Cardiac Transplantation

Cardiac Transplantation
1. Clinical Advancesaa
A. 1960 - Surgical technique reported
B. 1967 - Successful human transplant
C. 1970 - Recipient selection criteria standardized
D. 1973 - Surveillance endocardial biopsy
E. 1977 - Distant donor heart procurement
F. 1980 - Cyclosporine A
Causes of Death
Transplant Volume
2. Etiology or End-Stage Heart Disease
Etiology Percentage
Ischemia 44.8
Cardiomyopathy 46.2
Valvular 3.5
Congenital 1.8
Rejection 2.1
Other 1.6
3. Recipient Criteria
A. Terminal heart disease
B. Reasonable physiological
C. No renal or hepatic dysfunction
D. No acute infections
E. No recurrent pulmonary infections
F. Psychosocial stability
G. No alcohol, tobacco or drug abuse
4. Contradictions
A. Fixed pulmonary vascular resistance
B. Peripheral vascular disease
C. Acute malignancy
D. COPD of chronic bronchitis
E. Morbid obesity
F. ABO incompatibility
5. Donor Criteria
A. Brain death declared
B. Age <45 (special exceptions) C. No re-existent heart disease D. Few CAD risk factors E. No untreated acute infections F. No systemic malignancy G. No cardiac trauma H. Normal ECG I. Normal echocardiogram J. Negative HIV and Hepatitis screen 6. Unique Features of Cardiac Recipient A. Prone to infection (opportunistic) B. Denervated heart physiology C. Rejection at any time- few symptoms 7. Immunosuppressive Therapy A. Cyclosporine A B. Adrenocortical steroids C. Azathioprine D. OKT3 E. Anti-thymocyte globulin (ATG) Immunosuppression 8. Rejection A. Endomyocardial biopsy B. Acute rejeciton 1) Hospital 2) Out-patient 9. Registry Database A. Fifteenth Report- 1998 B. Total Transplants Reported- 45,993 C. Total Centers Reported- 257 D. Survival 1) 1 year- 79% 2) Thereafter- 4% per year mortality Total Survival Survival by ERA Survival by Age Survival with Retransplant 10. Risk Factors(p value < 0.001) A. Previous cardiac transplant B. Ventricular support C. Mechanical support (VAD) D. Recipient < 5 years of age E. Recipient > 60 years of age
F. Donor > 40 years of age
G. Donor female
H. Ischemic time >3.5 hours
11. Causes of Death after Transplantation
A. Rejection
B. Infection
C. Technical
D. CNS
E. Malignancy
Cause of Death Post Transplant
F. After First year
1) Graft Atherosclerosis
2) Infection
3) Malignancy- Lymphoma
4) Rejection
12. Improved Survival
A. Cyclosporine
B. Lower chronic steroid dose
C. Earlier diagnosis of rejection
D. Better patient selection
E. Diagnosis of infection
F. New antimicrobial agents
G. Medical and surgical experience
13. Functional Status Following Heart Transplant
A. Post Transplant Functional Status
B. Post Transplant Work Status
C. Post Transplant Rehospitalization
EXTENDED OUTLINE
1. Candidate Selection
A. Most often from idiopathic dilated or ischemic cardiomyopathies
B. “End stage…failure to respond to maximal therapy”; need to identify those who are likely to have sudden death or progressing heart failure
C. Adequacy of therapy prior to evaluation is key
D. Some guidelines for selection of candidates:
1) EF < 20% 2) Peak O2 consumption (VO2) < 10cc/kg/min 2. Cardiac Donor A. Only 10-20% of brain dead patients with suitable hearts become donors; cardiac transplantation is currently limited by donor availability B. Initial screening done by a local organ procurement agency C. Hep C generally OK D. Level of inotropic support E. Cardiovascular risk factors F. Substance abuse G. Ideally, donor body weight 80-120% of recipient’s weight H. Age limits I. Intensive fluid management of the donor is important; often these people are hypovolemic from trauma or dibetes insipidus 3. Donor Cardiectomy A. Visualize/palpate the heart B. Divide the: 1) SVC 2) Left superior pulmonary vein 3) Incise IVC C. Clamp aorta D. Administer cardioplegia E. Avoid coronary sinus injury during liver procurement F. Divide aorta and pulmonary artery 4. Recipient Operation A. Open RA along the AV groove anteriorly B. Extend this incision to CS inferiorly and to the right atrial appendage posteriorly C. Aorta and main pulmonary artery are divide at the valve commissures D. Incise roof of the left atrium between the aorta and SVC E. Connect the atrial incisions and extend the incision to the left atrial appendage F. Incision is then extended along the AV groove posteriorly to the CS G. Check donor heart for PFO H. Donor pulmonary veins are connected to fashion a left atrial cuff I. Left atrial anastomosis is completed and a vent is placed J. Right atrial anastomosis is completed K. Great vessels are anastomosed; PA first L. Deair, pacing wires, choronotropic/inotropic support Herotopic Cardiac Transplantation 5. Posttransplant Concerns A. Immunosuppression 1) as detailed previously 2) use of tacrolimus as both maintenance therapy and rescue therapy; 3) Pittsburgh group has evidence to prove that there are fewer repeat episodes of rejection and it is an effective agent for refractory rejection B. Transvenous myocardial biopsy 1) IJ approach 2) 3-5 specimens 3) weekly for the first 4 weeks 4) grading system developed by Billingham C. Coronary graft vasculopathy D. Infection 1) bacterial are most common followed by viruses, fungi, and protozoans 2) viral most common between months 1-6 3) fungal most common between months 1-2 4) protozoal infections peaked months 3-6 5) in the first 6 weeks of transplant, CMV, Herpes, or bacterial are equally likely; >2yrs is usually bacterial pneumonia is the most common infection
6) CMV can be cultured from almost all recipients; consider active infection in anyone with fever, fatigue, lymphocytosis, elevated LFT’s , neutropenia, and thombocytopenia; 25% will develop invasive GI or pulmonary disease; most severe infections seen in those seronegative prior to operation; Gangcyclovir is used to treat, but its use should be prophylactic
7) HSV usually causes mucocutaneous infections
8) Ebstein-Barr infection seems to be related to the development of posttransplant proliferative disorder; most effective treatment appears to be reduction of immunosuppression
9) Candidiasis is the most common severe fungal infection seen posttransplant; aspergillosis also has a significant cause of death
10) PCP usually presents with fever, dry cough and dyspnea and may be slow to respond to therapy; TMP-SMX or pentamidine prophylaxis can usually prevent it; diagnosis is usually confirmed by methenamine silver stains on BAL fluid; rapid reduction in immunosuppression may exacerbate the process in the lung
6. Renal Failure
Most important side effect of cyclosporin—from afferent arteriolar vasoconstriction and direct tubular cell injury; is dose related to some extent and will improve with reduction in the Cyclosporin dose; oliguria occurs in the early form of renal failure—late nephrotoxicity is characterized by a slow rise in serum creatinine
7. Other
Hirsutism, tremor, gingival hyperplasia, gout, elevated cholesterol, hyperglycermia, osteoporosis, and abdominal surgical complications
8. Survival
A. One year: >80%
B. 3-5 years: 70%
C. 12 years: ~40%
D. Bridge to transplant > 90% survival
E. Risk factors: previous transplant, preoperative ventillator dependence, age <5 or >60 recipient)
F. Risk factors: age >40, female sex, ischemic time >3.5 hours (donor) most common causes of early death: cardiac complications (40%); rejection (19%); infection (16%).
