Echocardiography in Pediatric and Adult Congenital Heart Disease, 2nd Ed.

28. Evaluation of the Transplanted Heart

INTRODUCTION

History

The first human-human heart transplant was performed on December 3rd, 1967, in Cape Town, South Africa, by Dr. Christiaan Barnard. This operation was performed on a 53-year-old man named Louis Washkansky, who had ischemic cardiomyopathy. The first transplant in a child was only 3 days later, performed by Dr. Adrian Kantrowitz in Brooklyn, New York. The patient was a 17-day-old infant with Ebstein anomaly and functional tricuspid atresia. The patient died within hours of the transplant due to acidosis, thought to be due to respiratory causes. Due to poor outcomes of early transplantation in children and adults, pediatric heart transplantation was essentially discontinued, and was not pursued actively again until the early 1980s. Since that time, transplantation has become accepted as an option for end-stage heart failure in children.

Current Incidence and Outcomes

Approximately 350–400 heart transplants are performed in children under the age of 18 years annually in the United States (Fig. 28.1). Around 25%–30% of these transplants are performed in infants less than one year of age, while 30%–35% are performed in patients between the ages of 11 and 17 years. In infants, congenital heart disease (CHD) is the most common indication for transplantation (Fig. 28.2). While transplantation may be performed for a myriad of reasons in infants with CHD, hypoplastic left heart syndrome (HLHS) is the most common congenital indication. In adolescents, cardiomyopathies (dilated, restrictive, hypertrophic) are the predominant indication for transplantation.

Figure 28.1. Number of heart transplants performed in children annually in the United States. (Data courtesy of UNOS).

Survival after pediatric heart transplantation is highly dependent on many factors. Pretransplant mechanical support, presence of congenital heart disease (i.e., non-cardiomyopathy), renal dysfunction, and hepatic dysfunction all portend worse outcomes after transplant. Posttransplant causes of mortality include acute allograft rejection, nonspecific graft failure, coronary artery vasculopathy, and malignancy. Survival rates after transplant according to International Society of Heart-Lung Transplant (ISHLT) data from after the year 2000 are 88%, 76%, and 62% at 1, 5, and 10 years, respectively.

Importance of Echocardiography

Echocardiography plays a critical role in the evaluation of the patient with end-stage heart failure, including diagnostic and specific functional assessments. Additionally, it is the current gold standard for assessment of potential donors. While routine assessment of the patient after transplantation requires several modalities working in concert, including interventional catheterization and laboratory studies, echocardiography clearly plays a major role in the clinical care of patients before, during, and after transplantation.

Figure 28.2.Indications for heart transplantation in children delineated by age group. (From Kirk R, Dipchand AI, Edwards LB, et al. The Registry of the International Society of Heart and Lung Transplantation: Fifteenth Pediatric Heart Transplantation Report - 2012. J Heart Lung Transplant.2012;31(10):1065–1072.)

ECHO EVALUATION PRIOR TO TRANSPLANT

Evaluation of Potential Donors

The selection of appropriate donor hearts includes a thorough assessment of the donor’s past medical history, history of infectious or toxic exposures, current clinical and hemodynamic status (including invasive measurements of central venous pressure and pulmonary arterial pressure), and laboratory values. Perhaps the most useful tool, however, in the assessment of the potential donor heart is echocardiography. Echocardiography is useful because it is widely available at most hospitals, it is portable, it allows comprehensive evaluation of all chambers of the heart as well as the systemic and pulmonary veins and arteries, and it does not require the use of radiation or nephrotoxic contrast.

Brainstem death is associated with intensive sympathetic nervous system activity, and includes a large surge of catecholamines released into the circulation. This can cause a systemic inflammatory reaction, alter vascular resistances, and induce myocardial ischemia. Management of this sympathetic storm can be critical to maintaining the affected organs suitable for transplantation. Due in part to this sympathetic storm, left ventricular (LV) dysfunction commonly occurs in donors after neurologic injury and brainstem death. It may present with global dysfunction, or may present with regional wall motion abnormalities, even in the absence of coronary artery disease. The apex is most commonly spared, with the basal segments most affected.

In the absence of other risk factors for the donor heart, mild abnormalities of LV systolic function do not preclude the use of the heart. Outcomes of critically ill patients who received hearts with mild LV systolic functional abnormalities and mitral regurgitation have not differed from those who received donor hearts with normal systolic function. In particular, regional wall motion abnormalities seen in young donors typically do not persist after transplantation.

