Cardiac allograft vasculopathy after heart transplantation: electrocardiographically gated cardiac CT angiography for assessment.

PURPOSE: To evaluate the diagnostic accuracy of cardiac computed tomographic (CT) angiography without the use of ß-blockers compared with that of invasive angiography for the detection of cardiac allograft vasculopathy (CAV) in heart transplant recipients. MATERIALS AND METHODS: The study was approved by the research ethics committee and informed consent was obtained. Heart transplant recipients (n = 138) scheduled for routine invasive angiography were prospectively enrolled to undergo CT to evaluate coronary artery calcification and retrospectively gated cardiac CT angiography with a 64-section scanner. The cardiac CT angiographic images were systematically analyzed for image quality. Degree of CAV was assessed by using a 15-coronary segments model. The area under the receiver operating characteristic curve, sensitivity, specificity, and negative and positive predictive values of cardiac CT angiography for detection of CAV with any degree of stenosis and greater than or equal to 50% stenosis were calculated. RESULTS: Coronary artery calcification was absent in 82 patients, five (6%) of whom had CAV with 50% or more stenosis. Interpretable image quality was obtained in 130 (96%) of the 136 patients who completed the study and 1900 (98%) of 1948 segments. At the patient level, cardiac CT angiography had an area under the receiver operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.880 (95% confidence interval: 0.819, 0.941), 98%, 78%, 77%, and 98%, respectively, for diagnosis of CAV with any degree of stenosis, but for CAV with 50% or more stenosis, the corresponding values were 0.942 (95% confidence interval: 0.885, 1.000), 96%, 93%, 72%, and 99%, respectively. None of the 61 patients with normal cardiac CT angiographic results had CAV on the basis of invasive angiographic images. CONCLUSION: The study results show that cardiac CT angiography compares favorably with invasive angiography in detecting CAV in heart transplant recipients and may be a preferable screening technique because of its noninvasive nature. The absence of coronary artery calcification alone is not reliable enough for excluding CAV.

Volumetric intravascular ultrasound assessment of mechanisms and results of stent expansion in heart transplant patients.

BACKGROUND: Percutaneous coronary intervention with stent placement for the treatment of patients with cardiac allograft vasculopathy is common, but data regarding stent behavior in this setting is lacking. OBJECTIVES: We investigated mechanisms and potential differences in stent expansion among transplant patients vs. patients with native coronary artery atherosclerotic disease ("controls"). METHODS: We compared pre- and poststent intravascular ultrasound in 12 transplant patients (17 lesions) and 33 control patients (34 lesions) matched according to age (60.1 ± 9.2 years), diabetes mellitus, and lesion location. Planar and volumetric analysis was conducted for every 1 mm at the lesion site as well as the first 5 mm proximal and distal to the stent edge. Focal stent expansion was defined as minimum stent area (MSA) divided by mean reference lumen area. Diffuse stent expansion was defined as mean stent area divided by mean reference lumen area. RESULTS: Transplant patients had more plaque than "controls" prestenting, but similar MSA and focal and diffuse stent expansion afterwards. The increase in mean lumen area correlated with the increase in mean vessel area in both groups, transplant (R = 0.64, P = 0.008) and controls (R = 0.70, P < 0.0001), but correlated inversely with changes in mean plaque area only in the transplant group (R = 0.55, P = 0.027). There were no differences in calcification between the two groups and no axial plaque distribution from the lesion into the reference segments in either group. CONCLUSIONS: The mechanism of stent expansion in transplant vasculopathy appears to be similar to de novo atherosclerosis-i.e., mainly vessel expansion to achieve similar acute results.

Functional assessment of donor and recipient left atrium in heart transplant patients using full-volume three-dimensional echocardiography.

