CARDIAC TRANSPLANT PREOP

EVALUATION & POST OP

MANAGEMENT

Dr . Srikanth N
 Topics

• Introduction
• History of heart transplantation
• Indications,contraindications
• Cardiac Transplantation evaluation
• Management of potential cardiac receipient&donor
• Donor cardiectomy,Organ preservation
• Transplantation techniques
• Allograft physiology&graft failure
• Immunosupression
• Complications
• Results
• Future prospectives
 Introduction
• The number of patients with heart failure is
growing.
• End stage heart failure is associated with
significant morbidity, need for recurrent
hospitalizations, decrease in quality of life, and
increased mortality.
• Cardiac transplantation has evolved as an
effective therapy for many of these patients.
• Tremendous advancements in the fields of
immunosuppression, rejection, and infection
have transformed what was once considered
an experimental intervention into a routine
treatment available worldwide.
• To date, over 60,000 heart transplants have
been performed worldwide at more than 200
heart transplant centers.
HISTORY OF HEART TRANSPLANTATION

• The innovative French

surgeon Alexis Carrel
performed the first
heterotopic canine
heart transplant with
Charles Guthrie in
1905.
• Frank Mann proposed the
concept of cardiac allograft
rejection,which involved
biologic incompatibility
between donor and
recipient manifested by an
impressive leukocytic
infiltration of the rejecting
myocardium.
• BIOLOGIC FACTOR
• In 1946 Vladimir
Demikhov successfully
implanted the first
intrathoracic heterotopic
heart allograft.
• The first human cardiac transplant was a
chimpanzee xenograft performed at the
University of Mississippi by James Hardy in
1964.
• South African
Christiaan Barnard
surprised the world
when he performed
the first human-to-
human heart
transplant on
December 3, 1967.
• The pioneering efforts of Shumway,Lower and
colleagues at Stanford eventually paved the
way for the reemergence of cardiac
transplantation in the late 1970s.
• The historical note would be incomplete
without introducing Medawar's concepts of
acquired immunologic tolerance for which he
received Nobel prize in 1961.
• The advent of the immunosuppressive agent
cyclosporine that dramatically increased
patient survival and marked the beginning of
the modern era of successful cardiac
transplantation in 1981.
• The introduction of transvenous endomyocardial
biopsy by Philip Caves in 1973 finally provided a
reliable means for monitoring allograft rejection.
INDICATIONS
A
CONTRA-INDICATIONS
 Pulmonary hypertension
• Pasp >50-60 mm hg ,PVR >5 WU or TPG>15-20
mmhg prohibitive risk for successful
transplant.
• Vasodilator testing—PASP > 50 mmhg,TPG>15
or PVR > 3 WU
• Pharmacologic –
Nitroprusside,PGE1,Nesiritide,Milrinone &
Dobutamine or inhaled Nitric oxide.
 Successful vasodilator challenge
• PVR <2.5 WOOD UNITS with
systolic arterial BP >85 mm hg
 Donor heart allocations
• First priority----local population with status 1

• Second priority---status 1 within 500 miles

• Third priority---status 2 patients (local)

