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History of Cardiac Transplant
• 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.
• South African Christiaan Barnard surprised the world when he performed the
first human-to-human heart transplant on December 3, 1967
The History Of Heart
3rd December 1967
Nearly 45 years and 90,000
History of cardiac transplant
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.
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 the field.
The pioneering efforts of Shumway and his colleagues at Stanford eventually paved the way for the reemergence of cardiac transplantation in the late 1970s. He is widely regarded as the father of heart
transplantation although the world's first adult human heart transplant was performed byChristiaan Barnard in
South Africa utilizing the techniques developed and perfected by Norman Shumway & Lower.
The introduction of transvenous endomyocardial biopsy by Philip Caves in 1973 finally 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.
Heart transplantation is now a widely accepted therapeutic option for end-stage cardiac failure, with more
than 2,700 procedures performed annually.
Cardiac transplant in INDIA
Organ transplantation act in India came in 1994
Journey of heart transplant program in India began on 3rd August 1994 at All India Institute of Medical
Sciences (AIIMS), New Delhi.
So far only about 70 heart transplants have been conducted across the country, out of which 26 have
performed at the All India Institute of Medical Sciences alone.
The cost of heart transplant surgery in India is anywhere between 8 lakhs to
10 lakhs and the monthly cost of immunosuppressant drugs is 15,000 to
Hyderabad first transplant was done in global hospital
3 heart transplants have been done in NIMS
• AORTIC STENOSIS WITH LV ENDOCARDIAL
• UNBALANCED AV CANAL WITH LV HYPOPLASIA
• HLHS EQUIVALENT
TA,D-TGA ,RV & AORTIC HYPOPLASIA
SINGLE VENTRICLE WITH AORTIC HYPOPLASIA
L-TGA WITH SINGLR VENTRICLE & HEART BLOCK
CARDIAC TUMOURS ( RHABDOMYOMAS,FIBROMAS)
FAILED RECONSTRUCTIVE AND PALLIATIVE OPERATIONS
• Brain death is necessary for any cadaveric
organ donation. This is defined as absent
cerebral function and brainstem reflexes with
apnea during hypercapnea in the absence of
any central nervous system depression.
• There should be no
hypothermia, hypotension, metabolic
abnormalities, or drug intoxication.
• If brain death is uncertain, confirmation tests
using EEG, cerebral flow imaging, or cerebral
angiography are indicated.
Continuous Heart Transplant Perfusion
"The rush factor will be taken out. I can go all the way to the West Coast
to get a heart," said Dr. Bruce Rosengard ofMassachusetts General Hospital
who performed the first beating heart transplant in the United Kingdom in 2006.
Matching Donors & Recipients
• Matching is based
• Allocation is determined
• ABO blood group
• Recipient’s priority on
• Body size compatibility (±
– Status code (1A, 1B, 2)
20% body weight)
– Time accrued within a status
• Antibody screen (PRA)
• Geographic location from
• No HLA prospective
matching done unless
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.
• 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 crossmatch should be performed.
• Patients with elevated PRA will need plasmapheresis,
immunoglobulins, or immunosuppresive agents to lower
Surgical Transplantation Techniques
• Orthotopic implantation is the most common – it
involves complete explantation of the native
– 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
– 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.
Surgical Transplantation Techniques
• Heterotopic implantation is an alternative technique in
which the donor heart functions in parallel with the
– 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
– Hypertopic transplantation is beneficial if the patient :
• Has pulmonary hypertension that would exclude orthotopic
• 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
• Contraindicated if the native heart has significant tricuspid or mitral
Operative technique- Explantation
Perioperative medications include immunosuppressive agents , antibiotic.
A median sternotomy is performed.
The pericardium is opened with a vertical incision extending from the diaphragm to
the pericardial reflection at the aorta.
Aortic cannulation should be high on the lesser curvature,The venae cavae are also
cannulated as distally as possible, and umbilical tape snares are placed around the
vessels and cannulae.
The superior vena cava (SVC) and inferior vena cava (IVC) are snared,the aortic
cross-clamp is applied, and the patient is placed on bypass and cooled to 32°C.
The aorta and PA are separated, and the aorta is divided just above the right
coronary artery’s origin.
In preparation for a bicaval anastomosis, the atrioventricular groove is opened, and the dissection is extended
under the SVC.
The right atrium is divided proximally to the SVC, leaving an atrium cuff on the proximal end of the cava
An incision is made in the left atrial dome below the aorta. The incision is extended counterclockwise across
the atrial septum, including the fossa ovalis, to the coronary sinus base.
.The left atrial anastomosis is performed first; the sequence of the other anastomoses can be
changed to decrease the ischemic time.
