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J A C C : H E A R T F A I L U R E V O L . 5 , N O . 1 2 , 2 0 1 7
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Evolving Areas in Heart Transplantation
Brittany N. Weber, MD,a Jon A. Kobashigawa, MD,b Michael M. Givertz, MDaABSTRACT
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It has been 50 years since Dr. Christiaan Barnard performed the first human-to-human heart transplant in December
1967 in South Africa. Remarkable progress has been made since that time, including changes in surgical techniques,
immunosuppression, donor and recipient selection, and post-transplant care. In this paper, we provide a perspective on
the changing face of heart transplantation and highlight key evolving areas. Topics that are covered include advances in
immunosuppression, screening for acute and chronic rejection, cardiac allograft vasculopathy, and ongoing advancements in
cardiac replacement therapy, including xenotransplantation, stem-cell research, tissue engineering, and the total artificial
heart. (J Am Coll Cardiol HF 2017;5:869–78) © 2017 by the American College of Cardiology Foundation.
T his month marks the 50th anniversary sincethe first human-to-human heart transplantwas performed by Dr. Christiaan Barnard in
South Africa in December 1967. Although a ground-breaking moment in history for cardiovascular medi-cine, this did not come as a surprise to the medicaland research community, as the groundwork hadbeen laid since the early 1900s. In celebration of thisanniversary, we offer the second part of a 2-partseries that discusses advances in immunosuppressionand evolving areas of complementary and alternativetherapies in the future of cardiac transplantation(Central Illustration).
NOVEL IMMUNOSUPPRESSION
In transplant biology, immunosuppression isprimarily targeted against the adaptive immunesystem, which involves both T and B cells. Manynovel potential therapeutic targets exist (Table 1),but have not been prospectively studied in thecardiac transplant population. Belatacept is a fusionprotein composed of the Fc fragment of a humanimmunoglobulin (Ig) G1 linked to the extracellulardomain of CTLA-4, which blocks T-cell costimula-tion. It has been studied in a randomized controlledtrial (RCT) in renal transplant recipients in 2different doses compared with cyclosporine (CSA).At 12 months, survival was similar between thegroups. The belatacept groups had higher glomerular
m the aCardiovascular Division, Brigham and Women’s Hospital, Harva
edars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, Calif
d/or research support from Novartis, CareDx, Alexion, and TransMedics. D
relationships relevant to the contents of this paper to disclose.
nuscript received August 24, 2017; revised manuscript received October 3
filtration rates, but more episodes of rejection, post-transplant lymphoproliferative disorder, and tuber-culosis infection. Belatacept is currently approvedfor calcineurin inhibitor (CNI)-free regimens in therenal population (1).
The Janus kinase–signal transducer and activatorof transcription signaling pathway is important forimmune activation. Tofacitinib is the first inhibitorof Janus kinase that is currently approved for treat-ment of rheumatoid arthritis. It has been comparedwith tacrolimus in the renal transplant populationand found to be equally effective (2). Compared withCSA, tofacitinib was associated with improved renalfunction, but also with a higher risk of infection andpost-transplant lymphoproliferative disorder (3).Sotrastaurin is an agent that blocks early T-cellactivation through inhibition of protein kinase C. Ithas been studied in both preclinical (rat) cardiactransplant models and renal transplant patients andwas found to prolong graft survival. However, higherrates of rejection in a CNI-free regimen wereobserved (4).
Tocilizumab (Actemra, Genentech, South SanFrancisco, California) is a humanized monoclonalantibody against the interleukin-6 receptor that iscurrently approved for refractory inflammatory dis-eases. In preclinical animalmodels, it reduces allograftrejection, expands T-regulatory cell population, andreduces memory B-cell response. In highly-sensitizedrenal transplant recipients, tocilizumab reduces
rd Medical School, Boston, Massachusetts; and the
ornia. Dr. Kobashigawa has received research grants
rs. Weber and Givertz have reported that they have
, 2017, accepted October 10, 2017.
