66. Cardiac Transplantation- Clinical Scenarios

Taylor Kantor, MD, John M. Trahanas, MD, Francis D. Pagani, MD, PhD

Concept 

• Patient selection and preoperative evaluation 
• Combined organ transplantation 
• DCD (donor after cardiac death vs. DBD (donor after brain death) transplantation 
• Operative technique 
• Postoperative care 
• Infection, rejection, and chronic complications 
• Cardiac retransplantation 
• Potential questions/alternative scenarios 
• Pearls/pitfalls 

Chief complaint 

“A 59 yo male with end-stage, symptomatic heart failure (HF) is referred for heart transplantation.”  

Patient selection 

Patient selection for cardiac transplantation involves a multidisciplinary committee to ensure appropriate allocation of organ resources. Inclusion and exclusion criteria do differ slightly amongst different centers; however, all centers aim to treat patients with end-stage cardiac disease refractory to alternative therapies who have the potential to resume a relatively normal quality of life.

Heart transplantation is indicated for advanced heart failure that is refractory to guideline directed medical therapy and the patient has an anticipated annual mortality of approximately 15 to 20% or greater.  All alternative therapies and support should be utilized with documented evidence of failure or lack of candidacy prior to listing for cardiac transplantation. Common etiologies for systolic heart failure with reduced left ventricular ejection fraction (HFrEF) include ischemic heart disease (i.e., history of coronary disease) or non-ischemic heart diseae such as idiopathic dilated cardiomyopathy from genetic or familial causes. Etiologies of heart failure with preserved ejection fraction (HFpEF) such as hypertrophic cardiomyopathy or amyloidosis may also lead to heart transplantation. 

Similar to other transplantation protocols, cardiac transplant recipients should have no medical contraindications, no active source of infection, negative workup for malignancy, be actively participating in their medical care while following their medication regimens, and have a good support system in place to aid through the pre- and post-operative transplant process. These restrictions for candidacy are in place due to the strict allocation of organ donations due to the limited resources. Common prognostic criteria to predict disease severity are below with EF and reduced VO_2max being the most important indicators: 

• Low ejection fraction (<20%) 

• Reduced VO₂max (<14 mL/kg/min or less than 50% of predicted) 

• Ventricular arrythmias 

• High PCWP (>25 mmHg) 

• Hyponatremia (Na <130) 

• BNP (>5000) 

Absolute contraindications for heart transplantation include advanced age (> 65 to 75 years of age depending on institution), fixed pulmonary hypertension (PVR > 4-6 Woods units), and systemic illness or disease such as neoplasms, immune compromise by HIV that is not adequately managed with antiviral therapy, active multisystem diseases such as SLE or sarcoid, and other irreversible end-organ dysfunction not amenable to co-transplantation. Relative contraindications include recent malignancy, moderate to severe COPD with an FEV₁ generally less than 50% of predicted, recent PE, diabetes resulting in end-organ damage with retinopathy, nephropathy or hemoglobin A1c > 7 to 8 gm/dl, PAD with evidence of claudication or non-healing ulcer, CVD, active peptic ulcer disease, diverticulitis, severe obesity (BMI greater than 38 to 40), severe osteoporosis, history of non-compliance, significant neurocognitive dysfunction, poor psychosocial support, and active substance abuse. 

Preoperative evaluation – Recipient 

Any patient referred for cardiac transplantation must have a comprehensive, systems-based examination with history and physical identifying past medical, surgical, social and family history. A psychiatric assessment should also be performed, and social work should be involved to determine adequate social and financial support. Additional evaluation includes routine hematologic and biochemical laboratory testing. 

For cardiac assessment, a dedicated heart failure team should assist with preoperative evaluation. Standard evaluations include ECG, Holter monitor to assess for ventriculr arrhythmias, echocardiography, and cardiopulmonary exercise testing to evaluate functional capacity. A well-established inverse relationship exists between VO_2max and heart failure mortality, thus making cardiopulmonary exercise testing the cornerstone of evaluation of heart failure prognosis. Right heart catheterization should also be performed to evaluate heart failure severity and presence of pulmonary hypertension (PH). Left heart catheterization w/ coronary angiography, PET scan, or cardiac MRI may also be useful in determining candidacy for revascularization and confirm the likely etiology of the heart failure. For patients in which the cause of heart failure is unknown, an endomyocardial biopsy should be performed. 

