Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3981_Библиотеки_им_академика_М_И_Перельмана.pdf
Cardiac Surgery: Answers
189
Booth J, Clayton T, Pepper J, et al., SoS Investigators. Randomized, controlled trial of
coronary artery bypass surgery versus percutaneous coronary intervention in patients with
multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial
(SoS). Circulation. 2008;118:381-388.
Daemen J, Boersma E, Flather M, et al. Long-term safety and efficacy of percutaneous
coronary intervention with stenting and coronary artery bypass surgery for multivessel
coronary artery disease: a meta-analysis with 5-year patient-level data from the ARTS,
ERACI-II, MASS-II, and SoS trials. Circulation. 2008;118:1146-54.
2.43 Answer: E
Coronary artery bypass grafting (CABG) has been an established treatment for ischaemic
heart disease for more than 3 decades. Using the internal thoracic artery graft has clearly
improved early and long-term results, and other arterial conduits have shown good early and
midterm results. However, because atherosclerosis is progressive, CABG is not curative, and
many patients will eventually become candidates for coronary reoperation.
Hospital mortality after reoperative CABG is higher than after primary CABG. There are
two reasons for this. First, reoperations are technically more demanding. Sternal reentry,
pericardial adhesions, in situ arterial grafts, and patent but diseased saphenous vein bypass
grafts all increase the complexity and risk of coronary reoperations. Second, patients
undergoing reoperation have a higher preoperative risk profile. They are older and more
likely to have vascular disease, left ventricular dysfunction, and extensive coronary artery
disease.
References
Sabik JF 3
rd
, Blackstone EH, Houghtaling PL, et al. Is reoperation still a risk factor in
coronary artery bypass surgery? Ann Thorac Surg. 2005;80:1719-27.
Davierwala PM, Maganti M, Yau TM. Decreasing significance of left ventricular dysfunction
and reoperative surgery in predicting coronary artery bypass grafting-associated
mortality: a twelve-year study. J Thorac Cardiovasc Surg. 2003;126:1335-44.
Yamamuro M, Lytle BW, Sapp SK, et al. Risk factors and outcomes after coronary
reoperation in 739 elderly patients. Ann Thorac Surg. 2000;69:464-74.
2.44 Answer: E
Risk of hospital death for both reoperative and primary coronary artery bypass grafting
(CABG) has decreased with increasing surgical experience. Although risk of reoperative
CABG has been consistently greater than that of primary CABG, the difference has narrowed
considerably, and risk of reoperative CABG now approaches that of primary CABG.
Increased surgical experience has neutralized the risk of reoperation attributable to greater
technical difficulty, and the increased risk of reoperative CABG now appears to be related to
the higher-risk profile of reoperative CABG patients.
Hospital mortality after reoperative CABG is higher than after primary CABG.
The
higher risk is attributable to (1) increased technical difficulty
of reoperative CABG and (2) the
higher-risk profile of reoperative
CABG patients. Reoperative CABG less than 1 year after
previous operation is
associated with significantly increased hospital mortality.
Shapira and
colleagues reported 10% mortality in patients
undergoing first-time reoperative coronary
surgery less than
1 year after primary surgery, versus only 2.6% in those undergoing
Shahzad G. Raja
190
reoperation at a later time (p < 0.05). Similar findings
were reported by Christenson and
colleagues. Early coronary
reoperations are due to failure to completely revascularize
or to
failure of revascularization. Both of these, as well as
dense mediastinal adhesions encountered
soon after the last
operation, would be expected to increase hospital risk of the
subsequent
operation.
References
Sabik JF 3
rd
, Blackstone EH, Houghtaling PL, et al. Is reoperation still a risk factor in
coronary artery bypass surgery? Ann Thorac Surg. 2005;80:1719-27.
van Eck FM, Noyez L, Verheugt FW, Brouwer RM. Preoperative prediction of early
mortality in redo coronary artery surgery. Eur J Cardiothorac Surg. 2002;21:1031-1036.
