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Impact of Donor-Transmitted Atherosclerosis on Early Cardiac Allograft Vasculopathy: New Findings by Three-Dimensional Intravascular Ultrasound Analysis

Yamasaki, Masao1; Sakurai, Ryota1; Hirohata, Atsushi1; Honda, Yasuhiro1; Bonneau, Heidi N.1,2; Luikart, Helen1; Yock, Paul G.1; Fitzgerald, Peter J.1; Yeung, Alan C.1; Valantine, Hannah A.1; Fearon, William F.1,3

doi: 10.1097/TP.0b013e31821ab91b
Clinical and Translational Research

Background. The influence of donor-transmitted coronary atherosclerosis (DA) on plaque progression during the first year after cardiac transplantation (Tx) is unknown.

Methods. Serial 3-dimensional intravascular ultrasound (IVUS) studies were performed within 8 weeks (baseline; BL) and at 1 year after Tx in 38 recipients. On the basis of maximum intimal thickness (MIT) at BL, recipients were divided into DA group (DA+; MIT≥0.5 mm, n=23) or non-DA group (DA−; MIT<0.5 mm, n=15). Plaque, lumen, and vessel volume indexes were calculated by volume/measured length (mm3/mm) in the left anterior descending artery. Univariate and multivariate regression analyses were attempted to reveal clinical predictors of change in coronary dimensions.

Results. During the first year after Tx, plaque volume index increased significantly in DA+ group, but did not change in DA− Group (DA+, 3.0±1.5 to 4.1±1.5 mm3/mm, P<0.0001: DA−, 1.2±0.4 to 1.3±0.5 mm3/mm, P=0.53). In both groups vessel volume index decreased significantly (DA+, 16.3±3.6 to 14.6±3.3 mm3/mm, P=0.003: DA−, 13.5±4.1 to 12.0±3.3 mm3/mm, P=0.01), as did lumen volume index (DA+, 13.2±3.1 to 10.5±2.7 mm3/mm, P<0.0001: DA−, 12.2±3.7 to 10.7±3.0 mm3/mm, P=0.004). Univariate and multivariate regression analyses revealed that DA was one of the strongest predictors for plaque progression.

Conclusions. DA was associated with significant plaque progression during the first year after Tx, and in conjunction with negative remodeling, may be an important determinant of cardiac allograft vasculopathy.

1 Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA.

2 Currently, Highlands Consulting, Inc., San Jose, CA.

This work was supported, in part, by National Institutes of Health, Heart Lung and Blood Institute and the Institute of Allergy and Infectious Disease, Bethesda, MD, grants 1 K23 HL072808-01A1 (W.F.F.) and 1 PO1-AI50153 (H.A.V.).

The authors declare no conflict of interest.

3 Address correspondence to: William F. Fearon, M.D., 300 Pasteur Drive, Room H2103, Stanford, CA 9430.


M.Y., H.N.B., and W.F.F. participated in the writing of the manuscript; M.Y., R.S., A.H., H.L., and W.F.F. contributed in analysis; and M.Y., R.S., A.H., H.L., Y.H., P.G.Y., P.J.F., A.C.Y., H.A.V., and W.F.F. participated in the performance of the research.

Received 9 July 2010. Revision requested 29 July 2010.

Accepted 15 March 2011.

Cardiac allograft vasculopathy (CAV), characterized by diffuse luminal narrowing, is a major determinant of long-term mortality in cardiac transplant patients (1, 2). Coronary artery narrowing after cardiac transplantation (Tx) is caused by a combination of donor-transmitted coronary atherosclerosis (DA) and changes in vascular geometry including negative remodeling and plaque progression. Several studies have shown poor clinical outcomes in patients with plaque progression detected by intravascular ultrasound (IVUS) during the first year after Tx (3–5). With increasing demand for Tx and a decreasing donor pool, more hearts with preexistent atherosclerosis are being transplanted (2); and thus, the impact of DA on CAV has become an important concern. Previous studies have suggested that donor lesions do not accelerate plaque progression early after Tx (6–8); however, these studies were based on two-dimensional IVUS analysis. The most sensitive and accurate approach to assessing changes in coronary structures is to perform serial three-dimensional IVUS analysis with an automated pullback system (9–11).

