CardioNerds (Amit Goyal and Karan Desai) enjoy a picnic at Charm City’s Inner Harbor with Dr. Manu Mysore, Dr. Shawn Samanta, and Dr. Rawan Amir from the University of Maryland division of Cardiology as they dive into important case discussion about a patient with of non-ischemic cardiomyopathy s/p orthotopic heart transplantation who presents with dyspnea due to cell mediated rejection. Dr. Gautam Ramani Medical Director of Clinical Advanced Heart Failure at the University of Maryland, provides the e-CPR segment.
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Patient Summary
A 58 year old woman with a history of non-ischemic cardiomyopathy s/p orthotopic heart transplantation in 2015 presented with worsening dyspnea upon exertion. Dyspnea in a post cardiac transplant brings forth a wide differential diagnosis spanning all the typical causes of dyspnea as well as causes more specific or common to the patient with a heart transplant. In this particular case, TTE showed newly reduced ejection fraction and valvular disease. Cell mediated rejection was considered highest on the differential and confirmed on endomyocardial biopsy. Given hemodynamic compromise with multiple foci of myocyte damage on biopsy, she was started on high dose steroids and anti-thymocyte globulin for treatment of rejection. Early identification and management of cell mediated rejection is crucial to the survival of patients like ours. Final diagnosis: orthotopic heart transplantation rejection.
Case Media - Orthotopic heart transplant rejection
Chest x-ray: Status post sternotomy. Patchy peripheral opacities in the bilateral lower lobes. Blunting of the costophrenic angles consistent with pleural effusion.
Sinus tachycardia, HR 111, RBBB, Sub millimeter STE in leads 1, aVL. STD in infero-posterior leads
TTE: Short axis
TTE: Long axis
TTE: Apical 4 Chamber
Coronary angiography: RCA
Coronary angiography: LAD/LCx
Episode Education
Pearls
New onset heart failure in a post cardiac transplant patient should raise concern for acute cardiac allograft rejection, as well as all the usual culprits in nontransplant patients.Younger African American women and those with elevated HLA mismatches are key risk factors for cell mediated rejection.Treatment for cell-mediated (i.e., T-Cell mediated) rejection includes steroids and antithymocyte immunoglobulin and regimens are based on the severity ofclinical and histologic features.Though infrequent as an initial presentation of acute cellular rejection, new onset arrhythmias in a post cardiac transplant patient should raise concern for rejection as a possible etiology. Reversal of rejection should be verified with endomyocardial biopsy following treatment for rejection. The timing and frequency of biopsy will likely depend upon whether corticosteroids and/or antithymocyte therapy was utilized.
Notes - Cell mediated rejection and more!
1) What are some common complications of cardiac transplantation?
Common complications following cardiac transplantation can be divided into two major categories: graft-related complications and non-graft-related complications.
Graft-related complications include:Early graft dysfunction (EGD) – reversible and irreversible injury related to organ procurement and reperfusion. Remember it is common for transplant patients to require inotropic and vasopressor support coming off cardiopulmonary bypass. Furthermore, LV diastolic dysfunction is also common after transplantation usually reflecting reversible ischemia or reperfusion injury and normally resolves over days to weeks, depending on the severity of reperfusion.Primary graft dysfunction (PGD) is a severe form of EGD that presents as a left, right or biventricular dysfunction occurring within the first 24 hours of transplantation for which there is no identifiable secondary cause (e.g. hyperacute rejection, prolonged ischemic time from massive intra-operative bleeding. The etiology is likely multifactorial including but not limited to reperfusion injury, the effect of donor brain death, and pre-existing donor heart disease.Early RV dysfunction related to pulmonary vascular resistance and fluid shifts early post-transplant may be particularly challenging. The RV is exposed to similar reperfusion injury or ischemic insults as the LV and typically RV dysfunction post-transplant includes RV dilation, subsequent poor coaptation of the tricuspid valve and tricuspid regurgitation. The “untrained” donor RV has to overcome potentially increased afterload (due to increased pulmonary vascular resistance) in the recipient, and as has been covered in previous Cardionerds episodes, the RV systolic function is highly sensitive to changes in afterload.Acute allograft rejection – either cellular-mediated