British Columbia Medical Journal, May 2010 issue Please download or visit this entire issue online at http://bcmj.org/may-2010

1. Ellamae Stadnick MD, MSc, FRCPC, Andrew Ignaszewski, MD, FRCPC
Cardiac transplantation
in British Columbia
Standard malignancy screening and aggressive management of
atherosclerotic risk factors are both needed after a heart transplant.
n December 1967 Christiaan blood lengthens the wait list not only
I
ABSTRACT: The first cardiac trans-
plantation in the world was per- Barnard performed the first human because more transplant candidates
formed in 1967. Since then it has cardiac transplantation in Cape have this blood type to begin with, but
become standard therapy for end- Town, South Africa. Louis Washkan- because type O patients can only re-
stage heart failure with over 200 sky, a 55-year-old man, survived for ceive an organ from a type O donor—
recipients in British Columbia over 18 days before succumbing to pneu- unlike type AB patients, who are uni-
the past 20 years. Cardiac trans- monia. Since then cardiac transplan- versal recipients.
plantation should be considered in tation has evolved to become a wide- On average patients spend 2 weeks
individuals with advanced heart dis- ly adopted therapeutic option for the in the hospital after transplantation,
ease who have a poor chance of treatment of end-stage heart failure. including 3 to 5 days in the ICU. This
long-term survival despite optimal By 2007 over 80 000 heart transplants is followed by weekly outpatient vis-
medical or surgical therapy. Con- were reported in the International its and endomyocardial biopsies for
traindications to transplant include Society of Heart and Lung Transplant the first month. Patients can expect
pulmonary hypertension, active in- (ISHLT) worldwide data registry.1 about 12 to 15 biopsies in the first year
fection, systemic illness, renal dys- In BC the first cardiac transplanta- following surgery. Frequent evalua-
function, recent malignancy, active tion was performed in 1988. Since tion is required to ensure graft sur-
smoking/substance abuse, or the then over 200 patients have undergone vival and the prevention of complica-
inability to undergo rehabilitation. transplantation. More than 70% of tions. All patients must remain in the
All patients require immunosuppres- patients survive the first 5 years fol- Lower Mainland during the first 3
sive therapy following transplanta- lowing transplant ( Figure 1 ). Increas- months following transplant.
tion to prevent allograft rejection. In ing recipient age, pre-existing renal
addition to rejection, common com- dysfunction, and an elevated body Indications
plications in the post-transplant mass index adversely affect long-term Cardiac transplantation should be con-
period include infections, malignan- survival. At any given time there are 5 sidered in individuals with advanced
cy, post-transplant lymphoprolifera- to 15 patients on the active transplant heart disease who have a poor chance
tive disorder, and allograft coronary list. The average wait list time in of long-term survival despite optimal
artery disease. Given the scarcity of British Columbia in 2007 was 141
available donor hearts in BC, efforts days ( Figure 2 ), with longer wait Dr Stadnick is a cardiology fellow at the
have been made recently to develop times for male patients (average 167 University of British Columbia. Dr Ignas-
mechanical ventricular assist de- days vs 65 for female patients) and zewski is head of the University of British
vices to support patients waiting for those with a higher body mass index Columbia Division of Cardiology at Provi-
donor organs. (average time 323 days if BMI > 31), dence Health Care (St. Paul’s Hospital). He
or more common blood type (average is also the acting medical director of the BC
223 days if type O). Having type O Transplant Heart Transplant Program.
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2. Cardiac transplantation in British Columbia
sumption (VO2) less than 10 mL/kg/
100% min is an absolute indication for trans-
plantation. A value between 11 mL/
90% kg/min and 14 mL/kg/min, or less than
80%
55% of the age-predicted peak, is a
relative indication.4
Survival rate
70% Individuals who may be consider-
ed for cardiac transplantation should
60% be referred to the Pre-Transplant Clin-
ic at St. Paul’s Hospital ( Table 1 ).
50%
Patients are required to undergo a series
40%
of investigations in order to determine
candidacy. These include a chest X-
30% ray, pulmonary function tests, an
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 abdominal ultrasound, a bone density
Years post-transplant scan, a mammogram (in women over
40), and a carotid duplex scan (if over
Figure 1. Graft survival for first heart transplantation in BC, 1988–2007. age 40). Because of the need for life-
Source: BC Transplant long immunosuppression therapy
after transplantation, all candidates
must be tested for prior exposure to
various pathogens and receive multi-
250
ple immunizations ( Table 2 ). Typi-
cally these investigations are coordi-
200 nated at the time of the patient’s first
visit to the clinic.
