We sought to explore differences in distribution and morphology of coronary lesions comparing cardiac allograft vasculopathy and native coronary atherosclerosis (NCA) using intravascular imaging with optical coherence tomography (OCT). At the time of routine surveillance angiography, 17 heart transplant (HT) recipients with a history of high-grade cellular rejection (HGR) and 43 HT recipients with none/mild (low)-grade rejection underwent OCT imaging of the left anterior descending and were compared to 60 patients with NCA without HT. Compared with patients with NCA, patients with HGR had similar intima areas but smaller external elastic lamina areas (7.9 mm 2 [6.3, 11.2] versus 6.6 mm 2 [4.8, 7.5], p = 0.02) resulting in smaller lumen areas (4.5 mm 2 [3.4, 6.6] versus 3.3 mm 2 [2.8, 4.7], p = 0.04) in distal segments and smaller lumen diameters in side branches (1.28 mm [1.19, 1.37] versus 1.09 mm [0.94, 1.24], p = 0.04). Compared with patients with NCA, lesions in patients with HT were more homogeneous, involving the entire coronary vascular tree. Patients with HGR had a higher prevalence of macrophages involving ≥1 quadrant in all 3 segments compared with patients with NCA. The number of microvessels was greater in patients with both HGR and LGR HT versus NCA. In conclusion, distinct findings in the distribution and morphology of coronary lesions between HT recipients and patients with NCA are evident by OCT imaging, suggesting that OCT might be useful to help differentiate cardiac allograft vasculopathy from NCA in vivo.
Cardiac allograft vasculopathy (CAV), a major limitation to the long-term success of heart transplantation (HT), is still not completely understood in terms of pathologic mechanisms. Innate and adaptive immune responses are involved in the pathogenesis of CAV. Compared with traditional native coronary atherosclerosis (NCA), CAV has both histopathologic similarities and distinct differences. CAV is regarded as an accelerated diffuse fibroproliferative process that affects the entire coronary vascular tree; conversely, traditional NCA typically involves proximal coronary artery segments. Optical coherence tomography (OCT) provides high-resolution (10∼20 μm) intravascular imaging in vivo to allow in vivo visualization of coronary artery microstructure, including macrophages and vasa vasorum in advanced atherosclerotic plaques, and measurements of intimal thickness. The main purpose of this study is to use OCT to compare the morphologic features of coronary lesions in transplanted hearts versus NCA.
Methods
From February 2011 to March 2015, 75 patients with HT at Columbia University Medical Center (New York, New York) were enrolled in the study. Fifteen subjects were excluded because of poor image quality secondary to incomplete blood washout during image acquisition (n = 7), previous stent implantation (n = 2), and non–left anterior descending (LAD) vessel imaging (n = 6). The remaining 60 subjects with OCT imaging of the LAD were included in the present study. Per protocol, all HT recipients underwent annual coronary angiography with right ventricular biopsy. Tissue rejection was graded according to the International Society of Heart and Lung Transplantation (ISHLT) classification proposed in 1990 and revised (R) in 2005 : grade 0 (0R): no rejection; grade 1A (1R), focal, mild acute rejection; grade 1B (1R), diffuse, mild acute rejection; grade 2 (1R), focal, moderate acute rejection; grade 3A (2R), multifocal, moderate rejection; grade 3B (3R), diffuse, borderline severe acute rejection; and grade 4 (3R), severe acute rejection. Of the 60 HT recipients included in the present study, there were 17 subjects in the high-grade cellular rejection (HGR) group (ISHLT ≥3 A/2R) and 43 subjects in the none/mild-grade rejection (low-grade cellular rejection; LGR) group (ISHLT 0 to 2/0 to1R). The rejection grade used for this comparison was the worst rejection grade event recorded since HT.
In the same time period, we identified 60 patients with NCA without HT who underwent OCT examination of de novo LAD lesions for clinical purposes at the operator’s discretion at the time of diagnostic angiography (n = 22) or percutaneous intervention (n = 38).
The prespecified analysis was to compare patients with HGR with patients with NCA and patients with LGR with patients with NCA. The study was approved by the institutional review board, and all patients gave written informed consent.
Quantitative coronary angiography analysis was performed offline using QAngio XA, version 7.2.34.0 (Medis Medical Imaging Systems, Leiden, the Netherlands) without knowledge of OCT findings. After guiding catheter calibration, proximal, middle, and distal LAD segments were identified based on the American Heart Association classification that corresponded to the areas of OCT analysis. The minimal lumen diameter (MLD) and reference vessel diameter were measured; the diameter stenosis (DS) was calculated in each segment.
