Significant Cardiac Allograft Vasculopathy Research Articles

Proteomics early after heart transplantation and relation to coronary intimal changes and prognosis

BackgroundLong-term survival after heart transplantation (HTx) is limited by cardiac allograft vasculopathy (CAV). The pathogenesis of CAV is poorly understood, and treatment has not yet been well-established. In this exploratory study, we aimed to identify novel immune and non-immune biomarkers correlated to CAV development, and biomarkers predicting CAV related events. MethodsUsing a proteomic panel, 92 cardiovascular disease-related proteins were evaluated in 26 de novo HTx patients at 3- and 12-months post transplantation. Intima area changes were assessed using optical coherence tomography (OCT). Major adverse cardiac events (MACE) included significant CAV progression, heart failure, and cardiovascular death. ResultsMedian follow up was 6.8 years. We found changes in four inflammatory biomarkers: Matrix metalloproteinase 3 (MMP-3) and matrix metalloproteinase 2 (MMP-2) were significantly increased after 3 months in the group of patients with highest intima proliferation, and after 12 months in patients experiencing MACE, respectively. Monocyte chemotactic protein 1 (MCP-1) was increased after 12 months in patients experiencing MACE. Platelet derived growth factor subunit A (PDGF-A) was significantly increased after 3 months in the group of patients with highest intima proliferation. ConclusionsWe identified four biomarkers that may be associated with CAV development which differed significantly between groups of intima proliferation and MACE; MMP-2, MMP-3, MCP-1 and PDGF-A. Further studies are needed to examine whether our findings offer the basis to seek for new markers of graft vasculopathy or treatment options.

Utility of 64-Slice Coronary Computed Tomography Angiography in Heart Transplant Recipients

Graft vasculopathy is a leading cause of death after heart transplantation (HTx). Diagnosing cardiac allograft vasculopathy (CAV) within this patient group poses significant challenges. This study aimed to evaluate the safety and efficacy of coronary computed tomographic angiography (CCTA) in patients after HTx. We enrolled 107 consecutive HTx recipients (26 women, mean age 50 ± 17 years); all were ≥3 years post-HTx with minimal or no evidence of CAV in a prior coronary angiography performed a minimum of 2 years before the current examination. The inclusion criteria comprised an estimated glomerular filtration rate (eGFR) of ≥30, absence of new heart failure symptoms, and no contraindications to iodine contrast or CT scans. All patients underwent a 64-slice CCTA. In cases of minimal or no changes, noninvasive follow-up examinations were conducted. Significant changes in CT prompted additional coronary angiography. Of the enrolled participants, 9 exhibited minimal changes; 98 displayed no changes in coronary angiography. The median time since transplant was 7 years, with IQR of 4 to 11.25 years. Significant changes were excluded in 98 patients. Among the 9 patients with suspected significant CAV, significant changes were confirmed in 8 patients, resulting in percutaneous transluminal coronary angioplasty (PTCA) performed in 6. One patient from this group died shortly after PTCA. No cardiovascular incidents were observed within the remaining group. The median follow-up period was 539 (IQR = 289-654 days). The mean left ventricular ejection fraction at follow-up was 58% ± 5% compared with 58% ± 4% at baseline. At follow-up, the mean eGFR was 64 ± 18 mL/kg/1.73 m2 compared with the baseline value of 67.2 mL/kg/1.73 m2. CCTA appears to offer a secure and efficient means of assessment in HTx recipients.

Abstract 17534: Safety and Feasibility of Adenosine Stress CMR for CAV Detection in Orthotopic Heart Transplant Recipients

Background: Stress perfusion cardiac magnetic resonance (CMR) imaging is recommended in international guidelines in class I in patients with known or suspected CAD. Patients undergoing cardiac transplantation (OHT) are at risk of developing cardiac allograft vasculopathy (CAV). Adenosine is relatively contraindicated after transplantation because of a presumed risk of atrioventricular block in denervated hearts. We sought to evaluate the safety and feasibility of adenosine stress CMR in patients with OHT and suspected CAV. Methods: In an outpatient cohort study, we measured the incidence of adverse effects of adenosine stress CMR in consecutive OHT recipients undergoing quantitative stress perfusion CMR for suspected CAV. We additionally stratified patients based on presence of significant CAV (grades 2-3 versus 0-1) on either invasive or computed tomography coronary angiography to evaluate potential CMR biomarkers of significant coronary disease in this population. Results: We identified 50 adenosine stress CMR studies performed in 45 individual patients at a median of 19 years after transplantation (IQR 4.7-24.4); 9% of studies were conducted within the first year post-transplantation. No life-threatening adverse events, brief or prolonged atrioventricular block or other arrythmias occurred after adenosine infusion. Significant myocardial ischemia (≥ 1.5 segments) was reported in 17% of patients. When stratified by CAV severity, stress MBF index, but not inducible ischemia on visual inspection, was found to significantly differentiate patients with severe CAV from those without significant coronary disease (ANOVA p = 0.028). Conclusion: Adenosine stress perfusion CMR is safe and feasible in OHT recipients. Quantitative measurement of stress MBF index may represent a promising marker of coronary disease with incremental value over qualitative assessment of ischemia, and should be evaluated in future studies.

