New Issues in Heart Transplantation for Heart Failure

Current Treatment Options in Cardiovascular Medicine (2012) 14:356–369DOI 10.1007/s11936-012-0184-7

Heart Failure (J Fang, Section Editor)

New Issues in HeartTransplantation for HeartFailureMichelle M. Kittleson, MD, PhD

Address8536 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USAEmail: [email protected]

Published online: 31 May 2012* Springer Science+Business Media, LLC 2012

Keywords Heart failure I Transplant I Biopsy I AlloMap I Cylex I Immunosuppression I Corticosteroids ICalcineurin inhibitors I Antimetabolites I Proliferation signal inhibitors I Antithymocyte globulin I Basiliximab IIntravenous immunoglobulin I Plasmapheresis I Photopheresis I Rituximab I Bortezomib

Opinion statement

Heart transplantation is the preferred therapy for patients with end-stage heart failurewith refractory symptoms despite optimal medical and device therapy. The major im-pediment to survival is rejection and infection in the short term and cardiac allograftvasculopathy and malignancy in the long term. Current therapies are focused on theprevention and treatment of rejection and limiting the long-term problems of cardiacallograft vasculopathy and malignancy. Advances in monitoring assays now allow bet-ter assessment of rejection and the level of immune response. This will allow clinicians,in the future, to tailor current therapies to the needs of individual heart transplantrecipients to maximize benefit and minimize toxicity.

IntroductionAdvances in medical therapy have dramatically im-proved the survival of patients with end-stage heartfailure [1]. However, despite these advances in phar-macologic and device treatment of chronic heart fail-ure, long-term morbidity and mortality remainunacceptably high: the 5-year mortality for patientswith symptomatic heart failure approaches 50 %,and may be as high as 80 % at 1 year for the end-stagepatients [1]. Over the past four decades, cardiac trans-plantation has become the preferred therapy for selectpatients with end-stage heart disease [2••]. In thistime, over 80,000 heart transplants have been per-formed internationally, with a 1-year survival near

90 % and a median survival of 13 years for those sur-viving the first transplant year [3].

Continuous efforts to optimize immunosuppres-sive regimens are critical to the success of heart trans-plantation, and heart transplant recipients can nowexpect excellent quantity and quality of life. The pur-pose of this review is to provide an overview of hearttransplantation in the current era. The review focuseson post-transplant monitoring of rejection and levelof immunosuppression; oral maintenance immuno-suppressive therapy; intravenous induction and rejec-tion immunosuppression therapy; other treatmentsfor rejection, including refractory rejection; and

emerging therapies. These advances have resulted in asubstantial decrease in acute allograft rejection and

long-term complications that limit the long-term sur-vival of transplant recipients.

TreatmentPost-transplant monitoring

& Endomyocardial biopsy is the gold standard for the diagnosis ofheart transplant rejection.

& Endomyocardial biopsies are graded for the presence of acute cellularand antibody mediated rejection (AMR). Biopsies are classified forcellular rejection as Grade 0R: no rejection; Grade 1R: mild rejection;Grade 2R: moderate rejection; or Grade 3R: severe rejection [4].Grade 2R or higher rejection on biopsy is considered significant andmerits treatment.

& Biopsies are classified for AMR as AMR0: negative, no histologic orimmunologic evidence of AMR; AMR1: suspicious, either histologicor immunologic evidence; AMR2: positive, both histologic and im-munologic evidence; or AMR3: severe, extensive findings of myo-cardial destruction [5••]. While traditionally, asymptomatic AMRwas left untreated, recent studies suggest that AMR2 or higher meritsshould be addressed [6, 7].

& A recent advance is the AlloMap (XDx Expression Diagnostics, Bris-bane, CA), an 11-gene expression signature derived from peripheralblood mononuclear cells that predicts cellular rejection and maydecrease the need for endomyocardial biopsies [8]. In a clinical trial,the AlloMap gene expression profile appears to be noninferior toendomyocardial biopsy in the diagnosis of cellular rejection inpatients more than 6 months post-transplant [9•].

& A major goal of immunosuppression is the individual tailoring oftherapy to optimally prevent rejection while minimizing toxicity andinfection. The Cylex immune monitoring (IM) assay (ImmuKnow;Cylex, Columbia, MD) is a blood test that characterizes the immunestate [10, 11]. For example, an immune monitoring score of less than200 ng adenosine triphosphate (ATP)/mL is an accurate predictor offuture infection, although high scores are not predictive of subse-quent rejection [12•].

Endomyocardial biopsy

Standard procedure The endomyocardial biopsy is most commonly performed via a right inter-nal jugular venous approach under fluoroscopic guidance. Alternatively,echocardiographic guidance may be used. Routinely, right heart catheteri-zation is also performed.