For acquisition of OCT images, the LightLab C7-XR Frequency Domain OCT system (St. Jude Medical, St. Paul, Minnesota) was used. After intracoronary nitroglycerin (100∼200 μg), the OCT imaging catheter (Dragonfly; St. Jude Medical) was advanced into the middle/distal segment of the LAD, and automatic pullback was initiated during continuous contrast injection (4 ml/s, 14∼18 ml total), with a pullback speed of 10 to 25 mm/s. Offline analysis of OCT images was performed by 2 independent investigators (PS and AM) blinded to clinical characteristics using LightLab ORW software, version C.0.4 (LightLab; Westford, Massachusetts) at an independent core laboratory (Cardiovascular Research Foundation, New York, New York) according to previously described method. After coregistration of OCT and angiographic studies, the OCT imaging runs were divided into 3 segments if all 3 (proximal, middle, and distal) angiographic segments had been visualized by OCT or 2 segments if only 2 (proximal and middle segments or middle and distal segments) angiographic segments had been visualized by OCT.
For quantitative analysis of each segment, we chose the frame with the minimum lumen area and the maximum plaque thickness (worst diseased site), and the frame with the maximum lumen area and the minimum plaque thickness (least diseased site), to measure external elastic lamina (EEL), internal elastic lamina (IEL), and lumen area for the distal segment but only the lumen area for the middle and proximal segments because of poor penetration in advanced plaques.
Percent media/EEL area, intima/EEL area, and intima/IEL area in the distal segments were calculated as follows :
For every visible side branch, the largest of the minimum diameters in consecutive OCT frames was measured.
The intima was considered eccentric if the minimal intimal thickness/maximal intimal thickness ratio was <0.5 or contained a lipid pool in ≥1 quadrants with normal intimal thickness (<0.3 mm) in the other quadrants. Microvessels within the intima appeared as signal-poor tubule luminal structures without connection to the vessel lumen in ≥3 consecutive frames. The maximum number of microvessels (flow voids) was counted, and the presence of multiple (at least 3 microvessels) in any 1 frame was tabulated. Calcium was a signal-poor region with sharply delineated borders. Macrophage accumulation was characterized by increased signal intensity within the lesion accompanied by heterogeneous backward shadows and tabulated as involving ≥1 or <1 quadrant. Lipidic plaque was characterized by a signal-poor region with diffuse borders accompanied by an overlying signal-rich band.
Baseline patient clinical characteristics were analyzed on a patient level; and angiographic and OCT characteristics were analyzed on a segment (proximal, middle, and distal) level. For patient and segment level data, categorical variables are presented as frequencies and compared with chi-square statistics or Fisher’s exact test; continuous variables are presented as median and 1st and 3rd quartiles and compared using the Mann–Whitney U test. A model with the generalized estimating equations approach was used to compensate for any potential cluster effect of multiple sites in the same patient (e.g., multiple side branches, multiple calcium deposits, and microvessels) and presented as least square means with 95% CIs. Statistical analysis was performed with SAS software, version 9.1.3 (SAS Institute Inc., Cary, North Carolina). A probability value <0.05 was considered statistically significant. The prespecified end point was a comparison of NCA versus either HGR or LGR in patients with HT.
Results
OCT imaging of all 3 LAD segments was available in all patients with HGR and NCA, but OCT imaging of either the distal or proximal LAD segment was incomplete in 3 patients with LGR.
Compared with the combined group of patients with HGR and LGR HT, patients with NCA had a higher prevalence of hypertension, dyslipidemia, and a history of coronary artery disease, had a more favorable lipid profile and more aggressive antiplatelet therapy with clopidogrel, but a lower prevalence of renal insufficiency and lower left ventricular ejection fraction ( Table 1 ). Half of the patients with NCA presented with an acute coronary syndrome (ACS); conversely, most transplant patients underwent routine invasive coronary imaging annually, and only 2 patients with HGR, but no patients with LGR presented with an ACS (p <0.01 for comparison between patients with NCA and the combined group of patients with HGR and LGR). Compared with patients with LGR, patients with HGR had longer intervals from transplantation to OCT imaging (p = 0.01) but similar donor age, cytomegalovirus reactivation and maintenance immunosuppression therapy, except for a trend for more sirolimus-based immunosuppression therapy (p = 0.09).
