- Email: [email protected]
Virtual Histology Intravascular Ultrasound
Journal of the American College of Cardiology © 2009 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Virtual Histology Intravascular Ultrasound Assessing the Risk of Cardiac Allograft Vasculopathy* Richard D. Patten, MD Boston, Massachusetts
Heart transplantation offers a means to improve longevity and quality of life in patients with end stage heart failure. Although survival following cardiac transplantation improved significantly following the advent of calcineurin inhibitors, the development of vascular disease within the arterial system of the grafted heart, known as cardiac allograft vasculopathy, is a major cause of morbidity and mortality (1,2). Graft vasculopathy, defined by an angiographically determined stenosis ⬎50% in an epicardial coronary artery, is present in 40% to 50% of patients by 5 years post-transplant and is the leading cause of death in recipients who survive past the first year (3,4). Unfortunately, ischemic symptoms in cardiac transplant patients are often nonspecific, and a common presentation of cardiac allograft vasculopathy is that of sudden cardiac death. Indeed, far too often, transplant cardiologists receive the most dreaded of phone calls from a bereaved spouse, child, or parent reporting the sudden death of a transplant recipient. Any modality that can increase our awareness of patients at high risk for developing progressive graft vasculopathy would be a welcome addition to the available tools for monitoring patients after cardiac transplant. See page 1279
In this issue of the Journal, Raichlin et al. (5) of the Mayo Clinic explore the utility of virtual histology intravascular ultrasound (VH-IVUS) to carefully examine coronary lesion morphology of transplant recipients and identify which type of coronary lesions may predict progression of allograft vascular disease. They examined the frequency and significance of coronary plaques con-
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Heart Failure and Cardiac Transplant Program, Tufts Medical Center, Boston, Massachusetts.
Vol. 53, No. 15, 2009 ISSN 0735-1097/09/$36.00 doi:10.1016/j.jacc.2009.01.028
taining both necrotic core and calcification from VHIVUS exams performed a mean of 3.6 years following transplant in 86 recipients. A subgroup of patients (n ⫽ 38) had a follow-up study after 12 months to explore the rate of progression of these necrotic core/dense calcium containing lesions. The investigators defined “noninflammatory” plaque as being composed of ⬍30% by volume of the combination of both necrotic core and calcium and “inflammatory” plaque as that composed of ⱖ30% necrotic core and calcium. They first compared these data to the total rejection score defined as the average rejection score of biopsies over 6 months using the revised histologic grading scheme. They observed more inflammatory plaques in patients with a total rejection score ⱖ0.3 than in those with a total rejection score ⬍0.3, supporting the idea that early rejection may contribute to inflammatory plaque development. In patients having inflammatory plaque identified in the initial study, there was a significant increase in plaque volume over 1 year compared with those without inflammatory plaque at the initial VH-IVUS examination. The investigators concluded that this coronary imaging modality may hold promise in identifying transplant patients who are at high risk of developing progressive graft vasculopathy. This retrospective analysis of compiled VH-IVUS (see review in Sangiorgi et al. [6]) as a tool to predict progression of graft vascular disease has inherent weaknesses that the investigators emphasize in the discussion. The rather arbitrary cutoff of 30% for plaque content of combined necrotic core and calcium to define an inflammatory plaque is based on prior autopsy data from nontransplanted hearts with coronary artery disease and not from coronaries of transplanted hearts. Given the differences in pathophysiology between allograft vasculopathy and atherosclerosis, it remains unclear that this VH-IVUS morphology represents inflammation. A dataset obtained in transplanted hearts at autopsy would be required to explore this further. Inherent in this retrospective analysis is the significant variability with which the timing of VH-IVUS was performed following transplantation. Nonetheless, data obtained by VH-IVUS presented by Raichlin et al. (5) represent a novel and potentially important approach for the early identification of patients at risk of developing graft vasculopathy. Nearly all patients after cardiac transplant are treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, antihypertensive medications, and aggressive diabetes control to combat treatable coronary artery disease risk factors. More recently, the addition of rapamycin to the immunosuppressive regimen of transplant recipients diagnosed with graft vasculopathy has been shown to stabilize the progression of vascular disease in many patients (7,8). Thus, in appropriately selected transplant recipients, the identification of high-risk coronary morphology might be an impetus to use earlier, more potent antiproliferative
1288
Patten Risk of Cardiac Allograft Vasculopathy
therapy such as rapamycin. Ultimately, earlier intervention may lead to improved survival in allograft vasculopathy patients. How this new imaging technology compares with standalone IVUS is not known. A multicenter consortium (9) performed IVUS at baseline in the early period following heart transplantation (4 to 6 weeks) with a repeat IVUS exam 1 year later. Kobashigawa et al. (9) reported that patients whose maximal intimal thickness increased ⬎0.5 mm over the first 12 months had a markedly higher mortality and graft loss than those whose maximal intimal thickness increased ⬍0.5 mm. Moreover, patients with greater maximal intimal thickness increases had double the incidence of angiographically determined graft vasculopathy at 5 years (65% vs. 32%). Before any striking conclusions can be drawn from the data presented in this novel study by Raichlin et al. (5), more clinical data must be collected to help strengthen (or refute) these preliminary observations. The most rapid means of gathering such data would be in the formation of a multicenter consortium to collect data prospectively and compare the predictive utility and prognostic value of intravascular ultrasound versus VH-IVUS from consistently timed, consecutive examinations following cardiac transplantation. These data may contribute importantly to our understanding of the pathophysiology underlying this progressive vasculopathy in cardiac transplant recipients. Moreover, with these data in hand, it may then be feasible to draw more definitive conclusions about the ability of this new technology to predict patients at risk of developing cardiac allograft vasculopathy.