Shapira I, Isakov A, Heller I, et al. Long-term follow-up after coronary artery bypass grafting
reoperation. Chest. 1999;115:1593-1597.
Christenson JT, Simonet F, Schmuziger M. The impact of a short interval (< or = 1 year)
between primary and reoperative coronary artery bypass grafting procedures. Cardiovasc
Surg. 1996;4:801-807.
2.45 Answer: C
Early after an acute myocardial infarction (AMI), between 17%
and 55% of patients
develop a mitral systolic murmur or echocardiographic evidence
of ischaemic mitral
regurgitation (IMR). Of patients who have cardiac catheterization
within 6 hours of the onset
of symptoms of AMI, 18% have IMR.
In 3.4% of these patients, the degree of mitral
insufficiency
is severe. Many of the murmurs early after AMI are transient
and disappear by
the time of discharge.
In one study, 19% of 11,748 patients who had elective cardiac
catheterization for
symptomatic coronary artery disease (CAD)
had ventriculographic evidence of mitral
regurgitation (MR).
In most of these patients, the degree of mitral insufficiency
was mild, but
in 7.2% of patients the degree of regurgitation was
2+ or greater, and in 3.4% MR was severe
with evidence of heart failure.
In another study of consecutive cardiac catheterizations, 10.9%
of 1739 patients with CAD had MR.
Carpentier‘s classification for MR provides an insightful way
to approach the specific
mechanisms of IMR. It is
a functional classification and categorizes the improper leaflet
coaptation of MR into three types based on leaflet and chordal
motion. In type I, the leaflet
motion is normal, and MR is a
result of mitral annular dilatation. Type II is MR as a result
of
leaflet prolapse or excessive motion. In type III, there
is leaflet restriction, or tethering, and
this type is subclassified
further into IIIa (i.e., tethering during diastole) and IIIb
(i.e.,
tethering during systole).
IMR can result from type I, type II, or type IIIb dysfunction. Acute
postinfarct MR can be
a result of type II dysfunction, where there
is papillary muscle rupture. However, acute IMR
is associated more
often with much more subtle changes in the mitral valve apparatus.
Chronic
IMR can be a result of type I or type IIIb dysfunction. Pure annular
dilatation with
normal leaflets (type I) results from left ventricular
remodeling and its geometric sequelae on
the mitral valve apparatus.
Type IIIb is the more common dysfunction associated with chronic
IMR, and it is the result of papillary muscle displacement and
tethering of leaflets. Often, both
type I and type IIIb dysfunctions are
seen in patients with chronic IMR and cardiomyopathy.
The pathophysiology is
a result of left ventricular remodeling as a consequence of
ischemia.
Cardiac Surgery: Answers
191
References
Tcheng JE, Jackman JD Jr, Nelson CL, et al. Outcome of patients sustaining acute ischemic
mitral regurgitation during myocardial infarction. Ann Intern Med 1992; 117:18-24.
Hickey MS, Smith LR, Muhlbaier LH, et al. Current prognosis of ischemic mitral
regurgitation: Implications for future management. Circulation 1988; 78:I-51-9.
2.46 Answer: C
Papillary muscle rupture is a rare complication, occurring in
1 to 5% of patients who die
after myocardial infarction (M)I. The rupture involves
the posteromedial papillary muscle in
approximately two-thirds
of acute, severe ischaemic mitral regurgitation (IMR). This is due to
the fact
that the vascular supply to the posteromedial papillary muscle depends
on one
coronary artery (the right coronary artery, or the circumflex
artery in a left-dominant system),
whereas the anterolateral papillary
muscle receives dual supply from the left anterior
descending and
circumflex arteries. Papillary muscle rupture results in prolapse
of the mitral
leaflets, often causing severe acute IMR and hemodynamic
instability. Acute mitral
regurgitation (MR) in this setting carries a poor prognosis
with high mortality rate.
