- Email: [email protected]
Echocardiographic Identification of Acute Cellular Rejection in Heart Transplant Recipients
Editorial Comment
Echocardiographic Identification of Acute Cellular Rejection in Heart Transplant Recipients Jerry D. Estep, MD, FACC, FASE, Houston, Texas Heart transplantation remains the most effective long-term intervention for patients with end-stage heart failure. Despite advances in immunosuppressive therapy, acute cellular rejection (ACR) remains common, with a prevalence up to 35% to 40%, and approximately 22% of patients require admission to the hospital for treatment within the first year after transplantation.1 ACR is also among the leading causes of death after heart transplantation.1 The gold-standard surveillance test to detect ACR is based on the histologic analysis of right ventricular (RV) myocardial tissue obtained at endomyocardial biopsy (EMB). Although this intervention is relatively safe in experienced hands, with a complication rate of approximately 0.5% to 1.5%, many of these complications, including myocardial perforation, pericardial tamponade, tricuspid valve injury causing significant tricuspid regurgitation, and access-site complications, create significant challenges for patients and physicians.2 In addition, the EMB procedure is expensive, is prone to sampling error due to the patchy nature of ACR, and, importantly, is disliked by many patients. Consideration of these reasons is important given that the current standard of care for ACR surveillance is to perform periodic EMBs during the first 6 to 12 postoperative months, which equates to more than several procedures during the first year of follow-up alone. For these reasons, noninvasive screening to detect significant ACR remains highly desirable. ACR is a T cell–mediated process resulting in myocardial inflammation, and it can cause different severities of myocyte damage. It is postulated that this process should result in some degree of subclinical cardiac dysfunction that can possibly be detected by different imaging techniques, including echocardiography.3 Several studies have suggested that myocardial strain and strain rate are more sensitive measures than those derived from conventional echocardiography.4 Two recent reports, one published in a recent issue and the other in the current issue of JASE, have further examined the role of speckle-tracking echocardiography to detect ACR to monitor heart transplantation patients. In the April 2015 issue of JASE, Ambardekar et al.5 reported an examination of myocardial strain and strain rate from speckle-tracking echocardiography to differentiate asymptomatic biopsy-proven cellular rejection in the first year after transplantation. Using Velocity Vector Imaging software from echocardiograms identified retrospectively at three time points in heart transplant recipients—at baseline (no rejection), during ACR, and after resolution of rejection— speckle-tracking strain and strain rate measurements were obtained from 30 patients. Asymptomatic biopsy-proven rejection was compared with a control cohort without ACR. There were three ma-
From the Houston Methodist Institute of Academic Medicine, Houston, Texas; and Methodist DeBakey Heart & Vascular Center, Houston Methodist, Houston, Texas. Reprint requests: Jerry D. Estep, MD, FACC, FASE, Houston Methodist Institute of Academic Medicine, 6550 Fannin Street, Suite 1901, Houston, TX 77030 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.08.004
jor findings. First, there were no significant differences in circumferential and longitudinal strain or strain rate among the baseline, rejection, and resolution studies. Second, there were also no significant differences in strain and strain rate in control transplantation patients during the first year (within the first month and at 6 and 12 months after transplantation). Third, in a prespecified subgroup analysis, there were no differences in any of the speckle-tracking echocardiographic parameters when limiting the analysis to those patients with mild (14 patients) versus moderate (16 patients) rejection over the course of the study time points. These investigators concluded that speckletracking analysis was unable to detect changes on serial studies from patients with asymptomatic rejection and thus cannot replace EMB.5 The strength of the study by Ambardekar et al.5 relates to the investigators’ examining the diagnostic value of changes in left ventricular (LV) strain and strain rate longitudinally in the same patient, which mirrors clinical practice, as opposed to cross-sectional studies comparing average strains in a group of patients with rejection versus those without rejection. Unfortunately, the latter approach has been used in