Heart transplantation

Dr. K V Siva Krishna

 Topic outline
• Definition
• Histrory
• Indications
• Recipient selection
• Donor selection
• Surgical proceedure
• Post operative management
• Immunosuppression
• Rejection
• Complications
• DEFINITION
• Cardiac transplantation is a therapeutic
procedure whereby the heart of a suitable
donor is implanted into a recipient
• Carrel and Guthrie first reported successful heterotopic
cardiac transplantation in dogs in 1905
• 1933 Mann and colleagues at Mayo Clinic reported
successful transplantation of the heart into the neck of dogs.
• Medawar was the first to develop concepts of immunology
applicable to transplantation.
• Lower and Shumway first reported successful experimental
orthotopic cardiac transplantation in 1960.
• Orman Shumway is widely regarded as the father of heart
transplantation although the world's first adult human heart
transplant was performed by a South African cardiac
surgeon,Christiaan Barnard, utilizing the techniques
developed and perfected by Shumway and Richard Lower.
• In 1964, Hardy and
colleagues performed the
first heart transplant into
a human, using a
chimpanzee heart.
• The first human-to-human
heart transplant (allograft)
was performed in Cape
Town, South Africa, by
Christiaan Barnard on
December 3, 1967.

The recipient was Louis Washkansky, a 53-year-old ex-boxer with end-stage

ischemic cardiomyopathy
-
 -
• Three days after the
Cape Town operation,
Adrian Kantrowitz
performed the second
human heart transplant in
Brooklyn.
• The recipient was an 18-
day-old neonate with
Ebstein anomaly,
refractory heart failure,
and previous
aortopulmonary shunt for
severe cyanosis
• Barnard performed the third human heart transplant on
Philip Blaiberg, a 46-year-old dental surgeon with
refractory heart failure, severe coronary artery disease,
and a large left ventricular aneurysm.
• He became the first long-term survivor, living for 18
months. Norman Shumway performed the fourth heart
transplant 4 days later, and this patient died 2 weeks
later.
• By the early 1970s, cardiac transplantation
had largely disappeared from clinical
practice.
• The report of Caves and colleagues
describing a method of transvenous
endomyocardial biopsy was an important
clinical advance because it allowed
monitoring cardiac allograft rejection on a
serial basis
DENTON COOLEY AND CARDIAC
TRANSPLANTATION
• Denton Arthur Cooley (born August 22,
1920) is
an American heart surgeon famous for
performing the first implantation of a total
artificial heart.
• Cooley had by far the largest experience.
• DeBakey, Cooley, and Shumway, had treated
two dozen patients; of them thirteen were
alive in 1970s.
 In INDIA
• Collectively, 129 heart transplants have been
performed in India since 1994 with 82 in
Chennai, 33 at AIIMS and 14 at other centres in
India.
• At KEM Hospital, Mumbai, Dr PK Sen and his
team performed the first heart transplant in India
in February 1968, months after the first attempt
at heart transplant was made by Christiaan N.
Barnard in December 1967 at South-Africa.
Barnards's patient lived for 18 days while Sen's
patient died within 24 hours, this was before
immuno-supressing drugs were made
• The Organ Transplant Bill 1994 was passed in
the Indian Parliament in May 1994 which cleared
the way for organ harvest from brain-dead
patients.
• Successively, Dr P Venugopal and his team
performed the first successful heart transplant
on August 3, 1994.
• The full extent of the law and notification
happened in 1995 after which other centres in
India performed the surgery successfully.
• Hyderabad first transplant was done in
global hospital.
• 6 heart transplants have been done in
NIMS
 Adult and Pediatric Heart Transplants
Number of Transplants by Year
5000

4500

4000
Number of transplants

3500

3000

4,939
4,838
4,802
4,754
4,735

4,683
2500

4,602
4,528

4,515

4,477
4,254
4,233
4,200

4,163
4,110

4,071
4,044

4,042
4,013
4,001
3,936
3,913
3,838
3,822

3,807
2000
3,525
2,998

1500
2,357

1000
1,261
322
187

500
671

NOTE: This figure includes only the heart transplants

that are reported to the ISHLT Transplant Registry. As
2015 such, the presented data may not mirror the changes in
the number of heart transplants performed worldwide.
JHLT.2015
JHLT. 2014Oct;
Oct;34(10):
33(10):1244-1254
996-1008
 Adult and Pediatric Heart Transplants
Number of Transplants by Year and Location
5000
Other
4500
Europe
4000
Number of transplants

North America
3500

3000

2500

2000

1500

1000

500

NOTE: This figure includes only the heart transplants

that are reported to the ISHLT Transplant Registry. As
2015 such, the presented data may not mirror the changes in
the number of heart transplants performed worldwide.
JHLT.2015
JHLT. 2014Oct;
Oct;34(10):
33(10):1244-1254
996-1008
 DIAGNOSIS IN ADULT HEART TRANSPLANTS
CAD
44% Misc. CAD
3% 38%
Misc.
Valvular ReTX 4%
3% Valvular
ReTX 3%
2%
2%
Congenital
Congenital Myopathy 2%
2% 46%
Myopathy
51%
1/1982-6/2008
1/2005-6/2008
70
% of Cases

60 Myopathy CAD
50
40
30
20

ISHLT
 cardiac transplantation during childhood aged less than 1 year.

