Catheterization and Cardiovascular Interventions 83:78–79 (2014)
Editorial Comment Transplant Coronary Atherosclerosis: Parallels with In-Stent Neoatherosclerosis
triglycerides are common and attributable in great part to immunosuppressive agents).
CAV: EVIDENCE FOR NEOATHEROSCLEROSIS James A. Goldstein,* MD, FACC, FSCAI Department of Cardiovascular Medicine, Beaumont Health System, Royal Oak, Michigan
In the present era, cardiac transplant patients typically enjoy years of excellent cardiac function and favorable survival rates over 10–15 years. In its early period, cardiac transplantation survival was limited by rejection and complications attributable to the requisite but very toxic immunosuppressive drugs. Over the past 20 years, advances in immunosuppressive regimens have largely tamed rejection, though the body is incessantly attempting to immunologically “reject” the foreign organ. Further, although the necessary immunosuppressive agents are less toxic, patients universally suffer their adverse effects, including many which are pro-atherogenic (e.g., hypertension and hyperlipidemia).
POST-TRANSPLANT CORONARY DISEASE
The development of post-transplant cardiac allograft vasculopathy (CAV) is a feared, common and relatively “silent” complication, a problem insidious by nature but potentially catastrophic, and difficult to treat. CAV is progressive over time and beyond the first year represents the second most common cause of death, after malignancy. Nearly one-third of patients manifest angiographic coronary artery disease (which underestimates its true prevalence) at five years and over half at 10 years. CAV is a “pan-arterial” process characterized by diffuse concentric intimal hyperplasia in the epicardial vessels, with relative preservation of the internal elastic lamina. The microvasculature often develops concentric medial disease which may be “obliterative” (and is untreatable). Classic CAV is thought to predominantly reflect a response to immune mediated endothelial damage. However, other factors appear to play a role, particularly hyperlipidemia (elevations in serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL-cholesterol, and C 2013 Wiley Periodicals, Inc. V
Preservation of the internal elastic lamina and lack of lipid are felt to distinguish CAV from “common garden variety” atherosclerosis which is typically lipidbased, extends beyond the internal elastic lamina into the media, and most often observed in the epicardial vessels. However, transplant recipients may develop proximal coronary artery disease with lesions more closely resembling traditional atherosclerosis pathologically. Observations from direct coronary imaging in the present study by Tomai et al [1] now emphasize that post-transplant patients are prone to atherosclerotic disease, manifesting plaque composition patterns which resemble in-stent neoatherosclerosis (ISN). The present study employed intravascular ultrasound virtual histology (IVUS-VH) to characterize plaque composition during annual invasive evaluations in 40 young adult heart transplant recipients, comparing those who were 5 years (Group B). Only the left anterior descending artery (LAD) was scanned and plaque characterized according to standard IVUS-VH criteria. The key findings of the study demonstrate a time-dependent difference in plaque composition, with group B patients showing higher percentage of necrotic core and calcific plaque, and the interesting finding that only such patients exhibit “inflammatory plaque” (defined as necrotic core þ calcium). Notably, group B patients had higher prevalence of hypertension and hyperlipidemia and suffered more adverse events (54% vs. 14%), which included need for percutaneous coronary intervention (PCI), but Conflict of interest: Dr. Goldstein is a consultant for and owns equity in InfraReDx, Inc. *Correspondence to: James A. Goldstein, MD, FACC, FSCAI, Department of Cardiovascular Medicine, William Beaumont Hospital, 3601 W. 13 Mile Road, Royal Oak, MI 48073. E-mail: [email protected] Received 6 November 2013; Revision accepted 10 November 2013 DOI: 10.1002/ccd.25287 Published online 18 December 2013 in Wiley Online Library (wileyonlinelibrary.com)
Transplant Coronary Atherosclerosis: Parallels with In-Stent Neoatherosclerosis
also non-coronary events such as rejection, renal failure, and malignancy. SIMILARITIES TO IN-STENT NEOATHEROSCLEROSIS
The pathologic patterns of transplant coronary atherosclerosis observed in the present study bear striking resemblance to and may share pathophysiologic underpinnings with ISN. Evidence suggests ISN is an important substrate for both time-dependent in-stent restenosis (ISR) and late stent thrombosis [2–5]. Recent OCT observations in patients with drug eluting stent (DES-ISR) demonstrate that fully half of lesions consisted of thin-cap fibroatheromas (TCFA)-containing neointima, and over 50% had in-stent neointimal rupture and intraluminal thrombi [5]. Further, fragments of atherosclerotic plaques, including foamy macrophages, cholesterol crystals, and thin fibrous caps have been identified in cases of early and very late stent thrombosis [4]. Inflammation and hyperlipidemia are shared pathophysiologic processes common to transplant atherosclerosis and both native and ISN. It is well established that inflammation plays a fundamental role in the process of native atherosclerosis, and although the pathophysiology of ISN has not been fully delineated, endothelial incompetence and activation of inflammation are thought to play roles as mediators for longterm reaction to stent placement [2]. These processes are likely to also play major roles in transplant neoatheroscerosis.