ABBR EV I A T I ON S
AND ACRONYMS
ACR = acute cellular rejection
AMR = antibody-mediated
rejection
CMR = cardiac magnetic
resonance
CNI = calcineurin inhibitor
CSA = cyclosporine
EMB = endomyocardial biopsy
IgG = immunoglobulin G
LGE = late gadolinium
enhancement
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alloantibody levels (5). Eculizumab, a hu-manized immunoglobulin G2/4 monoclonalantibody that inhibits complement by bindingto complement component C5, could also bebeneficial in antibody-mediated rejection(AMR). It reduced the incidence and severityof AMR in renal and lung transplant recipients(6,7); however, eculizumab has not beenstudied in heart transplantation, and cost willlikely be a barrier to widespread use.
Last, an enzyme from streptococcus pyo-genes, IdeS, is a unique agent that cleaveshuman IgG antibodies. In highly-sensitizedrenal transplant patients, it has been
shown to be effective in reducing alloantibody levels(8), with 2 further ongoing phase 2 clinical trials(NCT02790437 and NCT02426684). These agents allhave the potential to be utilized in cardiac transplantrecipients, and the field awaits studies in this popu-lation and potential future application.
SCREENING FOR ACUTE AND
CHRONIC REJECTION
Early detection of cardiac allograft rejection iscrucial for post-transplant care. Despite progress inimmunosuppression, acute cellular rejection (ACR)and AMR remain serious complications during andafter the first post-transplant year. Patients withearly treated rejection are at higher risk of latemorbidity and mortality (9). The current gold stan-dard for diagnosis is endomyocardial biopsy (EMB),although this is not ideal due to invasive risk, sam-pling error, and inter-reader variability. Despitedecades of basic and clinical research, biomarkersand imaging have been limited in their ability todiagnose and monitor treatment of rejection.Therefore, there is currently an unmet need tocreate an objective diagnostic test for cardiac allo-graft rejection.
NONINVASIVE IMAGING. Transthoracic echocardi-ography is a useful tool to monitor hemodynamically-significant rejection given wide availability and lowcost. Disadvantages include operator dependence andinter-reader variability. Many studies have examinedsystolic and diastolic predictive indexes of ACR (10).Although no single parameter can reliably diagnoserejection, if 1 or more parameters is abnormal, theprobability of ACR is higher. Three-dimensionalechocardiography can provide more accurate andreproducible measures of ventricular size and func-tion, but is not widely available. Global longitudinalstrain has been shown to be a predictor of subclinicalrejection (11). Studies of tissue Doppler parameters,
such as peak systolic and diastolic wall motion ve-locity, have yielded mixed results in predicting ACR.
Quantitative contrast myocardial perfusion echo-cardiography is a technique that can provide bothstructural and functional parameters and assess themicrovasculature. In a murine model of heart trans-plantation, contrast-enhanced echocardiographydemonstrated a decline in microvascular perfusion inmice that developed acute or chronic rejection(Figure 1). Notably, myocardial perfusion was restoredfollowing immunosuppressive therapy (12). A proof-of-concept study is currently underway to assess theefficacy of contrast-enhanced ultrasonography indetecting heart transplant rejection in humans(NCT02300870).
Nuclear imaging techniques have been studiedas a means for noninvasive screening of acute rejec-tion. 18FFluorodeoxyglucose positron emission to-mography imaging has been demonstrated to detectallograft rejection in a murine transplant model (13).Challenges in human transplantation include therequired protocol to suppress normal myocyteglucose consumption by a high-fat carbohydrate diet,and confounding diagnoses such as infectionand malignancy. Many other agents that targetcellular-specific components have been examinedin preclinical models, including 111indium-labeledantibody to myosin, 99mtechnetium-labeled annexin-V, and 111indium labeled oligonucleotides thatrecognize interleukin-2—all markers that are overex-pressed in acute rejection (14,15). None of theseagents, however, has been evaluated in large-scalehuman studies, and thus, the clinical translation isnot yet known.