BACKGROUND: Atrial function plays an important role in many cardiac conditions, how recipient and donor compartments of left atrium (LA) of transplanted hearts differentially contribute to overall LA function in transplanted hearts has not been described. We tested whether three-dimensional transthoracic echocardiography (3DE) could be used to calculate these compartment-specific atrial functions. METHODS AND RESULTS: We analyzed 3DE images of 22 consecutive transplant patients who had diagnostic imaging quality (ages 59 ± 16 years) using TomTec Research Arena. The contour of the recipient and total LA were traced frame by frame, and the donor LA volume was calculated as the difference of the total LA volume minus the recipient LA volume. The LA ejection fractions of total LA, donor LA, and recipient LA were also calculated as (LA atrial end-diastolic volume - LA atrial end-systolic volume)/LA atrial end-diastolic volume of each compartment. Interobserver variability of LA volumes for the total, recipient, and donor compartments were 5.6 ± 2.4, 5.4 ± 2.0, and 9.3 ± 3.2 mL, respectively (n = 11). The donor LA ejection fraction was higher than that of recipient (41 ± 18% vs. 30 ± 14%, P = 0.013). When the patients were categorized as asymptomatic (New York Heart Association functional class [NYHA] functional class I) and symptomatic (NYHA functional class II-III), indexed donor LA atrial end-diastolic volume was significantly lower in asymptomatic patients as compared with symptomatic patients. CONCLUSIONS: Compartment-specific LA volumes can be calculated in orthotopic heart transplant patients using full-volume 3DE. Our findings may suggest that unique contribution of each LA compartment of transplanted hearts toward the symptoms of these patients.

Ex vivo coronary angiography of a donor heart in the organ care system.

The international demand for donor hearts for transplantation is steadily increasing. Thus, longer transportation distances and explantation from sites with limited abilities for preexplantation diagnostics have to be considered. The development of the Organ Care System® (OCS) (TransMedics, Andover, MA, USA) may extend the extracorporeal period, with the possibility to constantly evaluate and interact during organ transport. One of the potential advantages of the OCS® is the ability to even perform coronary angiography of the donor heart, if a preexplantation angiography evaluation is not possible at the donor hospital and if significant evidence for coronary artery disease in the donor heart becomes known, because of the donor's medical history or after palpation of sclerotic coronary ostia. In this report, we present the first ex vivo coronary angiography evaluation of a potential donor heart that was performed in the OCS®. Upon explantation of the donor heart, sclerosis of the left coronary artery was palpated. After reaching the implantation site, a coronary angiography was performed by placing the OCS® on a catheterization table and inserting a 6F sheath into the access site of the OCS®. A 6F guide catheter was used to intubate the left coronary ostium. Injection of contrast agent led to strong contrast for visualization of the left coronary system. This procedure allowed sufficient assessment of the coronary arteries, which showed a slight diffuse sclerosis without any significant stenosis. This report demonstrates the advantage of the OCS® in the complex assessment of donor hearts after explantation. While the donor heart is still in the OCS®, not only is it possible to measure metabolic parameters and pressures, but even coronary angiography is feasible. With the increasing international demand for donor organs, such ex vivo examinations might play a more important role, because longer transportation distances can be accepted and organs from suboptimal donors without preexplantation diagnostics may be considered at donor sites with limited diagnostic options.

SPECT/CT lymphoscintigraphy of heterotopic cardiac grafts reveals novel sites of lymphatic drainage and T cell priming.

The normal function of lymphatic vessels is to facilitate the trafficking of antigen presenting cells to draining lymph nodes where they evoke an immune response. Donor lymphatic vessels are not connected to that of recipients' during organ transplantation. The pathophysiology of this disruption has received little attention. Murine heterotopic cardiac transplantation has been used extensively in transplantation research. Following vascularized organ transplantation, the main site of allosensitization is thought to be in the spleen of the recipient as a result of migration of donor passenger leukocytes via blood. Here, using Single Photon Emission Computed Tomography/Computerized Tomography (SPECT/CT) lymphoscintigraphy, we studied the pattern of lymphatic flow from mouse heterotopic abdominal cardiac grafts and identified mediastinal lymph nodes as the draining nodes for the donor graft. Staining with HY tetramer after transplantation of HY mismatched heart grafts and ELISPOT following allogeneic grafts to detect donor specific T cells revealed them as important sites for allosensitization. Our data indicates that mediastinal lymph nodes play a crucial role in the alloimmune response in this model, and should be used for ex vivo and adoptive transfer studies after transplantation in addition to the spleen.

Systolic prospectively ECG-triggered dual-source CT angiography for evaluation of the coronary arteries in heart transplant recipients.