| Variable | Native Coronary Atherosclerosis (n = 60) | High-grade Rejection (n = 17) | Low-grade Rejection (n = 43) | p Value | |
|---|---|---|---|---|---|
| Native Coronary Atherosclerosis vs High-grade Rejection | Native Coronary Atherosclerosis vs Low-grade Rejection | ||||
| Age (years) | 59 (51, 67) | 64 (46, 67) | 60 (52, 65) | 0.82 | 0.51 |
| Men | 42 (70%) | 10 (59%) | 32 (74%) | 0.39 | 0.62 |
| Body mass index (kg/m 2 ) | 28.0 (24.1, 30.8) | 27.5 (27.5, 30.8) | 27.8 (24.7, 32.3) | 0.39 | 0.59 |
| Hypertension | 49 (82%) | 8 (47%) | 18 (42%) | 0.001 | <0.0001 |
| Dyslipidemia | 44 (73%) | 10 (59% ) | 23 (54%) | 0.25 | 0.04 |
| Diabetes mellitus | 22 (37%) | 5 (29%) | 13 (30%) | 0.58 | 0.5 |
| Renal insufficiency ∗ | 12 (20%) | 9 (53%) | 10 (23%) | 0.01 | 0.69 |
| Smoker | 21 (35%) | 5 (29%) | 13 (30%) | 0.67 | 0.61 |
| Prior coronary artery disease | 45 (75%) | 9 (53%) | 19 (44%) | 0.08 | 0.001 |
| Prior peripheral vascular disease | 3 (5%) | 1 (6%) | 2 (5%) | 1.0 | 1.0 |
| Acute coronary syndrome presentation | 33 (55%) | 2 (12%) | 0 (0%) | 0.002 | <0.0001 |
| Low-density lipoprotein cholesterol (mg/dL) | 68 (54, 93) | 97 (73, 118) | 96 (82, 115) | 0.03 | 0.0003 |
| High-density lipoprotein cholesterol (mg/dL) | 36 (30, 42) | 45 (40, 60) | 45 (38 ,57) | 0.0006 | <0.0001 |
| Triglycerides (mg/dL) | 105 (74, 157) | 131 (121, 161) | 152 (101, 222) | 0.04 | 0.003 |
| Left ventricular ejection fraction (%) | 55 (48, 57) | 62 (57, 63) | 60 (52.5, 64.5) | 0.001 | <0.0001 |
| Medication at the time of optical coherence tomography imaging | |||||
| Aspirin | 59 (98%) | 15 (88%) | 39 (91%) | 0.12 | 0.16 |
| Clopidogrel | 53 (88%) | 3 (18%) | 0 (0%) | <0.0001 | <0.0001 |
| Statin | 48 (80%) | 11 (65%) | 33 (77%) | 0.21 | 0.69 |
| Steroid | 13 (77%) | 32 (74%) | |||
| Tacrolimus | 10 (59%) | 25 (58%) | |||
| Sirolimus | 4 (24%) | 3 (7%) | |||
| Mycophenolatemofetil | 9 (53%) | 30 (70%) | |||
| Mycophenolic acid | 1 (6%) | 7 (16%) | |||
| Cyclosporine | 7 (41%) | 15 (35%) | |||
| HT indication for ischemic cardiomyopathy | 7 (41%) | 14 (33%) | |||
| Duration post-heart transplantation (years) | 11.6 (10.1, 13.5) | 7.0 (5.0, 13.0) | |||
| Donor age (years) | 24 (21, 32.5) | 30 (21, 38) | |||
| Cytomegalovirus reactivation | 4 (24%) | 15 (35%) | |||
∗ Creatinine clearance <60 ml/min calculated with the Cockcroft–Gault formula.
Angiographic findings are listed in Table 2 . Compared with patients with NCA, patients with HGR had comparable values in the proximal LAD segment, larger MLDs and smaller DS in the middle segment, and smaller MLD and larger DS in the distal segment, whereas patients with LGR had larger MLDs in all 3 segments and smaller DS in both middle and proximal segments.
