Assessment Of Cardiac Allograft Vasculopathy Research Articles

Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy

BackgroundPositron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. ObjectivesThe authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. MethodsAdults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. ResultsA total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: −6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = −0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. ConclusionsThe 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786)

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 &gt;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.

Myocardial Flow Assessment After Heart Transplantation Using Dynamic Cadmium-Zinc-Telluride Single-Photon Emission Computed Tomography With 201Tl and 99mTc Tracers and Validated by 13N-NH3 Positron Emission Tomography.

Cardiac allograft vasculopathy (CAV) is an obliterative and diffuse form of vasculopathy and is the most common cause of long-term cardiovascular mortality in heart transplant patients. This study aimed to investigate the diagnostic performance of 99mTc and 201Tl tracers in the assessment of CAV using cadmium-zinc-telluride (CZT) single-photon emission computed tomography (SPECT) for myocardial blood flow (MBF) and myocardial flow reserve (MFR) quantification, which was further validated using 13 N-NH3 positron emission tomography (PET). Thirty-eight patients with prior heart transplantation who underwent CZT SPECT and 13 N-NH3 PET dynamic scans were included in this study. CZT SPECT with 99mTc-sestamibi was used in the first 19 patients and 201Tl-chloride for the remaining patients. To determine the diagnostic accuracy of angiographically defined moderate-to-severe CAV, the analysis included patients who underwent angiographic examinations within 1 year of their second scan. There were no significant differences in the patient characteristics between the 201Tl and 99mTc tracer groups. Both 201Tl and 99mTc CZT SPECT-derived stress MBF and MFR values globally and in 3 coronary territories showed good correlations with 13 N-NH3 PET. The 201Tl and 99mTc cohorts did not differ significantly in the correlation coefficients of CZT SPECT versus PET for MBF and MFR, except for stress MBF (201Tl:0.95 versus 99mTc:0.80, P=0.03). 201Tl and 99mTc CZT SPECT were satisfactory for detecting PET MFR <2.0 (201Tl area under the curve, 0.92 [0.71-0.99], 99mTc area under the curve, 0.87 [0.64-0.97]) and angiographically defined moderate-to-severe CAV, and CZT SPECT results were comparable to that of 13 N-NH3 PET (CZT area under the curve, 0.90 [0.70-0.99], PET area under the curve, 0.86 [0.64-0.97]). This small study suggests that CZT SPECT using 201Tl and 99mTc tracers showed comparable MBF and MFR, and the results correlated well with those of 13 N-NH3 PET. Hence, CZT SPECT with 201Tl or 99mTc tracers can be used to detect moderate-to-severe CAV in patients with prior heart transplantation. However, validation using larger studies is warranted.

Noninvasive Physiologic Assessment of Cardiac Allograft Vasculopathy Is Prognostic for Post-Transplant Events

BackgroundCardiac allograft vasculopathy (CAV) causes impaired blood flow in both epicardial coronary arteries and the microvasculature. A leading cause of post-transplant mortality, CAV affects 50% of heart transplant recipients within 10 years of heart transplant. ObjectivesThis analysis examined the outcomes of heart transplant recipients with reduced myocardial blood flow reserve (MBFR) and microvascular CAV detected by 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging. MethodsA total of 181 heart transplant recipients who underwent PET to assess for CAV were included with a median follow-up of 4.7 years. Patients were classified into 2 groups according to the total MBFR: >2.0 and ≤2.0. Microvascular CAV was defined as no epicardial CAV detected by PET and/or coronary angiography, but with an MBFR ≤2.0 by PET. ResultsIn total, 71 (39%) patients had an MBFR ≤2.0. Patients with an MBFR ≤2.0 experienced an increased risk for all outcomes: 7-fold increase in death or retransplantation (HR: 7.05; 95% CI: 3.2-15.6; P < 0.0001), 12-fold increase in cardiovascular death (HR: 12.0; 95% CI: 2.64-54.12; P = 0.001), and 10-fold increase in cardiovascular hospitalization (HR: 10.1; 95% CI: 3.43-29.9; P < 0.0001). The 5-year mean survival was 302 days less than those with an MBFR >2.0 (95% CI: 260.2-345.4 days; P < 0.0001). Microvascular CAV (adjusted HR: 3.86; 95% CI: 1.58-9.40; P = 0.003) was independently associated with an increased risk of death or retransplantation. ConclusionsAbnormal myocardial blood flow reserve, even in the absence of epicardial CAV, identifies patients at a high risk of death or retransplantation. Measures of myocardial blood flow provide prognostic information in addition to traditional CAV assessment.