most of the studies examining this topic. It is important to place the observations and conclusions made in this study into clinical context and to keep in mind the EMB grading nomenclature and how the histologic grade is used to guide treatment of ACR. In 2004, under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the EMB grading system was undertaken to address challenges and inconsistencies in its use.6 The revised categories of ACR were defined as follows: grade 0R, no rejection (no change from 1990); grade 1R, mild rejection (1990 grades 1A, 1B, and 2); grade 2R, moderate rejection (1990 grade 3A); and grade 3R, severe rejection (1990 grades 3B and 4). Knowing the revised category is important to understand how ACR is defined and to interpret published studies (Table 1) that incorporate EMB readings using the 1990 grading system (typically retrospective studies with EMB data before 2006). Clinically, asymptomatic patients with no or mild ACR (grade 1A, 1B, 2, or 1R) and stable cardiac allograft systolic function typically do not require an urgent change in immunosuppressant therapy, in contrast to those patients with moderate (grade 3A or 2R) or severe ACR (grade 3B, 4, or 3R), who require an adjustment or enhancement of underlying immunosuppression.7 The concern in those patients with moderate ACR is the potential for progressive myocardial inflammation and myocyte damage that could lead to cardiac allograft dysfunction and clinical heart failure, which could progress to overt pump failure (cardiogenic shock) and/or lethal ventricular dysrhythmias and death. On the basis of several studies in the midto late 1990s, it is currently widely accepted that that mild forms of ACR typically resolve without treatment in the majority of patients. This remains an important concept when reviewing studies (Table 1) that use a referent EMB-derived histologic grade of varying severities and include both the 1990 and revised 2004 grading schemes.6 In contrast to the rejection grade cutoff of moderate or greater severity to guide clinical management, EMB-proven ACR in Ambardekar et al.’s5 study included early mild rejection (grades 2 and 1R) in addition to moderate rejection (grades 3A and 2R). In 1157
1158 Estep
Journal of the American Society of Echocardiography October 2015
Table 1 Selected studies evaluating the accuracy of echocardiographic parameters including strain and strain rate to detect ACR Total patients (prevalence of ACR)*
Study 12
Marcinak et al. (2007)
31 (32%)
Method and parameters (cutoff values)
Gold-standard EMB grade
$1B
80%
92.7%
80%
86%
72.8%
90.1%
82.2%
82.3%
36.4%
97.3%
75.6%
74.9%
27.1%
96.1%
$3A
100%
71.0%
67.9%
100%
$2R
NR
NR
NR
NR
$2R
73.7%
95.1%
59.7%
97.3%
$1B‡
64%
63%
24.2%
90.4%
$2/1Rjj
NR
NR
NR
NR
$2R
85.7%
91.1%
42.9%
98.8%
LV longitudinal strain (<15.5%)
85.7%
81.4%
25.0%
98.8%
LV (<17%) and RV (<15.5%) strain
100%
77%
25.9%
100%
Color DTI $1B
LV longitudinal peak early diastolic SR (<2.8 sec1) 38 (38%)
DTI [(PWT + LVMI) (LV peak systolic strain + Sep-TS)] (#0)
Eleid et al. (2010)10
51 (35%)x
NPV
90%
LV longitudinal systolic strain(<27.4%)
Roshanali et al. (2010)13
PPV
85%
Mid LVPW radial peak systolic SR (<3.0 sec1) 35 (11%)
Specificity
Color DTI Mid LVPW radial peak systolic strain (#30%)
Kato et al. (2010)11
Sensitivity
2D speckle-tracking LV global longitudinal strain (NR) Global circumferential strain (NR) Global radial strain (NR)
14
Sato et al. (2011)
32 (9%)
2D speckle-tracking % change of LV torsion† (<25%)
15
Sera et al. (2014)
59 (16%)
2D speckle-tracking LV global longitudinal strain (<14.8%)
Ambardekar et al. (2015)5
98 (45%)x
2D speckle-tracking LV global longitudinal strain (NR) Global circumferential strain (NR)
Mingo-Santos et al. (2015)16
34 (5.1%)
Speckle-tracking Free wall RV longitudinal strain (<17%)
DTI, Doppler tissue imaging; LVMI, LV mass index; NPV, negative predictive value; NR, not reported with no noted differences in the examined echocardiographic indices comparing the rejection versus no-rejection cohorts in these investigations; PPV, positive predictive value; PWT, posterior wall thickness; Sep-TS, time to systole measured at the interventricular septum; SR, strain rate; 2D, two-dimensional. *Prevalence of ACR based on the percentage of EMBs with detected ACR on the basis of the EMB score defined cutoff and total EMBs performed per study. † Difference between basal and apical end-systolic rotations [(LV torsion at the observation baseline LV torsion)/baseline LV torsion] 100%. ‡ Reported as asymptomatic treatment requiring. x Prevalence on the basis of the percentage of patients with detected ACR using the EMB cutoff and total patients examined in the study. jj Defined as asymptomatic with mild or moderate rejection.