CLINICAL IMPLICATIONS
The authors should be congratulated for an important study that sheds further light on the pathophysiology of post-transplant coronary disease. There are of course
79
limitations that may influence interpretation of the results. First, this is a small study of 40 cases in whom only the LAD was scanned. Second, there is no correlative angiographic data in general, particularly absent is information to know if non-scanned vessels showed evidence of disease. It is also important to emphasize limitations of IVUS-VH: OCT is superior to IVUS-VH for delineation of architecture, especially intimal patterns. Further, other direct coronary imaging techniques, including both OCT and near infrared spectroscopy (NIRS-IVUS), may provide advantages in characterization of plaque composition. Regardless, the present study highlights an important and potentially devastating clinical problem. Owing to the posttransplant denervated state, such patients rarely manifest typical angina, but instead may present catastrophically with heart failure, arrhythmias and sudden death. Accordingly, as the authors emphasize, these patients require close monitoring by imaging.
REFERENCES 1. Tomai F, Adorisio R, De Luca L, Pilati M, Petrolini A, et al. Coronary plaque composition assessed by intravascular ultrasound virtual histology: Association with long-term clinical outcomes after heart transplantation in young adult recepients. Catheter Cardiovasc Interv 2014;83:70–77. 2. Finn AV, Otsuka F. Neoatherosclerosis: A culprit in very late stenthrombosis. Circ Cardiovasc Interv 2012;5:6–9. 3. Park SJ, Kang SJ. In-stent neoatherosclerosis: A final common pathway of late stent failure. J Am Coll Cardiol 2012;59:2051– 2057. 4. Yamaji K, Inoue K, Nakahashi T, Noguchi M, Domei T, Hyodo M, Soga Y, Shirai S, Ando K, Kondo K, Sakai K, Iawbuchi M, Yokoi H, Nosaka H, Nobuyoshi M, Kimura T. Bare-metal stent thrombosis and in-stent neoatherosclerosis. Circ Cardiovasc Interv 2012;5:47–54. 5. Kang SJ, Mintz GS, Akasaka T, et al. Optical coherent tomographic analysis of in-stent neo-atherosclerosis after drug-eluting stent implantation. Circulation 2011;123:2913–2915.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
Editorial Comment Transplant Coronary Atherosclerosis: Parallels with In-Stent Neoatherosclerosis
triglycerides are common and attributable in great part to immunosuppressive agents).
CAV: EVIDENCE FOR NEOATHEROSCLEROSIS James A. Goldstein,* MD, FACC, FSCAI Department of Cardiovascular Medicine, Beaumont Health System, Royal Oak, Michigan
In the present era, cardiac transplant patients typically enjoy years of excellent cardiac function and favorable survival rates over 10–15 years. In its early period, cardiac transplantation survival was limited by rejection and complications attributable to the requisite but very toxic immunosuppressive drugs. Over the past 20 years, advances in immunosuppressive regimens have largely tamed rejection, though the body is incessantly attempting to immunologically “reject” the foreign organ. Further, although the necessary immunosuppressive agents are less toxic, patients universally suffer their adverse effects, including many which are pro-atherogenic (e.g., hypertension and hyperlipidemia).
POST-TRANSPLANT CORONARY DISEASE
The development of post-transplant cardiac allograft vasculopathy (CAV) is a feared, common and relatively “silent” complication, a problem insidious by nature but potentially catastrophic, and difficult to treat. CAV is progressive over time and beyond the first year represents the second most common cause of death, after malignancy. Nearly one-third of patients manifest angiographic coronary artery disease (which underestimates its true prevalence) at five years and over half at 10 years. CAV is a “pan-arterial” process characterized by diffuse concentric intimal hyperplasia in the epicardial vessels, with relative preservation of the internal elastic lamina. The microvasculature often develops concentric medial disease which may be “obliterative” (and is untreatable). Classic CAV is thought to predominantly reflect a response to immune mediated endothelial damage. However, other factors appear to play a role, particularly hyperlipidemia (elevations in serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL-cholesterol, and C 2013 Wiley Periodicals, Inc. V
