Echocardiography in Cardiac Transplantation

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13 Echocardiography in Cardiac Transplantation

Atif N. Qasim, Amresh Raina

Introduction

• Approximately 2200 heart transplantations are performed yearly in the United States, with a little over half of all transplantations performed for nonischemic causes of heart failure.
• In 2009, the 5-year survival rate post-transplantation was 73% for men and 67% for women.
• Echocardiography remains a principle diagnostic modality in the process of heart transplantation, and is particularly important in the stages shown below, which will form the focus of this chapter:

• Assessing the appropriateness for transplantation in acute and chronic heart failure patients
• Evaluating suitability of the donor heart
• Assessing the transplanted heart postoperatively
• Echocardiographic determinants of cardiac rejection
• Long-term surveillance of heart transplantation survivors
• Guidance of endomyocardial biopsy

Assessing the Appropriateness of Heart Transplantation in Acute and Chronic Heart Failure Patients

• Establishing the suitability of heart failure patients for heart transplantation is a multidisciplinary process incorporating a variety of medical and psychosocial factors.
• In general, patients eligible for heart transplantation are less than 65 years old and have systolic or diastolic heart failure with New York Heart Association (NYHA) functional class IIIb or IV symptoms despite optimal medical therapy.
• Exclusion criteria for cardiac transplantation include cancer within the past 5 years, significant obesity, irreversible pulmonary hypertension, and other organ dysfunction not attributable to cardiac dysfunction.
• Echocardiography is an essential test used to evaluate potential heart transplant recipients and may provide information with regard to the etiology of heart failure and severity of the cardiomyopathy (ejection fraction in systolic heart failure, diastolic parameters in restrictive cardiomyopathies).
• Transthoracic echocardiography can provide clues to other abnormalities that should be addressed prior to consideration for transplantation, such as severe valvular abnormalities or constriction.
• In rare instances, a screening echocardiogram can reveal conditions that might preclude transplantation without further investigation, such as severe pulmonary hypertension, endocarditis, or cardiac neoplasm.

Evaluating Suitability of the Donor Heart

• Initial extracardiac factors, beyond those which exclude organ donation in general, may exclude the cardiac donor.
• These include advanced age (typically >55 years), prolonged ischemic time, or inappropriate donor size.
• Male donors over 70 kg are usually suitable in most cases. Body mass index and height are more accurately used for matching heart size to body weight in small donors.
• Echocardiography is now the imaging modality of choice in the evaluation of a potential cardiac donor, and special attention should be given to the echocardiographic factors noted below.

Step-By-Step Approach

Step 1: Assessment of Left Ventricular Hypertrophy

Key Points

• Anything more than mild left ventricular hypertrophy (LVH) in the donor heart typically precludes transplantation.
• It is important to obtain a true determination of LVH using both wall thickness criteria and, if possible, LV mass criteria. However, with poor acoustic windows, this may not always be feasible.
• Care should be taken to characterize the presence of LVH accurately because of pseudo-hypertrophy with an underfilled LV, or because of disproportionate upper septal thickening (which is a normal variant).

Step 2: Assessment of Valvular and Congenital Abnormalities

Key Points

• Complex congenital heart disease may occasionally exclude eligibility for transplant donation.
• Simple repairs can be made to the donor heart during transplantation for some conditions, making the donor heart still useable; these include valvular repair for mild insufficiency in select cases and repair of secundum atrial septal defects (ASDs).
• Bicuspid aortic valves in the donor heart that function normally do not necessarily preclude transplantation.

Step 3: Careful Assessment of Ejection Fraction, and Dobutamine Challenge if Indicated

Key Points

• Many hearts in the United States are declined for transplantation because of abnormal LV function.
• However, many young donor hearts that have depressed function resulting from secondary effects from brain death can recover normal function after transplantation.
• Those with mild LV dysfunction can be given a low-dose dobutamine infusion to see if LV function improves; appropriate augmentation of function suggests favorable transplantation outcome.

The Transplanted Heart in the Postoperative Period

Step-By-Step Approach

Step 1: Assessment of Atrial Structure and Function

Key Points

• Two major surgical approaches are used in heart transplantation that impact atrial structure and function: (1) the bi-atrial anastomosis (developed by Lower and Shumway), where recipient right and left atrial cuff tissue is left behind and sutured to the donor atria; and (2) the bicaval anastomosis, where a direct anastomosis is made to the venae cavae and a small portion of the recipient left atrium containing the pulmonary veins (Figure 13-1).
• In both cases, the left atrium is a composite of donor and recipient tissue and may look enlarged, especially as seen in the apical 4-chamber view (Figure 13-2).
• The right atrium, however, appears composite and enlarged only with the bi-atrial anastomosis.
• A dense ridge in the left atrium can be seen at the surgical anastomosis site and may be mistaken for a mass or thrombus, especially if a large cuff is present when there is donor and recipient size mismatch. This ridge otherwise allows discrimination between donor and recipient atrial tissue.
• The bi-atrial technique is associated with an increased risk of atrial thrombus, abnormalities in atrial filling, and poor LV hemodynamics. Hence the bicaval approach is now the technique of choice.
• Studies have shown that the bicaval anastomosis is associated with improved atrial geometry, decreased valvular insufficiency, decreased risk of arrhythmias, and decreased hospital stay.
image

Figure 13-1 Bi-atrial anastomosis (top panels) and bicaval anastomosis (bottom panels). The left atrial suture line is not readily visible on this anterior view of the heart.

image

Figure 13-2 Left atrial surgical cuff variants in two examples of bicaval anastomosis. Left panel: There is a barely recognizable suture line along the left atrium. Right panel: The left atrial cuff is quite marked. This should not be confused with a cardiac mass or thrombus.

