Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study)

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1 Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study) Sameer J. Khandhar, MD, a Hirosada Yamamoto, MD, b Jeffrey J. Teuteberg, MD, a Michael A. Shullo, PharmD, c Hiram G. Bezerra, MD,PhD, b Marco A. Costa, MD,PhD, b Faith Selzer, PhD, d Joon S. Lee, MD, a Oscar C. Marroquin, MD, a Dennis M. McNamara, MD, a Suresh R. Mulukutla, MD, a and Catalin Toma, MD a From the a Heart and Vascular Institute, Center for Quality, Outcomes, and Research, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; b Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve School of Medicine, Cleveland, Ohio; c Department of Pharmacy and Therapeutics, University of Pittsburgh, Pennsylvania; and the d Department of Epidemiology, University of Pittsburgh, Pennsylvania. KEYWORDS: optical coherence tomography; cardiac transplantation; coronary allograft vasculopathy; intima-to-media ratio BACKGROUND: Optical coherence tomography (OCT) is a novel intravascular imaging modality with excellent spatial resolution. This study explored the utility of OCT in cardiac transplantation for the detection and characterization of early changes associated with coronary allograft vasculopathy (CAV). METHODS: Fifteen consecutive patients, 1 to 4 years after transplant with no angiographic evidence of CAV, underwent successful OCT imaging using the Fourier-domain OCT system (C7-XR, St. Jude Medical, St. Paul, MN) in the left anterior descending artery. Analysis included measurements of the lumen, intima, and media layers, and characterization of atherosclerotic plaques. Patients were stratified by intima-to-media (I/M) ratio and classified as normal (r1) or abnormal (41). RESULTS: Patients were a mean of 2.8 years after transplant, 58 years old, and 92% were men. OCT imaging revealed 8 of 15 patients had intimal hyperplasia with an I/M ratio 41. Comparing those with I/M ratio of r1 and 41, the median (interquartile range) intimal thickness was greater (75 [70 101] vs 206 [97 269] mm, p ¼ 0.03), whereas the media thickness was no different (72 [70 103] vs 94 [73 113] mm, p ¼ 0.53). In addition, 7 of 15 patients had lipid-rich or calcified atherosclerotic plaques. CONCLUSIONS: OCT provides high-resolution quantitative imaging of the coronary arteries and its use allows for detailed assessment of the coronary artery wall and early morphologic changes that occur after cardiac transplantation. The clinical predictive value of these OCT-derived measurements remains to be determined. J Heart Lung Transplant 2013;32: r 2013 International Society for Heart and Lung Transplantation. All rights reserved. Coronary allograft vasculopathy (CAV) remains the leading cause of graft failure and second leading cause of Reprint requests: Sameer J. Khandhar, MD, Heart and Vascular Institute, University of Pittsburgh Medical Center, 200 Lothrop St, Ste A-333, PUH, Pittsburgh, PA Telephone: Fax: address: khandharsj@upmc.edu /$ - see front matter r 2013 International Society for Heart and Lung Transplantation. All rights reserved. death 3 years after cardiac transplantation. 1 CAV is a complex entity involving intimal thickening, atherosclerosis, and vasculitis by histology, 2,3 but ultimately, intimal hyperplasia is the predominant cause of lumen narrowing and graft failure. CAV progresses silently and tends to become symptomatic only in its most advanced stages, underscoring the

2 Khandhar et al. OCT for Characterization of CAV 597 importance of screening. Yearly angiography is the most frequently used method; however, angiography commonly underestimates the severity of disease. Intravascular ultrasound (IVUS) has become the gold standard for early CAV detection; however, IVUS and virtual histology-ivus (VH- IVUS) have limitations in being able to clearly distinguish the layers of the coronary vessel wall or characterize atherosclerotic plaques. Although a change in intima plus media of greater than 350 to 500 mm by IVUS at 1 year defines a high-risk transplant population, 4 8 the normal thickness of the intima and media layers is well below the 200-mm resolution of IVUS. Thus, IVUS cannot detect the more subtle changes in intimal thickness, and it remains