G. Infection is the most significant factor in late deaths, accounting for 40%

Heart/Lung and Lung Transplantation
1. History
A. Alexis Carrel- 1907
B. Demikhov- 1940s
C. Lower/ Shumway- 1960s
D. Clinical heart/lung transplantation
1) Cooley- 1968
2) Lillehei- 1969
3) Barnhard- 1971
4) Modern- era- Reitz
E. 1963- first human lung transplant
F. 1983- Cooper- first successful lung transplant
G. 1985- Cooper / Patterson- double lung transplant
2. Donor Selection
A. Age <60 years B. No history of pulmonary disease C. Smoking history < 20 packs/ year D. Normal chest x-ray E. Adequate gas exchange F. Normal bronchoscopy G. Acceptable sputum gram stain H. Normal serology I. ABO compatibility J. Adequate size matching 3. Absolute Donor Criteria A. Adequate gas exchange 1) PO2 >300 on FiO2 1.0
2) PO2 >100 on FiO2 0.4
B. Absense of significant infiltrates
C. Normal serology
D. ABO compatibility
4. Indications of Thoracic Transplantation
A. Single lung transplant
1) Pulmonary fibrosis
2) Emphysema
B. Primary pulmonary hypertension
C. Double lung transplants
1) Septic lung disease
2) Cystic fibrosis
3) Bronchiectasis
D. Emphysema
1) Primary pulmonary hypertension
E. Heart / Lung transplant
1) Irreversible disease of both heart and lung
5. Recipient Selection
A. Age <65 B. Other disease processes C. Previous surgery D. Steroids E. Smoking F. Nutrition G. Ventilator dependence H. Timing of transplant I. Psychosocial factors 6. Lung Preservation for Transplantation A. Hypothermia B. Lung inflation C. Pulmonary artery vasodilation- PGE1 D. Pulmonary artery flush- solutions include: 1) Modified eurocollins solution 2) Belzer's (Wisconsin) solution 3) Low potassium Dextran E. Low potassium, colloids, free radical scavengers 7. Early Complications of Lung Transplantation A. Reperfusion pulmonary edema B. Primary graft failure C. Hemorrhage D. Bronchial dehiscence E. Non-infectious pleural space problems 8. Infection in Lung Transplantation A. Transplanted organ exposed to external environment B. Target organ for CMV C. Bacterial, viral (CMV), fungal Protozoan (PCP) D. Infection increases expression of 1) HLA antigens 2) Adhesion molecules (ICAM-1) E. Can trigger rejection F. Transbronchial biopsy / bronchoalveolar lavage to differentiate 9. Rejection in Lung Transplantation A. Routine screening B. Lung allografts more antigenic and more vulnerable to rejection C. Symptoms: malaise, shortness of breath, lung infiltrate D. Differentiating infection from rejection difficult E. Transbronchial biopsy, bronchoalveolar lavage useful F. Serial daily spirometry (FEV1) 10. Bronchiolitis Obliterans A. Primary factor limiting long-term survival B. Exact etiology unknown (chronic rejection/infection) C. Most important cause of mortality and morbidity after lung transplantation D. Affects 50% of long-term survivors E. 50% will respond to enhanced immunosuppression F. The remainder will have progressive deterioration of lung function 11. Pediatric Lung Transplantation A. Higher incidence of bypass B. May be more vulnerable to bronchiolitis obliterans C. Immune advantage has not been clearly documented in pediatric population 12. Survival after Lung Transplantation By Diagnosis Diagnosis 30 Days 1 Year Emphysema (SL) 93% 78% A1A (SL) 90% 75% Cystic fibrosis (BL) 90% 70% Pulmonary fibrosis (SL) 82% 65% Pulmonary htn. (BL) 80% 75% By Transplant Transplant 1 Year 5 Years Single (SL) 70% 40% Bilateral (BL) 70% 48% EXTENDED OUTLINE 1. Introduction A. 1963-Hardy @ U Mississippi 1st human lung transplant à 18d survival B. 1963-83 - 44 lung transplants w/o success [bronchial anastomosis/MOF] C. 1983 - Toronto Lung Transplant Group @ 6-yr survival 2. End-Stage lung disease A. Obstructive lung disease 1) Chronic elevation in airway resistance a) Decreased exp flow rates (FEV1, FVC, FEV1/FVC) b) Air trapping ( TLC and FRC) 2) Prognostic factors = age, degree of airway obstruction (FEV1) 3) COPD 4) Alpha-1 antitrypsin deficiency emphysema a) Lack protection against neutrophil elastase in distal airways b) Severe bullous emphysema by 4th or 5th decade B. Cystic fibrosis (CF) (1/2,000 live births) 1) Most common end-stage obstructive disease 1st-3rd decades 2) Thick secretions, poor ciliary fxn => mucus plugging, pulm sepsis
C. Restrictive lung disease - idiopathic pulmonary fibrosis (IPF)
1) Decreased Lung volumes and exp flow
2) Decreased diffusing capacity
D. Pulmonary hypertension
1) Primary pulmonary hypertension (PPH):Mortality correlates w/CVP >10mmHg, PA(mean) >60mmHg, CI<2L/min 2) Eisenmenger’s syndrome:Ca-channel blockers may [increase or decrease???] PA pressures E. Others: sarcoidosis, chemo/RT-induced fibrosis, lymphangiomatosis 3. Recipient selection A. Mean waiting time 9-12 mo. (Wash U) 13.5 mo. (US) 4. Preoperative evaluation and management of recipients A. All pts enrolled in cardiopulmonary rehab 5. Choice of procedure A. Obstructive lung disease 1) Early single lung transplant (SLT)àhyperinflating native lung, crowding, V/Q mismatch a) Oversizing donor lung b) Proper preservation technique 2) SLT for: >55yo, high risk), prior surgery, asymmetric dz
3) Bilateral lung transplant (BLT) for: younger,bilat dz,small donor
B. CF (and other septic lung disease)=> BLT due to infection risk in native lung
C. IPF
1) SLT theoretically ideal- decrease compliance and PA pressures in native lung favor allograft ventilation and perfusion
