Author + information
- Received May 27, 2015
- Revision received July 13, 2015
- Accepted July 17, 2015
- Published online December 1, 2015.
- Kozo Okada, MD,
- Hideki Kitahara, MD,
- Hyoung-Mo Yang, MD,
- Shigemitsu Tanaka, MD,
- Yuhei Kobayashi, MD,
- Takumi Kimura, MD,
- Helen Luikart, RN,
- Paul G. Yock, MD,
- Alan C. Yeung, MD,
- Hannah A. Valantine, MD,
- Peter J. Fitzgerald, MD, PhD,
- Kiran K. Khush, MD, MAS,
- Yasuhiro Honda, MD and
- William F. Fearon, MD∗ ()
- Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University Medical Center, Palo Alto, California
- ↵∗Reprint requests and correspondence:
Dr. William F. Fearon, Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Drive, Room H2103, Stanford, California 04305-5218.
Objectives This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.
Background CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.
Methods In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].
Results After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).
Conclusions Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.
- cardiac transplant
- intravascular ultrasonography
- long-term mortality
- pathological remodeling
Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality and morbidity after heart transplantation (1). Although early heart transplantation studies focused primarily on coronary intimal thickening to assess the severity of CAV (2,3), vessel remodeling has been recognized as another important measure in recent investigations (4,5). Compared with contrast angiography, intravascular ultrasonography (IVUS) can directly visualize the arterial wall structure, offering a more sensitive method to detect intimal thickening and vessel remodeling (6).
Previous IVUS studies of CAV have reported controversial results with respect to arterial response early after heart transplantation, demonstrating variable degrees of coronary intimal thickening and vessel size alteration in opposite directions (negative vs. positive vessel remodeling) (4,5,7–9). The discrepancies in these studies are likely explained by the use of 2-dimensional (2D) IVUS analysis and/or cross-sectional study design using heterogeneous patient populations as opposed to longitudinal investigations of the same patients. The pathology of CAV, characterized by a combination of coronary intimal thickening and pathological vessel remodeling, also appears to vary at different locations in the coronary arteries (10,11). Hence, we hypothesized that comprehensive 3D volumetric IVUS analysis might measure the nature and severity of CAV more accurately than conventional 2D planar IVUS indices. The aims of this study, therefore, were to characterize the early arterial responses, particularly pathological vessel remodeling, and anatomic distribution of CAV as measured by 3D IVUS and to investigate their association with clinical outcomes after heart transplantation.
Between January 2002 and January 2013, heart transplantation recipients in stable condition with preserved renal function (serum creatinine concentration of ≤2.0 mg/dl at baseline), who successfully survived at least 1 year after heart transplantation and underwent scheduled serial IVUS imaging at baseline (within approximately 6 weeks) and at 1 year post-transplantation were eligible for enrollment in this retrospective study. Hospitalized or patients in unstable condition at 1 year were excluded. All recipients received standard immunosuppressive therapy, including induction therapy with daclizumab or rabbit antithymocyte globulin, corticosteroids, an antiproliferative agent (rapamycin or mycophenolate mofetil), and a calcineurin inhibitor (cyclosporine or tacrolimus). Patients were monitored for acute cellular rejection using right ventricular endomyocardial biopsy at scheduled intervals post-transplant: weekly during the first month, biweekly until the third month, monthly until the sixth month, and then at 9 and 12 months. Biopsy results were graded according to the International Society for Heart and Lung Transplantation (ISHLT) 2004 revised grading scale, and significant acute cellular rejection was defined as one or more episode(s) of a grade ≥2R during the first year post-transplant (12,13). Lipid parameters (total cholesterol and triglycerides) and left ventricular ejection fraction (LVEF), as measured by echocardiography, were also evaluated at 1 year post-transplantation. Patients were followed beyond the first year post-transplantation, and the primary endpoint of this study was major adverse events, defined as all-cause death or re-transplantation. The study protocol was approved by the Institutional Review Board at Stanford University, and every patient provided written informed consent.
