CardiacTransplantation and Prolonged Assisted Circulation¶
Chapter 271 | Part 6: Disorders of the Cardiovascular System · Part 6 – Cardiovascular Disorders · Chapter 271
Key Clinical Points¶
- Cardiac transplantation offers a 1-year survival >80% and median survival of 12.5 years (conditional survival of 14.8 years if the recipient survives the first year).
- Cardiac allograft vasculopathy (CAV) is a diffuse, aggressive form of coronary artery disease; IVUS and optical coherence tomography are more sensitive than angiography for early detection.
- Standard triple-drug immunosuppression includes a calcineurin inhibitor (e.g., Tacrolimus), a corticosteroid (e.g., Prednisone), and an antiproliferative agent (e.g., Mycophenolate Mofetil).
- The HeartMate 3 LVAS is a centrifugal, magnetically levitated pump with median survival >5 years and improved functional status (NYHA class I in 68%).
- CAV is often silent; it is present in ~30% of patients at 5 years and ~50% at 10 years post-transplant.
- Acute cellular rejection (ACR) is T cell–mediated, while antibody-mediated rejection (AMR) is noncellular/antibody-driven.
- The REMATCH trial demonstrated a 48% reduction in risk of death with LVAS compared to medical therapy alone.
- Infection rates for LVAS are 20-50% at 5 years, most often involving the driveline; infection predisposes to thrombosis and neurologic complications.
- Donor selection considers advanced disease severity, comorbidities, donor-recipient matching, and psychosocial factors.
- Retransplantation is the only definitive therapy for advanced CAV.
1. DEFINITION & OVERVIEW¶
• Cardiac Transplantation: A life-altering surgical intervention for patients with advanced heart failure who are otherwise healthy enough to receive it. • Clinical Context: ◦ Growing importance of diagnosing TTR amyloidosis (common in elderly) and AL amyloidosis (seen in younger patients). ◦ TTR amyloidosis can be diagnosed via noninvasive nuclear scanning rather than cardiac biopsy. • Survival Statistics: ◦ 1-year survival: >80% ◦ Median survival: 12.5 years ◦ Conditional survival: 14.8 years (if surviving the first year). • Candidate Selection Criteria (Table 271-1): ◦ Advanced disease severity: Refractory heart failure; VO <14 mL/kg per min (<12 if on beta blockers) or percent predicted VO <50%; cardiorenal syndrome; use of inotropic therapy to maintain stability. ◦ Comorbidity: Age is not an absolute contraindication, but frailty is a relative contraindication; BMI >35 kg/m² requires weight loss; eGFR <30 mL/min/1.73 m² is a relative contraindication.
1.2 Candidate Selection (Continued)¶
• Donor-recipient matching: ◦ Sensitized individuals require prospective or virtual cross match. ◦ Pulmonary vascular matching: PVR >3 Wood units, transpulmonary gradient >15, and absolute PA systolic pressure >50 mmHg (provided SBP >85 mmHg) are relative contraindications unless responsive to therapy. ◦ Psychosocial: ◦ Tobacco use must cease for ≥6 months. ◦ Substance abuse: Contraindicated if the individual cannot demonstrate control and cessation. ◦ Cognitive-behavioral disabilities/dementia: Contraindicated due to risk of self-harm.
2. EPIDEMIOLOGY¶
• Global Scale: >150,000 patients have undergone cardiac transplantation. • Amyloidosis Trends: ◦ T1R amyloidosis: Increasing prevalence in aging population. ◦ AL amyloidosis: Significant in younger populations. • Infection Prevalence: Chronic infections (Chagas' disease, tuberculosis, viral hepatitis) are increasingly relevant in the candidate pool.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Cardiac Allograft Vasculopathy (CAV): ◦ Characterized by proliferative thickening of the vascular intima. ◦ Initiated as diffuse endothelialitis from combined brain death, ischemia-reperfusion injury, and early immunologic insults. ◦ Chronic factors: Hypertension, hyperlipidemia, and disordered glucose regulation. • Rejection Mechanisms: ◦ Acute Cellular Rejection (ACR): T cell–mediated; lymphocytic infiltrates in myocardium; typically declines after 6 months. ◦ Antibody-Mediated Rejection (AMR): Noncellular antibody-driven; characterized by immunoglobulin deposition, complement fixation, and allograft arteriolar vasculitis. ◦ Clinical Impact: AMR leads to allograft dysfunction and higher risk of CAV compared to ACR.