Abstract 18188: Positron Emission Tomography Has Robust Negative Predictive Value for Development of Clinically Significant Cardiac Allograft Vasculopathy Over Time

Introduction: Cardiac allograft vasculopathy (CAV) affects >50% of OHT recipients by 10 years and is a leading cause of mortality. Standard CAV screening is via invasive coronary angiography (ICA). Recently it has been shown that PET with myocardial blood flow (PET/MBF) has excellent diagnostic ability for CAV, however, its prognostic value is not known. Hypothesis: CAV assessment by PET/MBF can prognosticate lack of significant angiographic progression of CAV over meaningful time scales. Methods: A retrospective analysis of 206 OHT recipients who underwent a PET/CT between ICAs was performed. CAV progression over time was assessed using intra-patient sequences of 1) baseline ICA, 2) interval PET, and 3) subsequent ICA. PET CAV grades were determined using the algorithm in Table 1. For each interval, NPV of CAV development was calculated. Results: Intervals between ICAs of 600, 800, 1000, and 1200 days were included with 77, 114, 106, and 22 patients respectively. Sequences were analyzed if the PET fell within middle third of interval. For development of ISHLT CAV 2/3 on subsequent ICA, PET CAV 0/1 had an NPV of 0.91, 0.94, 0.91, and 0.86 at each respective time point. For development of meaningful ISHLT CAV (presence of ≥ 30% vessel stenosis) on subsequent ICA, PET CAV 0/1 had an NPV of 0.80, 0.85, 0.85, 0.8 respectively (Figure 1). Conclusions: Non-invasive CAV assessment by PET/MBF provides robust NPV for development of varying degrees of clinically significant CAV over intervals up to 4 years. PET may be used as an adjunct to ICA for CAV screening and is a viable alternative among those with reasonable risk profiles. Prospective studies are needed to determine optimal interval lengths.

Detection of cardiac allograft vasculopathy on dual source computed tomography in heart transplant recipients: comparison with invasive coronary angiography.

We aimed to evaluate the diagnostic accuracy (DA) of dual-source CT coronary angiography (DSCTCA) against invasive coronary angiography (ICA) in assessing stenotic cardiac allograft vasculopathy (CAV) in heart transplant (HTX) recipients. Consecutive HTX recipients(n = 38) on annual surveillance, underwent DSCTCA prior to ICA on a 192-detector 384-slice DSCT scanner. Cases were classified as no CAV (no stenosis), any CAV (any degree of stenosis) or significant CAV (>50% stenosis). Mean age was 33.66 ± 11.45 years (M:F = 27:11, median time from HTX-23.5 months). Prevalence of any CAV on DSCTCA and ICA was 44.7%(n = 17) and 39.5%(n = 15), respectively and that of significant CAV was 21.1%(n = 8) and 15.8%(n = 6), respectively. 557 (96.7%) segments were interpretable on DSCTCA. Mean radiation dose was 4.24 ± 2.15 mSv. At patient-level, the sensitivity, specificity, positive-predictive value, negative-predictive value (NPV), and DA of DSCTCA for detection of any CAV and significant CAV were 100%, 91.3%, 88.2%, 100%, 94.73% and 100%, 94%, 75%, 100%, 95% respectively. The same on segment-based analysis were 96%, 97.6%, 80%, 99.6%, 97.5% and 100%, 99.6%,86.7%,100%, 99.6%, respectively. There was excellent agreement between the two modalities for detection of any CAV and significant CAV [κ = 0.892 and 0.826 (patient-level), 0.859 and 0.927 (segment-level)]. CAC score correlated significantly with the presence of any CAV on both modalities. A diagnosis of rejection on biopsy did not correlate with any/significant CAV on DSCTCA or ICA. High sensitivity and NPV of DSCTCA in the evaluation of stenotic CAV suggests that it can be an accurate and non-invasive alternative to ICA for routine surveillance of HTX recipients. DSCTCA detects the stenotic CAV non-invasively in transplant recipients with high sensitivity, specificity and NPV when compared with catheter coronary angiography, at lower radiation doses. There is excellent agreement between CT angiography and catheter coronary angiography for detection of any CAV and significant CAV. A diagnosis of rejection on biopsy does not correlate with any/significant CAV on CT angiography or catheter angiography.