Clinical implementation of coronary computed tomography angiography for routine detection of cardiac allograft vasculopathy in heart transplant patients.

SummaryCardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long‐term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post‐transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good–excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6–2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non‐cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing.

Oxygen-sensitive Magnetic Resonance Imaging: A Noninvasive Step Forward for Diagnosing Vasculopathy in the Cardiac Allograft.

Oxygen-sensitive Magnetic Resonance Imaging: A Noninvasive Step Forward for Diagnosing Vasculopathy in the Cardiac Allograft.

Early diagnosis and management of cardiac allograft vasculopathy: is it time for a standardized approach?

Cardiac allograft vasculopathy (CAV) still represents the main cause of long-term graft loss after heart transplantation. Its silent clinical presentation makes an early identification difficult, with relevant implications for a standardized follow-up. Although technological advances have provided sophisticated non-invasive techniques for CAV assessment, intravascular ultrasound in conjunction with coronary angiography is still the gold standard to detect rapidly progressive CAV and to provide prognostic information during follow-up. Current guidelines recommend annual coronary angiography during the first 5 years and every 2 years thereafter. Although commonly performed, coronary angiography has multiple limitations, especially in young patients and in case of chronic kidney disease. This article aims to review the literature about the monitoring of CAV and to propose an ideal and individualized pathway for early diagnosis of CAV in transplanted patients, based on their cardiovascular risk.

Association of Donor Age and Plasma Donor-Derived Cell-Free DNA Levels with CAV Development after Heart Transplant: SHORE Preliminary Data

<h3>Purpose</h3> Cardiac Allograft Vasculopathy (CAV) is a leading cause of long-term graft dysfunction and loss after HT. Elevated plasma donor-derived cell-free DNA (dd-cfDNA) levels may predict <i>de novo</i> HLA Class I &/or II elaboration after HT. We queried whether dd-cfDNA levels may reflect new or progressive CAV development in the observational <i>Surveillance HeartCare Outcomes Registry</i> (SHORE). <h3>Methods</h3> Over 1200 unique patients at 60 HT Centers across the United States were enrolled into surveillance by gene expression profiling (GEP; AlloMap®) and dd-cfDNA (AlloSure®) in concert with clinical, catheterization and pathologic data capture. Coronary assessments per angiography were classified as either "New" or "Progressive" while "Stable" or "None" comprised the comparison cohorts. We performed analysis by Cox Proportional Hazards Modeling and type III statistical testing with donor age and dd-cfDNA as covariates for development of CAV (p<0.05) <h3>Results</h3> We identified 195 unique HT recipients with dd-cfDNA data within the preceding 30-days of CAV assessment. There were 15 CAV events classified as either "New" or "Progressive" [TABLE]. Mean time from the last dd-cfDNA monitoring and CAV development was 6.07 days (9.95). Both dd-cfDNA (p=0.04) and donor-age (p=0.017) were significant covariates for CAV development. An association of donor-age (p=0.018) and a trend for dd-cfDNA plasma levels (p=0.079) with new onset / progressive CAV was demonstrated. <h3>Conclusion</h3> Preliminary data from SHORE demonstrated the correlation of donor-age and CAV, while elevated dd-cfDNA plasma levels trended towards the development of new onset or progressive CAV after HT. Further data development that encompasses longer-term follow-up and standard CAV methods of assessment, should provide value in refining the impact of CAV on dd-cfDNA.

