Download Full Text

Journal of the American College of Cardiology
© 2012 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 59, No. 14, 2012
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.11.050
STATE-OF-THE-ART PAPER
Heart Transplantation Research in the Next Decade—
A Goal to Achieving Evidence-Based Outcomes
National Heart, Lung, and Blood Institute Working Group
Monica R. Shah, MD, MHS, MSJ,* Randall C. Starling, MD, MPH,†‡ Lisa Schwartz Longacre, PHD,*
Mandeep R. Mehra, MD,§ on behalf of the Working Group Participants
Bethesda, Maryland; Cleveland, Ohio; and Boston, Massachusetts
The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) on August 5 to 6, 2010
in Bethesda, Maryland to discuss future directions of research in heart transplantation (HT). The WG was composed of researchers with expertise in the basic science, clinical science, and epidemiological aspects of advanced heart failure and HT. These experts were asked to identify the highest priority research gaps in the field
and make recommendations for future research strategies. The WG was also asked to include approaches that
capitalize on current scientific opportunities and focus on areas that required unique NHLBI leadership. Finally,
the WG was charged with developing recommendations that would have short- and long-term impact on the field
of HT. The WG participants reviewed key areas in HT and identified the most urgent knowledge gaps. These gaps
were then organized into the following 4 specific research directions: 1) enhanced phenotypic characterization of
the pre-transplant population; 2) donor-recipient optimization strategies; 3) individualized immunosuppression
therapy; and, 4) investigations of immune and non-immune factors affecting late cardiac allograft outcomes.
Finally, because the HT population is relatively small compared with other patient groups, the WG strongly urged
concerted efforts to enroll every transplant recipient into a clinical study and to increase collaborative networks
to optimize research in this field. (J Am Coll Cardiol 2012;59:1263–9) © 2012 by the American College of
Cardiology Foundation
Advances in immunosuppression, along with consensusdriven clinical care by multidisciplinary teams, have enhanced the early survival of patients undergoing heart
transplantation (HT). Despite improvements in early morbidity and mortality, late outcomes at 5 and 10 years still
remain poor for those HT recipients who have successfully
navigated the initial challenges of rejection and infection
(1). Although further optimization of therapeutic strategies
to prevent early rejection remains an important goal, there is
now a critical and growing need to develop a strong evidencebase that can identify strategies to tailor immunosuppressive
From the *National Heart, Lung, and Blood Institute, Division of Cardiovascular
Sciences, Bethesda, Maryland; †Cleveland Clinic Lerner College of Medicine of the
Case Western Reserve University School of Medicine, Cleveland Clinic, Cleveland,
Ohio; ‡The Cleveland Clinic Foundation, Cleveland, Ohio; and the §Harvard
Medical School and Brigham and Women’s Hospital, Boston, Massachusetts.
Support for the working group was provided by the Division of Cardiovascular
Sciences, NHLBI, NIH. Drs. Starling and Mehra served as Chairs of the Workshop.
Drs. Shah and Schwartz Longacre are employees of NIH. Dr. Starling has received
grant support from NIAID/NIH and Johnson and Johnson Corp., has served as a
consultant to Medtronic, WellPoint, Novartis, Anthem Ins., and Bio Control
Medical Ltd., and owns stock in Cardiomems that is worth ⬍$1,000. Dr. Mehra has
received grant support from NHLBI/NIH and served as a consultant to Medtronic,
St. Judes, Geron, J and J, and GlaxoSmithKline. A full list of the Working Group
Participants is listed in the Appendix at the end of the paper.
Manuscript received October 14, 2011; accepted November 18, 2011.
therapy, limit renal damage, manage coronary allograft vasculopathy, characterize newer forms of rejection, and ultimately,
improve late outcomes in these patients. Recognizing this, the
National Heart, Lung, and Blood Institute (NHLBI) sponsored a workshop entitled, “Cardiac Transplantation Research
in the Next Decade: A Goal to Evidence Based Outcomes” in
August 2010. The goals of the workshop were to identify the
highest-priority research gaps in the field of HT and to elicit
recommendations for future research strategies.
There currently exists limited randomized clinical trial evidence for standard management practices in HT beyond the
first year. Scientific evolution in the field of HT remains
dominated by registry-driven multicenter studies, single center
observational studies, and pharmaceutical industry-sponsored
randomized controlled trials (RCTs) focusing on early outcomes (2– 4). Although registry-based publications have
yielded groundbreaking information that has guided therapeutic directions, each of the landmark databases in cardiac
transplantation have significant limitations, including incomplete data, lack of adjudication, or a lack of comprehensive
patient enrollment beyond early time points (1,5–7). The field
has also been hampered by a lack of research infrastructure,
such as research networks or consortia, to facilitate multicenter
investigations.
1264
Shah et al.