rejection or antibody-mediated rejection, occurring due to the recipient’s immune system reacting against graft antigens (e.g., mainly, but not only, the human leukocyte antigen (HLA) mismatches). Hyperacute rejection is rare and commonly fatal complication of cardiac transplantation. It is mediated by preformed anti-donor antibodies and can lead to diffuse hemorrhage and thrombosis in the allograft. In the current era of panel-reactive antibody screening (PRA) where we screen for preformed anti-HLA recipient antibodies to donor lymphocytes, hyperacute rejection is rare but remains a possibility (especially in highly sensitized patients and/or depending on the technique of obtaining PRAs). See more below on antibody- and cell-mediated rejection.Cardiac Allograft Vasculopathy – an important cause of morbidity and mortality late following heart transplant related to both immune- and nonimmune-mediated coronary injury causing accelerated atherosclerosis and fibroproliferation with diffuse intimal hyperplasia resulting in allograft ischemia. For a detailed discussion on CAV, enjoy Ep #69.Non-Graft-Related ComplicationsInfections – related both to nosocomial exposures and immunosuppression, the typical infectious agents and syndromes predictably vary according to time from transplant. Early following transplant, the recipient is particularly susceptible due to post-operative nosocomial exposures (e.g., surgical wound, vascular access, urinary catheter, etc) and high dose peri-transplant immunosuppression. As such, wound/line/urinary infections and infections involving fungal and multidrug resistant bacterial organisms are common in the early phase (<1 month). In the mid-term (1-6 months), pneumonia, UTIs, and viral infections (CMV, HSV, VZV) are common. In the late-term, after the first post-transplant year, opportunistic infections become less common, and the typical community-based pathogens predominate.Acute and chronic renal injury – renal dysfunction is a common and important complication post-cardiac transplantation. Etiologies are varied and interrelated and include pre-transplant renal dysfunction, acute injury pre-operatively, calcineurin inhibitor toxicity, cardiorenal syndromes related to graft dysfunction, and chronic injury due to long-term metabolic complications (diabetes, hypertension).Malignancies – major problem in transplant recipients with rising cumulative risk over time. Post-transplant cancer risk is related to both immunosuppression dulling the normal immune system’s cancer surveillance and viral triggers for carcinogenesis. Common malignancies include lung cancer (especially as a significant proportion of patients with ischemic cardiomyopathy have a history of tobacco use), skin cancer, lymphomas, and breast and colon cancer. Post-transplant lymphoproliferative disorder (PTLD) is an EBV-associated proliferation of B-lymphocytes that is typically related to the degree of immunosuppression.
2) What are acute cell mediated rejection and antibody mediated rejection?
Acute cell mediated rejection (ACR) is a host T cell lymphocyte response directed towards allograft tissue, leading to T-cell mediated cytotoxicity of myocardial tissue. It can be seen anywhere from weeks to months after transplantation. Risk factors include younger donor and/or recipient age, African American ethnicity, and history of significant HLA mismatches. Acute antibody mediated rejection (AMR) constitutes graft injury by circulating antibodies (immunoglobulin M or G) targeting antigens expressed by graft endothelial cells. Injury may be complement mediated or complement independent (e.g., by other inflammatory pathways within endothelial cells and/or by natural killer cells).
3) What are clinical manifestations of acute cell mediated rejection?
Ideally, ACR is diagnosed prior to overt clinical manifestations from surveillance endomyocardial biopsies or Allomap testing (a blood test of gene-expression profiling of peripheral blood mononuclear cells used in select patients).Clinical manifestations of acute cell mediated rejection typically include symptoms of LV dysfunction including dyspnea, PND, orthopnea, palpitations, syncope or near-syncope. Signs of RV dysfunction causing right-sided congestion may include gastrointestinal symptoms such as nausea which could be a marker of hepatic congestion! Occasionally, patients can present with new onset atrial arrhythmias including atrial fibrillation or atrial flutter.Ultimately, cardiac transplant rejection is a form of myocarditis and so progressively severe forms may result in any of the manifestations of fulminant myocarditis including cardiogenic shock, atrial and ventricular arrhythmias, and conduction abnormalities. Thankfully,