Cardiac magnetic resonance (CMR) imaging is apromising screening modality for detection of rejec-tion. CMR lacks ionizing radiation and can survey theentire myocardium, decreasing the possibility offalse negatives due to sampling error as observed inEMB. T2-weighted imaging has been most widelyused, as T2 values prolong with higher water content,which increases in edema and inflammation (16). In astudy evaluating the diagnostic accuracy of CMRversus EMB for acute rejection, CMR had a highsensitivity (93%) and high negative predictivevalue (98%), highlighting that CMR could be utilizedas a screening test before routine EMB (17). Thepresence of late gadolinium enhancement (LGE) hasalso been investigated in small cohorts (18), but therole in transplant screening is not clear in theabsence of prospective data with larger samplesizes from multiple centers. Investigational contrastagents are also being developed to improve thesensitivity for detection of inflammation. Ultrasmall
CENTRAL ILLUSTRATION Evolving Areas of Heart Transplantation
Weber, B.N. et al. J Am Coll Cardiol HF. 2017;5(12):869–78.
This central illustration demonstrates 3 broad areas discussed in this review: novel immunosuppressive agents to treat allograft rejection,
new modalities in imaging and genomic medicine to screen for rejection, and future potential ways to increase the “donor” pool.
J A C C : H E A R T F A I L U R E V O L . 5 , N O . 1 2 , 2 0 1 7 Weber et al.D E C E M B E R 2 0 1 7 : 8 6 9 – 7 8 Evolving Areas in Heart Transplantation
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superparamagnetic iron oxide (USPIO) particles canbe injected intravenously, and following ingestionby macrophages, detected on T2-weighted CMR.This promising technique has been studied in ratmodels, but thus far, no human translational studiesexist (19).
A novel test that measures markers of oxidativestress has also been developed to assist in detection ofcardiac allograft rejection. Allograft rejection results in
increased production of myocardial reactive oxygenspecies, which are then degraded by lipid peroxidationand secreted as volatile organic compounds. TheHeartsbreath test (Menssana Research, Newark, NewJersey) analyzes the methylated alkane contour inexpired air that has been identified as a marker of sig-nificant (grade 3R) rejection (20). A prospectivemulticenter clinical trial is currently underway tovalidate these findings (NCT01397812).
TABLE 1 Novel Therapeutic Targets for Immunosuppression
Target Agent(s) Efficacy Risks/Barriers
Blockade of T-cell costimulationvia CTLA-4
Belatacept Similar survival compared to CSA in renal transplant patientsLess renal toxicity
Higher rates of rejection, PTLD, and TB infection
JAK-STAT inhibition Tofacitinib Effective in renal transplant patients compared with TAC and CSALess renal toxicity
Higher rates of infection and PTLD
Inhibition of protein kinase C Sotrastaurin Prolonged graft survival in pre-clinical cardiac studies andrenal transplant recipients
Higher rates of rejection compared to CNI regimenDose-dependent gastrointestinal toxicity
Inhibition of complement bybinding to C5
Eculizumab Reduction in AMR in renal and lung transplant patients Substantial cost
IL-6 receptor antagonist Tocilizumab Reduced allograft rejection and expansion of regulatoryT cells in animal models
Reduced alloantibody levels in renal transplant patients
No clinical studies in cardiac transplant recipients
Cleavage of human IgG antibodies IdeS Reduced alloantibody levels in sensitized renaltransplant patients
No clinical studies in cardiac transplant recipients
AMR ¼ antibody-mediated rejection; CNI ¼ calcineurin inhibitor; CSA ¼ cyclosporine; IgG ¼ immunoglobulin G; JAK-STAT ¼ Janus kinase–signal transducer and activator of transcription; IL ¼ interleukin;PTLD ¼ post-transplant lymphoproliferative disorder; TAC ¼ tacrolimus; TB ¼ tuberculosis.