2) BLT for large individual, especially with nl lung volumes
D. PPH - Ht-lung transplant, traditionally
1) SLT has been successful
a) Post-op management difficult, nearly all pulm flow to allograft
b) Late graft problem=severe V/Q mismatch
2) BLT may provide better long-term result
6. Timing of transplantation
A. Pts w/life expectancy 12-24 mo
B. ~30% will receive transplant w/in 1 year
C. Risk of dying on the waiting list:PPH, IPF, CF >>> COPD
7. Other criteria
A. Age (not absolute): BLT=55, SLT=65
B. Ventilatory support- no longer an absolute contraindication (already listed)
C. Corticosteroid therapy - data suggest:
1) low-dose prednisone does not airway complications
2) low-dose steroids may allograft bronchial circulation
D. Prior surgery - no longer a contraindication, in general
7. Criteria for donor lung suitability
A. 20-25% of multiple organ donors have suitable lungs
B. Size - TLC, VC estimated by height/weight - oversize 20% for SLT
C. Donor lung scarcity
1) Use “marginal” lungs
2) Single lung assessment (2-lumen ETT, PA clamping)
3) Living related donor (for pediatric CF patients)
Technique of Lung Preservation and Extraction
1. Lung preservation
A. Prostaglandin E-1 before inflow occlusion (vasodilatation + other benefits)
B. PA flush w/3L cold Euro-collins
C. Extraction of lungs semi-inflated w/100% O2 (grafts use it)
D. Transport under hypothermia (0-1°C)
E. Topical cooling during implantation
2. Donor lung extraction
A. Median sternotomy, dissection
1) Isolate SVC and IVC
2) Separate aorta and PA-Cardiopleg. cannula in aorta, cannulate distal PA
3) Incise posterior pericardium, exposing distal trachea
B. Graft flushing
1) Bolus PGE-1 (500 mg)
2) Inflow occlusion (ligate SVC, clamp IVC)
3) Vent R heart - transect IVC
4) X-C aorta, administer cardioplegia
5) Amputate tip of LA appendage, start lung flush
6) Flood chest w/ iced saline, ventilate w/100% O2
C. Extract heart
1) Transect cavae and aorta
2) LA incision is last, leaving a cuff of atrium
D. Extract lungs
1) Divide trachea between two firings of TA-30
2) (Divide esophagus superiorly and inferiorly)
3) Transect descending thoracic aorta
4) Transport on ice
Lung Transplantation Procedure
1. Anesthetic considerations
A. PA catheter
B. Left-sided 2-lumen ETT
C. Initial bronchoscopy and aspiration for CF patients
D. Avoid “pulmonary tamponade”
E. CPB for:
1) Hemodynamic instability
2) Pulmonary vascular dz
3) Poor allograft function in BLT
2. Technique
A. Incision
1) SLT-posterolateral thoracotomy
2) BLT- bilateral transverse thoracosternotomy (“clamshell”) {5th IC space for COPD, 4th for CF}
B. Choice of side - avoid surgery, remove better lung - in BLT, worse lung transplanted 1st
C. R/O PFO in PPH-intra-op TEE
D. In SLT, CPB is selective - trial of PA clamping
3. Lung implantation
A. Divide 1st PA branch between ligatures, the staple PA trunk
B. Mobilize both pulmonary veins (PV) intrapericardially
C. Transect bronchus-R=just proximal to RUL takeoff, L=1-2 rings above bifurcation- hemostasis
D. Topical cooling - iced gauze around graft
E. Brocnchial anastomosis
1) Continuous 4-0 mono-absorbable for membranous
2) Telescope cartilaginous arches figure-of-8 interrupted sutures
3) Ometopexy no longer used
F. PA anastomosis - 5-0 mono-non
G. LA anastomosis - 4-0 mono-non
H. De-air
1) Antegrade (release PA clamp)
2) Retrograde (release LA clamp)
I. Bronchoscopy
4. Post-operative Management
A. ICU post-op - quantitative perfusion scan
B. Pain control - epidural
C. Ventilator
1) SLT: COPD=no PEEP, PPH=10cm PEEP x 36h
2) Weaning - PPH=sedated, paralyzed x 36h, others=early wean
D. Postural drainage (lat x 24h), chest PT
E. Hemodynamics: dopamine for diuresis, PGE-1
F. Bronchoscopy - OR, POD1, pre-extubation, and prn
G. Infection
1) Abx prophylaxis: CF - per recipient cultures; others, per donor, or ancef x 3-4d
2) HSV prophylaxis: acyclovir 200mg BID for ³ 2 yr
3) PCP:Septra-DS - one bid q M-W-F
4) Candida: nystatin
5) CMV
a) Attempt to match, avoid CMV neg recip/CMV pos donor
b) Prophylaxis=gancyclovir
H. Immunosuppression
1) Triple regimen: cyclosporine, azathioprine, corticosteroids
2) Antithymocyte globulin (ATGAM) x 8 days
5. Follow-up strategies
A. Clinical f/u - remain in town x 3 months
B. PFTs - primarily FEV1 - Monthly in 1st year
C. CXR - schedule similar to PFT’s + prn
D. Bronchoscopy (FOB) with transbrochial bx (TBLB)
1) 3-4wk post-op, 3mo, 6mo, 1yr, then annually
2) Direct TBLB to areas w/infiltrates
E. Open lung bx-when TBLB inconclusive in face of clinical, physiologic deterioration
6. Problems (clinical-pathologic entities encountered in the lung transplant recipient)
A. Acute rejection -more common than other solid-organ allografts
1) Incidence unknown - “virtually all” in 1st 3-4wks post-tx
2) From 1st 3-5 days post-op to years later
3) Clinical manifestation variable-malaise, mild dyspnea, fever, decreasedFEV1, decreased PO2
4) Dx:FOB, TBLB => 84% sens, 100% spec (Ht-lung tx)
5) Tx: High-dose steroids, maintenance prednisone, ATGAM or OKT3 for refractory episodes
B. CMV infection
1) May mimic rejection
2) Dx by TBLB
3) Tx w/gancyclovir (documented infection)
C. Chronic rejection/Bronchiolitis Obliterans syndrome (BOS)
1) Inflammatory disorder of the small airways-histologically, dense fibrosis and scar obliterating bronchial wall and lumen
2) Prevalence as high as 50%