Contraindications Coagulopathy and inability to obtain central venous access.

Complications In addition to the complications of obtaining central venous access(bleeding, pneumothorax), specific biopsy-related complications includetricuspid valve injury and cardiac perforation, which occur in 0.5 % ofcases [13, 14].

New Issues in Heart Transplantation Kittleson 357

Special points Endomyocardial biopsy is not routinely performed after the first transplantyear at some centers, when the risk of rejection declines.

Cost/cost-effectiveness Medicare reimburses approximately $4,000 for an endomyocardial biopsy[15].

AlloMap gene expression profile

Standard procedure Peripheral blood mononuclear cells are isolated after standard phlebotomy.RNA is extracted and the levels of 11 immune response genes involved areassessed, resulting in an AlloMap score. A score below a given thresholdindicates a low risk of rejection, usually less than 1 in 1000. If the score isabove threshold, a confirmatory biopsy is performed. Negative predictivevalue appears to be reasonable outside of the first 6 months following car-diac transplantation.

Contraindications The AlloMap cannot be used in patients who have received blood transfu-sions or hematopoietic growth factors affecting leukocytes (such as granu-locyte-colony stimulating factor) within the past 30 days [8] or in patientsreceiving more than prednisone, 20 mg, daily (usually those patients in thefirst 2 months after transplantation).

Complications There are no complications to performing this blood test. However, bothunder- and over-diagnosis of cellular rejection may be problematic.

Special points AlloMap will not detect antibody-mediated rejection.

Cost/cost-effectiveness Medicare reimbursement for the AlloMap blood test is approximately $3,000and overall reduces expenses relative to routine endomyocardial biopsies[15].

Cylex immune monitoring assay

Standard procedure Lymphocytes are isolated from blood obtained by standard phlebotomy.These lymphocytes are activated in vitro by plant phytohemagglutinin, apotent T-cell mitogen and then lysed to measure ATP production.

Contraindications There are no contraindications to performing this blood test.

Complications There are no complications from this blood test.

Special points Physicians may target lower immunosuppressive medication trough levels inpatients with scores less than 200 ng ATG/mL, especially those with recurrentinfections [12•]. Whether dynamic changes in the immune monitoring scorein response to adjustments in immunosuppression alter patient outcomeshas not yet been determined.

Cost/cost-effectiveness The Cylex blood test costs approximately $2,000 for processing andreporting.

Pharmacologic treatment

Oral immunosuppressive medications& Oral immunosuppressive medications are the cornerstone of main-

tenance immunosuppressive therapy (Table 1). The purpose ofmaintenance immunosuppressive therapy is to prevent rejection.Standard triple-drug maintenance therapy consists of corticosteroids,a calcineurin inhibitor (cyclosporine or tacrolimus), and an anti-metabolite (azathioprine or mycophenolate mofetil [MMF]). In

358 Heart Failure (J Fang, Section Editor)

special situations outlined later in this article, a proliferation signalinhibitor (sirolimus or everolimus) may replace the antimetaboliteor calcineurin inhibitor.

& Corticosteroids alter the expression of genes involved in the immuneand inflammatory response, affecting the number, distribution, andfunction of all leukocytes.

& Cyclosporine and tacrolimus both block calcium-activated calci-neurin. Cyclosporine binds to cyclophilin and tacrolimus binds to FK

Table 1. Overview of types of rejection therapy

Goal AgentsMaintenance therapy Long-term rejection prevention Corticosteroids

MethylprednisolonePrednisoneCalcineurin inhibitorsCyclosporineTacrolimusAntimetabolitesAzathioprineMycophenolate mofetilProliferation signal inhibitorSirolimusEverolimus

Induction therapy Acute rejection prevention, delaycalcineurin inhibitor initiation topreserve renal function

Cytolytic therapyAntithymocyte globulinInterleukin 2-receptor antagonistBasixilimab

Rejection therapy Treat acute rejection Cytolytic therapyAntithymocyte globulinAffect antibody function and production acutelyIntravenous immune globulinPlasmapheresisMechanical circulatory support as bridge to recoveryIntra-aortic balloon pump

Persistent/refractoryrejection therapy

Treat a persistent symptoms afteran episode of acute rejection

Affect antibody function and production longer-termRituximabBortezomibAffect T cell functionPhotopheresis

Desensitization therapy Reduce or eliminate HLA antibodiespre- or post-transplantation

Inactivate antibodiesIntravenous immune globulinRemove antibodiesPlasmapheresisReduce production of antibodiesRituximabBortezomib

HLA human leukocyte antigen


binding protein. The complex then binds to and inhibits calcineurin,which is normally responsible for the dephosphorylation of NF-AT(nuclear factor of activated T cells) and the subsequent transcriptionof interleukin (IL)-2 and other cytokines.

