A 54-year-old African American woman with nonischemic cardiomyopathy, that is, LMNA-related familial cardiomyopathy, presented for advanced therapy evaluation based on recurrent admissions for volume overload and intravenous diuresis. She was diagnosed over 10 years ago, but ejection fraction declined to 15% on goal-directed medical therapy with carvedilol, valsartan, spironolactone, hydralazine, and nitrates. She was a nonresponder to cardiac resynchronization therapy despite underlying QRS of 140 ms. Hypotension resulted in reducing medication doses during the last few hospitalizations. Primary transplantation was discussed (blood type B), and cardiopulmonary exercise testing revealed a peak VO₂ of 13.1 mL/kg/min, 59% predicted with Ve/VCO₂ 30. Right heart catheterization found severe pulmonary hypertension with pulmonary capillary wedge pressure 31 mm Hg, PA 66/44, mean 52 mm Hg, PA sat 38%, and CI 1.5 L/min/m² by Fick. She was started on milrinone for inotrope support. However, her pulmonary HTN did not improve significantly despite diuresis, and clinical status was tenuous. Her PVR declined to 4 WU with diuresis despite improvement in cardiac output on milrinone. She was implanted with a Heartmate II left ventricular assist device (LVAD) with the goal of bridging to transplantation until PVR improved. Because of progressive right heart failure and deteriorating renal function after LVAD, percutaneous temporary right heart support helped improve her clinical status and renal function without the need for dialysis. However, she required milrinone as a chronic infusion with her LVAD for RV support. She was listed as a 1A for VAD complication involving right heart failure. Pulmonary hypertension reversed to normal values on LVAD, and PVR was 1.8 WU. She was successfully bridged to heart transplantation approximately 14 months after LVAD with creatinine level of 1.5 mg/dL, and she had an uncomplicated first year post-heart transplantation.

INTRODUCTION

Therapy for refractory heart failure (HF) has advanced both pharmacologically and nonpharmacologically in the past decades. Despite the survival benefit of defibrillators, cardiac resynchronization devices, and medical therapy, morbidity and mortality associated with advanced HF is excessive, up to 50% 5-year mortality and greater than 50% 1-year mortality for those considered end-stage. Such challenges are addressed with cardiac transplantation where the median survival ranges from 10 to 13 years based upon a patient’s surviving the first year.¹ Replacement of the heart is standard treatment for select patients with refractory symptoms, whereas mechanical support is the alternative for those who are either not candidates or require more immediate support. The early field of transplantation was plagued by poor survival and refining surgical techniques. Despite the first successful human heart transplant in South Africa in 1967 and the first U.S. case in 1968, survival was limited until the introduction of cyclosporine in the 1980s² and continues to improve with refinements in recipient and donor selection, donor management, immunosuppression, and treatment of comorbidities. Estimated annual transplant rates are >4000 cases with the limiting factor being donor availability.

EVALUATING THE TRANSPLANT CANDIDATE

INDICATIONS

Cardiac transplantation is reserved for advanced HF, refractory angina, and intractable ventricular arrhythmias (Table 40-1).³ Candidates for cardiac transplantation have New York Heart Association (NYHA) class III to IV symptoms despite optimal medical and device therapy, including resynchronization therapy and often surgical treatment of ischemic and/or valvular heart disease. Etiology of HF most commonly involves coronary artery disease (CAD) or nonischemic cardiomyopathy and less often restrictive cardiomyopathy and congenital heart disease (Figure 40-1). Candidates with repeated ventricular arrhythmias despite pharmacologic and ablative treatment are considered for evaluation often on an urgent basis due to the risk of sudden death and hemodynamic intolerance with the arrhythmias. Chronic angina unresponsive to medical therapy and not amenable to further revascularization is also an indication but often in the presence of HF. These indications are the result of end-stage disease failing maximal therapy and reducing quality of life and survival.

CONTRAINDICATIONS

The majority of contraindications to transplant are relative contraindications as opposed to absolute and are weighed according to the patient’s comorbidities and clinical status. These contraindications may vary among transplant centers as to absolute or relative in terms of patient candidacy (Table 40-2).