3) Dry or productive cough, dyspnea refractory to bronchodilators
4) Airflow obstruction with progressive ¯ in FEV1
5) Tx: Immunosuppression (empiric)-most pts will progress
D. Bronchial anastomotic complications
1) Usually result from ischemia which =>
a) Air leak or mediastinal collection (early)
b) Stenosis or malacia (late)
2) New dyspnea, stridor or wheeze
3) W/U=CXR, FOB, chest CT
4) Tx:
a) Early (dehiscence) = drainage and conservative measures
b) Late (stricture or malacia) - stent
7. Results
A. Survival
1) 92% hospital survival
2) 70% 1-yr, 43% 5-yr
3) Small benefit of BLT vs SLT (not significant)
B. Functional results
1) FEV1, ABG, 6-minute walk improved
2) FEV1, PaO2, significantly better after BLT vs SLT
3) BLT associated w/ higher complication rate
C. Pulmonary vascular dz
1) Decreased PAS, CVP, PVRI
2) NYHA class III-IV => I-II

Cardiomyopathy / Cardiac Transplant Donor & Recipient Selection
1. Cardiomyopathy definition
A. Any myocardial disease process that leads to clinically significant myocardial dysfunction
2. Cardiomyopathy classification
A. Dilated cardiomyopathy
B. Hypertrophic cardiomyopathy
C. Restrictive cardiomyopathy
D. Arrhythmogenic right ventricular dysplasia
E. Dilated, characterized by dilation and impaired contraction of left or both ventricles
1) Idiopathic
2) Familial/genetic
3) Viral and/or immune
4) Alcoholic/toxic
5) Presentation with heart failure, often progressive, arrhythmias, thromboembolism, and sudden death
F. Hypertrophic, characterized by left and/or right ventricular hypertrophy
1) Usually asymmetric with normal or reduced LV volume
2) Systolic gradient common
3) Familial disease with predominantly autosomal dominant inheritance
4) Myocyte hypertrophy and disarray surrounding areas of increased loose connective tissue
5) Arrhythmias and premature sudden death are common
G. Restrictive, characterized by restrictive filling and reduced diastolic volume of either or both ventricles with normal or near-normal systolic function and wall thickness
1) Idiopathic
2) Associated with other disease (amyloidosis; endomyocardial disease with or without eosinophilia
H. Arrhythmogenic right ventricular dysplasia, characterized by progressive fibrofatty replacement of right ventricular myocardium, initially with typical regional and later global right and some left ventricular involvement with relative sparing of the septum
1) Familial disease common, autosomal dominant inheritance and incomplete penetrance
2) Presentation with arrhythmias and sudden death is common, particularly in the young
3. Specific cardiomyopathies: heart muscle diseases that are associated with specific cardiac or systemic disorders
A. Ischemic
B. Valvular
C. Hypertensive
D. Inflammatory (e.g., myocarditis, Chagas' disease, HIV, etc.)
E. Metabolic (e.g., thyrotoxicosis, hypothyroidism, storage diseases, etc.)
F. General system disease (e.g., SLE, sarcoidosis, etc.)
G. Muscular dystrophies (e.g., Duchenne, Becker-type, etc.)
H. Neuromuscular disorders (e.g., Friedreich's ataxia)
I. Sensitivity and toxic reactions (e.g., anthracyclines, irradiation, alcohol)
J. Peripartal
4. Prognosis
Factor Possibly Predictive Not Predictive
Factor Predictive Possibly Predictive Not Predictive
Clinical Symptoms Acoholism, Peripartum, Family History Age, Duration, Viral Illness
Hemodynamic LVEF, CI LV size, LAP, RAP Viral Illness
Dysrhythmia IVCD, Complex ectopy AV block Simple ectopy
Histologic Myofibril volume
Neuroendocrine PI, NE, ANF, Serum Na
Cumulative Mortality
Probability of Death
Probability of Survival
5. Pharmacological Treatment of Heart Failure
A. Digoxin*
B. Diuretics
C. Afterload Reduction
D. Isosorbine dinitrate/hydralazine**
E. Angiotensin Converting Enzyme Inhibitors
F. Enalapril**
G. Captoril**
H. Lisinopril
I. Angiotensin II Receptor Inhibitors
1) Losartan
J. Calcium Channel Blockers
1) Amlodipine
6. Beta Blockers
A. Carvedilol**
B. Metoprolol*
C. Inotropic Agents
D. Beta Agonists
1) Dopamine
2) Dobutamine
E. Phosphodiesterase Inhibitors
1) Amrinone
2) Milrinone
F. Anticoagulation
1) *Decreases risk of hospitalization or decompensation
2) **Decreases mortality
7. Pharmacologic Treatment of Heart Failure
Improves Survival Decreases Hospitalization Decreases Survival
Enalapril Digoxin Dobutamine
Captropril Metoprolol Milrinone
Isosorbide dinitrate Vesnarinone
Carvedilol
8. Recipient Selection Process
A. Inclusion criteria
B. Exclusion criteria
C. Ongoing re-evaluation process
9. Inclusion Criteria
A. Absence of reversible or surgically amenable heart disease
B. NYHA Class III - IV symptoms despite optimal medical management
C. Maximal oxygen consumption < 14 ml/kg/minute D. Estimated 1 year survival without transplant < 50% 10. Insufficient Indications for Cardiac Transplantation A. Ejection fraction < 20% B. History of NYHA Class III - IV symptoms C. Low maximal oxygen consumption 11. Candidate exclusion criteria Criteria High Risk Moderate Risk Pulmonary Hypertension PVR > 8 Wood Units, unresponsive to nitroprusside X
PVR > 8 Wood Units, decreasing in response to nitroprusside, but not below 3 Wood Units X
Pulmonary artery systolic pressure > 70 mmHg despite nitroprusside X
Transpulmonary gradient > 15-20 mmHg (mean PAP - PCWP) X
Infection - active, untreated X
Irreversible hepatic disease X
Irreversible renal disease X
Irreversible pulmonary disease