Acute IMR often occurs with subtle changes in the mitral valve
apparatus in the absence
of leaflet prolapse. Annular dilatation traditionally
has been regarded as the mechanism of
acute IMR. Laboratory work
involving an ovine model from the Stanford group has
demonstrated the
importance of the septolateral (SL) dimension of the mitral
annulus in the
pathophysiology of IMR. The SL dimension,
the vertical distance of the mitral annulus from
the middle
of the anterior annulus to the middle of the posterior annulus, is
referred to
clinically as the anteroposterior (AP) dimension. Timek
and colleagues demonstrated that
correcting SL distance alone may
abolish acute IMR.
However, other experimental studies have demonstrated subvalvular geometric
changes
as an important contributor to the pathophysiology of
acute IMR.
References
Gorman RC, McCaughan JS, Ratcliffe MB, et al. Pathogenesis of acute ischemic mitral
regurgitation in three dimensions. J Thorac Cardiovasc Surg 1995;109:684-93.
Wei JY, Hutchins GM, Bulkley BH. Papillary muscle rupture in fatal acute myocardial
infarction: A potentially treatable form of cardiogenic shock. Ann Intern Med
1979;90:149-53.
Timek TA, Lai DT, Tibayan F, et al. Septal-lateral annular cinching abolishes acute ischemic
mitral regurgitation. J Thorac Cardiovasc Surg 2002; 123:881-88.
Timek TA, Lai DT, Liang D, et al. Effects of paracommissural septal-lateral annular cinching
on acute ischemic mitral regurgitation. Circulation 2004; 110:II-79-84.
2.47 Answer: E
The history and findings are suggestive of a left ventricular pseudoaneurysm with
ischaemic mitral regurgitation. Left ventricular pseudoaneurysm is quite a rare complication
following acute myocardial infarction or heart surgery. It results from ventricular wall rupture
with no cardiac tamponade. Free wall rupture is contained by perdicarcial adhesions, thus
producing the pseudoaneurysm. Due to the risk of rupture (30% to 45%) and death, urgent or
emergent surgical treatment is recommended when left ventricular pseudoaneurysm is
detected. Most commonly diagnosis is reached with the pseudoaneurysm in a chronic stage,
Shahzad G. Raja
192
which may go on for years with no rupture. However, a significant number of patients that
develop left ventricle pseudoaneurysm are not diagnosed in the acute stage due to early, fatal
rupture. Chronic cases are usually asymptomatic.
Non-invasive, imaging diagnostic methods - such as echocardiography or MRI – are
useful for the diagnosis of this complication and should be encouraged, so that more and more
cases can be detected in the acute stage. Left cine angioventriculography is the most accurate
diagnostic method. It is key for surgical treatment planning, since concurrent mitral valve
dysfunction is a common occurrence, and surgical myocardial revascularization is frequently
required.
Surgical treatment of left ventricular pseudoaneurysm immediately following or during
acute myocardial infarction is associated with high mortality rate (23% to 28%). But the
probability of pseudoaneurysm fatal rupture is higher than surgical risk. Heart failure and
mitral valve dysfunction increase surgical death rates.
Repair is accomplished by resection of the false aneurysm and primary closure of the
defect or closure with a patch. Concomitant coronary artery bypass surgery and mitral valve
repair are also performed.
References
Narin C, Ege E, Ozkara A, et al. Surgical treatment of postinfarction pseudoaneurysm of the
left ventricle. J Card Surg. 2008;23:294-8.
Moreno R, Gordillo E, Zamorano J, et al. Long term outcome of patients with postinfaction
left ventricular pseudoaneurysm. Heart. 2003;89:1144-6.
Prêtre R, Linka A, Jenni R, Turina MI. Surgical treatment of acquired left ventricular
pseudoaneurysms. Ann Thorac Surg. 2000; 70: 553-7.
Frances C, Romero A, Grady D. Left ventricular pseudoaneurysm. J Am Coll Cardiol. 1998;
32:557-61.
Komeda M, David TE. Surgical treatment of postinfarction false aneurysm of the left
ventricle. J Thorac Cardiovasc Surg. 1993; 106: 1189-91.