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GENOMIC MEDICINE AND IMMUNE ASSAYS. A newfrontier in cardiac transplant screening is the promiseof genomic medicine. Approaches currently underinvestigation include donor-derived cell-free deoxy-ribonucleic acid (DNA), microRNA, and gene expres-sion profiling. The AlloMap (CareDx, Brisbane,California) is a gene expression profile of peripheral
FIGURE 1 Use of MP Mapping to Detect Acute Cardiac Allograft Rej
Parametric perfusion maps of syngeneic and allogeneic cardiac allograft
groups compared with syngeneic groups over time. On day 8 post-trans
allogeneic hearts. Red and yellow represent higher echo-intensity chang
from John Wiley & Sons, Inc.
blood that has been incorporated into the Interna-tional Society of Heart and Lung Transplantation(ISHLT) guidelines (21). The test screens for a 20-genepanel with 11 rejection-related genes and 9 genes fornormalization and quality control. The result is re-ported as a single score on a scale of 0 to 40, whichindicates the probability of moderate or severe ACR
ection
s show a progressive decline in tissue perfusion in the allogeneic
plant, microvascular perfusion (MP) was markedly reduced in
e and higher MP. Reprinted from Fischer et al. (12) with permission
TABLE 2 Current Scorecard on Xenotransplantation
Advantages Disadvantages
Unlimited organ supply Size mismatch
Elective availability Ethical restrictions on primate use
Expansion of candidate pool Ecological restrictions on species use
Avoid effects of brain death oncardiac function
Hyperacute, acute, and chronic vascularrejection
Potential for genetic manipulation Coagulation dysfunction
Cost saving Transmission of zoonoses
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based on findings from the CARGO (Cardiac AllograftRejection Gene Expression Observational) study. The11 genes were identified based on the highest andmost statistically significant expression differences(22). The landmark IMAGE (Invasive MonitoringAttenuation through Gene Expression) trial randomlyassigned 602 low-risk patients to either AlloMap orEMB for routine rejection surveillance. Rates of allo-graft dysfunction, death, or retransplant were similarbetween groups, and patient satisfaction was higherin the AlloMap group due to less biopsies (23). How-ever, AlloMap is only predictive for ACR and notAMR, and has not proven effective for early screeningor in patients who are at higher risk for late rejection.
Graft-derived cell-free deoxyribonucleic acid(GcfDNA) has emerged as another possible biomarker.After transplantation and organ engraftment, GcfDNAwill reach its highest value up to >5% of total cfDNA,with a rapid decrease to <0.5% within 1 week. Duringan episode of rejection, GcfDNA are shed into the bloodand can be accompanied by a 5-fold increase that canbe measured by current assays. The release of GcfDNAoccurs earlier than other clinical markers of rejectionand could potentially be used to monitor transplantpatients at regular intervals to allow early diagnosisand treatment (24). Because GcfDNA and AlloMapmeasure different signals in the blood, a combinationof the 2 approaches could be additive, as AlloMap is ameasure of host immune response and GcfDNA moni-tors graft injury. Pilot studies are underway to comparethese 2 approaches to rejection monitoring.CARDIAC ALLOGRAFT VASCULOPATHY. Cardiacallograft vasculopathy (CAV), also known as chronicrejection, remains the leading cause of late mortalityfollowing heart transplantation resulting in 1 of 8deaths beyond 1 year (9). A complex interplayof immune-mediated inflammation and endothelialinjury and dysfunction ultimately leads to intimalhyperplasia andmicrovascular/epicardial disease (25).
Routine surveillance is critical for diagnosis ofCAV, as many patients are asymptomatic. Invasivecoronary angiography remains the standard of careand is a Class I screening recommendation; however,there is robust interest in newer noninvasive imagingtechniques for diagnosis and management. ISHLTgrading by coronary angiography is categorized into 3stages defined by severity of left main, primary, andbranch vessel stenoses and presence or absence ofallograft dysfunction (LVEF <45%) and restrictivephysiology (26). Noninvasive imaging has also beenutilized, but has not replaced invasive angiographydue to lower diagnostic accuracy. Currently availabletests (followed by ISHLT recommendation) includedobutamine stress echocardiography (Class IIa),
single-photon emission computed tomography (CT)(Class IIa), and coronary CT angiography (Class IIb).A normal dobutamine stress echocardiography hasa moderate negative predictive value (80% to 100%)for subsequent cardiac events (27). Similarly, single-photon emission CT imaging has moderate diag-nostic accuracy (sensitivity 63% to 84%, specificity70% to 78%) to detect minor to severe stenoses thatmay be secondary to a limited ability to detectbalanced ischemia, which often underlies CAV pa-thology (28). More recently, myocardial flow reserveassessed by 82rubidium positron emission tomogra-phy imaging has been shown to predict clinical out-comes post-heart transplant, although multicenterdata with long-term follow-up is lacking (29).