FEV1 < 1 L X FEV1 < 1.5 L X Recent pulmonary infarction X Age > 65 years X
Diabetes mellitus, Type 1, with significant end-organ damage X
Cerebrovascular disease
Symptomatic X
Asymptomatic X
Peripheral vascular disease
Symptomatic X
Peptic ulcer disease
Active bleeding X
Diverticulitis, recent X
Chronic Active Hepatitis X
HIV positive X
Malignancy, recent X
Malignancy, remote X
Psychiatric disease
Acute, unresolved X
Recent, resolved on treatment X
Substance abuse
Active, unresolved X
Recent,resolved X
12. Panel Reactive Antibody (PRA) Screen
A. AKA: HLA antibody or white blood cell antibody screen
B. Technique: Recipient sera placed in 40-60 wells containing lymphocytes with a wide variety of HLA antigens
C. Use: Determine presence of preformed antibodies
D. If > 10%: Prospective crossmatch
13. Management of Transplant Candidate While Waiting
A. Close follow-up
B. Low threshold for hospitalization
1) IV diuretics
2) Inotropic support
3) Mechanical assistance
C. Ongoing re-evaluation of candidacy
14. Ongoing Re-evaluation for Candidacy
A. Periodic assessment for degree of illness (VO2, EF, right heart pressures)
B. Periodic assessment of acceptability (development of a new or worsening of a pre-existing illness)
C. Periodic PRA determinations
15. Conditions Which Generally Preclude the Use of a Donor Heart
A. HIV positivity
B. Significant ventricular arrhythmia
C. Echocardiographic abnormalities
D. Significant global hypokinesis
E. Significant valvular abnormality
F. Significant coronary disease by arteriography or documented previous myocardial infarct
G. Any acute malignancy, except primary brain cancer
H. Inadequately treated systemic infection
I. HbsAG positive, unless recipient is also positive
J. Hepatitis C positivity, unless recipient is also positive
K. Death from carbon monoxide poisoning, with carboxyhemoglobin level > 20%
L. Significant cardiac contusion
M. Severe left ventricular hypertrophy by echo
N. History of intravenous drug use
16. Donor-recipient Matching
A. Size: Greater than 80% of recipient body weight
B. Blood type: Identical or compatible
C. HLA-matching: Generally not done
Transplant Immunology
Allograft Rejection
Th Cell Events
B & T Cell-Mediated Death
1. Phases of Immunosuppression
A. Early rejection prophylaxis
B. Maintenance rejection prophylaxis
C. Treatment of established rejection
2. Mechanism of Action of Immunosuppressive Agents
A. Inhibitors of Interleukin -2
B. Production
1) Cyclosporine A
2) Tacrolimus
C. Action
1) Rapamycin (Sirolimus)
2) SDZ RAD
3) Interleukin-2 Receptor Blockers
D. Daclizumab
E. Basiliximab
F. Inhibitors of purine or pyrimidine biosynthesis
G. Purine
1) Azathioprine
2) Methotrexate
3) Mycophenolate mofetil
4) Mizoribine (bredinin)
H. Pyrimidine
1) Brequinar sodium
2) Leflunomide
I. Both purine and pyrimidine
1) Cyclophosphamide
J. Opsonization of lymphocytes
1) Murine monoclonal anti-CD-3 antibody (OKT3)
2) Polyclonal antibodies (horse, rabbit)
I. Multiple mechanisms or not clearly defined mechanisms
1) Adrenocorticosteroids
2) 15-Deoxyspergualin
3. Murine Monoclonal CD-3 Antibody (OKT3)
A. Identification: IgG2a Murine Immunoglobulin
B. Mechanism: Inhibits signal transduction of antigen recognition, opsonizes CD-3 lymphocytes
C. Dose/route: 5-10 mg/day, IV
D. Side effects: First dose reactions, HAMA formation
E. Interactions: None
F. Use: Early rejection prophylaxis, treatment of rejection
G. Monitoring: CD-3 Counts, OKT3 levels
Total Lymphocytes
4. Polyclonal Antibodies
A. Identification: Horse (ATGAM) or rabbit (Thymoglobulin) immunoglobulin
B. Mechanism: RES-mediated removal of opsonized cells
C. Dose/route: ATGAM 10-20 mg/kg/day IV; Thymoglobulin 1.5mg/kg IV
D. Side effects: Leukopenia, thrombocytopenia, fever, arthralgias, serum sickness
E. Interactions: None
F. Use: Early rejection prophylaxis, treatment of rejection
G. Monitoring: CD-2 counts
5. Cyclosporine
A. Identification: Metabolite of tolypocladium inflatum gams
B. Mechanism: Inhibits m-RNA transcription of interleukin-2
C. Dose/route: 3-6 mg/kg/day orally; IV:Oral = 1:3
D. Side effects: Nephrotoxicity, hypertension, tremor, headache/paresthesias, hirsutism, gingival hyperplasia
E. Interactions: Increase clearance of cyclosporine
1) Rifampin
2) Isoniazid
3) Phenytoin
4) Phenobarbital
F. Decrease clearance of cyclosporine
1) Erythromycin
2) Ketoconazole
3) Diltiazem
4) Verapamil
5) Nicardipine
6) Cimetidine
7) Use: Maintenance immunosuppression
8) Monitoring: Blood or serum level determination
Cyclosporine Formulations
1. Sandimmune Liquid Liquid & Capsules
2. Neoral (microemulsion) Liquid Liquid & Capsules
3. Sang CYA (microemulsion) Liquid Liquid
6. Tacrolimus (FK-506)
A. Identification: Fermentation product of Streptomyces tsukubaenis
B. Mechanism: Inhibits mRNA transcription of interleukin-2
C. Dose/route: 0.05 - 0.075 mg/kg orally q 12 hours 0.03 mg/kg intravenously q 24 hours
D. Side-effects:
1) Nephrotoxicity
2) Hyperglycemia
3) Neurotoxicity
4) Hypertension
E. Interactions: Believed similar to cyclosporine
F. Use: Maintenance immunosuppression
G. Monitoring: Blood level determination
7. Azathioprine
A. Identification: Precursor to 6 mercaptopurine
B. Mechanism: Disrupts normal purine incorporation into ribonucleic acids
C. Dose/route: 1 - 4 mg/kg/day; IV:Oral = 1:1
D. Side effects: Hematologic, pancreatitis, cholestatic jaundice, hepatitis, interstitial pneumonitis