unknown whether the poor outcomes observed in patients with CAV defined by angiography or IVUS only reflects detection of an advanced disease state. Whether earlier detection using higher-resolution imaging methods can improve outcomes is not known. Coronary optical coherence tomography (OCT) received U.S. Food and Drug Administration approval for clinical use in 2010 as a new catheter-based intravascular imaging technology with a higher resolution than IVUS. OCT uses a near-infrared light source and is based on image reconstitution from reflected light that is coherent (ie, in phase) with the emitted light, thus eliminating the scattered light signal and allowing for high-resolution imaging. Frequency domain (or Fourier domain) OCT allows for rapid imaging of the coronary architecture with a radial resolution in the order of 20 mm. Measurements of intimal thickness 9 and plaque characterization 10 have been shown to be very accurate by OCT compared with histology; therefore, the use of OCT for quantification of CAV is appealing. In the current study, we aimed at assessing the ability of coronary OCT (1) to detect and quantify intimal thickening in patients early after transplant without angiographic disease, (2) qualitatively assess the structure of the intima when disease is present, and (3) characterize traditional atherosclerotic plaques after transplant. Methods Study population Between July 2011 and September 2012, 17 consecutive patients without angiographic evidence of CAV, who were 1 to 4 years after cardiac transplantation, underwent OCT imaging at the time of their annual routine surveillance left heart catheterization. Patients were excluded if they received their cardiac transplant as part of multiorgan transplant, had a creatinine clearance by Cockcroft- Gault of less than 30 ml/min, were receiving renal replacement therapy, or if they had angiographic evidence of CAV. Angiographic CAV was defined as greater than 30% epicardial stenosis 11 or significant distal pruning of vessels defined as B1, B2, or C lesions according to the Gao classification. 12 All data on patients who received transplants at the University of Pittsburgh Medical Center are collected prospectively in the Transplant Patient Management System (TPMS), and this was accessed to obtain patient demographic information. The Institutional Review Board approved this study and all patients signed the informed consent form before their data were entered into TPMS and undergoing OCT imaging. Performing OCT OCT imaging was performed at the same time as the patient s regularly scheduled surveillance cardiac catheterization. OCT imaging was performed with the commercially available secondgeneration frequency domain C7-XR system (St. Jude Medical, St. Paul, MN). The OCT catheter was advanced over a inch coronary guidewire into the middle left anterior descending artery (LAD), and imaging was performed by automated pullback triggered at a speed of 20 mm/s. This was performed after administration of 100 to 300 mg of intracoronary nitroglycerin and simultaneous injection of 14 ml of contrast by power injector through the guiding catheter. Image analysis The images were saved and sent to an independent OCT core laboratory (Cardiovascular Imaging Core Laboratory, University Hospitals Case Medical Center, Cleveland OH), which was blinded to patient characteristics. Image analysis was performed off-line by manually tracing the lumen, intima, and media layers on a dedicated OCT workstation. All cross-sectional images were initially reviewed for quality, and frames were excluded if a side branch occupied 4451 of the cross section or if the image had poor quality due to residual blood, artifact, or reverberation. OCT imaging routinely captures 54 mm of the vessel on each pullback, and this is divided into 256 frames. Tracing of the coronary wall layers and plaque characterization is performed every 5 2 frames for the entire segment. The layers were analyzed by OCT consensus standard definitions of the intima being a uniform signal-rich bright layer and the media being a signal-poor darker layer due to low backscatter. 