Although transthoracic echocardiography (TTE) usually is sufficient to assess the donor heart, in some cases, particularly in large adolescents, transesophageal echocardiography (TEE) may be necessary to delineate all anatomic structures and obtain a reliable assessment of cardiac function. Pharmacologic stress echocardiography has been proposed as an assessment of the marginal donor heart in adults. Preliminary data from studies in Europe using dipyridamole stress testing have shown that improvement in wall motion during stress in potential donor hearts is associated with normal function after transplant. While this methodology has not been well studied in pediatric patients, it carries promise for increasing the potential donor pool in the future.

In some cases, serial transthoracic echocardiography may be very useful, allowing for a repeat look at the potential donor heart after optimization of the donor’s metabolic and inflammatory conditions. Often, a heart that does not seem ideal may improve significantly on subsequent evaluation several hours later.

Evaluation of Potential Recipients

Echocardiography plays an important role in the evaluation and management of potential transplant recipients. It allows for assessment of chamber dimensions, valvular function, and systolic function of the ventricles, all of which correlate with risk of mortality while awaiting transplantation. In addition, echocardiography allows assessment of right-sided heart function and pressures. It is critical in the differentiation of constrictive pericardial disease (where the treatment is pericardiectomy) from restrictive cardiomyopathy (where the treatment is transplantation). Finally, echocardiography can be useful in the assessment and management of dyssynchrony.

Perhaps most importantly to the pediatric population, echocardiography plays an important role in identifying residual lesions in patients with congenital heart disease. These lesions may be contributing to the patient’s current “end-stage” heart failure symptoms, or are lesions that will require addressing at the time of transplantation. For instance, residual coarctation may be addressed at the time of transplantation in patients with a history of HLHS. Patients with heterotaxy, situs abnormalities, pulmonary venous abnormalities, interrupted inferior vena cava (IVC), or a left superior vena cava (SVC) may require modification of the surgical technique of transplantation, and are important to identify and plan for prior to the transplant.

ECHO EVALUATION DURING TRANSPLANT

Intraoperative TEE

TEE often will be performed in the operating room as the allograft is reperfused, to assess for any residual cardiac lesions, as well as to assess graft function. To adequately assess residual cardiac lesions and the graft anastomoses, an understanding of the specific surgical technique used is required. Traditionally, orthotopic heart transplantation (where one heart is removed and the other replaces it) was performed using the biatrial technique, where the surgeon anastomoses the allograft to retained cuffs of both left and right atrial tissue. With this technique, both atria will appear large on echocardiograms due to the presence of significant amounts of recipient and donor atrial tissue. Often, the suture lines will be visible in the mid-left and mid-right atrium. More recently, some surgeons perform transplantation using the bicaval technique. This involves leaving a cuff of left atrial tissue, leaving the pulmonary vein orifices intact, but removing the entirety of the right atrium by transecting the vena cavae. The allograft is then anastomosed to the left atrial cuff and to the IVC and SVC. Rarely, a heterotopic transplant may be performed, where the native heart is left in situ and the donor heart is placed next to the native heart. This allows for continued function of the native heart, and is used at some institutions in patients with elevated pulmonary vascular resistance, who would not otherwise be appropriate candidates for orthotopic heart transplantation.

One of the most important roles of echocardiography in the operating room is in the assessment of allograft function. LV function often is decreased after reperfusion; this may be due to prolonged ischemic time or a marginal donor heart. Transient mechanical support may be needed to allow the allograft time to recover function.

Right ventricular (RV) function is critical to assess in the operating room and in the first 24 hours after transplantation. Prior to transplant, many patients will have pulmonary hypertension secondary to elevated left-sided filling pressures. Often, the RV of the allograft will struggle after reperfusion to maintain sufficient pressures for lung perfusion. Inotropic support or nitric oxide administration may be necessary to support RV function. This is particularly problematic in patients with restrictive cardiomyopathy as their indication for transplant.

Rarely, hyperacute rejection may occur, and is typically evident immediately in the operating room (Fig. 28.3). This may present clinically to the surgeon as discoloration of the myocardium and poor hemodynamic function. On TEE, this presents as poor systolic function and increased wall thickness. Hyperacute rejection fortunately is rare, but is important to identify, as appropriate and immediate treatment is crucial.

Figure 28.3. Epicardial echocardiogram performed on a 25-year-old female with hyperacute rejection, taken 4 days after transplant. The patient had presented with immediate systolic and diastolic dysfunction on reperfusion at the time of transplant, with progressive thickening of the myocardium over the first few days despite intensive antirejection treatment and ECMO rescue. Note the diffuse, infiltrative appearance of the myocardium. (See Video 28.1.)