that study, patients with severe pathologic grades of rejection were symptomatic and therefore excluded. The conclusions made by Ambardekar et al. using the newest echocardiographic techniques remain consistent with the most recent International Society for Heart and Lung Transplantation guideline statement to not use echocardiography to replace EMB.7 It is also important to keep in mind that studies performed to minimize or replace the EMB as the gold standard to monitor heart transplant recipients have included the examination of imaging parameters derived from different imaging techniques, signal averaged
electrocardiograms, and peripheral blood markers, including gene expression profiling of peripheral blood mononuclear cells involved in T-cell priming and the inflammation process associated with ACR.8 Only gene expression profiling (available commercially as AlloMap; CareDx, Brisbane, CA) among these investigated techniques has been clinically adopted and is supported by the International Society for Heart and Lung Transplantation guidelines to rule out the presence of grade 2R or higher ACR in low-risk heart transplant recipients with a level of evidence better than expert opinion.7 The clinical adoption of AlloMap is based on using a score with a cutoff associated
Estep 1159
Journal of the American Society of Echocardiography Volume 28 Number 10
with a very high negative predictive value (NPV) of 99.6% for moderate or greater severity rejection (grade 3A or 2R or higher).9 As defined in Table 1 and consistent with the observations made by Ambardekar et al.,5 there has been little progress in the development of an echocardiographic technique associated with high enough sensitivity and specificity to accurately replace EMB.10-15 In this issue of JASE, Mingo-Santos et al.16 provide further evidence on using nonconventional echocardiographic techniques to define markers to exclude clinically meaningful ACR in heart transplant recipients. Their report was based on a prospective examination of 34 consecutive patients, with a total of 235 pairs of EMBs and echocardiograms, with the primary aim to evaluate which echocardiographic parameters (classical or speckle-tracking derived) are able to more accurately exclude ACR (defined as grade 2R or higher). In comparison with other studies, the strength of the study by Mingo-Santos et al. is the inclusion of an examination of RV free wall longitudinal strain in addition to LV strain parameters (Table 1). This is intriguing because ACR, reported as patchy in nature at times, is thought to involve both the left and right ventricles, and therefore a biventricular examination in theory may reflect a more complete screen of the myocardial inflammatory process. There were two major findings in Mingo-Santos et al.’s16 study. First, on the basis of a multivariate analysis, a free wall RV longitudinal strain value <17% and an LV global longitudinal strain value <15.5% were independently related to the presence of ACR of grade 2R or higher, with an NPV of 98.8% for each value. Similar to other trials (Table 1), the accuracy of isolated and combined echocardiographic parameters was not high enough to recommend these noninvasive techniques to replace EMB as the gold-standard surveillance strategy. Second, the combination of LV and RV longitudinal strain, based on the above cutoff values, as a new variable ‘‘LV + RV S’’ was normal in 106 echocardiograms (57.6% of all studies). None of the corresponding EMBs showed ACR of grade 2R or higher (NPV, 100% on the basis of sensitivity of 100%). The NPV to exclude ACR of grade 2R or higher in this study is among the highest in comparison with other echocardiographic studies (Table 1). The reproducibility of these measurements is reassuring, with reported intraclass correlation coefficients for RV longitudinal strain of 0.94 (95% CI: 0.76–0.98) and 0.97 (95% CI: 0.90–0.99) for inter- and intraobserver variability, respectively. There are distinct differences between the studies of MingoSantos et al.16 and Ambardekar et al.5 that merit discussion regarding the usefulness of speckle-tracking-derived strain and strain rate–based measurements to detect ACR. These studies had different methodologies (prospective vs retrospective), different referent EMB cutoff values (moderate vs mild and moderate ACR), differences regarding the incorporation or exclusion of the clinical status (not considered vs prioritization of the asymptomatic state), and, most important, different primary objectives (examination of echocardiographic variables to exclude or minimize EMBs vs determination if echocardiographic parameters are sensitive to detect asymptomatic ACR including mild rejection). The limitations of a single-center experience, small number of patients, and a limited number of moderate or greater ACR episodes apply to both studies. On the basis of the available evidence to date, including both of these studies, there is not an echocardiographic technique associated with high enough accuracy to replace EMB. To my knowledge, there has not been a prospective study, appropriately sized and powered, to best define the accuracy of echocardiography-based parameters (simultaneously obtained during the invasive EMB procedure) to