2.48 Answer: D
Heparin has both advantages and disadvantages; the
most notable advantages are
parenteral use, immediate onset
of action, and rapid reversal by protamine or recombinant
platelet
factor 4. Heparin does not directly inhibit coagulation,
but acts by accelerating the
actions of the natural protease,
antithrombin. Heparin-catalyzed antithrombin, however, does
not
inhibit thrombin bound to fibrin or factor Xa bound to platelets
within clots; thus heparin
only partially inhibits thrombin
in vivo. Antithrombin primarily binds thrombin; its action on
factors Xa and IXa is much slower. Heparin inhibits coagulation
at the end of the cascade
after nearly all other coagulation
proteins have been converted to active enzymes. In addition,
heparin
to varying degrees activates several blood constituents: platelets, factor XII,
complement, neutrophils, and monocytes. Heparin increases the sensitivity of platelets to
soluble agonists, inhibits binding to von Willebrand factor, and modestly increases
template
bleeding times. Thrombin concentrations cannot be
measured in real time and only
insensitive, indirect methods
are available to regulate heparin anticoagulation in the operating
room.
Cardiac Surgery: Answers
193
References
Bernabei AF, Gikakis N, Maione TE, et al. Reversal of heparin anticoagulation by
recombinant platelet factor 4 and protamine sulfate in baboons during cardiopulmonary
bypass. J Thorac Cardiovasc Surg. 1995;109:765-771.
Pixley RA, Cassello A, De La Cadena RA, et al. Effect of heparin on the activation of factor
XII and the contact system in plasma. Thromb Haemost. 1991;66:540-547.
Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and heparin fractions on
platelet aggregation. J Clin Invest. 1980;65:64-73.
2.49 Answer: A
Cardiac transplantation is reserved for a select group of patients with
end-stage heart
disease not amenable to optimal medical or surgical therapies.
Prognosis for 1-year survival
without transplantation should be
less than 50%. Prediction of patient survival involves
considerable subjective
clinical judgment by the transplant committee because no reliable
objective prognostic criteria are available currently. Low ejection
fraction (<20%), reduced
VO
2,max
(<14 mL/kg per minute),
arrhythmias, high pulmonary capillary wedge pressure (>25
mm Hg), elevated plasma norepinephrine concentration (>600 pg/mL),
reduced serum sodium
concentration (<130 mEq/dL), and more recently,
N-terminal probrain natriuretic peptide
(>5000 pg/mL) all
have been proposed as predictors of poor prognosis and potential
indications
for transplantation in patients receiving optimal medical therapy. Reduced left
ventricular ejection fraction and low VO
2,max
are widely
identified as the strongest
independent predictors of survival.
References
Stelken AM, Younis LT, Jennison SH, et al. Prognostic value of cardiopulmonary exercise
testing using percent achieved of predicted peak oxygen uptake for patients with ischemic
and dilated cardiomyopathy. J Am Coll Cardiol. 1996;27:345-352.
Rothenburger M, Wichter T, Schmid C, et al. Aminoterminal pro type B natriuretic peptide as
a predictive and prognostic marker in patients with chronic heart failure. J Heart Lung
Transplant. 2004;23:1189-97.
Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen
consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as
determinants of prognosis in heart failure. Circulation. 1993;87:V15-16.
2.50 Answer: C
Criteria for matching potential recipients with the appropriate donor
are based primarily
on ABO blood group compatibility and patient size.
ABO barriers should not be crossed in
heart transplantation because
incompatibility may result in fatal hyperacute rejection. Donor
weight should be within 30% of recipient weight except in pediatric patients,
where closer
size matching is required. In cases of elevated pulmonary
vascular resistance in the recipient
(5 to 6 Wood units), a
larger donor is preferred to reduce the risk of right ventricular failure
in
the early postoperative period. Although practices vary by
transplant program, generally, if
the percent of panel reactive antibody
(PRA) is greater than 10%, indicating recipient
presensitization to
alloantigen, a prospective negative T-cell cross-match between the
recipient and donor sera is mandatory prior to transplantation.