Dobutamine is the most frequently used pharma-cological stressor, with a sensitivity of 70% to 80% todetect significant CAV compared with coronary angi-ography. Exercise is less predictive due to chronotropicincompetence fromcardiac denervation,with a limitedsensitivity of 15% to 33%. Last, Doppler echocardiog-raphy can be used to calculate coronary flow reserve(CFR), which correlates with invasively-measuredcoronary flow reserve and has been shown to havehigh sensitivity and specificity for detecting CAV (11).
FUTURE PROSPECTS AND
ACTIVE AREAS OF RESEARCH
XENOTRANSPLANTATION. Xenotransplantation re-fers to the process of grafting or transplanting organsor tissues between members of different species.With increasing numbers of patients with end-stageheart failure and shortage of donors, there has beena renewed interest in the possibility of cardiac xeno-transplantation (Table 2) (30). Advantages include anunlimited supply and elective availability of donororgans, expansion of the candidate pool, and avoid-ance of detrimental effects of brain death on donororgan function. Although monkeys and baboons aremost phylogenetically like humans, given theecological and ethical restrictions, the pig is the onlyanimal available to replace human tissues. The pig is
FIGURE 2 Cardiopoietic Cell Therapy for Advanced Ischemic Heart Failure
(A) The primary efficacy outcome in CHART-1 (see text). The Mann-Whitney estimator, or
probability that the treatment group had a better outcome on the composite primary
endpoint, was 0.54 (95% confidence interval [CI]: 0.47 to 0.61; p ¼ 0.27). The
corresponding Mann-Whitney odds was 1.17 (95% CI: 0.89 to 1.55). (B) The primary
efficacy outcome in the subgroup of patients with left ventricular end-diastolic volume
(LVEDV) 200 to 370ml. The Mann-Whitney estimator, or probability that the treatment
group had a better outcome on the composite primary endpoint, was 0.61 (95% CI: 0.52
to 0.70; p ¼ 0.015). Corresponding Mann-Whitney odds was 1.57 (95% CI: 1.09 to 2.35).
Reprinted from Bartunek et al. (39) with permission from Oxford University Press on
behalf of the European Society of Cardiology.
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physiologically similar to humans and organ size iscomparable; it can be raised in controlled environ-ments and, more importantly, genetically modified.Main limitations to xenotransplantation are rejection,including hyperacute, acute, and chronic vascular,and risk of transmitting zoonoses. The developmentof genetically-modified pigs has allowed for theexpression of human antigens that can reduce the riskof rejection and provides hope to future feasibility.
Hyperacute rejection is a result of antibodiesagainst anti-aGal composed of polyclonal glycopro-teins that are naturally present in humans andrepresent 1% of circulating IgG. Porcine endothelialcells express Gal-a1, 3-Gal, which results in activationof the complement cascade and coagulation system.In turn, endothelial edema, interstitial hemorrhage,vascular deposit of immunoglobulins, and microvas-cular thrombosis occur within minutes to hours.Various techniques to counteract this response,including antibody removal through plasmapheresisor inhibition of complement cascade, have beendescribed. Although hyperacute rejection can beavoided, acute humoral rejection still occurs. Bothbarriers have been addressed with genetically engi-neered pigs. Pigs have been created with deletion ofthe enzyme (a1,3-galactosyltransferase) that pro-duces Gal (GTKO) and are transgenic for 1 or morehuman complement regulatory proteins (CRPs) (31).These proteins, including CD46, CD55, and CD59 (30),prevent the development of an acute humoral
response, whereas deletion of Gal blocks the hyper-acute response. Despite success with this approach,the T-cell mediated response also needs to be tar-geted to prevent graft failure. Strategiesinclude conventional immunosuppression and“costimulation” blockade. Genetic engineering with amutant major histocompatibility complex II or bytransgenic expression of an immunosuppressanttarget into transgenic pigs has demonstrated somesuccess (32).