Determinants of sudden cardiac death after heart transplantation

Heart transplant recipients are at high-risk of sudden cardiac death (SCD). However, risk factors of SCD in heart recipients remained poorly described. To assess the predictors of SCD beyond the first-year post-transplant. We enrolled consecutive patients transplanted between 2004 and 2017 in two French referral centres. We excluded patients deceased during the first year. Patients underwent an evaluation at the day of transplantation and during the first year, comprising clinical, biological, histological, immunological (circulating anti-HLA DSA) and interventional (cardiac allograft vasculopathy assessment) parameters. According to the last consensus, SCD was defined as an unexpected out-of-hospital cardiac arrest without obvious non-cardiac cause, in the first hour after initiation of symptoms. A total of 913 patients were included. The median follow-up post-HT was 5.9 years (IQR = 2.9–8.5). Among the 60 parameters tested in univariate analysis, we identified 4 independent factors independently associated with sudden death after 1 year post-HT: donor age (HR = 1.55; 95% CI: 1.14–2.11; P = 0.005), recipient age (HR = 0.74; 95% CI: 0.59–0.93; P = 0.011), ventricular ejection fraction (LVEF) < 55% any time after transplantation (HR: 3.95; 95% CI: 1.95–8.02; P < 0.001), the presence of circulating anti-HLA DSA at the time of transplantation (HR: 2.18; 95% CI: 1.15–4.11; P = 0.017). The incidence rate of SCD was 2.17 per 100 person-year (95% CI: 1.42–4.60) and 1.21 per 100 person-year (95% CI: 0.80–2.58) in patients with FEVG < 55% ( n = 73) and in patients with pre-formed DSA ( n = 260), respectively ( Table 1 ). In a large multicentric and highly phenotyped cohort of heart transplant recipients, we identified four independent factors associated with SCD beyond the first year. This study provides fresh evidence of SCD assessment for improving risk stratification of HT recipients.

Feasibility of Real-Time Myocardial Contrast Echocardiography to Detect Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients

Cardiac allograft vasculopathy (CAV) is an important adverse prognostic factor for pediatric heart transplant (HT) recipients. Invasive coronary angiography (ICA) is the gold standard for CAV detection but lacks sensitivity for early microvascular changes and cumulative radiation exposure is of concern. Real-time myocardial contrast echocardiography (RTMCE) using ultrasound enhancing (contrast) agents performed during dobutamine stress echocardiography (DSE) can assess myocardial function, perfusion, and microvascular integrity. The objective of this study was to determine the safety and feasibility of RTMCE during DSE to detect CAV in a pediatric HT population. HT patients 10-21years of age were recruited to undergo DSE with RTMCE to determine technical feasibility, test tolerability and adverse event rate, and detection of perfusion defects compared with ICA-detected CAV. Thirty-six patients from two centers were enrolled, with a mean age 13.5±4.3years; 21 (58%) were male. Wall motion and myocardial perfusion were qualitatively assessed and compared with ICA findings of CAV. Myocardial blood flow (MBF) at rest and peak stress was quantified, and myocardial blood flow reserve (MBFR) was defined as the ratio of peak to rest MBF. Five (14%) patients had CAV by ICA, two with obstructive disease and three with mild CAV. Real-time myocardial contrast echocardiography was feasible in 32 (89%) patients. Three patients had wall motion defects, including one with a mixed defect and two with fixed defects. A perfusion abnormality was present in five patients, two of whom had obstructive CAV and one with mild CAV. Sensitivity and specificity of RTMCE for CAV detection were 60% and 94%, respectively, and diagnostic accuracy was 89%. MBFR assessment was feasible in 20 (63%) patients. The mean MBFR was 3.4±0.7. Patients with CAV had lower MBFR than those without (2.0±0.2 vs 3.7±0.8; P<.01). There were no serious adverse events related to RTMCE. Dobutamine stress RTMCE appears to be safe and feasible for the assessment of CAV in pediatric HT recipients. Further assessment is warranted to determine whether this noninvasive technique could provide a reliable alternative to ICA.

