A heart transplant, or a cardiac transplant, is a surgical transplant procedure performed on patients with end-stage heart failure or severe coronary artery disease. As of 2008 the most common procedure is to take a working heart from a recently deceased organ donor (cadaveric allograft) and implant it into the patient. The patient's own heart is either removed (orthotopic procedure) or, less commonly, left in place to support the donor heart (heterotopic procedure). Post-operation survival periods average 15 years. Heart transplantation is not considered to be a cure for heart disease, but a life-saving treatment intended to improve the quality of life for recipients
Hypertrophic cardiomyopathy A. Class IV symptoms persist despite interventional therapies 1. Alcohol injection of septal artery 2. Myotomy and myomectomy 3. Mitral valve replacement 4. Maximal medical therapy 5. Pacemaker therapy
The International Society for Heart and Lung Transplantation (ISHLT) has recently published guidelines that address the use of cardiopulmonary stress testing results to guide transplant listing
This procedure can be considered if the donor heart is small enough to fit into the mediastinum without physical restriction of function.
The patients to have the surgery were Michelle Gribilas of 57-year-old, and Jan Damen, 43.
Heterotopic transplant. ICD implanted to maintain function of native heart (N). Donor heart visible in right chest (D).
At the onset of exercise, an increase in venous return results in a an increased stroke volume in accordance with the Frank-Starling principle, in which increased stretch or tension on cardiac muscle results in an increased force of contraction.
Later in exercise circulating peripheral catecholamines provide chronotropic support.
ECG of patient post-heart transplant. Two P waves visible.
Because of the large potential space left behind as the dilated and dysfunctional recipient left ventricle is replaced with a more appropriately sized donor left ventricle.
Calcineurin is a phosphatase enzyme that triggers transcription of new messenger RNA after activation of the T-cell receptor by an appropriate antigen, leading to increased gene expression of IL-2 and other important cytokines. Calcineurin antagonists inhibit this phosphatase activity, thereby preventing synthesis of these cytokines, which prevents B- and T-cell proliferation
TOR is activated after IL-2 stimulation of the Tcell IL-2 receptor, and is critical for lymphocyte growth and Proliferation Drug interactions: allopurinol (decrease dose by 75%) and TMP/Sulfa (worsens thrombocytopenia).
DR VISHWANATH HESARUR
DEPARTMENT OF CARDIOLOGY
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
The first human cardiac transplant was a chimpanzee
xenograft performed at the University of Mississippi by
James Hardy in 1964.
In 1967 – on December 3,
performed the first
transplant at the Groote
Schuur Hospital in Cape
Town, South Africa.
Denise Darvall - Donor Louis Washkansky - Recipient
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.
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.
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.
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 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
act in India came in
Dr. Venugopal led a
team of doctors to
perform the first
transplant in India on 3
This was the first of the
26 heart transplant
by Dr. Venugopal
LIST OF APPROVED HOSPITALS FOR HEART
TRANSPLANTATION IN INDIA
RECIPIENT SELECTION AND MANAGEMENT
Systolic heart failure (defined by LVEF <35%) with severe
functional limitations and/or refractory symptoms despite maximal
New York Heart Association Functional Class III–IV
Maximal oxygen uptake (O2 max) of 12–14 mL/kg/min exercise 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
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
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
Refractory heart failure after previous cardiac surgery
Significant cardiac allograft vasculopathy or chronic graft
dysfunction of a previous heart transplant
Role of Exercise Testing
In patients undergoing transplant evaluation,
measurement of peak oxygen consumption (O2) during
cardiopulmonary exercise testing provides an objective
assessment of functional capacity and is more useful than
NYHA classification, ejection fraction, or other markers
of heart failure severity, for assessing prognosis and
determining the optimal timing of listing for
Patients with a peak O2 of more than 14 mL/kg/min have
1- and 2-year survival rates that are comparable or better
than those achieved with transplantation, and patients
should be medically managed and undergo serial exercise
Patients with a peak O2 between 10 and 14
mL/kg/min constitute an intermediate risk group in
which continued medical therapy may offer a survival
benefit similar to heart transplantation among
selected patients that are able to tolerate beta
blockers, have low-risk Heart Failure Survival Scores
(HFSS's), and have the protection of an internal
The HFSS is a predictive model calculated from seven
prognostic variables that are commonly obtained during
the transplant evaluation process.