Residual Cardiac Lesions

Significant anastomotic stenoses are rare in the modern era of pediatric heart transplantation. Most stenoses, when present, are mild, and most commonly include supravalvar aortic or supravalvar pulmonary stenosis. However, any patient in whom a nontraditional technique is required due to anatomic concerns (situs abnormalities, pulmonary venous abnormalities, recurrent coarctation, interrupted inferior vena cava, or left superior vena cava) needs careful attention by the echocardiographer. Patients with a history of a bidirectional cavopulmonary anastomosis are at particular risk of having stenosis of the SVC anastomosis.

ECHO EVALUATION AFTER TRANSPLANT

Acute Allograft Rejection

Acute allograft rejection is one of the leading causes of significant morbidity and mortality in heart transplant patients in the first several years following transplant. The gold standard for diagnosis of rejection is pathologic examination of myocardial tissue, obtained from an endomyocardial biopsy (EMB). However, EMB is invasive, and carries risks, including tricuspid valve damage (leaflet perforation, disruption of chordae tendinae, injury to papillary muscles, all of which result in tricuspid regurgitation), myocardial perforation, arrhythmias, risks of repeated jugular and/or femoral venous access, and the standard risks of anesthesia.

Because of these risks, investigators have long sought to identify specific echocardiographic measures with which to reliably diagnose (or exclude) allograft rejection. With some notable exceptions, the majority of studies assessing echocardiography in pediatric heart transplant recipients have not demonstrated that echocardiography can reliably replace the EMB as the gold standard. However, there clearly is a role for echocardiography in the assessment of potential rejection, particularly in young children for whom repeated EMB is cumbersome, and in the asymptomatic patient with significant rejection.

Common Findings of Rejection

Pathologically, acute cellular rejection is characterized by lymphocytic infiltration, myocardial inflammation and edema, and, in advanced stages, myocardial necrosis. This disruption of myocyte function translates on the echocardiogram to myocardial thickening, pericardial effusion, systolic and diastolic dysfunction, and new valvar regurgitation, particularly of the atrioventricular valves. In many cases, this is very clear on echocardiography, particularly with severe episodes of rejection.

Interestingly, patients with acute rejection often can present in very different ways on echocardiography. For some patients, the first sign of rejection on echocardiography might be a new pericardial effusion, or markedly increased wall thicknesses (Fig. 28.4). For others, new-onset atrioventricular valve regurgitation and/or systolic dysfunction may be the first sign (Fig. 28.5). Diastolic dysfunction may be seen in some patients in the absence of other findings. Relaxation abnormalities may be evident to the echocardiographer on two-dimensional imaging of the ventricles, or it may become evident on standard Doppler diastolic assessment including mitral inflow velocities and tissue Doppler imaging (TDI) (Fig. 28.6).

Figure 28.4. Routine transthoracic echocardiogram performed in a 17-year-old female two months after transplant, including parasternal long-axis (A) and apical (B) images. The patient was asymptomatic at the time of the echocardiogram. Note the diffuse thickening and “edematous” appearance of the myocardial walls, and new posterior pericardial effusion. Of note, this patient had normal systolic function and normal AV-valve function. (See Video 28.2.)

Importantly, increased LV mass and wall thickness may occur in patients with rejection, but this is difficult to discern from a common increase in LV mass that occurs after transplantation. In adult transplant recipients, the mean LV mass is around 35% greater than in age-matched controls. While not entirely elucidated, there are several factors that are thought to contribute to this increased LV mass, including transient myocardial injury/edema, hypertension, myocardial denervation, and the immunosuppressive regimen being used (particularly if steroids are used). The hypertrophy can be visualized easily using echocardiography. It may occur in a concentric pattern, or may occur primarily in the ventricular septum (Fig. 28.7). In infants, this may result in an LV outflow gradient, similar to hypertrophic cardiomyopathy. Increased LV mass and wall thickness may also be evident because of donor-recipient mismatch—if a child received a heart from a larger donor, the wall thicknesses will appear increased relative to what is normal for the child. In these cases, the relative wall thicknesses may normalize over time.

Echo Markers When Rejection Is Not Obvious

The more difficult situation for the echocardiographer is when there are clinical symptoms suggestive of possible rejection (poor feeding, tachycardia, etc.), but no overt evidence on two-dimensional imaging to suggest acute rejection. In many cases, even with the highest ISHLT pathologic grading of rejection, systolic function may be normal, valvular function may be unchanged, and effusions may be absent. In these situations, more sophisticated techniques can be helpful in distinguishing rejection episodes, which will be discussed below.

Figure 28.5. Transthoracic echocardiogram performed in a 14-year-old female who presented 2 years after transplant with new-onset dyspnea. An apical 4-chamber view is shown with 2D only (A) and with color Doppler (B). The patient had a new small pericardial effusion, systolic and diastolic dysfunction, and new AV-valve regurgitation (both valves had been leaking trivially at the time of the prior echocardiogram). (See Video 28.3.)

