Cardiac Transplantation

1
Cardiac Transplantation Board Review
Brian W. Zagol, M.D. Department of
Cardiology University of Tennessee
2
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
  brain-death injuries, difficulty with ex-vivo
  preservation, heart disease among donors, and the
  complexity of the operation.

3
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.

4
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
  gt14ml/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 lt10 had the
  greatest survival benefit.

5
Contraindications to Cardiac Transplantation
6
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, PFTs 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.

7
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.

8
Status Listings

• Status I.
• Cardiac Assistance
• 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.

9
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.

10
Cardiac Donor Exclusion Criteria

• 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 gt than
  4-5 hours
• LVH or LV dysfunction on echocardiography
• Death of carbon monoxide poisoning
• IV drug abuse.

11
Care of Donor Before Transplantation

• Contact local organ procurement organization
  (OPO).
• Obtain patients 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.

12
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.

13
Care of Donor Before Transplantation

• Diabetes Insipidus should be suspected if urine
  output is gt300cc/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.

14
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.

15
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.

16
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 lt25ccs if possible. No LVgram
  unless absolutely necessary.

17
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 lt 10 to 20 then no
  cross-match is necessary. If PRA is gt 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 PRA.

18
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.

19
Surgical Transplantation Techniques

• Heterotopic implantation is an alternative
  technique in which the donor heart functions in
  parallel with the recipients 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.

20
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.

21
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

22
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.

23
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 lt10mmHg and PVR lt 6
  woods units
• If vasodilators, volume reduction with diuretics
  and ultrafiltration, and inotropic agents fail to
  improve RV function, then RVAD can be considered.
  

24
Treatment of Postoperative Complications

• Arrhythmias may signify acute rejection.
• Bradyarrhythmias
• 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.

25
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.

26
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.
• ECGs are obtained qday.

27
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.

28
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.

29
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).

30
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 gt3.0mg/dL (some renal
  insufficiency is expected). Other side effects
  include hypertension, hypertrichosis, tremor,
  hyperkalemia, hyperlipidemia, and hyperuricemia.
  
• Multiple drug interactions.

31
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.

32
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.

33
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.

34
Immunosuppressive Agents

• Muromonab-CD3 (OKT3) a murine monoclonal
  antibody to the CD3 complex on the T-cell
  lymphocyte designed for selective T-cell
  depletion.
• Usual dose is 5mg/d IV bolus over 10 to 14 days.
  
• CD3 cells are monitored with goal lt25cells/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.

35
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)

36
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.

37
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.

38
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.

39
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.

40
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.

41
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.

42
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.

43
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.

44
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.

45
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.

46
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.

47
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-Hodgkins 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.

48
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.

49
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.

50
Complications Tricuspid Regurgitation

• A rare complication is tricuspid regurgitation
  caused by biotome-induced trauma to the valve
  apparatus that rarely requires valve replacement.
  

51
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.

52
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 lt age 1 and
  approaching age 65.

53
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.

54
Outcomes

• Poor outcomes are associated with the following
  risk factors
• 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).

55
Question 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?
• Cardiac Index by right heart catheterization.
• Left ventricular ejection fraction by
  radioventriculography.
• Plasma norepinephrine concentration.
• Peak oxygen uptake by cardiopulmonary exercise
  testing.
• Left ventricular dimension by echocardiography.

56
Answer 1

• 1. D Multiple studies have shown that peak O2
  uptake determined by maximal CPX testing
  accurately predicts short-term (lt18 month)
  prognosis in patients with moderate to severe
  CHF. A peak VO2 lt 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 lt2.2 l/min/m2 is associated with a
  poor outcome, but is highly variable depending on
  patients volume status and afterload medications.
  Norepinephrine levels gt900 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.

57
Question 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 patients management?
• Increase Digoxin to 0.25 mg qd
• Increase Aldactone to 100mg qd
• Change patient from furosemide to torsemide
• Refer patient for cardiac transplantation
• Decrease dose of Coreg and titrate to off.

58
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
  patients 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.

59
Question 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
  post-transplant 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?
• Early / Subclinical opportunistic pulmonary
  infection.
• Cardiac allograft rejection.
• Myocardial ischemia.
• Anxiety.
• Recurrent cardiomyopathy.

60
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.

61
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 PVCs, temp 98.8.
  Skin showed several AKs 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.

62
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.

63
Question 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?
• Increase the dose of milrinone.
• Restart the B-Blocker at a lower dose.
• Change milrinone to dobutamine.
• Refer for cardiac transplantation.
• Refer for hospice care.

64
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.