In patients tolerating beta blockers, a peak O2 of <12
mL/kg/min has been suggested as an appropriate threshold
to identify individuals that are likely to derive a survival
benefit from transplantation.
Patients with a peak O2 of 10 mL/kg/min, regardless of beta
blocker use, have significantly reduced survival rates with
medical therapy compared to cardiac transplantation, and
these patients should be listed for transplantation.
Irreversible severe pulmonary arterial hypertension
Pulmonary vascular resistance (PVR) >5 Wood units
Pulmonary vascular resistance index (PVRI) >6
Transpulmonary gradient >16–20 mmHg
PA systolic pressure >50–60 mmHg or >50% of systemic
Advanced age (>70 years)
Active systemic infection
Active malignancy or recent malignancy with high
risk of recurrence
Diabetes mellitus with:
End-organ damage (neuropathy, nephropathy,
Poor glycemic control (HbA1c >7.5)
Marked obesity (BMI >30 kg/m2 or >140% of ideal body
Severe peripheral arterial disease not amenable to
Systemic process with high probability of recurrence in the
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 medical compliance
Uncontrolled psychiatric illness (anxiety, depression,
Active or recent substance abuse (alcohol, tobacco, or illicit
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.
CRITERIA FOR DETERMINING BRAIN DEATH
Mechanism of brain injury is sufficient to account for
irreversible loss of brain function
Absence of reversible causes of 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)
Apnea test for minimum of five minutes showing:
No respiratory movements
PCO2 >55 mmHg
No intracranial blood flow
DONOR SELECTION CRITERIA
Age <55 y
Absence of significant structural abnormalities
Left ventricular hypertrophy (wall thickness >13 mm by
Significant valvular dysfunction
Significant congenital cardiac abnormality
Significant coronary artery disease
Adequate physiologic function of donor heart
Left ventricular ejection fraction (LVEF) ≥45% or
Achievement of target hemodynamic criteria after
hormonal resuscitation and hemodynamic
Mean arterial pressure (MAP) >60 mmHg
Pulmonary capillary wedge pressure (PCWP) 8–12 mmHg
Cardiac index >2.4 L/min x m2
Central venous pressure 4–12 mmHg
Systemic vascular resistance 800–1200 dyne/seccm5
Dopamine or dobutamine requirement <10 g/kg/min
Negative hepatitis C antibody, hepatitis B surface
antigen, and HIV serologies
Absence of active malignancy or overwhelming
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 the donor organs.
Suggested cardiac donor evaluation
Past medical history and physical examination
Arterial blood gases
Laboratory tests (ABO, HIV, HBV, HCV)
Echocardiogram, pulmonary artery catheter evaluation, and in
selected cases, coronary angiogram
The main goals of organ donor management
are to ensure optimal organ function by
Optimizing cardiac output
Normalizing systemic vascular resistance
Maintaining adequate oxygenation
Correcting anemia, acid base, and electrolyte
Correcting hormonal imbalances that occur after
brain death and that can impair circulatory
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
A cold ischemic period of 4 to 6 hours in adult hearts is
generally considered safe
MATCHING DONORS & RECIPIENTS
Matching is based upon:
ABO blood group
Body size compatibility
(± 20% body weight)
Antibody screen - of
preformed reactive anti-
HLA antibodies (PRA)
No HLA prospective
matching done unless
high levels of pre-formed
antibodies on screening
(PRA > 10-20%)
Allocation is determined by:
Recipient’s priority on
Status code (1A, 1B, 2)
Time accrued within a status
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
SURGICAL TRANSPLANTATION TECHNIQUES
Orthotopic transplantation is the most common – it
involves complete explantation of the native heart.
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.
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
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.
Herteropic 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
Contraindicated if the native heart has significant tricuspid or
'Living organ' transplant
In February 2006, at the Bad Oeynhausen Clinic
for Thorax and Cardiovascular Surgery, Germany,
surgeons successfully transplanted a 'beating heart'
into a patient.
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
This technique can maintain the heart in a suitable
condition for much longer than the traditional
Dead heart transplant
In October 2014, Australian surgeons have recently
successfully transplanted dead hearts into patients
for the first time.
According to Surgeon Kumud Dhital, the incredible
development of the preservation solution with this
technology of being able to preserve heart,
resuscitate it and to assess the function of heart has
made this possible.
