Development Of Cardiac Allograft Vasculopathy Research Articles

Comparison of cardiac allograft vasculopathy incidence between simultaneous multiorgan and isolated heart transplant recipients in the United States

BackgroundPrior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multi-organ transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multi-organ heart transplants in the contemporary era. MethodsWe utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary endpoint was the development of angiographic CAV within 5 years of follow-up. ResultsAmong 20,591 patients included in the analysis, 1,279 (6%) underwent multi-organ heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ) and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years and 74% were male. There were no significant between-group differences in cold ischemic time between the groups. The incidence of acute rejection during the first year after transplant was significantly lower in the multi-organ group (18% vs. 33%, p<0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multi-organ group (p<0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multi-organ heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio=0.76, 95% confidence interval: 0.66-0.88, p<0.01). ConclusionsSimultaneous multi-organ heart transplantation is associated with significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era.

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.

Identification of Preoperative Risk Factors for the Development of Cardiac Allograft Vasculopathy: A Systematic Review

Identification of Preoperative Risk Factors for the Development of Cardiac Allograft Vasculopathy: A Systematic Review

Acetylsalicylic acid use and development of cardiac allograft vasculopathy: A national prospective study using highly automated 3-D optical coherence tomography analysis.

There is conflicting evidence on the role of acetylsalicylic acid (ASA) use in the development of cardiac allograft vasculopathy (CAV). A nationwide prospective two-center study investigated changes in the coronary artery vasculature by highly automated 3-D optical coherence tomography (OCT) analysis at 1 month and 12 months after heart transplant (HTx). The influence of ASA use on coronary artery microvascular changes was analyzed in the overall study cohort and after propensity score matching for selected clinical CAV risk factors. In total, 175 patients (mean age 52±12 years, 79% male) were recruited. During the 1-year follow-up, both intimal and media thickness progressed, with ASA having no effect on its progression. However, detailed OCT analysis revealed that ASA use was associated with a lower increase in lipid plaque (LP) burden (p=.013), while it did not affect the other observed pathologies. Propensity score matching of 120 patients (60 patient pairs) showed similar results, with ASA use associated with lower progression of LPs (p=.002), while having no impact on layered fibrotic plaque (p=.224), calcification (p=.231), macrophage infiltration (p=.197), or the absolute coronary artery risk score (p=.277). According to Kaplan-Meier analysis, ASA use was not associated with a significant difference in survival (p=.699) CONCLUSION: This study showed a benefit of early ASA use after HTx on LP progression. However, ASA use did not have any impact on the progression of other OCT-observed pathologies or long-term survival.

Role of HLA matching and donor specific antibody development in long-term survival, acute rejection and cardiac allograft vasculopathy

Although there are different data supporting benefits of HLA matching in kidney transplantation, its role in heart transplantation is still unclear. HLA mismatch (MM) between donor and recipient can lead to the development of donor-specific antibodies (DSA) which produces negative events on the outcome of heart transplantation. Moreover, DSAs are involved in the development of antibody-mediated rejection (AMR) and are associated with an increase in cardiac allograft vasculopathy (CAV). In this study it is analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, AMR and CAV in heart transplantation. For this retrospective study are recruited heart transplanted patients at the Cardiac Transplantation Centre of Naples between 2000 and 2019. Among the 155 heart transplant patients, the mean number of HLA-A, B, -DR MM (0 to 6) between donor and recipient was 4.5 ± 1.1. The results show a negative association between MM HLA-DR and survival (p = 0.01). Comparison of patients with 0–1 MM at each locus to all others with 2 MM, for both HLA class I and class II, has not showed significant differences in the development of CAV. Our analysis detected DSA in 38.1% of patients. The production of de novo DSA reveals that there is not an influence on survival (p = 0.72) and/or AMR (p = 0.39). Instead, there is an association between the production of DSA class II and the probability of CAV development (p = 0.03). Mean fluorescence intensity (MFI) values were significantly higher in CAV-positive patients that CAV-negative patients (p = 0.02). Prospective studies are needed to evaluate HLA class II matching as an additional parameter for heart allocation, especially considering the increment of waiting list time.

Enhancing the Prediction of Cardiac Allograft Vasculopathy Using Intravascular Ultrasound and Machine Learning: A Proof of Concept.