Donor left atrial cuff is sutured to the recipient left atrium using an extra long 3–0 prolene
Then, the donor IVC and SVC are anastomosed to the recipient IVC-atrial cuff and SVC-atrial
cuff, respectively. This is performed in an en to end manner using 4–0 polypropylene suture.
The PAs are anastomosed end-to-end using running 4–0 monofilament suture. Again, attention
must be paid to avoid constricting or rotating the anastomosis.
The donor and recipient aortas are anastomosed end-to-end with running 4–0 monofilament
• 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.
Management of Right Heart
• Optimize preload – avoid overdistension
• Ionotropic & Chronotropic support milrinone, dobutamine
• Maintain coronary perfusion –
• Lower PVR – nitrates, prostaglandins, NO
• Mechanical support – IABP, RV assist
Other Post-transplant Problems
• Left ventricular failure
• Bleeding- higher incidence if anticoagulated
preoperatively for assist devices
• Dysrhythmias (bradycardia, AV node dysfunction)
– Pacing and chronotropes for several weeks
– 4-7% require permanent pacemaker
• Anastamotic obstruction
• Hyperacute rejection
– occurs after reperfusion, results from preformed
antibodies to donor antigen
The Denervated Heart
• Electrical activity cannot cross suture line
– Recipient atrial activity present but not conducted
– Donor atrium denervated but source of electrophysiologic
• Loss of SNS, PNS innervation to donor heart
– Vagal stimulation has no effect on sinus and AV nodes
– No reflex tachycardia in response to hypovolemia, hypotension
• ECG has 2 P waves
• Indirect sympathomimetic agents have no effect
– Anticholinergics, anticholinesterases, pancuronium, ephedrine
• Direct acting sympathomimetics work
– isoproterenol, NE, epi, phenylephrine, dopamine
HETEROTOPIC HEART TRANSPLANTATION
During heterotopic transplantation, initially performed by Losman and Barnard in 1974, the
recipient heart remains in its native location .
This transplant type may be necessary in situations when there is irreversible high pulmonary
vascular resistance or significant donor–recipient size mismatch.
Greater lengths of SVC, aorta, and PA are harvested.
The SVC should be harvested to innominate vein level.
The aortic arch should be harvested along with the proximal aspect of all three head vessels. It
is especially important to harvest as much PA as possible to allow a direct donor–recipient
anastomosis and avoid the need for a Dacron interposition graft.
The tissue separating the left pulmonary veins is divided, connecting their orifices and creating
a single, large left atrial cuff.
HETEROTOPIC HEART TRANSPLANTATION
The aortic cannula should be placed as distally as possible in the ascending aorta.
SVC cannulation is achieved through the right atrial appendage.
IVC cannulation is performed at the IVC–diaphragmatic junction.
Venous inflow occlusion is achieved by snaring the SVC and IVC.
The native heart in the recipient is then cross-clamped.
The donor heart is placed in the right pleural cavity with the heart’s apex angled to
HETEROTOPIC HEART TRANSPLANTATION
The left atrial anastomosis is performed first using 3–0 monofilament polypropylene
suture, attaching the donor left atrium to the incision in the recipient left atrium
The recipient’s SVC is opened with a vertical incision, and the anastomosis is
performed attaching the donor SVC to the recipient SVC.
The aortic anastomosis is performed using 4–0 monofilament suture in an end-toside manner.
Either the right or left PA branch is oversewn, with the other participating in the
anastomosis with the donor PA.
A prosthetic graft may be required if the donor PA length is not adequate.
BICAVAL VS STANDARD TECHNIQUE
A biatrial anastomosis results in an abnormally enlarged atrial cavity and distorted atrial
geometry, producing atrioventricular (AV) valvular insufficiency . Additionally, bradyarrhythmias
may arise because of the close proximity of the right atrial suture line to the sinus node,
resulting in node injury .
Yacoub and Banner modified the standard technique described by Lower and Shumway . A
bicaval approach preserves the donor atria and combines the standard left atrial anastomosis
with a separate bicaval anastomosis .
Another approach is total orthotopic heart transplantation. This approach was described by
Webb and Neely in 1959 and introduced by Dreyfus and Yacoub in 1991 .
It involves complete recipient atrial excision with complete AV transplantation, in addition to
bicaval and pulmonary venous anastomoses . This technique’s major disadvantages are the
additional time required to complete the six anastomoses and the technical challenge of
performing the pulmonary vein island anastomoses
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
• Diastolic dysfunction is very common because
the myocardium is stiff from some degree of
rejection and possibly from denervation.
ADULT HEART TRANSPLANT RECIPIENTS:
Relative Incidence of Leading Causes of Death
(Deaths: January 1992 - June 2008)
Percentage of Deaths
0-30 Days (N 31 Days – 1
Year (N =
>1 Year – 3
Years (N =
>3 Years – 5 >5 Years – 10 >10 Years (N
Years (N =
Years (N =
• 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 2b.