Next Decade of Heart Transplant Research
Despite the low numbers of heart
transplants that occur in the United
States yearly, approximately 2,200,
AMR ⴝ antibody mediated
there are several compelling reasons
rejection
for the NHLBI to provide a naCAV ⴝ cardiac allograft
tional platform for conducting
vasculopathy
clinical studies in this field (1).
CNI ⴝ calcineurin inhibitor
First, compared with other mediHF ⴝ heart failure
cal and device-based therapies,
HT ⴝ heart transplantation
HT is associated with the most
LVAD ⴝ left ventricular
enduring gain in quality of life and
assist device
survival, with a median survival of
NHLBI ⴝ National Heart,
10 years (1). There are twice as
Lung, and Blood Institute
many patients listed for HT anRCT ⴝ randomized
nually as there are donor hearts
controlled trial
available, and despite parallel adWG ⴝ working group
vances in ventricular assist device
therapy, approximately 8% of
these patients die awaiting a suitable allograft (7). In
addition, the candidate pool is evolving and becoming even
more complex with the advent of mechanical circulatory
support, the growing number of adults with congenital heart
disease who have failing hearts with few reparative options,
and the rising population of end-stage heart failure (HF)
patients who require multi-organ transplantation (8). Additionally, more than 20% of patients who undergo HT do
not survive beyond 3 years. Of those that do survive beyond
3 years, a population of approximately 20,000 to 40,000
patients, the majority are afflicted with the long-term
complications associated with immunosuppression, such as
metabolic syndrome, chronic kidney disease, coronary allograft vasculopathy, and malignancy (1). This underscores a
need to address both morbidity as well as survival issues in
this large prevalent population of patients. Because HT
patients are meticulously followed, this population is
uniquely poised for enrollment in clinical trials.
The charge to the workshop participants was to focus on
those specific areas in HT that required unique NHLBI
leadership and to develop recommendations that were
visionary, practical, and that would have both short- and
long-term impact on the field. The working group (WG)
identified 4 broad challenges in HT and strongly encouraged incorporating basic science investigations into all
clinical studies. Because the HT population is relatively
small, the WG recommended concerted efforts to develop a
research infrastructure that facilitates enrollment of de-novo
and existing HT recipients into clinical trials to optimize
research within the field. Although the National Institute of
Allergy and Infectious Diseases has successfully supported
HT research as part of 2 consortiums addressing transplantation research in all organs, entitled Clinical Trials in
Organ Transplantation and Clinical Trials in Organ Transplantation in Children, there is a need for a complementary
but more specialized HT network that could potentially
facilitate multiple trials and studies focused on cardiac
issues. The 4 broad key challenges and corresponding recomAbbreviations
and Acronyms
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
mendations identified by the WG are listed in Table 1 and
discussed in the following text.
Challenge #1: Optimize and
Individualize Immunosuppression
Therapies and Improve Late Allograft Outcomes
Mediated by Immune and Non-Immune Factors
Greater efforts should be focused on developing optimal
practices that individualize immunosuppression therapies
and manage the long-term effects of these drugs. In addition, research strategies need to address the non-immune
complications of immunosuppression, such as diabetes mellitus, hypertension, obesity, the metabolic syndrome,
chronic kidney disease, and malignancies.
Recommendations. A key research priority should be to
develop clinical trials that evaluate how calcineurin inhibitor
(CNI) sparing and elimination approaches, coupled with
intensive strategies aimed at modifying non-immune risk
markers, affect late outcomes. Pharmacogenomic, systems
biology, and other basic science investigations into the
responses of the individual to immunosuppression should be
incorporated into these trials. Fundamental research aimed
at elucidating potential biomarkers that might help diagnose
and predict acute and chronic rejection could play a critical
role in advancing the clinical care of HT patients.
Discussion. Late outcomes in the HT population remain
poor with a median cardiac allograft survival of 11 years, a
statistic that has not improved in over a decade (1). The
major causes of late morbidity and mortality are chronic
kidney disease, cardiac allograft vasculopathy (CAV), and
malignancy (1).
Immediately after transplant, immunosuppression therapy typically consists of a CNI, cyclosporine or tacrolimus,
a purine synthesis inhibitor such as mycophenolate mofetil,
and corticosteroids (5). The dosing of these drugs, which
have a narrow therapeutic index, is typically based on the
weight and renal function of a patient (5). Although other
factors might play a significant role in the dosing and
selection of immunosuppressive drugs, individual characteristics such age, sex, race, and antibody status are not
currently taken into account routinely (5). In addition,
during follow-up, there are no algorithms that incorporate
individual characteristics into a standard assessment for
tailoring immunosuppression. Because the primary focus in
these patients is preventing rejection, many recipients receive higher doses of these drugs than might be needed.