Step 2: Assessment of Right Ventricular Dysfunction

Key Points

• Right ventricular dilatation and dysfunction are common immediately post-transplantation. The cause is multifactorial.
• In part this is related to chronic pulmonary venous hypertension and mild pulmonary vascular disease that may occur pre-transplantation in patients with chronic heart failure. There may also be associated ischemia and reperfusion injury during the process of transplantation.
• RV dysfunction is estimated to account for up to 50% of all cardiac transplantation complications and 20% of causes of early death after transplantation, as the donor ventricle cannot accommodate the acute increase in workload.
• The majority of cases of RV dilatation and dysfunction are treated medically and begin to improve over the course of 1 week post-transplantation.
• In the case shown in Figure 13-3, the marked RV dysfunction seen immediately postoperatively, with associated tricuspid regurgitation (TR), resolved with recovery to completely normal RV function and minimal TR within 1 month.
• Cases in which there is persistent RV dysfunction post-transplantation are associated with increased mortality.
image

Figure 13-3 RV dysfunction post-transplantation. Top panel: There is significant RV dilatation with TR at 1 day post-transplantation. Bottom panel: After 1 week, note that the size of the RV has decreased to normal and there is only mild TR. Note also the RV velocity-time integral (VTI) has markedly improved (see also Videos 13-8 and 13-9 on the Expert Consult website).

Step 3: Assessment for Presence and Mechanism of TR

Key Points

• Significant TR is the most common valvular abnormality after orthotopic heart transplantation (OHT). Significant regurgitation of the mitral and aortic valves, in contrast, is rare in the donor heart post-transplantation, unless there is acute rejection or prolonged ischemic time.
• Causes of TR early after transplantation include pulmonary hypertension, elevated pulmonary vascular resistance, and atrial dysfunction (more commonly seen with bi-atrial anastomosis). Typically TR improves with time as the pulmonary artery pressures normalize, usually over the first month after transplantation.
• Causes of TR that occur later include injury to the tricuspid valve and chordal apparatus by repeated endomyocardial biopsies, as well as allograft rejection. The TR from biopsy-related injury is usually more eccentric, and flail tricuspid valve leaflets may be seen (Figure 13-4).
• Bicaval anastomoses result in less TR, suggesting preservation of atrial structure and function and of tricuspid valve geometry are important in preventing TR.
• In cases of severe persistent TR, valve repair or replacement need to be considered.
image

Figure 13-4 TR caused by injury from endomyocardial biopsy. Left panel: A parasternal RV inflow view showing significant prolapse of the septal leaflet caused by trauma from repeated biopsy. Note the eccentric TR jet (right panel) (see also Videos 13-3 and 13-4 on the Expert Consult website).

Step 4: Assessment for Presence and Etiology of Pericardial Effusions

Key Points

• Pericardial effusions are common immediately post-transplantation, especially in patients with significant mismatch in size between donor and recipient.
• The differential diagnosis for an effusion postoperatively, however, includes acute allograft rejection and even purulent pericarditis, as these patients are immuno-compromised.
• Most postoperative effusions resolve within 1 month after transplantation without specific intervention.
• An enlarging pericardial effusion more than 1 month post-transplantation should raise concern for rejection or other causes, such as infection. Constriction is a rare complication post-transplantation, but has been reported.
• In cases in which the pericardial effusion is large and impairs RV or LV filling, percutaneous or surgical drainage may be necessary.

Step 5: Assessment of Left Ventricular Function and Mass

Key Points

• LV systolic function should be preserved immediately postoperatively unless there is prolonged ischemic time for the donor heart or there is acute allograft rejection.
• Frequently, transplant recipients are placed on a combination of inotropic drugs such that hyperdynamic function may occur.
• Over time (months to years), it is common to have an increase in LV mass and wall thickness.
• The cause of LVH post-transplant is multifactorial, involving: post-transplantation hypertension, repeat episodes of rejection, effect of the immunosuppression regimen (especially calcineurin inhibitors), effects of chronic tachycardia, or injury and remodeling of the donor heart at the time of transplantation.

Step 6: Assessment for Possible Technical Complications of Surgery

Key Points

• Echocardiography in the transplant recipient is very useful to examine the sites of anastomosis, using color and spectral Doppler interrogation, in areas that may otherwise be overlooked in a routine echocardiogram of the native heart.
• In bicaval anastomosis, increased gradients across the inferior vena cava (IVC) and superior vena cava (SVC) should be assessed as these have adverse long-term hemodynamic consequences, including hepatic dysfunction.
• It is less common to encounter problems with the anastomosis of the great arteries, however, pulsed wave (PW) and continuous wave (CW) Doppler should be used to interrogate the pulmonary artery and aorta, especially in cases of donor-recipient size mismatch.
• Additional attention should be paid to detect ASDs at the site of atrial anastomosis.

Echocardiographic Determinants of Cardiac Rejection

• Acute allograft rejection is common in the first year after OHT.
• At present, endomyocardial biopsy remains the gold standard in the diagnosis of acute rejection.
• However, profiling of inflammatory gene expression in combination with echocardiography may prove to be equivalent to routine scheduled biopsies in the diagnosis of rejection.
• Multiple echocardiographic techniques, including M-mode, two-dimensional (2D) echocardiography, conventional Doppler, and other indices of systolic and diastolic function, have correlated with episodes of biopsy-proven rejection.
• Unfortunately, no single echocardiographic technique to date has proved to have sufficient sensitivity and negative predictive value to be used as a sole predictor of acute rejection.