4. CLINICAL FEATURES¶
• Advanced Heart Failure Symptoms: ◦ Refractory to conventional therapy; high symptom burden; frequent hospitalization. ◦ Low cardiac output, elevated pulmonary pressures, and poor quality of life. • CAV Presentation: ◦ Often silent in development. ◦ Diffuse involvement throughout the coronary tree. ◦ Prevalence: ~30% at 5 years; ~50% at 10 years post-transplant. • Grading (Table 271-1): ◦ Based on angiographic disease extent and allograft dysfunction (echocardiography/restrictive physiology). ◦ Grades: CAV0 (absent), CAV1 (mild), CAV2 (moderate), CAV3 (severe).
5. DIFFERENTIAL DIAGNOSIS¶
• ACR vs. AMR: ACR is T cell-mediated; AMR is antibody-driven with complement/immunoglobulin markers. • CAV vs. Native CAD: CAV is diffuse and aggressive (immunologic/nonimmunologic); native CAD is typically focal. • Rejection vs. Infection: Must rule out CMV, Aspergillus, Nocardia, or toxoplasmosis. • Malignancy vs. Infection: Posttransplant lymphoproliferative disorders (EBV-driven) require reduced immunosuppression and antiviral therapy.
6. INVESTIGATIONS & DIAGNOSIS¶
• Imaging Modalities: ◦ Routine coronary angiography to assess for diffuse disease. ◦ IVUS or optical coherence tomography (OCT) are more sensitive than angiography for detecting early intimal thickening. • Prognostic Assessment: ◦ Noninvasive testing for coronary flow reserve used to arbitrate prognosis in CAV. • Pharmacotherapy for Prevention: ◦ Statin use to prevent CAV; PCSK9 inhibitors show promise as non-statin options. • Grading System: ◦ Standardized grading (CAV0–CAV3) based on angiographic extent and allograft dysfunction.
6.2 Diagnostic Algorithm for CAV¶
- Routine coronary angiography to assess for diffuse disease.
- If angiography is negative but suspicion remains → proceed to IVUS or optical coherence tomography (OCT).
- Assess coronary flow reserve using noninvasive testing → use to arbitrate prognosis in CAV.
- Evaluate allograft dysfunction via echocardiography or restrictive cardiac physiology.
7. MANAGEMENT & TREATMENT¶
• Immunosuppression Strategy: ◦ Standard: Triple-drug (Tacrolimus, Mycophenolate Mofetil, Prednisone). ◦ Induction (High risk/Renal dysfunction): Basiliximab or Antithymocyte globulin. ◦ ACR Treatment: Corticosteroid pulses; if hemodynamically compromised → rescue polyclonal antibodies + corticosteroids. ◦ AMR Treatment: Plasmapheresis, rituximab, bortezomib, eculizumab, and IVIG. • CAV Management: ◦ Medical options are limited; revascularization (PCI/CABG) only for focal lesions; retransplantation is the only definitive therapy for advanced CAV. • LVAS Management: 1. Blood Pressure: Target mean arterial pressure ≤90 mmHg using RAAS drugs or vasodilators. 2. Antithrombotic Regimen: Vitamin K antagonist (INR 2–3); omit aspirin to reduce bleeding risk. 3. Hemolysis/Anemia: Monitor for iron deficiency and acquired von Willebrand disease. 4. Right Ventricle: Diuretic therapy for congestion. 5. Arrhythmia: Antiarrhythmic therapy or ablation. 6. Infection: Local internal exploration and long-term suppressive antibiotics (20–50% incidence at 5 years). • Malignancy Management: ◦ Monitor for skin malignancies; reduce immunosuppression for EBV-driven lymphoproliferative disorders.