Age

The upper age limit for transplant has increased over the decades with improvement in outcomes in older patients. Previously, patients ≥65 years of age were excluded but current guidelines recommend considering patients ≤70 years of age based on improved survival in older patients.⁴ Long-term follow-up of patients >65 years of age after cardiac transplant revealed similar 10-year survival and outcomes when compared to those <60 and 60 to 64 years of age; additionally, older patients had significantly fewer rejection episodes, or immunosenescence, in which the immune system gradually deteriorates with age leading to a decline in a recipient’s protection against foreign pathogens.⁵ Select centers have also transplanted patients >70 years of age based on satisfactory outcomes, but contrary evidence has also supported reduced survival in older recipients.^6,7 Careful selection of older patients based on comorbidities, especially preoperative renal function, and “physiologic” age is critical. Upper age limit is perhaps one of the more undecided issues in transplantation; centers will determine their comfort zone in terms of age criteria and whether or not an absolute cutoff exists for their individual program based on chronologic age.

Obesity

Obesity in cardiac surgery is associated with adverse outcomes of poor wound healing, infectious risk, and pulmonary and thromboembolic complications with additional studies in transplantation identifying increased risk of rejection, vasculopathy, and mortality.⁸ Weight gain is a likelihood posttransplant often related to age and gender,⁹ while immunosuppression can also lead to weight gain and worsening blood sugar, which could further impact preexisting comorbidities. Therefore, recipient weight is critical and usually measured as body mass index (BMI, weight in kilograms per height in meters squared) or percent ideal body weight (PIBW) for a given height and gender. Both measurements take into account height as opposed to considering weight only. The International Society for Heart and Lung Transplantation (ISHLT) guidelines recommend a pretransplant BMI <30 kg/m² or PIBW <140%, and state it is reasonable to recommend weight loss in candidates who do not meet this criteria due to the association with poor outcomes.⁴ Given the prevalence of obesity, many centers accept a higher BMI or PIBW in recipients and an upper limit is usually center-specific.

Active Infection and Malignancy

Both active infection and malignancy (other than nonmelanoma skin cancer) are absolute contraindications to transplantation due to the risk of progression with immunosuppression. Traditionally, 5 years of remission has been utilized as a safety measure, but this is arbitrary and dependent on the type of cancer, response to treatment, and risk of recurrence.⁴ Malignancy that is in remission and has a low risk of recurrence will usually be considered after oncology consultation, especially when considering the urgency of the patient clinical presentation. For example, a patient with end-stage HF and prostate cancer within the past few years would be a reasonable candidate based on the “cure” rate and slow-growing nature of this cancer as opposed to a patient who presents with chemotherapy-induced cardiomyopathy a few months after treatment for breast cancer. Pretransplant evaluation includes routine screening for malignancy.

Active infection must be resolved before considering transplantation with documentation of negative cultures and resolving signs of infection. Somewhat more complicated is the consideration of chronic infections such as hepatitis B or C and human immunodeficiency virus.¹⁰ With growing experience, patients with these chronic infections have been successfully transplanted if they do not have extensive organ involvement with the disease; however, experience is limited and many centers still consider such infections a contraindication. Collaboration with transplant infectious disease specialists should be undertaken in these situations.

Irreversible Pulmonary Hypertension

Due to the risk of right HF posttransplant, irreversible pulmonary hypertension (PH) is an absolute contraindication to candidacy.⁴ In advanced HF, secondary or venous PH develops as a result of elevated filling pressures, which is usually considered reversible; however, persistent elevation may lead to irreversible or fixed PH as a result of chronic intimal changes and medial hypertrophy in the pulmonary vasculature. A donor heart cannot withstand the high afterload of an elevated pulmonary vascular resistance (PVR), which results in failure of the right ventricle and adverse outcomes including acute cardiogenic shock and mortality.¹¹ Therefore, routine evaluation of candidates includes invasive assessment of pulmonary pressures, filling pressures, cardiac output, and PVR. When the PVR >5 Woods units, pulmonary artery systolic pressure (PASP) >60 mm Hg, PVR index >6, or a transpulmonary gradient (TPG) >15 mm Hg (difference of the mean PA and wedge pressure), transplant candidacy is usually not considered unless provocative testing with a vasodilator reduces the pressures and PVR to an acceptable level while maintaining a systemic blood pressure >85 mm Hg.⁴ Patients with fixed, elevated PVR may also have underlying lung disease, concurrent obstructive sleep apnea, or chronic thromboembolic PH, which should be excluded.