Step-By-Step Approach

Step 1: M-mode and 2D Echocardiography of the Left Ventricle

Key Points

• Acute allograft rejection is characterized by a cellular infiltrate in the myocardium, resulting in myocyte inflammation, edema, and ultimately contractile dysfunction.
• M-mode of the left ventricle can detect the resulting increase in LV wall thickness, rise in LV mass, and decrease in LV fractional shortening and ejection fraction (Figure 13-5).
• 2D echocardiography complements M-mode findings but can also reveal an increase in myocardial echogenicity and the presence of an associated pericardial effusion (Figure 13-6).
• Unfortunately, neither M-mode nor 2D echo findings are specific for acute rejection; increases in wall thickness and LV mass can also occur as sequelae of hypertension, immuno-suppression, and chronic tachycardia post-transplantation.
• In the current era of potent immuno-suppression, acute rejection may present in a subtle fashion without frank symptoms or as a decline in LV systolic function until late in the course.
• Because decreases in M-mode and 2D measures of systolic function, such as fractional shortening and ejection fraction, may not occur until later in the presentation of acute rejection, these techniques are not sufficiently sensitive alone to exclude an episode of rejection.
image

Figure 13-5 M-mode of the left ventricle at baseline (top panel) and during an episode of acute rejection (bottom panel). Note the marked decrease in systolic thickening of the septum and posterior wall, with a decrease in fractional shortening during the episode of rejection. Also note the presence of a posterior pericardial effusion.

image

Figure 13-6 2D echocardiogram of the left ventricle from the parasternal long-axis view of the same patient at baseline (top panel) and during an episode of acute rejection (bottom panel). Notice the increased thickness and echogenicity of the myocardium in rejection and the presence of a significant pericardial effusion. (See also Videos on the Expert Consult website.)

Step 2: Evaluation of Diastolic Function Using Standard Doppler Echocardiography

Key Points

• Diastolic function is typically impaired at an earlier stage than systolic function during episodes of acute rejection.
• Measurement of standard Doppler indices of diastolic function and correlation of changes in diastolic function with episodes of rejection is therefore an appealing strategy for the detection of acute rejection.
• From the apical views, PW Doppler of the LV inflow allows measurement of E- and A-wave velocities, isovolumic relaxation time (IVRT), and E-wave deceleration times.
• Of these measures, rise in E-wave velocity, shortened IVRT and E-wave deceleration time have correlated best with episodes of rejection (Figure 13-7).
• However, these parameters have proved to have relatively low specificity for rejection episodes due to their dependence on loading conditions and heart rate.
• The myocardial performance index is theoretically a load- and heart rate–independent composite measure of systolic and diastolic function derived from standard Doppler of LV inflow and outflow: (IVCT + IVRT)/ET, where IVCT is the isovolumic contraction time and ET is the ejection time.
• Unfortunately, small echocardiographic studies evaluating episodes of acute rejection have yielded conflicting results with regard to the effect of rejection on the myocardial performance index.
image

Figure 13-7 PW Doppler of mitral inflow at baseline (top panel) and during an episode of acute rejection (bottom panel). Note the increase in the E/A ratio and decrease in the E-wave deceleration time during the rejection episode.

Step 3: Use of Tissue Doppler, Strain Imaging, and Advanced Techniques as Needed

Key Points

• Tissue Doppler imaging (TDI) conveys a major advantage over conventional Doppler of being much less dependent on heart rate and LV loading conditions.
• Studies of TDI of the mitral annulus have shown that a reduction in early diastolic velocities (E′) and lower systolic velocities (S) correlate well with acute episodes of rejection seen on endomyocardial biopsy (Figure 13-8).
• Myocardial strain and strain-rate imaging measure the actual deformation of the myocardium and have the promise of being significantly more sensitive than other indices for detecting early or subclinical rejection.
• Small, single-center studies have shown that reduced longitudinal peak systolic strain and reduced strain rate are predictive of episodes of acute rejection confirmed on endomyocardial biopsy.
• Contrast echocardiography of the left ventricle using leukocyte-targeted microbubbles is another promising technique in which a rise in myocardial signal intensity has correlated with episodes of acute rejection in animal studies, reflecting myocardial infiltration with leukocytes.
• Both myocardial strain/strain-rate imaging and contrast echocardiography need further validation in large, human studies.
image

Figure 13-8 TDI of the lateral mitral annulus at baseline (top panel) and during an episode of acute rejection (bottom panel). During rejection, there is a marked decrease in early diastolic velocities (E′) and systolic velocities.

Long-Term Surveillance of Heart Transplantation Survivors

• Patients post-transplantation are at risk for a wide spectrum of complications, including systemic hypertension, diabetes, side effects of repeated biopsies, episodes of acute rejection, and chronic allograft vasculopathy (CAV).
• Invasive angiography is the current gold standard for the detection of CAV.
• The sensitivity of conventional angiography is improved with the addition of intravascular ultrasound due to the diffuse nature of graft vasculopathy.
• Routine resting echocardiography and dobutamine stress echocardiography (DSE) both play an important role in monitoring for complications related to therapy for OHT and for the detection of CAV.

Step-By-Step Approach

Step 1: Use of Serial Resting 2D and Doppler Echocardiography

Key Points

• A new resting wall motion abnormality (WMA) on 2D echocardiography has a poor sensitivity but a relatively high specificity for detecting the presence of CAV.
• Although resting echocardiography cannot replace an invasive angiographic evaluation for the presence of CAV, a new WMA seen on resting 2D echocardiography should prompt further assessment with coronary angiography.
• Serial 2D transthoracic echocardiography is nevertheless useful in the post-transplantation patient for detecting the sequelae of episodes of asymptomatic rejection, potential side effects of procedures such as biopsy, and development of LVH and diastolic dysfunction.

Step 2: Use of DSE for Evaluation of CAV

Key Points

• DSE is currently the preferred noninvasive modality for the evaluation of CAV.
• Alternative commonly employed stress and imaging modalities are poorly studied and are generally less useful in the heart transplantation population.
• Exercise echocardiograms are often non-diagnostic because of blunted heart rate response in the denervated heart post-transplantation and the limited exercise capacity in many post-transplantation patients.
• Myocardial perfusion imaging with vasodilator stress is typically less sensitive in detecting the presence of coronary stenoses in post-transplantation patients, because of the diffuse nature of CAV and reliance on detecting differential flow reserve with vasodilator stress agents such as dipyridamole.
• DSE is generally performed on an annual basis in the first several years after transplantation, in the absence of symptoms of rejection.
• Dobutamine, a synthetic catecholamine, is infused in a stepwise fashion up to a peak dose of 40 µg/kg/min with or without use of atropine, until target heart rate is achieved.
• Dobutamine-induced WMA correlate well with angiographic coronary artery stenoses and predict future cardiovascular events in heart transplant recipients.
• Potential complications of DSE include atrial and ventricular arrhythmia, severe hypotension or hypertension, chest pain, and myocardial ischemia.