& Azathioprine is converted in cells to a purine analogue incor-porated into DNA, thus inhibiting its synthesis and subsequentlythe proliferation of T and B lymphocytes. MMF is an inhibitor ofa key enzyme in the de novo synthesis of guanine nucleotides.Because proliferating lymphocytes are dependent on this path-way for DNA replication (other cells use both de novo andsalvage pathways), MMF is a selective inhibitor of lymphocyteproliferation.

& Based on the results of clinical trials, the ideal regimen de novo post–heart transplantation is corticosteroids, tacrolimus, and MMF [16].

& Proliferation signal inhibitors, sirolimus and everolimus, inhibit akinase, mammalian target of rapamycin (mTOR), which is importantin the proliferation of T and B lymphocytes, smooth muscle cells,and endothelial cells.

& Sirolimus and everolimus decrease episodes of rejection, retardthe progression of cardiac allograft vasculopathy, and are associ-ated with fewer viral infections such as cytomegalovirus. Theseagents also may reduce the incidence and progression of certainmalignancies [17–22]. However, when prescribed as primaryimmunosuppressants, these agents increase renal dysfunction and bac-terial infections; sirolimus in particular increases the risk of sternalwound dehiscence [16, 23, 24].

Corticosteroids

Standard dosage Corticosteroids regimens vary by center. At our center, patients receive500 mg intravenous bolus of methylprednisolone on release of aorticcross-clamp intraoperatively, followed by three doses of 125 mg in-travenously at 12-hour intervals. Oral prednisone is then given in astandard taper, from 40 mg twice daily decreasing by 5 mg incrementsuntil the patient is on 10 mg twice daily. At 1 month post-transplant,the patient will start a prednisone taper so that by 3 months, theprednisone is reduced to 10 mg once daily and by 6 months, decreasedto 5 mg once daily. Patients with no rejection in the first 6 months arecandidates to wean off prednisone completely by 12 months post-transplant.

Contraindications Corticosteroids should be avoided in patients with active infections. The riskof tendonitis and tendon rupture may increase when fluoroquinolone anti-biotics are prescribed in conjunction with corticosteroids.

Main drug interactions There are no significant drug interactions with corticosteroids.

Main side effects Short-term side effects include tremors, emotional lability, easy bruisability,poor wound healing, weight gain, fluid retention, and hyperglycemia.Long-term adverse effects include hypertension, cataracts, ulcer disease, in-fection, and osteoporosis. Long-term administration of steroids mayresult in chronic adrenal suppression.


Cost/cost-effectiveness Corticosteroids are in general inexpensive drugs because they are generic at astandard retail pharmacy, a 30-day supply of prednisone, 5 mg daily, is $11.99.

Calcineurin inhibitors

Standard dosage Cyclosporine or tacrolimus is administered orally immediately followingtransplantation. For cyclosporine, the initial dose is usually 100 mg twicedaily and then titrated to achieve target therapeutic trough whole bloodlevels of 250–350 ng/mL, drawn 1 hour before scheduled dose administra-tion. While protocols vary by center, at our center the target level is 200–300 ng/mL for months 2 and 3, and after month 3, cyclosporine doses arereduced to achieve target trough levels between 100 and 200 ng/mL. Inspecial situations, such as in patients with active infection, malignancy, or alow Cylex level, target trough levels may be reduced to 75 to 125 ng/mL. Theinitial tacrolimus dose is usually 1 mg twice daily and then titrated to achievetarget therapeutic levels of 10 to 15 ng/mL initially postoperatively. Inmonths 2 and 3, levels of 8 to 12 ng/mL are targeted. In the long term, dosesare reduced to achieve target levels between 5 and 10 ng/mL. As with cy-closporine, in special situations, such as in patients with active infection,malignancy, or a low Cylex level, target trough levels may be reduced to 4 to6 ng/mL. In patients who cannot tolerate oral medications, a continuousintravenous infusions of the calcineurin inhibitor may be given in which thetotal dose over 24 hours is calculated as one third of the total oral dose, andthe goal random level is the same as the goal trough level.

Contraindications Inpatientswith renal insufficiency, initiationof the calcineurin inhibitormaybedelayed by 3 to 5 days to avoid worsening postoperative acute tubular necrosis.In this setting, induction therapywith antithymocyte globulin (ATG)or an IL-2–receptor antagonist may be given (as outlined in detail below).

Main drug interactions Calcineurin inhibitors are metabolized by the cytochrome p450 enzymes.Therefore, calcineurin inhibitor levels may be increased 30 %–50 % by azoleantifungal agents, verapamil, diltiazem, and macrolide antibiotics and decreasedby rifampin. When these drugs are administered, levels must be closely followed.