Determinants of sudden cardiac death after heart transplantation

Abstract Background Heart transplant recipients are at high-risk of sudden cardiac death (SCD). However, risk factors of SCD in heart recipients remained poorly described. Objective To assess the predictors of SCD beyond the first-year post-transplant. Methods We enrolled consecutive patients transplanted between 2004 and 2017 in two French referral centers. We excluded patients deceased during the first year. Patients underwent an evaluation at the day of transplantation and during the first year, comprising clinical, biological, histological, immunological (circulating anti-HLA DSA) and interventional (cardiac allograft vasculopathy assessment) parameters. Echocardiographies were routinely performed in all included patients according to a prespecified protocol. According to the last consensus, SCD was defined as an unexpected out-of-hospital cardiac arrest without obvious non-cardiac cause, in the first hour after initiation of symptoms. Cox model analysis was used to determine the parameters associated with sudden death risk. Results A total of 913 patients were included. The median follow-up post-HT was 5.9 years (IQR=2.9–8.5). Among the 213 deaths after one year, 44 patients (21%) died from SCD. In this population, the incidence rate of SCD was 0,82 per 100 person-year (95% CI: 0,51–2,05). Among the 60 parameters tested in univariate analysis, we identified 2 independent factors of sudden death after 1 year post-HT: left ventricular ejection fraction (LVEF) ≤55% any time after transplantation ( HR 4.07, 95% CI 1.94–8.53, p&amp;lt;0.001) and the presence of circulating anti-HLA DSA at the time of transplantation (HR 2.79, 95% CI 1.37–5.68, p=0.005). The incidence rate of SCD was 2.17 per 100 person-year (95% CI: 1.42; 4.60) and 1.21 per 100 person-year (95% CI: 0.80; 2.58) in patients with FEVG&amp;lt;55% (n=73) and in patients with pre-formed DSA (n=260), respectively. Conclusion In a large multicentric and highly phenotyped cohort of heart transplant recipients, we identified two independent factors associated with SCD beyond the first year. This study provides fresh evidence of SCD assessment for improving risk stratification of HT recipients. Funding Acknowledgement Type of funding source: None

Research Highlights

Research Highlights

Regional Variability of Cardiac Allograft Vasculopathy by Intravascular Ultrasound Assessment

Intravascular ultrasound (IVUS) assessment of cardiac allograft vasculopathy (CAV) provides diagnostic and prognostic information. Multivessel analysis has high sensitivity for detecting CAV, but is time consuming, costly and associated with procedural risks compared to single-vessel examination. We evaluated the regional distribution and plaque characteristics of CAV to guide clinical evaluation by IVUS. Consecutive heart transplant recipients referred for coronary angiography were prospectively evaluated with multivessel IVUS. Quantitative IVUS analysis was performed for every 1 mm axial slice to determine average maximal intimal thickness, intimal area and percentage intimal area. Virtual histology was utilized for plaque characterization. Forty patients completed evaluation at 4.8 ± 5.8 years post-transplant: mean age 56 ± 14 years, 31 (78%) male. Angiographic disease was present in 14 (35%) patients: 9 (23%) CAV1, 2 (5%) CAV2, 3 (8%) CAV3. Maximal stenosis was greater in the LAD (median 34% (IQR 20, 63) vs. 19% (IQR 0, 29) for LCx, 0% (IQR 0, 18) for RCA, (p=0.001)) and proximal segments (median 17% (IQR 12, 29) vs. 13% (IQR 9, 23) for mid, 12% (IQR 8, 16) for distal segments, p=0.005). A total of 268 segments in 101 vessels (40 left anterior descending (LAD), 35 circumflex (LCx), 26 right coronary artery (RCA)) were analyzed with IVUS. Mean coronary length examined was 64 ± 15 mm. Intimal disease on IVUS was greater in the LAD and proximal coronary segments (Table). On virtual histology, plaque composition was predominantly mixed atheromatous fibrotic and more prevalent in the LAD (72%) vs. LCx (54%) and RCA (42%), p=0.043. There was no isolated fibrotic plaque and low 13% prevalence of vulnerable thin cap fibroatheroma plaque. There is heterogeneous distribution of CAV with high disease burden in the LAD and proximal coronary segments. Single-vessel IVUS examination for CAV, beginning in the LAD could avoid risks of multivessel examination.

Assessment of Cardiac Allograft Vasculopathy from Oct Images: Automated Analysis is as Good as Expert-Guided Approach

