Cardiac transplantation

22/09/17HEART TRANSPLANTATION
1

Topic outline
History
Indications
Recipient selection
Donor selection
Post operative
management
Immunosuppression
Rejection
Complications
2

1933 Frank Mann successful transplantation of
the heart into the neck of
dogs
1960 Lower and ShumwayOrman Shumway -
father of heart transplantation
experimental orthotopic
cardiac transplantation
•1964 •Hardy first heart transplant into a
human, using a chimpanzee
heart
December 3,
1967
•Christiaan Barnard (student of
Lower)
first human-to-human heart
transplant -
Dec 6 1967 Adrian Kantrowitz second human heart transplant
in Brooklyn
First paediatric transplantation
Barnard third human HT
Norman Shumway fourth HT
1969 Denton Arthur Cooley first implantation of a total
artificial heart.
3

February 1968 KEM Hospital, Mumbai,
Dr PK Sen
first heart transplant
patient died within 24
hours
August 3, 1994. Dr P Venugopal-AIIMS first successful heart
transplant
ORGAN TRANSPLANATION ACT 1994
4

• first human-to-human
heart transplant -
Christiaan Barnard (Cape
Town, South Africa)
The recipient was Louis Washkansky, a 53-year-old ex-boxer with end-stage
ischemic cardiomyopathy 22/09/17HEART TRANSPLANTATION
5

early 1970s- cardiac transplantation had largely
disappeared from clinical practice.
Caves = transvenous endomyocardial biopsy in
1973
cyclosporine - 1981.
6

 Hyderabad - first transplant was done in global hospital.
7

8

ACC/AHA
Absolute indications
• refractory cardiogenic shock requiring IABP or MCS , dependence on IV
positive inotropic support to maintain vital organ perfusion
• peak VO2<10 ml/kg/min
• severe symptoms of ischemia not amenable to CABG or PCI
• recurrent, symptomatic VT refractory to medical therapy or catheter
ablation.
Relative indications
• peak VO2 between 10 and 14 ml/kg/min
• recurrent, unstable fluid balance/renal function not due to patient
nonadherence with medical therapy
Insufficient indications
• LV EF < 20%
• NYHA -class III or IV symptoms
• peak VO2 >15 ml/kg/min
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Seattle heart failure model calculator
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CARDIOPULMONARY
EXRECISE TEST
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12

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 Adherence with medical care?
 Psychological and emotional stability?
 Adequate caregiver support?
 Alcohol use?
 smoke cigarettes or chew tobacco?
 Illicit drug use: ?
 Cognitive abilities: ?
14

 Many patients with advanced ischemic cardiomyopathy-
benefit from PCI or CABG
 advanced heart failure secondary to stenotic or
regurgitant valvular disease - avoid or delay heart
transplant by high-risk valvular repair or replacement.
 reversible causes of severe heart failure =
tachyarrhythmias (managed with antiarrhythmics or
catheter ablation), heavy alcohol use, fulminant
myocarditis, or peripartum cardiomyopathy.
15

16

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Decision making is important
why?
1. Supply - inadequate
2. Allocation to a patient with a relatively better prognosis
would deprive a more seriously ill patient
3. not curative - not be offered to patients with
intermediate- or long-term survival approaching that of
transplantation.
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CONTRAINDICATIONS
malignancy
 Active or recent malignancy - absolute CI (solid tumors, lymphomas, and
leukemia)
 disease-free for at least 5 years with an absence of cancer-treatment
related side effects (e.g., bleomycin or radiation-induced lung disease) –not CI
 Skin cancer (except for melanoma) is not a contraindication
Infection
 Active infection with a treatable organism = relative CI
 Chronic active hepatitis B or C infection =CI unless viremia is cleared with
treatment and liver biopsy does not show cirrhosis or malignancy.
HIV/AIDS
 absolute contraindication
 opportunistic infection with immunosuppression
Ventricular assist device infection
 not a contraindication
21