However, even if the hyperacute, acute humoral,and T-cell responses are successfully blocked, graftsurvival remains limited to weeks or months sec-ondary to coagulation dysfunction, with featuressimilar to thrombotic microangiopathy. A similartheme of utilizing the power of genetic engineeringhas focused on the introduction of human anticoag-ulant and antithrombotic agents into GTKO/CRP pigs.Encouraging early results have been published in 2baboons with transplantation of GTKO/CD46/throm-bomodulin pig heart grafts with no features of graftvasculopathy after 1 to 2 years (33).
Studies discussed above are inOldWorld nonhumanprimates. Nonhuman primates express the oligosac-charide N-glycolylneuraminic acid (NeuGc) thatresults in antipig antibodies in humans. Before trans-lation to humans, pigs will need to be developed thatlack NeuGc. Fortunately, these studies are currentlyunderway (30,34).
STEM CELL THERAPY AND TISSUE ENGINEERING. Cellular-based therapy and tissue engineering are promisingapproaches to reversal of advanced heart failure.Landmark scientific work has demonstrated thatresident cardiomyocytes have the ability for self-renewal; annual cardiomyocyte turnover rate is w1%in young adults and decreases to 0.5% in the elderly(35). Promoting this endogenous repair process hasthe potential to enhance regenerative capacity andmodify or reverse adverse LV remodeling. Regenera-tive cell-based therapies ultimately aim to restorenormal myocardial function through both directcell-mediated and indirect paracrine-mediated repairmechanisms.
Initial enthusiasm, however, has been dampenedby inconsistent and modest benefits in clinical trials.These studies, which have been performed in acutemyocardial infarction, ischemic and dilated cardio-myopathy, and advanced heart failure, have beenextensively summarized (36). Differences in trialdesign, source of cardiac stem cell or progenitor cells,cell number and technique, and small sample sizesare some of the factors that have led to discrepantresults. However, recent meta-analyses, which now
FIGURE 3 Functional Maturation of EHM
(A) Force-frequency response of engineered human
myocardium (EHM) (at 4 weeks in culture) generated by the
starting protocol (red) that included a variety of undefined
matrix (Matrigel) and serum (horse serum, fetal calf serum,
chick embryo extract) components (n ¼ 8), and the serum-
free protocol (black) containing 4% B27 without insulin plus
transferring growth factor-b1, insulin growth factor-1,
fibroblast growth factor-2, and vascular endothelial growth
factor (n ¼ 21). *p < 0.05 by 2-way repeated measures
analysis of variance (ANOVA) followed by Sidak multiple
comparison test; §p < 0.05 vs. 1 Hz of the respective group
by 2-way ANOVA with the Tukey multiple comparison post
hoc test. (B) Representative force traces recorded from
EHM (at 4 weeks in culture) at 1.5-Hz stimulation with an
intermittent stimulation pause (10 s); enhanced force of
contraction (FOC) at the reintroduction of electric
stimulation (i.e., post-rest potentiation) is characteristic
for cardiomyocytes with mature intracellular calcium
storage and release (dotted line indicates pre-pause
baseline maximal FOC). Reprinted from Tiburcy et al. (43),
with permission from Wolters Kluwer Health, Inc.
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include a larger number of better-designed studies,have hinted at an overall benefit. Fisher et al. (37)analyzed 31 RCTs, including a total of 1,521 patients,that used a range of cell types, including bonemarrow-derived mononuclear cells and mesenchymalstem cells, skeletal myoblasts, and adipose tissue-derived cells. In addition to safety, a reduction inmortality and rehospitalization during long-termfollow-up was observed along with modest improve-ments in ejection fraction and heart failure symp-toms. However, only one-half of the trials wereblinded, and one-half failed to report the method ofallocation concealment. When analyzed separately,double-blind studies showed no significant differ-ences, raising concern for bias skewing overallresults.