Main side effects Cyclosporine causes nephrotoxicity, hypertension, dyslipidemia, neurologi-cal toxicity, hypertrichosis, and gingival hyperplasia. Tacrolimus has a similarside effect profile, but does not cause hypertrichosis or gingival hyperplasia.Hyperglycemia and neurological toxicity are more common with tacrolimus.

Special points Tacrolimus is the calcineurin inhibitor of choice because it offers a decreased riskof rejection [16, 25] althoughwithout a correspondingmortality benefit. Reasonsto initiate cyclosporine instead of tacrolimus include tacrolimus-induced neuro-toxicity (delirium or severe tremors), hyperglycemia, or cost. If cyclosporine isused, the microemulsion formulation is preferred for more reliable trough levels.

Cost/cost-effectiveness Both cyclosporine and tacrolimus have generic preparations that are usedclinically. At a standard retail pharmacy, a 30-day supply of generic micro-emulsion cyclosporine, 150 mg twice daily, is $431.98 and generic tacrolimus,3 mg twice daily, is $700.99.

Antimetabolites

Standard dosage Either azathioprine or MMF is given orally immediately after transplantation.Azathioprine doses range from 50 mg to 150 mg daily. Drug levels are notfollowed. MMF is usually prescribed at 1500 mg twice daily. While notstandardized nor a standard of care, mycophenolic acid trough levels can beused for therapeutic monitoring with a goal level of greater than 1 μg/mL.


More often, MMF dosage is titrated to the maximum tolerated dose based onside effects of leukopenia and gastrointestinal upset. MMF is also available inintravenous form with a 1:1 conversion.

Contraindications In patients with leukopenia, azathioprine or MMF may be held until leu-kopenia resolves.

Main drug interactions Azathioprine should not be prescribed with allopurinol because allopurinolinhibits xanthine oxidase, leading to increased accumulation of 6-mercap-topurine, a metabolite of azathioprine, and severe myelosuppression.

Main side effects The major side effect of azathioprine is myelosuppression. Major side effectsof MMF include nausea, vomiting, diarrhea, and myelosuppression (lessthan with azathioprine), which usually respond to a reduction in dosage.

Special points Compared with azathioprine, MMF-treated heart transplant recipients haveimproved survival, less rejection, and less cardiac allograft vasculopathy.MMF is the antimetabolite of choice for standard maintenance therapy [26].

Cost/cost-effectiveness Both azathioprine and MMF are available in generic form. At a standardretail pharmacy, a 30-day supply of generic azathioprine, 150 mg daily, is$480.59 and generic MMF, 1500 mg twice daily, is $1,249.99.

Proliferation signal inhibitors

Standard dosage Sirolimus is usually initiated at a dose of 1 mg once daily and then titrated totrough level 4–8 ng/mL. Everolimus is usually initiated at a dose of 0.75 mgtwice daily and then titrated to trough level 3–8 ng/mL. Both are availableonly in oral form.

Contraindications Sirolimus and everolimus are not routinely initiated in de novo hearttransplant recipients due to risk of nephrotoxicity and impaired woundhealing [16, 23, 24].

Main drug interactions Azole antifungals will increase the trough levels of proliferation signalinhibitors by 50 % and levels should be closely followed.

Main side effects The major side effects include hypertriglyceridemia, myelosuppression, fluidretention, diarrhea, fatigue, and oral ulcers. Everolimus may be better tol-erated than sirolimus in clinical trials.

Special points Sirolimus or everolimus may replace the calcineurin inhibitor or antime-tabolite in certain situations. They can replace the antimetabolite in patientswith rejection, cardiac allograft vasculopathy, malignancy, and viral infec-tions such as cytomegalovirus. They can replace the calcineurin inhibitor inpatients with renal dysfunction. Everolimus is currently only approved foruse in renal transplant recipients.

Cost/cost-effectiveness Sirolimus is available in generic formulation. At a standard retail pharmacy,a 30-day supply of generic sirolimus, 1 mg daily, is $417.99. Everolimus isnot available in generic formulation. A 30-day supply of everolimus, 0.75 mgtwice daily, is $1,183.99.

Intravenous agents& Antibody preparations are mainly used for induction and rejection

therapy (Table 1). Induction therapy reduces rejection in the first4–6 weeks post-transplant and allows the delayed introduction ofcalcineurin inhibitors to prevent worsening renal dysfunction.


However, induction therapy increases the risk of infection and ma-lignancy, and may simply delay the onset of rejection.

& ATG is prepared by immunizing rabbits or horses with humanlymphoid cells derived from the thymus or cultured B cell lines. Therabbit preparation is generally preferred due to favorable results inrenal transplant recipients [28]. ATG reverses rejection throughcomplement-dependent lysis or Fc receptor–mediated lysis andopsonization of activated T cells. There are no randomized trials ofATG for induction therapy.