8. PROGNOSIS & COMPLICATIONS¶
• CAV Progression: \sim30% at 5 years → \sim50% at 10 years. • LVAS Complications: ◦ Hemolysis (monitored via LDH). ◦ Thrombosis: Risk of pump malfunction; reoperation (pump exchange) is preferred but has mortality risk. ◦ Infection: Often driveline-related → leads to thrombosis and neurologic complications. ◦ Neurologic events: Ischemic/hemorrhagic strokes occur in both LVAS and advanced heart failure populations.
9. SPECIAL CONSIDERATIONS¶
• Donor Selection: ◦ Inclusion of donor organs from circulatory death (no difference in outcome vs. brain death). ◦ Consideration of chronic infections (Chagas, TB, Hepatitis) in candidates.
10. KEY PEARLS & CLINICAL TRAPS¶
• CAV Detection: IVUS is superior to angiography for identifying early intimal thickening. • LVAS Safety: HeartMate 3 significantly reduces pump thrombosis compared to older devices. • Antithrombotic Choice: Eliminating aspirin in LVAS patients significantly reduces bleeding complications without increasing stroke risk. • Immune Distinction: ACR (T-cell) vs. AMR (Antibody/Complement) dictates the use of steroids vs. plasmapheresis/rituximab.
Reference Tables¶
TABLE 271-1 Principles for Listing Candidates for Cardiac Transplantation PRINCIPLE Advanced disease severity¶
Harrison's 22e, p.2028
| PRINCIPLE | COMMENT |
|---|---|
| Advanced disease severity |
Refractory heart failure with a VO of <14 mL/kg per min (<12, if 2 on beta blockers) or percent predicted VO <50%; combination 2 of intolerance to disease-modifying therapy, cardiorenal syndrome, use of inotropic therapy to maintain stability, or need for a left ventricular assist system. |
| 271 | Cardiac Transplantation and Prolonged Assisted Circulation Mandeep R. Mehra |
| Donor- recipient matching |
Sensitized individuals with circulating antibodies should have a prospective or virtual cross match; pulmonary vascular resistance with a transpulmonary gradient >15, PVR >3 Wood units, and absolute PA systolic pressure >50 mmHg (provided the systolic blood pressure is >85 mmHg) is a relative contraindication unless reactive to therapy. |
TABLE 271-2 Immunoprophylaxis Drugs in Cardiac Transplantation¶
Harrison's 22e, p.2029
| DRUG CLASS | GENERIC DRUG | CELLULAR TARGET | MAJOR SIDE EFFECTS |
|---|---|---|---|
| Calcineurin inhibitors | Cyclosporine | Binds to cyclophilin, which then inhibits calcineurin | Hypertension, dyslipidemia, gum hypertrophy, hypertrichosis |
| Tacrolimus | Binds to immunophilin FK506 binding protein, which inhibits calcineurin |
Hypertension, dyslipidemia, alopecia, diabetes mellitus | |
| Rabbit ATG | T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis |
||
| Horse ATG | Same as above | ||
| Interleukin-2 receptor antagonists |
Basiliximab | Inhibition of CD-25 of interleukin 2 receptor | Well tolerated; rare hypersensitivity; increased infection risk if used with calcineurin inhibitors |
| Azathioprine | Imidazolyl derivative and prodrug of 6-mercaptopurine (cell cycle inhibitor) |
||
| Mycophenolate Mofetil |
Inhibits inosine monophosphate dehydrogenase, which controls guanine monophosphate in the de novo pathway of purine synthesis (inhibits T- and B-cell proliferation) |
||
| Proliferation signal inhibitors |
Sirolimus | Binds with FKBP12 and complex inhibits the mechanistic target of rapamycin (mTOR) |
Delayed wound healing, nonspecific pneumonia, pericardial effusion, hyperlipidemia (hypertriglyceridemia) |
| Everolimus | Binds to FKBP12, which inhibits mTORC1 (and not mTORC2) | Dyslipidemia, stomatitis, pericardial effusions, and pancytopenia |