OBJECTIVES: To assess feasibility, image quality, and radiation dose of prospectively ECG-triggered coronary CT angiography (CTA) in orthotopic heart transplant (OHT) recipients. METHODS: 47 consecutive OHT recipients (40 men, mean age 62.1 ± 10.9 years, mean heart rate 86.3 ± 14.4 bpm) underwent dual-source CTA to rule out coronary allograft vasculopathy in a prospectively ECG-triggered mode with data acquisition during 35% to 45% of the cardiac cycle. Two independent observers blindly assessed image quality on a per-segment and per-vessel basis using a four-point scale (1-excellent, 4-not evaluable). Scores 1-3 were considered acceptable for diagnosis. Multivariate analysis was performed to evaluate differences between image quality scores obtained at different reconstruction intervals. Effective radiation doses were calculated. RESULTS: 671 coronary segments were evaluated. Interobserver agreement on the image quality was κ=0.75. Diagnostic image quality was observed in 93.9%, 95.5% and 93.3% of the segments at 35%, 40% and 45% reconstruction intervals. Mean image quality score was 1.5 ± 0.7 for the entire coronary tree, 1.4 ± 0.7 for the RCA, 1.6 ± 0.8 for the LCA and 1.6 ± 0.7 for the Cx at the best reconstruction interval. Estimated mean radiation dose was 4.5 ± 1.2 mSv. CONCLUSION: Systolic prospectively ECG-triggered CTA allows diagnostic image quality coronary angiograms in OHT recipients at low radiation doses.

Annexin-V imaging for noninvasive detection of cardiac allograft rejection.

Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.

Reduced atrial emptying after orthotopic heart transplantation masquerading as restrictive transmitral Doppler flow pattern?*.

BACKGROUND: An elevated early (E) to late (A) diastolic filling velocities ratio, typically seen in advanced diastolic dysfunction, has also been observed after cardioversion of atrial fibrillation as a consequence of the depressed left atrial (LA) contractility. We hypothesized that the impaired LA contractile function demonstrated after orthotopic cardiac transplantation (OCT) could also lead to this "pseudorestrictive" pattern. METHOD: E/A ratio related to the tissue Doppler early mitral annular velocity (Ea) as preload-independent index of LV relaxation was evaluated in all consecutive OCT patients between 2005 and 2007. RESULTS: The study population comprised 48 patients 97 ± 77 months after OCT. Thirty-two patients (67%) had an E/A ratio > 2. LV systolic function and myocardial relaxation assessed by the Ea velocity were similar compared to patients with normal ratio (61 ± 6% vs. 60 ± 12%, P = 0.854 and 15 ± 4 cm/s vs. 14 ± 3 cm/s, r = 0.15, P = 0.323, respectively). On the other hand, the proportion of the recipient and donor LA cuffs as estimated by the recipient/global LA area ratio and the LA emptying fraction significantly correlated with the E/A ratio (r = 0.40, P = 0.005 and r =-0.33, P = 0.022, respectively). CONCLUSION: Our study shows that there is a high prevalence of elevated E/A ratio after standard OCT which seems mainly related to reduced LA contractility. Recognition of this "pseudorestrictive" pattern may avoid misdiagnosis of diastolic dysfunction.

Coronary flow reserve by transthoracic echocardiography predicts epicardial intimal thickening in cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality in heart transplantation (HT). We sought to investigate the role of coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) in CAV diagnosis. CAV was defined as maximal intimal thickness (MIT) assessed by intravascular ultrasound (IVUS) > or =0.5 mm. CFR was assessed in the left anterior descending coronary artery in 22 HT recipients at 6 +/- 4 years post-HT. CAV was diagnosed in 10 patients (group A), 12 had normal coronaries (group B). The mean MIT was 0.7 +/- 0.1 mm (range 0.03-1.8). MIT was higher in group A (1.16 +/- 0.3 mm vs. 0.34 +/- 0.07 mm, p < 0.0001). CFR was 3.1 +/- 0.8 in all patients and lower in group A (2.5 +/- 0.6 vs. 3.7 +/- 0.3, p < 0.0001). CFR was inversely related with MIT (r =-0.774, p < 0.0001). A cut point of < or =2.9, identified as optimal by receiver operating characteristics analysis was 100% specific and 80% sensitive (PPV = 100%, NPV = 89%, Accuracy = 91%). CFR assessment by CE-TTE is a novel noninvasive diagnostic tool in the detection of CAV defined as MIT > or =0.5 mm. CFR by CE-TTE may reduce the need for routine IVUS in HT.