Figure 28.6. Doppler measurements in the same patient from Figure 28.5, including Tissue Doppler from the mitral septal annulus (A) and the mitral inflow Doppler signal (B). Note the evidence of significant diastolic dysfunction, including a markedly decreased e’ velocity elevated E/e’ ratio, and short mitral valve deceleration time.

No matter the technique or screening strategy used however, the single most important thing the echocardiographer can do is to compare the current study with the patient’s most recent baseline study, preferably in a side-by-side manner. Numerous studies have demonstrated that any significant changes from the patient’s own baseline are, by far, the most sensitive marker of rejection, more so than any single measurement.

Tissue Doppler Imaging (TDI)

There have been several studies suggesting that TDI could help limit the need for surveillance biopsies in children after transplant. Dandel et al. reported that changes in diastolic TDI measurements in adults had a positive predictive value of 92% for rejection, and a negative predictive value of 96% for ruling our rejection. The diastolic TDI measurements they used included early diastolic velocities (e’) and relaxation time. Importantly, the investigators defined a significant change in TDI values to be a change of >10% from baseline values of myocardial velocities or time intervals, as their attempts to pick a specific cutoff value for either velocity or time were unsuccessful. Pauliks et al. demonstrated that similar changes in TDI measurements can be seen in children. Although the peak systolic and early diastolic myocardial velocities were decreased in children even years after transplant when compared to controls, the isovolumic acceleration (IVA) was similar to controls. During a rejection episode, all of these TDI measurements were decreased, and all resolved with successful treatment of the rejection episode (Fig. 28.8). Thus, while the peak myocardial velocities may be affected by a rejection episode, they already are abnormal after transplantation, making interpretation of changes somewhat difficult. IVA appears to be a more robust method for identifying rejection. However, this does require pristine TDI tracings and appropriate software to measure.

Figure 28.7. Routine transthoracic echocardiogram in a 14-year-old male 1 month after transplantation. There is prominent concentric hypertrophy seen in the left ventricular walls, however, no other evidence of rejection, including no new pericardial effusion, normal AV-valve function, and unchanged measures of diastolic dysfunction. (See Video 28.4.)

Most recently, Lunze et al. compared results in pediatric patients who had both an echocardiogram and a biopsy performed within 24 hours. Using the patient’s prior biopsy and echocardiogram as their own control, the authors found that several tissue Doppler parameters predicted the likelihood of rejection, including a >15% decrease in the left ventricular systolic (s’) velocity and a >5% decrease in the left ventricular late diastolic annular (a’) velocity. Importantly, when neither of these changes were present, there was a 99% likelihood of a negative biopsy. Ideally, this could be used in the future to help minimize the number of surveillance biopsies required in small children.

Myocardial Performance Index

Some authors have proposed using the myocardial performance index (MPI) as a way to detect rejection. The advantages of the MPI are that it is relatively easy to obtain, often from images that were already being obtained for a basic follow-up study, and is not as user-dependent as some other newer measures. Cain et al. demonstrated the utility of the MPI in pediatric heart transplant recipients. In their patients, an increase in the LV MPI value of at least 22% from baseline was 88% sensitive and 79% specific for detection of clinically significant rejection. While not a result that by itself can replace EMB, it can provide another piece of evidence to the question of rejection in a particular patient.

Deformational Imaging

Newer technologies, including deformational imaging, have become useful in many facets of echocardiography, particularly in areas where the myocardium is congenitally abnormal (dilated, hypertrophic cardiomyopathy) or as a result of toxins (anthracycline cardiomyopathy). Because rejection involves inflammation of the myocardium, deformational imaging theoretically should be very useful in detecting rejection. This has been demonstrated in pediatric patients by Jeewa et al., who found reduction in global longitudinal strain and global circumferential strain at the apex in patients with biopsy-proved rejection. However, the use of deformational imaging in this situation is not ideal. There is considerable variability in results among users, and using systems from different manufacturers can yield markedly different results. In addition, the potential utility of strain imaging in acute situations, including the inpatient setting and off-hours, is not clear.

Similar to TDI, deformational imaging studies have demonstrated that some aspects of assessable myocardial function never return to normal in the allograft, even in the absence of rejection. This has been hypothesized to be due to the ischemic time of the heart during transit from donor to recipient. Kailin et al. demonstrated using velocity vector imaging that global longitudinal strain is significantly lower even 1 year after transplant when compared with age-matched controls, while circumferential strain is identical to the same age-matched controls.

Figure 28.8. Tissue Doppler imaging velocities measured at the lateral mitral valve annulus in a transplant patient at baseline (A) and with evidence of rejection (B). Note the prominent depression in all TDI velocities, including systolic and diastolic velocities.