JACC Vol. 53, No. 15, 2009 April 14, 2009:1287–8
Reprint requests and correspondence: Dr. Richard D. Patten, Cardiomyopathy Program, New England Heart Institute, Catholic Medical Center, 100 McGregor Street, Manchester, New Hampshire 03102. E-mail: [email protected].
REFERENCES
1. Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol 2008;52:587–98. 2. Sipahi I, Starling RC. Cardiac allograft vasculopathy: an update. Heart Fail Clin 2007;3:87–95. 3. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant “atheroma.” Transplantation 2003;76:891–9. 4. Potena L, Valantine HA. Cardiac allograft vasculopathy and insulin resistance— hope for new therapeutic targets. Endocrinol Metab Clin North Am 2007;36:965– 81. 5. Raichlin E, Bae J-H, Kushwaha SS, et al. Inflammatory burden of cardiac allograft coronary atherosclerotic plaque is associated with early recurrent cellular rejection and predicts a higher risk of vasculopathy progression. J Am Coll Cardiol 2009;53:1279 – 86. 6. Sangiorgi GM, Clementi F, Cola C, Biondi-Zoccai G. Plaque vulnerability and related coronary event prediction by intravascular ultrasound with virtual histology: “it’s a long way to tipperary?” Catheter Cardiovasc Interv 2007;70:203–10. 7. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003;108:48–53. 8. Raichlin E, Bae J-H, Khalpey Z, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation 2007;116:2726 –33. 9. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol 2005;45:1532–7. Key Words: cardiac transplantation y rejection y coronary allograft y vasculopathy y intravascular ultrasound.
EDITORIAL COMMENT
Virtual Histology Intravascular Ultrasound Assessing the Risk of Cardiac Allograft Vasculopathy* Richard D. Patten, MD Boston, Massachusetts
Heart transplantation offers a means to improve longevity and quality of life in patients with end stage heart failure. Although survival following cardiac transplantation improved significantly following the advent of calcineurin inhibitors, the development of vascular disease within the arterial system of the grafted heart, known as cardiac allograft vasculopathy, is a major cause of morbidity and mortality (1,2). Graft vasculopathy, defined by an angiographically determined stenosis ⬎50% in an epicardial coronary artery, is present in 40% to 50% of patients by 5 years post-transplant and is the leading cause of death in recipients who survive past the first year (3,4). Unfortunately, ischemic symptoms in cardiac transplant patients are often nonspecific, and a common presentation of cardiac allograft vasculopathy is that of sudden cardiac death. Indeed, far too often, transplant cardiologists receive the most dreaded of phone calls from a bereaved spouse, child, or parent reporting the sudden death of a transplant recipient. Any modality that can increase our awareness of patients at high risk for developing progressive graft vasculopathy would be a welcome addition to the available tools for monitoring patients after cardiac transplant. See page 1279
In this issue of the Journal, Raichlin et al. (5) of the Mayo Clinic explore the utility of virtual histology intravascular ultrasound (VH-IVUS) to carefully examine coronary lesion morphology of transplant recipients and identify which type of coronary lesions may predict progression of allograft vascular disease. They examined the frequency and significance of coronary plaques con-
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Heart Failure and Cardiac Transplant Program, Tufts Medical Center, Boston, Massachusetts.