track individual patients before, during, and after meaningful ACR, defined as an EMB of grade 2R or higher, independent of the clinical status to mirror current post–heart transplantation surveillance practice. The findings reported by Mingo-Santos et al.,16 if further validated in a larger, ideally multicenter, prospective trial, would represent a step in the right direction. Excluding clinically important ACR remains important given that the symptoms and signs associated with rejection can vary significantly from patient to patient and can mimic other post–heart transplantation complications, including infection. Although it is a class I recommendation to perform EMB as early as possible if there is a suspicion for symptomatic acute heart allograft rejection,7 a noninvasive test associated with a high NPV may serve to reassure and guide clinicians while the EMB procedure is being arranged and the workup completed. In addition, patients with moderate rejection (grade 2R or higher) are often asymptomatic, so relying on the clinical status alone will exclude many patients at risk for progression and its associated complications. Therefore, a noninvasive echocardiographic technique such as speckle-tracking-derived strain and its associated very high NPV to exclude moderate rejection could prove to be very clinically useful to minimize the burden of frequent EMBs within the first year of follow-up after heart transplantation. If the results reported by Mingo-Santos et al.,16 including validation of the proposed cutoff values, are reproduced, consideration should be given to conduct a clinical trial to influence clinical adoption of this new variable, ‘‘LV + RV S.’’ The primary aim of such a trial would be to determine if this noninvasive echocardiography-based method of ACR surveillance is associated with safe patient outcomes, as was done to examine the safety and efficacy of using the gene expression profiling algorithm.17 In the end, the goal is to produce better surveillance strategies while minimizing risks from unnecessary diagnostic procedures in this patient population. REFERENCES 1. Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report— 2012. J Heart Lung Transplant 2012;31:1052-64. 2. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122:900-9. 3. Estep JD, Shah DJ, Nagueh SF, Mahmarian JJ, Torre-Amione G, Zoghbi WA. The role of multimodality cardiac imaging in the transplanted heart. J Am Coll Cardiol 2009;2:1126-40. 4. Geyer H, Caracciolo G, Abe H, Wilansky S, Carerj S, Gentile F, et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010;23:351-69. quiz 453–5. 5. Ambardekar AV, Alluri N, Patel AC, Lindenfeld J, Dorosz JL. Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation. J Am Soc Echocardiogr 2015;28: 478-85. 6. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-20. 7. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29: 914-56.
1160 Estep
8. Miller CA, Fildes JE, Ray SG, Dora H, Yonan N, Williams SG, et al. Noninvasive approaches for the diagnosis of acute cardiac allograft rejection. Heart 2013;99:445-53. 9. Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 2006;6:150-60. 10. Eleid MF, Caracciolo G, Cho EJ, et al. Natural history of left ventricular mechanics in transplanted hearts: relationships with clinical variables and genetic expression profiles of allograft rejection. JACC Cardiovasc Imaging 2010;3:989-1000. 11. Kato TS, Oda N, Hashimura K, Hashimoto S, Nakatani S, Ueda HI, et al. Strain rate imaging would predict sub-clinical acute rejection in heart transplant recipients. Eur J Cardiothorac Surg 2010;37:1104-10. 12. Marciniak A, Eroglu E, Marciniak M, Sirbu C, Herbots L, Droogne W, et al. The potential clinical role of ultrasonic strain and strain rate imaging in diagnosing acute rejection after heart transplantation. Eur J Echocardiogr 2007;8:213-21.
Journal of the American Society of Echocardiography October 2015
13. Roshanali F, Mandegar MH, Bagheri J, Sarzaeem MR, Chitsaz S, Alaeddini F, et al. Echo rejection score: new echocardiographic approach to diagnosis of heart transplant rejection. Eur J Cardiothorac Surg 2010;38:176-80. 14. Sato T, Kato TS, Komamura K, Hashimoto S, Shishido T, Mano A, et al. Utility of left ventricular systolic torsion derived from 2-dimensional speckle-tracking echocardiography in monitoring acute cellular rejection in heart transplant recipients. J Heart Lung Transplant 2011;30:536-43. 15. Sera F, Kato TS, Farr M, Russo, Jin Z, Marboe CC, et al. Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection. J Card Fail 2014;20:359-64. 16. Mingo-Santos S, Mo~ nivas-Palomero V, Garcia-Lunar I, Mitroi CD, Goirigolzarri-Artaza J, Rivero B, et al. Usefulness of two-dimensional strain parameters to diagnose acute rejection after heart transplantation. J Am Soc Echocardiogr 2015;28:1149-56. 17. Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med 2010;362:1890-900.