Diabetes Mellitus

Diabetes with end-organ damage (proliferative retinopathy, nephropathy, and neuropathy) or uncontrolled blood sugars is considered a relative contraindication at most institutions; previously, diabetes was considered an absolute contraindication. Single-center data, n = 161, have shown no difference in infection, rejection, and vasculopathy when compared to nondiabetic controls with similar 1-, 5-, and 10-year survival.¹² In contrast, larger reviews by Russo et al¹³ and Kilic et al,¹⁴ respectively, found uncomplicated diabetic patients have improved survival when compared to those with complicated diabetes, defined as the collective number of diabetic-related complications, and diabetes was associated with reduced 10-year survival, without mention of severity. Further evidence is lacking to further delineate what degree of end-organ involvement is acceptable, but guidelines recommend considering only those with nonproliferative retinopathy.⁴ In select cases of nephropathy, patients might be evaluated for a combined heart and kidney transplant. Consultation with an endocrinologist should be part of the evaluation process to improve hemoglobin A1c to <7.5 mg/dL.

Renal Dysfunction

Estimated glomerular filtration rate (eGFR) or creatinine clearance should be used to assess renal function, and evaluation includes workup of intrinsic renal disease (imaging and assessment of proteinuria) as this would indicate irreversible dysfunction that would not be expected to improve after correcting cardiac function. In a review of 1732 patients, patients with impaired renal function at the time of listing were more likely to develop chronic kidney disease (CKD) with function often deteriorating within the first year after transplantation, progressing from 50% with CKD stage III or higher immediately before transplantation to 77% during the first year.¹⁵ Patients with CKD stage IV and V had a higher mortality rate and progression of renal dysfunction after transplantation. Risk factors for developing CKD included recipient age, female gender, diabetes, and temporary dialysis or hemofiltration perioperatively.^15,16 ISHLT listing criteria state it is reasonable not to consider irreversible renal dysfunction with eGFR <40 mL/min for heart transplantation alone.⁴ Dual-organ candidacy should be considered where appropriate.

Peripheral Vascular Disease

Symptomatic cerebral or peripheral vascular disease is considered a contraindication to candidacy if clinically severe or not amenable to revascularization. However, asymptomatic disease will likely be considered, but is specific to individual centers. Retrospective data suggested progression of peripheral vascular disease posttransplant and possible risk factors associated with development include presence of pretransplant ischemic etiology and former smoking.⁴ Rehabilitation potential is essential in any candidate with vascular disease.

Psychosocial Factors

A detailed psychosocial assessment of all transplant candidates is a fundamental component in the evaluation process. This includes medication and clinic visit compliance, social support system, psychiatric history, and substance abuse history. Transplant programs have dedicated social workers who perform these assessments and meet with the patient’s social network. Often, patients will be referred to psychologists or psychiatrists based on their history and whether any active psychiatric illness is present. Substance abuse of alcohol, illicit drugs, or tobacco is a contraindication to listing and programs require 6 to 12 months of abstinence documented with negative toxicology screens; current alcohol and illicit drug use are absolute contraindications in transplant programs. Based on a patient’s history, various rehabilitation or substance abuse programs, counseling, sponsorship, or neurocognitive testing could also be required. Many patients are denied candidacy based on their psychosocial situation, as this has been critical to long-term success.¹⁷ Patients who have demonstrated poor medication compliance are not considered candidates, and dementia is considered a relative contraindication.⁴ Comprehensive screening tools are now utilized by many transplant programs in order to standardize this assessment and predict psychosocial outcome.¹⁸

