current_advances_in_heart_transplantation-enero.pdf

CURRENT ADVANCES IN HEART TRANSPLANTATION

CONTENTS

Editorial: Vascular Rejection in Heart Transplantation: When Ignorance

is NOT Bliss.

Jagat Narula and James B. Young

Preface

Mandeep R. Mehra

Understanding the Sensitized Patient

Ronald H. Kerman

New technologies have resulted in the ability to identify the presence of IgG human

leukocyte antigen (HLA) or non-HLA antibodies in the sera of potential solid organ

transplant recipients. Knowledge of the presence of these antibodies, their antigen

speciﬁcities, and strength (titer) is crucial to understanding a patient’s state of immuno-

logic sensitization and reactivity. Finally, these data, when correlated with sensitive

crossmatch results, allow clinicians to make more knowledgeable clinical decisions when

paring donors and recipients for transplant.

Contemporary Concepts in Noncellular Rejection

Jon A. Kobashigawa

Acute rejection is the major cause of morbidity and mortality in the ﬁrst year after

cardiac transplantation. Cellular rejection is the most common form of rejection ob-

served; however, noncellular rejection is being seen more often. This noncellular rejection

is mostly a result of less well-characterized antibody-mediated mechanisms. Antibody-

mediated rejection is associated more commonly with hemodynamic compromise,

increased graft loss, cardiac allograft vasculopathy, and increased mortality. Histologic,

immunoﬂuorescence, and immunoperoxidase studies of endomyocardial biopsies from

such patients often reveal intravascular macrophages and immunoglobulin and comple-

ment deposition in capillaries, in the absence of lymphoid inﬁltrates. Severely ill patients

require intense therapy, which includes high-dose corticosteroids, cytolytic agents,

intravenous heparin, intravenous gamma globulin, plasmapheresis, and/or antiproli-

ferative agents. Further understanding of noncellular rejection will lead to more effective

therapy.

Tolerance in Heart Transplantation: The Holy Grail, or an Attainable Goal?

Richard N. Pierson III

The father of cardiac transplantation, Norman Shumway, famously predicted that toler-

ance was the future of the ﬁeld, and always would be. Although his prediction remains

VOLUME 3 Æ NUMBER 1 Æ JANUARY 2007

true to date, signiﬁcant progress has been made toward this goal, the ‘‘Holy Grail’’ for

transplant clinicians. Current efforts are fueled by disappointing long-term outcomes

associated with chronic immunosuppression, and the promise that partial or complete

tolerance will impact long-term results favorably. This article provides a clinical deﬁni-

tion of tolerance primarily based on lessons learned from animal heart allograft models.

It reviews several promising strategies for inducing tolerance and detecting its presence

through the use of biomarkers in peripheral blood or the graft, and outlines a possible

path toward making this vision a clinical reality.

Induction Therapy in Cardiac Transplantation: When and Why?

David A. Baran

Induction therapy has continued to be a subject of controversy in heart transplantation

for more than 20 years. It is an example of a therapy that is logical, and ought to be better

than ‘‘doing without.’’ However, a careful review of the evidence suggests otherwise.

Except for patients where the beneﬁts clearly outweigh the short and long-term risks,

the use of induction therapy should be avoided. In immunosuppression, as in life, there

is no ‘‘free lunch.’’ Clinicians need to be certain they fully understand what they are

ordering when asking for induction therapy to be administered to their patients.

Immunosuppression on the Horizon

Howard J. Eisen

Many novel immunosuppressive agents are under active clinical investigation. In addi-

tion, creative approaches are being developed for the use of established immunosup-

pressive agents, with the goal of minimizing immunosuppression as early as possible

posttransplantation. The hope is that these approaches will minimize the toxicity of these

agents without sacriﬁcing efﬁcacy. Evidence suggests that the nephrotoxicity of

calcineurin inhibitors can be reduced using these approaches. The introduction of newer

immunosuppressive agents, including the proliferation signal inhibitors, raises the pos-

sibility that some of the long-term scourges of cardiac transplantation, including cardiac

allograft vasculopathy and malignancy, can be ameliorated. Finally, costimulatory path-

way inhibitors and other new immunosuppressive agents offer hope that all these goals

can be accomplished with very low long-term maintenance immunosuppression.