E. Interactions: Increased levels with allopurinol
F. Use: Maintenance immunosuppression
G. Monitoring: White blood cell count
8. Mycophenolate Mofetil (RS-61443)
A. Identification: Morpholinoethylester of mycophenolic acid, a fermentation product ofPenicillium species
B. Mechanism: Inhibits inosine monophostate dehydrogenase in the de novo pathway of guanine nucleotide biosynthesis
C. Dose/route: 1,000 - 1,500 mg orally q 12 hours
D. Side-effects: Leukopenia, Nausea, vomiting, diarrhea
E. Interactions: Probably with acyclovir
F. Use: Maintenance immunosuppression
G. Monitoring: None
9. Corticosteroids (Prednisone, hydrocortisone, methylprednisolone)
A. Mechanism:
1) Inhibit transcription of IL-1 and IL-6 encoding m-RNA in macrophages
2) Block antigen recognition, decrease IL-1 AND IL-6 driven effects
3) Redistribution of lymphocytes
B. Dose/route: Prednisone 1 mg = hydrocortisone 4 mg = methylprednisolone 0.8 mg
C. Side effects:
1) Cushing's syndrome, osteoporosis, myopathy, cataracts, peptic ulcers
2) Glucose intolerance, hypercholesterolemia, skin fragility, adrenal suppression
D. Interactions: None clinically significant
E. Use: Maintenance immunosuppression, rejection treatment
10. Immunosuppression: Early Rejection Prophylaxis
A. Standard Triple therapy
B. Preoperative
1) Cyclosporine: 2-6 mg/kg po based on renal function
2) Azathioprine: 4 mg/kg IV
C. Intraoperative
1) Methylprednisolone: 500 mg
D. Postoperative
1) Cyclosporine: 2-6 mg/kg po bid based on trough levels and renal function
2) Azathioprine: 2 mg/kg/day
3) Methylprednisolone: 125 mg IV every 8 hours for 3-4 doses, followed by prednisone
4) Prednisone: (beginning after Methylprednisolone)1 mg/kg/day tapering over 1 week to 0.5 mg/kg/day, followed by further tapering over 2-3 months to 0.2-0.3 mg/kg/day
E. Quadruple Therapy- OKT3 *
F. Preoperative
1) Cyclosporine: None
2) Azathioprine: 4 mg/kg IV
G. Intraoperative
1) Methylprednisolone: 500 mg
2) OKT3: 5-10 mg (or administer first dose of OKT3, 5 mg IV 24-48 hours postoperatively)
H. Post operative
1) OKT3: 5 mg/day IV for 7-10 days post operative
2) Cyclosporine: Beginning on the fourth post operative day, 2-6 mg/kg po bid based on trough levels and renal function
3) Azathioprine: 2 mg/kg/day
4) Methylprednisolone: 25 mg IV every 8 hours for 3-4 doses, followed by prednisone
5) Prednisone: (beginning after Methylprednisolone)0.25 mg/kg/day during the time of OKT3 administration. After OKT3 course completed, increase to 1 mg/kg/day for 7 days, then taper either completely off over 4 weeks or to 0.2-0.3 mg/kg/day by 1-3 months.
I. * OKT3 should be premedicated daily for three days with diphenhydramine 50 mg IV, acetaminophen 650 mg po or per rectum, and ranitidine 100 mg IV. OKT3should be post-medicated every 6, 12, and 18 hours after the first 3 doses with diphenhydramine 25 mg IV, acetaminophen 650 mg po or per rectum, and ranitidine 50 mg IV.
J. Quadruple Therapy - ATG/ALG/ALS**
K. Preoperative
1) Cyclosporine: None
2) Azathioprine: 4 mg/kg IV
L. Intraoperative
1) Methylprednisolone: 500 mg
M. Post operative
1) ATG/ALG/ALS: Daily dosing for 7-10 days, Dose depends on preparation
2) Cyclosporine: Beginning on the second or third post-operative day, 2 - 6 mg/kg po bid based on trough levels and renal function
3) Azathioprine: 2 mg/kg/day
4) Methylprednisolone: 125 mg IV every 8 hours for 3-4 doses, followed by prednisone
5) Prednisone: (beginning after Methylprednisolone) 0.25mg/kg/day during the time of ATG/ALG/ALS, followed by 1mg/kg/day for 7 days, then taper either completely off over 4 weeks or to 0.2-0.3 mg/kg/day by 1-3 months.
N. ** ATG/ALG/ALS should be pre-medicated daily with diphenhydramine 25-50 mg IV and acetaminophen 650 mg po or per rectum
11. Maintenance Immunosuppression Goal
A. Lowest overall level of immunosuppression to prevent rejection
B. Cyclosporine levels
1) Low therapeutic after 1-2 years
C. Azathioprine
1) 1-2 mg/kg/day after 1-2 years
D. Prednisone
1) 0 - 0.1 mg/kg/day after 1 year
12. Treatment of Rejection - Considerations
A. Histologic grade of biopsy
B. Allograft function
C. Time after transplantation
D. Past rejection history
E. Concomitant immunosuppression
F. Optimize cyclosporine/azathioprine
13. TREATMENT OF REJECTION
GRADE Mild
Moderate None or oral corticosteroid augmentation
Moderate Oral corticosteroid augmentation or IV corticosteroids
Severe TREATMENT IV corticosteroids and ATG/ALG OR OKT3
Immunosuppression Flow-chart
14. Other options
A. Alteration of maintenance regimen
1) Change from cyclosporine to Tacrolimus
2) Change from azathioprine to mycophenolate mofetil
3) Change from azathioprine to cyclophosphamide (vascular rejection)
B. Methotrexate course (2.5 - 7.5 mg. Q 12 hrs x 3 doses/week for 8-12 weeks)
C. Plasmapheresis (vascular rejection)
D. Total lymphoid irradiation
E. Photophoresis
F. Re-transplantation
EXTENDED OUTLINE
A. Major Histocompatability Complex (MHC)-prime physiologic role is to recognize “self” from “nonself”; in humans, this is known as the HLA system
B. HLA: class I—HLA-A, B, C; expressed on all cells of an organism. Class I molecules present antigenic peptides to activated T lymphocytes expressing CD8phenotype
C. class II—DP, DQ, DR; expressed on antigen presenting cells, e.g., B cells, T cells, macrophages, dendritic cells, and endothelium. Present to T lymphocytes expressing the CD4 phenotype.