ASSESSING EXERCISE CAPACITY

Cardiopulmonary exercise testing assesses peak oxygen consumption (VO₂) and provides an objective measure in addition to NYHA class, ejection fraction, blood pressure, heart rate, and other parameters of clinical status. A VO₂ result between 10 and 14 mL/kg/min is associated with a reduced survival; evaluation for transplantation is recommended. Guidelines mention ≤12 mL/kg/min if a patient is on a beta blocker and ≤14 mL/kg/min if not on a beta blocker.⁴ It is important that patients have a maximal study and reach anaerobic threshold, where carbon dioxide production exceeds oxygen consumption and is reported as the respiratory exchange ratio (RER) >1.05. Deconditioning often limits reaching the anaerobic threshold and parameters that do not reflect peak exercise should be evaluated, such as the ventilatory response to exercise or the ventilation to carbon dioxide slope (V_E/VCO₂), which can be measured throughout the length of exercise. This slope is higher in patients with low cardiac output, PH, and a higher dead space volume; V_E/VCO₂ >35 is a poor prognostic indicator.

PRETRANSPLANT WAITLIST MANAGEMENT

LISTING

Patients are waitlisted for heart transplant after decision by a multidisciplinary selection committee consisting of the various team members involved in the evaluation process: cardiac surgeons, HF cardiologists, coordinators, pharmacists, social workers, and subspecialty consultants such as pulmonology, nephrology, and infectious disease. Listing status consists of 3 levels, which from highest to lowest priority are 1A, 1B, and 2. See Table 40-3 for details on listing status.¹⁹ Patients accrue time on the waitlist regardless of status and are matched to available organs based on size, blood type, and medical urgency. The goal of organ allocation is to transplant those who are the most critical and have the shortest survival. Average wait times on the list will vary by region. Patients who are large and blood type O will typically wait longer than those who are smaller and not blood type O. For this reason, ventricular assist devices (VADs) are implanted in those who are less likely to survive the wait for an available organ and are termed bridge to transplantation. Some transplant programs have an alternate list for higher-risk recipients (age >70 years, renal dysfunction, retransplantation) and donors (high-risk behavior, older donors, or presence of CAD).

RIGHT HEART CATHETERIZATION

Routine right heart catheterization (RHC) is performed as part of the transplant evaluation and at 3- to 6-month intervals as part of waitlist management. A vasodilator challenge is indicated when PASP >50 mm Hg and TPG >15 mm Hg or PVR >3 Woods units; commonly utilized agents are nitroprusside or nitroglycerin as an acute vasodilator and milrinone or dobutamine for inotrope support while maintaining systolic blood pressure (SBP) >85 mm Hg. If the patient becomes hypotensive with SBP <85 mm Hg despite an appropriate decline in PVR with a vasodilator challenge, poor outcomes have been associated due to a high risk of right HF and mortality in this scenario.⁴ If this challenge is unsuccessful, unloading of the left ventricle (LV) will be attempted with diuretics, continuous inotrope infusion, or, in cases refractory to medical therapy, some type of mechanical support with temporary intra-aortic balloon pump (IABP) or long-term with left ventricular assist device (LVAD). Patients with a fixed component of PH, meaning PVR is elevated, should be evaluated for underlying pulmonary disease, chronic thromboembolic disease, and sleep apnea. RHCs are performed serially on all patients waitlisted for transplant; in our institution, we perform RHC every 3 months if a vasodilator study was required to reverse PH or the patient is on a chronic inotrope infusion and every 6 months for the rest of the patients.

It is critical for transplant success to accurately evaluate hemodynamics and determine reversibility of PH given the risk of right HF and mortality in the setting of PH. Fixed PH and pulmonary arterial hypertension (HTN) are considered contraindications to transplantation due to elevated and nonreversible PVR, but even reversible PH carries a significantly higher risk of mortality posttransplant¹¹ and a nonsignificant trend to increased mortality in another study²⁰ emphasizing careful monitoring of these patients pretransplant and posttransplant.