This higher exposure might contribute to complications of
obesity, chronic kidney disease, hypertension, and hyperglycemia. Strategies aimed at individualizing immunosuppression should minimize adverse events, preserve immunologic
outcomes, and have a beneficial impact on late outcomes.
To address this broad challenge, the WG recommended
pursuing trials that addressed 2 specific issues— evaluating
an early CNI sparing approach and investigating the impact
of intensive risk marker modification on early and late
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
outcomes, including major adverse cardiac allograft events,
solid cancers, renal failure, and graft and patient survival.
Because of the synergy of immune and non-immune variables on morbidity and mortality, the WG urged the
consideration of factorial trial designs that would be able to
address both questions concurrently. The WG also stressed
the importance of planning trials with adequate sample sizes
to ensure the study power necessary to evaluate hard endpoints
such as survival. The WG suggested pursuing adaptive clinical
trial strategies and other study design approaches to maximize
the yield of information. This would be best accomplished by
the development of a cooperative trial network or consortia to
optimize participation.
Potential ideas for trials that were discussed included
testing a CNI-free regimen or early weaning of this class of
drugs. The WG believed that trials evaluating lipid lowering
and blood pressure and glucose control would be relatively
straightforward to implement yet would have the potential
for significant impact on long-term cardiovascular outcomes. Emerging data suggest that targeting the reninangiotensin-aldosterone system after HT has a beneficial
impact on non-immune risk factors and particularly on the
development of CAV (9 –11). Possible investigations might
include identifying optimal therapeutic targets for lipid
lowering and blood pressure control, which have not yet
been defined in the HT population. Basic science studies
should be included in these clinical trials to understand
mechanisms of action and develop novel therapeutic targets.
The WG urged pursuing basic studies to investigate how to
prevent early injury and inflammation, induce tolerance,
target the innate immune system, and refine anti-proliferative
therapy.
The WG advised that histological and serological biospecimen collection and banking should be an integral part
of all NHLBI sponsored studies, either with well-formulated
prospective hypotheses or to facilitate retrospective ancillary
studies. To address the critical question about how to
personalize and provide a metric for optimal immunosuppression, the WG urged using high throughput pharmacogenomic technologies and a systems biology approach of
assessing individual responses to these therapies. Again, the
WG urged that focused basic science studies be included in
these approaches to better elucidate mechanisms of cardiac
allograft injury, repair, and fibrosis at a vascular and allograft
level.
Challenge #2: Expansion and Optimization of
the Donor and Recipient Candidate Population
The demand for donor hearts far outstrips the supply, and
novel approaches are needed to expand and optimize both
the donor and recipient population (7). This issue could be
addressed by comparing long-term mechanical support with
HT in specific populations and investigating methods to
standardize how donors are reviewed and used. Currently,
the definition for a “marginal donor” varies considerably
Shah et al.
Next Decade of Heart Transplant Research
1265
among institutions, and there is conspicuous reluctance to
use hearts from donors older than 60 years of age. Research
that informs the questions underlying this reluctance might
provide convincing data that ultimately leads to the expansion of the donor pool.
Recommendations. The WG recommended a randomized trial comparing the transplantation of hearts from older
donors with the implantation of left ventricular assist
devices (LVADs) as destination therapy in recipients ⬎70
years of age, in whom there is clinical equipoise about the
optimal therapy. Basic science investigations addressing
fundamental questions about senescence in aged donor
organs and recipient immune systems should be conducted
in parallel with studies in these populations. Further research to enhance donor use by exploring novel strategies to
limit development of ischemia-reperfusion injury should
also be pursued.
Discussion. The WG acknowledged the heterogeneity in
the evaluation of prospective donors and in the definition of
the “marginal” donor organ across centers and organ procurement organizations. Because the criteria used by the
United Network of Organ Sharing criteria and third-party
payers to assess the quality of transplant programs are based
largely on 1- and 3-year outcomes, most institutions exercise caution in using donor hearts that might be less than
perfect, citing an inability to assume such risk without
supporting evidence (12). However, single center studies
from large-volume centers that use donors rejected by many
centers as marginal have demonstrated satisfactory early and
intermediate outcomes (13–15). Examples of such cases
include marginal donors transplanted into older recipients
or into recipients with ongoing comorbidities such as
diabetes mellitus and peripheral vascular disease, which
would have otherwise precluded the use of donors from the
standard list.
The WG suggested that one strategy to expand the donor
pool might be to investigate the use of marginal donors in
elderly recipients, a population in whom there is clinical
equipoise about the optimal therapy for end-stage HF.