Clinical Utility of SPECT in the Heart Transplant Population: Analysis From a Single Large-volume Center.

Survival after heart transplant has greatly improved, with median survival now over 12 years. Cardiac allograft vasculopathy (CAV) has become a major source of long-term morbidity and mortality. Single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is used for CAV surveillance, but there is limited data on its prognostic utility. We retrospectively identified patients undergoing SPECT MPI for CAV surveillance at a single, large-volume center. Images were assessed with semiquantitative visual scoring (summed stress score [SSS] and summed rest score) and quantitatively with total perfusion defect (TPD). We studied 503 patients (mean age 62.5, 69.3% male) at a median of 9.0 years post-transplant. During mean follow-up of 5.1 ± 2.5 years, 114 (22.6%) patients died. The diagnostic accuracy for significant CAV (ISHLT grade 2 or 3) was highest for SSS with an area under the curve of 0.650 and stress TPD (area under the curve, 0.648), with no significant difference between SSS and stress TPD (P = 0.061). Stress TPD (adjusted hazard ratio, 1.07; P = 0.018) was independently associated with all-cause mortality, while SSS was not (P = 0.064). The prognostic accuracy of quantitative assessment of perfusion tended to be higher compared with semiquantitative assessment, with the highest accuracy for stress TPD (area under the receiver operating curve 0.584). While SPECT MPI identified a cohort of higher risk patients, with quantitative analysis of perfusion demonstrating higher prognostic accuracy. However, the overall prognostic accuracy was modest and alternative noninvasive modalities may be more suitable for CAV surveillance.

Coronary Flow Velocity Reserve and Myocardial Deformation Predict Long-Term Outcomes in Heart Transplant Recipients

After heart transplantation (HTx), invasive coronary angiography is the gold standard for surveillance of cardiac allograft vasculopathy (CAV). Noninvasive CAV surveillance is desirable. The authors examined left ventricular global longitudinal strain (LVGLS) and noninvasive coronary flow velocity reserve (CFVR) related to CAV and prognosis after HTx. Doppler echocardiographic CFVR and LVGLS were evaluated in 98 HTx patients. All-cause mortality and major adverse cardiac events (MACE), including hospitalization for heart failure, cardiovascular death, and significant CAV progression, were recorded. Median follow-up duration was 3.3years (range: 1.7-5.4years). Patients with low CFVR (<2.0; n=20) showed reduced MACE-free survival (hazard ratio, 4.3; 95% CI, 2.2-8.4; P<.0001) and increased all-cause mortality (hazard ratio: 4.7; 95% CI: 2.0-11.3; P<.0001) compared with patients with high CFVR (≥2.0; n=78). Worsened LVGLS (≥-15.5%) was also a strong independent predictor of MACE and cardiovascular and all-cause mortality. Combined low CFVR and worsened LVGLS provided incremental prognostic value, even after adjustment for CAV and time since HTx. The prevalence of low CFVR increased significantly with CAV severity, and the prevalence of combined low CFVR and/or worsened LVGLS was high in patients with moderate CAV (86%) and those with severe CAV (83%). The negative predictive value of combined high CFVR and improved LVGLS to rule out significant CAV was 94.5% (95% CI, 86.2%-98.4%), whereas the positive predictive value was 39.0% (95% CI, 25.3%-54.3%). The model had sensitivity of 84.2% (95% CI, 63.6%-95.3%) and specificity of 67.5% (95% CI, 56.6%-77.2%) for one or more abnormal parameters. In HTx patients with severe CAV, a higher prevalence of low CFVR and worsened LVGLS was observed. Both measurements were strong independent predictors of MACE and all-cause mortality in HTx patients. Combined CFVR and LVGLS provided incremental prognostic value and showed an excellent ability to rule out significant CAV and may be considered as part of routine CAV surveillance of HTx patients.

Implementing Coronary CT for Routine Annual Surveillance of Cardiac Allograft Vasculopathy in Heart Transplant Patients