Evaluation of cardiac allograft vasculopathy by multidetector computed tomography and whole-heart magnetic resonance coronary angiography.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major complication that limits the long-term survival of recipients of heart transplants. In the present study the feasibility of 2 noninvasive approaches for detecting CAV (multidetector computed tomography (MDCT) and whole-heart magnetic resonance coronary angiography (MRCA)) was compared with conventional coronary angiography (CCAG). METHODS AND RESULTS: Of 22 heart transplant recipients who underwent CCAG screening, 13 had only MDCT, 16 had only MRCA, and 7 had both noninvasive modalities. The coronary arterial tree was divided into 9 segments. Detection of vasculopathy by coronary segments was compared between 16-/64-detector computed tomography (CT) or MRCA and CCAG. The sensitivity of both 16- and 64-detector CT for diagnosing CAV was 69.6%, and specificity was 96.8%. The sensitivity and specificity by 64-detector CT alone were 90.0% and 97.5%, respectively; its positive and negative predictive values were 81.8% and 98.7% respectively. For MRCA, sensitivity was 60%, specificity, 100%, positive predictive value, 100% and negative predictive value, 92.2%. MRCA showed no false positives. CONCLUSIONS: MDCT, especially 64-detector CT, is feasible for detecting CAV, whereas MRCA currently shows limited sensitivity.

Angiographic assessment of cardiac allograft vasculopathy: results of a Consensus Conference of the Task Force for Thoracic Organ Transplantation of the German Cardiac Society.

Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa=0.371, P<0.001). The kappa value for peripheral obliteration was 0.331 (P=0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.

Relative vs. absolute values: using patient and population norms for echocardiography in pediatric cardiac transplant recipients.

Intrapatient consistency and relative utility of TDI as well as other echocardiographic parameters are incompletely understood in pediatric HTx recipients. We sought to evaluate the relative strength of common echocardiographic parameters used in the evaluation of pediatric HTx recipients, including TDI. We reviewed 388 echocardiograms and 73 catheterizations from 34 pediatric HTx recipients without coronary disease over an 18-month period. Data included systolic and diastolic parameters, with VCFc and mitral annular TDI velocities. We used descriptive statistics, and analyzed intrapatient variability using MSR from one-way anova. Echocardiographic data were compared with invasively measured hemodynamic data. For most echocardiographic parameters, including TDI velocities, intrapatient variability was smaller than total population variability. VCFc was higher than normal in most patients. TDI parameters were approximately 10% slower than in previously published studies of normal subjects. Pediatric HTx normal ranges are not the same as healthy population norms, and the range of findings in healthy HTx recipients without rejection is relatively broad. Serial assessment is important when interpreting echocardiograms in pediatric HTx recipients.

Tricuspid regurgitation after orthotopic heart transplantation.

BACKGROUND: Tricuspid regurgitation (TR) is a relatively common abnormality in normal adults as well as after orthotopic heart transplantation (OHT). A few studies have shown reduction in the incidence of TR after OHT by total bicaval surgical anastomosis technique. Other studies reported no significant difference in the rates of TR between the standard and bicaval techniques. OBJECTIVE: Evaluate and compare the degree of TR after OHT by standard and bicaval anastomosis techniques. METHOD: Echocardiograms from the first 56 consecutive patients that had the total bicaval surgical technique performed were retrospectively reviewed and compared with the last 57 consecutive patients who had the standard biatrial technique performed. Patients with adequate two-dimensional and Doppler echocardiograms were included. RESULTS: No statistical difference was observed for each grade of TR at both early and late time points. No significant difference was observed between the TR velocities of both biatrial and bicaval anastomosis patients at different periods. CONCLUSION: There appears to be no difference between the TR severity and TR velocity at early and late time points regardless of anastomotic technique.

The role of Tissue Doppler imaging in the noninvasive detection of chronic rejection after heterotopic cardiac transplantation in rats.