IVUS Imaging Protocol
After diagnostic coronary angiography was performed, 3,000 to 5,000 units of heparin were administered intravenously, and 200 μg of intracoronary nitroglycerin were administered through a 6-F guide catheter in the left coronary artery. A 0.014-inch guide wire was advanced to the mid to distal left anterior descending artery (LAD). IVUS imaging was performed using a mechanical IVUS system with a 40-MHz imaging catheter (Galaxy with Atlantis SR Pro or OptiCross with iLab; Boston Scientific Corp., Marlborough, Massachusetts). The catheter was advanced to the mid to distal LAD, and an automated pullback was performed at 0.5 mm/s. Images of the first 50 mm of the LAD were recorded and analyzed offline (4,12,13).
IVUS analysis was performed with a validated quantitative IVUS analysis system (echoPlaque, Indec Systems, Santa Clara, California) at the Stanford University Cardiovascular Core Analysis Laboratory, blinded to clinical and angiographic information (4). Vessel, lumen, and intimal areas (calculated as: vessel minus lumen) were manually traced at 1-mm intervals throughout the first 50 mm of each LAD, and the interpolated measurements of the remaining frames were automatically generated. Vessel, lumen, and intimal volumes were calculated using the Simpson method and standardized as volume index (defined as: volume / analyzed length, mm3/mm) (4). To represent pathological arterial response over time, paradoxical vessel remodeling was defined as increased intimal volume with negative vessel remodeling (decreased vessel volume) or decreased intimal volume with positive vessel remodeling (increased vessel volume) during the first year post-transplantation (14), calculated mathematically as: [Δvessel volume/Δintimal volume <0]. Maximal intimal thickness (MIT) was also obtained as a conventional 2D IVUS index. According to previous reports, significant increase in MIT was defined as ΔMIT ≥0.5 mm during the first year post-transplantation (2,3), and preexisting donor atherosclerosis was defined as MIT ≥0.5 mm at baseline (15). In addition to entire vessel analysis, segmental analysis was performed in 3 equally divided subsegments: proximal, middle, and distal segments of the first 50 mm of the LAD.
Data are frequencies and percentages for categorical variables and mean ± SD for continuous variables. Categorical comparisons were performed using the chi-square test or Fisher exact test. Continuous values were compared by using unpaired or paired Student t test, Wilcoxon signed-rank test, Mann-Whitney U test, or 1-way analyses of variance, as appropriate. A 2-way repeated measures 1-way analysis of variance was used to test for group and time effects and their interactions. Correlation between continuous variables was investigated by using linear regression analysis. Survival analysis was performed by applying the Kaplan-Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were analyzed with Cox proportional hazards regression models to identify factors associated with the primary endpoint of the study. Factors analyzed were: recipient profile at heart transplantation including age, sex, body mass index, cytomegalovirus (CMV) serologic testing results, medical history (diabetes, hyperlipidemia, hypertension, presence of ischemic cardiomyopathy); recipient data at 1 year post-transplantation, including use of statins, rapamycin, LVEF, and total cholesterol and triglyceride concentrations; acute cellular rejection of grade ≥2R during the first year post-transplantation; donor characteristics, including age and sex; allograft cold ischemic time; and IVUS indices. Variables with a p value of ≤0.15 on univariate analysis were entered into the multivariate model. A p value of <0.05 was considered statistically significant. Statistical calculations were performed using JMP version 10 software (SAS Institute Inc., Cary, North Carolina).