13 The lumen, intima, and media layers for each frame were traced to obtain average thickness and area. Values from 35 consecutive millimeters were averaged to yield average thickness and area. The intima-to-media ratio (I/M) was calculated by dividing the average area of each layer over the 35 mm of the vessel analyzed. An I/M ratio of 41 was defined as abnormal. Volumetric assessment of the vessel was performed in a similar manner to prior the IVUS-based studies Vessel lumen, intimal, and medial volumes were calculated based on the crosssectional area multiplied by segment length, which was usually 1 mm. Plaque volume was defined as the intimal plus media volume by tracing the lumen and media-adventitia border (external elastic membrane), similar to IVUS studies. Vessel volume was defined by tracing the media-adventitia border and included the vessel lumen. The plaque index was calculated by dividing plaque volume by vessel volume. Plaque characterization was performed off-line in a similar manner. Every 5 2 frames over the entire 54 mm of the vessel were analyzed by dividing each frame into quadrants, and the presence of lipid or calcified plaque was recorded for each quadrant. Lipid-rich regions were defined as an area of low signal with poorly defined margins and signal attenuation or shadowing behind the plaque. Calcified regions were identified as sharply delineated areas of decreased signal with significant signal attenuation, as previously described. 13,17,18 Statistical analysis Patients were stratified by I/M ratio and classified as normal (r1) or abnormal (41). Descriptive statistics are summarized as means standard deviation or medians and interquartile range for

3 598 Table 1 Baseline Demographics in Patients With and Without Cardiac Allograft Vasculopathy a The Journal of Heart and Lung Transplantation, Vol 32, No 6, June 2013 Variable b Overall I/M ratio r 1 I/M ratio 4 1 (n ¼ 15) (n ¼ 7) (n ¼ 8) p-value Age, years Sex, % male 14 (93) 7 (100) 7 (88) Race, % white 14 (93) 7 (100) 7 (88) Time from transplant to OCT, years Indication for transplant, % ICM 10 (67) 5 (71) 5 (63) Donor age, years Ischemic time, (min) PRA 420 at transplant CMV mismatch 4 (27) 3 (43) 1 (13) 0.28 Induction with Campath c 14 (93) 7 (100) 7 (88) treated acute cellular rejections Immunosuppression Tacrolimus 14 (93) 7 (100) 7 (88) Mycophenolate mofetil 12 (80) 6 (86) 6 (75) Sirolimus 2 (13) 1 (14) 1 (13) Azathioprine 2 (13) 0 (0) 2 (25) 0.47 Diabetes 9 (60) 5 (71) 4 (50) 0.61 Aspirin use 1 (7) 1 (14) 0 (0) 0.46 Statin use 13 (87) 6 (86) 7 (88) Total cholesterol, mg/dl LDL cholesterol, mg/dl Triglycerides, mg/dl CMV, cytomegalovirus; I/M, intima to media; ICM, ischemic cardiomyopathy; LDL, low-density lipoprotein; OCT, optical coherence tomography; PRA, panel reactive antibody. a Cardiac allograft vasculopathy defined as I/M ratio of 41. b Continuous data are presented as mean standard deviation and categoric data as counts (percentage). c Genzyme, Cambridge, Massachusetts. continuous variables, depending on normality, and percentages for categoric variables. Overall comparisons between those with normal and abnormal vessel thickness were made using Student s t-tests or Wilcoxon nonparametric tests for continuous variables and the chisquare test or Fisher s exact test for categoric variables. Linear mixed models were used to evaluate the association between vessel measurements and location along the vessel (distal to proximal). The correlation within patients was accounted for by the inclusion of different random intercepts for each patient. Analyses were performed with SAS 9.3 software (SAS Institute Inc, Cary, NC), and a 2-sided p-value of r0.05 was considered to indicate statistical significance. Results All patients tolerated the procedure well, and there were no complications from OCT imaging. Image quality in 15 of the 17 patients was adequate for analysis by the core laboratory. Two patients had poor image quality for detailed core laboratory analysis due to incomplete blood washout during image acquisition. The baseline characteristics of all patients at the time of OCT imaging are listed in Table 1. At the time of imaging, patients were an average of years after transplant, an average age of years, 93% were men, 93% were white, and 60% had diabetes. Patients with an I/M ratio of 41 tended to be later after transplant ( vs years, p ¼ 0.02) and