Systematic Approaches

There are numerous single measurements that have been associated with biopsy-proven rejection, including fractional shortening, LV mass, LV posterior wall diastolic thinning, the velocity of circumferential fiber contractility, mitral valve E velocity and pressure half time, isovolumic relaxation time, isovolumic acceleration time, myocardial performance index, mitral valve propagation velocity, tissue Doppler systolic and early diastolic peak myocardial velocities, and peak global longitudinal strain. However, these single measurements may be discrepant in an individual patient, and none of them, on their own, can supplant the EMB as a standard for rejection surveillance in children after heart transplant.

These results emphasize the need for a systematic approach to the diagnosis of rejection by echocardiography, not relying on a single measurement, but rather on multiple measurements and assessments. Mark Boucek et al. published several studies in the 1990s and early 2000s describing a scoring system to detect rejection. The results improved drastically once they began to use the patient as his/her own control, increasing positive predictive values from ~10% to ~40%, while keeping negative predictive values near 100%. The Boucek scoring systems (Echo-A and Echo-B) relied heavily on offline M-mode analysis of digitized tracings, but unfortunately these results were not reproducible at many other institutions. At our institution, we have used a simplified version of the Boucek system with some success. However, we have found that the direct side-by-side comparison of the current study to the patient’s most recent baseline study has been the most important aspect in diagnosing rejection by echocardiography.

Long-Term Follow-Up of Residual Lesions

As discussed previously, significant anastomotic stenoses are rare in the modern era of pediatric heart transplantation, and most commonly are present when nontraditional techniques are required. Patients with a history of a bidirectional cavopulmonary anastomosis are at risk for developing stenosis at the SVC anastomosis, and this should be monitored regularly by echocardiography. If an aortic arch reconstruction is required as part of the transplantation, there is up to a 20% risk of recoarctation, most commonly diagnosed in the first 2 years following transplant. In any patient for whom aortic arch reconstruction has been performed, regular arch imaging should be performed, gradients assessed, and abdominal aortic Doppler flow interrogated.

Monitoring during Biopsy

EMB continues to be the gold standard for diagnosis of allograft rejection; however, it is associated with risks, as described previously. The tricuspid valve support apparatus can be compromised during biopsy, resulting in significant tricuspid regurgitation. Although EMB often is performed using fluoroscopic guidance, EMB also can be performed under transthoracic echocardiographic guidance (Fig. 28.9). The use of echocardiography in this situation can obviate the potential exposure to radiation from fluoroscopy, and help direct the bioptome to an appropriate biopsy site away from tricuspid valve tissue. Three-dimensional echocardiography has also been reported for EMB guidance.

CORONARY ARTERY VASCULOPATHY

Coronary artery vasculopathy (CAV) is the most frequent late cause of mortality following heart transplantation. While it most commonly affects allografts late after transplantation, there are cases reported of early vasculopathic changes resulting in significant clinical decompensation within the first 2 years after transplant. The clinical course of the transplant patient with severe CAV is variable, but progression is common and retransplantation is often required (Fig. 28.10). Traditionally, annual coronary angiography has been performed to diagnose CAV, and to help guide management. Detection of CAV has become increasingly important in recent years as several immunosuppressive regimens have been shown to help attenuate CAV plaque burden, and early detection allows for earlier modification of immunosuppressive regimens.

Intravascular Ultrasound

Intravascular ultrasound (IVUS) has become increasingly popular, particularly in adults with coronary artery disease and in adults following heart transplantation. The procedure involves directing an ultrasound-tipped catheter into a primary coronary artery (most commonly the LAD), creating a cross-sectional image of the coronary vessel, and pulling the device back slowly to obtain a full review of the coronary intimal layers from distal coronary to proximal coronary artery (Fig. 28.11). IVUS can provide in-depth assessment of the coronary vessel walls, allowing for diagnosis of significant coronary artery disease that may not be evident on traditional intraluminal angiography. More recent technology also may allow for detailed assessment of intimal thickening, including detection of fibrous and calcific changes (Fig. 28.12). IVUS has been demonstrated to be safe to perform in children, though most operators will perform IVUS only after a certain age. IVUS is highly user-dependent, and requires advanced expertise both in the acquisition and interpretation of the images.

Figure 28.9. Transthoracic echocardiographic image demonstrating a bioptome in the right ventricle prior to a myocardial biopsy.

