Cardiac Transplantation
Board Review
Brian W. Zagol, M.D.
Department of Cardiology
University of Tennessee
Introduction
• More than 4000 patients in the United States are
registered with the United Organ Sharing
Network (UNOS) for cardiac transplantation.
• There are only about 2500 heart donors yearly.
• Scarcity of donors is complicated by the use of
single organs, heart injury with common braindeath injuries, difficulty with ex-vivo
preservation, heart disease among donors, and
the complexity of the operation.
Class I Indications for Cardiac
Transplantation
• Cardiogenic shock requiring mechanical assistance.
• Refractory heart failure with continuous inotropic infusion.
• NYHA functional class 3 and 4 with a poor 12 month
prognosis.
• Progressive symptoms with maximal therapy.
• Severe symptomatic hypertrophic or restrictive
cardiomyopathy.
• Medically refractory angina with unsuitable anatomy for
revascularization.
• Life-threatening ventricular arrhythmias despite aggressive
medical and device interventions.
• Cardiac tumors with low likelihood of metastasis.
• Hypoplastic left heart and complex congenital heart disease.
Indications of Cardiac Transplantation
• Patients should receive maximal medical therapy before
being considered for transplantation. They should also
be considered for alternative surgical therapies including
CABG, valve repair / replacement, cardiac septalplasty,
etc.
• VO2 has been used as a reproducible way to evaluate
potential transplant candidates and their long term risk.
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.
Contraindications to Cardiac
Transplantation
Evaluation of Cardiac Transplantation
Recipient
• Right and Left Heart Catheterization.
• Cardiopulmonary testing.
• Labs including BMP, CBC, LFT, UA, coags, TSH, UDS,
ETOH level, HIV, Hepatitis panel, PPD, 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.
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.
• Zones are established to give local priority to
recipients within 500 to 1000 mile radius
centered on donor site.
Status Listings
• Status I.
– Cardiac Assistance
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Total artificial heart
Ventricular assist devices
Intraaotic balloon pump
Ventilator
– Inotrope dependent for maintaining cardiac output and in
hospital intensive care unit
– Younger than 6 months
• Status II. Patients not status I according to criteria
• Status VII. Patients improved and not in immediate
need of transplantation or with new complication making
transplantation contraindicated.
Cardiac Donor
• 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.
Cardiac Donor – Exclusion Criteria
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Age older than 55 years.
Serologic results (+) for HIV, Hepatitis B or C.
Systemic Infection.
Malignant tumors with metastatic potential (except primary
brain tumors)
Systemic comorbidity (diabetes mellitus, collagen vascular
disease)
Cardiac disease or trauma
Coronary artery disease
Allograft ischemic time estimated to be > than 4-5 hours
LVH or LV dysfunction on echocardiography
Death of carbon monoxide poisoning
IV drug abuse.
Care of Donor Before Transplantation
• Contact local organ procurement organization
(OPO).
• Obtain patient’s height and weight.
• Collect CBC, CMP, ABO / Rh testing, HIV, Hepatitis
panel, and CMV Ab.
• EKG.
• Echocardiogram. (Fellow should be paid for this,
especially if after hours)
• Consider cardiac catheterization if man over 40-45
or woman over 45-50.
• Insert arterial line and right heart catheter.
Care of Donor Before Transplantation
• Donors with beating hearts are often volume
depleted because of therapy directed at reducing
cerebral edema.
• As soon as consent for organ transplantation is
obtained (usually by OPO), normal saline should be
started or sparingly blood.
• A goal CVP should be 5 to 10 and PCWP of 10 to
16.
• Arterial systolic BP should be maintained at least
100mmHg. If CVP and PCWP are adequate and
hypotension persists dopamine and / or dobutamine
should be initiated.
Care of Donor Before Transplantation
• Diabetes Insipidus should be suspected if urine
output is >300cc/hr or if hypernatremia begins to
develop. Vasopressin and hypotonic solutions can
be used in this setting.
• Electrolytes should be measured and corrected
hourly until organ procurement. Hypertension as a
result of sympathetic discharge can be managed
with IV NTG.