The isolation of refined cell types continues toevolve. Initial trials utilized “first-generation” cell-based therapies, which predominantly consisted ofunselected progenitor cells, mesenchymal stem cells,and endothelial progenitor cells from bone marrow.Although these populations have the potential todifferentiate into cell types within the myocardium,homing and differentiation are not guaranteed. Inresponse, the field has moved to “second- or next-generation” therapies. These include isolation andexpansion of cardiac resident stem cells or thecreation of cardiopoietic stem cells through lineage-specific differentiation of bone marrow–derivedprogenitors, commonly referred to as cardiopoiesis.Cardiopoietic stem cell therapies have demonstratedpromise in proof-of-concept studies, including theC-CURE (Cardiopoietic Stem Cell Therapy in HeartFailure) trial (38). However, a large pivotal trial,CHART-1 (Congestive Heart Failure CardiopoieticRegenerative Therapy), failed to confirm theseresults.
In the CHART-1 trial, 271 patients with ischemiccardiomyopathy were randomized to endocardialdelivery of cardiopoietic cells or sham procedure at 30centers. At 39 weeks, there was no significant differ-ence between groups in the primary hierarchicalcomposite endpoint of all-cause mortality, worseningheart failure, quality-of-life score, 6-min walk dis-tance, LV end-systolic volume, and ejection fraction(39). A subgroup analysis, however, did suggest abeneficial effect in patients with severe LV dilation(Figure 2) (40). Similar promising results were seen inthe ixCELL-DCM (Ixmyelocel-T Administered ViaTransendocardial Catheter-based Injections to Sub-jects With Heart Failure Due to Ischemic DilatedCardiomyopathy) study using a proprietary technique(Vericel, Cambridge, Massachusetts) that selectivelyexpands 2 types of bone marrow mononuclear cells
(CD90þ mesenchymal stem cells and CD45þ CD14þ
autofluorescentþ activated macrophages). In thisdouble-blind RCT, 109 patients with advancedischemic cardiomyopathy were randomized to
FIGURE 4 Total Cardiac Replacement for Irreversible Biventricular Heart Failure
(A) Carmat total artificial heart (TAH). Advantages include a blood-contacting side of membrane comprised of pericardial bovine tissue,
bioprosthetic valves, and sensors to measure flow and pressure; disadvantages include its complex design, risk of valve or chamber failure,
several moving parts, bulky size, and high risk of thromboembolism. (B) BiVACOR TAH. Advantages include magnetic bearings, compact size
with single rotational component, high-flow capabilities, controller to balance left and right blood flows, and low thrombus risk; disad-
vantages include the complex control system to maintain centered location of rotating impeller. Adapted from Fox et al. (46) with
permission from John Wiley & Sons, Inc.
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receive cell therapy or placebo via transendocardialdelivery. At 12 months, there was a 37% reduction inthe primary endpoint of death, cardiovascular hos-pitalization, or clinic visits for worsening heart failurein the cell therapy group (p ¼ 0.034), and there weremore serious adverse events in the placebo group(p ¼ 0.02) (41).
Cardiac tissue engineering is another novelapproach to regenerative therapy that uses engi-neered human myocardium (EHM) (42). The seminalfindings that human embryonic stem cells andhuman-induced pluripotent stem cells can bedirected into organ-specific cell types, along withavailability and scalability, have led to their use asbona fide cardiomyocytes in tissue engineering. Thechallenge of EHM is to create functional car-diomyocytes with the electromechanical properties ofhuman myocardium. In a recent study, cellular andchemical components for EHM generation wereoptimized, resulting in advanced cardiomyocytematuration (43). Also, for the first time, a positiveforce frequency and other evidence of functionalmaturation were demonstrated (Figure 3). In-vestigators also transferred EHM into nude rats usingan epicardial approach leading to revascularization ofthe grafts. However, electromechanical coupling tonormal myocardium was not clearly seen. Although
not yet ready for clinical trials, EHM is a promisingapproach to cardiac repair that may soon be feasible.