CONTRAINDICATIONS
Systemic illness
 Systemic illness with multiorgan involvement or
associated with life-expectancy of < 2 years is CI
 advanced sarcoidosis, SLE, and scleroderma.
 Renal dysfunction: stage 4 or 5 CKD.
 Hepatic dysfunction: biopsy-proven cirrhosis
 Pulmonary dysfunction: FEV1 <1.0 L. FVC, TLC, or
DLCO <40% to 50%
 Progressive and irreversible neurologic or
neuromuscular disorder
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CONTRAINDICATIONS
 amyloidosis ( AL type) = sequential cardiac and stem cell
transplantation, with or without adjuvant chemotherapy.
 rule out other organ involvement (i.e., Scr<2.0 mg/dl, ALP< 250 U/L, no
pleural effusions, no orthostatic hypotension).
 familial amyloidosis = heart + liver transplant.
 Active peptic ulcer disease, GI bleeding, and recent stroke or seizure
= relative acute contraindications
 Acute PTE = systemic anticoagulation for at least 2 to 3 months
 Cardiac cachexia (BMI <18) = oral caloric supplementation or cycled
tube feedings
 severe PAD or cerebrovascular disease that is not amenable to
revascularization-CI
 uncorrected AAA>5 cm -CI
23

CONTRAINDICATIONS
 Age - no absolute age cut-off
 uncomplicated diabetes –Not CI
 diabetes associated with moderate-to-severe end-organ
dysfunction = relative CI
 diabetic nephropathy = combined heart and kidney
transplant
 Obesity-relative CI
24

Donor Selection Criteria
 Age <55 y
 Absence of significant structural abnormalities
 LVH (wall thickness >13 mm )
 Significant valvular dysfunction
 Significant congenital cardiac abnormality
 Significant CAD
 Adequate physiologic function of donor heart
 LVEF ≥45% or
 Achievement of target hemodynamic criteria after hormonal resuscitation and hemodynamic
management
 MAP >60 mmHg
 PCWP 8–12 mmHg
 Cardiac index >2.4 L/min x m2
 CVP-4–12 mmHg
 SVR-800–1200 dyne/seccm5
 Dopamine or dobutamine requirement <10 g/kg/min
 Negative hepatitis C , hepatitis B , and HIV
 Absence of active malignancy or overwhelming infection
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Extended Criteria (Marginal)
Donor Heart
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Matching Donors & Recipients
 Matching;
• ABO blood group
• Body size compatibility (±
20% body weight)
• Antibody screen (PRA)
• No HLA prospective
matching done unless
high levels of pre-formed
antibodies on screening
(PRA > 10-20%)
 Allocation :
• Recipient’s priority on
waiting list
– Status code (1A, 1B, 2)
–
• Geographic location from
donor
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Matching Donor and Recipient
 renal transplant - prospective lymphocyte cross-
matching
 not feasible for thoracic transplantation
29

Recipient management
 Degree of sensitization - sera of prospective recipients
against a panel of lymphocytes
 panel-reactive antibody (PRA) screen.
 PRA >10% = sensitization.
1. lymphocyte cytotoxic antibody screening
(complement-dependent cytotoxicity) - less accurate
2. flow cytometry-more accurate
30

 Elevated PRA titres
multiple transfusions
 previous allograft transplant
multiparous women.
VADs-immunological reaction at the blood-VAD
interface
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32

Over-sizing
• inability to close the chest without hemodynamically
important cardiac compression
• majority of male-to-female transplants were
oversized
• hyperperfusion syndrome - headache, drowsiness
• survival –not altered
Severe under-sizing
• Donor–recipient weight ratio <0.8 -inferior survival
• small donor heart may be unable to support the
circulation of a much larger recipient
Donor-Recipient Size Matching
33

 Determination of donor/recipient size match is
complicated by the poor relationship between echo adult
heart size and body weight.
 donor weight should be within 30% of the recipient
weight for adults.
34

cold preservation
 organ is initially perfused with a cold solution and then
packed in sterile ice
 Ischemic injury occurs
 During this time the organ is without blood or oxygen
35