Currently, the major factors that are taken into account
when matching donors to recipients are blood type, height,
and weight (5), but there are no standard guidelines for the
weighting of other relevant factors in decision-making,
resulting in considerable inconsistencies in the types of
donor hearts that are accepted at different institutions. For
example, in some institutions, donor hearts with slightly
depressed ejection fractions or mild left ventricular hypertrophy might be deemed adequate, whereas in other programs such donor hearts would be discarded. Without clear
evidence about the outcomes associated with different donor
characteristics informing the donor selection process, it is
probable that many potentially useful organs are currently
being discarded (16,17). Because an important rate limiting
factor in HT is the number of available donor organs,
studies that define how to optimize donor use and develop
biomarkers to define organ utility might increase the donor
1266
Shah et al.
Next Decade of Heart Transplant Research
pool by providing evidence that would support the use of
those organs deemed to be less than perfect.
The WG also encouraged research to optimize donor
organ use by limiting the ischemia-reperfusion injury that
commonly occurs in donor hearts. Strategies that prevent
prolonged ischemia time or render hearts resistant to injury,
such as hypothermia or the use of agents that mimic
preconditioning or target the mitochondrial permeability
transition pore or other mediators of this innate protective
mechanism, might achieve tissue preservation and maintain
viability for transplantation (18,19).
Challenge #3: Characterize
and Address the Comorbidities
Encountered in the Pre-Transplant Population
The lack of standard clinical approaches creates considerable
variability in treatment assignments in different institutions
and even among cardiologists within the same institution.
The WG participants agreed that continuing advances in
mechanical circulatory support have had a profound impact
on the field of HT and have significantly changed the
candidate population (20 –22). The patients currently evaluated with advanced HF differ markedly from those seen 10
years ago, but medical therapy and triage decisions are based
only on data derived from earlier populations that did not
receive the benefits of early institution of current HF
therapies to delay disease progression. The WG participants
recognized that there is a critical need for evidence-based
management strategies for many aspects of the clinical
management of the pre-transplant population. However,
they felt it was imperative to address three major clinical
issues—the cardio-renal syndrome, the progression of secondary pulmonary hypertension, and right ventricular failure—and called for RCTs evaluating these specific problems. The WG recommended developing robust clinical
tools to characterize the pre-transplant population and
optimize the timing and selection of candidates for HT
directly, for mechanical circulatory support as a bridge to
transplantation, and for mechanical circulatory support as an
alternative to transplantation for patients with substantial
comorbidity burden or other risks for good post-transplant
survival.
Recommendations. Clinical trials evaluating management
strategies for renal insufficiency, secondary pulmonary hypertension, and right ventricular failure in the pre-transplant
population should be emphasized. Researchers should develop
a database that would capture the evolving phenotypes of the
advanced HF population, define the most current pretransplant risk factors, and allow investigators to identify the
most optimal candidates from the limited donor pool.
Discussion. The WG recognized that there were myriad
approaches to handling pulmonary hypertension and the
cardio-renal syndrome in the pre-transplant population
(23–28). To address the optimal management strategy for
pulmonary hypertension, the WG urged pursuing a trial
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
evaluating the impact of a strategy of early LVAD implantation versus chronic inotropic therapy as a primary bridge
to transplantation in patients with end stage HF and
elevated pulmonary artery pressures due to chronic left HF
and pulmonary venous hypertension.
Similarly, the WG group urged pursuing a randomized
trial to evaluate best practices for the cardio-renal syndrome.
The cardio-renal syndrome, a poorly understood process, is
associated with adverse post-transplantation outcomes and
is often exacerbated by the inherent nephrotoxicity of
immunosuppressive drugs (1,5). The WG recommended a
randomized trial to assess outcomes of combined heartkidney transplantation versus other renal-sparing strategies
in candidates with diminished renal function.
The WG strongly advised that basic science investigations and bio-specimen repositories should be embedded
within any randomized trial evaluating these 2 major clinical
challenges. In particular, they felt that it was important to
emphasize the role of renal histology in understanding the
cardio-renal syndrome.
The WG also recognized that increasing the number of
HT that occurs annually depends not only on an enhanced
understanding of the donors but also on a greater knowledge
of the current phenotypes of recipients. At present, there are
no ongoing, complete, adjudicated databases that define the
pre-transplant population adequately to provide a clear
window into the most current clinical issues that afflict this
population. The WG recommended developing a funded
database with a bio-specimen bank that would better define
pre-transplant risk factors—including clinical features, biomarkers, and genes—that would allow clinicians and investigators to track the changes in this population as it evolves
and progresses with the advent of novel therapies. The WG
suggested creating a national database, with all transplant
centers enrolling patients listed each year for HT.
Challenge #4: Characterize and
Understand Antibody Mediated Rejection
In the past, the major immunological challenge to survival
in the early post-transplant period was cellular rejection.
However, there is growing recognition that antibody mediated rejection (AMR) might account for significant early
and late morbidity and mortality (29,30). Much progress
needs to be made to better understand AMR at a histological, serological, and clinical level. In addition, there are few
evidence-based strategies for the prevention and amelioration of AMR.