Preservation of the internal elastic lamina and lack of lipid are felt to distinguish CAV from “common garden variety” atherosclerosis which is typically lipidbased, extends beyond the internal elastic lamina into the media, and most often observed in the epicardial vessels. However, transplant recipients may develop proximal coronary artery disease with lesions more closely resembling traditional atherosclerosis pathologically. Observations from direct coronary imaging in the present study by Tomai et al [1] now emphasize that post-transplant patients are prone to atherosclerotic disease, manifesting plaque composition patterns which resemble in-stent neoatherosclerosis (ISN). The present study employed intravascular ultrasound virtual histology (IVUS-VH) to characterize plaque composition during annual invasive evaluations in 40 young adult heart transplant recipients, comparing those who were 5 years (Group B). Only the left anterior descending artery (LAD) was scanned and plaque characterized according to standard IVUS-VH criteria. The key findings of the study demonstrate a time-dependent difference in plaque composition, with group B patients showing higher percentage of necrotic core and calcific plaque, and the interesting finding that only such patients exhibit “inflammatory plaque” (defined as necrotic core þ calcium). Notably, group B patients had higher prevalence of hypertension and hyperlipidemia and suffered more adverse events (54% vs. 14%), which included need for percutaneous coronary intervention (PCI), but Conflict of interest: Dr. Goldstein is a consultant for and owns equity in InfraReDx, Inc. *Correspondence to: James A. Goldstein, MD, FACC, FSCAI, Department of Cardiovascular Medicine, William Beaumont Hospital, 3601 W. 13 Mile Road, Royal Oak, MI 48073. E-mail: [email protected] Received 6 November 2013; Revision accepted 10 November 2013 DOI: 10.1002/ccd.25287 Published online 18 December 2013 in Wiley Online Library (wileyonlinelibrary.com)
Transplant Coronary Atherosclerosis: Parallels with In-Stent Neoatherosclerosis
also non-coronary events such as rejection, renal failure, and malignancy. SIMILARITIES TO IN-STENT NEOATHEROSCLEROSIS
The pathologic patterns of transplant coronary atherosclerosis observed in the present study bear striking resemblance to and may share pathophysiologic underpinnings with ISN. Evidence suggests ISN is an important substrate for both time-dependent in-stent restenosis (ISR) and late stent thrombosis [2–5]. Recent OCT observations in patients with drug eluting stent (DES-ISR) demonstrate that fully half of lesions consisted of thin-cap fibroatheromas (TCFA)-containing neointima, and over 50% had in-stent neointimal rupture and intraluminal thrombi [5]. Further, fragments of atherosclerotic plaques, including foamy macrophages, cholesterol crystals, and thin fibrous caps have been identified in cases of early and very late stent thrombosis [4]. Inflammation and hyperlipidemia are shared pathophysiologic processes common to transplant atherosclerosis and both native and ISN. It is well established that inflammation plays a fundamental role in the process of native atherosclerosis, and although the pathophysiology of ISN has not been fully delineated, endothelial incompetence and activation of inflammation are thought to play roles as mediators for longterm reaction to stent placement [2]. These processes are likely to also play major roles in transplant neoatheroscerosis.
CLINICAL IMPLICATIONS
The authors should be congratulated for an important study that sheds further light on the pathophysiology of post-transplant coronary disease. There are of course
79
limitations that may influence interpretation of the results. First, this is a small study of 40 cases in whom only the LAD was scanned. Second, there is no correlative angiographic data in general, particularly absent is information to know if non-scanned vessels showed evidence of disease. It is also important to emphasize limitations of IVUS-VH: OCT is superior to IVUS-VH for delineation of architecture, especially intimal patterns. Further, other direct coronary imaging techniques, including both OCT and near infrared spectroscopy (NIRS-IVUS), may provide advantages in characterization of plaque composition. Regardless, the present study highlights an important and potentially devastating clinical problem. Owing to the posttransplant denervated state, such patients rarely manifest typical angina, but instead may present catastrophically with heart failure, arrhythmias and sudden death. Accordingly, as the authors emphasize, these patients require close monitoring by imaging.
REFERENCES 1. Tomai F, Adorisio R, De Luca L, Pilati M, Petrolini A, et al. Coronary plaque composition assessed by intravascular ultrasound virtual histology: Association with long-term clinical outcomes after heart transplantation in young adult recepients. Catheter Cardiovasc Interv 2014;83:70–77. 2. Finn AV, Otsuka F. Neoatherosclerosis: A culprit in very late stenthrombosis. Circ Cardiovasc Interv 2012;5:6–9. 3. Park SJ, Kang SJ. In-stent neoatherosclerosis: A final common pathway of late stent failure. J Am Coll Cardiol 2012;59:2051– 2057. 4. Yamaji K, Inoue K, Nakahashi T, Noguchi M, Domei T, Hyodo M, Soga Y, Shirai S, Ando K, Kondo K, Sakai K, Iawbuchi M, Yokoi H, Nosaka H, Nobuyoshi M, Kimura T. Bare-metal stent thrombosis and in-stent neoatherosclerosis. Circ Cardiovasc Interv 2012;5:47–54. 5. Kang SJ, Mintz GS, Akasaka T, et al. Optical coherent tomographic analysis of in-stent neo-atherosclerosis after drug-eluting stent implantation. Circulation 2011;123:2913–2915.
Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Published on behalf of The Society for Cardiovascular Angiography and Interventions (SCAI).