A cross-match is always
performed retrospectively, even if the
PRA is absent or low. Retrospective studies also have
Shahzad G. Raja
194
demonstrated
that better matching at the HLA-DR locus results in fewer episodes
of rejection
and infection with an overall improved survival.
Because of current allocation criteria and
limits on ischaemic
time of the cardiac allograft, routine prospective HLA matching
is not
possible logistically.
References
Betkowski AS, Graff R, Chen JJ, et al. Panel-reactive antibody screening practices prior to
heart transplantation. J Heart Lung Transplant. 2002;21:644-50.
Jarcho J, Naftel DC, Shroyer TW, et al. Influence of HLA mismatch on rejection after heart
transplantation: A multi-institutional study. J Heart Lung Transplant. 1994;13:583-95.
2.51 Answer: E
Denervation of the transplanted heart leads to loss of autonomic nervous
system
modulation of the heart‘s electrophysiologic properties.
Parasympathetic denervation causes
loss of basal suppression of
SA node automaticity, leading to a persistent increase in resting
heart
rate and a loss of normal, rapid heart rate modulation. This parasympathetic
loss also
causes elimination of the chronotropic effects of
digoxin and atropine after heart
transplantation. At the same
time, sympathetic denervation causes a decrease and delay in
exercise- or stress-induced augmentation of SA node automaticity,
resulting in a decreased
maximum heart rate with exercise.
Sinus or junctional bradycardia occurs in up to half of transplant recipients.
Risk factors
for sinus node dysfunction include prolonged organ
ischemia, angiographic nodal artery
abnormalities, biatrial as
opposed to bicaval anastomosis, preoperative amiodarone use,
and
rejection. Adequate heart rate is achieved
with inotropic drug infusions and/or temporary
epicardial pacing.
Most bradyarrhythmias resolve over 1 to 2 weeks. Theophylline
has been
effective in patients with bradyarrhythmias and has
decreased the need for permanent
pacemakers in this patient population.
Atrial fibrillation, atrial flutter, and other supraventricular arrhythmias
have been reported
in 5 to 30% of patients after heart transplantation.
Individual assessment of the risk:benefit
ratio for anticoagulation
therapy is necessary. Supraventricular tachycardia (SVT) in
transplant patients should be treated in the same manner as
in nontransplant patients but with
lower doses. Recurrent arrhythmias
from reentry circuits or defined ectopic foci often can be
cured
by radiofrequency ablation.
References
Stecker EC, Strelich KR, Chugh SS, et al. Arrhythmias after orthotopic heart transplantation.
J Card Fail. 2005;11:464-72.
Bertolet BD, Eagle DA, Conti JB, et al. Bradycardia after heart transplantation: Reversal with
theophylline. J Am Coll Cardiol. 1996;28:396-99.
2.52 Answer: B
Currently, the "standard" maintenance immunosuppression protocols
for heart
transplantation (so-called triple therapy) include (1)
a calcineurin inhibitor such as
cyclosporine or tacrolimus, (2)
an antiproliferative agent such as azathioprine, mycophenolate
mofetil, or rarely, cyclophosphamide, and (3) corticosteroids such
as prednisone or
prednisolone. Many centers also add an antilymphocyte antibody
perioperatively such as
Cardiac Surgery: Answers
195
antithymocyte globulin (ATG), OKT3, or
an interleukin-2 (IL-2) receptor blocker
(basiliximab or daclizumab) to
create a quadruple-drug regimen. In recent years, sirolimus
(Rapamycin) and everolimus (a derivative of Rapamycin), which
act by blocking several
events downstream of the IL-2 receptor,
have been introduced into clinical heart
transplantation. In
the setting of pretransplant renal insufficiency, a popular
protocol involves
delaying the initiation of the calcineurin
inhibitors for 1 to 2 weeks postoperatively to allow
for recovery
of renal function and using antilymphocyte antibody therapy
in the interim, so-
called sequential therapy. The use of
a multidrug regimen permits adequate
immunosuppression with
reduced doses of individual agents to minimize their toxicity.