had lower total cholesterol values, although there was no difference in statin use. Statins were used in 13 of 15 patients and titrated to a target low-density lipoprotein level of o100 mg\dl. Two patients were intolerant to multiple statin agents and therefore did not receive one. No patients had a panel reactive antibody 420% at time of transplant or 42 episodes of treated acute cellular rejection. A combination of tacrolimus and azathioprine or mycophenolate mofetil was used in 13 of 15 patients for maintenance immunosuppression. Two patients received sirolimus-based immunosuppression, with 1 patient receiving a regimen of sirolimus and mycophenolate mofetil due to renal insufficiency, and the other receiving sirolimus and dose-reduced tacrolimus due to intolerance of mycophenolate mofetil. Characterization of intima-media layers The median (interquartile range) lumen area for the investigated coronary segments was 6.25 ( ) mm 2 ; intimal thickness, 100 (75 218) mm; media thickness, 82 (70 107) mm; I/M ratio, 1.25 ( ); intimal volume, ( ) mm 3 ; plaque volume, ( ) mm 3 ; and plaque index, ( ). Findings are summarized in Table 2. Representative cross-sectional OCT images from patients with and without significant intimal thickening are shown in Figures 1 and 2. Clear delineation of the internal and external elastic

4 Khandhar et al. OCT for Characterization of CAV 599 Table 2 Vessel Analysis and Comparison Between Groups Based on Intima-to-Media Ratio Variables a Overall I/M ratio r 1 I/M ratio 4 1 (n ¼ 15) (n ¼ 7) (n ¼ 8) p-value b Lumen area, mm ( ) 6.25 ( ) 5.94 ( ) 0.69 Intimal thickness, mm 100 (75 218) 75 (70 101) 206 (97 269) 0.03 Media thickness, mm 82 (70 107) 72 (70 103) 94 (73 113) 0.53 Intimal volume, mm ( ) ( ) ( ) 0.01 Media volume, mm ( ) 23.0 ( ) ( ) 0.24 Plaque volume, mm ( ) ( ) ( ) Plaque index, % ( ) ( ) ( ) I/M ratio 1.25 ( ) 0.85 ( ) 1.53 ( ) I/M, intima to media. a Values are presented as median (interquartile range). b The p-value is not provided for I/M ratio because it defines the 2 groups. membranes is seen, allowing for tracing of the lumen, intima, and media layers. The media has a distinct low-intensity signal compared with the brighter intima that allows for identification of the boundaries between the intima, media, and adventitia layers even when neointimal thickening is present. Given that CAV is a disease of the intima, we sought to further characterize the intima layer and used an average I/M ratio of 41 to define abnormal. As determined by this ratio, 8 of 15 patients had clearly abnormal intimal thickening. Comparing groups, patients with a ratio of r1 had a significantly thinner intima that those with a ratio of 41 (median [interquartile range] thickness was 75 [70 101]vs 206 [97 269] mm, p ¼ 0.03). Even in the 7 patients with an average I/M ratio of r1, isolated slices with a maximal I/M ratio of 41 did exist. However, only 16.6% of all slices in this group had a maximal I/M ratio 41, and the average of the I/M ratio when 41 was only Therefore, it is unlikely that patients with an average I/M ratio of o1 will have focal areas of severe intimal thickening. Longitudinal distribution of CAV We performed a longitudinal analysis of lumen area, intima and media thickness, and I/M ratio over the middle segment of the LAD. Figure 3A summarizes the average increase in lumen area from the distal to proximal segment over the 35 mm of the LAD that was analyzed compared with the I/M ratio. Figure 3B shows the average change in intima and media thickness over the same distance. There was a significant linear correlation between intima and media thickness as measured by OCT with the lumen dimension; that is, both layers were thicker in the proximal larger portion of the LAD (p o 0.001). Importantly, the I/M ratio over the analyzed segment of the LAD did not change from the distal to proximal points, indicating that this parameter is independent of the caliber or segment of the coronary artery. Characterization of traditional atherosclerotic plaque In addition to intimal hyperplasia, quantification of lipidrich and calcified atherosclerotic plaques was performed. Overall, 7 of 15 patients had a combination of lipid and calcified plaques. Sample images of lipid-rich plaques are shown