Cardiac Transplantation - University Exam Answer

1. Introduction and Historical Background

1. Cyclosporine-based immunosuppression (1980s) - dramatically reduced acute rejection
2. Endomyocardial biopsy - enabled histopathologic monitoring of rejection
3. Careful recipient and donor selection protocols

• Robbins, Cotran & Kumar Pathologic Basis of Disease
• Harrison's Principles of Internal Medicine 22E

2. Indications

• Ischemic cardiomyopathy (most common in adults in developed countries)
• Idiopathic dilated cardiomyopathy (DCM) - younger patients
• Valvular heart disease, viral myocarditis, congenital heart disease
• Restrictive/hypertrophic cardiomyopathy, amyloidosis, sarcoidosis
• Sabiston Textbook of Surgery, 21e

3. Contraindications

• Pulmonary vascular resistance (PVR) >6 Wood units - heart-lung transplantation should be considered instead
• GFR <30 mL/min/1.73 m² - heart-kidney transplant should be considered
• Active malignancy (depends on prognosis)
• Active systemic infection
• Non-compliance or inability to adhere to lifelong immunosuppression

• PVR 4-6 Wood units (efforts to reduce PVR medically first)
• Age >70 (relative, center-dependent)
• Diabetes with end-organ damage or HbA1c >7.5% persistently
• Symptomatic peripheral/cerebrovascular disease not amenable to revascularization
• Severe irreversible pulmonary disease
• Morbid obesity (BMI >35)
• Active substance abuse (alcohol, drugs, tobacco)
• Severe psychiatric disorder
• Inadequate social support
• Sabiston Textbook of Surgery (Table 57.1)
• Braunwald's Heart Disease

4. Pre-Transplant Evaluation

• Laboratory: CBC, metabolic panel, LFTs, urinalysis, coagulation, thyroid, urine drug screen, HIV, hepatitis B/C, TB screen, CMV IgG/IgM, RPR/VDRL, panel reactive antibodies (PRA), ABO/Rh blood type, lipids, HbA1c
• Cardiac: ECG, right and left heart catheterization (to assess PVR), cardiopulmonary exercise testing (CPET) with VO2 max
• Pulmonary: CXR, pulmonary function tests
• Screening: Age-appropriate malignancy screening
• Psychosocial: Substance abuse history, mental health assessment, social support

5. Donor Selection

5a. Brain Death vs. Circulatory Death Donors

• Donation after Brain Death (DBD): Historically the standard. The cardiopulmonary system remains functional at procurement - no warm ischemia. Brain death declared when there is absence of brainstem reflexes, motor responses, and respiratory drive in a normothermic patient without metabolic derangements.
• Donation after Circulatory Death (DCD): Increasingly used; requires controlled withdrawal of life support and cessation of spontaneous circulation before procurement. Carries a period of warm ischemia, which is injurious. Advances in preservation strategies (normothermic machine perfusion) have made DCD heart transplantation feasible.

5b. Donor Assessment Criteria

• Echocardiography: Normal or near-normal LV/RV function (EF ≥45% generally acceptable); mild depression may improve with time
• ABO compatibility (mandatory)
• HLA matching: Cross-matching performed; virtual crossmatch using PRA
• Size matching: Donor/recipient weight ratio; female donor to male recipient increases risk of primary graft dysfunction
• Ischemic time: Cold ischemia <4-6 hours optimal
• Coronary angiography in older donors
• No active malignancy or transmissible infection

6. Surgical Technique

6a. Recipient Preparation

• Median sternotomy and cardiopulmonary bypass (CPB)
• Anticoagulation with heparin
• Recipient heart is explanted

6b. Orthotopic Heart Transplantation

• Posterior walls of the recipient left and right atria are preserved
• Donor atria anastomosed to remaining recipient atrial cuffs
• Five anastomoses: LA, RA, pulmonary artery, aorta
• Disadvantage: leaves native sinoatrial (SA) node tissue - can cause two distinct P-wave rhythms and tricuspid regurgitation

• Entire right atrium of recipient is excised
• Direct superior vena cava (SVC) and inferior vena cava (IVC) anastomoses between donor and recipient
• Left atrial anastomosis around pulmonary vein orifices
• Plus pulmonary artery and aortic anastomoses (total 5-6 anastomoses)
• Advantages: Preserves normal atrial geometry, less tricuspid regurgitation, better sinus node function, lower incidence of arrhythmias

7. Cardiac Allograft Preservation

• Cold static storage in cardioplegic solution (University of Wisconsin solution, Custodiol HTK) is standard
• Optimal cold ischemic time: <4 hours (ideally), maximum 6 hours
• Normothermic machine perfusion (NMP): Emerging technology allowing ex-vivo assessment and preservation of DCD hearts - extends viable ischemic time and allows hearts to be assessed before transplantation
• The heart is transported packed in cold saline in a cooler

8. Immunosuppression

Standard Maintenance Regimen

Induction Immunosuppression

• Basiliximab (IL-2 receptor antagonist, anti-CD25) - monoclonal antibody; well-tolerated
• Antithymocyte globulin (ATG) - polyclonal; causes T-cell depletion via complement-dependent lysis; side effects: cytokine release syndrome, leukopenia, thrombocytopenia