Registry of the International Society of Heart and Lung Transplantation. J Heart Lung
Transplant 2007;26:796–807
 Cardiac transplantation aged from 1 to 10 years

Registry of the International Society of Heart and Lung Transplantation. J Heart Lun
Transplant 2007;26:796–807
 Adult and Pediatric Heart Transplants
Kaplan-Meier Survival
(Transplants: January 1982 – June 2013)
100
Median survival = 11 years
Median survival conditional on surviving 1st year = 13 years

75
Survival (%)

50

N = 112,521
N at risk at 30 years = 16
25

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Years
2015
JHLT.2015
JHLT. 2014Oct;
Oct;34(10):
33(10):1244-1254
996-1008
 Adult and Pediatric Heart Transplants
Kaplan-Meier Survival by Age Group
(Transplants: January 1982 – June 2013)
100
Adult (N=100,806)
Pediatric (N=11,384)
75

p < 0.0001
Survival (%)

50

25
Median survival (years):
Adult=10.3; Conditional=13.0
Pediatric=15.3; Conditional=20.0
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Years

2015
JHLT.
JHLT. 2015
2014 Oct;
Oct; 34(10):
33(10): 1244-1254
1009-1024
 Surviving stars

Louis Washkansky was the first recipient of heart transplant in South Africa by Dr Christian Barnard. He survived the
operation and lived for 18 days

Tony Huesman is the world's longest living heart transplant recipient who survived 31 years. He received a heart in 1978
at the age of 20 after viral pneumonia severely weakened his heart. Huesman died on August 10, 2009 of cancer. He was
operated at Stanford University under heart transplant pioneer Dr Norman Shumway

Elizabeth Craze, now 32 years old, an IT employee working for Facebook in Palo Alto is one of the youngest successful
heart transplant recipients in the world who received transplant at the age of two years and 10 months
 Indications for heart transplantation
The ACC/AHA guidelines include the following indications for
cardiac transplantation:
1. Refractory cardiogenic shock requiring intra-aortic balloon pump
counterpulsation or left ventricular assist device (LVAD);
2. Cardiogenic shock requiring continuous intravenous inotropic
therapy (i.e., dobutamine, milrinone, etc.);
3. Peak VO2 (VO2max) less than 10 mL/kg per min;
4. NYHA class of III or IV despite maximized medical and
resynchronization therapy;
5. Recurrent life-threatening left ventricular arrhythmias despite an
implantable cardiac defibrillator, antiarrhythmic therapy, or catheter-
based ablation;
6. End-stage congenital HF with no evidence of pulmonary
hypertension
7. Refractory angina without potential medical or surgical therapeutic
options.
ESC: Features that must be met before consideration for heart transplant
which are more specific and include, functional, structural and symptoms
parameters:
1. Severe symptoms, with dyspnea at rest or with minimal exertion
(NYHA class III or IV);
2. Episodes of fluid retention (pulmonary or systemic congestion,
peripheral edema) or of reduced cardiac output at rest (peripheral
hypoperfusion);
3. Objective evidence of severe cardiac dysfunction (at least one of
the following):
• Left ventricular ejection fraction less than 30%,
• Pseudonormal or restrictive mitral inflow pattern on Doppler
echocardiography,
• High left and/or right ventricular filling pressure
• Severely impaired functional capacity demonstrated by one of the
following: inability to exercise, 6-minute walk test distance less than
300 m (or less in women or patients who are age 75 and older), or
peak oxygen intake less than 12 to 14 mL/kg/min;
4. One or more hospitalizations for HF in the past 6 months.
 • Recipient Evaluation and Selection