Next priority---status 1 within 1000 miles

Next priority---status 1 within 1500 miles

Cardiac Transplant Recipient Evaluation Tests
Laboratory :
• Complete blood count with differential and platelet
count,creatinine, blood urea nitrogen,
electrolytes,liver panel, lipid panel, calcium,
phosphorus, total protein,
• Albumin, uric acid, thyroid panel, antinuclear
antibodies,
• ESR, rapid plasma reagin (RPR), iron binding tests,
partial thromboplastin time,prothrombin timeBlood
type, IgG and IgM antibodies against cytomegalovirus,
herpes simplex virus, HIV,varicella-zoster virus,
hepatitis B surface antigen, hepatitis C antigen,
toxoplasmosis, other titers when indicated.
 Laboratory (contd)
• Tuberculin skin test.
• Prostate-specific antigen (male 50 years).
• Mammogram and Pap smear (female 40 years)
• Screening against a panel of donor antigens
(panel reactive antibodies) and human leucocyte
antigen phenotype.
• 24-hour urine for creatinine clearance and total
protein, urinalysis, urine culture.
• Baseline bacterial and fungal cultures, stool for
ova and parasites if indicated.
Cardiac
• 12-lead ECG, 24-hour Holter monitor
• Echocardiogram
• Thallium-201 imaging, positron-emission tomographic
(PET) scan, or cardiac magnetic resonance imaging (MRI)
to assess viability if indicated.
• Exercise stress test and respiratory gas analysis with
oxygen uptake measurements:
• Peak exercise oxygen consumption (V˙ O2,max).
• Right- and left-sided heart catheterization at the
transplant center.
• Myocardial biopsy on selected patients in whom etiology
of heart failure is in question.
Vascular
• Peripheral vascular studies
• Carotid Doppler and duplex ultrasound 55 years
Renal
• Renal ultrasound and or intravenous pyelogram if indicated
Pulmonary
• Chest x-ray
• Pulmonary function tests
• Chest CT scan to evaluate abnormal chest x-ray or thoracic aorta
in older patients (usuall y 65 years)
Gastrointestinal
• Upper endoscopy/colonoscopy if indicated
• Upper gastrointes tinal series and/or barium enema if indicated
• Percutaneous liver biopsy if indicated
• Metabolic: Bone densitometry
• Neurologic Screening evaluation
• Psychiatric Screening evaluation
• Dental Complete dental evaluation
• Physical therapy Evaluation
• Social work Patient attitude and family
support, medical insurance, and general
financial resources
• Transplant coordinator Education
• The ultimate success of transplantation depends
on the psychosocial stability and compliance of
the recipient.
• Demands commitment on the part of the patient.
• A history of psychiatric illness, substance abuse,
or previous noncompliance(particularly with
medical therapy for end-stage heart failure) may
be sufficient cause to reject the candidacy of a
patient. Lack of a supportive social system is an
additional relative contraindication.
DONOR SELECTION
 Management of the Potential Cardiac Recipient
• Plasmapheresis,intravenous immunoglobulins,
cyclophosphamide, and mycophenolate mofetil all
have been used to lower the PRA levels with
variable results.
Pharmacologic bridge to transplantation
• Critically compromised patients require admission
to the intensive-care unit for intravenous inotropic
therapy.
• Dobutamine, a synthetic catecholamine, remains
the prototype of this drug group.
• Milrinone is similarly effective.
• In candidates in whom an inotropic infusion
has progressed to higher doses, combinations
of dobutamine with milrinone are used.
• For transplant candidates dependent on
inotropic infusions, eosinophilic myocarditis
may develop as an allergic response to the
dobutamine and may result in accelerated
decline.
• VADs are being considered earlier.
 Mechanical bridge to transplantation
• Placement of an intra-aortic balloon pump (IABP)
may be necessary in patients with heart failure who
are refractory to initial pharmacologic measures.
• The landmark Randomized Evaluation of
Mechanical Assistance in Treatment of Chronic
Heart Failure (REMATCH) trial provided evidence
that LVAD support provided a statistically significant
reduction in the risk of death from any cause when
compared with optimal medical management.
• The total artificial heart (TAH) positioned
orthotopically replaces both native cardiac ventricles
and all cardiac valves.
• Potential advantages of this device include eliminating
problems commonly seen in the bridge to
transplantation with left ventricular and biventricular
assist devices, such as right-sided heart failure,
valvular regurgitation, cardiac arrhythmias, ventricular
clots, intraventricular communications, and low blood
flows.
• Since these devices cannot be weaned, it is imperative
that the patient’s candidacy for transplantation be
scrutinized prior to placement of the device.
Life-threatening ventricular arrhythmias

• Symptomatic ventricular tachycardia or

fibrillation and a history of sudden cardiac
death are indications for placement of AICD,
long-term antiarrhythmic therapy with
amiodarone,or occasionally, radiofrequency
catheter ablation, which have shown
improved survival.
• Patients considered for transplantation should
be examined at least every 3 months for
reevaluation of recipient status.
• Yearly right-sided heart catheterization is
indicated for all candidates on the waiting
list.
 Intraoperative screening of donor
• Direct visualization of the heart is performed for
evidence of ventricular or valvular dysfunction,
previous infarction, or myocardial contusion
secondary to closed-chest compressions or blunt
chest trauma.
• The coronary arterial tree is palpated for gross
calcifications indicative of atheromatous disease. If
direct examination of the heart is unremarkable, the
recipient hospital is notified, and the procurement
surgeons proceed with donor cardiectomy, usually in
conjunction with multiorgan procurement.
 Management of the Cardiac Donor
• Brain death is associated with an “autonomic and
cytokine storm.” The release of noradrenaline
leads to subendocardial ischemia.
• Subsequent cytokine release results in further
myocardial depression. This is accompanied by
pronounced vasodilatation and loss of
temperature control.
• Rapid afterload reduction may be achieved with
sodium nitroprusside, whereas volatile
anesthetics assist in reducing the intensity of
sympathetic bursts.
• The initial period of intense autonomic activity is
followed by loss of sympathetic tone and a
massive reduction in systemic vascular resistance.
• Overall, brain stem death results in severe
hemodynamic instability, the degree of which
appears to be directly related to the severity of
the brain injury and may result from vasomotor
autonomic dysfunction, hypovolemia,
hypothermia, and dysrhythmias.
 DONOR CARDIECTOMY