Even though the WG identified AMR as a major research
gap, they also emphasized that AMR and cellular rejection are
different aspects of the process of rejection. The group concurred that the overall course of rejection is mediated by both
cellular and soluble antibody factors, acting in concert over
time, with changing roles in the lifetime of a graft, and with
varying contributions in different patients.
Shah et al.
Next Decade of Heart Transplant Research
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
Recommendation. The WG urged the development of a
large-scale robust analytical database with a bio-bank to
characterize the pathophysiology and natural history of
AMR. In addition, therapeutic interventions for prevention
and treatment of manifest AMR require study in RCTs.
Discussion. Antibody mediated rejection is now increasingly recognized in the HT population, typically occurs
early, in the setting of sensitization to the allograft, and is
associated with hemodynamic compromise and late development of CAV. Recent evidence suggests that even
asymptomatic AMR is associated with a higher risk of CAV
and worse cardiovascular mortality (31,32). The augmented
immunosuppression required during treatment of AMR is
more aggressive and complex than that for cellular rejection
and is associated with a higher incidence of infection and
predisposition to malignancy.
To gain a better understanding of this unique form of
rejection, the WG recommended creating an observational longitudinal database, which would include a
bio-specimen bank and phenotype information. A biorepository that would collect, catalog, and store tissue,
serum, and DNA would be a critically important feature.
Such a database would help investigators characterize the
pathophysiology of AMR, create standardized definitions
of this entity, identify individual risk factors, identify
biomarkers, and ascertain the impact of this form of
rejection on long-term outcomes (33). Importantly, researchers should develop a standardized approach to the
histological definition of AMR and optimal surveillance
strategies for early detection of this entity. In addition,
randomized trials need to be conducted to evaluate the
efficacy of various strategies that attempt to prevent this
form of rejection (34).
1267
Clinical Trials in HT
Conducting clinical trials in HT presents unique challenges,
of which perhaps the most daunting is addressing the small
population of HT patients, the majority of whom are taking
multiple concurrent medications and have many comorbidities. Thus, patient recruitment is a critical rate limiting step.
Some potential solutions might be to form national and
international networks of committed investigators and proactively identify strategies for recruitment and retention as
well as strategies for coordination of sites across North
America and globally. In addition, a crucial step would be to
conduct pilot studies to evaluate the best methods for
screening and recruitment.
To ensure the quality of future clinical trials in HT,
investigators should also proactively address essential issues
of trial conduct such as blinding, crossovers, drop-outs,
surrogate endpoints, and adaptive monitoring designs. Importantly, investigators must address how these elements
must be uniquely modified or interpreted in the context of
the HT population. In addition, investigators should design
rigorous endpoint definitions, efficient data collection
forms, and streamlined and comprehensible informed consent forms that reflect the challenges distinct to HT. To
ensure the highest quality clinical trials, investigators should
also plan to invest time and funding into organizing
standardized oversight committees, such as Data Safety and
Monitoring Boards, Protocol Review Committees, Executive Committees, Clinical Events Committees, and Publications Committees. Finally, a critical step to ensure that the
highest quality fundamental and translational science investigations take place within future HT clinical trials will be to
proactively plan basic and mechanistic studies at the beginning
of the trials and ensure that efforts are made to secure funding
High-Priority
Knowledge Gaps
in Heart
Transplantation
and Potentialand
Research
Approaches
Table 1 High-Priority
Knowledge
Gaps
in Heart Transplantation
Potential
Research Approaches
Gap in Knowledge
Individualizing Immunosuppression
● Improving Late Outcomes
●
Clinical Approach
Fundamental Science Approach
●
RCT of Calcineurin Inhibitor Sparing or Elimination
Approaches in Immunosuppression
● RCT of Intensive Risk Marker Modification
●
Pharmacogenomics, Systems Biology, and Other
Basic Science Approaches to Elucidate:
ΠHow to Individualize Immunosuppression
ΠMechanisms of Cardiac Allograft Injury, Repair and
Fibrosis
● Understand the Role of Biomarkers in Predicting and
Diagnosing Rejection
●
Expand and Optimize Donor and Recipient
Candidate Populations
●
RCT of Destination LVAD vs. Older Donors in Elderly
Recipients
● Novel Strategies to Limit Ischemia-Reperfusion Injury
●
●
Characterizing and Addressing
Comorbidities Encountered in the PreTransplant Population
●
RCT of LVAD vs. Inotropes for Treatment of Pulmonary
Hypertension Associated with End-Stage HF
● RCT of Combined Heart-Kidney Transplant vs. Other
Renal Sparing Strategies
● Database to Capture Evolving Phenotypes of
Advanced HF Population
●
●
Characterize and Understand AMR
●
Large-Scale Longitudinal Database with a Biobank
Repository
● Therapeutic RCT Based on Emerging Fundamental
Science
●
AMR ⫽ antibody mediated rejection; HF ⫽ heart failure; LVAD ⫽ left ventricular assist device; RCT ⫽ randomized controlled trial.