For less ill patients whose survival is

acceptable with medical or Patients closest to death
nontransplant surgical therapy from end-stage heart
disease, the associated
noncardiac organ
If patients were selected dysfunction.
primarily on the basis of
highest expected
posttransplant survival
and quality of life at 1, 5,
and 10 years,
transplantation
would be recommended
 Decision making is important why?
1. Supply of organs is inadequate
2. Allocation of a donor heart to a patient with a relatively
better prognosis would deprive a more seriously ill
patient with a short life expectancy (but preserved
noncardiac organ function) the opportunity for
transplantation at a time when his or her benefit would
still be maximal, and
3. Cardiac transplantation is not curative, is associated with
its own chronic morbidity and survival limitation, and
should therefore not be offered to patients with
intermediate- or long-term survival approaching that of
transplantation.
Seattle heart failure model calculator
 Absolute contraindications
1. Systemic illness with a life expectancy 2 y despite HT, including
Active or recent solid organ or blood malignancy within 5 y (eg.
leukemia, low-grade neoplasms of prostate with persistently
elevated prostate-specific antigen)
2. AIDS with frequent opportunistic infections
3. Systemic lupus erythematosus, sarcoid, or amyloidosis that has
multisystem involvement and is still active
4. Irreversible renal or hepatic dysfunction in patients considered for
only HT
5. Significant obstructive pulmonary disease (FEV1 1 L/min)
6. Fixed pulmonary hypertension
• Pulmonary artery systolic pressure 60 mm Hg
• Mean transpulmonary gradient 15 mm Hg
• Pulmonary vascular resistance 6 Wood units
 Donor selection
• Brain death is a hostile environment for
the donor heart that undoubtedly
contributes to the occurrence of primary
graft failure (PGF) after HT.
Extended Criteria (Marginal) Donor Heart
 Matching Donors & Recipients
• Matching is based • Allocation is determined
upon: by:
• ABO blood group • Recipient’s priority on
• Body size compatibility (± waiting list
20% body weight) – Status code (1A, 1B, 2)
– Time accrued within a status
• Antibody screen (PRA)
• No HLA prospective • Geographic location from
matching done unless donor
high levels of pre-formed
antibodies on screening
(PRA > 10-20%)
 Matching Donor and Recipient
• Because ischemic time during cardiac transplantation is
crucial, donor recipient matching is based primarily not
on HLA typing but on the severity of illness, ABO blood
type (match or compatible), response to PRA, donor
weight to recipient ratio (must be 75% to 125%),
geographic location relative to donor, and length of time
at current status.
• In the renal transplant population, prospective
lymphocyte cross- matching is routinely performed;
however, prospective donor recipient cross-matching is
often not feasible for thoracic transplantation
 Recipient management

• The degree of sensitization of cardiac transplant

recipients is most commonly assessed by testing the
sera of prospective recipients against a panel of
lymphocytes known as the panel-reactive antibody
(PRA) screen.
• A PRA higher than 10% is considered to represent
sensitization.
• PRA determination using lymphocyte cytotoxic antibody
screening (complement-dependent cytotoxicity) is less
accurate in the detection of truly sensitized patients than
screening using flow cytometry.
• Elevated PRA titres are found more frequently in patients
with a history of multiple transfusions and previous
allograft transplant, and in multiparous women.
• Elevated PRA has more recently been identified in
patients with VADs
• The mechanism responsible for the increased production
of HLA antibodies in VAD patients is likely multifactorial
and includes T cell deregulation with prominent B cell
activation.
• Recipients of VADs who do not receive blood products
may become fully sensitized because of an
immunological reaction at the blood-VAD interface
• A commonly reported regimen consists of
monthly treatment with IV Ig at a dose of 2 g/kg.
• Plasmapheresis has been used to reduce HLA
antibody alloreactivity with variable success.
 Donor-Recipient Size Matching
• Oversizing of a donor heart can occur
• (1) in pediatric HT when the size of the donor heart for a smaller recipient
is misjudged;
• (2) when the native heart disease does not result in cardiomegaly and a
larger donor heart is implanted; or
• (3) after multiple previous operations resulting in rigidity of the
mediastinum despite maneuvers such as opening the left side of the
pericardium to allow the donor heart to protrude into the left pleural
space.
• These situations may be associated with inability to close the chest
without hemodynamically important cardiac compression.
• Severe undersizing is also an important issue, since a small donor heart
may be unable to support the circulation of a much larger recipient.
Making the determination of the adequacy of the size of a donor for a
specific recipient and judgment is required.
• Determination of donor/recipient size match is
complicated by the poor relationship between
echocardiographic adult heart size and body weight.
• As a general rule, the donor weight should be within 30%
of the recipient weight for adults.
• However, in non-urgent recipients survival was not
adversely affected by undersizing of donor hearts up to a
donor to recipient body weight ratio of 0.8.
• In contrast, survival was inferior in UNOS status 1
recipients, if they received an undersized heart
presumably due to a smaller cardiac reserve.
 Surgical Transplantation Techniques
Heart transplantation