in Figure 4 and calcified plaques in Figure 5. In patients with an average I/M ratio of r1, 3 patients had lipid plaque that comprised o1% of quadrants analyzed. These small plaques were noted in focal areas of intimal thickening. In the group with an I/M ratio of 41, 4 of 8 patients had evidence of atherosclerotic plaque (3 with lipid and 1 with calcified) comprising 4.2% of quadrants analyzed, of which 1 patient had significant lipid-filled plaques comprising 22% of quadrants analyzed. Discussion The current study explores the feasibility of detecting the early morphologic changes of the intima in heart transplant recipients without clinical or angiographic evidence of disease. We have demonstrated that OCT provides detailed assessment of the coronary wall, allowing for the quantification of early-stage intimal thickening and the characterization of atherosclerotic plaques. In the patients without angiographic evidence of CAV, 8 of 15 patients had abnormal intimal thickening that was defined when the I/M ratio is 41. As expected, these patients had a thicker intima, greater plaque volume, and plaque index, whereas thickness of the media layer was no different. In this group of patients early after transplantation, the main difficulty resides in defining a threshold for abnormal intimal thickening. The normal coronary endothelium is a thin layer of cells residing on the internal elastic membranes, whereas the media is a thicker layer consisting of smooth muscle cells. 19 Histology studies have shown that CAV tends to primarily affect the intimal layer, leading to neointimal hyperplasia with sparing of the media. 2 Therefore, the normal I/M ratio is o1, and as intimal hyperplasia occurs, this ratio increases to On the basis of these histologic considerations, we propose that an I/M ratio of 41, as measured by OCT, as abnormal. This simple measurement may serve as a useful cutoff for determining early changes that lead to the development of clinical CAV. This ratio, as opposed to an absolute value based on point measurements, is likely to be less subjected

5 600 The Journal of Heart and Lung Transplantation, Vol 32, No 6, June 2013 Figure 1 Optical coherence tomography imaging of a patient with significant intimal hyperplasia shows tracing of intima and media layers. (A) A cross-sectional slice of the coronary artery and (B) method of tracing intima and media layers are shown. (C) The lines on the longitudinal view of vessel show every millimeter to illustrate the 35 slices taken for analysis. Figure 2 Optical coherence tomography imaging of a patient with no significant intimal hyperplasia shows tracing of intima and media layers. (A) A cross-sectional slice of the coronary artery and (B) method of tracing intima and media layers are shown. to measurement artifacts when the OCT catheter is off-axis or sliced obliquely, in which case the vessel wall can appear artificially thicker. Furthermore, our data show that intima and media thickness varies relative to the vessel caliber, and a single cross-sectional measurement of only intima or intima plus media thickness does not provide accurate assessment of the diffuse nature of CAV along the coronary tree. 3,20 The I/ M ratio, however, stays uniform throughout the vessel, supporting the argument that this may be a better measurement and one that can be done anywhere along the vessel. OCT is a relatively novel imaging modality, and its use has only recently been described for detection of CAV. Garrido et al 21 reported its use in patients months after transplant and showed that OCT findings correlated with well with IVUS. This group performed OCT in patients late after transplant, with mean maximal intimal thickness of 420 mm, and it is not clear whether patients already had angiographic disease. 21 The strong correlation between OCT and IVUS in patients with severe intimal hyperplasia is expected because the resolution of IVUS will allow detection at that degree of intimal thickness. Hou et al, 22 in a letter to the editor, described the use of OCT in 7 patients between 1.5 and 17 years after transplantation and found OCT detected intimal thickness defined as a point measurement of 4100 mm in 66% of patients, whereas IVUS detected intimal hyperplasia in only 14%.