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects heart transplant (HT) patients. Routine surveillance for CAV is warranted. We evaluated the feasibility, utility and safety of cardiac CT to screen for CAV in HT patients. <h3>Methods</h3> From Feb 2018 to Jul 2019 all HT patients >four years post-HT were converted from using stress myocardial perfusion imaging for the annual CAV surveillance to cardiac CT (calcium score scan and CT angiography (CTA)). All first scans were included. Scans were scored for image quality (non-diagnostic, moderate, good, excellent), Agatston calcium score and coronary stenosis (0%, <50% or ≥50%). CAV score (similar to ISHLT guidelines) based on CT findings was compared to the most recent CAV score (based on invasive angiography and perfusion imaging). Major adverse cardiovascular events (MACE) were scored one-year post-CT. <h3>Results</h3> In total, 141 CT scans were included. CTA was performed in 140 out of 141 patients who were planned for cardiac CT (55 (43-64) years, 66% men, and 11 (8-16) years post-HT). One patient only had a calcium score due to no IV access. Mean heart rate during CTA was 75±11 beats per minute with beta-blockers given in 90 patients. Image quality was good/excellent in 124 (89%) scans. Median radiation dose was 2.1 (1.6-2.9) mSv. Median Agatston calcium score was 4 (0-73), 56 (40%) patients had no detectable calcium. CTA showed new obstructive coronary disease (≥50% stenosis) in 25 (18%) patients (Figure 1). CTA reclassified CAV score in 49 (35%) patients (p<0.001). There were 78 CAV0, 30 CAV1, 15 CAV2 and 17 CAV3 patients. MACE occurred in 8 (6%) patients in the year post-CCTA (2 deaths (rejection + cancer), 5 CVAs, 2 myocardial infarctions (type 4 MI + NSTEMI in known CAV)). <h3>Conclusion</h3> Cardiac CT can be performed successfully in HT patients with good/excellent image quality and low radiation dose. CTA successfully detects significant CAV which leads to substantial reclassification of CAV grades.

Coronary Flow Reserve Predicts Major Adverse Cardiac Events and All-Cause Mortality in Heart Transplant Recipients

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) affects the epicardial arteries and veins and also the coronary microcirculation. In the absence of proximal epicardial artery stenosis, coronary flow velocity reserve (CFVR) reflects the function of the myocardial microcirculation. We aimed to determine the prognostic value of 1) CFVR and 2) a combination of CFVR and left ventricular global longitudinal strain (LVGLS) in HTx patients. <h3>Methods</h3> CFVR was evaluated using pulsed wave Doppler echocardiography in 98 HTx patients (median 6.9 years from HTx) examined with coronary angiography. Patients were enrolled from 2013 to 2018 and prospectively followed until June 1^st 2020. All-cause mortality and major adverse cardiac events (MACE) including heart failure, significant CAV progression, coronary intervention or cardiovascular death, were recorded. <h3>Results</h3> Median follow-up was 3.2 [interquartile range 1.9-5.1] years. Patients with low CFVR (<2.0, n=20) had a significantly reduced event-free survival rate compared with patients with high CFVR (≥2.0, n=78) (35% vs. 82%, hazard ratio (HR) 4.6, 95% CI 2.3-9.1, <i>p</i><0.0001) and had a higher rate of mortality than patients with high CFVR with an absolute difference of 43.3% (65.3% vs. 22.0%; HR 5.0, 95% CI 2.1-11.9, <i>p</i><0.0001). By combining low CFVR and low LVGLS magnitude (>-15.5%), we obtained a strong predictive model for MACE (HR 10.5, 95% CI 4.5-24.5, <i>p</i><0.0001) and all-cause mortality (HR 10.3, 95% CI 3.5-30.6, <i>p</i><0.001), which remained strong after adjustment for angiographic CAV. <h3>Conclusion</h3> CFVR strongly predicts MACE and all-cause mortality in HTx-patients. A model combining low CFVR and low LVGLS magnitude was a strong model for MACE and all-cause mortality prediction and could be considered as a non-invasive method for routine CAV surveillance.

Regadenoson Mycardial Contrast Echocardiography Perfusion Imaging for Detection of Allograft Coronary Vasculopathy

<h3>Purpose</h3> Due to the often asymptomatic nature of cardiac allograft vasculopathy (CAV) serial surveillance is recommended for all cardiac transplant (OHT) recipients. Ideally, CAV surveillance should be non-invasive, not involve ionizing radiation, and discriminate diffuse CAV from focal obstructions. We hypothesized that vasodilator stress myocardial contrast echocardiography (MCE) perfusion imaging can non-invasively detect microvascular impact of diffuse or focal CAV. <h3>Methods</h3> The study was a retrospective, single center analysis of OHT recipients undergoing MCE between 1/20 and 10/20 (n=11). MCE at rest and after regadenoson was performed using a continuous infusion of lipid-shelled microbubbles. Images were analyzed by evaluating time-intensity after a destructive pulse sequence in all vascular territories. MCE data were correlated with wall motion assessment by conventional stress echocardiography and invasive coronary angiography (ICA). Grading of MCE as normal, mild, severe; and focal vs. diffuse was performed by one experienced reviewer in a blinded fashion. <h3>Results</h3> Mean age was 63 ± 3.3 years post OHT, at an average of 10.8 ± 3.3 years post OHT. Severe perfusion abnormalities during MCE were able to distinguish high grade CAV (2+) from low grade CAV (0-1) utilizing ICA as the gold standard. While stress echocardiographic wall motion assessment failed to indicate early CAV grade 1, abnormal MCE perfusion was found in 3 of 7 cases with angiographic CAV grade 1. <h3>Conclusion</h3> MCE is a practical, non-invasive perfusion imaging technique that may be useful for detecting significant CAV in OHT recipients. Perfusion deficits correlate with significant coronary artery stenosis identified by standard stress echocardiography and ICA, and may identify diffuse small vessel disease more effectively than current noninvasive techniques. Larger, prospective studies are needed to support this hypothesis and ultimately provide a rationale for routine use of MCE for CAV surveillance.