Therefore, the aim of this prospective, longitudinal study was to use serial, three-dimensional IVUS analysis to investigate the impact of DA on plaque progression early after Tx.

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Characteristics of Patients and the Coronary Arteries

There were 183 Txs performed during the enrollment period (January 2002 to June 2005), 152 of which met the inclusion criteria. Of these, 99 recipients consented to this study, but 35 did not have a baseline IVUS of the left anterior descending (LAD) artery because of clinical reasons (e.g., elevated creatinine). Of the 64 patients who had baseline IVUS, 15 patients did not have a 1-year IVUS because of clinical reasons or patient refusal. As a result, serial IVUS imaging was performed in a total of 49 patients at baseline and 1 year after Tx. Of the 49 patients, 11 patients were excluded due to recording length less than 50 mm or incomplete imaging. Therefore, a total of 38 patients with complete 50-mm pullback of the matched LAD were eligible for the analysis.

On the basis of maximum intimal thickness (MIT) at baseline, 38 recipients with serial IVUS images were divided into DA group (DA+: MIT ≥0.5 mm, n=23) or non-DA group (DA−: MIT <0.5 mm, n=15) (Fig. 1). The clinical characteristics of these patients are outlined in Table 1. Although there was a history of tobacco use in only DA+ group, there were no recipients actively using tobacco in group pre- or post-Tx. Every recipient received sirolimus or mycophenolate mofetil as an antiproliferative agent, cyclosporine or tacrolimus as an immunosuppressive agent, and any statin including atorvastatin, pravastatin, lovastatin, and simvastatin during the first year after Tx. Among recipients with diabetes mellitus, there were four and two recipients with insulin-dependent diabetes mellitus in DA+ and DA− group, respectively. There were no significant differences in prevalence of the clinical variables between the two groups except mean donor age, which was significantly higher in DA+ group than in DA− group.





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Serial Changes in IVUS Results

As Figure 2 shows, the lumen and vessel volume index decreased significantly in both groups. Both groups showed negative remodeling in the same degree (10% in DA+ and 11% in DA− group). Although the plaque volume index and the % plaque burden did not change in DA− group, both of these increased significantly in DA+ group. In DA+ group, plaque progression was responsible for 39% of the lumen loss, whereas plaque progression did not contribute to lumen loss in the DA− group. Coronary angiography revealed no significant stenosis at baseline, 1-year, and mean 1.6-year (up to 4-year) follow-up.



There was no difference in the location of the MIT site at baseline between DA+ group and DA− group (13.2±13.9 mm vs. 10.3±9.9 mm from the orifice of the LAD, respectively, P=0.48). The MIT at baseline did not change when compared with the matched cross-section at year 1 in group (1.22±0.49 to 1.21±0.60 mm in DA+, P=0.97: 0.33±0.10 to 0.32±0.11 in DA−, P=0.66) but did increase significantly when compared with the MIT at year 1 in the DA+ group (1.22±0.49 vs. 1.41±0.54 in DA+, P=0.03: 0.33±0.10 vs. 0.40±0.16 in DA−, P=0.11). Of 23 MIT sites in the DA+ group, the overall distance between the MIT site at baseline and at year 1 was 4.5±6.4 mm, (six MIT sites were located ≥3 mm proximal to the MIT site at baseline, six MIT sites were ≥3 mm distal to the MIT site at baseline, and 11 MIT sites were within 3 mm distance from the MIT site at baseline). There was a trend towards a higher rate of new lesions in the DA+ group compared with the DA− group (48% vs. 20% respectively, P=0.08). Rapidly progressive vasculopathy occurred in eight of 23 cases in DA+ group, but in only one of 15 cases in DA− group (35% vs. 6.7%, respectively, P=0.046). Of eight rapidly progressive vasculopathy cases in the DA+ group, six cases had a rapid progression in the sites with intimal thickness (IT) more than or equal to 0.5 mm at baseline and two cases did in the sites with IT less than 0.5 mm at baseline.