Organ Care System (OCS)
 maintained in a beating state - reduce ischemic injury
 perfused and oxygenated with its own blood supply
36

 limit the donor ischemic time to less than 6 hours and
preferably less than 4 hours.
 Always limited to around 4 hours
 donor heart is marginal (older donor)
 recipients with increased PVR.
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Heart
transplantation
Orthotropic
heart
transplantation
Bi atrial
approach
Bicaval
approach
Heterotpic
heart
transplantation
38

Biatrial anastomosis
ischemic time is shorter
atrial dysfunction - size mismatch of atrial
remnants
arrhythmia (sinus node dysfunction,
bradyarrhythmias, and AV conduction
disturbances)
PPM =10-20%
40

Bicaval anastomosis
Préserves normal atrial morphology, sinus node function, and
valvular function.
Decreases risk for MR or TR
 narrowing of the SVC and IVC- make biopsy surveillance difficult
decreased atrial arrhythmias and the need for PPI
increased ischemic time
41

Heterotopic heart
transplantation
donor heart being connected in parallel with the recipient heart
End
42

< 0.3% of heart transplants.
beneficial if the patient :
Has PAH
Has HF that is potentially reversible (myocarditis)
allowing future removal of the transplant.
 negative aspects :
 difficult operation
No anginal relief.
Need for anticoagulation (the native heart can
cease to function and thrombose).
Contraindicated if the native heart has significant TR
or MR
43

heterotopic technique
 native heart functions as an “assist device” and can
maintain circulation during:
 1. 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
 5. a period of chronic rejection
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 Emboli - thrombi in the poorly contracting native LV
 significant right lower lobe atelectasis -position of the
heterotopic heart
 persistent pulmonary dysfunction and recurrent
pneumonia.
45

Post transplant physiology
Cardiac denervation
 atrial remnant of the recipient remains innervated, but no impulses
will cross the suture line.
 donor atrium is responsible for heart rate generation.
 higher intrinsic rate (90 to 110 bpm)
 reduced rate variability.
 acceleration of heart rate is slower during exercise
 Diurnal changes in blood pressure are abolished
 Normal responses to changes in position(orthostatic changes),
Valsalva manoeuvre, carotid sinus massage are lost
46

 Intrinsic functions such as cardiac impulse formation and
conduction are intact.
 Frank-Starling mechanism is also intact
 normal - acute response to a sudden reduction in
intravascular volume is a simultaneous increase in both heart
rate and contractility.
 denervated heart- initial response via the Frank-Starling
mechanism is an increase in stroke volume dependent on an
adequate LV end diastolic volume.
 critically preload dependent; higher filling pressures are
needed.
 Bi-atrial connection means less atrial contribution to
stroke volume
 Diastolic dysfunction is very common ( stiff myocardium
from some degree of rejection and from denervation)
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Early Post-operative Care of the
Heart Transplant Recipient
48

Peri-operative and Post-operative
Monitoring:
Post-operative Monitoring
 continuous ECG monitoring
 invasive arterial pressure monitoring
 direct measurement of RAP or CVP
 measurement of PCWP
 intermittent measurement of CO
 continuous measurement of PaO2
 intra-operative TEE
 continuous assessment of UO
49

Hemodynamic Management
 donor heart - 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
50

Acute distention and failure of
the RV
 severe mechanical dysfunction without anatomic
(surgical) or immunologic causes such as hyperacute
rejection.
 requiring 2 or more inotropes, or the need for mechanical
circulatory support( IABP or a VAD ) within 24 hours of
HT.
 1.4% to 30.7%.
 RV, LV, or biventricular failure.
51

Even heart allografts that display excellent early
function typically experience a functional decline
over the first 12 postoperative hours.
due to
ischemia
 reperfusion
 myocardial edema
52

Reduced myocardial
contractility
donor organ trauma
Size mismatch
preservation and
ischemia
Air embolism into
RCA
catecholamine
depletion
donor brain death.
myofibrillar
degeneration
sympathetic storm
accompaning brain
herniation 22/09/17HEART TRANSPLANTATION
53