Figure 28.10. Coronary artery vasculopathy (CAV) diagnosed in a 14-year-old male 9 years post–heart transplant. The patient had a normal coronary angiogram the year prior, but presented with syncope with exercise. Angiography (A) revealed severe proximal narrowing of the left anterior descending coronary artery. The stenosis was treated with stenting (B), and the patient was relisted for transplantation along with placement of an ICD. Despite aggressive therapy with clopidogrel, aspirin, and pravastatin, follow-up angiography 3 months later demonstrated progression of the CAV throughout the left coronary system (C). The patient was successfully retransplanted 1 month later.

Stress Echocardiography

Stress echocardiography is a useful tool in the evaluation of transplant patients, particularly for the diagnosis or exclusion of coronary artery vasculopathy. Dobutamine stress echocardiography correlates well with angiographic CAV, and can be used in young patients. Di Filippo et al. reported in 2003 on 18 pediatric heart transplant patients who had dobutamine stress echocardiography. In this study, patients with a negative stress study were free of CAV at the time of angiography. Additionally, stress echocardiography may help identify patients most at risk for death or graft failure, even in the absence of obvious angiographic CAV (i.e., patients with microvascular involvement). Because of potential false negative results, stress echocardiography has not replaced routine coronary angiography at most institutions, though it can be used intermittently to try to reduce the frequency of follow-up angiography in low-risk patients.

Figure 28.11. Intravascular ultrasound (IVUS) at baseline and 1-year follow-up in a transplant patient. Note the intimal thickening on the follow-up image, which would have otherwise not been readily visible on routine angiographic images.

Figure 28.12. IVUS image taken during evaluation of a 19-year-old patient 14 years after transplant. Virtual Histology (Volcano Corporation) technology reveals scattered tissue densities surrounding the vessel lumen, including fibrous and calcific changes (red and white, asterisk) and intimal thickening (green, asterisks), suggestive of graft vasculopathy. The patient had a normal coronary angiogram, and graft vasculopathy would not have been diagnosed without the use of IVUS.

SUMMARY

Echocardiography plays a significant role in the evaluation of the patient before, during, and after transplantation, as well as in assessment of potential donors. Echocardiography is extremely useful in the assessment of allograft rejection, and is often used serially in this fashion. The most important maneuver in the diagnosis of rejection is the comparison of the current study to the patient’s most recent baseline study. IVUS and dobutamine stress echocardiography play a critical role in the evaluation of coronary artery vasculopathy. Novel methodologies including deformational imaging and three-dimensional imaging remain unproven in this population, but have promise in the detection of rejection and guidance of endomyocardial biopsies.

SUGGESTED READING

Aggarwal M, Drachenberg C, Douglass L, et al. The efficacy of real-time 3-dimensional echocardiography for right ventricular biopsy. J Am Soc Echocardiogr. 2005;18:1208–1212.

Almond CS, Gauvreau K, Canter CE, et al. A risk-prediction model for in-hospital mortality after heart transplantation in US children. Am J Transplant. 2012;12(5): 1240–1248.

Asante-Korang A, Fickey M, Boucek MM, et al. Diastolic performance assessed by tissue Doppler after pediatric heart transplantation. J Heart Lung Transplant. 2004;23:865–872.

Bombardini T, Gherardi S, Arpesella G, et al. Favorable short-term outcome of transplanted hearts selected from marginal donors by pharmacologic stress echocardiography. J Am Soc Echocardiogr. 2011;24(4):353–362.

Boucek MM, Mathis CM, Kanakriyeh MS, et al. Donor shortage: use of the dysfunctional donor heart. J Heart Lung Transplant. 1993;12(6 Pt 2):S186–S190.

Cain N, Tatum G, Feingold B, Webber S. Drant S. Use of myocardial performance index for detection of acute cellular rejection in pediatric heart transplant recipients. J Am Coll Cardiol. 2011;57(14 Supp 1):E471.

Canter CE, Shaddy RE, Bernstein D, et al. Indications for heart transplantation in pediatric heart disease: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;115:658–676.

Canter CE, Kirklin JK, eds. ISHLT Monograph Series Volume 2 - Pediatric Heart Transplantation. Philadelphia, PA: Elsevier; 2007.

Cheung MM, Redington AN. Assessment of myocardial ventricular function in donor hearts: is isovolumic acceleration measured by tissue Doppler the Holy Grail? J Heart Lung Transplant. 2004;23(9 Suppl):S253–S256.

Costello JM, Wax DF, Binns HJ, et al. A comparison of intravascular ultrasound with coronary angiography for evaluation of transplant coronary disease in pediatric heart transplant recipients. J Heart Lung Transplant. 2003;22:44–49.

Dandel M, Hummel M, Muller J, et al. Reliability of tissue Doppler wall motion monitoring after heart transplantation for replacement of invasive routine screenings by optimally timed cardiac biopsies and catheterizations. Circulation. 2001;104(12 Suppl 1):I184–I191.