Guidance of Endomyocardial Biopsy

• Routine endomyocardial biopsies are common in the first several years post-transplantation, even in asymptomatic patients, due to the inability of a noninvasive means to reliably diagnose rejection.
• The most common complications of endomyocardial biopsy include cardiac tamponade and damage to the tricuspid valve or chordal apparatus/papillary muscles, resulting in significant TR. Echocardiography can be used to quickly diagnose both of these conditions.
• Several centers use transthoracic echocardiography to help guide the bioptome, in addition to fluoroscopy, to lower the risk of these complications as well as radiation dose. Standard 2D transthoracic echocardiography from the apical 4-chamber view can ensure appropriate position of the bioptome toward the ventricular septum, and across the tricuspid valve.
• Emerging real-time three-dimensional (3D) techniques allow better visualization (see example shown in Figure 13-9) of the bioptome, and in some series have demonstrated that the bioptome was not in an ideal septal position for biopsy when guided conventionally by fluoroscopy alone.
• Larger prospective studies are needed to determine whether echocardiographic guidance of endomyocardial biopsy reduces long-term procedural complications.
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Figure 13-9 Real-time 3D transthoracic echocardiography of the bioptome during endomyocardial biopsy. Left panel: The 3D echocardiogram is used to assist in proper placement of the bioptome. Middle panel: The bioptome is shown in the correct position along the septum. Right panel: The view used while the biopsy is taken. In this case the biopsy was done on a native heart (see also Videos 13-5 to 13-7 on the Expert Consult website).

(Courtesy of Frank Silvestry and Daniel Kolansky, the Hospital of the University of Pennsylvania.)

Suggested Readings

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

Fifteen patients underwent 32 right ventricular biopsies, half with real-time 3D echocardiography alone and half with biplane fluoroscopy. All 3D echocardiography–guided biopsy specimens were comparable to fluoroscopic samples with respect to interpretability for rejection.

2 Akosah KO, McDaniel S, Hanrahan JS, Mohanty PK. Dobutamine stress echocardiography early after heart transplantation predicts development of allograft coronary artery disease and outcome. J Am Coll Cardiol. 1998;31:1607-1614.

In this small study of 22 new heart transplant subjects, dobutamine stress echocardiography testing was predictive of worse outcome only for those who developed persistent wall motion abnormalities during testing.

3 Akosah KO, Mohanty PK, Funai JT, et al. Noninvasive detection of transplant coronary artery disease by dobutamine stress echocardiography. J Heart Lung Transplant. 1994;13:1024-1038.

Dobutamine stress echocardiography in this study of heart transplant recipients (on average 5 years out from transplant) had the following characteristics for detection of transplant coronary artery disease: sensitivity, 95%, specificity, 55%, positive predictive value, 69% and negative predictive value, 92%.

4 Aranda JMJr, Weston MW, Puleo JA, Fontanet HL. Effect of loading conditions on myocardial relaxation velocities determined by Doppler tissue imaging in heart transplant recipients. J Heart Lung Transplant. 1998;17:693-697.

Twenty transplant subjects were given nitroglycerin for preload and afterload reduction with tissue Doppler imaging performed pre and post. There was no significant change in myocardial relaxation velocities despite significant reductions in PCWP and mean arterial blood pressure suggesting loading conditions on the heart have little influence on relaxation velocities in transplant recipient, perhaps making it useful for the diagnosis of rejection.

5 Aziz TM, Burgess MI, Rahman AN, Campbell CS, Deiraniya AK, Yonan NA. Risk factors for tricuspid valve regurgitation after orthotopic heart transplantation. Ann Thorac Surg. 1999;68:1247-1251.

Tricuspid regurgitation was assessed in 249 heart transplant subjects with color Doppler. Those with greater early TR tended to be those who did not have a bicaval technique, episodes of ≥ grade 2 rejection, an increased transpulmonary gradient preoperatively and elevated PVR. The number of biopsies was also correlated with increased TR farther out from transplant.

6 Bacal F, Moreira L, Souza G, et al. Dobutamine stress echocardiography predicts cardiac events or death in asymptomatic patients long-term after heart transplantation: 4-year prospective evaluation. J Heart Lung Transplant. 2004;23:1238-1244.

Thirty-nine subjects an average of 86 months after transplant underwent thallium scintigraphy, treadmill stress testing, dobutamine stress echocardiography (DSE), and coronary angiography to detect allograft vasculopathy. Both positive DSE results and positive angiography were associated with cardiac events across 4 years of follow-up and in the absence of coronary angiography. DSE was a unique independent predictor of cardiac events.

7 Bedanova H, Necas J, Petrikovits E, et al. Echo-guided endomyocardial biopsy in heart transplant recipients. Transpl Int. 2004;17:622-625.

In a single series of 1262 endomyocardial biopsies in transplant subjects obtained using echocardiography guidance, the success rate of obtaining 4-5 specimens was 96% with few complications overall and the need for conversion to X-ray guidance occurred in only 11 subjects.

8 Bhatia SJ, Kirshenbaum JM, Shemin RJ, et al. Time course of resolution of pulmonary hypertension and right ventricular remodeling after orthotopic cardiac transplantation. Circulation. 1987;76:819-826.