Moderate Association of Coronary Artery Calcium and Cardiac Allograft Vasculopathy in Heart Transplant Recipients on Non-Gated CT

<h3>Purpose</h3> Cardiac allograft vasculopathy (CAV) is common in patients who have undergone orthotopic heart transplant (OHT) and is associated with significant morbidity and mortality. Non-invasive methods for identifying CAV are an appealing alternative to standard clinical practice of routine invasive angiography. We explored the association of CAV with incidental coronary artery calcium (CAC) from non-ECG gated, clinically indicated chest CT scans. <h3>Methods</h3> This is a single-center, retrospective, observational study of OHT patients >1 year from transplant who underwent left heart catheterization between 2015 and 2019 and had a clinically indicated, non-ECG gated chest CT obtained for a variety of indications within 6 months of the catheterization. CAC was graded by a blinded reviewer in a semi-quantitative manner based on extent and distribution across the coronary tree. Angiographically significant CAV was obtained from left heart catheterizations results obtained per standard institutional protocol. <h3>Results</h3> 73 patients were included, 56 (77%) were male, mean age was 60±12 years and median time from heart transplant was 4 years [IQR 2, 8]. 34 patients (47%) were found to have CAC, of which 7 (21%) were found to have moderate or severe CAC. 38 patients (52%) were found to have CAV on angiography. In the CAC group, 25 were found to have CAV (74%). Of those with moderate to severe CAC, 7 (100%) were found to have CAV. In the no CAC group, 13 (33%) were found to have CAV. The presence of CAC had a sensitivity, specificity, positive predictive value and negative predictive value of 66%, 74%, 73%, and 67% respectively for the diagnosis of CAV. <h3>Conclusion</h3> The absence of CAC on non-ECG gated CT demonstrated a moderate ability to rule out CAV, while moderate to severe CAC was strongly associated with CAV. As chest CT scans are common in this population, informing clinical decision making with this "free" information is potentially beneficial.

Micro- and macrovascular cardiac allograft vasculopathy in relation to 91 cardiovascular biomarkers in heart transplant recipients-An exploratory study.

Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro- and macrovascular CAV and major adverse cardiac events in HTx patients. We evaluated 91 cardiovascular disease-related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro- and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and 15 O-H2 O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death. We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p<.05) and significantly decreased paraoxonase 3 (PON3) (p<.05). N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly increased in patients with microvascular CAV (p<.05) and borderline significantly increased in patients experiencing major adverse cardiac events (p=.10) and patients with macrovascular CAV (p=.05). We identified consistent changes in two proteins involved in cholesterol homeostasis which may be important players in the pathogenesis of CAV: PON3 and PCSK9. NT-proBNP also showed consistent changes across all groups but only reached statistical significance in patients with microvascular CAV. Our results warrant further validation in future studies.

HLA Matching in Cardiac Transplantation - Impact on Cardiac Allograft Vasculopathy, Rejection and Donor Specific Antibodies

Introduction HLA matching is not current practice in heart transplant (HT) donor allocation due to scarcity of donor organs and ischemic time. However HLA mismatch might adversely affect transplant outcomes. Even if HLA matching is not possible the degree of HLA mismatch might help inform clinicians on a patients risk for long term transplant complications. Hypothesis We hypothesize that the degree of HLA mismatch affects long-term complications in a stable HT cohort. Methods 65 clinically stable HT recipients (no cellular (ACR) or antibody mediated rejection (AMR) in the preceding 6 months) ≥ 2 years post transplant were enrolled. Serologic HLA typing was obtained for donor and recipients (D/R) pairs and the number of matches was analyzed combined for HLA class I and HLA II. Study endpoints were donor specific antibody (DSA) formation and significant cardiac allograft vasculopathy (CAV). Results HLA-A,-B,-C, -DR and-DQ (ABCDRQ) typing were available for 37 D/R pairs and were analyzed for matches. Additionally, 53 D/R pairs had HLA-A,-B, -DR (ABDR) typing. Meantime post HT was 8.5±5.4 years. A total of 28 patients had CAV and 9 patients had DSA. Among the ABCDRDQ cohort the number of matches was 1.54 ± 1.17 and 1.00 (0.00-1.00) in the ABDR cohort. There were no differences in the number of HLA matches for both cohorts among those with and without DSA and those with and without CAV (Table).However among the ABCDRDQ cohort there was a trend towards higher number of HLA matches in those without DSA 1.63 ± 1.19 versus 1.14 ± 1.07 in the DSA group (p 0.32), this was likely limited by the small sample size.There was no significant relationship between total HLA matches and number of ACR episodes (p 0.89). The incidence of AMR was too low for analysis. Conclusion In this highly selected cohort of clinically stable long time transplant survivors the degree of serological HLA matching was not associated with the development of CAV or ACR. However, there was a trend towards less DSA formation in those with more D/R HLA matches. Future longitudinal studies should evaluate the development of long-term complications as a function of HLA matching and potentially incorporate HLA mismatch as an indicator for the need of enhanced clinical surveillance.