Orthotopic cardiac transplantation, donor cardiectomy.

 DONOR CARDIECTOMY

• A, Inferior vena cava is divided at its junction with the right atrium.
• Most of the intrapericardial inferior vena cava is left behind attached to the
liver because nearly all these operations are for multiorgan procurement.
• The right pulmonary vein is incised to vent the left heart. The aorta is
occluded when the heart empties. Cold cardioplegic solution is administered
through catheter to aortic root to achieve total electromechanical arrest.
• B, The heart is retracted superiorly, exposing and dividing pulmonary veins
and left pulmonary artery.
• C, Aorta, superior vena cava, and right pulmonary artery are divided at or
above pericardial reflection for maximal length on the great arteries.
• The heart is taken from the body and aorta and pulmonary trunk separated,
atrial septum checked for defect, and cardiac valves and cardiac chambers
inspected. It is packed in saline solution in triple sterile bags for transport.
Donor allograft preparation for orthotopic heart transplantation.
Pulmonary vein orifices joined to form left atrial cuff.
 Cardiac ischemic time
• The decision to use a specific donor is based in part on
the feasibility of keeping cardiac ischemic time to less
than 180 minutes,
• Cardiac ischemic time includes the time required to
remove the heart from the donor after the aorta is
clamped, transport the heart to the recipient's
operating room (including air transport time, because
most cardiac procurement is from distant sites),
suture the donor heart into the recipient, and release
the recipient's aortic clamp or begin controlled aortic
root reperfusion.
 Organ Preservation
• Current clinical graft preservation techniques generally
permit a safe ischemic period of 4 to 6 hours.
• Factors contributing to the severity of postoperative
myocardial dysfunction include insults associated with
suboptimal donor management, hypothermia, ischemia-
reperfusion injury, and depletion of energy stores.
• A single flush of a cardioplegic or preservative solution
followed by static hypothermic storage at 4 to 10⁰C is
the preferred preservation method by most transplant
centers.
• Crystalloid solutions of widely different
compositions are available.Depending on their
ionic composition, solutions are classified as
intracellular or extracellular.
• Intracellular solutions, characterized by moderate
to high concentrations of potassium and low
concentrations of sodium, purportedly reduce
hypothermia-induced cellular edema by
mimicking the intracellular milieu. Commonly
used examples of these solutions include
University of Wisconsin, Euro-Collins, and in
Europe, Bretschneider (HTK) and intracellular
Stanford solutions.
• Extracellular solutions, characterized by low to
moderate potassium and high sodium
concentrations, avoid the theoretical potential
for cellular damage and increased vascular
resistance associated with hyperkalemic
solutions.
• Hopkins, Celsior, Krebs, and St. Thomas Hospital
solutions are representative extracellular
cardioplegic solutions. Several comparisons of
the different types of intracellular and
extracellular solutions have shown variable
results.
• Potential benefits of continuous hypothermic
perfusion (CHP) preservation such as uniform
myocardial cooling, continuous substrate
supplementation, and metabolic by-product
washout are currently overshadowed by
exacerbation of extracellular cardiac edema and
logistical problems inherent to a complex perfusion
apparatus.
 Donor-Recipient Matching
• 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.
• 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 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
ischemic time of the cardiac allograft, routine
prospective HLA matching is not possible logistically.
• Biatrial or “standard” technique for orthotopic heart transplantation. A,
Cannulation technique is similar to routine cardiac procedures with central
cannulation. Tapes have been placed around the superior and inferior venae cavae,
and the aorta has been cross-clamped to exclude the heart from the circulation.
The recipient’s heart has been excised at the atrioventricular groove. The superior
vena cava (SVC) of the donor’s heart has been ligated, and the left atrial
anastomosis has been started. B, The left atrial anastomosis has been completed.
The incision in the right atrium of the donor heart is curved away from the SVC and
the adjacent sinoatrial node. The right atrial anastomosis is begun. C, The right
atrial, pulmonary artery, and aortic anastomoses are completed. The aortic cross-
clamp is removed, and the patient is weaned from cardiopulmonary bypass (CPB).
• In the original description of the standard technique,
anastomoses were performed in the following order:
left atrium, right atrium, pulmonary artery, and aorta.
• In an attempt to achieve earlier reperfusion, some
surgeons have altered the sequence of anastomoses.
• For example, the aortic anastomosis can be
performed immediately after the left atrial or right
atrial anastomoses and then the aortic cross-clamp
can be removed.
•Orthotopic cardiac transplantation, transposed great arteries.
•A, Cardiac transplantation is not difficult where great arteries are
transposed, because venae cavae, pulmonary veins, and left atrium are in
usual position. Although the pulmonary trunk originates posteriorly from
the left ventricle, its bifurcation is located in more or less usual position at
the pericardial reflection. As the aorta exits the pericardial sac, it is usually
anterior and to the right of the pulmonary bifurcation. Thus, dividing it just
above the sinus rim provides sufficient length to allow orthotopic
transplant.
•B, Aorta is completely mobilized to the pericardial reflection. Atria and
pulmonary trunks are anastomosed as usual. The recipient aorta is simply
rotated to the right for anastomosis in end-to-end fashion to donor aorta.
 Orthotopic Cardiac Transplantation or
Autotransplantation for Cardiac Neoplasm
• Cardiac explantation, extracorporeal resection of the tumor
with cardiac reconstruction, and cardiac autotransplantation
have been used to overcome the technical problems associated
with primary resection.
• Partial ex situ surgery of the heart has also been proposed for
tumors of the posterior left ventricle with transection of the
inferior vena cava and left atrium, leaving the aorta,
pulmonary trunk, and superior vena cava intact.
• These techniques have best application in benign cardiac
neoplasms .
• Another approach to consider for these is cardiectomy and
replacement with total artificial heart, either as a permanent
implant or as a bridge to transplantation after several months,
to determine freedom from metastatic disease.
• Although bicaval is more technically difficult
than standard orthotopic transplantation, some
series have reported shorter hospital stays,
reduced postoperative dependence on diuretics,
and lower incidences of atrial dysrhythmias,
conduction disturbances, mitral and tricuspid
valve incompetence, and right ventricular
failure.
• A study comparing biatrial versus bicaval
transplant showed an improved 12-month
survival in the bicaval group.
Heterotopic Heart Transplantation

