2. HISTORY OF HEART TRANSPLANTATION
The innovative French surgeon Alexis Carrel performed
the first heterotopic canine heart transplant with Charles
Guthrie in 1905.
Frank Mann at the Mayo Clinic further explored the idea
of heterotopic heart transplantation in the 1930s
In 1946, after unsuccessful attempts in the inguinal region,
Vladimir Demikhov of the Soviet Union 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.
3. In 1967 – on December3,
Christiaan Barnard
performed the first
human-to-human heart
transplant at the Groote
Schuur Hospital in Cape
Town, South Africa.
5. Adrian Kantrowitz performed
the first pediatric heart
transplant in the world on
December 6, 1967 at
Maimonides Hospital in
Brooklyn, New York barely 3
days after Christiaan
Barnard.
6. Over the next several years, poor early clinical results led
to a moratorium on heart transplantation, with only the
most dedicated centers continuing experimental and
clinical work in thefield.
The pioneering efforts of
Shumway and his
colleagues at Stanford
eventually paved the way
for the re-emergence of
cardiac transplantation in
the late 1970s.
7. He is widely regarded as the father of heart transplantation
although the world's first adult human heart transplant
was performed by Christiaan Barnard in South Africa
utilizing the techniques developed and perfected
by Norman Shumway &Lower.
The introduction of transvenous endomyocardial biopsy by
Philip Caves in 1973finally provided a reliable means for
monitoring allograft rejection.
The advent of the immuno-suppressive agent cyclosporine
dramatically increased patient survival and marked the
beginning of the modern era of successful cardiac
transplantation in 1981.
8. Heart transplantation is now a widely accepted therapeutic
option for end-stage cardiac failure, with more than 4000
procedures performed annually.
9. CARDIAC TRANSPLANT
IN INDIA
Organ transplantation
act in passed by
Indian parliament in
May 1994
Dr. P.Venugopal led a
team of doctors to
perform the first
successful heart
transplant in India on 3
August 1994.
This was the first of the
26 heart transplant
procedures performed
by Dr. Venugopal
10. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immuno-suppression
Rejection of graft
Complications
11. RECIPIENT SELECTION AND
MANAGEMENT
Indications
Systolic heart failure (defined by LVEF<35%) with severe
functional limitations and/or refractory symptoms despite maximal
medical therapy (NYHA Functional Class IIIb–IV)
Maximal oxygen uptake (VO2 max) of <12–14ml/kg/min &/or VO2
max <50% of predicted &/or VE/VCO2 slope >35 on
cardiopulmonary exercise stress testing
Cardiogenic shock not expected to recover
Ischemic heart disease with intractable angina not amenable to
surgical or percutaneous revascularization and refractory to
maximal medical therapy
Intractable ventricular arrhythmias, uncontrolled with standard
antiarrhythmic therapy, device therapy, and/or ablative therapy
Severe symptomatic hypertrophic or restrictive cardiomyopathy
Congenital heart disease in which severe fixed pulmonary
hypertension is not a complication
Cardiac tumors with low likelihood of metastasis
12. Cardiomyopathy (ie, dilated, hypertrophic, or restrictive)
Anatomically uncorrectable congenital heart disease (eg,
HLHS, pulmonary atresia with intact ventricular
septum plus sinusoids, congenitally corrected
transposition of the great arteries with single ventricle and
heart block, and severely unbalanced atrioventricular
septal defects)
Potentially correctable congenital heart disease associated
with greatly increased operative risk (eg, severe Shone
complex, interrupted aortic arch and severe subaortic
stenosis, critical aortic stenosis with severe endocardial
fibroelastosis, and Ebstein anomaly in a symptomatic
newborn)
Refractory heart failure after previous cardiac surgery
Significant cardiac allograft vasculopathy or chronic graft
dysfunction of a previous heart transplant
13. GOAL OF HEART TRANSPLANT
EVALUATION :-
• SICK ENOUGH
• WELL ENOUGH
• CAN ADAPT A NEW TRNAPLANT
LIFESTYLE
14. • The most potent predictor of outcome in ambulatory
patients with heart failure has been a symptom-
limited metabolic stress test to calculate peak
oxygen consumption or peak VO2.
• Generally a peak VO2 >14ml/kg/min has been
considered “too well” for transplant as
transplantation has not been shown to improve
survival over conventional medical therapy.
• Peak VO2 10 to 14 ml/kg/min had some survival
benefit, and peak VO2 <10 had the greatest
survival benefit
15.