• Hyperpyrexia or hypothermia should be addressed
with surveillance cultures, empiric broad-spectrum
antibiotics, cooling / warming blankets.
Care of Donor Before Transplantation
• Metabolic acidosis from loss of adrenal and
thyroid hormone secretion of brain death can
depress myocardial contractility and cause
vasodilatation. Acidosis should be corrected.
• Ventricular dysfunction sometimes responds to
levothyroxine 4 micrograms/kg/hr and
methylprednisolone 100mg IV qhr and can be
tried in this situation. Some recommend empiric
treatment with these agents.
Care of Donor Before Transplantation
• Echo should be performed as soon as possible
on the donor heart for assessment of LV
function. If unexpected dysfunction is found in a
young person, LVEDD and wall thickness should
be measured. If dimensions are normal then
corticosteroid and thyroid replacement should
begin and any acidosis should be corrected.
• Particular attention should be paid to wall motion
abnormalities (especially in individuals with more
advanced age), aortic stenosis, and significant
mitral valve abnormalities.
Care of Donor Before Transplantation
• Coronary angiography should be performed on
men older than 45 and women older than 50.
• Precise definition of coronary anatomy is not the
goal! Quick exclusion of severe lesions is!
• The sheath should be sutured in place for ICU
monitoring and blood sampling. Removal may
also be complicated by coagulopathy.
• Risk to potential donor kidneys necessitates
limiting contrast exposure. Use non-ionic
contrast and <25cc’s if possible. No LVgram
unless absolutely necessary.
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
PRA.
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.
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.
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.
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
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.
Treatment of Postoperative
Complications
• Treatment is directed at maintaining organ perfusion,
oxygenation, acid-base balance, avoiding RV failure, and
managing arrhythmias.
• If needed drugs to maintain perfusion include dopamine,
milrinone, NTG, Nitroprusside, isoproterenonol.
• Managing RV failure is difficult.
• Improve hypoxemia, acidosis, uremia, and electrolyte imbalance.
• Keep transpulmonary gradient <10mmHg and PVR < 6 woods units
• If vasodilators, volume reduction with diuretics and ultrafiltration,
and inotropic agents fail to improve RV function, then RVAD can be
considered.
Treatment of Postoperative
Complications
• Arrhythmias – may signify acute rejection.
– Bradyarrhythmias
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Isoproterenol 0.01 to 0.02 micrograms/kg/min.
AV sequetial pacing.
Most resolve in 1 to 2 weeks.
AV disturbances in the early postoperative period may
indicate incomplete myocardial preservation, pulmonary
hypertension, acute rejection, or cardiac edema.
– Tachyarrhythmias
• Amiodarone, Lidocaine, B-blockers, etc.
Postoperative Management
• Initiation of medications, particularly
immunosuppressive agents begins on the day of
the operation.
– 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.
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 2b.
• Anticoagulation is started if heterotopic transplantation
has been performed.
• Amylase and lipase are measured on day 3 to detect
pancreatitis.
• ECG’s are obtained qday.
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 (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.
Long-term Management
• 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.
Immunosuppressive Agents
• Azathioprine: 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 are bone marrow suppression (dose related),
increased incidence of skin cancer (use sunscreen),
cutaneous fungal infections, and rarely liver toxicity and
pancreatitis.
• Drug interactions: allopurinol (decrease dose by 75%) and
TMP/Sulfa (worsens thrombocytopenia).
Immunosuppressive Agents
• Cyclosporin: inhibits T-cell lymphokine production.
Highly lipophilic.
• Dosage is 8 to 10mg/kg/day in 2 divided doses. IV doses are 1/3 of
oral doses in a continuous infusion.
• Drug levels are frequently measured for dosage and toxicity, but
levels are not highly predictive of actual immunosuppressive effect.
Drug levels are reflected for 5 to 10 days because of a long half life.