Upon heart transplant listing, patient urgency for heart transplantation is established by a 6-tier allocation system provided by the United Network for Organ Sharing (UNOS). The current heart transplant allocation system went in effect October 2018 and is provided below:

• Status 1: patients on VA ECMO support, non-dischargeable biventricular support devices, or mechanical support with life-threatening ventricular arrythmias.
• Status 2: non-dischargeable LVAD, persistent or recurrent VT or VF, mechanical support w/ malfunction, or patients requiring percutaneous endovascular meachnical support or IABP. Also, for TAH, BiVAD, RVAD, or VAD patient’s with a single ventricle.
• Status 3: LVAD < 30 days, requiring multiple inotropes and hemodynamic monitoring, mechanical support with hemolysis, thrombosis, RHF, device infection, mucosal bleeding, or aortic insufficiency, VA ECMO >7 days, non-dischargeable LVAD >14 days, percutaneous mechanical support >14 days, or IABP >14 days.
• Status 4: Dischargeable LVAD >30 days, inotropes w/o hemodynamic monitoring, CHD, ischemic heart disease w/ intractable angina, amyloidosis, hypertrophic, or restrictive cardiomyopathy, heart re-transplant.
• Status 5: On waitlist for heart and second organ.
• Status 6: All other candidates suitable for transplant.
• Status 7: Inactive due to change in condition. 

Preoperative evaluation – Donor 

Organ donors undergo a three-phase screening regimen to determine potential for cardiac donation. Primary screening is undertaken by an organ procurement agency and includes routine laboratory data and demographics. Secondary screening is undertaken by a cardiac team to determine candidacy for donation as well as the necessary hemodynamic support until time of procurement. Donor selection criteria include the following:  

• Normal biventricular function and normal valve function

• Minimal left ventricular hypertrophy, generally a septal wall thickness less than 1.2cm 

• Donor to recipient weight ratio of 0.7 

• Age <50-60. Donors aged 40 or older or who have 3 or more risk factors for CAD, or history of cocaine use should have a coronary angiogram.

• Absence of prolonged cardiac arrest or hypotension, preexisting cardiac disease, severe chest trauma, sepsis, malignancy, positive viral serologies (HIV, HepB, or HepC) [Note: many institutions have recently established programs to accept HepC+ donors with use of antiviral therapy post-transplant to eradicate post-transplant viremia]

• <50% lesion in two or more coronary arteries is a contraindication to donation 

The final screening is undertaken at time of procurement. Procurement surgeons will proceed with donor cardiectomy if no evidence of cardiac dysfunction is present. Of note, some centers participate in expanded donor criteria due to the heart donor shortage that exists. By expanding the donor pool to apply marginal donors to marginal recipients, more heart transplants can take place. Criteria include older donors, decreased height ratio of donor:recipient, donors w/ CAD, mild LV dysfunction, positive viral serologies, or history of cocaine abuse but not IV drug abuse. 

Combined Organ Transplantation 

In patients with end-stage heart failure with other end-organ dysfunction, sole cardiac transplantation should not be performed. However, these patients may benefit from multiorgan transplantation. The most common combined organ transplants are for patients with end-stage HF and renal failure who undergo combined heart-kidney transplantation. Prior to consideration for heart-kidney transplantation, the patient should receive maximal medical therapy to determine reversibility of the renal dysfunction. However, patient’s with modest kidney impairment may also benefit from combined heart-kidney transplantation due to the risk of further renal injury both intra-operatively and via calcineurin inhibitors as part of the post-operative immunosuppression therapy. Additionally, some studies have shown there are fever episodes of cardiac allograft rejection and cardiac allograft vasculopathy with combined heart-kidney transplantation. 

