2728 Crossref PubMed Scopus (0) Google Scholar , 834 De Jong FH Mallios C Jansen C Scheck PAE Lamberts SWJ. Etomidate Suppresses Adrenocortical Function by Inhibition of 1 lβ-Hydroxylation. The Journal of Clinical Endocrinology & Metabolism. 1984; 59: 1143-1147 Crossref PubMed Google Scholar , 835 Gronwald C Vowinkel T Hahnenkamp K. Regional anesthetic procedures in immunosuppressed patients: risk of infection. Current Opinion in Anaesthesiology. 2011; 24: 698-704 Crossref PubMed Scopus (0) Google Scholar , 836 Koglin J Gross T Uberfuhr P von Scheidt W. Time-dependent decrease of presynaptic inotropic supersensitivity: physiological evidence of sympathetic reinnervation after heart transplantation. J Heart Lung Transplant. 1997; 16: 621-628 PubMed Google Scholar , 837 Sidi A Kaplan RF Davis RF. Prolonged neuromuscular blockade and ventilatory failure after renal transplantation and cyclosporine. Canadian Journal of Anaesthesia. 1990; 37: 543-548 Crossref PubMed Scopus (0) Google Scholar 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. Open table in a new tab Table 14Sample Procedures for Pathological examination of the explanted hearts [936] Leone O Angelini A Bruneval P Potena L. The Pathology of Cardiac Transplantation A clinical and pathological perspective. 1. illustrations, 2016: 448 Google Scholar Appropriated photographic documentation of the intact and the sectioned hearts should be performedPreferably 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 approach5) Histological sampling of the entire circumferential midventricular transverse cut and of the coronary arteries for multiple appropriate staining including immunohistochemistry6) 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. Open table in a new tab 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). [22] 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. The Journal of Heart and Lung Transplantation. 2014; 33: 289-297 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar *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. dc = discontinued; NS = not stated; SS = statistically significant; AE = adverse event