• Currently, heterotopic heart transplants are

performed rarely but may be indicated in
patients with irreversible pulmonary
hypertension or significant donor-recipient
size mismatch.
• The heterotopic cardiac transplant. (A) Posterior view of
the donor heart after preparation for anastomosis. (B)
Left atriotomy. (C) Left atrial anastomosis. (D) Right atrial
anastomosis. (E) Aortic anastomosis. (F) Completed
anastomoses with a pulmonary-to-pulmonary arterial
graft.
 Heart allograft physiology
• The intact heart is innervated by antagonistic
sympathetic and parasympathetic fibers of
the autonomic nervous system.
• Transplantation necessitates transection of
these fibers, yielding a denervated heart
with altered physiology. Devoid of autonomic
input, the sinoatrial (SA) node of the
transplanted heart fires at its increased
intrinsic resting rate of 90 to 110 beats per
minute.
• The allograft relies on distant noncardiac sites as its
source for catecholamines; thus its response to
stress (e.g., hypovolemia, hypoxia, and anemia) is
somewhat delayed until circulating catecholamines
can exert their positive chronotropic effect on the
heart.
• Carotid sinus massage, Valsalva maneuver, and
atropine have no effect on SA node firing or
atrioventricular conduction.
• Cardiac denervation brings in several consequences,
which may include a chronotropic and an inotropic
supersensitivity to exogenous catecholamines
Post operative period
Peri operative haemodynamic instability

• Hypotension—reperfusion injury,
inflammatory response, elevated PVR, labile
fluid status----epinephrine, dobutamine,
dopamine infusion
• Mechanical circulatory support ,
plasmapheresis---ECMO(primary graft failure)

• Younger age, lower weight, longer ischemic

 Bleeding & Volume status
• Extensive dissection , cardiopulmonary
bypass, multiple suture lines, pre transplant
heparinisation, poor pre-op nutrition