Patient Characteristics and Clinical Outcomes
There were a total of 118 consecutive heart transplantation recipients who met inclusion and exclusion criteria and underwent scheduled serial IVUS examination at baseline and 1 year later. Among them, 18 patients were excluded because of poor quality IVUS images due to nonuniform rotational distortion or air bubbles (n = 10) or insufficient image length for analysis (n = 8). As a result, IVUS data from 100 patients were analyzed. Patients were followed for up to 12 years (median follow-up period: 4.7 years). During this follow-up period, late major adverse events after 1 year occurred in 20 patients (19 deaths and 1 re-transplantation). Of the 19 deaths, 14 were cardiac deaths, 1 was from cancer, 1 was from sepsis/multiple organ failure, and 3 deaths were of unknown causes. Patients with and without late major adverse events showed similar profiles at heart transplantation, except for younger recipient age and lower prevalence of hypertension observed in patients with late major adverse events (Table 1). Baseline IVUS indices were also similar, except for a slightly lower intimal volume at the proximal and distal LAD segments in patients with late major adverse events (Table 2). The triglyceride concentration and use of rapamycin at 1 year post-transplantation were higher in patients with late major adverse events than in those without, whereas the total cholesterol level and use of statins at 1 year were not significantly different between the 2 groups. During the first year post-transplantation, 29 patients (29%) experienced one or more episode(s) of acute cellular rejection of grade ≥2R, and the incidence of acute cellular rejection was significantly higher in patients with late major adverse events than those without. The percentage of female donors tended to be higher in patients with late major adverse events (p = 0.10) whereas the prevalence of donor-recipient sex mismatch tended to be lower (p = 0.12) in patients with late major adverse events compared to those without.
Overall Serial Changes in IVUS Indices
Figure 1 shows serial changes in IVUS indices over the entire vessel and within the 3 subsegments of the LAD. The majority of patients showed a decrease in vessel volume (79%) and/or an increase in intimal volume (72%) during the first year post-transplantation. Overall, both the vessel volume (from 15.2 ± 3.4 mm3/mm to 14.0 ± 3.6 mm3/mm; p < 0.0001) and lumen volume (from 12.4 ± 2.8 mm3/mm to 10.7 ± 2.9 mm3/mm; p < 0.0001) decreased significantly, whereas intimal volume (from 2.7 ± 1.4 mm3/mm to 3.3 ± 1.7 mm3/mm; p < 0.0001) and MIT (from 0.8 ± 0.5 to 1.0 ± 0.6 mm; p < 0.0001) increased significantly from baseline to 1 year post-transplantation. The decrease in lumen volume correlated with the increase in intimal volume (r = −0.32; p = 0.001); however, a stronger correlation was observed between the changes in lumen and vessel volumes (r = 0.86; p < 0.0001). In segmental analysis, decreases in vessel volume were comparable among the 3 subsegments of the LAD, whereas increases in intimal volume (and decreases in lumen volume) were progressively greater toward the proximal segment of the LAD. The same results were found after correcting each volume change by baseline vessel size.
Comparison Between Patients With and Without Death and/or Re-Transplantation
Figure 2 shows a comparison of the changes in IVUS indices between the patients with and without death or re-transplantation. In the entire vessel analysis, the patients with these late major adverse events showed significantly greater decreases in vessel (p = 0.03 for interaction) and lumen (p = 0.01 for interaction) volumes at 1 year compared to those without. In segmental analysis, the differences in vessel and lumen volume changes were seen predominantly at the proximal (vessel: p = 0.06; lumen: p = 0.007 for interaction) and distal (vessel: p = 0.02; lumen: p = 0.01 for interaction) segments of the LAD. In contrast, increases in intimal parameters (intimal volume and MIT) were comparable between the patients with and those without late major adverse events in both the entire and segmental analyses. The proportion of the patients with significant increases in MIT (≥0.5 mm during the first year) was numerically higher among the patients with late major adverse events than those without (20% vs. 10%, respectively; p = 0.24); however, differences did not reach statistical significance.
Comparison Between Patients With and Without Acute Cellular Rejection
The patients who experienced significant acute cellular rejection (grade ≥2R) during the first year had a greater increase in intimal volume than those without rejection in the entire vessel analysis (0.9 ± 1.0 mm3/mm vs. 0.4 ± 0.8 mm3/mm; p = 0.01) as well as in the segmental analysis (1.3 ± 1.4 mm3/mm vs. 0.6 ± 1.2 mm3/mm; p = 0.01 for proximal; 1.0 ± 1.2 mm3/mm vs. 0.4 ± 1.0 mm3/mm; p = 0.02 for middle; 0.5 ± 1.0 mm3/mm vs. 0.1 ± 0.7 mm3/mm; p = 0.09 for distal segment) with significant group-by-time interaction effects. MIT also tended to be greater in the patients with rejection episodes (0.23 ± 0.29 mm vs. 0.13 ± 0.33 mm; p = 0.06). In contrast, the changes in vessel and lumen volumes did not differ between the patients with and without rejection in complete vessel or segmental analyses.