Echocardiography in the Cardiac Transplant Recipient

Eric M. Thorn and Christopher R. de Filippi

Despite the widespread use of echocardiography in the cardiac allograft recipient, the

clinical usefulness of this practice is not well deﬁned. In this article, the authors review

the spectrum of echocardiographic ﬁndings in the adult heart transplant patient. Appre-

ciation of typical alterations from ‘‘normal’’ allows the transplant physician to identify

clinically signiﬁcant changes and to avoid unnecessary invasive procedures based on

misinterpretation of these differences. Though abnormalities of systolic and diastolic

function correlate with episodes of acute rejection, the primary diagnostic usefulness

of echocardiography in acute rejection is guiding the endomyocardial biopsy. Addion-

ally, echocardiography has found a role as a supplement to invasive angiography in

the diagnosis of cardiac allograft vasculopathy.

Biomarkers After Heart Transplantation: Nongenomic

Thomas J. Dengler, Christian A. Gleissner, Roland Klingenberg, Falk-Udo Sack,

Philipp A. Schnabel, and Hugo A. Katus

Patient monitoring following heart transplantation aims to detect complications (eg, acute

graft rejection, vasculopathy, infection) early and contributes to risk prognostication.

CONTENTS

Numerous biomarkers of different biologic pathways have been evaluated as ancillary

diagnostic and prognostic tools to reduce the need for invasive and expensive technical

investigations. With the possible exception of cardiac troponins and N-type natriuretic

peptides, no biomarkers have become established ﬁrmly in posttransplant patient

surveillance. This article aims to show that the identiﬁcation of a single biomarker that

meets all needs (noninvasive diagnosis of rejection, prediction of transplant vasculopa-

thy, survival prognostication) is unlikely. Rather, multiple marker strategies, including

gene-based tests, are likely to enhance future monitoring quality and enable individual-

ized risk-adapted patient management.

Genomic Biomarkers and Heart Transplantation

Mandeep R. Mehra and Patricia A. Uber

Clinicians have entered into a new paradigm for managing heart transplant patients

with use of multimarker gene expression proﬁling. Early after transplantation, when

corticosteroid modiﬁcation is the main concern, gene expression testing might assist in

optimizing the balance of immunosuppression, defraying the occurrence of rejection,

and avoiding crisis intervention. Late after transplantation, the reliance on endomyocar-

dial biopsy could be lessened. These advances, if continually validated in practice, could

usher in an era of decreased immunosuppression complications, lesser need for invasive

surveillance, and more clinical conﬁdence in immunosuppressive strategies.

Cardiac Allograft Vasculopathy: An Update

Ilke Sipahi and Randall C. Starling

Allograft vasculopathy remains the nemesis of long-term survival in heart transplanta-

tion. Possible modifying risk factors such as obesity, diabetes, and hypertension should

continue to be pursued aggressively. All patients should receive statins. Clinical trials

will provide the evidence needed to ascertain whether mammalian target of rapamycin

inhibitors should be used in de novo cardiac transplant recipients to attenuate cardiac

allograft vasculopathy (CAV). Intravascular ultrasound appears to play a key role in

the diagnosis and evaluation of new treatments, and may indeed represent a surrogate

marker that can be used to tailor management and improve outcomes. A better under-

standing of CAV is needed to develop targeted preventive therapies. Ongoing research

in native atherosclerosis and vascular biology may provide answers within the next

decade.

When is Retransplantation a Viable Option?

Maryl R. Johnson

As the number of recipients of heart transplantation grows over time and they survive

longer, more are at risk for developing severe cardiac allograft vasculopathy and allo-

graft dysfunction, which might lead to consideration for retransplantation. Clearly, out-

comes following cardiac retransplantation are compromised, and with donor shortage,

the selection of candidates must be judicious. Retransplantation appears most appropri-

ate for those patients more than 6 months following original heart transplantation, who

have severe cardiac allograft vasculopathy and associated left ventricular dysfunction, or

allograft dysfunction and progressive symptoms of heart failure in the absence of acute

rejection. Relative contraindications to transplantation (ie, advanced age, comorbidities,

psychosocial issues) require thorough assessment when retransplantation is being

considered.