Orthotropic heart Heterotpic heart

transplantation transplantation

Techniques

Bi atrial Bicaval approach

approach
• It is important to carefully plan the entire operation to
attempt to limit the donor ischemic time to less than 6
hours and preferably less than 4 hours.
• Ischemic times should also be limited to around 4 hours
or less in situations where the donor heart is marginal
(older donor) as well as in recipients with increased
pulmonary vascular resistance.
• Both the bicaval and the biatrial technique can be safely
performed with excellent long-term outcomes in patients
with endstage heart failure.
• Numerous studies have been performed comparing both
these techniques with varied results.
• The bicaval technique preserves normal atrial
morphology, sinus node function, and valvular function.
• As a result, it has consistently been associated with a
decreased incidence of atrial arrhythmias and the need
for pacemaker implantation.
• However, potential disadvantages include an increased
ischemic time and the possibility of narrowing of the
caval anastomosis.
Standard median sternotomy is The vena cavae are also cannulated
Performed (preferably with right-angled metal tip
cannulas) as distally as possible
 Recipient cardiectomy
the aorta is cross-clamped

cavo-atrial junction

cuff of posterior left atrial tis

BIATRIAL TECHNIQUE
incision is ideally made : medially through
The SVC is doubly ligated and the right
the ostium of the coronary sinus and
atrium is opened from the lateral IVC
laterally through the floor of the fossa
toward the right atrial appendage, to avoid
ovalis
the sinus node
Donor heart The superior vena caval cuff is trimmed at
the level of the azygous vein opening and
more if adequate recipient cuff is present

The left atrial cuff

Connecting incisions
between each of
the 4 pulmonary veins
Orthotopic heart transplantation: bicaval anastomosis
technique

Suturing the LA

Superior and inferior vena caval anastomosis

Pulmonary artery and aortic anastomosis.

Orthotopic heart transplantation:
biatrial anastomosis technique

The right atrial anastomosis is initiated at the superior end of the atrial incision. A
long 3-0 Prolene suture is used and the suture ends are carried both inferiorly and
superiorly to first complete the septal anastomosis, and then they are joined at the
lateral wall of the septum.
 Completed orthotopic heart transplantation

Reperfusion
Look for LA anastomotic site
bleed
RA RV site
Inotropic support
Vasodilators
 CPB separation
• May develop bradyarrythmias
– Require direct acting sympathomimetics, pacing
• Most grafts recover normal ventricular function
– Dysfunction secondary to ischemia
– Concern with early recognition of right ventricular failure
• RV failure
– PVR > 4 Woods units with little or no reversibility preop
– Low CO with elevated CVP (> 15) and elevated PAP (>
40). PCWP may be low.
• The most common reason for failure to
wean a heart transplant recipient from
cardiopulmonary bypass is right-sided
heart failure, evidenced by a low cardiac
output despite a rising central venous
pressure.
 Heterotopic heart transplantation

Heterotopic heart transplantation involves a donor heart being connected in parallel with
the recipient heart. The end result involves four surgical anastomoses: at the levels of
the right atria, left atria, aortas, and pulmonary trunks.
• Advantages to the heterotopic technique compared with
the traditional orthotopic approach.
• The native heart basically functions as an “assist device”
and usually can maintain circulation during:
• I. recovery of donor heart function from ischemia
sustained during transplantation.
• 2. severe rejection episodes.
• 3. the period of adaptation of a small donor heart to the
demands of the circulation.
• 4.the period of adaptation during which the PVR
decreases after transplantation and
• 5. a period of chronic rejection, while the patients awaits
retransplantation.
• There are, however, a few distinct disadvantages
inherent in heterotopic transplantation that cannot be
ignored.
• These include:
• I. the continuing risk of embolic episodes originating from
thrombi in the poorly contracting native left ventricle;
• 2. angina, which may be secondary to persistent
ischemia in the native myocardium, and
• 3. functionally significant right lower lobe atelectasis
secondary to the position of the heterotopic heart. This
can be a source of persistent pulmonary dysfunction and
recurrent pneumonia.
 Post transplant physiology
• Cardiac denervation is an inevitable consequence : a
denervated donor heart.
• The atrial remnant of the recipient remains innervated,
but no impulses will cross the suture line.
• As a result, the donor atrium is responsible for heart rate
generation.
• The transplanted heart has a higher intrinsic rate and
reduced rate variability.
• Resting heart rates range from 90 to 110 beats per
minute.
• Normal responses to changes in position, e.g. orthostatic
changes, are lost as are the variations in response to
stimuli such as the Valsalva manoeuvre, carotid sinus
massage.
• Intrinsic functions such as cardiac impulse formation and
conduction are intact.
• The Frank-Starling mechanism is also intact
• In the innervated heart, the normal acute response to a
sudden reduction in intravascular volume is a
simultaneous increase in both heart rate and contractility.
• In the denervated heart, however, the initial response via
the Frank-Starling mechanism is an increase in stroke
volume dependent on an adequate left ventricular end
diastolic volume.
• The increased contractility secondary to heart rate is a
secondary effect and is dependent on circulating
catecholamines.
• The transplanted heart is, therefore, critically preload
dependent; higher filling pressures are needed.
Early Post-operative Care of
the
Heart Transplant Recipient
 Peri-operative and Post-operative Monitoring:
• Recommendations on the Post-operative Monitoring
of Heart Transplant Recipients
• Class I:
• Peri-operative monitoring of heart transplant recipients
should include (1) continuous ECG monitoring; (2)
postoperative 12-lead ECG; (3) invasive arterial pressure
monitoring; (4) direct measurement of RAP or CVP; (5)
measurement of left atrial or pulmonary artery wedge
pressure (PAWP); (6) intermittent measurement of CO;
(7) continuous measurement of arterial oxygen
saturation; (8) intra-operative TEE; (9) continuous
assessment of urinary output.
• Level of Evidence: C.
 Hemodynamic Management