Prognostic Value of Dobutamine Stress Echocardiography in Heart Transplant Recipients

Dobutamine stress echo (DSE) carries a class IIa recommendation for screening of cardiac allograft vasculopathy (CAV). Positive DSEs have a modest ability to predict development of CAV, but normal DSE has a low negative predictive value for CAV. Ability of a positive DSE to predict outcomes is controversial. Outcomes following a normal DSE have not been assessed in large, modern cohorts. We sought to analyze the prognostic value of DSE in heart transplant recipients. All adult heart transplants performed at our institution from 2000 to 2010 were reviewed. Multi organ, recipients who expired within the first year, and those who did not have a DSE were excluded. Patients were grouped according to their DSE result and CAV grade and survival were analyzed. We also analyzed outcomes in patients with a normal DSE and predictors for CAV in this cohort. Unpaired t-test used for analysis. Kaplan-Meier survival curves generated. P value <0.05 considered significant. 179 (mean age 56.6 yrs, 77.6% male) heart transplant recipients were included. 26 (14.5%) patients had a positive DSE. 143 (79.9%) patients subsequently underwent coronary angiography [median duration 9 (1.1 - 17.2) yrs after transplant]. Positive DSE was associated with development of angiographically significant CAV (40% vs 12.2%, P=0.0015) and higher grade CAV (mean grade 1.2±1.2 vs 0.6±0.8, P=0.0077). Those with a positive DSE had a worse 10 yr survival (45.8% vs 68.7%, P=0.0092). Of those with a normal DSE, 15 (12.2%) developed significant CAV. In the normal DSE cohort, there were no differences in demographics, CMV mismatch status, HLA DR mismatch level or donor age between those who developed significant CAV and those who did not. Following a normal DSE, there was no difference in 10 yr survival (80% vs 77.7%, P=0.88) between those who developed and did not develop CAV. Positive DSE is associated with development of significant CAV and worse survival. Normal DSE is associated with better survival, regardless of development of CAV.

Influence of HLA-DR Mismatches on Long Term Outcomes Following Heart Transplant

There are conflicting reports on the effect of donor-recipient HLA-DR matching in heart transplantation. Studies have shown HLA-DR matching reduces the incidence of graft rejection within the first year and improves short term graft survival It is not known if HLA-DR matching impacts long term outcomes. We sought to analyze the effect of HLA-DR mismatch on long term survival, and also explain possible mechanisms. All adult heart transplants performed at our institution from 2000 to 2010 were retrospectively reviewed. Multi-organs, patients who expired within the first year after transplant and those with missing data were excluded. Patients were grouped according to number of HLA-DR mismatches: 0, 1 or 2. We analyzed allograft function [using most recent ejection fraction (EF)], development of significant (ISHLT grade ≥2) cardiac allograft vasculopathy (CAV) and survival. ANOVA used for analysis. Kaplan-Meier survival curves generated. P value <0.05 considered significant. 172 heart transplant recipients were included in the analysis. HLA-DR mismatch status was as follows: 9 (5.2%) had 0, 63 (36.6%) had 1, and 100 (58.1%) had 2 mismatches. There were more men in the group with 2 mismatches (82% vs 74.6% vs 66.7%, P<0.0001).There was no difference in the development of significant CAV in the three groups (33.3% vs 17% vs 12%, P=0.23). There was no difference in the severity of CAV (mean ISHLT grade 1.11±1 vs 0.7±1 vs 0.57±0.8, P=0.23). Mean EF was no different between the three groups (63.9±12.9% vs 68±6.4% vs 68.5±5.5%, P=0.12). 10 yr survival was similar in the three groups (77.8% vs 68.1% vs 58.4%, P=0.44). In our cohort, HLA-DR mismatches did not influence graft function, development of and severity of angiographically significant CAV. There was no impact on long term patient survival. HLA-DR matching prior to heart transplant may not be justified given the increased cost and logistical burden of HLA matching and longer cold-ischemic times that may result from reliance on tissue typing.