& Basiliximab is a chimeric (mouse/human) IL-2–receptor (IL2-R)monoclonal antibody that binds the α subunit of IL-2R expressed onantigen-activated T cells. This prevents binding of IL-2 to the IL-2R,inhibiting proliferation of T cells. Daclizumab, another IL2-R an-tagonist that is no longer in production, demonstrated an increasedrisk of infection and death in heart transplant recipients, althoughdelayed the onset of rejection [27].

& Intravenous immunoglobulin (IV Ig) is highly purified polyvalentimmunoglobulin G (IgG) derived from pooled human plasma fromthousands of volunteer donors. While the mechanisms of action areincompletely understood, IV Ig suppresses inflammatory and im-mune-mediated processes.

& Antibodies against CD3-positive lymphocytes (OKT3) are no longercommercially available.

Treatment decisions& Rejection therapy is immunosuppressive therapy given to treat an epi-

sode of rejection (Table 1). The intensity of rejection therapy dependsupon the clinical context. For example, most transplant rejection isasymptomatic but the presence of heart failure, reduced ejection frac-tion, or hemodynamic compromise (Table 2) generally requires anaggressive escalation of immunosuppression. Protocols differ by center,in large part due to the lack of randomized trials for treating rejectionand the evolution from surgical practice.

& Grade 2R or higher cellular rejection or AMR2 or higher antibody-mediated rejection on biopsy merits treatment. If the patient has noheart failure symptoms and normal left ventricular function, treat-ment options include oral or intravenous pulse steroids [29], tar-geting higher levels of immunosuppressive medications, switchingfrom cyclosporine to tacrolimus [16, 25], or switching from MMF toa proliferation signal inhibitor [23, 24, 30].

& For patients with a reduced ejection fraction, treatment should bemore aggressive, including intravenous corticosteroids and poten-tially ATG in addition to the adjustments in immunosuppressivemedications outlined above. If there is evidence of AMR2 or higher,such patients also may receive IV Ig.

& In patients presenting with cardiogenic shock after cardiac


transplantation, empiric aggressive treatment of rejection should bestrongly considered, regardless of biopsy findings. Treatments may in-clude intravenous corticosteroids, cytolytic therapy, plasmapheresis, IVIg, and intravenous heparin (as patients often have thrombotic occlu-sion of the cardiac microvasculature on postmortem examination [31,32]). Hemodynamic support with intra-aortic balloon counterpulsa-tion or even extracorporealmembrane oxygenation (ECMO) should beused as indicated. Finally, accelerated coronary vasculopathy shouldalso be considered in the right clinical context.

Antithymocyte globulin

Standard dosage ATG is administered intravenously at 1.5 mg/kg for 5–7 days. The dose maybe halved or reduced if the patient develops significant leukopenia orthrombocytopenia.

Contraindications Prior adverse reaction or active infection

Main drug interactions Other medications that cause pancytopenia or suppress the immune systemshould be avoided, including IL-2R antagonists [27]. However, it is accept-able to continue standard maintenance oral immunosuppressive therapy.

Main side effects Cytokine release syndrome (which ranges from flu-like symptoms to a sys-temic inflammatory response syndrome), pancytopenia, increased risk ofinfection, and long-term increased risk of malignancy.

Special points Premedication with antipyretic therapy such as acetaminophen, antihist-amines, and corticosteroids may reduce side effects.

Cost/cost-effectiveness The average wholesale price of ATG, 1.5 mg/kg daily for 5 days, is $14,400.

Basiliximab

Standard dosage 20 mg given intravenously within the first hour postoperatively and a seconddose 4 days later.

Table 2. Treatment of rejection

Asymptomatic Reduced EF Heart Failure/ Cardiogenic Shock

Cellular rejectionTreatment is similar for cellular and antibody mediated rejection:• Target higher calcineurin inhibitor levels• Oral steroid bolus + taper • Switch antimetabolite to a proliferation signal inhibitor

• Oral steroid bolus/taperor• IV pulse steroids

Treat regardless of biopsy findings:• IV pulse steroids• Cytolytic therapy (antithymocyte globulin)• Plasmapheresis• IV immune globulin• Inotropic therapy• IABP or ECMO support

Antibody-mediated rejection

• Oral steroid bolus/taperor• IV pulse steroids+/-• IV immune globulin (unique to antibody mediated rejection)

EF ejection fraction; IV intravenous; IABP intra-aortic balloon pump; ECMO extracorporeal membrane oxygenation


Contraindications Active infection

Main drug interactions Other medications that suppress the immune system should be avoided,including ATG [27]. However, it is acceptable to initiate standard triple-drugoral immunosuppressive therapy.

Main side effects Hypersensitivity, increased risk of infection.

Special points Daclizumab, another IL-2R antagonist, is no longer available.