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Clinical Determinants for Plaque Progression

Table 2 shows the clinical predictors of plaque progression identified by univariate regression analysis using the all clinical variables in Table 1 as independent variables. Multivariate analysis revealed DA and history of recipient smoking were the only significant predictors for plaque progression.



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The main findings of this detailed serial three-dimensional IVUS analysis during the first year after Tx are as follows: (1) there was significantly more plaque progression in recipients with DA compared with those without it; (2) negative remodeling occurred in all recipients, irrespective of the presence of DA; (3) DA was one of the strongest predictors of plaque progression. To our knowledge, these are the first serial three-dimensional IVUS observations regarding the influence of DA on vascular geometric changes early after Tx.

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Serial Changes in Vessel Structures

This study showed that 61% (23 of 38) of recipients had donor lesions defined as MIT more than or equal to 0.5 mm at baseline IVUS examination, which was relatively high compared with previous studies showing 30% to 56% using the same criteria (5, 7–9, 12, 13). Most importantly in this study, we found that significant plaque progression occurred in recipients with DA, but did not in recipients without DA during the first year after Tx. Although previous IVUS studies have consistently shown significant plaque progression during the first year after Tx (1, 3–8), none have demonstrated a correlation between plaque progression and DA. The discrepancy between previous data and our study may be explained by the fact that previous work used two-dimensional IVUS analysis, which is likely unrepresentative of whole vascular changes. Our study used serial three-dimensional IVUS analysis with automated pullback in a strictly selected and precisely matched longer portion of the LAD. In the current study, the bifurcation of LAD and left circumflex artery served as distinct and solid landmark of the origin of LAD. The accuracy of longitudinal length measurements using motorized pullback have been validated in clinical settings and reported by multiple investigator groups (10, 14, 15). Therefore, the results of the present study can offer a more complete reflection of the changes in coronary artery structure after Tx (9–11).

In this study, the MIT at baseline did not change when compared with the matched cross-section at year 1 in those with and without DA, whereas it did increase significantly when comparing the cross section with the MIT at baseline to any cross section with the MIT at year 1 in those with DA. Moreover, in general, the MIT site at year 1 in patients with DA was at a different location compared with the baseline MIT. These results suggest that DA does not provide a nidus for accumulating intimal growth, which is consistent with previous studies, but is a marker for subsequent plaque progression elsewhere. Not only was there a trend for development of new lesions when comparing patients with DA with those without it, but there was also significantly more rapidly progressive vasculopathy in this group. Rapid plaque progression in the first year after Tx predicts all-cause mortality, nonfatal myocardial infarction, and the subsequent development of angiographically severe coronary artery disease (4, 5). Although there was no incidence of CAV in both DA+ and DA− group at relatively short-term follow-up, this relationship between DA and rapid plaque progression may explain the poor long-term outcomes in patients with DA, which was previously attributed to a greater plaque burden at baseline.

There are conflicting data with respect to changes in coronary artery vessel size based on IVUS imaging early after Tx. Some studies describe associated positive remodeling with little change in lumen dimensions (16–18), whereas others reveal negative remodeling in the most diseased segments with significant lumen narrowing (19–22). By using three-dimensional IVUS analysis, we recently reported overall negative remodeling associated with lumen loss during the first year after Tx (11). In the present study, we found that negative remodeling occurred in both patients with and without DA and that lumen loss occurred solely due to negative remodeling in patients without DA, while in patients with DA a combination of negative remodeling and plaque progression resulted in lumen loss. Little is known about the influence of DA on vascular remodeling. This study found that coronary arteries with donor lesions did not show compensatory vessel enlargement as further plaque progression occurred. This observation suggests that the presence of DA may impede compensatory expansive remodeling as plaque progression occurred. Expansive remodeling may be a compensatory mechanism in the early development of native and transplant atherosclerotic lesions, which prevents luminal loss (13, 16, 17, 22, 23). The ability to undergo compensatory vessel enlargement in the presence of plaque formation seems to be dependent on intact endothelial function. In sites with DA, more endothelial cell dysfunction and adventitial fibrosis may inhibit vessel enlargement as plaque progression occurs after Tx (24).