Cardiac Allograft Vasculopathy (CAV) is a frequent complication after heart transplantation (HTx). To help identify patients at risk of CAV, 3D quantitative analysis of coronary wall thickening is of major importance. Until now, substantial manual tracing effort was required. We report a fully automated approach using optical coherence tomography (OCT) imaging. Lumen surface, intimal and medial layers were identified using our LOGISMOS segmentation framework. Coronary wall regions with layered appearance were automatically identified in each OCT frame using deep learning. These segmentation and classification approaches were newly combined in one fully automated system. The comparison between fully automated and expert-guided analyses was performed in 116 patients with OCT imaging at 1 and 12 months after HTx (1M, 12M). The expert-guided analysis used our previously-reported semi-automated layer segmentation method with expert-identified analyzable regions thus yielding an independent standard. The table shows that our fully automated approach yields quantitative indices of CAV progression that are statistically indistinguishable from the independent standard using Wilcoxon signed-rank test. The observed measurement errors are very small fractions of the OCT pixel size (∼10 μm/pixel). While the expert-guided definition of the independent standard required 2-15 minutes of user-guided segmentation and at least 30 minutes of manual definition of layered wall regions per pullback, the new automated analysis required less than 2 minutes of computer processing for each coronary pullback (median length 38.7 mm). Our approach is fully automated, efficient, and facilitates accurate layer-specific quantification of coronary wall thickness and their changes 1M-12M after HTx. The fully automated method can replace the manual or expert-guided analyses of OCT image sequences while maintaining high levels of accuracy.

Use of Cardiac CT in the Routine Assessment of Cardiac Allograft Vasculopathy in Heart Transplant Patients: Results from the First 100 Consecutive Patients

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects heart transplant patients (HTx). Routine screening for CAV is warranted. We evaluated the feasibility and utility of cardiac CT to screen for CAV in 100 consecutive HTx patients at our center. From Feb 2018 to Jan 2019 all consecutive HTxs who were more than five-years post-transplant were converted from using stress myocardial perfusion imaging to cardiac CT for the annual assessment of CAV. CAV was scored (0 (absent), 1 (mild), 2 (moderate), 3 (severe)) based on coronary CT angiography (CCTA) findings and compared with the most recently known CAV score before CCTA. CCTA was performed in 99 out of 100 patients who were planned for cardiac CT (56 (42-63) years, 65% men, and 11 (8-16) years post-transplant), 1 patient underwent only a calcium scan due to IV access problems. The median Agatston calcium score was 6 (0-85), and 38 patients had no detectable calcium. CCTA showed new obstructive coronary disease (>50% stenosis) in 20 patients. The CAV score was reclassified based on CCTA findings in 37 patients (p<0.001) (Figure 1). There were 53 CAV0, 22 CAV1, 11 CAV2 and 14 CAV3 patients. Mean heart rate during scanning was 75±11 beats per minute and beta-blockers were required in 63 patients. Median radiation dose was 2.5 (1.9-3.5) mSv. Two cases are presented in Figure 2. Cardiac CT can be successfully performed in HTxs with a low radiation dose. CCTA detects patients with significant coronary disease which leads to substantial reclassification of CAV grades.

Role of Genetics in Development of Cardiac Allograft Vasculopathy

Even though a wide range of cardiac allograft vasculopathy (CAV) risk factors have been identified, the real genesis of this disease remains elusive. Identification of genes involved in the process of CAV may provide a novel insight on pathophysiology and lead to new therapeutic options. Paired single nucleotide polymorphism (SNP) genotyping using custom-designed chip from Fluidigm Corp. was performed in both heart transplant (HTx) donors and recipients. DNA analysis included 44 SNPs selected within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (IMT), and in nitric oxide synthase gene. For CAV assessment, coronary OCT imaging was performed at 1 month and 12 months after HTx. A total of 38 consecutive patients with paired genotyping and OCT studies were included. During the first post-transplant year, significant reduction in the mean luminal area (p = 0.028) and progression in mean intimal thickness (p = 0.001) were observed. In the random forest analysis, HTx recipient ADAMTS7 (rs3825807) and CBFA2T3 (rs844396) loci showed best association with coronary intimal thickness progression (Image). These loci were previously reported to be involved in the process of coronary atherosclerosis and carotid IMT progression. Genetic variability may play an important role in CAV development. Identification of risk alleles associated with accelerated CAV may be useful in CAV risk stratification and post-transplant management individualisation. This project was supported by following national research grants (CMH 16-27465A and NIH R01-EB004640).

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.