Donor-Derived Cell-Free DNA is Associated with Cardiac Allograft Vasculopathy

There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non-invasive tool to detect acute antibody and cellular mediated rejection. However the role of dd-cfDNA in detecting and monitoring cardiac allograft vasculopathy (CAV) in the absence of acute rejection remains unknown. We hypothesized that dd-cfDNA levels would correlate with the presence of CAV. 65 clinically stable heart transplant recipients ≥ 2 years post-transplant, with no rejection episodes in the preceding 6 months were enrolled. CAV was assessed by routine coronary angiogram and intravascular ultrasound. Patients were stratified by time since transplant (2-5, 5-10 and ≥ 10 years post transplant) and high versus low levels of dd-cfDNA defined as above and below the median. Significant CAV was defined as Stanford III-IV or angiographic disease. A targeted amplification, next generation-sequencing assay (AlloSure®; CareDx, Inc.) was used to detect dd-cfDNA. Of 58 patients with known CAV status, 30 had high levels of ddcf-DNA (≥0.14%) and 28 had low levels (<0.14%). There was no difference in left ventricular ejection fraction between the groups but CAV was present in 63% of patients with high levels of ddcf-DNA compared to 36% in the low ddcf-DNA group (p 0.047). Donor-specific antibodies were present in 27% of the high ddcf-DNA group compared to 3.6% of the low ddcf-DNA group (p 0.026) (Table). There were no differences in the frequency of cellular and antibody medicated rejection episodes between the groups. Importantly, there were also no differences in time post-transplant between patients with high versus low ddcf-DNA. dd-cfDNA levels were associated with CAV in a cohort of stable transplant recipients >2 years post HT and thus might help to identify those in need for invasive assessment. Further studies should investigate if there is an association between dd-cfDNA levels and CAV severity and whether dd-cfDNA levels can predict CAV progression.

Intravascular Imaging for Assessment of Cardiac Allograft Vasculopathy Following Heart Transplantation

Cardiac allograft vasculopathy (CAV) is a significant cause of morbidity and mortality in the post-cardiac transplant patient population. Current guidelines recommend annual angiographic surveillance for CAV; however, angiography alone has several limitations and can lead to systematic underestimation of disease burden and the inability to sensitively track disease progression. We provide an overview of intravascular imaging in the initial and longitudinal evaluation of CAV, with a focus on the use of intravascular ultrasound (IVUS). Multiple studies have demonstrated that progression of maximal intimal thickness (MIT) on serial IVUS evaluation, particularly ≥ 0.5 mm over the first year, post-transplant, is predictive of both future development of angiographically significant CAV as well as major adverse cardiac events, including graft loss and mortality. There are also emerging data that in vivo plaque characterization, as assessed by the attenuated-signal plaque score or by virtual histology intravascular ultrasound (VH-IVUS), may provide prognostic value in this population. OCT-derived intimal measurements have been noted to correlate well with IVUS findings and may also aid in early identification of CAV. In addition to early identification and prognostication, several studies have used intravascular imaging to assess therapeutic impact of various immunosuppressive regimens on progression of established CAV. Intravascular ultrasound, and more recently, optical coherence tomography (OCT) have emerged as valuable adjuncts to angiography in the evaluation of CAV, particularly with regard to early detection, objective prognostication, and differentiation of CAV from donor-derived coronary artery disease (CAD). Furthermore, intravascular imaging may guide changes to the immunosuppressive regimen and/or percutaneous coronary intervention, when necessary.

Comparative Prognostic and Diagnostic Value of Myocardial Blood Flow and Myocardial Flow Reserve After Cardiac Transplantation

Cardiac allograft vasculopathy (CAV) is a major cause of graft failure after cardiac transplantation. CAV is characterized by diffuse involvement of epicardial coronary arteries and the microvasculature. PET allows quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR), which may be accurate markers of CAV severity. We compared the diagnostic and prognostic utility of stress MBF and MFR after cardiac transplantation. Methods: This was a cohort study of consecutive cardiac transplant patients undergoing 82Rb PET scans. Semiquantitative regional analysis and global measurement of stress MBF and MFR were performed. Associations with all-cause mortality were assessed with multivariable Cox analysis. The diagnostic accuracy for significant CAV (grade 2/3) and the prognostic accuracy of stress MBF and MFR, corrected and uncorrected for rate-pressure product, were compared. Results: In total, 99 patients, mean age 68.8 y and 75.8% male, were followed for a median of 3.4 y, during which 26 deaths occurred. Stress MBF and MFR had similar diagnostic accuracy for significant CAV. However, uncorrected MFR had improved discrimination for all-cause mortality compared with stress MBF (area under the curve, 0.748 vs. 0.639; P = 0.048). Higher MFR (adjusted hazard ratio, 0.30; P < 0.001), but not stress MBF (adjusted hazard ratio, 1.14; P = 0. 656), was associated with reduced all-cause mortality. Preserved MFR (>2.0) identified relatively low-risk patients (annual mortality, 4.7%), whereas the presence of a left ventricular ejection fraction lower than 45% and MFR lower than 1.7 identified high-risk patients (annual mortality, 51.6%). Conclusion: Quantitative PET analysis, and particularly MFR, has diagnostic and prognostic utility after heart transplantation. Preserved MFR identifies low-risk patients, whereas the presence of multiple abnormal parameters identifies high-risk patients.