Patients with end-stage HF and end-stage lung disease may benefit from combined heart-lung transplantation. The most common indication is for patients with congenital heart disease with Eisenmenger syndrome, but the procedure is also performed in patients with diseases such as idiopathic pulmonary arterial hypertension (IPAH) or cystic fibrosis (CF) causing right heart failure (RHF), and patients with cardiomyopathy leading to chronic lung disease. (See Ch.20: Lung Transplantation for additional details on selection for single and double lung transplantation) 

Combined heart-liver transplantation is a potential option for patients with end-stage HF symptoms and cirrhosis. However, this procedure is not commonly performed, and candidates must be selected very carefully due to the number of comorbidities generally involved and the risk of operating on cirrhotic patients. The most common indications include amyloidosis, hepatitis C-associated cirrhosis, hemochromatosis, and congestive hepatopathy leading to cirrhosis. 

DCD vs. DBD Heart Transplant 

While DBD donors remain more common, the first DCD heart transplants were performed in the United States in late 2019. Outside of the U.S., centers in England and Australia have shown outcomes after DCD heart transplants that are equivalent to those of brain-dead donors. The procurement of a DCD heart requires a postmortem assessment of the heart using a normothermic perfusion system such as the Transmedics OCS, or in situ normothermic regional perfusion.   

Index scenario (additional information) 

“The patient is a 47 yo M with a history of ischemic cardiomyopathy with reduced EF of 10%. He is currently on mechanical support with LVAD therapy for bridge to transplant. He is admitted to the ICU with hematuria, elevated pump power, decreased pulse index, and evidence of pump thrombosis.

The patient is upgraded from Status 4 to Status 2. Within days, an offer is accepted for DBD heart transplantation.” 

Operative steps 

Donor (DBD)  

• Communication and coordination with implant team and other procurement teams at every step is key! 
• Median sternotomy 
• Open pericardium and create pericardial well 
• Inspect heart, taking note of contractile function, coronary calcification, any distention, contusion or injury, and congenital anatomic abnormalities  
• If acceptable communicate that to implant team and determine need for explant delay 
• Dissect and isolate aorta, SVC, and IVC. If lungs will be harvested develop inter-atrial groove 
• Control SVC superior to azygos with tie, clamp, or Rommel 
• Ligate and divide azygos 
• Heparinize (250 to 300 u/kg) 
• Place cardioplegia cannula into ascending aorta 
• Occlude SVC, vent the left heart (place yankour), incise IVC, cross clamp aorta, initiate cold preservative solution, place ice slush in the field 
• Continuously check that aortic root pressure adequate and heart not distended 
• Complete division of IVC just above pericardial reflection 
• Divide SVC, aortic arch vessels, main PA at level of the bifurcation 
• Divide pulmonary veins at level of pericardium (or if lungs are being procured create left atrial cuff around orifices of pulmonary veins) 
• Pack in three sterile bags with preservation solution and ice slush, or use commercially available perfusion system 
• Upon arrival at the implant center on back table, divide posterior left atrium to create cuff. Close a PFO if it exists. Close the left atrial appendage if it was used to vent 

Donor (DCD) 

• For DCD donor, sternotomy must be rapid but controlled. 
• Insert canula in right atrium to vent the heart and collect blood for perfusate. No preservation solution for any organ should be infused prior to collecting 1.5L of blood to prime normothermic perfusion device.  
• Then, cardioplegia cannula placed in ascending aorta, cross clamp applied, and flush begins.  
• The left atrial appendage is amputated to vent the left side of the heart and ice slush put on the field.  
• The remainder of the donor explant is similar to a DBD procurement, except that the heart is placed on a normothermic perfusion device for preservation and evaluation.  