D. Pivotal cells moderating rejection are the T cells expressing the CD4 complex. These T cells recognize foreign Class II antigens on antigen presenting cells (APCs)—these cells not only present, but also provide signals (lymphokines/adhesion molecules) for T cell activation (second signal). There are two pathways for this to occur—direct and indirect routes of sensitization
E. Activated CD4 cells are divided into Th1and Th2 populations: Th1 subpopulation produces: IL-2 (CD8 differentiation), INF (MHC class II differentiation), TNF (NO radicals/O2/Prostaglandins) Th2: IL-4,5,10—augments B cell mediated responses
G. Effectors of Graft Rejection:
1) CD8 activation is thought to involve recognition of class I antigen (first signal) in a setting of increased levels of IL-2 (second signal) secreted by activated CD4 cells. Graft destruction ensues.
2) Hyperacute rejection is secondary to pre-exisiting blood group antibodies, anti-MHC antibodies, or natural antibodies which react with the endothelial antigens—complement, coagulation, and kallikrein/bradykinin cascades activated. Leads to graft edema, hemorrhage, and vascular thrombosis.
3) Accelerated rejection from IgM/IgG antibodies formed in response to the donor graft. Biopsy shows vascular destruction with a paucity of cellular infiltrate.
H. Hallmark of cellular rejection is graft infiltration:
1) leukocyte attachment to the endothelium
a) mediated by cell adhesion molecules: selectins (rolling effect), integrins (bind the attached molecules), immunoglobin superfamily-related molecules. This is followed by diapedesis—ICAM-1 and LFA-1 interaction
2) transmigration through the vessel wall
3) migration within the graft
4) selective retention of activated cells in the graft
5) local proliferation of cells
1. Rejection Prevention
A. MHC matching
B. Immunosuppression
1) Cyclosporin (CyA) and FK506—inhibit lymphocyte proliferation and lymphokine production by binding to cytosolic intracellular receptors known as immunophilins (CyA-cyclophilins/FK506-FK506 proteins). These complexes inhibit calcineurin an intracellular protein phosphatase which plays a crucial role in the induction of lymphokine genes (IL-2). Side effects: renal dysfunction, GI, CNS, hypertension, and diabetes
2) Corticosteroids—negatively affecting the release of IL-1 and IL-6 from macrophages and thereby inhibiting IL-2 release. Side effects include hypertension, diabetes, cushingoid features, poor wound healing and asceptic bone necrosis
3) Azathioprine works non specifically by virtue of its antimetabolite effects to inhibit lymphocyte proliferation
4) OKT3—mouse monoclonal antibody against T cell receptor CD3 which nonspecifically suppresses all T cell functions. Use is generally in acute rejection episodes. Side effects: cytokine release causing fever, chills, and pulmonary edema; antibody production against the maurine antibody which precludes future courses; dramatic increase in lymphoproliferative disorders.
5) Rapamycin—homolog of FK506, but does not inhibit calcineurin. Mode of action is unclear. Has prevented development of cardiac allograft vasculopathy in rat allografts
6) 15-Deoxyspergualin (DSG)—binds cytoplasmic protein Hsc70 and interferes with antigen presentation and T and B cell development. Good for pancreatic islet cell survival. Causes myelosuppression
7) Mycophenolate mofetiln—inhibits inosine monophosphate dehydrogenase which blocks the de novo pathway for purine synthesis. This pathway is crucial for the proliferative response of T and B cell response. There is a low side effect profile.
8) Brequinar inhibits dihydrooratate dehydrogenase and blocks the de novo synthesis of pyrimidines. The proliferative response is attenuated.
C. Induction therapy
1) its use is associated with a greater cumulative rejection frequency
2) does not delay the onset of first rejection
3) does not reduce the cumulative number of episodes of rejection
D. Tolerance
1) refers to the elimination of the immune response to the antigens of the transplant while the immune response to all other antigens remains intact
2) Anergy—inactivation of cells reactive to the foreign antigen; thought to be the result of T cells binding specific antigen, but not receiving the appropriate second signal from APCs or CD4 cells. IL-2 experimentally has been shown to reverse this
3) Clonal deletion—elimination of cells reactive to the foreign atigen; occurs primarily in the thymus by a process known as negative selection
4) Suppression—suppression of cells responsive to the foreign antigens by another, regulatory immulogic process. Veto cell—inhibits the activity of T cells reactive with antigens on its surface thereby suppressing the activity of the attacking cells
2. Chronic Rejection
A. Cardiac allograft vasculopathy (CAV)
1) is now the leading cause of death or graft failure after the first year.
a) manifested by diffuse and accelerated form of coronary arteriosclerosis—often involves the full length of the artery.
2) virtually all transplant recipients have these findings.
3) rapidly progresses to vessel occlusion and MI
a) pathologic finding is a diffuse intimal thickening and perivascular inflammation extending from large epicardial arteries into medium sized arteries and arterioles
b) the endothelial response to injury theory likely forms the common bond; stimulated endothelial and smoth muscle cells produce cytokines and growth factors causing cell proliferation and smooth muscle and macrophage migration to the intima resulting in concentric lipid-laden calcium-poor plaque. There is evidence to document an inflammatory stage prior to the smooth muscle cell proliferation and also an impairment of endothelial-derived relaxation factor.
c) immune mechanisms are probably at work because the vasculopathy is selective for the allograft which it effects diffusely; the cause of the presumed endothelial injury is unknown
d)Risk factors??—lipid levels, hypertension, smoking, diabetes, and a history of previous atherosclerosis have not correlated with an increased risk of CAV. Only CMV infection has shown a strong association with either death or retransplantation from CAV.
4) use of dobutamine stress echocardiography to follow vs. angiography
a) best addressed by repeat transplantation although this is associated with a 30% or greater lower rate of survival
B. Xenotransplantation
1) widespread preformed antibodies in humans which are reactive for antigens of other species—e.g. pig to human transplant results in hyperacute rejection (discordant) [Concordant rejection is when closely related species reject transplants in a manner similar to allograft rejection]
2) cells and organs from one species may not be able to function in a xenogenic environment
3) cell mediated xenografic rejection may differ from allogeneic rejection and thus require different immunosuppression
4) the future may lie in manipulating the donor organ endothelial system expression of complement inhibitory proteins and therefore mediate hyperacute rejection by preventing complement activation.