16. • A newer score developed by Myers & colleagues based on CPX
stress testing includes ventilator efficiency , VO2 max , HR recovery
, oxygen uptake efficiency slope , expired co2 & chronotropic
response, a score of >15 portends a high 1-year mortality rate in
excess of 40 %
17. Contraindications
Irreversible severe pulmonary arterial hypertension
Pulmonary vascular resistance (PVR) >5 Wood units
Transpulmonary gradient >15–20mmHg
PAsystolic pressure >50–60 mmHg or >50% of systemic
pressures
Advanced age (>70years)
Active systemic infection
Active malignancy or recent malignancy with high
risk of recurrence
Diabetes mellitus with:
End-organ damage (neuropathy,nephropathy,
proliferative retinopathy)
18. Marked obesity (BMI >30 kg/m2 )
Advanced non-cardiac vascular disease – symptomatic
cerebro-vascular disease or Severe peripheral arterial
disease not amenable to revascularization
Systemic process with high probability of recurrence in the
transplanted heart
Amyloidosis
Sarcoidosis
Hemochromatosis
Chagas disease
Irreversible severe renal, hepatic, or pulmonary disease
Psychosocial factors that may impact on patient's ability to
comply with complex medical regimen
History of poor medicalcompliance
Uncontrolled psychiatric illness (anxiety,depression,
psychosis)
Active or recent substance abuse (alcohol, tobacco, or illicit
drugs)
19. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
20. Evaluation of Cardiac Transplantation
Recipient
• Right and Left Heart Catheterization.
• Cardiopulmonary testing.
• Labs including CBC, LFT, UA, coags, TSH, UDS, ETOH
level, HIV, Hepatitis panel, CMV IgG, RPR / VDRL, PRA
(panel of reactive antibodies), ABO and Rh blood type,
lipids.
• CXR, PFT’s including DLCO, EKG.
• Substance abuse history and evidence of abstinence for
at least 6 months and enrollment in formal rehabilitation.
• Mental health evaluation including substance abuse hx
and social support.
• Financial support.
• Weight no more than 140% of ideal body weight.
21. Status Listing
• Once accepted as a transplant candidate, a
patient is entered on the list and given a status
based upon severity of illness.
• If status changes, time accrual starts over.
Status I heart recipients are given preference
over status I heart / lung recipients who are
given preference over status II heart recipients.
• geographic Zones are established to give local
priority to recipients within 500 to 1000 mile
radius centered on donor site.
23. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
24. DONOR SELECTION AND
MANAGEMENT
Acceptance of the concept of irreversible brain death,
both legally and medically
Patients with irreversible brain injury accompanied
by the intent to withdraw life support are considered
to be potential organ donors.
The heart does not need to stop for valid
declaration of death & complete absence of
brainstem function is not required…
UNIFORM DETERMINATION OF DEATH ACT
1981
25. CRITERIA FOR DETERMINING BRAIN DEATH
Clinical Evaluation
Mechanism of brain injury is sufficient to account for
irreversible loss of brain function
Absence of reversible causesof CNS depression
CNS depressant drugs
Hypothermia (<32°C [85°F])
Hypotension (MAP <55 mmHg)
Absence of neuromuscular blocking drugs that may confound
the results of the neurologic exam
No spontaneous movements, motor responses, or posturing
No gag or cough reflexes
No corneal or pupillary light reflexes
No oculovestibular reflex (cold calorics)
26. Confirmatory Tests
Apnea test for minimum of five minutes showing:
No respiratory movements
PCO2 >55mmHg
pH <7.40
No intracranial blood flow
27. DONOR SELECTION CRITERIA
Age <55 y
Absence of significant structuralabnormalities such as
Left ventricular hypertrophy (wall thickness >13 mm by
echocardiography)
Significant valvulardysfunction
Significant congenital cardiacabnormality
Significant coronary artery disease
28. Adequate physiologic function of donor heart
Left ventricular ejection fraction (LVEF) ≥45% or
Achievement of target hemodynamic criteria after hormonal
resuscitation and hemodynamic management
Mean arterial pressure (MAP) >60 mmHg
Pulmonary capillary wedge pressure (PCWP) 8–12 mmHg
Cardiac index >2.4 L/minx m2
Central venous pressure 4–12 mmHg
Systemic vascular resistance 800–1200 dyne/seccm5
No inotrope dependence
Donor –recipient body size match ( usually within 20-30%
of height & weight)
Negative hepatitis C antibody, hepatitisB surface antigen,
and HIVserologies
Absence of active malignancy or overwhelming infection
29. Donor Evaluation
Once a potential donor is identified, the procurement
process is initiated by contacting the local, or host, organ
procurement organization (OPO).