150
Contraindications
Days
There are multiple contraindications
100
to cardiac transplantation ( Table 3 ).4
Pulmonary hypertension is one of the
50 most important. Right ventricular dys-
function in the presence of high pul-
0 monary pressures is a common cause
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 of primary graft failure and death fol-
Year lowing transplant. All patients require
a right heart catheterization during
Figure 2. Average waiting days for heart transplantation in BC, 1998–2007. their initial pre-transplant assessment.
Source: BC Transplant Pulmonary press ure reversibility
should be assessed if the pulmon -
medical or surgical therapy. This low mean arterial blood pressure, ary artery pressure (PAP) is greater
includes patients with end-stage heart intraventricular conduction defects on than 50 mm Hg, the transpulmonary
failure (ischemic or nonischemic), ECG, and a low aerobic threshold dur- gradient is greater than 14 mm Hg
refractory ventricular arrhythmias, or ing cardiopulmonary exercise test- (PAP–pulmonary capillary wedge
congenital heart defects not amenable ing.3 Patients with markedly impaired pressure), or the pulmonary vascular
to surgical repair.2 Predictors of mor- left ventricular function and NYHA resistance (PVR) is more than 3 Wood
tality in this patient population include class III or IV symptoms should units. This usually involves continu-
poor left ventricular function, hypona- undergo cardiopulmonary exercise ous administration of inhaled nitric
tremia, elevated BNP, ischemic heart testing to objectively assess their oxide or infusion of an inotrope such
disease, elevated resting heart rate, functional capacity. Peak oxygen con- as milrinone, which has vasodilatory
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3. Cardiac transplantation in British Columbia
Table 1. Transplant resources for Table 2. Pre-transplant serology and Table 3. Contraindications to cardiac
physicians and patients. immunizations. transplantation.5
• St. Paul’s Transplant Program: Serology Immunizations • Pulmonary hypertension (TPG > 15 mm
www.heartcentre.ca Hg, SPAP > 50 mm Hg, PVR > 4 WU,
Human PVRI > 6)
• BC Transplant: www.transplant.bc.ca immunodeficiency Poliovirus
• Organ Donor Registry: virus • Systemic disease (anticipated to limit
www.transplant.bc.ca/onlinereg/ long-term survival)
bcts.asp Hepatitis B and C Meningococcus • Elevated creatinine (> 200 µmol/L)
• International Heart and Lung Epstein-Barr virus Pneumococcus • Active infection
Transplant Society: www. ishlt.org • Psychosocial (substance abuse,
Hemophilus smoking, medical noncompliance)
Cytomegalovirus
influenzae B
• Malignancy (within 5 years)
properties. The following values rep- Varicella zoster virus Influenza • Morbid obesity (> 140% ideal body
resent an absolute contraindication to weight)
VDRL Tetanus • Marked cachexia (< 60% ideal body
transplantation:
weight)
• PVR > 6 Wood units Diphtheria
• Osteoporosis
• Transpulmonary gradient > 16 mm Hg Measles/mumps/
Toxoplasma titers • Peripheral or cerebrovascular disease
• PVR > 2.5 Wood units following a rubella
• Diabetes mellitus with end organ
vasodilatory challenge2 Varicella damage
Additional contraindications in-
clude active infection, systemic ill-
ness, renal dysfunction (Cr > 200), Immunosuppressive therapeutic dosing and to avoid toxic
recent malignancy (within 5 years), therapy side effects. These may include hy-
active smoking/substance abuse, or All patients require immunosuppres- pertension, hyperlipidemia, hyper-
the inability to undergo rehabilitation sive therapy following transplantation glycemia, tremor, headaches, elec-
following transplantation. Osteoporo- in order to prevent allograft rejection. trolyte imbalances, hepatotoxicity,
sis is a relative contraindication be- All donors and recipients are matched gingival hyperplasia, and hypertri-
cause of the need for steroids as part for ABO compatibility. HLA match- chosis. Many drugs affect the serum
of the initial immunosuppressive ing is not performed; however, a concentrations of calcineurin inhibit-
regimen. Age itself is not an absolute panel-reactive antibody (PRA) screen ors. Caution should be taken when
contraindication; however, increasing is performed prior to transplantation.5 prescribing medications such as cal-
recipient age is associated with de- This test measures the amount of pre- cium channel blockers, antifungals,
creased survival rates.1 Furthermore, formed antibodies to a panel of donor anti-inflammatories, allopurinol, anti-
older patients often have a greater lymphocyte HLAs. A PRA greater seizure medications, and H2-blockers
number of comorbidities that may pre- than 10% is associated with an in- to these patients.4
clude transplant candidacy. creased risk of rejection and mortali-
A psychosocial assessment is ty. Higher PRA titers are common in Post-transplant
completed for all potential candidates. multiparous females, patients who complications
The transplant team has a dedicated have received multiple blood transfu- The most common complications post-
social worker and psychologist to sions, or those with a ventricular assist transplant are rejection, infections,
facilitate this. It is imperative that device (VAD).6 The initial immuno- malignancy, post-transplant lympho-
patients have a strong support network suppression generally consists of proliferative disorder, and allograft
during the initial period following prednisone, a calcineurin inhibitor coronary artery disease (ACAD).