References
Taylor DO. Cardiac transplantation: Drug regimens for the 21st century. Ann Thorac Surg.
2003;75:S72-S78.
2.53 Answer: D
Cyclosporine (Sandimmune) is an 11-amino-acid cyclic peptide
produced by the fungus
Tolypocladium inflatum. It inhibits
the calcium-calcineurin pathway. This pathway is one of
the three signal transduction
pathways that activate transcription factors triggering the
expression of molecules with important roles in the immune response,
including IL-2, CD154,
and CD25. Consequently, cytotoxic T-lymphocyte
proliferation is abated. Cyclosporine
provides
more selective immunosuppression than azathioprine and corticosteroids as it spares
macrophages, neutrophils,
suppressor T lymphocytes, and some B lymphocytes. It also has
allowed the reduction in corticosteroid doses
in maintenance immunosuppression.
Introduction of cyclosporine in the early 1980s in clinical heart transplant has significantly
improved prognosis after heart transplant. The ISHLT Registry in 2001 reported that
approximately 50% of patients
who underwent heart transplantation after 1982 survived more
than 10 years. This improved survival of cardiac recipients in
the cyclosporine era is mainly a
result of a reduction in
infection-related mortality presumably associated with a relative
preservation of host defense against microbials. Doses of
cyclosporine are adjusted to achieve
trough serum levels of
between 150 and 300 ng/mL. The low therapeutic index of
cyclosporine
and wide variation in individual pharmacokinetics demanss close
monitoring of
levels. Cyclosporine temporarily may be administered as a continuous
infusion to reduce wide
fluctuations in serum levels for patients who develop renal insufficiency. The original oil-
based formulation was largely replaced by a
new microemulsion formulation (Neoral) in
1995. Neoral has greater bioavailability and
more predictable intestinal absorption and
pharmacokinetics.
References
Hausen B, Demertzis S, Rohde R, et al. Low-dose cyclosporine therapy in triple-drug
immunosuppression for heart transplant recipients. Ann Thorac Surg. 1994;58:999-1004.
Patel JK, Kobashigawa JA. Cardiac transplant experience with cyclosporine. Transplant
Proc. 2004;36:323S-330S.
2.54 Answer: B
Tacrolimus (FK506) is a macrolide antibiotic from Streptomyces tsukubaensis. It binds to
another immunophilin, FK506-binding protein 12
(FKBP12). The complex formed as a result
Shahzad G. Raja
196
inhibits calcineurin with
greater molar potency than does cyclosporine and decreases the
formation
of IL-2. Comparison of the standard oil-based cyclosporine formulation with
tacrolimus
in association with azathioprine and steroids has been undertaken in two
prospective, multicenter, randomized trials,
one in Europe and the other in the United States.
The two calcineurin
inhibitors showed similar efficacies in preventing rejection
and death
within the first year after transplant. However, compared with cyclosporine tacrolimus caused
fewer cases of hypertension and hyperlipidemia.
Similarly, the two drugs
have been shown
to
be associated with similar incidences of rejection and death
in the 18-month results of a large
multicenter tacrolimus
versus cyclosporine microemulsion study. This study also reported that
recurrent rejection was less severe and the incidences
of hypertension and hyperlipidemia
were lower if tacrolimus
was used. Furthermore, FK506 has been found to be most effective
in reversing recalcitrant rejection. This has prompted some
institutions to employ FK506 as a
"rescue"
agent. It also has been suggested that ethnic disparity in clinical
outcome after heart
transplantation is abolished using tacrolimus-based
immunosuppression.
At present, neither cyclosporine nor tacrolimus has been shown to
prevent cardiac
allograft vasculopathy (CAV) or to reduce the
progression of this complication during long-
term follow-up. Tacrolimus may lower the risk of CAV associated with hypertension
and
hyperlipidemia. On the other hand, the risk associated with
impaired glucose metabolism may
be higher with tacrolimus usage. With both drugs,
the risk of CAV is increased by the
concomitant use of corticosteroids.