In 24 transplant recipients studied with serial echocardiography and right heart catheterizations, the right and left heart filling pressures declined together and reached a range near the upper limit of normal by 2 weeks. An increase in right ventricle size was seen on day 1 after surgery, and this size increase was maintained at 1 year follow-up although the incidence of tricuspid regurgitation decreased.

9 Bolad IA, Robinson DR, Webb C, Hamour I, Burke MM, Banner NR. Impaired left ventricular systolic function early after heart transplantation is associated with cardiac allograft vasculopathy. Am J Transplant. 2006;6:161-168.

Quantitative coronary angiography (QCA) was performed on 121 heart transplant subjects at baseline and at 1 year and found that echocardiographic fractional shortening was inversely related to mean coronary artery lumen diameter loss, suggesting ventricular systolic dysfunction early after heart transplantation may be associated with subsequent development of allograft vasculopathy.

10 Ciliberto GR, Mascarello M, Gronda E, et al. Acute rejection after heart transplantation: Noninvasive echocardiographic evaluation. J Am Coll Cardiol. 1994;23:1156-1161.

Various echocardiographic measurements were taken over 1400 serial echocardiograms among 130 transplant recipients within 24 hours of endomyocardial biopsy. Overall echocardiography had a poor sensitivity for mild rejection but was better (80%) for signs of moderate rejection.

11 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(suppl I):I184-I191.

Echocardiography with tissue Doppler imaging was performed just prior to 408 endomyocardial biopsies in heart transplant recipients to assess diagnostic value for rejection. In those without any significant diastolic parameter changes, acute rejection was unlikely with negative and positive predictive values of 96% and 92%.

12 Desruennes M, Corcos T, Cabrol A, et al. Doppler echocardiography for the diagnosis of acute cardiac allograft rejection. J Am Coll Cardiol. 1988;12:63-70.

Same day Doppler echocardiography was performed on 55 heart transplant subjects undergoing endomyocardial biopsy. Those with mild or moderate rejection had decreased isovolumic relaxation time and pressure half-time without change in heart rate or peak early mitral flow velocity. These changes recovered after immunosuppressive therapy. Those without rejection had Doppler indexes that remained unchanged.

13 El Gamel A, Yonan NA, Grant S, et al. Orthotopic cardiac transplantation: A comparison of standard and bicaval Wythenshawe techniques. J Thorac Cardiovasc Surg. 1995;109:721-729. discussion 729-730

Seventy-five patients were randomized to either the bicaval or conventional bi-atrial technique during orthotopic heart transplantation. Overall the bicaval technique implantation was associated with lower right atrial pressures, a lower incidence of atrial tachyarrhythmias, less need for pacing, less mitral regurgitation, lower doses of diuretics and a shorter length of hospital stay.

14 French JW, Popp RL, Pitlick PT. Cardiac localization of transvascular bioptome using 2-dimensional echocardiography. Am J Cardiol. 1983;51:219-223.

This article contains one of the initial case series in which 2D echocardiography was added to fluoroscopy for guidance of bioptome. Eight children underwent 12 biopsies, all without complications, with the advantage of reducing radiation exposure.

15 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;25:510-517.

Among 53 heart transplantation recipients in children, tricuspid, but not mitral, S and E tissue Doppler imaging velocities deteriorated to low levels 3 to 6 months before the terminal graft failure. Right ventricular deterioration occurred during the final 3 months before death and severely reduced left ventricular velocities.

16 Grande AM, Minzioni G, Martinelli L, et al. Echo-controlled endomyocardial biopsy in orthotopic heart transplantation with bicaval anastomosis. G Ital Cardiol. 1997;27:877-880.

Among 38 transplant recipients with bicaval anastomosis, 339 endomyocardial biopsies were performed, 309 under echocardiographic guidance and 30 under fluoroscopy. Echocardiographic guidance allowed for better choice of biopsy site, reduced the risk of damaging cardiac structures, and allowed immediate monitoring of heart performance. Complications overall were rare.

17 Kato TS, Oda N, Hashimura K, et al. Strain rate imaging would predict sub-clinical acute rejection in heart transplant recipients. Eur J Cardiothorac Surg. 2010;37:1104-1110.

Statistically significant differences in systolic and diastolic strain rate were found among a group of 35 transplant recipients across 396 endomyocardial biopsies for those with (45) and without (351) acute rejection (considered to be grade 1b or higher in this study).

18 Kociolek LK, Bierig SM, Herrmann SC, Labovitz AJ. Efficacy of atropine as a chronotropic agent in heart transplant patients undergoing dobutamine stress echocardiography. Echocardiography. 2006;23:383-387.

In this retrospective review of 68 OHT subjects, 21 required atropine in an attempt to reach target heart rate during a standard DSE protocol. Only half of those receiving atropine actually reached target HR. No clear risk factors predicted responsiveness to atropine. Those however with a high resting heart rate appeared to have a better response to dobutamine.

19 Kono T, Nishina T, Morita H, Hirota Y, Kawamura K, Fujiwara A. Usefulness of low-dose dobutamine stress echocardiography for evaluating reversibility of brain death-induced myocardial dysfunction. Am J Cardiol. 1999;84:578-582.

Serial changes in LV fractional shortening (FS) was measured in 30 brain-dead patients. Twenty-three patients had ≥ 30% fractional shortening and seven had < 30% fractional shortening. Dobutamine stress echocardiography was performed in this latter group. Of the seven, four showed no response to dobutamine as FS remained decreased whereas in the three dobutamine-responsive wall motion FS became normal at 7 days after brain death. This suggests that some brain death-induced myocardial dysfunction is reversible and can be detected by low dose dobutamine infusion.

20 Leonard GTJr, Fricker FJ, Pruett D, Harker K, Williams B, Schowengerdt KOJr. Increased myocardial performance index correlates with biopsy-proven rejection in pediatric heart transplant recipients. J Heart Lung Transplant. 2006;25:61-66.