The mechanism for the acceleration of plaque progression by DA is unclear. Although all the coronary arteries of the donor heart are similarly exposed to cardioplegic conditions during Tx, and the long-acting immunologic reaction and traditional nonimmunologic risk factors, such as hyperlipidemia, hypertension, and hyperglycemia after Tx, we have observed discordant plaque progression between the recipients with and without DA in the current study, suggesting additional local mechanisms in plaque progression with DA. Endothelial dysfunction has been found early posttransplantation before the development of plaque progression (25). Endothelial injury predisposes the transplant coronary artery to the common risk factors of atherosclerosis. In certain sites with DA, more endothelial cell dysfunction, altered shear stress, and local insult may further accelerate plaque progression.

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Clinical Correlates to Plaque Progression

The univariate and multivariate regression analyses revealed that DA and history of recipient smoking were the only significant predictors of plaque progression after Tx. Considering no recipient actively using tobacco pre- or post-Tx, DA seems to be the strongest predictor for plaque progression. The mean age in hearts with DA was 16 years older than transplant hearts without DA in this study, similar to previous studies (12, 13). This finding may help predict hearts with DA in choosing donor hearts.

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Clinical Implications

We found that DA accelerates plaque progression during the first year after Tx, which may be an important determinant of CAV in the future. Therefore, identifying donor hearts with DA seems to be important to prevent future CAV. Aggressive monitoring and treatment of Tx recipients with DA, particularly during the first year after Tx may hopefully decrease the incidence of CAV in this group.

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Study Limitations

This study involved a small number of selected patients at a single center. However, the prospective cohort design and serial three-dimensional IVUS evaluation of a relatively longer portion of the precisely matched LAD in the same patients represent distinct advantages over previous studies.

The study population has an inherent selection bias toward less severe disease, because patients with aggressive CAV and a complicated posttransplant course may not have follow-up IVUS images.

Data for this study were obtained only from a limited vascular region. A large variability of CAV is involved between different coronary arteries and segments within individual patients (26); therefore, a heterogeneous distribution of CAV should be considered when analyzing a limited number of coronary trees and segments.

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In this detailed, prospective, serial, three-dimensional IVUS analysis, we found that DA accelerated plaque progression and was associated with rapidly progressive vasculopathy during the first year after Tx. Along with negative remodeling, DA may be an important determinant of future CAV. The discrepancy between previous data and our results may be based on the differences in analysis methods, two-dimensional IVUS analysis in the previous works and serial three-dimensional IVUS analysis in the current study. Further investigation using three-dimensional IVUS analysis in a larger and longer follow-up cohort is warranted to validate these results.

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Study Design and Patient Population

Consecutive cardiac transplanted recipients at Stanford University Medical Center between January 2002 and June 2005 were asked to participate in this prospective longitudinal study. Those patients who were clinically stable with a serum creatinine less than or equal to 2 mg/dL, and were not undergoing a repeat Tx are included in this analysis. All patients were scheduled for a baseline coronary angiogram and IVUS study within 8 weeks of Tx and a follow-up coronary angiogram and IVUS study 1 year after Tx. Donor and recipient clinical characteristics, medications, and rejection episodes were prospectively entered into an electronic database developed and supervised by the Data Coordinating Center of the Biostatistics department at Stanford University. The study was approved by Stanford University's Administrative Panel on Human Subjects, and written informed consent was obtained from all patients before study enrollment.