Di Filippo S, Semiond B, Roriz R, et al. Non-invasive detection of coronary artery disease by dobutamine-stress echocardiography in children after heart transplantation. J Heart Lung Transplant. 2003;22:876–882.

Fyfe DA, Ketchum D, Lewis R, et al. Tissue Doppler imaging detects severely abnormal myocardial velocities that identify children with pre-terminal cardiac graft failure after heart transplantation. J Heart Lung Transplant. 2006;5:510–517.

Jeewa, A, Sexon-Tejtel SK, Cui Q, et al. The utility of speckle tracking echocardiography (STE) derived strain for the detection of acute rejection after pediatric heart transplantation. J Heart Lung Transpl. 2013;32(4):S190–S191.

Lunze, FI, Colan, SD, Gauvreau, K, et al. Tissue Doppler imaging for rejection surveillance in pediatric heart transplant recipients. J Heart Lung Transpl. 2013;32(10):1027–1033.

Kailin JA, Miyamoto, SD, Younoszai AK, Landeck BF. Longitudinal myocardial deformation is selectively decreased after pediatric cardiac transplantation: a comparison of children 1 year after transplantation with normal subjects using velocity vector imaging. Pediatr Cardiol.2012;33(5):749–756.

Kantrowitz A, Haller JD, Joos H, et al. Transplantation of the heart in an infant and an adult. Am J Cardiol. 1968;22(6):782–790.

Kirk R, Dipchand AI, Edwards LB, et al. The Registry of the International Society of Heart and Lung Transplantation: Fifteenth Pediatric Heart Transplantation Report - 2012. J Heart Lung Transplant. 2012;31(10):1065–1072.

Kuhn MA, Jutzy KR, Deming DD, et al. The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation. J Am Coll Cardiol. 2000;36:250–254.

Larsen RL, Applegate PM, Dyar DA, et al. Dobutamine stress echocardiography for assessing coronary artery disease after transplantation in children. J Am Coll Cardiol. 1998;2:515–520.

Mahle WT, Cardis BM, Ketchum D, et al. Reduction in initial ventricular systolic and diastolic velocities after heart transplantation in children: improvement over time identified by tissue Doppler imaging. J Heart Lung Transplant. 2006;25:1290–1296.

Pauliks LB, Pietra BA, DeGroff CG, et al. Non-invasive detection of acute allograft rejection in children by tissue Doppler imaging: myocardial velocities and myocardial acceleration during isovolumic contraction. J Heart Lung Transplant. 2005;24(7 Suppl):S239–S248.

Pauliks LB, Pietra BA, Kirby S, et al. Altered ventricular mechanics in cardiac allografts: a tissue Doppler study in 30 children without prior rejection events. J Heart Lung Transplant. 2005;24:1804–1813.

Putzer GJ, Cooper D, Keehn C, Asante-Korang A, Boucek MM, Boucek RJ Jr. An improved echocardiographic surveillance strategy following pediatric heart transplantation. J Heart Lung Transplant. 2000;19(12):1166–1174.

Raichlin E, Bae J H, Khalpey Z, et al., Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation. 2007;116(23):2726–2733.

Shirali GS, Cephus CE, Kuhn MA, et al. Posttransplant recoarctation of the aorta: a twelve year experience. J Am Coll Cardiol. 1998;32:509–514.

Topilsky Y, Hasin T, Raichlin E, et al. Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation. Circulation. 2012;125(5):708–720.

Questions

1.What is the most common indication for heart transplantation in infants?

A.Dilated cardiomyopathy

B.Myocarditis

C.Restrictive cardiomyopathy

D.Congenital heart disease

E.Hypertrophic cardiomyopathy

2.Where did the first heart transplant performed in a child occurr?

A.Cape Town, South Africa

B.Brooklyn, NY

C.London, England

D.Palo Alto, CA

E.Stockholm, Sweden

3.In assessing a marginal donor heart, which of the following pharmacologic agents has been used to predict myocardial recoverability after transplant?

A.Dipyridamole

B.Dopamine

C.Epinephrine

D.Thyroxine

E.Nitroglycerine

4.On a transesophageal echocardiogram performed immediately following reperfusion in a heart transplant recipient, you notice decreased biventricular systolic function (EF ˜25%) with increased wall thickness. Which of the following is the most likely diagnosis?

A.Allergic reaction to immunosuppressive medications

B.Coronary artery occlusion

C.Hyperacute rejection

D.Pulmonary hypertension

E.Opportunistic infection

5.What is the single most important maneuver the echocardiographer can do to rule out rejection in a heart transplant recipient?