transplantation, during which time (tacrolimus or cyclosporine), and a Rejection accounts for less than
multiple outpatient hospital visits are purine synthesis inhibitor such as my- 20% of all deaths within the first year
required. Medical compliance is also cophenolate mofetil.4 In the absence following transplant. This value drops
imperative to ensure graft survival, of rejection, prednisone is frequently to 5% after the third year.1 The major-
meaning that a history of noncompli- withdrawn over the first 6 months ity of patients with microscopically
ance is a relative contraindication to post-transplant. Tacrolimus and cyclo- proven rejection are asymptomatic
candidacy. sporine levels are monitored to ensure and only diagnosed at the time of
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4. Cardiac transplantation in British Columbia
Treatment requires reduction or with-
0.20 drawl of immunosuppressive therapy,
0.18 and may include the addition of antivi-
0.16
ral therapies, intravenous immuno-
globulin, or monoclonal antibody
Rejection episodes
0.14
therapy such as rituximab.8 Consulta-
0.12 tion with hematology or oncology is
0.10 generally required.
0.08 Allograft coronary artery disease
0.06 is the most common cause of morbid-
0.04 ity and mortality following transplan-
tation. It is responsible for 18% of
0.02
deaths after 5 years and 33% of deaths
0.00
0–90 91–180 181–365 366–730 731–1825 after 10 years.7 Unlike atherosclerotic
Days post-transplant
coronary artery disease, ACAD in-
volves concentric, diffuse intimal
thickening without resultant focal
Figure 3. Acute rejection episodes per 100 patient days in BC, 1988–2007, implanted into the
left ventricular apex and connected to the ascending aorta. The device generates nonpulsatile stenoses. All vascular components of
flow as blood is continuously pulled from the ventricle and delivered to the ascending aorta. the allograft are involved. Up to 50%
Source: BC Transplant of patients have evidence of ACAD
by 10 years.7 The cause is likely mul-
endomyocardial biopsy. Symptoms and recipient. Seronegative recipients tifactorial and includes both tradition-
consistent but not specific with graft receive prophylaxis if their donor was al atherosclerotic risk factors and
rejection include fever, malaise, re- seropositive for a given pathogen. After immunological factors.9 Because of
duced exercise tolerance, hypotension, the initial 6 months post-transplant the cardiac denervation that occurs
and clinical signs of congestive heart patients remain at risk for common at the time of transplantation, most
failure. Biopsies are initially per- pathogens such as pneumococcal pneu- patients do not experience anginal
formed weekly for the first month and monia and influenza. An annual flu symptoms. Screening for ACAD may
then gradually decrease in frequency shot is recommended along with the be performed noninvasively with do-
until the patient is on a stable, well- pneumonia vaccine every 5 years. Shin- butamine stress echocardiography or
established immunosuppressive regi- gles is common in this population. invasively by coronary angiography.
men. The long-term rates of rejection Malignancy is a frequent cause of The diffuse nature of the disease
in British Columbia have decreased mortality in patients who survive the makes intravascular ultrasound10 the
over the past 2 decades with the advent first 5 years after transplant. Solid best method for detecting ACAD;
of improved regimens. Rejection rates organ or skin cancer occurs in about however, this is a highly specialized
fall steadily after transplant, with the 13% of patients at 5 years and 30% of imaging technique that may not be
6 months of the first year posing the patients at 10 years.7 Skin malignan- readily available at all centres. Dobu-
highest risk for acute rejection cies are the most common. All patients tamine stress echo is routinely per-
( Figure 3 ). are advised to use sunscreen and bar- formed in post-transplant cardiac
The most common opportunistic rier protection while outdoors. An an- patients in British Columbia. Pre-
infections in the first 6 months follow- nual skin examination is imperative. vention of ACAD requires aggressive
ing transplantation are caused by cy- Standard age-appropriate screening management of traditional risk fac-
tomegalovirus, herpes simplex virus, tests (mammograms, Pap tests, and tors. All patients are placed on statin
Pneumocystis carinii (PCP), Asper- rectal exams) should be performed. therapy ( target LDL < 2 mmol/L) fol-
gillus, Nocardia, and Toxoplasma Post transplant lymphoprolifera- lowing surgery. Fasting blood sugars
gondii. All patients receive PCP pro- tive disorder refers to a spectrum of should be followed and hypertension
phylaxis for the first year following diseases from mononucleosis to B- ( > 140/90) should be aggressively
transplant. Prophylaxis against other cell monoclonal malignancies. It is treated. There is no effective therapy
opportunistic infections is dependant associated with Epstein-Barr virus for advanced ACAD and the prognosis
upon the serologic status of the donor and has many clinical presentations. remains poor.