Fundamental Investigations of Senescence and the
Immune System
● Develop Strategies to Prevent the Deleterious Effects
of Ischemia and Reperfusion injury
Understanding the Role of Renal Pathology and the
Cardio-Renal Syndrome
● Focusing on Renal Pathology as a Predictor of
Outcomes
Identify Biomarkers to Diagnose and Predict Onset of
AMR
● Define Pathological Correlates of Therapeutic Targets
and Outcomes
1268
Shah et al.
Next Decade of Heart Transplant Research
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
Selected
Mechanisms
Table 2 Grant
Selected
Grant Mechanisms
Funding Mechanism
Title
Description
P01
Program Project Grants
Supports collaborative research efforts to accelerate the acquisition of knowledge more effectively
than a simple aggregate of research projects that have no interaction or thematic integration
R01
Regular Research Project Grant
Supports a discrete project related to the investigator’s area of interest and competence
R34
Clinical Trial Pilot Studies
Supports pilot studies to obtain data critical to the successful design of a full-scale clinical trial.
for dedicated core laboratories that focus on specific areas, such
as biological markers, DNA banks, and imaging.
Pursuing significant scientific questions is essential to
moving the field of HT forward. However, the WG noted,
an equally important factor to advancing knowledge in this
field will be how well those questions are answered through
rigorous trial design and conduct.
The Role of the NHLBI in Facilitating HT Research
There is a critical need for studies in HT that evaluate
prevention and treatment strategies rather than evaluating
the efficacy of single drugs or interventions. In addition,
research in HT needs to expand from focusing on early
outcomes to also addressing late morbidity and mortality.
National Heart, Lung, and Blood Institute and other federal
agency support of such efforts might be particularly important, because industry sources are unlikely to independently
fund research in these areas. The WG believed the best way
to address many of the current scientific gaps was through
RCTs, with complementary basic science and mechanistic
investigations embedded in the studies. In addition, the
WG encouraged the NHLBI scientific staff to educate the
HT research community about the opportunities and mechanisms for research support that are already available
through the Institute.
Investigators in HT have a critical responsibility to apply
for grants and generate interest and enthusiasm in the
academic medical community for research and enrolling
patients. When developing new research proposals, the
NHLBI encourages investigators to capitalize on novel
scientific opportunities, public-private partnerships, and
attainable short-term goals. There are a number of mechanisms at the NHLBI available to HT investigators interested in pursuing research support (Table 2). The standard
R01 mechanism can provide up to $499,999 per year in
direct costs for smaller projects in basic or clinical science. In
addition, mechanisms exist for investigator-initiated projects exceeding $500,000/year. These mechanisms include
grants for large, multi-center clinical trials (R01 or U01) and
program project grants (P01). A complete description of
how to apply for these large grants can be found at the
NHLBI website (35).
Individuals interested in submitting an application covered by these guidelines are strongly encouraged to begin
informal discussions with NHLBI scientific staff as early as
possible in the process of planning their research proposal.
Proposals with budgets exceeding $1.51 million/year require
investigators to make a presentation to NHLBI staff and
submit a letter requesting permission to submit a large application.
Funding opportunities for clinical trial pilot studies (R34)
are also available at the NHLBI. The purpose of the R34
planning grants is to provide funding for preliminary
studies to obtain data critical to the successful design of
a full-scale clinical trial. An R34 can provide key early
data that might help applicants develop a robust and
competitive investigator-initiated clinical trial (36).
Summary
It is imperative that researchers address the critical scientific
gaps in HT by developing high-quality RCTs and concurrent basic science studies that investigate the fundamental
processes of immunology, pharmacogenomics, inflammation, and repair. Moving the field of HT forward will
depend on an improved understanding of individualized
immunosuppression, a greater knowledge of how to select
and manage donors and recipients, and a strong focus on
improving long-term outcomes by increasing the 10-year
cardiac allograft disease-free survival. Through dedicated
efforts by the research community and the support of the
NHLBI, the goal to develop evidence-based outcomes in
HT over the next decade can evolve from concept to reality.
Reprint requests and correspondence: Dr. Monica R. Shah,
Heart Failure and Arrhythmias Branch, Division of Cardiovascular Sciences, NHLBI, Two Rockledge Center, 6701 Rockledge
Drive, MSC 7956, Bethesda, Maryland 20892-7956. E-mail:
[email protected].
REFERENCES
1. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the
International Society for Heart and Lung Transplantation: twentyseventh official adult heart transplant report—2010. J Heart Lung
Transplant 2010;29:1089 –103.
2. George JF, Taylor DO, Blume ED, et al. Minimizing infection and
rejection death: clues acquired from 19 years of multi-institutional
cardiac transplantation data. J Heart Lung Transplant 2011;30:151–7.
3. Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC,
Ramee SR. Presence of severe intimal thickening by intravascular
ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant 1995;14:632–9.
4. Eisen HJ, Tuzcu EM, Dorent R, et al., for the RAD B253 Group.
Everolimus for the prevention of allograft rejection and vasculopathy
in cardiac-transplant recipients. N Engl J Med 2003;349:847–58.
5. Constanzo MR. The International Society for Heart and Lung
Transplantation Guidelines for the Care of Heart Transplant Recipients. J Heart Lung Transplant 2010;29:914 –156.
Shah et al.
Next Decade of Heart Transplant Research
JACC Vol. 59, No. 14, 2012
April 3, 2012:1263–9
6. Nativi JN, Brown RN, and the Cardiac Transplant Research Database
Group. Temporal trends in heart transplantation from high-risk
donors: are there lessons to be learned? A multi-institutional analysis.
J Heart Lung Transplant 2010;29:847–52.
7. 2009 OPTN/SRTR Annual Report: Transplant Data 1999 –2008.
U.S. Organ Procurement and Transplantation Network and the
Scientific Registry of Transplant Recipients. Available at: http://optn.
transplant.hrsa.gov. Accessed February 16, 2012.
8. Hunt SA, Haddad F. The changing face of cardiac transplantation.
J Am Coll Cardiol 2008;52:587–98.
9. Mehra MR, Ventura HO, Smart FW, Collins TJ, Ramee SR,
Stapleton DD. An intravascular ultrasound study of the influence of
angiotensin-converting enzyme inhibitors and calcium entry blockers
on the development of cardiac allograft vasculopathy. Am J Cardiol
1995;75:853– 4.
10. Bae JH, Rihal CS, Edwards BS, et al. Association of angiotensinconverting enzyme inhibitors and serum lipids with plaque regression
in cardiac allograft vasculopathy. Transplantation 2006;82:1108 –11.
11. Erinc K, Yamani MH, Starling RC, et al. The effect of combined
angiotensin-converting enzyme inhibition and calcium antagonism on
allograft coronary vasculopathy validated by intravascular ultrasound.
J Heart Lung Transplant 2005;24:1033– 8.
12. UNOS Bylaw Appendix B: Criteria for Institutional Memberships—
Transplant Hospitals—2010. Available at: http://www.unos.org/docs/
Appendix_B_II.pdf. Accessed February 16, 2012.
13. Forni A, Luciani GB, Chiominto B, Pilati M, Mazzucco A, Faggian
G. Impact of donor quality on outcome of heart transplantation. Eur
J Cardiothorac Surg 2010;38:788 –94.
14. Lietz K, John R, Mancini DM, Edwards NM. Outcomes in cardiac
transplant recipients using allografts from older donors versus mortality on the transplant waiting list; implications for donor selection
criteria. J Am Coll Cardiol 2004;43:1553– 61.
15. Laks H, Marelli D, Fonarow GC, et al. Use of two recipient lists for
adults requiring heart transplantation. J Thorac Cardiovasc Surg
2003;125:49 –59.
16. Chen JM, Sinha P, Rajasinghe HA, et al. Do donor characteristics
really matter? Short-and long-term impact of donor characteristics on
recipient survival, 1995-99. J Heart Lung Transplant 2002;21:608 –10.
17. Young JB, Naftel DC, Bourge RC, et al. Matching the heart donor
and heart transplant recipient. Clues for successful expansion of the
donor pool: a multivariable, multi-institutional report. J Heart Lung
Transplant 1994;3:353–365.
18. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia:
a delay of lethal cell injury in ischemic myocardium. Circulation
1986;74:1124 –36.
19. Peart JN, Headrick JP. Sustained cardioprotection: exploring unconventional modalities. Vascul Pharmacol 2008;49:63–70.
20. Patlolla V, Patten RD, DeNofrio D, Konstam MA, Krishnamani R.
The effect of ventricular assist devices on post-transplant mortality: an
analysis of the United Network for Organ Sharing Thoracic Registry.
J Am Coll Cardiol 2009;53:264 –271.
21. Aaronson KD, Eppinger MJ, Dyke DB, Wright S, Pagani FD. Left
ventricular assist device therapy improves utilization of donor hearts:
evaluation studies. J Am Coll Cardiol 2002;39:1247–54.
22. Nativi JN, Drakos SG, Kucheryavaya AY, et al. Changing outcomes in
patients bridged to heart transplantation with continuous- versus
pulsatile-flow ventricular assist devices: an analysis of the registry of
the International Society for Heart and Lung Transplantation. J Heart
Lung Transplant 2011;30:854 – 61.
23. Ahmed MS, Wong CF, Pai P. Cardiorenal syndrome—a new classification and current evidence on its management. Clin Nephrol
2010;74:245–57.