SURGICAL MANAGEMENT OF THE TRANSPLANT PATIENT

DONOR SELECTION AND ORGAN ALLOCATION

Evaluation and management of potential donors is the responsibility of the local organ procurement organization (OPO), and it involves a comprehensive medical and social history; laboratory studies including blood type, infectious serologies (human immunodeficiency virus, hepatitis B and C, and cytomegalovirus); and evaluation of cardiac function with an echocardiogram. Further cardiac studies (ie, coronary catheterization) are recommended based upon donor cause of death or risk factors, especially age. Substantial left ventricular hypertrophy (LVH), obstructive coronary disease, excessive inotrope use, ventricular arrhythmias, or reduced ejection fraction <40% are cardiac abnormalities that in general are not accepted for use in transplantation.²¹ Donors with chest trauma should be carefully assessed for any damage to the heart. Donor comorbidities will influence decisions on organ utilization, also. The process of identifying an appropriate donor is not standardized, and data are limited on the impact of concerning donor risk factors on outcomes because these hearts are not usually transplanted.

Donor management optimizes organ function through support of blood pressure, volume resuscitation, oxygenation, and correction of electrolyte and metabolic abnormalities including hormonal imbalances noted in brain death (insulin, corticosteroids, arginine vasopressin, triiodothyronine). The ischemic time, also termed the cold ischemic time, is the total time from organ procurement in the donor to reperfusion in the recipient. Warm ischemic time refers to the duration of implantation or removal of the organ from ice until reperfusion, but the total ischemic time is utilized when evaluating a potential donor. General recommendations are for an ischemic time between 4 and 6 hours with preference ≤4 hours for older donor organs.²¹ ABO incompatibility is a long-established contraindication in adults due to hyperacute rejection. Size matching is usually within 20% to 30% of recipient body size. An average-size male donor of 70 kg should typically be an appropriate size match for any recipient. Gender mismatching carries increased mortality risk and poor outcomes.^22,23 Size mismatch with a female donor to male recipient is disconcerting in that a female heart tends to be smaller and would be incapable of meeting the demands of a larger male recipient or higher PVR. This was demonstrated in a large UNOS database review of 18,240 transplants between 1999 and 2007 with the lowest 5-year survival in female donors/male recipients and no difference in female recipients of gender-matched or gender-mismatched organs.²³ Male donors/male recipients had the highest 5-year survival at 74.5%. With an endpoint of 10 years rather than 5 years (n = 857 from 1994-2008) in a single-center study, Kittleson et al found a reduced 10-year actuarial survival in both types of gender mismatches suggesting an immunologic effect could also have a role in outcomes (Figure 40-2).²² There was no difference among the cause of death for gender-matched and gender-mismatched recipients.

Utilization of donor hearts has decreased in the past decade and is around 40% in recent data.²⁴ Current practice was reviewed by Khush et al within the California Transplant Donor Network from 2001 to 2008 with turndown of 1872 donors. Potential donors who were not accepted were the following: age >50 years, female sex, cerebrovascular accident (CVA) as the cause of death, HTN, diabetes, positive troponin, LV dysfunction with regional wall motion abnormalities, and LVH.²⁴ Only CVA as the donor cause of death minimally predicted prolonged recipient posttransplant hospitalization (odds ratio, 1.41 [1.00-2.00]), whereas diabetes mellitus was the only donor predictor of reduced recipient survival. Experts have suggested that our current criteria for donor selection are contributing to our shortage of donors due to non-use of potential donors and likely donor characteristics have a small contribution to posttransplant adverse events based on available data.²⁵ Efforts to expand donor selection and organ perfusion are ongoing, but heart transplantation remains limited by donor availability.

Organs are allocated according to region, status on the waitlist, and matching by size and blood type. The allocation policy changed on June 12, 2006, to concentric 500-mile zones with the goal of prioritizing higher-risk recipients (status 1A and 1B), and increasing the availability of a donor. Prior to this updated policy, organs were offered to all status patients within a UNOS region before they were available to bordering regions (Figure 40-3). Waitlist mortality has decreased significantly from 13.3% to 7.9% up to 180 days (p < 0.001) while waitlist time has increased—maybe partly related to the rise in LVAD bridging, which was found to vary by region.²⁶ Currently, LVAD patients have 30 days of 1A time regardless of a complication, but discussion is ongoing about the low waitlist mortality of continuous-flow LVAD patients, which is similar to status 2 but lower than status 1A and 1B in a review of the UNOS database between 1999 and 2011.²⁷ However, patients with biventricular or temporary support or an LVAD complication were found to have a higher mortality. It is important to note that current UNOS recommendations of 30 days of 1A time in an uncomplicated LVAD recipient are based on the pulsatile-flow era where LVAD patients had a mortality rate that was similar to status 1B and, therefore, higher than status 2.