• Platelet rich plasma,FFP, recombinant factor

vii,leucocyte reduced PRBC
• Fluid management(cvp 5-12 mm hg)
 Hypertension
• Baro reflex mediated
hypertension,catecholamine dysregulation
from low output state(pre
transplant),significant pre existing renal
injury,corticosteroids and calcineurin
inhibitors

• Treatment-CCB,ACE i
 Systemic hypertension
• In the early postoperative period, intravenous
sodium nitroprusside or nitroglycerin usually is
administered.
• Nicardipine infusion has been reported to
control postoperative hypertension more
rapidly and was superior to sodium
nitroprusside in maintaining left ventricular
performance immediately after drug infusion.
 DONOR SIZE MISMATCH
• Big heart syndrome(donor/recipient weight >
2)—HTN associated with seizures and coma.
• Small donor size—post op Heart failure
• Dilated heart replaced with normal sized heart
that fills with fluid
 ARRYTHMIAS
• Post transplant sinus node dysfunction is
common with a reported high prevalence as
high as 44%.
• Due to diastolic dysfunction and impaired
filling of the transplanted heart– AV synchrony
and adequate HR is required to maintain
output.
• Target heart rate is 90/min.
 Arrhythmias

• 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.
• Sustained ventricular tachycardia (VT) and
ventricular fibrillation presumably are
responsible for a significant portion of the 10%
of sudden and unexplained deaths in heart
transplant patients.
 PULMONARY VASCULAR RESISTANCE

• Pre Transplant PVRi(>6 WU/m2)---75% risk of

RV failure,15% mortality.
• Indwelling pulmonary artery pressure line
• Sedation with neuro muscular blockade, avoid
hypoxia, hypercapnia and serum alkalinisation.
• Inhaled nitric oxide, Iloprost & sildenafil
 Primary graft failure
• Early post transplant failure without identifiable
immunologic or anatomic etiology
• 20-30% patients within first 30 days post transplant
• Recipient CHD, pre-transplant mech support,
increasing donor ischemic time, anoxia mediated
donor death, prolonged donor resuscitation time,
increasing donor/recipient ratio---risk factors for graft
failure.
• O+ blood group and hyperdynamic systolic function
are protective
ABO incompatible tranplant
 ABO incompatible
• Standard immuno-suppression regimens are
used in ABO incompatible transplants with no
increased risk of rejection compared to ABO
compatible patients
• Iso hemagluttinin mediated antibodies must
be considered as a potentional cause of acute
graft failure.
 Early allograft failure