Isolated RV failure
MC than biventricular failure
elevated RAP > 20 mm Hg
LAP < 10 mm Hg
decreasing CO
high PASP
falling MAP.
54

pathophysiology
-multifactorial.
recipient
PAH
increased PVR
prior MCS
donor
characteristics
prolonged
donor ischemia
time
poor organ
preservation
development of
ROS. 22/09/17HEART TRANSPLANTATION
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56

Pericardial Effusion
> 20%
 tamponade-uncommon
exploration and evacuation of the hematoma to
improve RV mechanics and function.
57

OUTCOMES AFTER CARDIAC
TRANSPLANTATION
Survival rate
1-year survival rate 82%
3 - year survival rate
74%
10-year survival
50%
United States Scientific Registry MCC of mortality - CAV
58

initial high-dose
graft acceptance
minimize early
rejection
induction of
tolerance
maintenance chronic acceptance
augmented
immunosuppression
reverse episodes of
acute rejection.
Immunosuppression
59

Induction therapy
 Daclizumab or basiliximab ( block IL-2 receptors ) or
 Antithymocyte globulin or OKT3
60

Maintenance
immunosuppression
Triple drug
regimens
1. steroids
2. calcineurin
inhibitors (CyC,
TAC),
3. anti-proliferative
drugs (AzA, MMF)
modified triple-drug
protocol
skipping
corticosteroids
after a certain time
61

62

Rejection
Hyper
acute
Hours To Days
Acute
Days To Week
Cellular Humoral
Chronic
Months to years .CAV
63

64

65

Hyperacute rejection
abrupt loss of allograft function
 within minutes to hours
 rare
 preexisting antibodies to allogeneic antigens on
the vascular endothelial cells of the donor organ.
66

Acute cellular rejection or cell-mediated rejection
 first week to several months after
up to 40% of patients during the first year
IL -2 = CD4+ cells and to a lesser extent by
CD8+ cells
EMB- gold standard
67

 Grading of acute cellular rejection.
68

younger recipient age
female sex
female donor
positive CMV serologic test
prior infections
black recipient race
number of HLA mismatches.
Risk factors for rejection
69

Identifying a Rejection Episode:
 Echo –low specificity
 EMB–gold standard
 unexplained fever, joint pain, personality change, and any
symptom that can result from cardiac failure - emergency
endomyocardial biopsy
 acute depression of systolic function (ejection fraction <
50%) without another clearly identified cause-EMB
70

71

 Mild rejection - no intervention.
 Moderate rejection - intensification of
immunosuppression( oral or intravenous bolus of
corticosteroid, and an increase in regular therapies)
 haemodynamic compromise requires haemodynamic
support - aggressive intensification of immunosuppression.
72

 1 to 8 pulses of IV
methylprednisolone ( 10 – 20
mg/kg )
 Persistent rejection - ATG or
anti CD3 monoclonal
antibodies(OKT3).
 Reccurent refractory
episodes - tacrolimus (0.1mg
/kg /day).
73

Antibody-mediated rejection
 serious complication
 7% to 20%.
 “graft dysfunction” or hemodynamic abnormalities in the
absence of cellular rejection on biopsy
 High risk
A. women
B. high PRA level
C. positive crossmatch.
74

 Immunofluorescence studies are currently the primary modality for
identifying fibrinogen, IgG, IgM, and complement components in the
endomyocardial biopsy,H2 which indicates humoral rejection.
75

Chronic rejection, or late graft failure
irreversible gradual deterioration of graft function
 antibodies
ischemia
76

Complications
Infection
 20% of deaths within the first
year
 morbidity and mortality
throughout the recipient’s life.
first month - nosocomial bacterial
and fungal infections
77

 Mortality
 fungal > protozoal> bacterial> viral infections.
 Aspergillosis and candidiasis-mc
 Viral infections( cytomegalovirus) = enhance
immunosuppression→ opportunistic infections.
 Chagas reactivation can occur posttransplant -
prophylactic antitrypanosomal therapy
78

79

DM
Glucocortic
oids
Calcineurin
inhibitors
Insulin
resistance
Increased
BMI
African
Americans
80