Steroid Weaning

• Harrison's Principles of Internal Medicine 22E, Table 27-2
• Sabiston Textbook of Surgery

9. Allograft Rejection

9a. Acute Cellular Rejection (T-cell mediated)

• Most common type
• Pathology: Interstitial lymphocytic infiltrate + myocyte damage (resembles myocarditis)
• May include interstitial edema
• Cytokines can impair contractility without overt myocyte damage
• Monitoring: Routine endomyocardial biopsy (RV) - the only reliable means to diagnose rejection before irreversible damage
• ISHLT Grading:
  • Grade 0: No rejection
  • Grade 1R (Mild): Interstitial/perivascular infiltrate with ≤1 focus of myocyte damage
  • Grade 2R (Moderate): ≥2 foci of infiltrate with myocyte damage
  • Grade 3R (Severe): Diffuse infiltrate with multifocal myocyte damage ± edema, hemorrhage, vasculitis
• Treatment: Augmented immunosuppression; IV methylprednisolone pulse therapy; anti-T-cell therapy for resistant cases

9b. Antibody-Mediated Rejection (Humoral)

• Caused by donor-specific antibodies (DSA) directed against MHC (HLA) antigens on donor endothelium
• Mechanism: Complement activation + Fc-receptor-bearing cell recruitment → endothelial injury → microvascular thrombosis
• Pathology: Mild perivascular edema, scattered intravascular inflammatory cells, plump activated endothelium
• Diagnosis confirmed by: Immunohistochemistry for C4d (complement component) in capillaries - strong brown staining
• Treatment: Plasmapheresis, IVIG, anti-B cell therapy (rituximab), aggressive immunosuppression

9c. Chronic Rejection = Allograft Vasculopathy

10. Cardiac Allograft Vasculopathy (CAV)

• Nature: Late, progressive, diffuse concentric intimal proliferation predominantly in the coronary arteries
• Distinct from native atherosclerosis (which is eccentric, focal, and calcified)
• Caused by chronic immune injury to the graft endothelium (both T-cell and antibody-mediated mechanisms)
• Consequence: Ischemic injury, silent MI (denervated heart - no angina), graft dysfunction, sudden cardiac death
• Within 5 years, significant CAV develops in a substantial proportion of recipients
• CMV infection is associated with accelerated development of CAV
• Monitoring: Annual coronary angiography; intravascular ultrasound (IVUS) more sensitive
• Treatment: Statins (reduce severity), mTOR inhibitors (sirolimus, everolimus - slow progression), PCI for focal lesions, but retransplantation is the only definitive option

11. Other Complications

Early Complications

Infections

• Bacterial: Most common in early post-operative period (pneumonia, wound infections)
• CMV: Most important viral pathogen - affects GI tract and lung; prophylaxis with valganciclovir (900 mg/day for 3-6 months); CMV+ donor to CMV- recipient = highest risk
• EBV: Associated with post-transplant lymphoproliferative disorder (PTLD) - ~50% of PTLD cases are EBV-associated; treatment includes immunosuppression reduction
• Aspergillus: Invasive pulmonary aspergillosis - mortality >50%; treat with voriconazole or amphotericin B
• PCP (Pneumocystis jiroveci): Prophylaxis with TMP-SMX

Malignancy

• Chronic T-cell immunosuppression increases risk
• EBV-associated B-cell lymphomas (PTLD) - most important
• Skin cancers, Kaposi sarcoma

Renal Dysfunction

• Calcineurin inhibitors are nephrotoxic
• CKD develops in a significant proportion of long-term recipients
• May require kidney transplantation

12. Outcomes and Survival

• Early (<30 days): Primary graft dysfunction, surgical complications
• 1 month - 1 year: Rejection, infections
• >1 year: CAV (leading long-term cause), malignancy, rejection

13. Organ Allocation (OPTN/UNOS System)

• Status 1: VA-ECMO, VAD malfunction, life-threatening arrhythmias
• Status 2: IABP, TAH, non-dischargeable BiVAD/LVAD
• Status 3: Dischargeable LVAD candidates, certain VAD complications
• Status 4: Device-based therapy or continuous inotropic support
• Status 5: Re-transplantation, adult congenital HD, low EF + restrictive/hypertrophic CMP
• Status 6: All other candidates

14. Bridging to Transplantation

• Inotropic infusions (dobutamine, milrinone)
• Intra-aortic balloon pump (IABP)
• Left Ventricular Assist Device (LVAD): Most common; "bridge to transplantation" or "destination therapy"; outcomes with LVAD bridge are equivalent to direct transplantation
• Total Artificial Heart (TAH): For biventricular failure
• VA-ECMO: Short-term bridge in acute cardiogenic shock

Summary Table

• Robbins, Cotran & Kumar - Pathologic Basis of Disease (10th ed.)
• Sabiston Textbook of Surgery (21st ed.)
• Braunwald's Heart Disease (12th ed.)
• Harrison's Principles of Internal Medicine (22nd ed., 2025)
• Fuster and Hurst's The Heart (15th ed.)