SURGERY

Donor procurement is coordinated between the procuring and transplanting teams with the goal of organ preservation and minimizing ischemic time. The organ is placed in a cold cardioplegia solution and transported to the transplanting center (Figure 40-4). Experimental animal models have shown promise in using novel techniques to help reduce ischemia and reperfusion injury: targeted complement inhibition in recipients,²⁸ cardioplegia solution supplemented with erythropoietin,²⁹ a hypothermic hydrogen-rich water bath,³⁰ and ex vivo heart perfusion after cardiocirculatory death.³¹ These methods clearly need further investigation before incorporating into standard procedure.

Early transplantation was performed in the orthotopic position by the forefathers of heart transplantation: Norman Shumway, Richard Lower, Adrian Kantrowitz, and Christiaan Barnard. Lower and Shumway described biatrial anastomosis in 1960.³² Initial anastomosis was biatrial and has progressed to the bicaval technique currently. Biatrial anastomosis involves midatrial transection of both donor and recipient hearts along with transection of the great vessels just above the semilunar valves. This method keeps the pulmonary venous connection to the left atrium intact in the recipient and includes the donor sinoatrial node in the right atrium. Reanastomosis begins with the atrial septum followed by the great vessels. The bicaval technique, first reported in 1991 by Dreyfus et al, differs in that the atria are not resected and anastomosis occurs at the inferior and superior vena cavae and pulmonary veins, which keeps the donor atria intact.³³ An advantage of the biatrial method is fewer connections with only 2 in the atria versus 6 atrial connections in the bicaval method (2 to the vena cavae and 4 to the pulmonary veins), possibly reducing ischemic time.³⁴ The disadvantages to the biatrial technique are the large geometry of the atria and its possible effect on hemodynamics and arrhythmia risk along with the chance of damaging the sinoatrial node. The purpose of modifying the implantation technique was to reduce atrial size, atrial arrhythmias, tricuspid valve regurgitation, and bradycardia requiring a pacemaker, which were considered to occur with more frequency in the biatrial method. Davies et al reviewed almost 21,000 transplants from 1997 to 2007 with 59.3% biatrial and 38.1% bicaval anastomoses performed; they found bicaval anastomosis less often required postoperative pacemaker implantation and had a significant yet small survival advantage at 30 days and 1, 5, and 10 years.³⁴ Despite the increasing use of the bicaval anastomosis, tricuspid regurgitation persists after transplantation to a certain extent due to repeated endomyocardial biopsies.

PHYSIOLOGY OF THE TRANSPLANTED HEART

When transplanted, the new heart is surgically denervated without afferent and efferent nerve supply.³⁵ The afferent supply from the heart to the central nervous system is responsible for angina and is not generally present in transplant patients for this reason. Without angina, patients who are ischemic tend to present with HF symptoms or arrhythmias instead. Loss of the efferent nerve supply from the central nervous system to the heart results in loss of vagal tone leading to a higher resting heart rate often up to 110 beats per minute and lack of response to drugs that rely upon the autonomic nervous system, such as atropine. A blunted response to exercise is a hallmark of transplantation related to efferent denervation because the recipient is now reliant upon circulating catecholamines for chronotropic effect; therefore, a patient’s heart rate slowly recovers postexercise as these levels decline. The baroreceptor reflex is not intact in these patients either, due to sympathetic and parasympathetic denervation, which leads to a more sensitive orthostatic response and absent effect of carotid sinus massage. Re-innervation is a phenomenon that tends to transpire with time based on lower resting heart rate and the presence of angina but is not a consistent occurrence as to who, when, or how much.³⁶