Overall, the choice of calcineurin inhibitor currently
seems
to be dictated by their adverse-effect profiles, by the results
obtained for individual
patients, and possibly by institutional preference.
The 2005 ISHLT report indicates that
tacrolimus has just excelled
cyclosporine as the most commonly used calcineurin inhibitor.
References
Taylor DO. Cardiac transplantation: Drug regimens for the 21st century. Ann Thorac Surg.
2003;75:S72-S78.
Crespo-Leiro MG. Calcineurin inhibitors in heart transplantation. Transplant Proc
2005;37:4018-4020.
2.55 Answer: C
Azathioprine, an imidazole derivative from 6-mercaptopurine, is an antimetabolite that
inhibits DNA synthesis during the
crucial synthetic (S) phase of cell replication. This results
in the inhibition of the antigen-stimulated proliferation of
lymphocytes. Dosage adjustments
are made to maintain the
leukocyte count at between 4000 and 5000/mm
3
. Azathioprine
causes a
dose-related bone marrow suppression. This side effect can be profound if
it is
administered synchronously with allopurinol.
References
Taylor DO. Cardiac transplantation: Drug regimens for the 21st century. Ann Thorac Surg.
2003;75:S72-S78.
Denfield SW. Strategies to prevent cellular rejection in pediatric heart transplant recipients.
Paediatr Drugs 2010;12:391-403.
Cardiac Surgery: Answers
197
2.56 Answer: A
Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid, inhibits a
key
step in the de novo biosynthesis of purines, selectively
affecting cells (such as lymphocytes)
that are unable to use
salvage pathways. In the latest reported randomized, double-blind,
controlled trial comparing MMF with azathioprine, the MMF groups
had reduced mortality
and graft loss up to 3 years after transplantation
(11.8% versus 18.3%, p < .01). Time to
retransplantation or
patient death was significantly shorter for azathioprine- than for
MMF-
treated patients (p = .029). Congestive heart failure, atrial
arrhythmia, and leukopenia were
more common in the azathioprine group,
whereas diarrhea, esophagitis, herpes simplex,
herpes zoster, and
CMV tissue invasion were more common in MMF-treated patients. Several
other studies in the past also demonstrated the superiority of
MMF. Furthermore, MMF has
novel properties that may contribute
to the prevention of cardiac allograft rejection and also
provide
benefits in reducing the progression of CAV. In a study by Pethig
and colleagues,
cardiac transplant patients receiving MMF had
lower levels of high-sensitive C-reactive
protein, a marker
of inflammation having a strong association with cardiovascular
disease,
than did patients receiving azathioprine. However,
there was no significant difference in
intimal hyperplasia,
although there was a weak trend toward vascular enlargement
by
intravascular ultrasound in the MMF group. MMF largely has
replaced azathioprine and
currently is the predominant antiproliferative
agent, used in more than 75% of heart transplant
recipients.
References
Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart
and Lung Transplantation: Twenty-second official adult heart transplant report—2005. J
Heart Lung Transplant 2005;24:945-55.
Eisen HJ, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind,
controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant
recipients. J Heart Lung Transplant 2005;24:517-25.
Kobashigawa JA, Meiser BM. Review of major clinical trials with mycophenolate mofetil in
cardiac transplantation. Transplantation 2005;80:S235-43.
Pethig K, Heublein B, Wahlers T, et al. Mycophenolate mofetil for secondary prevention of
cardiac allograft vasculopathy: Influence on inflammation and progression of intimal
hyperplasia. J Heart Lung Transplant 2004;23:61-66.