• Cardiac function of the donor heart is usually good but is

subject to influences of total denervation and
consequences of myocardial ischemia attending explant
and transplant.
• Cardiac denervation may temporarily lower heart rate;
consequently, a chronotropic catecholamine agent may
be indicated.
• Isoproterenol in doses of 0.01 to 0.1 μg · kg−1 · min−1 or
atrial pacing can be used to maintain an appropriate
heart rate for patient age and size
• Acute distention and failure of the right ventricle resulting
from excessive right ventricular afterload is occasionally
observed, most commonly in the presence of preexisting
recipient pulmonary hypertension or reactive pulmonary
vasoconstriction from CPB or protamine administration.
• Various agents may dilate pulmonary vasculature, but
the most effective combination appears to be milrinone
at 0.3 to 1 μg · kg−1 · min−1 and nitric oxide.
• Rarely, right ventricular mechanical support is required.
• The frequency and severity of RV dysfunction after HT is
variable and may be anticipated in patients with risk
factors such as
• Elevated pulmonary vascular resistance (PVR),
• Excessive bleeding,
• Pulmonary edema,
• Poor donor heart preservation before implant, poor RV
protection during allograft implantation,
• Ischemia from air embolization into the right coronary
artery, or
• Significant donor/recipient size mismatch.
• Even heart allografts that display excellent early
function typically experience a functional decline
over the first 12 postoperative hours.
• This decrease in function is believed to be due
to the effects of ischemia and reperfusion and
myocardial edema, which result in both systolic
and diastolic dysfunction.
• Reduced myocardial contractility is frequently seen after
HT as a result of donor organ trauma, preservation and
ischemia, catecholamine depletion, and donor brain
death.
• In addition, myofibrillar degeneration can result from the
sympathetic storm accompaning brain herniation
• Infusion of one or more inotropes in the early post-
operative period usually provides the hemodynamic
support needed in the first few post-operative days as
the heart allograft recovers.
• These agents are usually weaned over the first post-
operative week.
 Primary Graft Failure and Right Ventricular
Dysfunction.
• Primary graft failure after HT is the presence of severe
mechanical dysfunction without obvious anatomic
(surgical) or immunologic causes such as hyperacute
rejection.
• Primary graft failure has been variably defined in the
literature as heart allograft dysfunction requiring 2 or more
inotropes, or the need for mechanical circulatory support,
either with an IABP or a VAD within 24 hours of HT.
• The true prevalence, therefore, depends upon the criteria
used for diagnosis, but estimates range from
approximately 1.4% to 30.7%.82, 83, 96-100
• It is important to recognize that PGF can result in RV, LV,
or biventricular failure.
• Isolated RV failure is more common than
biventricular failure.
• Cardinal features include an elevated RAP > 20
mm Hg, left atrial pressure < 10 mm Hg, with
decreasing CO and high pulmonary artery (PA)
pressures, and a falling mean arterial pressure,
or normal PA pressures with falling CO.
• The pathophysiology that underlies PGF is
generally multifactorial.
• It includes recipient characteristics such as
• pulmonary arterial hypertension and
• increased PVR, and
• prior MCS,
• donor characteristics and factors such as
prolonged donor ischemia time, poor organ
preservation, and development of reactive
oxygen species.
 Pharmacologic Management of Primary Graft Failure
and Right Ventricular Dysfunction