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
PHYSIOLOGY OF THE TRANSPLANTED HEART
The transplanted heart is initially completely denervated.
Following recovery of donor sinus node function within
the first 2 to 3 postoperative days, the denervated donor
heart exhibits a faster resting heart rate usually between
95 to 110 beats/min caused by the intrinsic tachycardic
rate of the sinus node and absence of the counter-
regulatory effects of the parasympathetic system.
Cardiac denervation has several important clinical
First, the cardiac allograft is slower to increase its heart
rate in response to exercise and exhibits a slower heart
Second, many heart transplant patients will not
experience angina with ischemia of the cardiac allograft
and may present instead with congestive heart failure
caused by graft dysfunction, myocardial infarction, or
Third, drugs that act primarily through the autonomic
nervous system will have little to no effect on the
denervated heart. For example, atropine works via a
vagolytic mechanism to increase heart rate and is
ineffective when used to increase heart rate in the
transplanted heart. Isoproterenol is better suited for this
purpose because of its direct effect on receptors, causing
both increased chronotropy and inotropy.
Reinnervation of the cardiac allograft is felt to occur after
the first year, but the timing and degree of reinnervation is
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
Most common - Pericardial effusion with or without
Early graft dysfunction
1. Left ventricular systolic dysfunction.
It is common for transplant recipients to require inotropic
support as they come off cardiopulmonary bypass. The
most commonly used inotropic agents in this setting are
dobutamine, milrinone, and isoproterenol, used alone or in
2. Left ventricular diastolic dysfunction
Results from reversible ischemia or reperfusion injury to
the donor organ or donor-recipient mismatch and usually
resolves over a period of days to weeks.
3. Right ventricular dysfunction
In patients with preexisting pulmonary hypertension.
Right ventricle is subjected to similar ischemic or
reperfusion injury risks as the left ventricle.
Right ventricular dilation and the failure of
coaptation of the tricuspid valve leaflets, leading to
severe tricuspid regurgitation.
The treatment for perioperative right ventricular
dysfunction is usually intravenous milrinone and
nitrates to increase cardiac output and lower the PVR
improve over a period of days to weeks.
Most transplant recipients require perioperative temporary
Sinus node dysfunction is very common, probably because of a
combination of surgical trauma, ischemia or reperfusion injury,
Reduced by the bicaval anastomosis technique
With time, the sinus node usually recovers, and a permanent
pacemaker is unnecessary.
Preoperatively, many transplant recipients have some degree of
impaired renal function. There is a risk of worsening renal
This risk is compounded by the fact that the major
immunosuppressive agents (i.e., cyclosporine and tacrolimus)
Triple-therapy, which constitutes the cornerstone of modern
immunosuppressive regimens in cardiac transplantation,
Calcineurin inhibitor (such as cyclosporine or tacrolimus),
Antiproliferative agent (such as MMF or azathioprine), and
A dose of 500 to 1000 mg of IV Solu-Medrol is usually given
before being brought to the operating room, and then 125 to 150
mg is usually repeated every 8 hours, for a total of three more
If the patient is extubated, oral prednisone 1 mg/kg/day for 8-9
weeks and then wean .
Some centers continue to advocate the indefinite use of
low-dose prednisone (2.5 to 5 mg daily).
If a decision is made to withdraw steroids completely, it
should be done approximately 1 month before the next
scheduled biopsy to ensure continued lack of acute cellular
If a patient has acute cellular rejection associated with
hemodynamic compromise, 1 g of intravenous Solu-Medrol
daily for 3 days, and If no hemodynamic compromise , 100
mg of oral prednisone daily for 3 days is usually sufficient,
followed by repeat biopsy, at most 2 weeks later to ensure
Variable pattern of bioavailability
Narrow therapeutic range , monitoring serum levels important
to prevent toxicity
Nephrotoxicity is the most important side effect and is related
to renal afferent arteriolar vasoconstriction and the resultant
reduced renal perfusion.
Other side effects include systemic hypertension, gingival
hyperplasia, and tremors.
Postoperatively, once the patient is hemodynamically stable
with good urine output, cyclosporine is initiated via continuous
infusion at 1 mg/hour & then orally 100 mg twice daily, with
adjustments in the dose based on serum trough levels
The dose of tacrolimus is 0.01 mg/kg per day administed
by continuous infusion & then changed to 0.5 to 2 mg
twice daily, with dose adjustment based on serum levels.