Recipient Explant  

• If recipient is a re-do sternotomy, expose or place sheaths in femoral vessels for rapid cannulation in the event of cardiac injury during re-entry sternotomy 
• Sternotomy is performed and the superior and inferior vena cava are dissected, and snares are placed around them.  
• The ascending aorta is cannulated as well as the cavae, and bypass is established 
• If the recipient is a redo sternotomy the SVC, IVC, and ascending aorta should be exposed early so that cannulation can be performed to facilitate the remainder of the explant 
• IF a ventricular assist device exists the outflow graft is dissected free and should be clamped just before the initiation of bypass. After bypass is initiated the apex of the heart and the device should be dissected free. Over aggressive munipulation prior to bypass should be avoided to minimize the risk of entraining air or dislodging clot.  
• A cross clamp is applied, and the aorta and pulmonary artery are transected just above the valves 
• The SVC and IVC are transected at their junction with the right atrium, and the swan-ganz catheter removed from the heart and preserved for replacement in the donor.  
• If a bi-atrial anastomosis is planned, the RA is divided to create a cuff including SVC and IVC but eliminating the recipient right atrial appendage. The inter-atrial septum is divided to open the left atrium and create the LA cuff 
• Any permanent pacing leads are placed on tension and divided  
• The dome of the left atrium is incised, and a left atrial cuff created 
• The recipient heart is then removed  
• The driveline is removed from the field, but the remainder is not removed from the sub cutaneous tissues until after the chest is closed as this is a contaminated field.  

Donor Implant (Bi-Caval Technique) 

• The bicaval technique better preserves normal atrial morphology, sinus node, and valvular function, and is associated with shorter hospital stay and rate of pacermaker placement. 
• The donor heart should be brought onto the field and the vessel lenths assessed and trimmed. Cardioplegia should be administered prior to beginning the implant 
• Steroids are administered 
• Implantation starts with the left atrium using a long arm 3-0 polypropylene suture. A left ventricular vent should be placed via the right superior pulmonary vein. The suture line is begun at the left superior pulmonary vein of the recipient which is aligned with the base of the donor left atrial appendage 
• The subsequent order of anastomosis may vary depending on surgeon preference, but typically procedes LA, then PA, followed by aorta, IVC and SVC 
• The PA catheter should be replaced prior the completion of the PA anastamosis 
• If there is a long ischemic time, the left atrium and aorta can be completed and the cross clamp removed, with the right sided anastomoses completed with the heart perfused. 
• With all anastomosis it is imperative to assess size discrepancy and correct while sewing, as well to size the length appropriately to prevent kinking (some redundancy in the aortic anastomosis may be desired to facilitate hemostasis of back wall).  
• The SVC anastamsois is especially prone to narrowing and should be performed with many small bites or triangulated with stay sutures.  
• The heart is de-aired, and the cross clamp is removed and the donor heart re-perfused. Atrial pacing or isoproterenol should be used to keep the donor heart rate 100-120 to prevent RV distention.  
• Bypass is weaned, and the recipient is decannulated. Any pre-existing pacemaker or ICD generator should be removed prior to closing the chest. After closing the chest, the driveline is removed at the skin 

Donor Implant (Bi-Atrial Technique) 

• This is the original technique popularized by Shumway and Lower.  
• The left atrial anastomosis is completed with the front wall sewed to the inter-atrial septum 
• The donor heart is then prepped for the right atrial anastomosis by incising the donor from the base of the IVC up onto the right atrial appendage, thus preserving the donor sinoatrial node. The right atrial anastomosis is then completed with the back wall sewn to the inter-atrial septum.  
• The PA and aortic anastomoses are completed in the standard fashion as above.  

Postoperative care 

Care of the post-transplant patient is similar to any post cardiomyotomy patient. 

• Depletion of myocardial catecholamine stores in donor hearts, and vasoplagia in patients who previously had continuous flow durable left ventricular assist devices may lead to a prolonged need for high dose catecholamines in the post-operative period.  
• Severe primary graft dysfunction refractory to pharmacologic therapy may necessitate mechanical support. Pulmonary vasodilators may be useful for right heart failure, which remains the leading cause of early mortality. 
• Arrythmias should warrant further investigation to rule out cardiac ischemia, rejection, or infection.   

Infections, Rejection, and Chronic Complications  

Hyperacute rejection is rare due to screening for preformed antibiodies. It manifests as a mottled graft within minutes to hours of implantation.

Most rejection episodes in heart transplants are represented by cellular rejection. Acute rejection may occur in the first 6 months after transplant and is typically asymptomatic, but may present with low grade fever, malaise, arrythmias, and heart failure. Heart transplant recipients are frequently monitored for this complication via right heart biopsy. Biopsy typically occurs every 7-10 days for the first few months and then the interval is extended. Rejection is graded in severity according to a standardized ISHLT Grading scheme with Grade 0R being no rejection, and Grade 3R indicating severe rejection. Most episodes are effectively treated with steroids.