Echocardiographic Identification of Acute Cellular Rejection in Heart Transplant Recipients Jerry D. Estep, MD, FACC, FASE, Houston, Texas Heart transplantation remains the most effective long-term intervention for patients with end-stage heart failure. Despite advances in immunosuppressive therapy, acute cellular rejection (ACR) remains common, with a prevalence up to 35% to 40%, and approximately 22% of patients require admission to the hospital for treatment within the first year after transplantation.1 ACR is also among the leading causes of death after heart transplantation.1 The gold-standard surveillance test to detect ACR is based on the histologic analysis of right ventricular (RV) myocardial tissue obtained at endomyocardial biopsy (EMB). Although this intervention is relatively safe in experienced hands, with a complication rate of approximately 0.5% to 1.5%, many of these complications, including myocardial perforation, pericardial tamponade, tricuspid valve injury causing significant tricuspid regurgitation, and access-site complications, create significant challenges for patients and physicians.2 In addition, the EMB procedure is expensive, is prone to sampling error due to the patchy nature of ACR, and, importantly, is disliked by many patients. Consideration of these reasons is important given that the current standard of care for ACR surveillance is to perform periodic EMBs during the first 6 to 12 postoperative months, which equates to more than several procedures during the first year of follow-up alone. For these reasons, noninvasive screening to detect significant ACR remains highly desirable. ACR is a T cell–mediated process resulting in myocardial inflammation, and it can cause different severities of myocyte damage. It is postulated that this process should result in some degree of subclinical cardiac dysfunction that can possibly be detected by different imaging techniques, including echocardiography.3 Several studies have suggested that myocardial strain and strain rate are more sensitive measures than those derived from conventional echocardiography.4 Two recent reports, one published in a recent issue and the other in the current issue of JASE, have further examined the role of speckle-tracking echocardiography to detect ACR to monitor heart transplantation patients. In the April 2015 issue of JASE, Ambardekar et al.5 reported an examination of myocardial strain and strain rate from speckle-tracking echocardiography to differentiate asymptomatic biopsy-proven cellular rejection in the first year after transplantation. Using Velocity Vector Imaging software from echocardiograms identified retrospectively at three time points in heart transplant recipients—at baseline (no rejection), during ACR, and after resolution of rejection— speckle-tracking strain and strain rate measurements were obtained from 30 patients. Asymptomatic biopsy-proven rejection was compared with a control cohort without ACR. There were three ma-
From the Houston Methodist Institute of Academic Medicine, Houston, Texas; and Methodist DeBakey Heart & Vascular Center, Houston Methodist, Houston, Texas. Reprint requests: Jerry D. Estep, MD, FACC, FASE, Houston Methodist Institute of Academic Medicine, 6550 Fannin Street, Suite 1901, Houston, TX 77030 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2015 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2015.08.004
jor findings. First, there were no significant differences in circumferential and longitudinal strain or strain rate among the baseline, rejection, and resolution studies. Second, there were also no significant differences in strain and strain rate in control transplantation patients during the first year (within the first month and at 6 and 12 months after transplantation). Third, in a prespecified subgroup analysis, there were no differences in any of the speckle-tracking echocardiographic parameters when limiting the analysis to those patients with mild (14 patients) versus moderate (16 patients) rejection over the course of the study time points. These investigators concluded that speckletracking analysis was unable to detect changes on serial studies from patients with asymptomatic rejection and thus cannot replace EMB.5 The strength of the study by Ambardekar et al.5 relates to the investigators’ examining the diagnostic value of changes in left ventricular (LV) strain and strain rate longitudinally in the same patient, which mirrors clinical practice, as opposed to cross-sectional studies comparing average strains in a group of patients with rejection versus those without rejection. Unfortunately, the latter approach has been used in most of the studies examining this