Medical Complications of Cardiac Transplant
1. Cardiac
A. Ventricular dysfunction
B. Sinus node dysfunction
C. Tricuspid regurgitation
D. Allograft rejection
E. Allograft coronary artery disease
F. Decreased exercise tolerance
G. Infection
1) Bacterial
2) Viral
3 Parasitic
4) Fungal
H. Non-cardiac, Non-infectious
1) Renal insufficiency
2) Hypertension
3) Osteoporosis
4) Hyperlipidemia
5) Malignancy
6) Psychologic/behavioral/societal
7) Glucose intolerance
8) Pancreaticobiliary disease
9) Obesity
2. Cardiac Allograft Rejection
A. Propensity decreases with time
B. Types
1) Hyperacute
2) Acute
3) Chronic (ACAD)
4) Cellular
5) Vascular (Humoral)
C. Diagnosis
1) Endomyocardial biopsy
2) Non-invasive
3) Clinical
D. Treatment
Insertion of Bioptome
3. International Society for Heart & Lung Transplantation Endomyocardial Biopsy Grading Scheme
Grade Finding Rejection Severity
0 No infiltrates None
1A Focal (perivascular of interstisial infiltrates without necrosis Mild
1B Diffuse but not sparse infiltrate without necrosis Mild
2 One focus only with aggressive infiltrate and/or myocyte damage Focal Moderate
3A Multifocal addressive infiltrates and/or myocyte damage Moderate
3B Diffuse inflammatory infiltrates with necrosis Borderline severe
4 Diffuse aggressive polymorphous infiltrate with edema, hemorhage and vasculitis, with necrosis Severe
Cellular biopsy Cellular biopsy Cellular biopsy Angiogram Vascular biopsy
4. Allograft Coronary Artery Disease
A. Leading cause of death > 1 year after transplantation
B. Equivalent to:
1) "Chronic rejection" in renal allografts
2) "Vanishing bile ducts" in hepatic allografts
3) "Bronchiolitis obliterans" in pulmonary allografts
C. Prevalence of angiographically detectable disease
1) 1 year: 10-2O%
2) 5 years: 30-50%
D. Potential risk factors
E. Non-transplant specific
1) Age
2) Sex
3) Family history
4) Hypertension
5) Diabetes mellitus
6) Smoking
7) Hyperlipidemia
F. Transplant specific
1) HLA mismatch, at DR locus
2) Immunosuppressant drugs
3) CMV infection
4) Donor age
G. Symptomatic
1) Angina
2) Acute myocardial infarction
3) Sudden death
H. Asymptomatic
1) Coronary angiography
2) Nuclear (thallium/sestamibi)
3) Dobutamine stress echocardiography
4) Intravascular ultrasound
Vascular Lesion Survival post Angiogram Survival post Transplant Infection post Transplant
5. Infectious Complications
A. Phases
B. Early (< 1 month), Nosocomial Phase 1) Wound 2) Catheter-related 3) Hospital acquired pneumonia C. Middle (2-5 months), Opportunistic Phase 1) Toxoplasmosis 2) Herpes viruses (cytomegalovirus, herpes simplex) 3) Pneumocystis carinii 4) Nocardia 5) Fungi D. Late (> 6-12 months) , "Normal" Phase
6. Infectious Prophylaxis
Pathogenic Organism Prophylactic Agent
Cytomegalovirus Gancyclovir, Acyclovir, IVIg
Herpes simplex Acyclovir
Toxoplasmosis Pyrimethamine and Leucovorin
Pneumocystis TMP/SMX, Dapsone, Pentamidine
Oral candidiasis Nystatin, Mycelex troches
Malignancy
7. Malignancy
A. Incidence 1-2 %/year
B. Cutaneous Malignancy
1) Squamous cell carcinoma
2) Basal cell carcinoma
C. Lymphoma (PTLD)
1) Frequency: Most common tumor in cyclosporine-based immunosuppression
2) Timing: 12-18 months post transplant
3) Location: Intraabdominal most common
4) Etiology: B cell origin induced by Epstein-Barr virus
5) Treatment: Reduce immunosuppression
6) Acyclovir
7) Chemotherapy/radiation
8. Cyclosporine-induced Nephrotoxicity
A. Characteristics
1) Major decline in renal function in first 6 months
2) Disproportionate azotemia
3) Hyperkalemia
4) Increased uric acid levels
5) Mild proteinuria
6) Decreased fractional excretion of sodium
B. Pathogenesis
C. Renal vasoconstriction (afferent arterioles)
1) Prostaglandins
2) Endothelin
3) Direct effect on smooth muscle
D. Direct tubular toxicity
Hypertension and Renal Dysfunction
9. Cyclosporine-induced Hypertension
A. Incidence: 50-90% of heart transplant recipients
B. Occurrence: Weeks to months
C. Treatment goal: BP < 140/90 mmHg D. Moderate limitation of salt intake E. Maintenance of ideal body weight F. Moderate exercise G. ACE inhibitors (captopril, enalapril, lisinopril) H. Calcium channel blockers (diltiazem, nifedipine, verapamil, amlodipine, and others) I. Diuretics J. Others (Clonidine, B-blockers, hydralazine, prazocin) Hyperlipidemia and Diabetes 10. Hypercholesterolemia A. Incidence: 60-80% of heart transplant recipients B. Occurrence: - 8 months C. Magnitude: Increase of 30-80 mg/dl D. Positive relationship to: 1) Prior history of ischemic heart disease 2) Preexisting lipid abnormalities 3) Cumulative dose of corticosteroids 4) Cyclosporine E. Treatment goals: Serum cholesterol > 240 mg/Dl (or LDL cholesterol > 160 mg/dl)
1) Moderate limitation of fat intake
2) Maintenance of ideal body weight
3) Moderate exercise
4) Minimize corticosteroid dose
F. Gemfibrozil
G. HMG-CoA reductase inhibitors
1) Lovastatin
2) Simvastatin
3) Pravastatin
4) Fluvastatin
H. Bile acid sequestrants (Cholestyramine, Colestipol)
1) Nicotinic Acid
2) Probucol
3) Fish oil (Omega-3 Free Fatty Acids)
11. Osteoporosis
A. Incidence:
1) 10% of heart transplant recipients
B. Risk factors:
1) Corticosteroids
2) Older age
3) Lower bone mass before transplantation
4) Low cardiac output states
5) Prolonged use of loop diuretics
6) Physical inactivity
7) Cardiac cachexia
8) Heparin administration
9) Postmenopausal status