Antibody-mediated rejection is less common but occurs within the first year and may manifest as hemodynamic instability requiring inotropic support. Plasmapheresis, steroids, heparin, and IgG may be required. Chronic low-grade vascular rejection may play a role in the development of allograft coronary artery disease.

Despite preventative measures, post-transplant infection is common. Hospital acquired organisms such as Pseudomonas and Staphylococcus occur as they do with any surgical patient. CMV infection has considerable morbidity as it may be associated with precipitating acute rejection and post-transplant lymphoproliferative disease. Fungal infections such as candidiasis may occur frequently, and more dangerous fungal infections such as aspergillus and mucormycosis have been known to occur in these immunocompromised hosts. Protozoa such as Pneumocystis carinii and Toxoplasma gondii may also infect heart transplant recipients.

Cardiac allograft vasculopathy (CAV) is a diffuse intimal proliferation causing diffuse luminal stenosis of the coronary arteries. It is the leading cause of death after the first year and is present in 40-50% of recipients by 5 years. Eventually this process may lead to silent myocardial ischemia and decline of allograft function. Given the diffuse nature of the process, angioplasty and stenting are ineffective, and only the only treatment is retransplantation.

Hypertension, hyperlipidemia, renal dysfunction, and malignancy are also common common long-term complications of heart transplantation.

Cardiac Re-transplantation 

Cardiac transplantation is a seldom performed operation accounting for approximately 2-3% of all cardiac transplants yearly. Primary indications include hyperacute/acute graft failure, cardiac allograft vasculopathy, and refractory acute rejection. For patients who need early re-transplantation, overall one-year survival is lower than that of primary cardiac transplant recipients; however, the survival is near equivalent for patients requiring re-transplantation after 2 or more years. Age is a significant factor as each decade increases likelihood of graft failure at one year by approximately 20%. Patients bridged to transplant also do considerably worse, speculatively due to immune activation and increased inflammatory response, most notably in patients undergoing bridging via ECMO. Careful selection of patients to undergo re-transplantation can result in favorable outcomes. 

Potential questions/alternative scenarios 

“A 35-year-old male patient with ischemic heart failure undergoes a heart transplant. His intraoperative course had no complications and he was transferred to the ICU on low inotropic and vasopresser support. Within hours, his inotropic support drastically increases, and bedside echo shows an EF of 5% w/ a diffusely edematous allograft. What is the primary concern?” 

The primary concern would be that the patient is undergoing hyperacute allograft rejection. Today, this is rare due to the screening of ABO blood typing and PRA screening. Hyperacute rejection occurs within minutes to hours and results in immediate heart failure due to antibody deposition with interstitial hemorrhage and edema. This must be treated emergently with plasmapheresis, IVIG, and initiation of mechanical support usually with VA ECMO. Re-transplantation is the only salvage therapy but is generally not recommended due to the high mortality. 

“A 42-year-old female underwent heart transplantation approximately 6 months ago.  Recently, she has been experiencing intermittent fevers, occasional feeling of palpitations, reduced exercise tolerance, and lower extremity edema.  What diagnostic procedure should be performed?” 

The patient is exhibiting symptoms which may be consistent with acute allograft rejection. With today’s current immunosuppression regimens, patients with acute allograft rejection often go undetected sometimes until late in the disease process as symptoms can be very mild. Routine right ventricular endomyocardial biopsies are the gold standard for diagnosis. Most institutions have biopsies performed within the first two weeks of surgery with the patient undergoing subsequent biopsies every 3-6 months. Any suspicion of rejection warrants additional endomyocardial biopsies. Grade of rejection is based on histologic parameters and will help to determine if the patient needs alteration of immunosuppression regimen or may require re-transplantation. Corticosteroids are the main supplements used to curtail rejection. 

“A 37 -year-old female with previous ischemic cardiomyopathy s/p heart transplantation over one year ago is seen in clinic for inceased dyspnea on exertion and reduced exercise tolerance. The patient undergoes stress testing which is positive. A LHC is performed and shows diffuse stenosis of all major vessels and peripheral pruning. What is the most likely diagnosis?” 