All patients received induction therapy with the anti-interleukin-2 receptor inhibitor, dacluzimab. Maintenance immunosuppression consisted of a three-drug regimen including a calcineurin inhibitor (cyclosporine administered at 2–4 mg/kg/day or tacrolimus at 0.05–0.1 mg/kg/day), an antiproliferative agent (sirolimus at 1–4 mg/day or mycophenolate mofetil at 1000–3000 mg/day), and prednisone started at 1 mg/kg/day and tapered to 0 by month 12. The decision to use sirolimus or mycophenolate mofetil was based on the standard protocol at the time of enrollment (27). From January to June in 2002, all patients were treated with mycophenolate mofetil. From July 2002 to November 2003, all newly transplanted patients received sirolimus as part of their initial maintenance regimen. Patients undergoing Tx from December 2003 to June 2005 received mycophenolate mofetil as part of their initial maintenance regimen. This change occurred after it became apparent that early treatment with sirolimus resulted in sternal wound healing complications (28). Recipients were monitored for rejection by performance of right ventricular endomyocardial biopsy every 3 months during the first year after Tx. Rejection was graded using the standard scoring system of the International Society for Heart and Lung Transplantation (29). A grade of more than or equal to 3A was chosen as a cutoff value, based on previous work and on the fact that we generally treat this degree of rejection (30). All recipients received standard cytomegalovirus (CMV) prophylaxis consisting of intravenous ganciclovir for 4 weeks. Those recipients who were CMV antibody negative and received a heart from a CMV antibody positive donor received an aggressive CMV prophylaxis consisting of additional 3-month course of CMV hyperimmune globulin (150 mg/kg administered within 72 hr of Tx, 100 mg/kg at week 2, 4, 6, and 8, then 50 mg/kg at week 12 and 16), and up to 80 days of valganciclovir orally. Presence of CMV IgG antibody was tested before Tx and again at 1 year after Tx. All patients were treated with a calcium channel blocker and statin unless adverse side effects occurred. Angiotensin converting enzyme inhibitor or angiotensin receptor blocker was used if patients were intolerant to calcium channel blockers or required additional antihypertensive therapy.

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IVUS Imaging

After intravenous administration of heparin (3000–5000 units) and intracoronary nitroglycerin (200 μg), coronary angiography was performed, followed by IVUS imaging using 0.5 mm/s automated pullback of 40 MHz transducer, connected to a Galaxy IVUS system (Boston Scientific, Natick, MA). IVUS images of the first 50 mm of the LAD originated from the bifurcation of LAD and left circumflex artery were recorded for offline analysis.

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IVUS Analysis

All measurements were performed at Stanford's IVUS Core Laboratory, using planimetry software (echoPlaque, Indec Systems, Mountain View, CA). Vessel and lumen areas were manually traced in the first 50-mm in 0.5-mm increments. Plaque area was calculated as (vessel area−lumen area). Each volume, computed using Simpson's method, was standardized by calculating volume index (=mean area), defined as (volume/measured length) (mm3/mm). Percent plaque burden was calculated as plaque volume/vessel volume. The MIT was recorded at baseline and the IT was measured at the same spot at year 1. In addition, the MIT was measured at year 1.

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The following definitions for lesion characteristics were used (5): a donor lesion was defined as a site with MIT more than or equal to 0.5 mm at baseline study. A new lesion was defined as MIT more than or equal to 0.5 mm on follow-up study at a site where IT was less than 0.5 mm on the baseline study. Rapidly progressive vasculopathy was defined as the presence of at least one site with an increase of more than or equal to 0.5 mm in MIT from baseline to 1-year measurement. Significant angiographic disease was defined as any new lesion more than or equal to 50% in severity by quantitative coronary angiography.

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Statistical Analysis

Statistical analysis was performed using StatView version 5.0 (SAS Institute, Cary, NC). Continuous variables were expressed as mean±standard deviation and compared by a two-tailed paired t test. Categorical variables were presented as percentage (%) and compared by Fisher's exact probability test. Univariate and multivariate regression analyses were attempted to reveal clinical predictors of change in coronary dimensions. All parameters with a P value of less than 0.1 by univariate regression analysis were included into multivariate regression analysis. A P value less than 0.05 was considered statistically significant.

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Cardiac transplantation; Donor-transmitted atherosclerosis; Cardiac allograft vasculopathy; 3-D IVUS

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