Methods

The study population included all HTx patients who had undergone cardiac catheterization during a 1-year period (December 2008 to December 2009). Among 92 HTx patients with follow-up periods after HTx ≥1 year, 21 patients were included: 18 were scheduled for routine follow-up cardiac catheterization in accordance with our hospital protocol, and 3 were catheterized to rule out CAV because of the presence of left ventricular systolic dysfunction. Immediately before cardiac catheterization, blood samples were obtained and transthoracic echocardiography was carried out on all patients. The study was approved by the local ethics committee, and informed consent was obtained from each patient at inclusion.

Immunosuppression was induced with methylprednisolone and was complemented by daclizumab from 2004 onward. Maintenance of immunosuppression was based on methylprednisolone, cyclosporine/tacrolimus, and mycophenolate mofetil. Previous acute cellular rejection was considered as the presence of International Society for Heart and Lung Transplantation grade ≥1R at any time and requiring treatment with intravenous steroids as decided by the responsible cardiologist.

N-terminal pro–B-type natriuretic peptide, cardiac troponin T, and hsTnT levels were measured using electrochemiluminescence immunoassays with a Modular Analytics E170 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). N-terminal pro–B-type natriuretic peptide had a total coefficient of variation <3% and an analytic range from 5 to 35,000 pg/ml. The detection limits were 0.01 ng/ml for conventional cardiac troponin T and 2 pg/ml for hsTnT. C-reactive protein was measured using an immunoturbidimetric test with a Modular P 800 analyzer (Roche Diagnostics GmbH).

Transthoracic echocardiography was performed according to current recommendations. For coronary flow reserve evaluation, Doppler signals were recorded in the distal left anterior descending coronary artery under baseline conditions and 10 minutes after dipyridamole infusion (0.84 mg/kg/min over 6 minutes) using an ultrasound system (Philips iE33; Phillips Medical Systems, Eindhoven, The Netherlands) connected to a high-frequency (12-MHz) transducer.

Left cardiac catheterization and coronary arteriography were performed using a femoral approach with 6Fr guiding catheters. All patients received weight-adjusted intravenous heparin to maintain activated clotting time >300 seconds. Coronary artery intimal proliferation was assessed using 2 methods, IVUS and OCT. IVUS data were acquired using the Atlantis 40-MHz catheter Boston Scientific Corporation, Natick, Massachusetts with an automated motorized pullback device at a constant speed of 0.5 mm/s, and a Boston Scientific iLab Ultrasound Imaging System (Boston Scientific Corporation) was used for analysis. OCT data were acquired using a commercially available system for intracoronary imaging (LightLab Imaging, Westford, Massachusetts) and a 0.019-inch ImageWire (LightLab Imaging) with automated pullback at 1 mm/s. No balloon occlusion was performed (nonocclusive technique). Coronary artery intimal thickness was obtained by measuring the region between the left main coronary artery and the mid portion of the left anterior descending coronary artery. On the basis of the Stanford classification, patients were classified according to their most severe sites, and maximal intimal thickness (MIT) and luminal area (LA) were determined. Plaque type was determined by OCT on the basis of the following histopathologic types : fibrotic, fibrofatty, fibrotic-calcific, and fibroatheroma (confluent area of the necrotic core). The typical plaque type for CAV on the basis of histopathologic studies is the fibrofatty lesion. To assess interobserver variability, all IVUS and OCT data were obtained by 2 independent observers.

Continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test. Given the skewed distribution of N-terminal pro–B-type natriuretic peptide, cardiac troponin T, C-reactive protein, and creatinine, these values are expressed as median (interquartile range), and for statistical analysis, their natural logarithms was used. HsTnT had a normal distribution. Comparison between parameters measured with OCT and IVUS was made using linear regression and the Bland-Altman test. Interobserver agreement (reproducibility) was assessed by determining the mean and standard deviation of the between-observer differences and correlation coefficients. The analysis of the determinants of intimal thickness was carried out using Pearson’s correlation analysis for continuous variables and Student’s t test for dichotomous variables. The mean of the 4 MIT measurements for each patient was used for these analyses. Multiple linear regression analysis was performed including those variables with p values <0.10 in the univariate analysis. HsTnT comparisons between severe and nonsevere CAV cohorts were performed using Student’s t test. Comparisons across CAV grades of hsTnT were performed using analysis of variance. To assess the utility of hsTnT, a marker of severe CAV, receiver-operating characteristic curve analysis was performed. A p value <0.05 was considered statistically significant. The statistical analysis was performed using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois).

Results

The baseline characteristics of the patient population are listed in Table 1 . All patients tolerated the procedure well and did not present any complications.