A.TAPSE

B.Pulmonary vein Doppler

C.Longitudinal LV strain

D.Tissue Doppler of the tricuspid lateral annulus

E.Compare the current study with the patient’s most recent baseline study

6.In the Lunze et al study, which change in parameters best predicted the likelihood of rejection in pediatric heart transplant recipients?

A.Greater than 15% decrease in the left ventricular s’ velocity and a >5% decrease in the left ventricular a’ velocity.

B.At least a 50% decrease in the systolic component of the pulmonary vein Doppler

C.A 5% decrease in left ventricular ejection fraction

D.A 3% decrease in shortening fraction

E.A 3% decrease in averaged global longitudinal strain.

7.In patients for whom aortic arch reconstruction is required at the time of transplant, what is the rate of recoarctation requiring intervention?

A.<1%

B.5%

C.20%

D.50%

E.95%

8.Which of the following is an advantage of IVUS imaging?

A.IVUS can be used in patients of all ages, even infants

B.IVUS allows for detection of coronary disease that may not be evident on routine angiography

C.IVUS does not require a significant amount of training or expertise

D.IVUS can be used at the bedside in any setting

E.IVUS can provide in-depth imaging of the coronary lumen

9.A transplant is performed in an infant, and the surgeon anastomoses the allograft to retained cuffs of the recipient’s left and right atrium. What is this technique called?

A.Bicaval technique

B.Barnard technique

C.Kantrowitz technique

D.Bi-atrial technique

E.Atrioventricular technique

10.Approximately how many transplants are performed annually in the United States in patients under 18 years of age?

A.1-10

B.50-100

C.350-450

D.700-800

E.>1,000

Answers

1.Answer: D. In infants, the most common indication for heart transplantation is congenital heart disease, with hypoplastic left-heart syndrome being the most common form of congenital heart disease. In adolescents, the cardiomyopathies are more common indications for transplant.

2.Answer: B. The first heart transplant in a child was performed in 1967 by Adrian Kantrowitz in Brooklyn, New York. The first adult heart transplant was performed by Christiaan Barnard in Cape Town.

3.Answer: A. Preliminary data from studies in Europe using dipyridamole stress testing have shown that improvement in wall motion during stress in potential donor hearts is associated with normal function after transplant. While this methodology has not been well studied in pediatric patients, it carries promise for increasing the potential donor pool in the future.

4.Answer: C. Hyperacute rejection may occur rarely, and is typically evident immediately in the operating room. This may present clinically to the surgeon as discoloration of the myocardium and poor hemodynamic function. On TEE, this presents as poor systolic function and increased wall thickness. Hyperacute rejection fortunately is rare, but important to identify, because appropriate and immediate treatment is crucial.

5.Answer: E. Regardless of the technique or screening strategy used, the single most important thing the echocardiographer can do is to compare the current study with the patient’s most recent baseline study, preferably in a side-by-side manner. Numerous studies have demonstrated that any significant changes from the patient’s own baseline are, by far, the most sensitive markers of rejection, more so than any single measurement. This is particularly the case when rejection is not obvious.

6.Answer: A. Lunze et al compared results in patients who had both an echocardiogram and a biopsy performed within 24 hours. Using the patient’s prior biopsy and echocardiogram as their own control, the authors found that several tissue Doppler parameters predicted the likelihood of rejection, including a >15% decrease in the left ventricular s’ velocity and a >5% decrease in the left ventricular a’ velocity. Importantly, when neither of these changes were present, there was a 99% likelihood of a negative biopsy.

7.Answer: C. If an aortic arch reconstruction is required as part of the transplantation, there is up to a 20% risk of recoarctation, most commonly diagnosed in the first two years following transplant. In any patient for whom aortic arch reconstruction has been performed, regular arch imaging should be performed, gradients assessed, and abdominal aortic Doppler flow interrogated.

8.Answer: B. IVUS can provide in-depth assessment of the coronary vessel walls, allowing for diagnosis of significant coronary artery disease that may not be evident on traditional intra-luminal angiography. More recent technology also may allow for detailed assessment of intimal thickening, including detection of fibrous and calcific changes. IVUS is safe to perform in children (not infants), although most operators will only perform IVUS after a certain age. IVUS is highly user-dependent, and requires advanced expertise both in the acquisition and interpretation of the images. It is typically performed in the cardiac catheterization laboratory.

9.Answer: D. Traditionally, heart transplantation was performed using the biatrial technique, where the surgeon anastomoses the allograft to retained cuffs of both left and right atrial tissue. With this technique, both atria will appear large on echocardiograms due to the presence of significant amounts of recipient and donor atrial tissue. Often, the suture lines will be visible in the mid-left and mid-right atrium.

10.Answer: C. Approximately 350-400 heart transplants are performed in children under the age of 18 annually in the United States.