• Side effects: nephrotoxicity caused by afferent arteriolar
constriction and manifested by oliguria. Loop diuretics may
exacerbate this side effect. Dosage adjustments should only be
made if creatinine level is >3.0mg/dL (some renal insufficiency is
expected). Other side effects include hypertension, hypertrichosis,
tremor, hyperkalemia, hyperlipidemia, and hyperuricemia.
• Multiple drug interactions.
Immunosuppressive Agents
• Corticosteroids: immunosuppressives of
uncertain mechanism. Used for maintenance of
immunosuppression and to manage acute
rejections.
• High doses used initially tapered over the 1st 6 months to 5 to
15mg/d prednisone.
• Side effects include mood and sleep disturbances, acne,
weight gain, obesity, hypertension, osteopenia, and
hyperglycemia.
Immunosuppressive Agents
• Mycophenolate mofetil: selectively inhibits
lymphocyte proliferation.
• Dosage is 2g/d po.
• Side effects include GI disturbances. Does not cause
significant bone marrow suppression.
• FK-506 (tacrolimus): Lymphophilic macrolide
that inhibits lymphokine production similar to
cyclosporine.
• More toxic than cyclosporine.
• Side effects include nephrotoxicity and neuotoxicity.
Immunosuppressive Agents
• Antilymphocyte globulin: Horse polyclonal
antibody designed to inhibit T cells by binding to
surface antigens.
• It is generally used at the time of transplantation for induction
therapy or during acute rejections.
• Dosage is 10 to 15 mg/kg qd through a central venous
catheter.
• Goal is to keep T lymphocyte count ~200cells/microL.
• Side effects include fevers, chills, urticaria, serum sickness,
and thrombocytopenia.
Immunosuppressive Agents
• Muromonab-CD3 (OKT3): a murine monoclonal antibody
to the CD3 complex on the T-cell lymphocyte designed
for selective T-cell depletion.
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Usual dose is 5mg/d IV bolus over 10 to 14 days.
CD3 cells are monitored with goal <25cells/mL.
Used in patients with renal insufficiency.
Side effects include cytokine release syndrome (fever, chills,
nausea, vomiting, mylagia, diarrhea, weakness, bronchospasm, and
hypotension), pulmonary edema.
• Rapamycin: Similar mechanism of action of FK-506
except that it antagonizes the proliferation of nonimmune
cells such as endothelial cells, fibroblasts, and smooth
muscle cells.
• Not routinely used at present.
• May have a roal in prevention of immunologically mediated coronary
allograft vasculopathy.
Basic Drug Regimen
• Immunosuppressives
• Antibiotic prophylaxis
• PCP: TMP/Sulfa or Dapsone or Pentamidine aerosols.
• CMV infection: Ganglyclovir, acyclovir.
• Fungal infections: Nystatin.
• Antihypertensives
• Diuretics as needed
• Potassium and Magnesium replacement (cyclosporin leads to
wasting of thes electrolytes.
• Lipid-lowering agents. (Avoid allograft vasculopathy).
• Glucose lowering agents (DM and steroids)
• Anticoagulation if transplant heterotopic.
• Cyclosporin dose lowering meds (Diltiazem / Verapamil /
Theophyilline)
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
arrhythmias). 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
recipient age.
– It is more difficult to treat than acute cellular rejection,
is associated with hemodynamic instability, and
carries a worse prognosis.
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
myocyte injury.
• Grade 1B — multifocal or diffuse sparse infiltrate without myocyte
injury.
• 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
injury.
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. Otherwise
additional agents will need to be added. 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
humoral rejection).
• 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
infection.
Complications – Rejection
Allograft Vasculopathy
• 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
locations.
• 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
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.
• It is important to remember that immunosuppressed
transplant patients can develop severe infections in
unusual locations and remain afebrile.
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 longterm oral prophylaxis with
acyclovir.
• If the recipient is CMV positive a less potent regimen can be
used.
• Bone marrow toxicity related to treatment can occur and be
confused with that due to azathioprine treatment.
Opportunistic Infections
• Toxoplasma gondii: Primary infection can be
serious while reactivation is rarely a serious
clinical problem.
• 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.
Opportunistic Infections
• 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
antilymphocyte antibodies.
• 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
hearts.