Index

107

CONTENTS

vii

FORTHCOMING ISSUES

April 2007

The Role of Surgery, Part I

Stephen Westaby, BSc, MS, PhD

and Mario C. Deng, MD, Guest Editors

July 2007

The Role of Surgery, Part II

Stephen Westaby, BSc, MS, PhD

and Mario C. Deng, MD, Guest Editors

October 2007

Diastolic Dysfunction and Heart Failure

Mani Vannan, MBBS, MRCP, MRCPI

and Bertram Pitt, MD, Guest Editors

RECENT ISSUES

October 2006

Valvular Disease

Blase Anthony Carabello, MD, Guest Editor

July 2006

Natriuretic Peptides

Roger M. Mills, MD, W. H. Wilson Tang, MD

and John C. Burnett, MD, Guest Editors

April 2006

Noninvasive Imaging of Heart Failure

Vasken Dilsizian, MD, Mario J. Garcia, MD

and David Bello, MD, Guest Editors

January 2006

Diabetic-Hypertensive PreeHeart Failure

Patient

David S.H. Bell, MB, Guest Editor

THE CLINICS ARE NOW AVAILABLE ONLINE!

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Heart Failure Clin 3 (2007) ix–x

Editorial

Vascular Rejection in Heart Transplantation:

When Ignorance is NOT Bliss...

Jagat Narula, MD, PhD James B. Young, MD

Consulting Editors

The late failure of a cardiac allograft has been

attributed to the development of chronic rejection,

including allograft vasculopathy and ventricular

dysfunction. Chronic rejection shortens the car-

diac allograft life markedly in comparison with re-

nal allograft. It has been tacitly believed that

vasculitis early after transplantation may be the

basis of subsequent vasculopathy. This belief is

based on a uniform, concentric, and centripetal

pattern of involvement of the coronary vascula-

ture. However, we do little to detect vasculitis in

our early management of allograft recipients. On

the other hand, the presence of arteritis in renal al-

lografts raises the level of rejection to maximum

levels, and management is upgraded accordingly.

Unfortunately, small muscular arteries are rarely

observed in endomyocardial biopsy because bi-

opsy specimens are much smaller than those ob-

tained in kidney; also, unlike kidneys, there is no

reliable biochemical indicator of myocardial dam-

age. Left ventricular ejection fraction and

hemodynamics are very crude markers and per-

turbed only late in the rejection process. Based

on the description of vasculitis in renal allograft

biopsies, the presence of immunoglobulin and

complement ﬁxation in capillaries has been used

as a surrogate marker for vasculitis in cardiac al-

lografts. It has been suggested that such indicators

of humoral rejection should upstage the level of

rejection to a severe category. In clinical practice,

we neither search for humoral rejection routinely,

nor do we know that complement ﬁxation is

equivalent to arteritis. Furthermore, we do not

know whether overtreatment based on comple-

ment ﬁxation data will result in better graft sur-

vival. To summarize, we do not know much

about the vascular rejection, we often do not get

to see small muscular arteries in endomyocardial

biopsies, and we do not have other diagnostic tests

that will give us insight into this problem. Is igno-

rance bliss? We think not!

Interestingly, we have used noninvasive and

invasive tools to look for concentric vasculopathy

almost on annual basis, knowing almost certainly

that identiﬁcation of chronic vasculopathy is of

limited value. Whereas coronary angiography can

demonstrate gradually worsening pruning of the

distal vasculature in allograft arteriopathy, myo-

cardial perfusion studies often remain more or less

normal due to balanced ischemia; thus the rub of

studies that rely on ‘‘relative’’ perfusion or wall

motion diﬀerences!

doi:10.1016/j.hfc.2007.03.005

heartfailure.theclinics.com

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