Remodeling Patterns and Paradoxical Vessel Remodeling
Figure 3 shows the remodeling patterns (vessel changes in response to intimal changes) observed over the entire vessel and the 3 subsegments of the LAD. Overall, positive correlations between the changes in vessel and intimal volumes (i.e., adaptive vessel response) were observed, except for the proximal LAD segment, with stronger coefficients toward the distal LAD segment. At 1 year post-transplantation, paradoxical vessel remodeling (intimal increase with negative vessel remodeling or intimal decrease with positive vessel remodeling) was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal segments of the LAD, respectively. In the entire vessel analysis, paradoxical vessel remodeling at 1 year was significantly more frequent in patients with subsequent major adverse events compared to those without, which was primarily attributed to the marked difference in paradoxical vessel remodeling at the proximal LAD segment (Figure 4). Paradoxical vessel remodeling of the proximal LAD segment was also more frequently seen in patients with significant acute cellular rejection than those without rejection, which was not found in the middle or distal segment analysis (Figure 4). The majority of paradoxical vessel remodeling was caused by intimal increase with negative vessel remodeling (94.7%, 95.1%, 90%, and 90% for the entire, proximal, middle, and distal segment of the LAD). Patients with paradoxical vessel remodeling of the proximal LAD segment had a greater decrease in lumen volume than those without (−2.5 ± 1.7 mm3/mm vs. −1.2 ± 1.4 mm3/mm; p < 0.001), whereas lumen reduction over time did not differ significantly between patients with and without paradoxical vessel remodeling at the distal LAD segment (−1.9 ± 1.5 mm3/mm vs. −1.6 ± 1.8 mm3/mm; p = 0.39).
Factors Associated With Major Adverse Events
Kaplan-Meier analysis over a median follow-up period of 4.7 years demonstrated a significantly lower event-free survival in patients with paradoxical vessel remodeling of the proximal LAD segment at 1 year post-transplantation compared to those without paradoxical vessel remodeling, which was not present in the other LAD segments or the entire vessel analysis (Figure 5). Greater decreases in lumen and vessel volumes at 1 year also tended to be associated with subsequent major adverse events on univariate analysis (Table 3). In contrast, changes in intimal parameters (intimal volume or MIT) at 1 year were not associated with long-term prognosis. Although preexisting donor atherosclerosis (MIT ≥0.5 mm at baseline) was associated with a greater increase in intimal volume during the first year post-transplantation (0.7 ± 1.0 mm3/mm vs. 0.2 ± 0.6 mm3/mm; p = 0.003), preexisting donor atherosclerosis, including baseline intimal volumes at the entire segment and subsegments of the LAD, did not predict late major adverse events (Tables 3 and 4⇓). In multivariate analysis including all variables with a p value ≤0.15 on univariate analysis, paradoxical vessel remodeling of the proximal LAD segment at 1 year was independently associated with subsequent major adverse events (Table 3). This association was preserved in the analysis for cardiac death and re-transplantation (n = 15) (Table 4). Acute cellular rejection during the first year post-transplantation and donor sex (female) were also associated with all-cause death or re-transplantation on univariate analysis, but not in multivariate analysis. Occurrence of acute cellular rejection was independently associated with cardiac death or re-transplantation (Tables 3 and 4).
The main findings of this study are as follows: 1) despite the diffuse nature of CAV, degrees of coronary intimal thickening and vessel remodeling vary at different locations within the LAD 1 year after heart transplantation; and 2) paradoxical vessel remodeling (intimal increase with negative vessel remodeling or intimal decrease with positive vessel remodeling) at the proximal LAD segment at 1 year was an independent predictor of long-term mortality or re-transplantation in patients with heart transplantation. Of note, coronary intimal thickening or vessel remodeling alone did not predict late major adverse events in the multivariate analysis. To the best of our knowledge, this is the first study to suggest the potential utility of the combined assessment of coronary intimal thickening and vessel remodeling using 3D IVUS in the prediction of long-term prognosis after heart transplantation.