• Early cardiac failure still accounts for up to 20% of

perioperative deaths of heart transplant recipients.
• The cause may be multifactorial, but the most
important etiologies are myocardial dysfunction
owing to donor instability, pulmonary hypertension,
ischemic injury during preservation,and acute
rejection.
• Mechanical support with an intra-aortic balloon
pump or ventricular assist device can be attempted
in patients refractory to pharmacologic
interventions, although this measure, as well as
retransplantation, is associated with very high
mortality.
 Renal Function
• Preoperative renal insufficiency owing to chronic
heart failure and the nephrotoxic effects of
calcineurine inhibitors cyclosporine place the
recipient at increased risk of renal insufficiency.
• Concurrent administration of mannitol with
calcineurine inhibitor cyclosporine may reduce its
nephrotoxicity.
• Most centers administer a cytolytic agent in the
immediate postoperative period and delay the
initiation of calcineurine inhibitor cyclosporine
therapy.
 IMMUNOSUPPRESSIVE THERAPY
• The ultimate goal of immunosuppressive
therapy is selective modulation of the
recipient’s immune response to prevent
rejection while concurrently sparing immune
defenses against infections or neoplasia and
minimizing the toxicity associated with
immunosuppressive agents
• Changes in immunosuppressive therapy have
had a major impact on improving survival after
heart transplantation, as evidenced by the
decreasing number of deaths owing to
rejection in recent years.
• Consists of an early induction phase followed
by a long-term maintenance phase
• Currently, the “standard” maintenance
immunosuppression protocols for heart
transplantation (so-called triple therapy) include
• (1) a calcineurin inhibitor (CNI) such as cyclosporine or
tacrolimus,
• (2) an antiproliferative agent such as azathioprine
(AZA),mycophenolate mofetil (MMF), or rarely,
cyclophosphamide, and
• (3) corticosteroids such as prednisone or
prednisolone.
• Many centers also add an antilymphocyte antibody
perioperatively such as antithymocyte globulin
(ATG), OKT3, or an interleukin-2 (IL-2) receptor
blocker (basiliximab or daclizumab) to create a
quadrupledrug 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.
• 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.
Individual Immunosuppressive Agents
 Hyperacute Rejection
• Hyperacute rejection results from preformed donor-specific
antibodies in the recipient.
• ABO blood group and panel reactive antibody screening have made
this condition a rare complication.
• The onset of hyperacute rejection occurs within minutes to several
hours after transplantation, and the results are catastrophic.
• Gross inspection reveals a mottled or dark red, flaccid allograft, and
histologic examination confirms the characteristic global interstitial
hemorrhage and edema without lymphocytic infiltrate.
• Immunofluorescence techniques reveal deposits of
immunoglobulins and complement on the vascular endothelium.
• Immediate plasmapheresis, intravenous immunoglobulin (IVIG),
and mechanical support are instituted, and retransplantation may
be the only successful strategy.
 ACUTE REJECTION
• Cardiac allograft rejection is the normal host response to
cells recognized as nonself.
• The vast majority of cases are mediated by the cellular limb
of the immune response through an elegant cascade of
events involving macrophages,cytokines, and T lymphocytes.
• Humoral-mediated rejection (also called vascular rejection)
is less common. The highest risk factors are allografts from
younger and female donors (irrespective of recipient sex).
• Although about 85% ofepisodes can be reversed with
corticosteroid therapy alone,rejection is still a major cause
of morbidity in cardiac transplant recipients
 Diagnosis of Acute Rejection
• In the precyclosporine era, the classic clinical
manifestations 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 characteristically are insidious, and patients can
remain asymptomatic even with late stages of rejection.
Thus routine surveillance studies for early detection are
crucial to minimize cumulative injury to the allograft.
Right ventricular endomyocardial biopsy remains the
“gold standard” for the diagnosis of acute rejection.
• There is greater risk of rejection during the
first 6 months following transplantation.
• Biopsies are performed initially every 7 to 10
days in the early postoperative period and
eventually tapered to 3- to 6-month intervals
after the first year.
• Suspicion of rejection warrants additional
biopsies
Treatment algorithm for acute rejection in heart transplant recipients
 Acute Vascular Rejection
• Vascular rejection is mediated by the humoral limb of the
immune response. Unlike cellular rejection, hemodynamic
instability often necessitating inotropic support is common in
cases of vascular rejection.
• Diagnosis requires evidence of endothelial cell swelling on light
microscopy and immunoglobulin-complement deposition by
immunofluorescence techniques.
• Aggressive treatment of patients with allograft dysfunction
consists of plasmapheresis, high-dose corticosteroids, heparin,
IgG, and cyclophosphamide.
• Despite these interventions, symptomatic acute vascular
rejection is associated with a high mortality.
 INFECTIOUS COMPLICATIONS IN
HEART TRANSPLANTATION
• Infection is a leading cause of morbidity and mortality in
the cardiac transplant population.
• The introduction of new chemoprophylactic regimens and
the prevention of serious disease caused by CMV have
resulted in significant reductions in the number of
infectious episodes and a delay in presentation after heart
transplantation.
• Patients are at greatest risk of life-threatening infections in
the first 3 months after transplantation and following
increases in immunosuppression for acute rejection
episodes or retransplantation.
 INFECTIONS
• 25% of patients in early post operative period--
Staphyloccus, pseudomonas and Enterobacter.
• 7% of patients—fungal (candida,
moulds(aspergillus)---nystatin and clotrimazole
after extubation.
• Pneumocystis jirovei—4% of post transplant—
3-24 m prophylaxis— cotrimaxazole ,
pentamidine, pyrimethamine
 infections
• CMV most common infectious agent identified
after transplant who have not received CMV
prophylaxis is 60-90%.
• Present guideline—oral or IV ganciclovir or
Valganciclovir for CMV positive or negative
mismatched recipients.
Infections in Cardiac Transplant Recipients
Preventive Measures and Prophylaxis against Infection
 CHRONIC COMPLICATIONS FOLLOWING
HEART TRANSPLANTATION
• Cardiac Allograft Vasculopathy:
• CAV is a unique, rapidly progressive form of atherosclerosis in
transplant recipients that is characterized in its early stages by
intimal proliferation and in its later stages by luminal stenosis of
epicardial branches, occlusion of smaller arteries, and myocardial
infarction.
• Long-term survival of cardiac transplant recipients is limited
primarily by the development of CAV, the leading cause of death
after the first year posttransplantation.
• Angiographically detectable CAV is reported in approximately
40 to 50% of patients by 5 years after transplantation
• In particular, intimal
proliferation is
concentric rather
than eccentric, and
the lesions are
diffuse, involving
both distal and
proximal portions of
the coronary tree.
• Calcification is
uncommon, and the
elastic lamina
remains intact.
 Pathogenesis of CAV