The host OPO is responsible for obtaining consent for
organ donation, verifying pronouncement of death,
evaluating and managing the donor, and equitably
allocating thedonor organs.
Suggested cardiac donorevaluation
Past medical history and physical examination
Electrocardiogram
Chest roentgenogram
Arterial blood gases
Laboratory tests (ABO, HIV, HBV,HCV)
Echocardiogram, pulmonary artery catheter evaluation, and in
selected cases, coronaryangiogram (male 45 yr & female
50yr )
30. Donor Management
The main goals of organ donor management
are to ensure optimal organ function by
providing
Volume resuscitation
Optimizing cardiacoutput
Normalizing systemic vascular resistance
Maintaining adequate oxygenation
Correcting anemia, acid base, and electrolyte
abnormalities, and
Correcting hormonal imbalances that occur after
brain death and that can impair circulatory
function.
31. Standardized algorithms incorporating early use of
invasive hemodynamic monitoring along with aggressive
hemodynamic management and hormonal resuscitation
with insulin, corticosteroids, triiodothyronine, and
arginine vasopressin have been proposed to improve
cardiac donor management and maximize organ use,
particularly in patients with a left ventricular ejection
fraction of <45 percent on initial echocardiography.
Currently, most donor hearts are harvested from the
donor by a transplant donor team from the
transplantation center and transported back to the center
for implantation.
A cold ischemic period of 4 to 6 hours in adult
hearts is generally considered safe
DONATION AFTER CIRCULATORY DEATH (DCD) - NEWER
CONCEPT*
32. 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.
• The PRA is a rapid measurement of preformed reactive
anti-HLA antibodies in the transplant recipient. In general
PRA < 10 to 20% then no cross-match is necessary. If
PRA is > 20% then a T and B-cell cross-match should be
performed.
• Patients with elevated PRA will need plasmapheresis,
immunoglobulins, or immunosuppresive agents to lower
PRA.
33. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
34. Surgical Transplantation Techniques
• Orthotopic implantation is the most common – it
involves complete explantation of the native
heart.
– Biatrial anastomosis: Most common because the
ischemic time is shorter.
– Complications include atrial dysfunction due to size
mismatch of atrial remnants and arrhythmia (sinus
node dysfunction, bradyarrhythmias, and AV
conduction disturbances) that necessitate PPM
implantation in 10-20% of patients.
– Bicaval anastomosis: Decreases incidence of
arrhythmias, the need for a pacemaker, and risk for
mitral or tricuspid regurgitation. However narrowing
of the SVC and IVC make biopsy surveillance difficult
and ischemic times can be prolonged.
38. Surgical Transplantation Techniques
• Heterotopic implantation is an alternative technique in
which the donor heart functions in parallel with the
recipient’s heart.
– It accounts of less than 0.3% of heart transplants.
– This procedure can be considered if the donor heart is small
enough to fit into the mediastinum without physical restriction of
function.
– Hypertopic transplantation is beneficial if the patient :
• Has pulmonary hypertension that would exclude orthotopic
transplantation.
• Has heart failure that is potentially reversible (myocarditis) allowing
future removal of the transplant.
– The negative aspects of this approach include:
• A difficult operation.
• No anginal relief.
• Need for anticoagulation (the native heart can cease to function and
thrombose).
• Contraindicated if the native heart has significant tricuspid or mitral
regurgitation.
39. 'Living organ' transplant
In February 2006, at the Bad Oeynhausen Clinic
for Thorax and Cardiovascular Surgery, Germany,
surgeons successfully transplanted a 'beating heart'
into apatient.
Rather than cooling the heart, the living organ
procedure keeps it at body temperature and connects
it to a special machine called an Organ Care System
that allows it to continue pumping warm, oxygenated
blood.
This technique can maintain the heart in a suitable
condition for much longer than the traditional
method.
41. Physiologic concerns of Transplant
• Biatrial connection means less atrial contribution
to stroke volume.
• Resting heart rate is faster (95 to 110 bpm) and
acceleration of heart rate is slower during
exercise because of denervation.
• Diurnal changes in blood pressure are
abolished.
• Diastolic dysfunction is very common because
the myocardium is stiff from some degree of
rejection and possibly from denervation.
44. Postoperative Complications
• Surgical
– Aortic pseudoaneurism or rupture at cannulation site
– Hemorrhagic pericardial effusion due to bleeding or
coagulopathy
• Medical
– Severe tricuspid regurgitation
– RV failure
• Pulmonary artery compression
• Pulmonary hypertension
– LV failure
• Ischemia
• Operative Injury
• Acute rejection
45. Postoperative Complications
• Rhythm disturbances
• Asystole
• Complete heart block.