24. Birks EJ, Yacoub MH, Anyanwu A, Smith RR, Banner NR,
Khaghani A. Transplantation using hearts from primary pulmonary
hypertensive donors for recipients with a high pulmonary vascular
resistance. J Heart Lung Transplant 2004;23:1339 – 44.
25. Pascual JM, Fiorelli AI, Bellotti GM, Stolf NA, Jatene AD. Prostacyclin in the management of pulmonary hypertension after heart
transplantation. J Heart Transplant 1990;9:644 –51.
1269
26. Chen EP, Bittner HB, Davis RD, Van Trigt P. Hemodynamic and
inotropic effects of milrinone after heart transplantation in the setting
of recipient pulmonary hypertension. J Heart Lung Transplant 1998;
17:669 –78.
27. Nair PK, Kormos RL, Teuteberg JJ, et al. Pulsatile left ventricular
assist device support as a bridge to decision in patients with end-stage
heart failure complicated by pulmonary hypertension. J Heart Lung
Transplant 2010;29:201– 8.
28. Zimpfer D, Zrunek P, Sandner S, et al. Post transplant survival after
lowering pulmonary hypertension using left ventricular assist devices.
J Cardiothoracic Surg 2007;83:1697–706.
29. Kfoury AG, Hammond EH. Controversies in defining cardiac
antibody-mediated rejection: need for updated criteria. J Heart Lung
Transplant 2010;29:389 –94.
30. Moseley EL, Atkinson C, Sharples LD, Wallwork J, Goddard MJ.
Deposition of C4d and C3d in cardiac transplants: a factor in the
development of coronary artery vasculopathy. J Heart Lung Transplant
2010;29:417–23.
31. Wu GW, Kobashigawa JA, Fishbein MC, et al. Asymptomatic
antibody-mediated rejection after heart transplantation predicts poor
outcomes. J Heart Lung Transplant 2009;28:417–22.
32. Kfoury AG, Hammond ME, Snow GL, et al. Cardiovascular mortality among heart transplant recipients with asymptomatic antibodymediated or stable mixed cellular and antibody-mediated rejection.
J Heart Lung Transplant 2009;28:781– 4.
33. Kobashigawa J, Cresp-Leiro MG, Ensminger SM, et al., Consensus
Conference Participants. Report from a consensus conference on
antibody-mediated rejection in heart transplantation. J Heart Lung
Transplant 2011;30:252– 69.
34. Nair N, Ball T, Uber PA, Mehra MR. Current and future challenges
in therapy for antibody-mediated rejection. J Heart Lung Transplant
2011;30:612–7.
35. NHLBI Website. Available at: http://www.nhlbi.nih.gov/funding/
policies/500kweb.htm. Accessed February 16, 2012.
36. NHLBI Clinical Trial Pilot Studies (R34)—Program Announcement
Number: PAR-10-005. Available at: http://grants.nih.gov/grants/
guide/pa-files/PAR-10-005.html. Accessed February 16, 2012.
Key Words: heart transplantation y NHLBI y research y working
group.
APPENDIX
Working Group Participants
Mark Barr, MD, University of Southern California and Children’s Hospital,
Los Angeles; Howard Eisen, MD, Drexel University College of Medicine;
Gary Francis, MD, University of Minnesota; John Fung, MD, PhD, Cleveland
Clinic; Kathleen Grady, PhD, APN, Northwestern University; Valluvan
Jeevanandam, MD, University of Chicago Medical Center; Maryl Johnson,
MD, University of Wisconsin; Abdallah Kfoury, MD, Utah Cardiac Transplant
Program at Intermountain Medical Center; James Kirklin, MD, University of
Alabama at Birmingham; Jon Kobashigawa, MD, Cedars-Sinai Heart Institute; Robert Kormos, MD, University of Pittsburgh Medical Center; Joren
Madsen, MD, DPhil, Massachusetts General Hospital; Donna Mancini, MD,
Columbia University Medical Center; Bruce McManus, MD, PhD, University
of British Columbia; Christopher O’Connor, MD, Duke University Medical
Center; Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital; Richard
Pierson, III, MD, University of Maryland; Elaine Reed, PhD, University of
California, Los Angeles; Daniel Salomon, MD, The Scripps Research
Institute; Charles Steenbergen, MD, PhD, The Johns Hopkins Hospital;
Lynne Stevenson, MD, Brigham and Women’s Hospital; LaRee Tracy, PhD,
Food and Drug Administration; Liewei Wang, MD, PhD, The Mayo Clinic.
National Institutes of Health Staff Participants
Michael Flessner, MD, National Institute of Diabetes and Digestive and Kidney
Diseases; Jonah Odim, MD, PhD, National Institute of Allergy and Infectious
Diseases; Lynn Rundhaugen, MPH, National Heart, Lung, and Blood Institute.