The most common appearance of the vessel wall with the 2 techniques consisted of varying amounts of intimal thickening. The mean MIT by IVUS was 0.41 ± 0.17 mm compared to 0.42 ± 0.17 mm by OCT, and the correlation between the 2 techniques was good (r = 0.82, p <0.001; OCT MIT = 0.84[IVUS MIT] + 0.73). The Bland-Altman test also showed good agreement between OCT and IVUS, with a mean difference of 0.0033 (95% confidence interval −0.049 to 0.043) ( Figure 1 ).

Bland-Altman plots showing the differences in intimal thickness and LA between IVUS and OCT (A,C) (reference lines showing mean ± 1.96 SDs). Correlation for intimal thickness and LA between IVUS and OCT (B,D) .

However, LA at the most severe site of intimal thickness was not measured by OCT in 3 patients, because of the lack of complete vision (<270° of vessel circumference) when the site was located in proximal segments of the left coronary artery. Finally, complete vision was obtained in 10 patients and partial vision (270° to 360°) in 8 patients. In these patients (n = 18), the mean LA was 7.60 ± 18.16 mm ² by IVUS and 6.92 ± 18.10 mm ² by OCT. The correlation between the 2 techniques was good (r = 0.82, p <0.001) (OCT LA = 0.74[IVUS LA] + 2.57), and the Bland-Altman test showed good agreement, with a mean difference of 0.65 (95% confidence interval −0.38 to 1.69) ( Figure 1 ).

Interobserver differences were lower for measurements of LA and MIT by OCT. In the case of MIT, the correlation coefficient was r = 0.94 (mean difference −1.60 ± 6.01) for OCT versus r = 0.78 (mean difference −1.60 ± 11.97) for IVUS. In the case of LA, the correlation coefficient was r = 0.96 (mean difference −0.28 ± 0.75) for OCT versus r = 0.87 (mean difference −0.31 ± 1.34) for IVUS.

Findings on OCT, analysis of plaque distribution, and plaque type analysis pattern are listed in Table 2 . Representative optical coherence tomographic images and the corresponding IVUS images are shown in Figure 2 . OCT provided additional morphologic information over IVUS, with clear identification of intimal hyperplasia, the internal and external elastic laminae, and the echolucent regions. This differentiation of the architecture was not so clear by conventional IVUS.

Correlation between IVUS images (A,C,E,G) and optical coherence tomographic images (B,D,F,H) of coronary artery plaques in HTx patients. (A) IVUS image and (B) optical coherence tomographic image of a patient with mild concentric CAV with a predominantly fibrous plaque. (C) IVUS image and (D) optical coherence tomographic image of a patient with moderate concentric CAV with predominantly fibrous plaque. (E) IVUS image and (F) optical coherence tomographic image of a patient with severely concentric CAV with predominantly fibrofatty plaque. (G) IVUS image and (H) optical coherence tomographic image of a patient with eccentric CAV who had plaque with a lipid pool and an overlying dense fibrous cap.

As listed in Table 3 , MIT was correlated positively with time after transplantation, C-reactive protein, and hsTnT. No correlation was found between MIT and coronary flow reserve, LVEF and E/E′ ratio, N-terminal pro–B-type natriuretic peptide, or conventional cardiac troponin T. No differences in MIT were found between patients who had experienced several previous rejections or cytomegalovirus reactivation. When all these variables were entered in a multiple linear regression model, time after transplantation (β = 0.488, p = 0.004) and hsTnT (β = 0.392, p = 0.011) were the only independent predictors of MIT (R ² = 0.591).

HsTnT concentrations were significantly higher in those patients with severe CAV (MIT >0.5 mm) compared to those with mild to moderate CAV (56.6 ± 34.5 vs 22.1 ± 14.1 pg/ml, p = 0.006). Considered as a function of CAV grade ( Figure 3 ), hsTnT showed a graded linear association with the severity of CAV according to the Stanford classification (p = 0.023). receiver-operating characteristic curve analysis showed an area under the curve of 0.854 (95% confidence interval 0.688 to 1.000, p = 0.009) for hsTnT ( Figure 4 ). The optimal value of hsTnT for identifying severe CAV was 26 pg/ml, which maximized sensitivity (87%) and specificity (75%), with a positive predictive value of 70% and a negative predictive value of 90%; at a value of 21 pg/ml, sensitivity reached 100% and specificity was 58%. No differences were found between hsTnT concentrations or any of the other parameters according to the plaque distribution pattern or morphology evaluated by OCT ( Table 2 ). Finally, LA reduction was correlated negatively with the left ventricular ejection fraction, but no other correlations were found ( Table 4 ). No differences in LA reduction were found between patients with previous rejections or cytomegalovirus reactivation.

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