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5. Cardiac transplantation in British Columbia
Ventricular assist devices are currently
approved as a bridge to transplant or recovery
of the native heart in patients who are
transplant candidates.
Figure 4. Heartmate II ventricular assist
device (Thoratec Ltd.). The device is
surgically implanted into the left
ventricular apex and connected to the
ascending aorta. The device generates
nonpulsatile flow as blood is continuously
Mechanical support anticoagulation (INR 2 to 3) to prevent pulled from the ventricle and delivered to
the ascending aorta.
devices thromboembolic events.
In 2007 12.5% of the patients on the The Impella (Abiomed Inc., Mass-
transplant wait list died before an achusetts) is a temporary, percuta-
organ became available. Due to the neously inserted assist device that is
scarcity of donor hearts, efforts over placed retrograde across the aortic
the past decade have been dedicated valve into the left ventricle via the
to the development of mechanical femoral artery ( Figure 5 ). It also gen-
ventricular assist devices (VADs) to erates nonpulsatile flow via a rotary
support patients until an organ be- device. It is designed for short-term
comes available. In 1992 the Heart (7 to 10 days) support. Unlike an intra-
Centre at St. Paul’s Hospital implant- aortic balloon pump it has no effect on
ed the first VAD in the province. Since afterload, and purely augments car-
then 52 patients have received VADs. diac output.
Thirty-four (65%) of these patients Up to 50% of patients undergoing
are still alive. Seven (13.5%) were cardiac transplantation have pre-exist-
successfully weaned off mechanical ing VAD support.11 Ventricular assist
support, 19 (35%) received a trans- devices are currently approved as a Figure 5. Impella assist device
plant, and 8 (15%) reside in the com- bridge to transplant or recovery of the (Abiomed Inc.). The device provides
temporary left ventricular support and is
munity with a VAD. The average native heart in patients who are trans- placed retrograde through the aortic valve
duration of mechanical support is plant candidates. Destination therapy via the femoral artery.
155 days. The current device utilized (implantation of a VAD into a patient
in BC is the Heartmate II (Thoratec who is not a candidate for transplanta-
Ltd., California). It generates con- tion) is not yet approved; however, this symptoms and no contraindications
tinuous, nonpulsatile blood flow remains an area of ongoing discussion. should be referred for evaluation. The
through a rotary impellar, thereby assessment and management of these
draining blood from the left ventri- Conclusions patients require a multidisciplinary
cle to the ascending aorta ( Figure 4 ). Cardiac transplantation remains a team. Standard malignancy screening
Compared with its predecessors, which life-saving therapy for patients with and aggressive management of classic
produced pulsatile flow, this device is end-stage heart failure. Patients with atherosclerotic risk factors are imper-
smaller and requires less aggressive NYHA class III or IV heart failure ative for patients after transplantation
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6. Cardiac transplantation in British Columbia
Table 4. Health monitoring for cardiac
transplantation patients.
• Target BP < 140/90 mm Hg The ongoing scarcity of available
• Target LDL < 2 mmol/L donor organs has led to the development of
• Smoking cessation
ventricular assist devices . . . as these devices
• Minimal alcohol
• Sunscreen SPF 30 when outdoors advance, there may come a day when
• Annual skin exam mechanical support replaces the allograft.
• Regular mammogram, Pap test,
rectal exam
• Adequate calcium and vitamin D
• Monitor fasting blood sugar
• May drive 6–8 weeks postoperatively
• Annual flu shot
• Regular exercise
( Table 4 ). The ongoing scarcity of 4. Ross H, Hendry P, Dipchand A, et al. 2001 and quantitative angiography for evalua-
available donor organs has led to the Canadian Cardiovascular Society Con- tion of coronary artery disease in the
development of ventricular assist sensus Conference on cardiac transplan- transplanted heart. Ann Transplant 1996;
devices. These may allow patients to tation. Can J Cardiol 2003;19:620-654. 1:31-33.
survive long enough to receive an 5. Betkowski AS, Graff R, Chenn JJ, et al. 11. Taylor DO, Edwards LB, Boucek MM, et
organ. Alternatively, as these devices Panel-reactive antibody screening prac- al. Registry of the IHLST: Twenty-fourth
advance, there may come a day when tices prior to heart transplantation. J official adult heart transplant report—
mechanical support replaces the allo- Heart Lung Transplant 2002;21:644-650. 2007. J Heart Lung Transplant 2007;
graft. 6. Itescu S, John R. Interactions between 26:769-781.
the recipient immune system and the left
Competing interests ventricular assist device surface: Im-
None declared. munological and clinical implications.
Ann Thorac Surg 2003;75(6 suppl):S58-
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