6 Khandhar et al. OCT for Characterization of CAV 601 Figure 3 Longitudinal measurement by optical coherence tomography (OCT) of (A) average lumen size and intima-to-media ratio over the length of vessel and (B) average intima and media thickness over the length of vessel. LAD, left anterior descending artery. Unlike these studies, we focused exclusively on the early post-transplant period and on patients without angiographic disease. We believe that OCT will likely have its greatest impact in characterizing CAV in its early stages, at which time subtle or small changes of the intima that are below the resolution of IVUS may be important. In addition, we attempted to describe the full potential of OCT by analyzing a complete segment of the vessel rather than just performing between 1 and 5 point measurements of maximal intimamedia thickness. 4,5,22,23 We now know that traditional atherosclerosis likely plays a role in graft failure and death in addition to intimal hyperplasia after transplant. Patients with graft failure requiring repeat transplantation were found to frequently have traditional atherosclerosis on gross pathology. 2 In our cohort, 7 of 15 patients had some evidence of traditional atherosclerotic plaque. The plaques noted in patients without intimal hyperplasia was very focal and limited to o1% of all quadrants analyzed, whereas, 50% of patients with intimal hyperplasia had traditional atherosclerotic plaques and 1 patient had significant lipid plaque in 22% of the quadrants analyzed. The effect this has on outcomes after transplant and whether this is donor atherosclerosis or develops after transplantation is still under investigation. Similar characterization of plaque has been attempted with IVUS and VH-IVUS, 4,6,24 but when done by Hernandez et al 4 for this purpose, only 14% of patients could have reliable assessment for atherosclerosis by VH-IVUS because intimal hyperplasia further decreases the resolution of VH- IVUS. OCT allowed for plaque characterization in all 15 patients, even in those with intimal hyperplasia, which is a limitation of VH-IVUS. Our study is limited by the relatively small number of patients, the lack of serial measurements, and the lack of long-term follow-up data. OCT and IVUS have been compared extensively in the non-transplant literature, and we did not perform a head-to-head comparison because OCT has been shown to have superior spatial resolution. Because OCT is a new imaging modality, long-term prospective data are lacking on whether OCT measurements predict cardiac events in a manner similar previous IVUS studies 25 and if these measurements can redefine clinically significant CAV. This is the main limitation of our study, and further longitudinal studies will be required to assess whether the more subtle degrees of intimal thickness detected by OCT, I/M ratios, and OCT-detected atherosclerotic plaques correlate with outcomes. Figure 4 plaque. A slice divided into quadrants (1 4) illustrates a lipid Figure 5 A slice divided into quadrants (1 4) and illustrates a calcified plaque.

7 602 The Journal of Heart and Lung Transplantation, Vol 32, No 6, June 2013 OCT technology itself does have certain limitations, mainly that complete blood washout from the coronary is necessary to good image quality and does not provide the deep tissue penetration that IVUS does. The tissue penetration of OCT is 1.5 to 3 mm, which is less than IVUS, 17 but this is still sufficient to image the intima and media layers and still was sufficient in our study to image the intima and media layers even in patients with significant intimal thickening. In conclusion, OCT allows for accurate high-resolution quantitative imaging of the coronary arteries and characterization of the early neointimal hyperplasia changes that occur after heart transplantation. We are proposing an I/M ratio of 41 as a specific and easy to use cutoff for defining abnormal intimal thickening by OCT. OCT-derived measurements may be valuable tools in future CAV therapy trials and for risk stratification. However, further prospective studies are needed to understand how OCT-derived measurements, including the I/M ratio, correlate with outcomes and how they define clinically significant CAV. Disclosure statement The authors thank the clinical research coordinators Mary Catherine Coast, Lisa Baxendell, Laurie Dennis, and Melissa Enlow, and heart transplant coordinators Cynthia Grabowski, Chavonne Newman, and Colleen Yost for their help with this study. The American Heart Association Clinical Research Program Grant in part supported this project and S.K. M.C. has a consulting relationship with St Jude, which is modest (4$10,000). H.B. has a consulting relationship with St Jude, which is modest (4$10,000). None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. References 1. Stehlik J, Edwards LB, Kucheryavaya AY, et al. 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