• 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
develop hypertension.
• Treatment is empiric with a diuretic added to a
calcium channel blocker, B-blocker, or Ace
inhibitor.
• 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
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.
Complications – Tricuspid
Regurgitation
• A rare complication is tricuspid regurgitation
caused by biotome-induced trauma to the valve
apparatus that rarely requires valve
replacement.
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
performed:
• Blood, urine and sputum cultures, BMP, CBC
• CXR, Echocardiography (for LV function and effusion).
• Consider endomyocardial biopsy for rejection.
Outcomes
• 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 vasculopathy.
• The UNOS data suggested some group differences with
3-year 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.
Outcomes
• 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
vasculopathy.
• In the later stages (after the perioperative
period) arrhythmia may be signs of acute
rejection or of an allograft vasculopathy.
Outcomes
• Poor outcomes are associated with the following
risk factors:
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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.
Diabetes mellitus.
Ischemic time longer than 4 hours of transplanted heart.
Sarcoidosis or amyloidosis as reason for transplant (as they
may occur in the transplanted heart).
Question 1
1.
A 38 y/o woman is seen for a second opinion regarding the management of her
chronic left ventricular dysfunction and symptomatic heart failure. She first
developed symptoms 7 years with DOE. A CXR revealed cardiomegally and a
subsequent echo revealed 4 chamber enlargement EF 25% without significant
valvular abnormalities. Coronary angiography and endomyocardial biopsy were
unrevealing and dx of idiopathic dilated cardiomyopathy was made. On good
medical regimen including Digoxin, Lasix, AceI, Coreg, KCl, and metolazone prn.
Continues to have class 2 to 3 symptoms and has been hospitalized 3 times in the
last year. The patient has been advised by her internist that she should be listed
immediately for cardiac transplantation and has been referred to you. She has
learned to live with her physical limitation, but wishes to know more about her
prognosis with medical therapy. Which diagnostic test is most useful in predicting
her likelihood for survival over the next year?
A. Cardiac Index by right heart catheterization.
B. Left ventricular ejection fraction by radioventriculography.
C. Plasma norepinephrine concentration.
D. Peak oxygen uptake by cardiopulmonary exercise testing.
E. Left ventricular dimension by echocardiography.
Answer 1
1. D: Multiple studies have shown that peak O2 uptake determined by
maximal CPX testing accurately predicts short-term (<18 month) prognosis
in patients with moderate to severe CHF. A peak VO2 < 10 to 12 ml/kg/min
is associated with a 1 year survival of only 60% and is a powerful indicator
of the need for transplant listing in suitable candidates. Its predictive value
is only valid when patient reaches his anaerobic threshold ie cardiac limit.
Conversely patients whose VO2 exceeds 15 ml/kg/min are likely to
experience one year survival rates similar or better than after cardiac
transplantation. LVEF loses its independent predictive value when below
25% and in patients with advanced symptomatic CHF. Cardiac index <2.2
l/min/m2 is associated with a poor outcome, but is highly variable depending
on patients volume status and afterload medications. Norepinephrine levels
>900 picrograms/ml are predictive of poor two year outcome, but are
seldom measured outside of clinical trials. LV dilation portends a worse
prognosis, but its prognosis in the setting of chronic CHF is unclear.
Question 2
2.
A 45 y/o male business man presents to your office with a hx of
nonischemic, dilated cardiomyopathy. He was dx 5 years earlier when he
presented with CHF. In the past 3 months he has become increasingly
difficult to treat with 4 hospitalizations in that time period. Today he
complains of fatigue and breathlessness when he walks around his house.
Meds include Digoxin 0.125mg qd, Aldactone 50mg qd, lisinopril 40mg qd,
Lasix 80mg bid, Metolazone 5mg qd, and Coreg 25mg bid. Recent labs
include Na 129, K 4.5, BUN 35, Cr 1.2, Digoxin 0.6 ng/ml, and Hgb 12.0.
Echo 2 months earlier unchanged from previous with EF 25%. PE is
significant for P 85, BP 85/60, Pox 95% RA, JVP 10cm, laterally displaced
PMI, S3, 2/6 HSM at apex, cool extremities with pitting edema to knees.