Left ventricular myocardial performance index (LVMPI), the sum of the isovolumic contraction time and isovolumic relaxation time divided by aortic ejection time, was measured in 21 heart transplant subjects across 36 echocardiography studies at the time of endomyocardial biopsy. Significant differences were noted between those without rejection (n = 23), those with moderate to severe rejection (n = 5) and those with focal moderate rejection (n = 8). The LVMPI was 0.42 ± 0.03 (mean ± SEM) for the group without rejection, 0.57 ± 0.06 for those with Grade 2 rejection and 0.73 ± 0.05 for those with Grade 3 rejection.

21 Lewis JF, Selman SB, Murphy JD, Mills RMJr, Geiser EA, Conti CR. Dobutamine echocardiography for prediction of ischemic events in heart transplant recipients. J Heart Lung Transplant. 1997;16:390-393.

Dobutamine stress echocardiography (DSE) was performed in 63 consecutive heart transplant recipients as part of routine yearly evaluation. Twenty-one patients had abnormal wall motion at baseline or during dobutamine infusion. Over a mean follow-up of 8 months five major adverse cardiac events occurred in those with abnormal results; whereas one event occurred in those with a normal DSE, suggesting that normal wall motion during DSE are at lower risk for development of cardiac events.

22 Mahle WT, Cardis BM, Ketchum D, Vincent RN, Kanter KR, Fyfe DA. 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.

Tissue Doppler imaging studies were serially performed during 6 months post-heart transplantation in 13 children and demonstrated a steady increase in both systolic tissue velocities at the tricuspid annulus, systolic tissue velocities at the mitral annulus as well as early diastolic (E) velocities at the tricuspid annulus and mitral annulus. The systolic and diastolic velocities were reduced in children after heart transplantation when compared with controls.

23 Mankad S, Murali S, Kormos RL, Mandarino WA, Gorcsan J3rd. Evaluation of the potential role of color-coded tissue Doppler echocardiography in the detection of allograft rejection in heart transplant recipients. Am Heart J. 1999;138:721-730.

Seventy-eight consecutive transplant recipients underwent 89 echocardiography exams with tissue Doppler imaging within 1 hour of endomyocardial biopsy. Significant rejection was seen in 14 by biopsy. A tissue Doppler peak-to-peak mitral annular velocity >135 mm/s had 93% sensitivity, 71% specificity, and 98% negative predictive value for detecting rejection.

24 Mannaerts HF, Balk AH, Simoons ML, et al. Changes in left ventricular function and wall thickness in heart transplant recipients and their relation to acute rejection: An assessment by digitised M mode echocardiography. Br Heart J. 1992;68:356-364.

M-mode echocardiography was used for measuring left ventricular wall thickness, internal dimension, and fractional shortening across 4-6 consecutive expiratory beats in 32 transplant recipients and 10 healthy volunteers. Two hundred and sixty-three consecutive M-mode studies were examined in relation to concurrent biopsy results. While M-mode echocardiography did not predict acute rejection, most patients with rejection had a slow left ventricular relaxation pattern.

25 Mannaerts HF, Simoons ML, Balk AH, et al. Pulsed-wave transmitral Doppler does not diagnose moderate acute rejection after heart transplantation. J Heart Lung Transplant. 1993;12:411-421.

The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined across 347 recordings in 32 transplant recipients. There was significant overlap of common pulsed-wave Doppler measurements among those with or without rejection.

26 Marciniak A, Eroglu E, Marciniak M, et al. The potential clinical role of ultrasonic strain and strain rate imaging in diagnosing acute rejection after heart transplantation. Eur J Echocardiogr. 2007;8:213-221.

Among 31 consecutive heart transplant recipients who underwent 106 routine follow-up endomyocardial biopsies, strain and strain rate imaging appeared to be a good technique for detecting > or =IB grade of acute rejection.

27 McCreery CJ, McCulloch M, Ahmad M, deFilippi CR. Real-time 3-dimensional echocardiography imaging for right ventricular endomyocardial biopsy: A comparison with fluoroscopy. J Am Soc Echocardiogr. 2001;14:927-933.

Among 63 routine right ventricular biopsy procedures (total of 315 biopsy attempts) in 33 cardiac allograft recipients, the use of real-time 3-dimensional (RT3D) echocardiography helped guide the bioptome against the intraventricular septum along with biplane fluoroscopy. Bioptome visualization in multiple planes helped with localization of the biopsy site.

28 Mena C, Wencker D, Krumholz HM, McNamara RL. Detection of heart transplant rejection in adults by echocardiographic diastolic indices: A systematic review of the literature. J Am Soc Echocardiogr. 2006;19:1295-1300.

This systematic review looked at the quality of published data that included diastolic indices to predict heart transplant rejection. Nineteen studies fit the inclusion criteria, although they had widely varying quality. Diastolic indices included E-wave pressure half-time, IVRT, and E′ and A′ velocities. Sensitivity of these parameters was inconsistent, as was the quality of studies, making it difficult to recommend these parameters as a routine screening test for allograft rejection without additional, more rigorous study.

29 Mondillo S, Maccherini M, Galderisi M. Usefulness and limitations of transthoracic echocardiography in heart transplantation recipients. Cardiovasc Ultrasound. 2008;6:2.

This general review discusses the major uses of Doppler echocardiography in heart transplant recipients and discusses the normal findings in the transplant recipient as well as the limitations in diagnosing acute allograft rejection. It also nicely reviews the use of stress echocardiography for the detection of cardiac graft vasculopathy.

30 Morgan JA, Edwards NM. Orthotopic cardiac transplantation: Comparison of outcome using biatrial, bicaval, and total techniques. J Card Surg. 2005;20:102-106.

This review provides a discussion of three different surgical techniques for heart transplantation described in 39 comparative studies published since 1994. The authors conclude that the bicaval technique has several anatomic and functional advantages in addition to decreasing valvular regurgitation, arrhythmias, and length of hospital stay. However, the studies included were quite heterogeneous and this paper was not a formal meta-analysis.