Side effects - nephrotoxicity and neurotoxicity (most
Selectively inhibits lymphocyte proliferation
1 g taken twice daily
SE- gastrointestinal symptoms (nausea, vomiting, and
diarrhea) and myelosuppression.
Purine analogue that works by nonspecific suppression of T and
B-cell lymphocyte proliferation.
Dosage is 1 to 2 mg/kg per day.
Side effects - bone marrow suppression (dose related), increased
incidence of skin cancer (use sunscreen), cutaneous fungal
infections, and rarely liver toxicity and pancreatitis.
Inhibitors of the target of rapamycin (TOR) enzyme:
sirolimus and everolimus
Block the cellular response cytokines.
Inhibit vascular smooth muscle cell growth and proliferation in
response to various growth factors
Dosage . Sirolimus -1 to 5 mg/day, and for everolimus, it is 1.5 to 3
Sirolimus appears to lower the incidence of acute cellular
rejection in humans and to slow the progression of transplant
Horse polyclonal antibody designed to inhibit T cells by
binding to surface antigens.
Dosage is 10 to 15 mg/kg qd through a central venous
Goal is to keep T lymphocyte count ~200cells/microL.
Side effects include fevers, chills, urticaria, serum
sickness, and thrombocytopenia.
A murine monoclonal antibody to the CD3 complex on
the T-cell lymphocyte designed for selective T-cell
Usual dose is 5 mg/d IV bolus over 10 to 14 days.
Side effects - cytokine release syndrome (fever, chills,
nausea, vomiting, mylagia, diarrhea, weakness,
bronchospasm, and hypotension), pulmonary edema
According to ISHLT registry , 30% rejection during
Caused by preforemd antibodies against the donor in the
It occurs within minutes to hours and is uniformly fatal.
PRA screening is the best method in avoiding hyperacute
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.
Rejection of the cardiac allograft is usually clinically silent
unless it is accompanied by significant hemodynamic
compromise (i.e., congestive heart failure).
As a result, endomyocardial biopsies are routinely
performed for rejection surveillance.
Biopsy grades ≥ 2R warrant accentuation of
Cardiac Allograft Vasculopathy (Cav)
Progressive, neointimal proliferative process in the
epicardial coronary vasculature and the microcirculation.
It is common with incidence of 20%,30% & > 50% at 3,5 &
10 yrs after transplant
It is a significant cause of mortality beyond the first year
after transplantation, accounting for 30% to 50% of
deaths at 5 years.
The pathophysiology of CAV is not completely
Chronic, subclinical, immune-mediated injury at the level
of the donor coronary endothelium creates a chronic
Because donor hearts are denervated at explantation, the
transplant recipient typically will not experience cardiac
angina from advanced allograft coronary vasculopathy.
Owing to the usually asymptomatic nature of vasculopathy,
transplant recipients have frequent surveillance studies to
detect significant vasculopathy, including coronary
angiography with or without intravascular ultrasound
(IVUS), cardiac perfusion magnetic resonance imaging, and
Statins - improve survival, regardless of the patient's lipid
The antiproliferative effects of TOR inhibitors (sirolimus
and everolimus) suggest a significant reduction in coronary
neointimal proliferation and, therefore, transplantation
In severe, advanced CAV, frequently the only viable option is
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.
Treatment involves reduction of immunosuppressive agents,
administration of acyclovir, and chemotherapy for widespread
Skin cancer is common with azathioprine use.
As many as 75% of transplant recipients treated with
cyclosporine or corticosteroids eventialy develop hypertension.
Treatment is empiric with a diuretic added to a calcium channel
blocker, B-blocker, or Ace inhibitor.
OUTCOMES AFTER CARDIAC
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%.
However ,10-year survival after cardiac transplantation is
The most common cause of mortality was cardiac allograft
SOME FAMOUS PERSONALITY
Tony Huesman was the world's longest living heart transplant
recipient, having survived for 30 years, 11 months and 10 days,
before dying of cancer.
As of December 2013, the record holder for longest living heart
recipient is Englishman John McCafferty, 71. He received his
heart on 20 October 1982
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 Ironman competition.
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 24, 2012