| Variable | Native Coronary Atherosclerosis (n = 60) | High-grade Rejection (n = 17) | Low-grade Rejection (n = 43) | p Value | |
|---|---|---|---|---|---|
| Native Coronary Atherosclerosis vs High-grade Rejection | Native Coronary Atherosclerosis vs Low-grade Rejection | ||||
| Distal segment | 60 | 17 | 42 | ||
| Minimal lumen diameter (mm) | 2.0 (1.8, 2.4) | 1.8 (1.4, 2.0) | 2.3 (1.9, 2.6) | 0.03 | 0.05 |
| Reference vessel diameter (mm) | 2.3 (2.1, 2.8) | 2.1 (2.0, 2.5) | 2.6 (2.3, 2.8) | 0.17 | 0.09 |
| Diameter stenosis (%) | 11.8 (7.6, 15.4) | 18.4 (14.6, 27.3) | 11.5 (8.4, 15.1) | 0.004 | 1.0 |
| Middle segment | 60 | 17 | 43 | ||
| Minimal lumen diameter (mm) | 1.8 (1.4, 2.0) | 2.3 (1.8, 2.5) | 2.5 (2.2, 2.8) | 0.02 | <0.0001 |
| Reference vessel diameter (mm) | 2.7 (2.4, 3.0) | 2.7 (2.3, 2.8) | 2.8 (2.4, 3.2) | 0.54 | 0.49 |
| Diameter stenosis (%) | 34.4 (25.3, 43.4) | 14.7 (9.6, 27.3) | 11.9 (8.2, 18.0) | 0.001 | <0.0001 |
| Proximal segment | 60 | 17 | 41 | ||
| Minimal lumen diameter (mm) | 2.7 (1.9, 3.2) | 2.8 (2.5, 3.3) | 3.2 (2.6, 3.5) | 0.29 | 0.01 |
| Reference vessel diameter (mm) | 3.4 (2.9, 3.8) | 3.3 (3.0, 3.5) | 3.7 (3.3, 4.2) | 0.61 | 0.08 |
| Diameter stenosis (%) | 16.7 (8.5, 35.9) | 12.5 (11.0, 17.9) | 10.4 (8.2, 15.7) | 0.44 | 0.009 |
OCT quantitative findings are provided in Table 3 , Figure 1 , and Figure 2 . At the maximally diseased site and compared with patients with NCA, patients with HGR had a similar lumen area in the proximal segment and a larger lumen area in the middle segment; however, patients with HGR had a smaller media area, comparable intima area, and smaller lumen area (because of a smaller EEL and IEL area) in the distal segment. Conversely, patients with LGR had a larger lumen area in all 3 segments as well as a smaller media area and intima area in the distal segment. At the minimally diseased sites, patients with HGR had no significant differences in the lumen area in all 3 segments, whereas patients with LGR had a larger lumen area in all 3 segments versus patients with NCA.
| Variable | Native Coronary Atherosclerosis (n = 60) | High-grade Rejection (n = 17) | Low-grade Rejection (n = 43) | p Value | |
|---|---|---|---|---|---|
| Native Coronary Atherosclerosis vs High- grade Rejection | Native Coronary Atherosclerosis vs Low-grade Rejection | ||||
| Distal segment | |||||
| Worst diseased site | |||||
| EEL area (mm 2 ) | 7.9 (6.3, 11.2) | 6.6 (4.8, 7.5) | 8.2 (5.7, 10.8) | 0.02 | 0.52 |
| IEL area (mm 2 ) | 6.8 (5.4, 10.1) | 5.9 (4.2, 6.6) | 7.2 (5.1, 9.6) | 0.03 | 0.78 |
| Lumen area (mm 2 ) | 4.5 (3.4, 6.6) | 3.3 (2.8, 4.7) | 6.1 (4.0, 8.1) | 0.04 | 0.01 |
| Media area (mm 2 ) | 1.0 (0.8, 1.4) | 0.7 (0.6, 0.9) | 0.7 (0.5, 1.2) | 0.01 | 0.007 |
| Intima area (mm 2 ) | 2.3 (1.1, 3.7) | 1.8 (0.9, 3.3) | 0.8 (0.5, 1.8) | 0.32 | <0.0001 |
| %media/EEL area | 12.8 (10.2, 15.1) | 11.5 (9.2, 15.4) | 10.3 (8.1, 11.8) | 0.70 | 0.0006 |
| %intima/EEL area | 27.0 (17.1, 39.4) | 36.0 (15.1, 45.2) | 12.2 (7.9, 16.4) | 0.49 | <0.0001 |
| %intima/IEL area | 30.8 (19.1, 45.8) | 42.0 (17.3, 51.0) | 13.6 (8.8, 19.1) | 0.47 | <0.0001 |
| Least diseased site | |||||
| IEL area (mm 2 ) | 7.5 (5.6, 9.4) | 6.5 (5.9, 7.1) | 7.8 (5.6, 10.6) | 0.17 | 0.86 |
| Lumen area (mm 2 ) | 5.3 (4.1, 7.4) | 5.1 (3.2, 6.4) | 6.5 (4.6, 8.8) | 0.21 | 0.05 |
| Middle segment | |||||
| Lumen area at worst diseased site (mm 2 ) | 3.0 (2.2, 4.5) | 6.3 (3.8, 6.9) | 8.2 (6.0, 10.9) | 0.0005 | <0.0001 |
| Lumen area at least diseased site (mm 2 ) | 7.3 (5.9, 9.7) | 7.1 (5.9, 8.9) | 10.2 (7.4, 12.7) | 0.53 | 0.002 |
| Proximal segment | |||||
| Lumen area at worst diseased site (mm 2 ) | 6.4 (4.4, 9.5) | 8.1 (6.6, 12.0) | 11.6 (8.4, 15.1) | 0.21 | <0.0001 |
| Lumen area at least diseased site (mm 2 ) | 9.8 (8.1, 12.4) | 9.0 (7.9, 13.7) | 13.6 (9.9, 16.2) | 0.55 | 0.002 |
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