Cardiac Allograft Vasculopathy is Linked to Impaired Generation of Regulatory M2 Macrophages

Purpose There is mounting evidence for the role of innate immunity in acute cardiac allograft rejection, but this does not necessarily extend to cardiac allograft vasculopathy (CAV) and predictors of CAV remain elusive. We hypothesized that circulating monocytes and their derived macrophage subtypes correlate with CAV. Methods 49 consecutive heart transplant recipients ≥ 2 years post-transplant were enrolled. CAV was assessed on angiogram with IVUS by ISHLT and Stanford classification grading. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, with monocytes stained and measured by flow cytometry for classical (CD14++/CD16−), intermediate (CD14++/CD16+), and nonclassical (CD14lo/CD16++) subtypes. Monocytes were cultured into macrophages, driven by M-CSF, and assayed for polarization markers CD86 and CD206. Results were also compared to 22 non-transplant patients with atherosclerotic coronary artery disease (CAD) and healthy controls (no CAD). Results 22 patients had no significant CAV (Stanford class I-II) while 27 had significant CAV (class III-IV). Other than time since transplant (no CAV 77±13 vs CAV 135±12 months), there were no significant differences, including immunosuppression, between the two groups. There were no differences between monocyte subgroups in isolation, but when combined with derived macrophage polarization, patients with CAV had significantly lower M2 (CD206+) macrophage production (0.19±0.04%) than those without CAV (0.45±0.13%), p Conclusion CAV patients are characterized by reduced ability to generate regulatory M2 macrophages. The circulating monocyte and macrophage subtypes differ from those of native CAD and these cell-based markers could be useful to differentiate high vs. low CAV risk phenotypes.

Abstract 16605: Peripheral Blood-Derived Myeloid Subtypes Are Associated With Cardiac Allograft Vasculopathy

Introduction: The evidence for innate immunity’s role in cardiac allograft rejection does not necessarily extend to cardiac allograft vasculopathy (CAV), and predictors of CAV remain elusive. We hypothesize that circulating monocytes and their derived macrophage subtypes, as well as associated inflammatory and angiogenesis markers, correlate with CAV. Methods: 49 consecutive heart transplant recipients over 2 years post-transplant were enrolled. Peripheral blood mononuclear cells were isolated, with monocytes stained and measured by flow cytometry for classical (CD14 ++ /CD16 - ), intermediate (CD14 ++ /CD16 + ), and nonclassical (CD14 lo /CD16 ++ ) subtypes. Monocytes were cultured into macrophages, driven by M-CSF, and assayed for polarization markers CD86 and CD206. Serum concentrations of multiple factors including IL8, IL6, TNFα, angiopoietin-2, and VEGF-A were measured by immunoassay. CAV was assessed by angiogram and intravascular ultrasound (IVUS). Results: 22 patients had no significant CAV (Stanford class I-II) while 27 had significant CAV by angiogram or IVUS (class III-IV). Other than time since transplant (77±13 vs 135±12 months), baseline characteristics of the two groups were similar. There were no differences between monocyte subgroups in isolation, but when combined with derived macrophage polarization, patients with CAV tended toward lower M2 (CD206 + ) macrophage production (0.18±0.04%) than those without CAV (0.35±0.11%). The CAV monocyte/macrophage profile was distinct from that of a reference native CAD population. IL8 was higher late post-transplant (&gt;7.5 years) compared to early post-transplant (1.8±0.3 vs 1.0±0.1 pg/ml). There was also higher expression of angiopoietin-2 with time after transplant and with CAV. Conclusions: The reduced ability of CAV patients to generate regulatory M2 macrophages and their higher circulating IL8 and angiopoietin-2, both linked to inflammatory macrophage signatures, support a model in which pro-inflammatory myeloid phenotypes are connected to development of CAV, and notably, these circulating monocyte and macrophage subtypes differ from those of native CAD. These cell-based and paired circulating markers could be useful to differentiate high vs. low CAV risk phenotypes.