Cost/cost-effectiveness The average wholesale price of 2 doses of basiliximab, 20 mg, is $5,338.

Intravenous immunoglobulin

Standard dosage 1 g/kg given intravenously daily for 2 days to a maximum total dose of144 g.

Contraindications None

Main drug interactions None

Main side effects Volume overload, renal dysfunction related to the osmotic load of the su-crose additive may be reduced with sucrose-free preparations.

Special points May be used in the treatment of antibody-mediated rejection or in the reductionof human leukocyte antigen (HLA) antibodies pretransplantation [33].

Cost/cost-effectiveness The average wholesale price of intravenous immune globulin, 2 g/kg, is $16,562.

Other treatments& Nonpharmacologic treatments may be used for acute rejection or as

chronic therapies to address refractory rejection (Table 1).& Plasmapheresis, also known as therapeutic plasma exchange, is an ex-

tracorporeal blood purification technique for the removal of largemolecular weight substances from the plasma, notably autoantibodiesand immune complexes. While there are no clinical trials of plasma-pheresis in heart transplant recipients, it may be used for acute rejectionassociated with hemodynamic compromise. It also may be used in re-fractory rejection or as part of a desensitization protocol in highlyallosensitized patients awaiting transplant.

& While cellular rejection generally responds to corticosteroids and cytolytictherapy [34], management of antibody-mediated rejection is often morecomplicated. Patients often have a persistent reduction in ejection frac-tion, restrictive physiology leading to recurrent heart failure symptoms,and accelerated progression of transplant coronary artery disease [34].

& The management of patients with a persistent drop in ejection fractionor restrictive physiology after treatment of symptomatic rejection is notwell established. Therapies to reduce the levels of donor-specific anti-HLA antibodies, including rituximab and bortezomib, as well as long-term photopheresis to alter the function of T cells (Table 1) have beentried. Rituximab and bortezomib are discussed in greater detail below.

& Photopheresis is a form of extracorporeal photochemotherapy in which


peripheral lymphocytes are collected via apheresis and treated with

Plasmapheresis

Standard procedure Under the guidance of a hematologist, a large-bore catheter in a central vein(most commonly a dialysis catheter) is used. Plasma exchanges may beperformed daily or every other day for 5 to 7 days. Plasma is replaced mostcommonly by albumin or saline, but fresh frozen plasma (FFP) may be usedin cases of coagulopathy.

Contraindications Inability to place a central vein catheter due to coagulopathy.

Complications Hypotension due to fluid removal, coagulopathy due to depletion of clottingfactors (if FFP is not used), systemic inflammatory response syndrome (if FFP isused), removal of other medications (such as ATG, which should be adminis-tered after plasmapheresis), and complications related to vascular catheters.

Special points Heart transplant rejection is considered a Category III indication (not clearlyindicated) for plasmapheresis by the American Association of Blood Banksand the American Society for Apheresis.

Cost/cost-effectiveness Each plasmapheresis treatment is billed at approximately $3,000 at our center.

Photopheresis

Standard procedure Under the guidance of a hematologist, a large-bore catheter in a central veinis used. Outpatient treatments occur over a 6-month period, most often twiceweekly for the first month and then monthly for 5 months.

Contraindications Inability to place a central venous catheter.

Complications There are no complications except those related to vascular access.

Special points Photopheresis is considered a maintenance therapy for the treatment of re-current rejection and is not used in the treatment of active rejection.

Cost/cost-effectiveness Each photopheresis treatment is billed at approximately $9,000 at our center.

Emerging therapies& The treatment of the sensitized patient is a major challenge in heart

transplantation [5••, 37••]. Sensitized patients are those with pre-formed anti-HLA antibodies, usually from pregnancy, transfusions,ventricular assist devices, or prior transplantation. Donor-specificantibodies can cause hyperacute rejection, increase the risk of rejec-tion post-transplantation [37••], and predispose patients to the de-velopment of cardiac allograft vasculopathy [5••]. Protocols to targetsuch antibodies rely on inactivation (IV Ig [33]), removal (plasma-pheresis), and decreased production (rituximab [33] and bortezomib[38]) of these antibodies (Table 1).

& Rituximab is amonoclonal antibodydirectedagainst theCD20antigenonB-lymphocytes. It is most commonly used for B-cell lymphoma but also


8-methoxypsoralen and ultraviolet light, causing T cell apoptosis. Al-thoughonly a small proportionof the total T cells are affected, the processappears to downregulate the entire population of activated T cell clones.Photopheresis has been used for the primary prevention of rejection [35]and treatment of recurrent rejection in heart transplant recipients [36].

reduces HLA antibodies in patients awaiting kidney transplanta-tion [33].