Geographic Distribution of CAV
Previous 2D IVUS studies that investigated CAV early after heart transplantation showed conflicting data with respect to coronary intimal thickening and associated vessel remodeling (4,5,7–9). The present study used 3D IVUS to demonstrate significant increases in intimal parameters (intimal volume and MIT) as well as substantial decreases in vessel and lumen volumes during the first year post-transplantation. In segmental analysis, the increase in intimal volume showed a geographic predilection toward the proximal segment of the LAD, whereas vessel volume decrease (negative remodeling) occurred throughout the LAD. The results of this study also suggest that, unlike early atherosclerosis (16), a considerable percentage of heart transplant recipients fail to show compensatory vessel remodeling in response to coronary intimal thickening even in the early phase of CAV, particularly at the proximal LAD segment where a positive correlation between the changes in vessel and intimal volumes (i.e., adaptive vessel response) was not observed whereas the majority of patients with late adverse events showed paradoxical vessel remodeling. The exact pathophysiology of arterial responses and distribution of CAV after heart transplantation has not been completely elucidated; however, endothelial dysfunction and adventitial inflammation with subsequent fibrosis appear to play important roles, which may not be distributed uniformly over coronary segments after heart transplantation (14,17–19). In addition, other studies have indicated that the proximal LAD segments have less propensity to enlarge in response to expanding plaque compared to distal segments; this may be because larger arteries have less smooth muscle and more elastic and collagen fibers than smaller ones (20). Therefore, discordant arterial response to coronary intimal thickening could be observed in the same artery due to variable responses of the local vessel and the interaction of systemic immunologic processes with preexisting pathology (8).
Coronary Intimal Thickening
In contrast to historical 2D IVUS studies in which a rapid increase in MIT (≥0.5 mm during the first year post-transplantation) was predictive of long-term mortality (2,3), the current study failed to show a significant association between the changes in intimal parameters alone (intimal volume or MIT) and subsequent major adverse events. One possible reason for this discrepancy might have been the improvement of medical management post-transplantation, including better immunosuppression and greater use of statins (21). Recent transplantation recipients are treated more frequently with tacrolimus-based immunosuppressive regimens, and several studies have reported less coronary intimal proliferation seen during the first year post-transplantation in patients with tacrolimus-based treatments than cyclosporine-based treatment regimens (21). The use of statins has also increased: 34% to 38% of the patients in previous studies (2,3) compared with 95% in the present study. Therefore, in the era of modern medical treatment regimens, early intimal thickening alone, particularly assessed by 2D IVUS, may not be sufficiently sensitive in predicting late major adverse events. Indeed, in the present study, coronary intimal thickening remained numerically greater in the patients with late major adverse events, although it did not reach statistical significance.
Paradoxical Vessel Remodeling
Arterial remodeling is a bidirectional vessel response represented as an increase or decrease in vessel size that occurs during the development of coronary disease or after vessel wall injury by coronary intervention (16). The increase in vessel size (positive remodeling) can compensate for luminal narrowing caused by intimal thickening, whereas the decrease in vessel size (negative remodeling) can directly compromise lumen dimensions even with minimal intimal growth. Also, in heart transplantation, the pathology of CAV often involves not only the intimal layer but deeper arterial structures including the media, adventitia and even perivascular tissues (14,18,19). Thus, it is reasonable to hypothesize that the combined assessment of vessel remodeling and intimal thickening could measure the severity of CAV more accurately than standalone evaluation of each component.