• The detailed pathogenesis of CAV is unknown, but there

are strong indications that immunologic mechanisms that
are regulated by nonimmunologic risk factors are the
major causes of this phenomenon.
• The immunologic mechanisms include acute rejection
and anti-HLA antibodies, and some of the implicated risk
factors are donor age, hypertension, hyperlipidemia, and
preexisting diabetes.
• The side effects often associated with immunosuppression
with calcineurin inhibitors or corticosteroids, e.g., CMV
infection, nephrotoxicity, and new-onset diabetes, after
transplantation also play significant roles
• CAV may begin within several weeks posttransplantation
and progress insidiously at an accelerated rate to complete
obliteration of the coronary lumen with allograft failure
secondary to ischemia.
• Ventricular arrhythmias, congestive heart failure, and
sudden death are commonly the initial presentation of
significant CAV.
• An annual coronary angiogram usually is performed for
CAV surveillance.
• Intravascular ultrasound (IVUS) is better equipped to
provide important quantitative information regarding
vessel wall morphology and the degree of intimal
thickening.
• Currently, the only definitive treatment for advanced CAV is
retransplantation, which has risks for the patient and poses
problems associated with scarcity of donor organs.
• Owing to the diffuse and distal nature of the disease,
procedures such as stenting and angioplasty are inherently less
effective than in nontransplant patients and result in a higher
need for repeated procedures.
• Several studies have demonstrated a decrease in CAV in patients
treated with a calcium channel blocker and angiotensin-
converting enzyme (ACE) and HMG-CoA reductase inhibitors.
• Newer immunosuppressive drugs, specifically the proliferation
signal inhibitors (e.g., everolimus and sirolimus), may be useful
in reducing the incidence and severity of CAV and slowing
disease progression.
• Other Chronic Complications
• Hyperlipidemia eventually develops in the
majority of recipients and is managed with dietary
restrictions, exercise, and lipid-lowering agents.
• Other complications that commonly contribute to
posttransplant morbidity include osteoporosis,
obesity, cachexia, and gastrointestinal
complications,notably cholelithiasis.
 CARDIAC RETRANSPLANTATION
• Retransplantation accounts for fewer than 3% of the
cardiac transplants currently performed.
• Primary indications for retransplantation are early
graft failure, allograft coronary artery disease, and
refractory acute rejection.
• The operative technique and immunosuppressive
regimen are similar to those employed for the initial
transplantation.
• Despite reduced mortality in the cyclosporine era,
actuarial survival remains markedly reduced.
• Intertransplant interval of 6 months or less
was associated with a dismal 1-year survival of
50% in this analysis.
• Conversely, when the interval between
primary and retransplantation was more than
2 years, 1-year survival after retransplantation
approached that of primary transplantation.
RESULTS OF HEART TRANSPLANTATION
• The superiority of heart transplantation is more
clearly evident in the medium- and high-risk patients
with end-stage heart failure.
• The overall results actually are improving despite
increasing risk profiles.
• Studies examining the health-related quality of life
(HRQOL) in patients following cardiac transplantation
demonstrate marked improvement, particularly in the
absence of complications, and approaches the general
population by 10 years after transplantation.
 THE FUTURE
• The clinical outcome of heart transplantation
has improved dramatically.
• Development of reliable, noninvasive
diagnostic studies will permit more frequent
evaluations for the early detection of rejection
and for monitoring the effectiveness of
therapy.
• Future improvements in organ preservation
permitting extension of the storage interval will have
several benefits.
• Xenografts eventually may be an additional source of
donor organs, although extended xenograft survival
remains an elusive goal.
• Complicating this alternative are unresolved ethical
issues concerning transgenic experimentation and
the potential for transmission of veterinary
pathogens to an immunosuppressed recipient.
• Thank you!