31 Palka P, Lange A, Galbraith A, et al. The role of left and right ventricular early diastolic Doppler tissue echocardiographic indices in the evaluation of acute rejection in orthotopic heart transplant. J Am Soc Echocardiogr. 2005;18:107-115.

This study of 44 consecutive transplant patients with and without rejection suggests that for those with acute rejection, abnormal tissue Doppler indices suggests that late isovolumic relaxation myocardial velocity gradient and early diastolic timing intervals are markers that may be useful for surveillance of acute rejection.

32 Peteiro J, Redondo F, Calvino R, Cuenca J, Pradas G, Castro Beiras A. Differences in heart transplant physiology according to surgical technique. J Thorac Cardiovasc Surg. 1996;112:584-589.

Twenty subjects with biatrial anastomosis were compared to 11 with bicaval anastomosis and with the use of quantitative echocardiography, those with bicaval anastomosis had lower right sided filling pressures, improved right atrial contraction and lower left atrial dimension in the bicaval approach. There were no differences in left ventricular end-diastolic pressure or cardiac index.

33 Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362:1890-1900.

Six hundred and two transplant patients were randomly assigned to either gene-expression profiling (which looks at expression levels of 11 informative genes and generates a score) or the use of routine endomyocardial biopsy for the monitoring of rejection in addition to usual care. The composite primary outcome of first occurrence of rejection with hemodynamic compromise, graft dysfunction from other causes, death, or re-transplantation was similar between groups, as was the 2-year death rate. Those in the gene-expression profiling arm had fewer biopsies per patient-year.

34 Prakash A, Printz BF, Lamour JM, Addonizio LJ, Glickstein JS. Myocardial performance index in pediatric patients after cardiac transplantation. J Am Soc Echocardiogr. 2004;17:439-442.

Myocardial performance index (MPI) was found to be higher in 41 children post cardiac transplantation who had no evidence of microscopic rejection compared to 31 pediatric control subjects. Isovolumic relaxation time was higher in the transplant group but isovolumic contraction time was similar between groups, suggesting the difference may be due to abnormal diastolic function.

35 Rodney RA, Johnson LL. Myocardial perfusion scintigraphy to assess heart transplant vasculopathy. J Heart Lung Transplant. 1992;11:S74-S78.

36 Roshanali F, Mandegar MH, Bagheri J, et al. Echo rejection score: New echocardiographic approach to diagnosis of heart transplant rejection. Eur J Cardiothorac Surg. 2010;38:176-180.

This paper derives an echo rejection score from 50 endomyocardial biopsy specimens in transplant recipients who also had preprocedure transthoracic echocardiography. Important predictors of rejection appear to be peak systolic strain at the lateral left ventricular base and interventricular septal base as well as posterior wall thickness, and left ventricular mass index. However the score needs validation in other cohorts.

37 Santos-Ocampo SD, Sekarski TJ, Saffitz JE, et al. Echocardiographic characteristics of biopsy-proven cellular rejection in infant heart transplant recipients. J Heart Lung Transplant. 1996;15:25-34.

In a pediatric population of 32 consecutive heart transplantations performed in infants <20 months old and followed over 2.5 years with concurrent endomyocardial biopsy and M-mode echocardiography, left ventricular mass index appeared to increase in cellular rejection but were only significant when more than 1 month from transplantation. Measurements were compounded by significant inter-observer and intra-observer variability.

38 Scheurer M, Bandisode V, Ruff P, Atz A, Shirali G. Early experience with real-time three-dimensional echocardiographic guidance of right ventricular biopsy in children. Echocardiography. 2006;23:45-49.

Real-time transthoracic 3D echocardiography was used in endomyocardial right ventricular biopsies in 28 consecutive biopsy procedures in a pediatric population and was found to be safe without any complication, with decreased need for fluoroscopic guidance of the bioptome into the right ventricle.

39 Spes CH, Mudra H, Schnaack SD, et al. Dobutamine stress echocardiography for noninvasive diagnosis of cardiac allograft vasculopathy: A comparison with angiography and intravascular ultrasound. Am J Cardiol. 1996;78:168-174.

Fifty-six transplant recipients with normal coronary angiograms an average of 41 months out from transplantation underwent both DSE and intravascular ultrasound. Seventy percent of patients had abnormal findings by either one or both tests (six were abnormal by DSE alone), suggesting only a minority of patients several years out are free of pathologic coronary artery changes when assessed by these techniques.

40 Stork S, Behr TM, Birk M, et al. Assessment of cardiac allograft vasculopathy late after heart transplantation: When is coronary angiography necessary? J Heart Lung Transplant. 2006;25:1103-1108.

Fifty-four consecutive transplant recipients were studied with 1) intravascular ultrasound (IVUS), 2) angiography, 3) dobutamine stress echocardiography and 4) immunofluorescence staining against anti-thrombin III (AT-III) in endomyocardial biopsies. The authors found that when compared with IVUS, cardiac transplant vasculopathy was reliably identified using a combination of information on donor age, wall motion score at rest and AT-III staining late after transplant.

41 Sun JP, Abdalla IA, Asher CR, et al. Non-invasive evaluation of orthotopic heart transplant rejection by echocardiography. J Heart Lung Transplant. 2005;24:160-165.

This study of 406 transplant patients undergoing biopsy and echocardiography on the same day attempted to generate a predication model for rejection. Although Doppler E/A ratio, IVRT, recipient age, and the presence of a pericardial effusion were predictors of acute allograft rejection, no single predictor was strong enough to be able to eliminate the need for surveillance biopsies.

42 Sundereswaran L, Nagueh SF, Vardan S, et al. Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol. 1998;82:352-357.

Fifty transplant patients had right-sided cardiac catheterization and Doppler echocardiography simultaneously and found that mean wedge pressure and mean right atrial pressure can be estimated in heart transplants with reasonable accuracy using the ratio of E/Ea.