• Intravenous Vasoactive Medications

• Class I:
• 1. Continuous infusion of an inotropic agent should be
used to maintain hemodynamic stability post-operatively.
Inotropes should be weaned as tolerated over the first 3
to 5 days. The lowest effective dose should be used.
Level of Evidence: C.
• 2. The following therapies are suggested: a.
isoproterenol 1 to 10 μg/min OR b. dobutamine 1 to 10
μg/kg/min ± dopamine 1 to 10 μg/kg/min OR c.
isoproterenol 1 to 10 μg/min ± dopamine 1 to 10
μg/kg/min OR d. milrinone 0.375 to 0.75 μg/kg/min
Level of Evidence: C.
• 3. Continuous infusion of α-adrenergic agonists including
phenylepherine, norepinepherine or epinephrine can be
used to maintain adequate mean arterial pressure.
Level of Evidence: C.
• 4. Low dose vasopressin (0.03-0.1 U/min) or methylene
blue can be added to α-agonist for vasodilatory shock.
Level of Evidence: B.
 Pulmonary Vasodilators
• Prostaglandin E1
• Prostanoids
• Prostacyclin(pg I2)
• Inhaled Nitrous oxide
• Sildenafil (PDE inh)
• Pericardial Effusion
• The development of pericardial effusion has
been shown to occur in more than 20% of HT
recipients.
• It is uncommon for pericardial effusions to
progress to cardiac tamponade.
• Echocardiography is important for recognition and timely
return to the operating room for exploration and
evacuation of the hematoma to improve RV mechanics
and function.
• Although early reports identified an association between
acute heart allograft rejection and the development or
rapid increase of post-operative pericardial effusions,
this finding was not confirmed in newer retrospective
studies.
• The three factors that predicted the development
of post-operative pericardial effusion were
absence of a previous cardiac surgery, the intra-
operative use of aminocaproic acid, and lower
recipient weight.
 Immunosuppression
• Three situations require specific combinations of
immunosuppressive therapies:
• (1) initial high-dose immunosuppression to facilitate graft
acceptance, minimize the chance of early rejection, and
potentially favour induction of tolerance;
• (2) maintenance therapy for chronic acceptance of the
allograft; and
• (3) augmented immunosuppression to reverse episodes
of acute rejection.
• Induction therapy generally includes one of two
approaches:
• 1. Daclizumab or basiliximab, which block IL-2 receptors
• 2. Antithymocyte globulin or OKT3, which targets the T-
cell receptor and causes it to be removed from the cell
surface or induces destruction of the entire cell through
multiple mechanism
• The rationale of induction therapy is to provide more
intensive immunosuppression at the time when the
alloimmune response is most intense.
• Although induction therapy is used by approximately
one-half of transplant programs, a survival benefit
attendant on its use has not been clearly established.
• Maintenance immunosuppression
• Three main group of drugs
• 1. steroids
• 2. calcineurin inhibitors
• 3. antiproliferative drugs
Hirsutism, gingival hyperplasia, and hyperlipidemia are more frequent with cyclosporine,
and diabetes and neuropathy are more frequent with tacrolimus
TICTAC trial
• Plasmapheresis
• Plasmapheresis involves removing blood from the
patient, separating plasma by centrifugation or
membrane filtration, and reconstituting the remaining
blood to the original volume with fresh plasma or 5%
albumin.
• Immunoadsorption
• Whereas plasmapheresis is a passive process in which
immunoglobulins.
• pass through the filtration membranes with the removed
plasma, immunoadsorption involves removing specific
antibodies using columns containing immunoadsorbents
that specifically bind to immunoglobulins.
• Photopheresis
• Photopheresis is an immunomodulatory
therapy based on leukapheresis.
• Total Lymphoid Irradiation
• Total lymphoid irradiation (TLI) is low-dose radiotherapy
that targets lymphoid tissues, including the cervical,
axillary, mediastinal, periaortic, and iliofemoral lymph
nodes, thymus, and spleen.
• Nonlymphoid tissue is shielded during treatment
• Both T cells and B cells are susceptible to radiation
injury.
• Rejection
• Rejection involves cell- or antibody-
mediated cardiac injury resulting from
recognition of the cardiac allograft as non-
self.
Hyper acute
• Three types Cellular rejection
Acute
Humoral rejection
Chronic
• Hyperacute rejection results when an abrupt
loss of allograft function occurs within minutes to
hours after circulation is reestablished in the
donor heart and is rare in modern-day
transplantation.
• Mediated by preexisting antibodies to allogeneic
antigens on the vascular endothelial cells of the
donor organ.
• Fix complement thrombosis, graft
failure.
• Acute cellular rejection or cell-mediated rejection
is a mononuclear inflammatory response,
predominantly lymphocytic, directed against the
donor heart;
• It is most common from the first week to several
years after transplantation, and it occurs in up to
40% of patients during the first year after
surgery.
• The key event in both the initiation and the
coordination of the rejection response is T cell
activation, moderated by interleukin-2, a
cytokine.
• Interleukin-2 is produced by CD4+ cells and to a
lesser extent by CD8+ cells and exerts both an
autocrine and a paracrine response.
• The endomyocardial biopsy remains the gold
standard for the diagnosis of acute rejection.
• Grading of acute cellular rejection.
Risk factors for rejection
Risk factors for early rejection
include younger recipient age,
female sex, female donor, positive
cytomegalovirus serologic test
results, prior infections, black
recipient race, and number of HLA
mismatches.
Other Diagnostic Modalities