• Sinus node dysfunction with bradyarrhythmias (25% permanent but
most resolve within 1-2 weeks).
• Atrial fibrillation.
• Ventricular tachycardia.
• Coagulopathy induced by cardiopulmonary bypass
• Respiratory failure
• Cardiogenic pulmonary edema.
• Noncardiogenic pulmonary edema.
• Infection.
• Renal or hepatic insufficiency
• Drugs.
• CHF.
46. • 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. The right side of the heart can be seen in the surgical field
to dilate and to contract poorly.
• Intraoperative transesophageal echocardiography shows a dilated,
poorly contracting right ventricle and an underfilled, vigorously
contracting left ventricle.
• Right ventricular function may be enhanced with iontropes and
pulmonary vasodilators, but the prognostic importance of
preoperative pulmonary vascular resistance becomes obvious in
these first few hours after surgery
47. Postoperative Management
• Pneumocystis carinii prophylaxis is started within the first
week after transplant.
• If patient or donor is CMV positive then ganciclovir is
started on postop day 2.
• Endomyocardial biopsy is performed on postop day 4
and steroids can begin to be tapered if there is no
rejection greater than grade 2R.
• Anticoagulation is started if heterotopic transplantation
has been performed.
• Amylase and lipase are measured on day 3 to detect
pancreatitis.
• ECG’s are obtained q day.
48. Long-term Management
• Endomycardial biopsy is performed once a week for the first
month and then less frequently depending on the presence or
absence of rejection (usual regimen is qweek x 4 weeks,
qmonth x 3 months, q3months in 1st year, q4months in 2nd
year, 1 to 2 times per year subsequently).
• If the donor was CMV positive a Hickman or peripherally
inserted central catheter is placed for IV gangciclovir . If the
recipient was CMV negative then oral acyclovir is admisitered
orally.
• Cardiac catheterization is performed annually for early
detection of allograft vasculopathy
49. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
50. Immunosuppressive Agents
General principles –
(1) Highest immune reactivity & graft rejection tendency –
1st 3-6 months augmented immunosuppresion or
INDUCTION therapy X 1 year
(2) Use of lowest dose of several drugs to avoid toxicity –
MAINTENANCE therapy
(3) Avoid excessive immunosuppresion side effects –
infection & malignancy
52. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
53. Complications - Rejection
• Avoidance with preoperative therapy with cyclosporin,
corticosteroids, and azathioprine.
• If rejection is suspected then workup should include:
measurement of cyclosporine level ,CKMB level,
echocardiography for LV function , endomyocardial
biopsy & donor-specific Anti HLA antibody (DSA)
• Signs and symptoms of rejection only manifest in the late
stages and usually as CHF (rarely arrhythmias).
• ALLOMAP – 11 gene expression signature derived from peripheral blood
mononuclear cells – high NPV , non-invasive --- dx ACR – non-inferior biopsy
• CELL FREE DNA TECHNOLOGY -URINE & BLOOD of transplant recipients
54. Complications - Rejection
• Hyper-acute Rejection: Caused by preformed
antibodies against the donor in the recipient. It
occurs within minutes to hours and is uniformly
fatal. PRA screening is the best method in
avoiding hyperacute rejection.
• Acute Cellular Rejection: Most common form
and occurs at least once in about 50% of cardiac
transplant recipients. Half of all episodes occur
within the first 2 to 3 months. It is rarely
observed beyond 12 months unless
immunosuppression has been decreased.
55. Complications - Rejection
• Vascular (humoral) Rejection: AMR- not well
defined.
– Characterized by immunoglobulin and complement in
the microvasculature with little cellular infiltrate.
– It is associated with positive cross match,
sensitization to OKT3, female sex, and younger
recipient age.
– It is more difficult to treat than acute cellular rejection,
is associated with hemodynamic instability, and
carries a worse prognosis.
56. Staging of Acute Rejection (ISHLT -
revised )
• If acute rejection is found, histologic review of endomyocardial
biopsy is performed to determine the grade of rejection.
• Grade 0 — no rejection
• Grade 1R -MILD - perivascular &/or interstitial infiltrate with up to 1
focus of myocyte damage
• Grade 2R – MODERATE- 2 or more foci of infiltrate with associated
myocyte damage
• Grade 3R -SEVERE — Diffuse infiltrate with multifocal myocyte
damage +/- edema +/- hemorrage +/- vasculitis
57. Treatment of Acute Rejection
• Grade 1R:- No treatment is necessary.