The role of optical coherence tomography and other intravascular imaging modalities in cardiac allograft vasculopathy

Orthotopic heart transplantation (OHT) is the standard-of-care for end-stage heart disease. Although a significant improvement in the prognosis of patients after OHT has been observed in recent years, their overall mortality remains relatively high, with a median survival of approximately 10 years after transplantation. One of the primary causes of death in patients after OHT is cardiac allograft vasculopathy (CAV), the condition developing specifically in the coronary vasculature after OHT, the pathophysiology of which is still inadequately known. It is estimated that CAV development and progression is responsible for approximately 30% of deaths within five years post-OHT. According to the International Society for Heart and Lung Transplantation (ISHLT) Nomenclature for CAV, its presence should be assessed primarily by the coronary angiography performed routinely after OHT, mostly due to its wide availability, reproducibility, and low complication rate. However, the analysis of CAV in coronary angiography has limitations, mostly concerning its – sometimes inadequate – sensitivity and specificity. Hence, there is a growing need for the introduction of more accurate methods of CAV assessment, such as intravascular imaging, which through a thorough evaluation of the arterial wall structure and thickness allows the drawbacks of routine angiography to be minimised. The aim of the article was to critically summarise the current findings derived from the analysis of CAV by optical coherence tomography, the other intravascular imaging modalities, such as intravascular ultrasound (IVUS) and IVUS-derived virtual histology, along with physiological assessment with the use of the fractional flow reserve.

Semi-quantitative myocardial perfusion MRI in heart transplant recipients at rest: repeatability in healthy controls and assessment of cardiac allograft vasculopathy

BackgroundCardiac Allograft Vasculopathy (CAV) is a major cause of chronic cardiac allograft failure. Invasive coronary angiography (ICA) and intravascular ultrasound (IVUS) are the current diagnostic methods. Myocardial perfusion MRI has become a promising non-invasive method to evaluate myocardial ischemia, but has not been thoroughly validated in CAV. Our objective was to assess the repeatability of myocardial rest-perfusion MRI in healthy volunteers and its feasibility in detecting CAV in transplant patients (Tx). MethodsTwelve healthy volunteers and twenty transplant patients beyond the first year post- transplant underwent cardiac MRI at 1.5 T at rest including first-pass perfusion imaging in short axis (base, mid, apex) after injection of gadolinium. Volunteers underwent repeated cardiac MRI on different days (interval = 15.6 ± 2.4 days) to assess repeatability. Data analysis included semi-automatic contouring of endocardial and epicardial borders of the left ventricle (LV) and quantification of peak perfusion, time-to-peak (TTP) perfusion, and upslope of the perfusion curve. ResultsBetween scans and re-scans in healthy volunteers, peak signal intensity, slope, and TTP demonstrated moderate agreement (ICC = 0.53, 0.48, and 0.59, respectively; all, p < .001). Peak signal intensity, slope, and TTP were moderately variable with COV values of 23%, 42%, and 35%, respectively. Peak perfusion was significantly reduced in CAV positive (n = 9 Tx patients) compared to CAV negative (n = 11 Tx patients) groups (90.7 ± 27.0 vs 139.5 ± 30.2, p < .001). ConclusionCardiac MRI is a moderately repeatable method for the semi-quantitative assessment of first-pass myocardial perfusion at rest. Semi-quantitative surrogate markers of LV perfusion could play a role in CAV detection.

Looking into the Future: Optical Coherence Tomography for the Assessment of Cardiac Allograft Vasculopathy

Introduction Current guidelines recommend coronary angiography with intravascular ultrasound (IVUS) as a screening and surveillance tool for the assessment of cardiac allograft vasculopathy (CAV). The role of optical coherence tomography (OCT) has not been thoroughly evaluated for patients with CAV. Case Description A 59 M with history of ICM with subsequent OHT in 2016 with evidence of an eccentric LAD plaque and CAV with IMT of 0.66 mm on IVUS being treated with Rosuvastatin and Sirolimus presented for second annual follow up angiogram. On coronary angiography all of his vessels appeared angiographically “pristine” without evidence of vasculopathy (Figure 1). OCT showed show evidence of extensive subintimal hyperplasia (0.45 mm at thickest area) with negative vessel remodeling, unappreciable on the coronary angiography (Figure 2). Conclusion IVUS has traditionally been used for the assessment of CAV. OCT has a much higher resolution (10microns) compared to IVUS (80microns) and provides exceptional tissue characterization similar to a light microscope. OCT should hence be considered for the routine evaluation and surveillance of CAV.