Although electrocardiographic analysis, cytoimmunologic monitoring,

and a variety of radionuclide techniques have been investigated,
echocardiography is the primary modality (other than endomyocardial
biopsy) routinely used for rejection surveillance.

When acute depression of systolic function (ejection fraction < 50%) is

observed without another clearly identified cause, acute cellular or
humoral rejection should be assumed to be present and appropriately
treated, with or without confirmation from endomyocardial biopsy.
• Identifying a Rejection Episode:
• A major part of care after cardiac transplantation is
directed toward identifying rejection.
• Endomyocardial biopsy remains the most important
method of identification and, along with echocardiographic
evaluation, is generally performed every 7 days for the
first 4 to 6 postoperative weeks.
• Biopsy frequency is gradually reduced to every 3 to 4
months.
• Subltle symptoms that include unexplained fever, joint
pain, personality change, and any symptom that can
result from cardiac failure are an indication for emergency
endomyocardial biopsy and immediate institution of
therapy if results are positive.
• Mild rejection does not require specific intervention.
• Moderate rejection usually requires some degree of
intensification of immunosuppression, which generally
includes an oral or intravenous bolus of corticosteroid, and
an increase in regular therapies.
• Any rejection with haemodynamic compromise requires
haemodynamic support commensurate with the clinical
presentation, and aggressive intensification of
immunosuppression.
• 1 to 8 pulses of intra venous
methylprednisolone in doses
of 10 – 20 mg/kg each.
• Persistent rejection may need
biological immune modulators
such as ATG or anti CD3
monoclonal
antibodies(OKT3).
• Reccurent refractory
episodes may respond to
tacrolimus (0.1mg /kg /day).
• Antibody-mediated rejection is a serious complication
after heart transplantation and is manifested as “graft
dysfunction” or hemodynamic abnormalities in the
absence of cellular rejection on biops
• Patients at greatest risk for antibody-mediated rejection
are women and patients with a high PRA level or a
positive crossmatch.
• It is estimated that significant antibody-mediated
rejection occurs in about 7% of patients, but the rate may
be as high as 20%.
• Immunofluorescence studies are currently the primary modality for
identifying fibrinogen, IgG, IgM, and complement components in the
endomyocardial biopsy,H2 which indicates humoral rejection.
• Chronic rejection, or late graft failure, is an
irreversible gradual deterioration of graft function
that occurs in many allografts months to years
after transplantation
• The current concept suggests that donor heart
dysfunction in the chronic stages of maintenance
immunosuppression is either related to chronic
rejection mediated by antibodies, or a result of
progressive graft loss from ischemia.
 Complications
Infection
• Infections cause
approximately 20% of deaths
within the first year after
transplantation and continue
to be a common contributing
factor in morbidity and
mortality throughout the
recipient’s life.
The most common infections in the first
month after surgery are nosocomial
bacterial and fungal infections related to
mechanical ventilation, catheters, and
the surgical site
• Mortality is highest for fungal infections, followed by
protozoal, bacterial, and viral infections.
• Aspergillosis and candidiasis are the most common
fungal infections after heart transplantation.
• Viral infections, especially those due to cytomegalovirus,
can enhance immunosuppression, potentially resulting in
additional opportunistic infections.
• Pneumocystis jirovecii, and herpes simplex virus
infections and oral candidiasis, to be used during the first
6 to 12 months after transplantation.
• Prophylactic intravenous ganciclovir or oral
valganciclovir generally is given for variable periods in
cytomegalovirus-seronegative recipients of a transplant
from a cytomegalovirus-positive donor.
• Medical Complications and Comorbid
Conditions.
Glucocorticoids Calcineurin inhibitors Insulin resistance