Hypertension
 Calcineurin inhibitors
 Cyclosporine >
TACROLIMUS
 difficult to control -
combination of several
antihypertensive agents
Hyperlipidemia
 ↑ TC /LDL-C /TG
 increase by 3 months
 fall somewhat after the
first year.
 Cyclosporine= increases
serum LDL
81

Malignancy
preexisting malignancies
transmission of malignancy
from donor to recipient
de novo malignancy (100
times that of the non–age-
controlled general population)
82

MALIGNANCY
carcinoma of the lung
Lymphoma
posttransplantation
lymphoproliferative disorder
(PTLD), a type of non-Hodgkin’s
lymphoma - EBV.
skin cancer
carcinoma of the bladder
83

treatment of PTLPD
(1)reduction of immunosuppression,
(2)surgical extirpation,
(3) chemotherapy,
(4) antivirals,
(5) anti–B-cell antibodies,and
(6) cell-based therapies
84

annual incidence - 5% to 10%.
8% -first year
32% -first 5 years
43% -first 8 years
Cardiac allograft vasculopathy
85

86

 neointimal proliferation of vascular smooth muscle cells
 generalized process
 concentric narrowing - epicardial to the intramyocardial
 rapid tapering, pruning, and obliteration of third-order
branch vessels
87

88

clinical manifestation
MC - asymptomatic
myocardial ischemia and MI
 HF
 VT
 SCD
Angina is rare (denervation )
89

 usually asymptomatic - frequent surveillance


90

Invasive Detection of CAV
 IVUS- most sensitive - actual lumen diameter and
appearance and thickness of the intima and media
91

92

93

94

Dobutamine Stress Echocardiography
 more sensitive than exercise
 sensitivity -80%.
 specificities of up to 88%.
 Regional deformation parameters - improve sensitivity.
 peak systolic longitudinal strain rate of <0.5/s
 Mitral annular systolic, early diastolic, and late diastolic
velocities at peak dobutamine-stress
95

SPECT
 high negative predictive value
 limited sensitivity - rely on the development heterogeneity in
MBF or contractility(CAV is diffuse)
 screening for significant CAV.
Multidetector CT
 sensitivity and specificity of 86% and 99%
 High resting heart-rate + delayed and variable β-blocker
response –challenge
 limited ability to assess smaller vessels
 CAC scoring - limited value (calcification is absent )
96

Adenosine Supersensitivity
Enhanced sensitivity of the denervated
sinus and AV nodes
higher rates of sinus pauses and second-
degree and third-degree AV block
Dobutamine > exercise >adenosine
97

Guidelines
Level of Evidence
DSE and SPECT class II a B
CTA
class II b C
PET and CMR
-
Annual or biannual
invasive coronary
angiography
Class 1 C
International Society of Heart and Lung Transplantation Guidelines
98

Therapeutic Options
 Statins
 Vasodilators
 CCB- slow the progression of CAV
 ACE inhibitors --partially improve allograft microvascular endothelial dysfunction
 synergistic beneficial effect - CCB and an ACE inhibitor
 Endothelial Protection
 Infection and CAV ( CMV INFECTION)-Ganciclovir treatment /aggressive CMV
prophylaxis
 Immunosuppression
 Tacrolimus> cyclosporine
 MMF>AZA
 Sirolimus/everolimus
99

Revascularization
PCI
 only palliative
 no long-term survival benefit
 restenosis rate after PCI -high
 stenting only in patients with discrete lesions who have an abnormal stress
test or symptoms suggestive of myocardial ischemia.
CABG
 high periprocedural mortality of up to 40%
 limited midterm success
severe, advanced CAV- repeat transplantation.
100

RE-TRANSPLANTATION
 3%-4% of heart transplants(HT)
 survival - significantly worse than primary heart transplantation
 1year --- 55% +/- 8%
 5 years-- 55% +/- 8%,
 10 years-- 22% +/- 7%
 graft atherosclerosis
 allograft rejection
101

Thank you
10
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Cardiac transplantation

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