BACKGROUND: Chronic rejection is a risk factor for the development of cardiac allograft vasculopathy (CAV) in heart transplant recipients. A useful animal model to study the role of immunosuppressive strategies in the prevention of chronic rejection involves heterotopic abdominal cardiac transplantation in rats. The detection of rejection and concurrent CAV traditionally involves subjective serial palpation of the graft from a scale of 0 to 4, with 4 indicating vigorous beats. Recent advances in murine echocardiography, in particular Tissue Doppler imaging (TDI), may allow for objective in vivo monitoring of chronic rejection in this transplant model. OBJECTIVE: The objective of this study was to compare the diagnostic accuracy of murine echocardiography as compared to the abdominal palpation heart score for the noninvasive detection of chronic cardiac graft rejection. METHODS: In an animal model of heterotopic cardiac transplantation, 18 male Fischer and Lewis rats were used as donors and recipients, respectively. Abdominal palpation and murine transthoracic echocardiography were performed to assess in vivo function of the transplanted heart. Left ventricular (LV) structure and function and TDI indices, including endocardial velocity (Vendo) and strain rate (SR), were evaluated in the ectopic heart. Graft tissues were processed for histological examination and graded for chronic rejection. RESULTS: Abdominal palpation scores were obtained in all 18 rats; score 1 (n = 5); score 2 (n = 4); score 3 (n = 6); and score 4 (n = 3). The mean LV ejection fraction was significantly (P <0.01) lower in score 3 and 4 grafts as compared to score 1 grafts. There was no correlation between the abdominal palpation score and LV systolic function. There was a significant relationship between decreasing Vendo or SR values and increasing grades of rejection (r = 0.65, P <0.05 and r = 0.75, P < 0.05, respectively). CONCLUSION: TDI of the transplanted heart in rats is feasible, reproducible, and more sensitive than palpation for the detection of chronic rejection.

Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients.

AIMS: The cellular mechanisms underlying cardiac hypertrophy may result from changes in cardiac myocyte growth and differentiation. We tested whether sirolimus, an immunosuppressive agent that inhibits mTOR, a protein that regulates cell division and differentiation, might modify cardiac hypertrophy after cardiac transplantation. METHODS AND RESULTS: Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus. Eighty-three control subjects were maintained on CNIs. After 12 months, left ventricular (LV) mass decreased from 196.15 +/- 48.28 to 182.21 +/- 43.56 g (P = 0.05) and LV mass index from 99.25 +/- 20.08 to 93.82 +/- 20.22 g/m(2) (P = 0.031) in sirolimus-treated subjects but did not change in controls. The left atrial volume index of sirolimus-treated subjects decreased from 52.44 +/- 17.22 to 48.40 +/- 15.14 cc/m(2) (P = 0.008) and increased from 52.07 +/- 19.45 to 57.03 +/- 19.93 cc/m(2) (P = 0.0012) in controls. The difference between the groups was independent of blood pressure. The number of cells in myocardial biopsies positive for p27Kip1, a protein induced by mTOR inhibition, increased in sirolimus-treated subjects (P = 0.0005) and did not change in controls (P = 0.54) suggesting sirolimus acted directly on myocardium. CONCLUSION: Sirolimus may inhibit adverse ventricular remodelling resulting in cardiac hypertrophy and have potential in the treatment of conditions in which severe hypertrophy compromises cardiac function.

Myelofibrosis on 18F-FDG-PET/CT in a case suspicious for post-transplant lymphoproliferative disorder.

Recent studies have advocated the utility of fluorine-18 fluorodeoxyglucose-positron emission tomography (18)F-FDG-PET imaging in evaluation of various hematological disorders. We report a case of a 61-year-old man with clinical suspicion of post-transplant lymphoproliferative disorder (PTLD) where (18)F-FDG-PET/CT (computerized tomography) was helpful in identifying myelofibrosis. This paper aims to reveal the potential diagnostic value of PET/CT as an imaging modality in the evaluation of myelofibrosis.

[Global evaluation of the heart in heart transplant recipients using dual-source computed tomography]. / Valoración global del corazón en el paciente con transplante cardiaco mediante tomografía computarizada de doble fuente.

In routine clinical practice surveillance of heart transplant recipients is usually performed using echocardiography and conventional coronary angiography. The latter permits diagnosis and follow-up of coronary allograft vasculopathy. However, this procedure is invasive and is not free of complications. Conventional multislice computed tomography (MSCT) has been shown to be a useful non-invasive tool for ruling out coronary artery disease and evaluating cardiac function. However, due to its limited temporal resolution betablocker administration is required, and its usefulness in certain patient populations with restricted response to this medication, such as heart transplant recipients, may therefore be limited. Dual-source CT (DSCT) allows evaluation of the coronary arteries in all individuals independent of their heart rate. In the case presented here, we demonstrate that DSCT may be useful for evaluating cardiac function and ruling out coronary allograft vasculopathy in heart transplant recipients.