topic. It is important to place the observations and conclusions made in this study into clinical context and to keep in mind the EMB grading nomenclature and how the histologic grade is used to guide treatment of ACR. In 2004, under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the EMB grading system was undertaken to address challenges and inconsistencies in its use.6 The revised categories of ACR were defined as follows: grade 0R, no rejection (no change from 1990); grade 1R, mild rejection (1990 grades 1A, 1B, and 2); grade 2R, moderate rejection (1990 grade 3A); and grade 3R, severe rejection (1990 grades 3B and 4). Knowing the revised category is important to understand how ACR is defined and to interpret published studies (Table 1) that incorporate EMB readings using the 1990 grading system (typically retrospective studies with EMB data before 2006). Clinically, asymptomatic patients with no or mild ACR (grade 1A, 1B, 2, or 1R) and stable cardiac allograft systolic function typically do not require an urgent change in immunosuppressant therapy, in contrast to those patients with moderate (grade 3A or 2R) or severe ACR (grade 3B, 4, or 3R), who require an adjustment or enhancement of underlying immunosuppression.7 The concern in those patients with moderate ACR is the potential for progressive myocardial inflammation and myocyte damage that could lead to cardiac allograft dysfunction and clinical heart failure, which could progress to overt pump failure (cardiogenic shock) and/or lethal ventricular dysrhythmias and death. On the basis of several studies in the midto late 1990s, it is currently widely accepted that that mild forms of ACR typically resolve without treatment in the majority of patients. This remains an important concept when reviewing studies (Table 1) that use a referent EMB-derived histologic grade of varying severities and include both the 1990 and revised 2004 grading schemes.6 In contrast to the rejection grade cutoff of moderate or greater severity to guide clinical management, EMB-proven ACR in Ambardekar et al.’s5 study included early mild rejection (grades 2 and 1R) in addition to moderate rejection (grades 3A and 2R). In 1157
1158 Estep
Journal of the American Society of Echocardiography October 2015
Table 1 Selected studies evaluating the accuracy of echocardiographic parameters including strain and strain rate to detect ACR Total patients (prevalence of ACR)*
Study 12
Marcinak et al. (2007)
31 (32%)
Method and parameters (cutoff values)
Gold-standard EMB grade
$1B
80%
92.7%
80%
86%
72.8%
90.1%
82.2%
82.3%
36.4%
97.3%
75.6%
74.9%
27.1%
96.1%
$3A
100%
71.0%
67.9%
100%
$2R
NR
NR
NR
NR
$2R
73.7%
95.1%
59.7%
97.3%
$1B‡
64%
63%
24.2%
90.4%
$2/1Rjj
NR
NR
NR
NR
$2R
85.7%
91.1%
42.9%
98.8%
LV longitudinal strain (<15.5%)
85.7%
81.4%
25.0%
98.8%
LV (<17%) and RV (<15.5%) strain
100%
77%
25.9%
100%
Color DTI $1B
LV longitudinal peak early diastolic SR (<2.8 sec1) 38 (38%)
DTI [(PWT + LVMI) (LV peak systolic strain + Sep-TS)] (#0)
Eleid et al. (2010)10
51 (35%)x
NPV
90%
LV longitudinal systolic strain(<27.4%)
Roshanali et al. (2010)13
PPV
85%
Mid LVPW radial peak systolic SR (<3.0 sec1) 35 (11%)
Specificity
Color DTI Mid LVPW radial peak systolic strain (#30%)
Kato et al. (2010)11
Sensitivity
2D speckle-tracking LV global longitudinal strain (NR) Global circumferential strain (NR) Global radial strain (NR)
14
Sato et al. (2011)
32 (9%)
2D speckle-tracking % change of LV torsion† (<25%)
15
Sera et al. (2014)
59 (16%)
2D speckle-tracking LV global longitudinal strain (<14.8%)
Ambardekar et al. (2015)5
98 (45%)x
2D speckle-tracking LV global longitudinal strain (NR) Global circumferential strain (NR)
Mingo-Santos et al. (2015)16
34 (5.1%)
Speckle-tracking Free wall RV longitudinal strain (<17%)
DTI, Doppler tissue imaging; LVMI, LV mass index; NPV, negative predictive value; NR, not reported with no noted differences in the examined echocardiographic indices comparing the rejection versus no-rejection cohorts in these investigations; PPV, positive predictive value; PWT, posterior wall thickness; Sep-TS, time to systole measured at the interventricular septum; SR, strain rate; 2D, two-dimensional. *Prevalence of ACR based on the percentage of EMBs with detected ACR on the basis of the EMB score defined cutoff and total EMBs performed per study. † Difference between basal and apical end-systolic rotations [(LV torsion at the observation baseline LV torsion)/baseline LV torsion] 100%. ‡ Reported as asymptomatic treatment requiring. x Prevalence on the basis of the percentage of patients with detected ACR using the EMB cutoff and total patients examined in the study. jj Defined as asymptomatic with mild or moderate rejection.