• Grade 2R or higher: High dose corticosteroids (Solumedrol 1mg/kg
IV). If no response then ATGAM (OTK3 also an option, but causes
more intense cytokine reaction). Switching cyclosporinetacrol ,
MMFPSI
• Grade 3R with hemodynamic compromise : High dose IV
corticosteriods plus ATGAM or OTK3. If AMR gd 2 or more Add
IVIg , DSA +ve –rituximab or bortezomib + plasmapheresis , IABP
OR ECMO support
•
• It is critical that an endomyocardial biopsy be performed
to document reversal of rejection after 2 weeks
treatment .
58. Complications - Rejection
• Allograft vasculopathy (Chronic rejection):
Transplant coronary artery disease that is the leading
cause of death in patients more than 1 year after
transplantation.
• Incidence- 42% - 5 yrs & 50 % -10 yrs (unchanged)
• Likely a proliferative response to immunologically
mediated endothelial injury (chronic humoral rejection).
• NATIVE CAD VS TRANSPLANT CAD-
• panvascular ds , concentric lesions, predominately
subendocardial location, lack/late of calcification,
generally lipid poor , can be rapidly progressive and lack
of angina pectoris & intraluminal thrombosis rare.
59. Cardiac Allograft Vasculopathy
• first clinical manifestation of CAV may be myocardial
ischemia and infarction, heart failure, ventricular
arrhythmia or sudden death
• Routine surveillance angiography – usually 1 year
interval
• CAG Vs IVUS ( >0.5 mm/1 yr )
61. Complications – Rejection
Allograft Vasculopathy
• Treatment is mainly prevention with statins, diltiazem,
PSI and antioxidant vitamins.
• Treatment with percutaneous interventions and CABG is
limited due to its diffuse nature and subendocardial
locations.
• Re-transplantation
62. Complications - Infection
• There are two peak infection periods after
transplantation:
• The first 30 days postoperatively: nosocomial infections related
to indwelling catheters and wound infections.
• Two to six months postoperatively: opportunistic
immunosuppresive-related infections.
• There is considerable overlap, however as fungal
infections and toxoplasmosis can be seen during the first
month.
• Infections cause approximately 20% of deaths within the
first year after transplantation
• Immune monitoring assay ( immuknow)ATP release from
activated lymphocytes <200 ng ATP / ml
63. Opportunistic Infections
• CMV: most common infection transmitted donor
to recipient.
• Manifested by fever, malaise, and anorexia. Severe infection
can affect the lungs, gastrointestinal tract, and retina.
• If donor is CMV positive and the recipient is CMV negative,
prophylaxis with IV ganciclovir or foscarnet is given for 6
weeks and followed by long term oral prophylaxis with
acyclovir.
Toxoplasma gondii:
• Manifested as encephalitis, myocarditis, or pneumonitis.
• Treated with pyrimethamine and sulfadiazine.
64. Opportunistic Infections
Pneumocystis carinii: Prophylactic therapy with
TMP/Sulfa is highly effective in preventing progressive
bilateral interstitial pneumonia caused by this protozoan.
• Dapsone (Requires G6PD testing) and pentamidine aerosols
(does not protect lung apices) are quite effective for those
with sulfa allergies.
• Aspergillus organisms
65. Topic outline
Indications and Contraindications
Recipient Selection
Donor Selection
Transplant surgical procedure
Post operative management issues
Immunosuppression
Rejection of graft
Complications
66. Complications - Malignancy
• 100-fold
• Post Transplantation Lymphoproliferative Disorder (PTLD), a type
of non-Hodgkin’s lymphoma believed to be related to EBV.
• The incidence is as high as 50% in EBV-negative recipients of EBV-
positive hearts.
• Treatment involves reduction of immunosuppressive agents, administration
of acyclovir, and chemotherapy for widespread disease.
• Skin cancer is most common type -SqCC & BCC , with azathioprine
& voriconazole use. PSI decreases risk.
68. Complications - Dyslipidemia
• As many as 80% of transplant recipients
eventually have lipid abnormalities related to
immunosuppression medications.
• These dyslipidemias have been linked to
accelerated allograft arteriopathy.
• These disorders should be treated aggressively
with statins and fibrates to hopefully alleviate
transplant coronary vasculopathy.
69. Outcomes
• The survival rate according to ISHLT Registry the 1-year
survival rate was almost 90% and 3 year survival rate to
be 74%.
• The most common cause of mortality Is cardiac allograft
vasculopathy & malignancy