Vol. 53, No. 15, 2009 ISSN 0735-1097/09/$36.00 doi:10.1016/j.jacc.2009.01.028
taining both necrotic core and calcification from VHIVUS exams performed a mean of 3.6 years following transplant in 86 recipients. A subgroup of patients (n ⫽ 38) had a follow-up study after 12 months to explore the rate of progression of these necrotic core/dense calcium containing lesions. The investigators defined “noninflammatory” plaque as being composed of ⬍30% by volume of the combination of both necrotic core and calcium and “inflammatory” plaque as that composed of ⱖ30% necrotic core and calcium. They first compared these data to the total rejection score defined as the average rejection score of biopsies over 6 months using the revised histologic grading scheme. They observed more inflammatory plaques in patients with a total rejection score ⱖ0.3 than in those with a total rejection score ⬍0.3, supporting the idea that early rejection may contribute to inflammatory plaque development. In patients having inflammatory plaque identified in the initial study, there was a significant increase in plaque volume over 1 year compared with those without inflammatory plaque at the initial VH-IVUS examination. The investigators concluded that this coronary imaging modality may hold promise in identifying transplant patients who are at high risk of developing progressive graft vasculopathy. This retrospective analysis of compiled VH-IVUS (see review in Sangiorgi et al. [6]) as a tool to predict progression of graft vascular disease has inherent weaknesses that the investigators emphasize in the discussion. The rather arbitrary cutoff of 30% for plaque content of combined necrotic core and calcium to define an inflammatory plaque is based on prior autopsy data from nontransplanted hearts with coronary artery disease and not from coronaries of transplanted hearts. Given the differences in pathophysiology between allograft vasculopathy and atherosclerosis, it remains unclear that this VH-IVUS morphology represents inflammation. A dataset obtained in transplanted hearts at autopsy would be required to explore this further. Inherent in this retrospective analysis is the significant variability with which the timing of VH-IVUS was performed following transplantation. Nonetheless, data obtained by VH-IVUS presented by Raichlin et al. (5) represent a novel and potentially important approach for the early identification of patients at risk of developing graft vasculopathy. Nearly all patients after cardiac transplant are treated with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, antihypertensive medications, and aggressive diabetes control to combat treatable coronary artery disease risk factors. More recently, the addition of rapamycin to the immunosuppressive regimen of transplant recipients diagnosed with graft vasculopathy has been shown to stabilize the progression of vascular disease in many patients (7,8). Thus, in appropriately selected transplant recipients, the identification of high-risk coronary morphology might be an impetus to use earlier, more potent antiproliferative
1288
Patten Risk of Cardiac Allograft Vasculopathy
therapy such as rapamycin. Ultimately, earlier intervention may lead to improved survival in allograft vasculopathy patients. How this new imaging technology compares with standalone IVUS is not known. A multicenter consortium (9) performed IVUS at baseline in the early period following heart transplantation (4 to 6 weeks) with a repeat IVUS exam 1 year later. Kobashigawa et al. (9) reported that patients whose maximal intimal thickness increased ⬎0.5 mm over the first 12 months had a markedly higher mortality and graft loss than those whose maximal intimal thickness increased ⬍0.5 mm. Moreover, patients with greater maximal intimal thickness increases had double the incidence of angiographically determined graft vasculopathy at 5 years (65% vs. 32%). Before any striking conclusions can be drawn from the data presented in this novel study by Raichlin et al. (5), more clinical data must be collected to help strengthen (or refute) these preliminary observations. The most rapid means of gathering such data would be in the formation of a multicenter consortium to collect data prospectively and compare the predictive utility and prognostic value of intravascular ultrasound versus VH-IVUS from consistently timed, consecutive examinations following cardiac transplantation. These data may contribute importantly to our understanding of the pathophysiology underlying this progressive vasculopathy in cardiac transplant recipients. Moreover, with these data in hand, it may then be feasible to draw more definitive conclusions about the ability of this new technology to predict patients at risk of developing cardiac allograft vasculopathy.
JACC Vol. 53, No. 15, 2009 April 14, 2009:1287–8
Reprint requests and correspondence: Dr. Richard D. Patten, Cardiomyopathy Program, New England Heart Institute, Catholic Medical Center, 100 McGregor Street, Manchester, New Hampshire 03102. E-mail: [email protected].
REFERENCES
1. Hunt SA, Haddad F. The changing face of heart transplantation. J Am Coll Cardiol 2008;52:587–98. 2. Sipahi I, Starling RC. Cardiac allograft vasculopathy: an update. Heart Fail Clin 2007;3:87–95. 3. Valantine HA. Cardiac allograft vasculopathy: central role of endothelial injury leading to transplant “atheroma.” Transplantation 2003;76:891–9. 4. Potena L, Valantine HA. Cardiac allograft vasculopathy and insulin resistance— hope for new therapeutic targets. Endocrinol Metab Clin North Am 2007;36:965– 81. 5. Raichlin E, Bae J-H, Kushwaha SS, et al. Inflammatory burden of cardiac allograft coronary atherosclerotic plaque is associated with early recurrent cellular rejection and predicts a higher risk of vasculopathy progression. J Am Coll Cardiol 2009;53:1279 – 86. 6. Sangiorgi GM, Clementi F, Cola C, Biondi-Zoccai G. Plaque vulnerability and related coronary event prediction by intravascular ultrasound with virtual histology: “it’s a long way to tipperary?” Catheter Cardiovasc Interv 2007;70:203–10. 7. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation 2003;108:48–53. 8. Raichlin E, Bae J-H, Khalpey Z, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation 2007;116:2726 –33. 9. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol 2005;45:1532–7. Key Words: cardiac transplantation y rejection y coronary allograft y vasculopathy y intravascular ultrasound.