• Anticoagulation is started if heterotopic transplantation
has been performed.
• Amylase and lipase are measured on day 3 to detect
• ECG’s are obtained qday.
• Initiation of medications, particularly
immunosuppressive agents begins on the day of
– Cyclosporin started IV on day of the surgery and
usually continued until day 3 at which time converted
to po. Usual IV dose is 0.5 mg/kg at 2 mg/min qd
– Azathioprine 2 mg/kg IV qd until day 3 and then
converted to po.
– Solumedrol 125mg IV q8h until tolerating po and then
Prednisone 0.6 mg/kg/day.
– +/- Muromonab-CD3 (OKT3) started on postop day 1
at 5mg IV qd.
• 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 (5mg/kg
IV bid x 14 days then 6mg/kg IV qd x 14 days.
• If the recipient was CMV negative then oral acyclovir is
admisitered orally. If the recipient is CMV seropositive then
the antiviral agent can be discontinued. If seroconversion
occurs during treatment (and check at 1, 2, 3, and 6 month
intervals), then ganciclovir is initiated for at least an additional
2 week period.
• Cyclosporine levels are checked periodically by
individual center protocols.
• Echocardiography is useful periodically and as an
adjunct to endomyocardial biopsy.
• Cardiac catheterization is performed annually for
early detection of allograft vasculopathy.
• There is probably no need for routine exercise or
nuclear stress testing.
– Aortic pseudoaneurysm or rupture at cannulation site
– Hemorrhagic pericardial effusion due to bleeding or
– Severe tricuspid regurgitation
– RV failure
• Pulmonary artery compression
• Pulmonary hypertension
– LV failure
• Operative Injury
• Acute rejection
• Rhythm disturbances
• 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.
• Renal or hepatic insufficiency
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,
and endomyocardial biopsy.
• Signs and symptoms of rejection only manifest
in the late stages and usually as CHF (rarely
• Due to close surveillance, most rejection is
picked up in asymptomatic patients.
Complications - Rejection
• Hyperacute Rejection: Caused by preforemd
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.
Complications - Rejection
• Vascular (humoral) Rejection: 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
– It is more difficult to treat than acute cellular rejection,
is associated with hemodynamic instability, and
carries a worse prognosis.
• Invasive surveillance
biopsies are the best
established method for
• Typically 13-15 biopsies
are done in the first year
• Each biopsy requires a
minimum of 3 samples
from 3 different sites to be
• A new biopsy grading has
been developed for
Identifying Allograft Rejection
and myocyte necrosis
Heart failure and
Gene Expression Profiling
Immune Function Assays
Staging of Acute Rejection
• If acute rejection is found, histologic review of endomyocardial
biopsy is performed to determine the grade of rejection.
• Grade 0 — no evidence of cellular rejection
• Grade 1A — focal perivascular or interstitial infiltrate without
• Grade 1B — multifocal or diffuse sparse infiltrate without myocyte
• Grade 2 — single focus of dense infiltrate with myocyte injury.
• Grade 3A — multifocal dense infiltrates with myocyte injury.
• Grade 3B — diffuse, dense infiltrates with myocyte injury.
• Grade 4 — diffuse and extensive polymorphous infiltrate with
myocyte injury; may have hemorrhage, edema, and microvascular
Treatment of Acute Rejection
• Grade 1A and Grade 1B: No treatment is necessary.
• Grade 2: Probably no treatment is necessary. Short course of
steriods (Prednisone 100mg qd x 3 days) is optional.
• Grade 3A and Grade 3B: High dose corticosteroids (Solumedrol
1mg/kg IV). If no response then ATGAM (OTK3 also an option,
but causes more intense cytokine reaction).
• Grade 3 with hemodynamic compromise or Grade 4: High dose
corticosteriods plus ATGAM or OTK3.
• It is critical that an endomyocardial biopsy be performed to
document reversal of rejection after treatment A biopsy is
obtained 1 week after initial biopsy showed rejection and then 1
week after therapy complete.
• If ATGAM or OTK3 is used biopsy should be obtained at the end
of a course of therapy (usually 7 to 14 days) and then again 1
week later off therapy.
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.
• Likely a result of a proliferative response to
immunologically mediated endothelial injury (chronic
• It differs from native CAD in that it is manifested by
concentric stenoses, predominately subendocardial
location, lack of calcification, can be rapidly progressive
and lack of angina pectoris.
• Risk factors include degree of histocompatibility,
hypertension, hyperlipidemia, obesity, and CMV
Complications – Rejection
• Treatment is mainly prevention with statins, diltiazem,
and antioxidant vitamins. Rapamycin is an agent that
has shown promise in preventing this complication.