Previous studies showed the association between acute cellular rejection and CAV progression (12,13). In the present study, paradoxical vessel remodeling of the proximal LAD segment assessed at 1 year post-transplantation was also associated with acute cellular rejection during the first year; however, it independently and more strongly predicted subsequent major adverse events compared to acute cellular rejection, indicating the incremental predictive value for long-term prognosis. Paradoxical vessel remodeling typically consisted of a combination of intimal growth and negative vessel remodeling (90% to 95% for the entire segment and 3 subsegments of the LAD in this study), and this remodeling pattern was also associated with late major adverse events (HR: 5.75; 95% CI: 1.41 to 26.74; p = 0.0141). In terms of lumen compromise, this combination leads to the greatest luminal narrowing as compared with other combinations. In a minority of patients, the paradoxical vessel remodeling was caused by decreased intimal volume (vessel wall thinning) with positive vessel remodeling. Previous studies have reported that various cytokine systems (Th1 and Th2 cytokines) are involved in pathological vessel remodeling (14). Th1 cytokines are associated with occlusive lesions, whereas Th2 cytokines may influence the expression of extracellular matrix catabolic enzymes by infiltrating inflammatory cells and result in matrix degradation that manifests as aneurysm formation. In native human vascular disease, aneurysmal lesions typically exhibit greater inflammatory cell infiltration than do stenotic lesions (22), although the pathophysiology of this remodeling pattern in CAV has yet to be elucidated.
The predictive value of this phenomenon in clinical prognosis appears to be most apparent at the proximal segment of the LAD. In addition to the histological differences discussed previously, several possible explanations for this geographic variance could be proposed. First, the proximal LAD segment supplies coronary blood flow to the largest myocardial territory (23), and therefore, the disease involving this segment may have the greatest impact on patient outcomes as in the case of atherosclerosis (24). Second, involvement of the proximal LAD segment may represent a more advanced stage of CAV, because CAV preferentially starts from distal coronary segments (small and medium-sized arteries) (11). In clinical settings, focusing on the proximal LAD segment rather than on the entire LAD may help reduce the time and effort required for 3D IVUS analysis. Further studies are warranted to confirm these findings, including the optimal measurement length for segmental analysis.
First, this study was on the basis of a retrospective analysis of prospectively acquired data at a single center and will need to be confirmed in a prospective trial with predefined endpoints. Second, heterogeneous immunosuppressive regimens were used in this population. Finally, this was a single-vessel analysis (i.e., LAD only). Although the LAD has been recognized as the important determinant of patient prognosis (23,24), it remains unknown whether 3-vessel analysis could offer additional prognostic value.
This 3D volumetric IVUS study revealed that despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year post-transplantation was the primary determinant of long-term mortality or re-transplantation. The combined assessment of arterial remodeling with coronary intimal thickening may enhance the prognostic value of IVUS to identify high-risk patients who may benefit from closer follow-up and targeted medical therapies.
COMPETENCY IN MEDICAL KNOWLEDGE: This study represents the utility of combined assessment of coronary intimal thickening and pathological vessel remodeling using 3D IVUS in prediction of long-term prognosis after heart transplantation. In the study, paradoxical vessel remodeling at the proximal LAD segment at 1 year post-transplantation was independently associated with subsequent death or re-transplantation. Focusing on the proximal LAD segment, rather than on the entire LAD may also help reduce the time and effort required for 3D IVUS analysis.
TRANSLATIONAL OUTLOOK: Further studies are warranted to confirm the incremental predictive values of our 3D IVUS findings and to investigate the cutoff values of the 2 different types of paradoxical vessel remodeling for long-term prognosis. It also remains unknown whether three-vessel analysis could offer additional prognostic value.
This study was supported by National Institutes of Health Heart, Lung and Blood Institute grants R01 HL093475-01A1 to Dr. Fearon and 1 PO1-AI50153 to Dr. Valantine. Dr. Kobayashi has received honoraria from Volcano. Dr. Fearon has received research grants from Medtronic and St. Jude; and speakers fees from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- cardiac allograft vasculopathy
- intravascular ultrasonography
- left anterior descending artery
- left ventricular ejection fraction
- maximal intimal thickness
- Received May 27, 2015.
- Revision received July 13, 2015.
- Accepted July 17, 2015.
- American College of Cardiology Foundation
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