The future success of regenerative medicine willdepend on scientists and clinicians working togetherto achieve validity and utility with the long-term goalof widespread use. Quality control manufacturingand delivery of products in a uniform way are criticalto this effort. In addition, patient-specific factors thatcan affect regenerative fitness, such as age, sex, andcomorbidities, must be accounted for. Not every in-dividual harbors stem cells with uniform regenerativecapacity, and tools are needed to predict the likeli-hood of effectiveness at the patient level.TOTAL ARTIFICIAL HEART. The development of atotal artificial heart (TAH) to replace the failing hearthas been a focus of global research for decades. Thefirst successful use of a TAH was by Dr. Denton Cooleyin 1969 in a patient bridged to heart transplant.Although the patient died within 36 h of transplantsurgery, proof of concept was demonstrated. Sincethen, multiple devices have been developed withlimited success. The only device currently approvedby the U.S. Food and Drug Administration is the70cc SynCardia Temporary Total Artificial Heart(TAH-t) (SynCardia Systems, Tucson, Arizona). TheTAH-t is currently indicated as a bridge to transplantin patients with irreversible biventricular failure,
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refractory hemodynamic instability, or ventriculararrhythmias, and a contraindication to left ventricu-lar assist device. Despite the marked increase in leftventricular assist device use, demand for the TAHremains low. According to the Interagency Registryfor Mechanically Assisted Circulatory Support, therewere 22 TAH implants in 2007, and this increased toonly 54 in 2014 (44). The TAH-t consists of 2pneumatically-operated chambers that provide totalsystemic and pulmonary flow. A large pneumaticdriver supplies pulses of compressed air to the leftand right chambers, with unidirectional flow (up to 10l/min) achieved with 4 titling valves. Patients requireanticoagulation and are at risk of thrombotic orhemorrhagic stroke. Infections are common due totube exit sites as portals of entry. Despite the devel-opment of a portable driver, published experiencewith discharge to home is limited to only 11 patientswith 88 readmissions (81% unplanned) after a medianfollow-up of 349 days (45).
In 2013, the U.S. Food and Drug Administrationapproved 2 humanitarian use device designations fora smaller 50cc TAH-t to be used for destination ther-apy and pediatric bridge-to-transplant. Thus far, 28devices have been implanted and there is currently anongoing 3-arm clinical trial to investigate safety andbenefit to both pediatric and adult transplant-eligiblepatients (NCT02459054). Patients with congenitalheart disease and advanced heart failure may beespecially appropriate for this smaller device. Otherdevices currently under development for total cardiacreplacement include the Carmat TAH (Carmat, Vilizy-Villacoublay, France) (Figure 4A), a continuous-flow
TAH being developed at the Cleveland Clinic with aunique design that is part bovine and part machine;and the BiVACOR device (BiVACOR, Houston, Texas)(Figure 4B), which uses a third-generation magneticsuspension technology (46).
CONCLUSIONS
It has been 50 years since Dr. Christiaan Barnardperformed the first human-to-human heart transplantin South Africa. Advances in immunosuppression,donor and recipient selection, surgical techniques,and post-transplant care have resulted in excellentmedium- and long-term outcomes for the majority ofpatients with end-stage heart failure currently un-dergoing transplant. However, significant barriersremain, including early and late risks of organ rejec-tion and vasculopathy along with continuous risk ofinfection and malignancy. Although the donor pool iscautiously being expanded, it is unlikely to ever fillthe needs of a continuously growing and sick patientpopulation. The future depends on further progressin stem cell research, tissue engineering, and xeno-transplantation, while optimizing post-transplanthealth through improved immunosuppression andprevention of acute and chronic rejection. Thereversal of heart failure to avoid the need for organreplacement is also paramount.
ADDRESS FOR CORRESPONDENCE: Dr. Michael M.Givertz, Cardiovascular Division, Brigham andWomen’s Hospital, 75 Francis Street, Boston,Massachusetts02115. E-mail:[email protected].
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KEY WORDS cardiac allograftvasculopathy, heart transplantation,immunosuppression, stem cells, tissueengineering, transplant rejection