1.
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What are the selection
criteria for heart transplantation?
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| Absolute indications for transplantation include peak VO2
<10 ml/kg/min with achievement of anaerobic metabolism, severe ischemia limiting
routine activity which is not amenable to angioplasty or bypass surgery, and recurrent
symptomatic ventricular arrhythmias refractory to all accepted therapeutic interventions.
Relative indications include peak po2 <14 ml/kg/min and major limitation of
daily activities, recurrent unstable ischemia not amenable to standard interventional
measures. The following criteria are not indications for transplantation: ejection
fraction <20%, history of functional class III symptoms of heart failure, previous
ventricular arrhythmias, and maximum VO2 >15 ml/kg/min without other
indications. |
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2.
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Why has the donor age
increased?
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| In past years, the majority of organ donors was a result of traumatic
injuries involving automobiles and motorcycles. In recent years, there has been a distinct
change in the cause of death. In one region of the country, the New England Organ Bank
reported that over a 7 year period, the number of donors dying from motor vehicle
accidents decreased from 37.6% to 20.6%. Concomitant with this decrease in fatalities with
motor vehicle accidents, has been an increase in the cause of death from central nervous
system events from 25.3 to 48.9%. With this shift in cause of death, the average age of
donors has increased from 23.9 ± 0.6 years to 48.2 ± 0.5 years. This remarkable change
in donor demographics can be attributed to a variety of reasons but predominately due to
safety measures promulgated during the late 1980's and early 1990's. |
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3.
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What are the risk factors
associated with 1 year survival?
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As reported by the Registry of the International Society for Heart
Transplantation, April of 1997, there are a variety of risk factors associated with 1 year
mortality. This Registry represents 13,695 patients who have undergone orthotopic cardiac
transplantation. The risk factors with their associated odds ratio, P-values, and 95%
confidence interval are listed below.
| Variable |
Odds Ratio |
P-value |
95% Confidence
Interval |
| Repeat Transplantation |
3.51 |
>0.0001 |
2.82-4.37 |
| Ventilator |
2.39 |
>0.0001 |
1.91-2.99 |
| Center Volume < 9 tx/yr |
1.29 |
0.0002 |
1.13-1.47 |
| ICU and Life Support |
1.21 |
0.0010 |
1.08-1.36 |
| Non-white recipient |
1.18 |
0.0100 |
1.04-1.34 |
| Cold Ischemic Time |
1.13 |
>0.0001 |
1.08-1.19 |
| ABO not Type A |
1.10 |
0.0400 |
1.01-1.21 |
| Donor Female |
1.22 |
>0.0001 |
1.10-1.35 |
| Non-white Donor |
1.15 |
0.0200 |
1.02-1.29 |
| Donor age (linear) |
|
>0.0001 |
|
| Donor age (quadratic) |
|
0.0020 |
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4.
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What are the primary
causes of death stratified by time?
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| The primary cause of early death, defined as 0-30 days is non-specific
graft failure. This represents approximately 35% of all deaths. During the intermediate
period, defined as 31 days-1 year, acute rejection and infection represent the two major
causes of death. Following 1 year, the three major causes of death include allograft
coronary artery disease, malignancy, and acute rejection. |
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5.
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How is transplant coronary
artery disease diagnosed and treated?
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| Diagnosis of transplant coronary artery disease has conventionally
been by coronary angiography. Non-invasive studies have had variable sensitivities. Since
the morphology of this type of coronary artery disease can be intimal hyperplasia, the
vessels can undergo diffuse luminal narrowing and requires careful comparison with
previous angiograms to detect the disease. The introduction of intracoronary ultrasound
has resulted in a more sensitive method of detecting early intimal hyperplasia. Treatment
has consisted of medical management, coronary artery angioplasty, coronary artery bypass
grafting and retransplantation. Since the morphology of this disease is generally diffuse,
most individuals are not benefited by the former treatments and retransplantation
represents the primary method to address this life threatening complication. |
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6.
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What is the
pathophysiology of transplant coronary artery disease?
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| Graft coronary artery disease is the primary factor limiting long-term
survival of patients undergoing cardiac transplantation. It also represents the major
indication for retransplantation. It has been documented to occur in approximately 40% of
survivors at 5 year follow-up. The introduction of cyclosporine has not changed its
incidence. The cause of the development of transplant coronary artery disease is
undoubtedly multifactorial. It has a similar occurrence in patients whose recipient
diagnosis is coronary artery disease or idiopathic cardiomyopathy. There have been
numerous studies in the literature purporting various independent risk factors. These have
included older donor age, older recipient age, increased lipids, presence of
cytomegalovirus infection, and increased number of rejection episodes. Experimentally,
there appears to be an underlying immunologic mechanism leading to the initial coronary
endothelial injury. |
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7.
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What are the indications
and outcomes in patients undergoing re-transplantation?
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| In the majority of multivariate analyses that have been conducted
throughout the years, including the data from the International Society for Heart and Lung
Transplantation Registry, re-transplantation usually is the number one risk factor that
adversely affects 1 year survival. Re-transplantation has been performed for both acute
rejection, non-specific graft failure immediately following transplantation, and the
development of graft coronary artery disease. The two prior indications result in
extremely poor outcomes. Although there are differing opinions regarding the efficacy of
re-transplantation, acute re-transplantation for emergency situations should be
discouraged. However, re-transplantation for the development of graft coronary artery
disease has resulted in good early survival in carefully selected patients. Our acceptance
criteria for patients undergoing re-transplantation are the same for those patients
undergoing their first operation. Although good early survival is seen in patients
undergoing re-transplantation for allograft coronary artery disease, unfortunately, the
incidence of recurrent coronary artery disease in the second heart seems to be high. |
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8.
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What are the newer
immunosuppressive drugs involved in cardiac transplantation?
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| Two drugs have been recently investigated in cardiac transplantation.
FK506 or tacrolimus exerts its immunosuppressive effects by interfering with the
transcription of cytokines genes. Specifically, it inhibits the activity of calcineurin
subsequent to its combining with its cytoplasmic binding protein (FKPB). FK506 binds much
more strongly to FKBP compared with cyclosporine and its binding to cyclophilin. This
makes tacrolimus a very potent immunosuppressant medication. The University of Pittsburgh
group has shown it to be beneficial in reversing recalcitrant rejection as well as being
efficacious as a primary immunosuppressant in lung transplantation. Since it is similar to
cyclosporine, its primary side effect is nephrotoxicity. The second drug that has been
investigated in a randomized prospective trial is mycophenolate mofetil or Cellcept. This
new drug is an inhibitor of DNA synthesis. It is a more selective immunosuppressant drug
compared to azathioprine. Because T and B cells rely on a de novo pathway for synthesis of
purine nucleotides, they cannot use the alternative salvage pathway for purine
biosynthesis. This drug is a selective inhibitor of T & B cell DNA synthesis because
it blocks the activity of a single enzyme responsible for the synthesis of purines in the
de novo pathway. It has been used in renal transplant trials and has been found to be
efficacious in its ability to reverse rejection as well as a primary immunosuppressant
drug. At the most recent International Society for Heart and Lung Transplantation annual
meeting, a multicenter randomized trial comparing mycophenolate mofetil with azathioprine
was reported. The report consisted of two groups of patients. The first group or the
intention to treat group demonstrated that there was no significant difference in the
incidence of rejection. However, in the treated group (those who actually took the study
drug), there was a significant difference in the incidence of rejection as well as in the
luminal diameter as assessed by intracoronary ultrasound. Although this was the initial
report, it is a continuing study which will result in subsequent two and three year
reports. |
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