CPX reveals VO2 of 12ml/min/kg with peak systolic BP during the test
115mmHg. What would be your next best treatment in this patient’s
management?
A. Increase Digoxin to 0.25 mg qd
B. Increase Aldactone to 100mg qd
C. Change patient from furosemide to torsemide
D. Refer patient for cardiac transplantation
E. Decrease dose of Coreg and titrate to off.
Answer 2
2. D. This patient is failing on appropriate regimen for CHF. His recent VO2
max score of less than 14ml/min/kg and inability to achieve BP of 120mmHg
are markers for poor prognosis. Given patient’s age and lack of
comorbidities, transplantation should strongly be considered. A study from
the DIG trial demonstrated an increase mortality from serum digoxin dosing
above 0.5 to 0.8 ng/ml range. The potential benefits of higher Aldactone
dosing have not be demonstrated. The RALES trial used as dose of 25mg
qd titrated to 50mg qd. Changing to torsemide from furosemide may benefit
the patient if bowel wall edema is leading to decreased absorption and thus
the effectiveness of furosemide, but would not be expected to affect the
patients prognosis. The use of B-blockers have been shown to improve
mortality and exercise tolerance in patients with cardiomyopathy.
Question 3
3. You are called to the ER to see a 30 y/o African American male patient of
yours who had a heart transplant for idiopathic dilated cardiomyopathy six
years previously. He has come in complaining of a 2 day history of
generally feeling unwell with nausea and mild dyspnea at rest. His posttransplant course has previously been uncomplicated and he has returned
to work as a computer programmer and been very compliant with medical
follow up. His last surveillance heart biopsy 3 months ago showed no
rejection, his immunosuppressive regimen has been stable and consists of
cyclosporin and mycophenolate mofetil. His other medications include
diltiazem, ASA, pravastatin, and TMP/sulfa. His last cath was 2 years ago
and normal. On exam he appears apprehensive with NAD, BP 105/60,
pulse 110 regular, O2 sat 99%. No signs of CHF and his cardiac exam is
only significant for an S3 gallop. CXR is unremarkable. ECG reveals sinus
tach with IRBBB unchanged from previous but new repolarization
abnormality. A bedside echocardiogram reveals mild generalized LV
hypokinesis. Screening labs, including cardiac enzymes is unremarkable.
Your leading diagnostic suspicion at this point should be which of the
following?
A. Early / Subclinical opportunistic pulmonary infection.
B. Cardiac allograft rejection.
C. Myocardial ischemia.
D. Anxiety.
E. Recurrent cardiomyopathy.
Answer Question 3
3. C. The transplanted heart remains denervated (with rare exceptions) and
thus transplant patients are incapable of experiencing the subjective
symptom of angina pectoris. The cardiac allograft is prone to develop a
very diffuse form of coronary vasculopathy this is independent of the usual
coronary risk factors, is increasingly prevalent with time after
transplantation, and can be rapidly progressive. A long-term transplant
recipient who is on a stable low-dose immunosuppressive regimen is
unlikely to develop allograft rejection or opportunistic infection, although
both are within the realm of possibility. Patient is relatively hypotensive and
to write his symptoms off to anxiety or an upper respiratory infection would
be a great disservice.
Question 4
4. A 54 y/o male heart transplant recipient arrives for an unscheduled visit in transplant clinic following
2 weeks of progressive fatigue, anorexia, and worsening SOB. He underwent transplantation 5
years ago for lymphocytic myocarditis and had an early postoperative course complicated by 2
bouts of symptomatic CMV viremia, and 2 episodes of moderate (ISHLT grade 2 rejection at 3
months; and ISHLT grade 3A rejection at 6 months) cellular rejection. Both episodes rapidly
resolved after intervenous treatment with methylprednisolone. Subsequent biopsies have been
ISHLT grade 0 or 1A. Chronic maintenance therapy has consisted of cyclosporin (3mg/kg qd),
azathioprine (1.5mg/kg qd), amlodipine (10mg qd), and simvastatin (20mg qd). He has been
entirely well and walking about 1 hour qd until symptoms suddenly appeared. PE revealed mildly
Cushingoid appearance / NAD, BP 160/95, P 115 with occasional PVC’s, temp 98.8. Skin showed
several AK’s over sun-exposed skin surfaces. Lung exam showed fine crackles at b/l bases.