that study, patients with severe pathologic grades of rejection were symptomatic and therefore excluded. The conclusions made by Ambardekar et al. using the newest echocardiographic techniques remain consistent with the most recent International Society for Heart and Lung Transplantation guideline statement to not use echocardiography to replace EMB.7 It is also important to keep in mind that studies performed to minimize or replace the EMB as the gold standard to monitor heart transplant recipients have included the examination of imaging parameters derived from different imaging techniques, signal averaged
electrocardiograms, and peripheral blood markers, including gene expression profiling of peripheral blood mononuclear cells involved in T-cell priming and the inflammation process associated with ACR.8 Only gene expression profiling (available commercially as AlloMap; CareDx, Brisbane, CA) among these investigated techniques has been clinically adopted and is supported by the International Society for Heart and Lung Transplantation guidelines to rule out the presence of grade 2R or higher ACR in low-risk heart transplant recipients with a level of evidence better than expert opinion.7 The clinical adoption of AlloMap is based on using a score with a cutoff associated
Estep 1159
Journal of the American Society of Echocardiography Volume 28 Number 10
with a very high negative predictive value (NPV) of 99.6% for moderate or greater severity rejection (grade 3A or 2R or higher).9 As defined in Table 1 and consistent with the observations made by Ambardekar et al.,5 there has been little progress in the development of an echocardiographic technique associated with high enough sensitivity and specificity to accurately replace EMB.10-15 In this issue of JASE, Mingo-Santos et al.16 provide further evidence on using nonconventional echocardiographic techniques to define markers to exclude clinically meaningful ACR in heart transplant recipients. Their report was based on a prospective examination of 34 consecutive patients, with a total of 235 pairs of EMBs and echocardiograms, with the primary aim to evaluate which echocardiographic parameters (classical or speckle-tracking derived) are able to more accurately exclude ACR (defined as grade 2R or higher). In comparison with other studies, the strength of the study by Mingo-Santos et al. is the inclusion of an examination of RV free wall longitudinal strain in addition to LV strain parameters (Table 1). This is intriguing because ACR, reported as patchy in nature at times, is thought to involve both the left and right ventricles, and therefore a biventricular examination in theory may reflect a more complete screen of the myocardial inflammatory process. There were two major findings in Mingo-Santos et al.’s16 study. First, on the basis of a multivariate analysis, a free wall RV longitudinal strain value <17% and an LV global longitudinal strain value <15.5% were independently related to the presence of ACR of grade 2R or higher, with an NPV of 98.8% for each value. Similar to other trials (Table 1), the accuracy of isolated and combined echocardiographic parameters was not high enough to recommend these noninvasive techniques to replace EMB as the gold-standard surveillance strategy. Second, the combination of LV and RV longitudinal strain, based on the above cutoff values, as a new variable ‘‘LV + RV S’’ was normal in 106 echocardiograms (57.6% of all studies). None of the corresponding EMBs showed ACR of grade 2R or higher (NPV, 100% on the basis of sensitivity of 100%). The NPV to exclude ACR of grade 2R or higher in this study is among the highest in comparison with other echocardiographic studies (Table 1). The reproducibility of these measurements is reassuring, with reported intraclass correlation coefficients for RV longitudinal strain of 0.94 (95% CI: 0.76–0.98) and 0.97 (95% CI: 0.90–0.99) for inter- and intraobserver variability, respectively. There are distinct differences between the studies of MingoSantos et al.16 and Ambardekar et al.5 that merit discussion regarding the usefulness of speckle-tracking-derived strain and strain rate–based measurements to detect ACR. These studies had different methodologies (prospective vs retrospective), different referent EMB cutoff values (moderate vs mild and moderate ACR), differences regarding the incorporation or exclusion of the clinical status (not considered vs prioritization of the asymptomatic state), and, most important, different primary objectives (examination of echocardiographic variables to exclude or minimize EMBs vs determination if echocardiographic parameters are sensitive to detect asymptomatic ACR including mild rejection). The limitations of a single-center experience, small number of patients, and a limited number of moderate or greater ACR episodes apply to both studies. On the basis of the available evidence to date, including both of these studies, there is not an echocardiographic technique associated with high enough accuracy to replace EMB. To my knowledge, there has not been a prospective study, appropriately sized and powered, to best define the accuracy of echocardiography-based parameters (simultaneously obtained during the invasive EMB procedure) to