2.57 Answer: E
The first monoclonal antibody (mAb) available for therapeutic
use in the treatment and
prevention of allograft rejection was
OKT3. It is a murine mAb directed against the chain of
CD3
molecule, which is part of the T-cell recognition (TCR) complex
and functions to
modulate the receptor and inactivate T-cell
function. By engaging the TCR complex, OKT3
blocks not only
the function of naive T cells but also the function of established
cytotoxic T
cells. As with polyclonal preparations, administration
of OKT3 also can eliminate almost all
circulating T lymphocytes,
although its monoclonal specificity prevents it from having
a
cytolytic effect on other circulating cells. Monitoring
of T3 subpopulation cell counts can be
used to determine adequacy
of therapy. While it has been used for induction therapy, OKT3
has demonstrated its greatest benefit on rescue therapy.
Studies comparing the results
obtained with OKT3 versus horse
or rabbit polyclonal antibodies have yielded conflicting
Shahzad G. Raja
198
results.
OKT3 appears to be more aggressive therapy and has been associated
with serious
adverse effects, which include the following: (1)
the development of a cytokine release
syndrome owing to the
ability of OKT3 to activate T cells, ranging in severity from
a mild
febrile illness to a syndrome of severe volume overload
and hemodynamic compromise, (2)
the appearance of human antimouse
antibodies that decrease the efficacy or preclude the use
of
subsequent OKT3 courses and can mediate humoral rejection,
(3) the increased incidence
of opportunistic infections such
as those caused by CMV, and (4) the increased incidence
of
posttransplant lymphoproliferative disorders. Interestingly, the
2005 ISHLT report showed
that patients receiving OKT3 as part of
an induction protocol have higher rejection rates
during the
first year after transplant than those receiving polyclonal
or IL-2 antibody induction
and those receiving no antibody induction.
Overall, the perioperative use of OKT3 as an
induction agent
continues to decrease (only 4% of heart transplant procedures
in 2001–2004).
References
Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart
and Lung Transplantation: Twenty-second official adult heart transplant report—2005. J
Heart Lung Transplant 2005;24:945-55.
Laske A, Gallino A, Schneider J, et al. Prophylactic cytolytic therapy in heart transplantation:
Monoclonal versus polyclonal antibody therapy. J Heart Lung Transplant 1992;11:557-
63.
Johnson MR, Mullen GM, O'Sullivan EJ, et al. Risk/benefit ratio of perioperative OKT3 in
cardiac transplantation. Am J Cardiol 1994;74:261-6.
2.58. Answer: B
The great majority of cardiac allograft rejection cases are mediated by the cellular
arm of
the immune response through a sophisticated cascade of events
involving macrophages,
cytokines, and T lymphocytes. Humoral-mediated rejection
(also called vascular rejection) is
less common. The major risk factors are allografts from younger and female donors
(irrespective
of recipient sex). Rejection is
still a major cause of morbidity in cardiac
transplant recipients despite the fact that approximately 85% of episodes can be
reversed with
corticosteroid therapy alone.
In the precyclosporine era, the classic clinical features of
acute rejection included low-
grade fever, malaise, leukocytosis, pericardial
friction rub, supraventricular arrhythmias, low
cardiac output,
reduced exercise tolerance, and signs of congestive heart failure.
In the
cyclosporine era, however, most episodes of rejection typically
are insidious, and patients can
remain asymptomatic even with
late stages of rejection. Thus routine surveillance studies for
early detection are critical to reduce cumulative injury to
the allograft. Right ventricular
endomyocardial biopsy for the diagnosis of acute rejection remains
the "gold standard". The
most commonly used technique for orthotopic allografts is
a percutaneous approach through
the right internal jugular vein.
Interventricular septal specimens are fixed in formalin for
permanent section. Occasionally
frozen sections are performed if urgent diagnosis is
necessary. Haemodynamic variables also
may be obtained with a pulmonary artery (Swan-
Ganz) catheter. Complications
secondary to endomyocardial biopsy are infrequent (1 to 2%).
These include venous hematoma, carotid
puncture, pneumothorax, arrhythmias, heart block,
and right ventricular
perforation and injury to the tricuspid valve. The exact schedule
for
endomyocardial biopsies varies among institutions but reflects
the increased risk of rejection