& Bortezomib is a proteasome inhibitor against plasma cells. It is mostcommonly used for the treatment of multiple myeloma but alsoreduces HLA antibodies in patients awaiting heart transplantation [38].

Rituximab

Standard dosage Rituximab, 1 g intravenously, on day 7 and 22 with IV Ig given 1 g/kg on day1 and 30



Main side effects May cause a systemic inflammatory response during infusion, gastrointesti-nal upset, or infections

Special points The CD20 count may be monitored for treatment effect

Cost/cost-effectiveness The average wholesale price for two doses of rituximab is $14,772.

Bortezomib

Standard dosage 1.3 mg/m2 on days 1, 4, 8, and 11; may repeat cycles every 2 weeks



Main side effects Peripheral neuropathy that usually resolves after the cycle is completed butmay be persistent after multiple cycles, infections, systemic inflammatoryresponse during infusion

Special points To increase effectiveness, the protocol at our center combines bortezomib withplasmapheresis over a 2-week cycle with plasmapheresis on the day before andday of bortezomib administration (days 0, 1, 3, 4, 7, 8, 10, and 11) [38].

Cost/cost-effectiveness The average wholesale price for four doses of bortezomib is $6,892.

DisclosureNo conflicts of interest relevant to this article are reported.

References and Recommended Reading

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. McMurray JJ. Clinical practice. Systolic heart failure.N Engl J Med. 2010;362:228–38.

2.•• Costanzo MR, Costanzo MR, Dipchand A, et al. TheInternational Society of Heart and Lung Transplan-

tation Guidelines for the care of heart transplantrecipients. J Heart Lung Transplant. 2010;29:914–56.

These guidelines are a comprehensive reference and resourceon the management of heart transplant recipients.


3. Stehlik J, Edwards LB, Kucheryavaya AY, et al. TheRegistry of the International Society for Heart andLung Transplantation: twenty-seventh official adultheart transplant report–2010. J Heart Lung Transplant.2010;29:1089–103.

4. Stewart S, Winters GL, Fishbein MC, et al. Revision ofthe 1990 working formulation for the standardiza-tion of nomenclature in the diagnosis of heart re-jection. J Heart Lung Transplant. 2005;24:1710–20.

5.•• Kobashigawa J, Crespo-Leiro MG, Ensminger SM, etal. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J HeartLung Transplant. 2011;30:252–69.

This is a summary of the current state of the art on the di-agnosis and treatment of antibody-mediated rejection basedon the consensus of experts in the field.6. Wu GW, Kobashigawa JA, Fishbein MC, et al.

Asymptomatic antibody-mediated rejection afterheart transplantation predicts poor outcomes. J HeartLung Transplant. 2009;28:417–22.

7. Kfoury AG, Stehlik J, Renlund DG, et al. Impact ofrepetitive episodes of antibody-mediated or cellularrejection on cardiovascular mortality in cardiactransplant recipients: defining rejection patterns. JHeart Lung Transplant. 2006;25:1277–82.

8. Deng MC, Eisen HJ, Mehra MR, et al. Noninvasivediscrimination of rejection in cardiac allograft recipi-ents using gene expression profiling. Am J Transplant.2006;6:150–60.

9.• PhamMX, Teuteberg JJ, Kfoury AG, et al. Gene-expres-sion profiling for rejection surveillance after cardiactransplantation. N Engl J Med. 2010;362:1890–900.

This was the first trial of the use of the AlloMap gene expressionprofile to detect rejection in heart transplant recipients.10. Kowalski R, Post D, Schneider MC, et al. Immune cell

function testing: an adjunct to therapeutic drugmonitoring in transplant patient management. ClinTransplant. 2003;17:77–88.

11. Kowalski RJ, Post DR, Mannon RB, et al. Assessingrelative risks of infection and rejection: a meta-anal-ysis using an immune function assay. Transplanta-tion. 2006;82:663–8.

12.• Kobashigawa JA, Kiyosaki KK, Patel JK, et al. Benefitof immune monitoring in heart transplant patientsusing ATP production in activated lymphocytes. JHeart Lung Transplant. 2011;29:504–8.

This is one of the largest studies to date in heart transplantrecipients examining the utility of the Cylex blood test in thedetection of subsequent infection and rejection.13. Saraiva F, Matos V, Goncalves L, et al. Complications

of endomyocardial biopsy in heart transplantpatients: a retrospective study of 2117 consecutiveprocedures. Transplant Proc. 2011;43:1908–12.

14. Baraldi-Junkins C, Levin HR, Kasper EK, et al.Complications of endomyocardial biopsy in hearttransplant patients. J Heart Lung Transplant.1993;12:63–7.

15. Evans RW, Williams GE, Baron HM, et al. The eco-nomic implications of noninvasive molecular testingfor cardiac allograft rejection. Am J Transplant.2005;5:1553–8.