track individual patients before, during, and after meaningful ACR, defined as an EMB of grade 2R or higher, independent of the clinical status to mirror current post–heart transplantation surveillance practice. The findings reported by Mingo-Santos et al.,16 if further validated in a larger, ideally multicenter, prospective trial, would represent a step in the right direction. Excluding clinically important ACR remains important given that the symptoms and signs associated with rejection can vary significantly from patient to patient and can mimic other post–heart transplantation complications, including infection. Although it is a class I recommendation to perform EMB as early as possible if there is a suspicion for symptomatic acute heart allograft rejection,7 a noninvasive test associated with a high NPV may serve to reassure and guide clinicians while the EMB procedure is being arranged and the workup completed. In addition, patients with moderate rejection (grade 2R or higher) are often asymptomatic, so relying on the clinical status alone will exclude many patients at risk for progression and its associated complications. Therefore, a noninvasive echocardiographic technique such as speckle-tracking-derived strain and its associated very high NPV to exclude moderate rejection could prove to be very clinically useful to minimize the burden of frequent EMBs within the first year of follow-up after heart transplantation. If the results reported by Mingo-Santos et al.,16 including validation of the proposed cutoff values, are reproduced, consideration should be given to conduct a clinical trial to influence clinical adoption of this new variable, ‘‘LV + RV S.’’ The primary aim of such a trial would be to determine if this noninvasive echocardiography-based method of ACR surveillance is associated with safe patient outcomes, as was done to examine the safety and efficacy of using the gene expression profiling algorithm.17 In the end, the goal is to produce better surveillance strategies while minimizing risks from unnecessary diagnostic procedures in this patient population. REFERENCES 1. Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report— 2012. J Heart Lung Transplant 2012;31:1052-64. 2. Yilmaz A, Kindermann I, Kindermann M, Mahfoud F, Ukena C, Athanasiadis A, et al. Comparative evaluation of left and right ventricular endomyocardial biopsy: differences in complication rate and diagnostic performance. Circulation 2010;122:900-9. 3. Estep JD, Shah DJ, Nagueh SF, Mahmarian JJ, Torre-Amione G, Zoghbi WA. The role of multimodality cardiac imaging in the transplanted heart. J Am Coll Cardiol 2009;2:1126-40. 4. Geyer H, Caracciolo G, Abe H, Wilansky S, Carerj S, Gentile F, et al. Assessment of myocardial mechanics using speckle tracking echocardiography: fundamentals and clinical applications. J Am Soc Echocardiogr 2010;23:351-69. quiz 453–5. 5. Ambardekar AV, Alluri N, Patel AC, Lindenfeld J, Dorosz JL. Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation. J Am Soc Echocardiogr 2015;28: 478-85. 6. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005;24:1710-20. 7. Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29: 914-56.
1160 Estep
8. Miller CA, Fildes JE, Ray SG, Dora H, Yonan N, Williams SG, et al. Noninvasive approaches for the diagnosis of acute cardiac allograft rejection. Heart 2013;99:445-53. 9. Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 2006;6:150-60. 10. Eleid MF, Caracciolo G, Cho EJ, et al. Natural history of left ventricular mechanics in transplanted hearts: relationships with clinical variables and genetic expression profiles of allograft rejection. JACC Cardiovasc Imaging 2010;3:989-1000. 11. Kato TS, Oda N, Hashimura K, Hashimoto S, Nakatani S, Ueda HI, et al. Strain rate imaging would predict sub-clinical acute rejection in heart transplant recipients. Eur J Cardiothorac Surg 2010;37:1104-10. 12. Marciniak A, Eroglu E, Marciniak M, Sirbu C, Herbots L, Droogne W, et al. The potential clinical role of ultrasonic strain and strain rate imaging in diagnosing acute rejection after heart transplantation. Eur J Echocardiogr 2007;8:213-21.
Journal of the American Society of Echocardiography October 2015
13. Roshanali F, Mandegar MH, Bagheri J, Sarzaeem MR, Chitsaz S, Alaeddini F, et al. Echo rejection score: new echocardiographic approach to diagnosis of heart transplant rejection. Eur J Cardiothorac Surg 2010;38:176-80. 14. Sato T, Kato TS, Komamura K, Hashimoto S, Shishido T, Mano A, et al. Utility of left ventricular systolic torsion derived from 2-dimensional speckle-tracking echocardiography in monitoring acute cellular rejection in heart transplant recipients. J Heart Lung Transplant 2011;30:536-43. 15. Sera F, Kato TS, Farr M, Russo, Jin Z, Marboe CC, et al. Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection. J Card Fail 2014;20:359-64. 16. Mingo-Santos S, Mo~ nivas-Palomero V, Garcia-Lunar I, Mitroi CD, Goirigolzarri-Artaza J, Rivero B, et al. Usefulness of two-dimensional strain parameters to diagnose acute rejection after heart transplantation. J Am Soc Echocardiogr 2015;28:1149-56. 17. Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med 2010;362:1890-900.