43 Thorn EM, de Filippi CR. Echocardiography in the cardiac transplant recipient. Heart Fail Clin. 2007;3:51-67.

This article reviews the spectrum of echocardiographic findings in the adult heart transplant patient. Appreciation of typical alterations from “normal” allows the transplant physician to identify clinically significant changes and to avoid unnecessary invasive procedures based on misinterpretation of these differences. Though abnormalities of systolic and diastolic function correlate with episodes of acute rejection, the primary diagnostic usefulness of echocardiography in acute rejection is guiding the endomyocardial biopsy. Additionally, echocardiography has found a role as a supplement to invasive angiography in the diagnosis of cardiac allograft vasculopathy.

44 Tona F, Caforio AL, Montisci R, et al. Coronary flow reserve by contrast-enhanced echocardiography: A new noninvasive diagnostic tool for cardiac allograft vasculopathy. Am J Transplant. 2006;6:998-1003.

The authors assessed coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography in the left anterior descending coronary artery of 73 transplants who were 8±4.5 years post transplant. CFR was found to be lower in patients with graft vasculopathy but the sensitivity varied widely based on where the CFR cutpoint was taken.

45 Tona F, Caforio AL, Montisci R, et al. Coronary flow velocity pattern and coronary flow reserve by contrast-enhanced transthoracic echocardiography predict long-term outcome in heart transplantation. Circulation. 2006;114(suppl I):I49-I55.

This study of 66 consecutive transplant patients primarily compared coronary flow reserve measured by contrast-enhanced echocardiography against a qualitative angiographic grading system found CFR to be an independent predictor of major adverse cardiac events.

46 Valantine HA, Fowler MB, Hunt SA, et al. Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection. Circulation. 1987;76(suppl V):V86-V92.

Serial Doppler echocardiography measurements were made in 23 normal volunteers and in 22 transplant subjects within 24 hours of endomyocardial biopsy. Heart rate and mean arterial pressure were significantly higher in transplant recipients than in normal subjects. Left ventricular filling dynamics were markedly different: IVRT and PHT were significantly longer and mitral flow velocity was similar.

47 Valantine HA, Yeoh TK, Gibbons R, et al. Sensitivity and specificity of diastolic indexes for rejection surveillance: Temporal correlation with endomyocardial biopsy. J Heart Lung Transplant. 1991;10:757-765.

This study looked at Doppler echocardiographic indexes of diastolic function among sequential endomyocardial biopsies (114 Doppler echocardiographic studies and biopsies done in 39 transplant recipients) to assess for possible factors accounting for false-positive and false-negative results seen in prior studies.

48 Vandenberg BF, Mohanty PK, Craddock KJ, et al. Clinical significance of pericardial effusion after heart transplantation. J Heart Transplant. 1988;7:128-134.

Fifty-two consecutive patients undergoing heart transplantation were evaluated with echocardiography at frequent intervals for 12 weeks after transplantation and at three monthly intervals for one year. In a selective group of 38 of 52 patients with adequate 2D echocardiograms performed serially post transplant over the first year, a common finding was pericardial effusion (40%) which was moderate in two (5%) and small in seven patients (18%). A large pericardial effusion was seen in six of 38 patients (16%) and three (8%) developed cardiac tamponade physiology leading to prompt pericardiocentesis. The presence of pericardial effusion was not independently correlated with cyclosporine therapy, acute rejection, level of blood urea nitrogen (BUN), infection or preoperative diagnosis of idiopathic dilated cardiomyopathy.

49 Venkateswaran RV, Townend JN, Wilson IC, Mascaro JG, Bonser RS, Steeds RP. Echocardiography in the potential heart donor. Transplantation. 2010;89:894-901.

This study looked at echocardiographic parameters in 66 donor hearts in which both echocardiography and right heart catheterization were performed. Fifty-eight percent had abnormal LV systolic function on initial evaluation, but in over half of the cases, LV function and invasive hemodynamics improved upon repeat assessment after careful management. Therefore, low or borderline ejection fraction on initial evaluation does not always preclude suitability as a donor.

50 Weller GE, Lu E, Csikari MM, et al. Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1. Circulation. 2003;108:218-224.

This animal study took contrast microbubbles targeted to the endothelial cell (EC) inflammatory marker intercellular adhesion molecule-1 (ICAM-1) and found preferential adherence to rejecting versus nonrejecting rat cardiac transplant myocardium as seen by ultrasound.

51 Wong RC, Abrahams Z, Hanna M, et al. Tricuspid regurgitation after cardiac transplantation: An old problem revisited. J Heart Lung Transplant. 2008;27:247-252.

This article provides a useful review of TR in the transplanted heart and discusses functional and anatomic causes of this condition post-transplantation. Management strategies, including the possibility of valve repair or replacement, are discussed, as well as the concept of prophylactic donor heart tricuspid valve annuloplasty.

52 Yankah AC, Musci M, Weng Y, et al. Tricuspid valve dysfunction and surgery after orthotopic cardiac transplantation. Eur J Cardiothorac Surg. 2000;17:343-348.

In a study of 647 of 889 patients who survived heart transplantation for more than 30 days, mild, moderate and severe tricuspid regurgitation was seen in 14.5%, 3.1% and 2.5%, respectively. Severe tricuspid regurgitation in transplanted hearts was associated mainly with biopsy-induced injury or endocarditis. Valvular surgery in these cases had acceptable mortality, low morbidity and excellent intermediate-term clinical results without significant detrimental effect on the right ventricular performance.

53 Zaroff JG, Rosengard BR, Armstrong WF, et al. Consensus conference report. Maximizing use of organs recovered from the cadaver donor: Cardiac recommendations. Circulation. 2002;106:836-841.

This statement provides recommendations for improving evaluation and utilization cardiac donors and describes the utility of echocardiography in the assessment of donor heart function before recovery.

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