• Treatment with percutaneous interventions and CABG is
limited due to its diffuse nature and subendocardial
• Retransplantation for this disorder is an option, but
retrospective analysis have shown this approach does
not improve mortality as patients do significantly worse
with a second transplant as compared with the first.
Complications - Infection
• There are two peak infection periods after
• The first 30 days postoperatively: nosocomial infections related
to indwelling catheters and wound infections.
• Two to six months postoperatively: opportunistic
• There is considerable overlap, however as fungal
infections and toxoplasmosis can be seen during the
• It is important to remember that immunosuppressed
transplant patients can develop severe infections in
unusual locations and remain afebrile.
• CMV: most common infection transmitted donor
• 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 longterm oral prophylaxis with
• If the recipient is CMV positive a less potent regimen can be
• Bone marrow toxicity related to treatment can occur and be
confused with that due to azathioprine treatment.
• Toxoplasma gondii: Primary infection can be
serious while reactivation is rarely a serious
• Manifested as encephalitis, myocarditis, or pneumonitis.
• Treated with pyrimethamine and sulfadiazine.
• 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: Invasive Aspergillus
infection, typically of the lung or upper
respiratory tract is extremely difficult to manage.
• It is fortunately rare, and usually occurs among patients who
are severely immunocompromised from use of
• Standard treatment is with IV Amphotericin.
Complications - Malignancy
• Transplant recipients have a 100-fold increase in the prevalence of
malignant tumors as compared with age-matched controls.
• Most common tumor is posttransplantation 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
• Treatment involves reduction of immunosuppressive agents, administration
of acyclovir, and chemotherapy for widespread disease.
• Skin cancer is common with azathioprine use.
• Any malignant tumor present before transplantation carries the risk
for growth once immunosuppresion is initiated because of the
negative effects on the function of T-cells.
Complications - Hypertension
• As many as 75% of transplant recipients treated
with cyclosporine or corticosteroids evential
• Treatment is empiric with a diuretic added to a
calcium channel blocker, B-blocker, or Ace
• If either diltiazem or verapamil is used, the
dosage of cyclosporin should be reduced.
Complications - Dyslipidemia
• As many as 80% of transplant recipients
eventually have lipid abnormalities related to
• 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.
Complications – Tricuspid
• A rare complication is tricuspid regurgitation
caused by biotome-induced trauma to the valve
apparatus that rarely requires valve
Hospitalization of Transplanted Patients
• If nausea and vomiting prevent administration of oral
medications, the regimen should be changed to an IV
one i.e. transplant patients should not be without
immunosuppressives for even a short period of time!!!
• Cyclosporin IV dose is 1/3 of oral dose.
• If fever develops then the following should be
• Blood, urine and sputum cultures, BMP, CBC
• CXR, Echocardiography (for LV function and effusion).
• Consider endomyocardial biopsy for rejection.
• The survival rate according to the United States Scientific
Registry for Organ Transplantation reports the 1-year
survival rate to be 82% and 3 year survival rate to be 74%.
• The most common cause of mortality was cardiac allograft
• The UNOS data suggested some group differences with 3year survival rate for white persons 75%, Hispanics
71%, and African Americans 68%
• Similar survival rates between men and women.
• Lowest survival in patients < age 1 and approaching age 65.
• The typical causes of death in the first year are
due to acute rejection and infection.
• After the 1st year the primary cause of death is
• In the later stages (after the perioperative
period) arrhythmia may be signs of acute
rejection or of an allograft vasculopathy.
• Poor outcomes are associated with the following
Age less than 1 year or approaching age 65.
Ventilator use at time of transplant.
Elevated pulmonary vascular resistance.
Underlying pulmonary disease.
Diffuse atherosclerotic vascular disease.
Small body surface area.
The need for inotropic support pre-transplant.
Ischemic time longer than 4 hours of transplanted heart.
Sarcoidosis or amyloidosis as reason for transplant (as they
may occur in the transplanted heart).
2012 and Beyond
• 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
• Challenges in performing long-term adequately
powered multi-centered trials
SOME FAMOUS PERSONALITY
Kelly Perkins climbs mountains around the world to promote positive awareness of organ
donation. Perkins was the first recipient to climb the peaks of Mt. Fuji, Mt. Kilimanjaro,
Twenty-two years after Dwight Kroening's heart transplant, he was the first recipient to finish an
Fiona Coote was the second Australian to receive a heart transplant in 1984 (at age 14) and the
youngest Australian. In the 24 years after her transplant she became involved in publicity and
charity work for the Red Cross, and promoted organ donation in Australia.
Race car driver and manufacturer Carroll Shelby received a heart transplant in 1990. Mr Shelby
died on May 10, 2012, making him one of the longest living heart recipients.
Golfer Erik Compton qualified for the PGA Tour at age 32, after his second heart transplant.[
Former Vice President of the United States Dick Cheney received a heart transplant on March