Cardiac exam showed non-displaced PMI, S2 paradoxically split, loud S4, 2/6 HSM at LLSB. JVD
8cm; 1+ peripheral edema. CXR showed mild CMG and 2+ pulmonary vascular redistribution.
ECG showed Sinus tach at 114, occasional PVC, biatrial enlargement, LBBB, diffuse
repolarization abnormalities, WBC 5600, Plt 210, pO2 80, pCO2 32, pH 7.45. An echo, RHC, and
endomyocardial bx is contemplated. The most likely diagnosis is:
A. Chronic cellular rejection.
B. Acute mitral regurgitation.
C. Reactivation of cytomegalovirus pneumonitis.
D. Recurrent lymphocytic myocarditis.
E. Transplant coronary vasculopathy.
Answer Question 4
4. E. Accelerated coronary vasculopathy is the most common cause of
symptomatic LV dysfunction in heart transplant recipients who survive
beyond the 1st 3 years. The patients clinical presentation is characteristic of
post-transplant vasculopathy. The patient probably had a “silent” AMI
approximately 2 weeks ago due to an epicardial coronary occlusion. The
cardiac allograft typically remains denervated in the majority of transplant
recipients so typical anginal pain is typically absent. Heart faliure and
sudden cardiac death are the two most common clinical presentation. This
frequent complication remains the “Achilles heel” of heart transplantation
and is the major cause of mortality in long-term transplant recipients.
Angiographic evidence of coronary vasculopathy is evident in at least 50%
of patients at 5 years. CMV infection is a significant risk factor for this
complication. HMG co-reductase inhibitors have been shown to lower the
incidence of transplant vasculopathy. Cellular rejection occurs in over 70%
of transplant recipients but is rarely observed beyond 12 months unless
immunosuppression has been decreased. CMV can produce an interstitial
pneumonitis but reactivation of disease after 7 years in the absence of
enhanced immusuppression is unlikely. The lack of fever or leukopenia also
argues against this diagnosis. Finally recurrent lymphocytic and giant cell
myocarditis in the cardiac allograft has been described, but is exceedingly
rare.
Question 5
5.
You are asked by the family of a 53 y/o Hispanic woman to consult and
render a second opinion regarding her care. She has a 5 year hx of CHF
and thorough evaluation has led to the diagnosis of idiopathic, dilated
cardiomyopathy. She is otherwise in good health. She has been treated
with a flexible diuretic regimen, digoxin, Ace I, aldactone, and until current
admission, B Blocker. She has been hospitalized 4 times in the past 6
months with exacerbations of her heart failure despite good compliance
with medical and dietary regimen. She was readmitted 3 days ago with
increasing dyspnea and orthopnea. The B-blocker was stopped and she
has improved on IV milrinone. On exam she is resting comfortably. She
is able to converse and is oriented and wishes to go home. BP 80/60
and P 98. Mild bibasilar crackles, PMI laterally displaced, 2/6 HSM, and
loud S3 gallop. Her extremities are cool and free of edema. S-G
catheter reveals RA 8, PAP 40/16/25, wedge 16, CO 2.6, and CI 1.7. At
this point you should suggest which of the following?
A. Increase the dose of milrinone.
B. Restart the B-Blocker at a lower dose.
C. Change milrinone to dobutamine.
D. Refer for cardiac transplantation.
E. Refer for hospice care.
Answer Question 5
5. D. The patient clearly fits the definition of “advanced heart failure” and is a
candidate for “specialized” therapies. If she were elderly or had major
comorbidities, a hospice referral would be appropriate. In this case she is
an excellent candidate for cardiac transplantation. There is probably little to
be gained in the long-term by minor adjustments in her medications.