16. Kobashigawa JA, Miller LW, Russell SD, et al. Tacro-limus with mycophenolate mofetil (MMF) or siroli-mus vs. cyclosporine with MMF in cardiac transplantpatients: 1-year report. Am J Transplant.2006;6:1377–86.

17. Mathew T, Kreis H, Friend P. Two-year incidence ofmalignancy in sirolimus-treated renal transplantrecipients: results from five multicenter studies*. ClinTransplant. 2004;18:446–9.

18. Campistol JM, Eris J, Oberbauer R, et al. Sirolimustherapy after early cyclosporine withdrawal reducesthe risk for cancer in adult renal transplantation.2006. p. 581–589.

19. Salgo R, Gossmann J, Schöfer H, et al. Switch to asirolimus-based immunosuppression in long-termrenal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in aprospective, randomized, assessor-blinded, con-trolled clinical trial. Am J Transplant. 2010;10:1385–93.

20. Jensen P, Hansen S, Moller B, et al. Skin cancer inkidney and heart transplant recipients and differentlong-term immunosuppressive therapy regimens. JAm Acad Dermatol. 1999;40:177–86.

21. Dantal J, Soulillou JP. Immunosuppressive drugs andthe risk of cancer after organ transplantation. N Engl JMed. 2005;352:1371–3.

22. Caforio ALP, Fortina AB, Piaserico S, et al. Skin can-cer in heart transplant recipients : risk factor analysisand relevance of immunosuppressive therapy. 2000.p. III–222–III–227.

23. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus forthe prevention of allograft rejection and vasculop-athy in cardiac-transplant recipients. N Engl J Med.2003;349:847–58.

24. Keogh A, Richardson M, Ruygrok P, et al. Sirolimusin de novo heart transplant recipients reduces acuterejection and prevents coronary artery disease at2 years: a randomized clinical trial. Circulation.2004;110:2694–700.

25. Kobashigawa JA, Patel J, Furukawa H, et al. Five-yearresults of a randomized, single-center study oftacrolimus vs microemulsion cyclosporine in hearttransplant patients. J Heart Lung Transplant.2006;25:434–9.

26. Eisen HJ, Kobashigawa J, Keogh A, et al. Three-yearresults of a randomized, double-blind, controlledtrial of mycophenolate mofetil versus azathioprine incardiac transplant recipients. J Heart Lung Transplant.2005;24:517–25.

27. Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumabto prevent rejection after cardiac transplantation. 2005.p. 2705–2713.


28. Gaber AO, First MR, Tesi RJ, et al. Results of thedouble-blind, randomized, multicenter, phase IIIclinical trial of Thymoglobulin versus Atgam in thetreatment of acute graft rejection episodes after re-nal transplantation. Transplantation. 1998;66:29–37.

29. Kobashigawa JA, Stevenson LW, Moriguchi JD, et al.Is intravenous glucocorticoid therapy better than anoral regimen for asymptomatic cardiac rejection? Arandomized trial. J Am Coll Cardiol. 1993;21:1142–4.

30. Mancini D, Pinney S, Burkhoff D, et al. Use ofrapamycin slows progression of cardiac transplanta-tion vasculopathy. Circulation. 2003;108:48–53.

31. Arbustini E, Roberts WC. Morphological observationsin the epicardial coronary arteries and their surround-ings late after cardiac transplantation (allograft vasculardisease). Am J Cardiol. 1996;78:814–20.

32. Fishbein MC, Kobashigawa J. Biopsy-negative cardiactransplant rejection: etiology, diagnosis, and therapy.Curr Opin Cardiol. 2004;19:166–9.

33. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab andintravenous immune globulin for desensitization

during renal transplantation. N Engl J Med.2008;359:242–51.

34. Patel JK, Kittleson M, Kobashigawa JA. Cardiac allo-graft rejection. Surgeon. 2011;9:160–7.

35. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresisfor the prevention of rejection in cardiac transplan-tation. Photopheresis Transplantation Study Group.N Engl J Med. 1998;339:1744–51.

36. Kirklin JK, Brown RN, Huang ST, et al. Rejection withhemodynamic compromise: objective evidence forefficacy of photopheresis. J Heart Lung Transplant.2006;25:283–8.

38.•• Kobashigawa J, Mehra M, West L, et al. Report from aconsensus conference on the sensitized patientawaiting heart transplantation. J Heart Lung Trans-plant. 2009;28:213–25.

This is a summary of the current state of the-art on thediagnosis and management of sensitized heart transplantcandidates based on the consensus of experts in the field.38. Patel J, Everly M, Chang D, et al. Reduction of

alloantibodies via proteosome inhibition in cardiactransplantation. J Heart Lung Transplant.2011;30:1320–6.


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