This patient is exhibiting signs and symptoms of cardiac allograft vasculopathy or CAV. This is a rapid and progressive form of diffuse atherosclerosis characterized by intimal proliferation rather than atherosclerotic plaques. It is in fact the leading cause of death in the first year after transplant and the limiting factor to long-term survival in transplant recipients. Clinical diagnosis can be difficult to make due to denervation of the heart and the absence of typical chest pain. For this, LHC’s are performed routinely, usually annually, for the first several years after transplant. Everolimus and sirolimus have been shown to possibly inhibit the severity of CAV, however, once it occurs, the only form of treatment is re-transplantation. These patients are not candidates for coronary revascularization procedures. 

“A 45-year-old male underwent a cardiac transplant and is now POD5. He has had a relatively uneventful post-operative course, however, becomes acutely bradycardic to the 30’s with a drop-in blood pressure. Atropine is emergently administered but has no effect. What could be the possible cause?” 

A transplanted heart has altered physiology as the heart was denervated during transplantation. This alters the heart’s response to certain therapeutic interventions and physiologic conditions. For example, the transplanted heart relies on circulating catecholamines rather than direct sympathetic stimulation during episodes of stress such as hypovolemia, hypoxia, or anemia and results in a delayed tachycardia response. In addition, vasovagal maneuvers such as carotid sinus massage and Valsalva, or therapeutic interventions with anticholinergics, such as atropine, are no longer effective. 

“A 47-year-old male underwent cardiac transplantation one week ago and is scheduled to undergo his first trans-jugular biospy. The interventionalist notes that the jugular vein is very full and easy to access, but has difficulty passing the biopsy catheter into the heart. What could be the cause?”  

The SVC anastomosis is relatively narrow in caliber and is notoriously easy to narrow or purse-string if not sewed with proper technique. This may manifest as difficulty accessing the heart from the neck vessels for post-transplant biopsy. Severe cases may resemble SVC syndrome with facial flushing and edema and require revision of the SVC anastomosis.  

“A 59-year-old female with a history of ischemic cardiomyopathy and a left ventriclular assist device is in the operating room awaiting arrival of a donor heart. The heart is dissected free of adhesions, aorto-bicaval bypass instituted, and the LVAD turned off. Despite vacuum assisted drainage, the heart remains full and the perfusionist notes difficulty maintaining an adequate mean arterial pressure. What did the surgeon forget?” 

As an LVAD is designed for continueos forward flow, the outflow grafts do not contain a valve to prevent reverse flow, and for this reason must be clamped when the device is turned off. If not, a large circular shunt will be established in which aortic blood can return to the left side of the heart causing distention and poor forward flow. The outflow graft must be handled carefully, as catastrophic arterial bleeding can occur if injured, especially if injured on re-entry with the sternal saw. This may require emergent bypass and circulatory arrest to repair. 

Pearls/Pitfalls 

• No irreversible steps should be taken during recipient explant until the donor heart has arrived safely
• Care must be taken during construction of left atrial anastomosis to properly align IVC and SVC 
• The LV should be vented to prevent accumulation of pulmonary vein effluent which may warm donor heart prior to reperfusion 
• Great vessels and vena cavae should be trimmed to proper length to avoid kinking 

Suggested readings 

• Cohn LH, Adams DH. Heart Transplantation. Chapter 60. Shemin RJ, Deng M. Cardiac Surgery in the Adult. 5th Edition. 2018. 
• Messer S, Page A, Axell R, Berman M, Hernandez-Sanchez J, Colah S, et al. Outcome after heart transplantation from donation after circulatory-determined death donors. J Heart Lung Transplant. 2017 Dec;36(12):1311–8. 
• Sharma A, Peltz M, Wait MA, Ring SW, Mathur A, Jessen ME, et al. The conduct of thoracic organ procurement. Asian Cardiovasc Thorac Ann. 2020;28(3):158–67. 
• Cheng A, Slaughter MS. Heart transplantation. J Thorac Dis. 2014;6(8):1105‐1109. doi:10.3978/j.issn.2072-1439.2014.07.37