New onset diabetes

Increased BMI
African Americans

Patient survival and graft survival, may be adversely affected

Renal Insufficiency
Hypertension
• The excess risk of
hypertension is related
primarily to the use of
• Calcineurin inhibitors
because of both direct effects
of the drugs on the kidney
and the associated renal
insufficiency that also is
highly prevalent. The
incidence of hypertension
may be lower with tacrolimus
than with cyclosporine
• Post-transplantation
hypertension is difficult to
control and often requires a
combination of several
antihypertensive agents..
Hyperlipidemia
• Typically,
• total cholesterol, low-density
lipoprotein (LDL) cholesterol,
and triglycerides increase by 3
months after transplantation
and then
• generally fall somewhat after
the first year.
• Cyclosporine increases serum
LDL cholesterol and binds
• to the LDL receptor, decreasing
its availability to absorb
cholesterol
• from the bloodstream.
• Malignancy
• Neoplastic disorders after cardiac transplantation arise
from three major causes: preexisting malignancies,
transmission of malignancy from donor to recipient, and
de novo malignancy arising after transplantation.
• Tumors most likely to recur in heart transplant recipients
are carcinoma of the lung, lymphoma, skin cancer, and
carcinoma of the bladder
• The incidence of de novo recipient malignancy is
approximately 100 times that of the non–age-controlled
general population.
The basic options for treatment of PTLPD
(1) reduction of immunosuppression,
(2) surgical extirpation,
(3) chemotherapy,
(4) antivirals,
(5) anti–B-cell antibodies,and
(6) cell-based therapies
• Cardiac allograft vasculopathy: annual incidence
rate of 5% to 10%.
• CAV is detectable by angiography in 8% of
survivors within the first year, in 32% within the
first 5 years, and in 43% within the first 8 years
after HTx.
• Severe CAV is positively correlated with
persistent inflammation and a higher degree of
HLA mismatch.
• In contrast with eccentric lesions seen in atheromatous
disease, CAV results from neointimal proliferation of
vascular smooth muscle cells, so that it is a generalized
process.
• Characterized by concentric narrowing that affects the
entire length of the coronary tree, from the epicardial to
the intramyocardial segments, leading to rapid tapering,
pruning, and obliteration of third-order branch vessels
• The first clinical manifestation of CAV may be
myocardial ischemia and infarction, heart failure,
ventricular arrhythmia,or sudden death.
• Angina is rare because of denervation of the
heart.
Pathophysiology is multi factorial
• Invasive Detection of CAV
• Intravascular Ultrasound Intravascular ultrasound (IVUS)
is the most sensitive tool for the diagnosis of CAV. IVUS
allows a reproducible view of both actual lumen diameter
and the appearance and thickness of the intima and
media
• Rapidly progressive CAV, defined as an increase of 0.5
mm in maximal intimal thickness within the first year after
HTx, is associated with a significantly increased risk of
all-cause death, myocardial infarction, and the
subsequent development of angiographically severe
CAV.
• Coronary Angiography
• Coronary angiography is still the standard for the
diagnosis of CAV in most transplant centers, and the
angiographic detection of significant epicardial coronary
stenoses conveys a poor prognosis.
• CAV is detectable by angiography in 30% to 50% of HTx
survivors after 5 years
• Noninvasive Screening
• Dobutamine Stress Echocardiography The sensitivity of
dobutamine stress echocardiography compared with
coronary angiography is 80%.
• When intimal thickening by intravascular ultrasound is
taken as the “gold standard,” dobutamine stress
echocardiography shows specificities of up to 88%.63
• Single-Photon Emission CT
• Annual myocardial single-photon emission CT (SPECT)
has a high negative predictive value and appears to be
well suited to screening for significant CAV.
• Multidetector CT
• MDCT with adaptive multisegment reconstruction has a
sensitivity and specificity of 86% and 99%, respectively
• Biomarkers and Gene Profiling
• Elevated C-reactive protein concentrations are
associated with progression of CAV,
• Whereas persistently elevated levels of troponin I
are associated with a significantly increased risk
for subsequent development of CAV.
• The clinical use of brain natriuretic peptide (BNP)
levels as a predictor of survival after HTx remains
controversial.
• Therapeutic Options
• Statins
• Vasodilators
• Endothelial Protection
• Infection and CAV ( CMV INFECTION)
• Immunosuppression: mTOR inhibitors
• The use of everolimus from the time of
HTx has shown to preserve the coronary
artery lumen at 1 year.
• Emerging New Strategies for the Prevention or
Treatment of CAV
• Three different strategies for CAV are emerging: (1)
inhibition of growth factors, cytokines, and circulating
antibodies; (2) cell therapy; and (3) tolerance
induction.
• New therapeutic strategies should be directed against
matrix formation
• Sensitive methods for detecting circulating antibodies
and improved therapeutic strategies
(eg:photophoresis) against these antibodies are
currently under investigation.
• FUTURE PERSPECTIVES
• Need for improved immunosuppression with less
rejection, cardiac allograft vasculopathy and side
effects
• Need for better non-invasive methods to detect
acute and chronic rejection
• Need to focus on improved survival and quality
of life
• Challenges in performing long-term adequately
powered multi-centered trials
Thank you