Cardiac allograft vasculopathy (CAV) is the leading cause of late graft dysfunction in heart transplantation. Building on previous unsupervised learning models, we sought to identify CAV clusters using serial maximal intimal thickness and baseline clinical risk factors to predict the development of early CAV. This is a single-center retrospective study including adult heart transplantation recipients. A latent class mixed-effects model was used to identify patient clusters with similar trajectories of maximal intimal thickness posttransplant and pretransplant covariates associated with each cluster. Among 186 heart transplantation recipients, we identified 4 patient phenotypes: very low, low, moderate, and high risk. The 5-year risk (95% CI) of the International Society for Heart and Lung Transplantation-defined CAV in the high, moderate, low, and very low risk groups was 49.1% (35.2%-68.5%), 23.4% (13.3%-41.2%), 5.0% (1.3%-19.6%), and 0%, respectively. Only patients in the moderate to high risk cluster developed the International Society for Heart and Lung Transplantation CAV 2-3 at 5 years (P=0.02). Of the 4 groups, the low risk group had significantly younger female recipients, shorter ischemic time, and younger female donors compared with the high risk group. We identified 4 clusters characterized by distinct maximal intimal thickness trajectories. These clusters were shown to discriminate against the development of angiographic CAV. This approach allows for the personalization of surveillance and CAV-directed treatment before the development of angiographically apparent disease.

Quantitative flow ratio computed from invasive coronary angiography as a predictor for cardiac allograft vasculopathy after cardiac transplant.

Cardiac allograft vasculopathy (CAV) is a significant determinant of long-term survival in heart transplant recipients. Standard CAV screening typically utilizes invasive coronary angiography (ICA). Quantitative flow ratio (QFR) is a computational method for functional testing of coronary stenosis, and may add diagnostic value to ICA in assessing CAV. Consecutive subjects who received heart transplantation and underwent two separate routine coronary angiograms between January 2013 and April 2016 were enrolled. Coronary angiograms and IVUS were performed per local protocol at 1, 2, 3 and 5years post-transplant. QFR was calculated offline. CAV was assessed semi-quantitively based on coronary angiogram results. Twenty-two patients were enrolled. Mean time from transplant to first included ICA was 2.1years. QFR in at least 1 coronary vessel was interpretable in 19/22 (86%) of initial ICA (QFR1). QFR1 correlated well with the CAV score derived from the second ICA (CAV2) with a clustering of CAV at lower QFR values. In a receiver-operating characteristic (ROC) analysis, an optimal QFR threshold of 0.88 yielded 0.94 sensitivity and 0.67 specificity (AUC of 0.79) for at least non-obstructive subsequent CAV. Initial angiographically and intravascular ultrasound derived CAV severity poorly predicted subsequent CAV severity. QFR derived from invasive coronary angiography predicts subsequent development of CAV more accurately than angiography and intravascular ultrasound. This novel method of coronary flow assessment in recipients of heart transplantation may be useful to diagnose and predict subsequent CAV development.

Elevated lipoprotein a level in heart transplant patients is associated with cardiac allograft vasculopathy

Abstract Introduction Lipoprotein A (LpA) is considered a cardiovascular disease (CVD) risk factor and its interest has grown in recent years. High LpA levels (above 50 mg/dL) are associated with an increase in the occurrence of CVD and degenerative aortic valve disease despite treatment with statins and low LDL levels. The prevalence of elevated LpA levels after heart transplantation (HT) and the implication on the development of cardiac allograft vasculopathy (CAV) is not well known. Objective To assess the prevalence of elevated LpA levels in patients with HT and the relationship between higher LpA levels and CAV at 1 year. Methods Retrospective, unicentric and observational study based on the historical cohort of HT patients. We selected those patients in whom a pre-transplant serum sample was available in the biobank for LpA analysis. CAV was diagnosed with coronary angiography. Results We studied 80 HT patients. Baseline characteristics are in table 1. Median LpA levels were 14.5 (5.0-35.3), and from the 80 HT patients, 16 (20,0%) had LpA≥50 mg/dl (figure 1A). Out of the 80 patients, 68 had a coronary angiography at 1 year follow up (3 died before 1 year and 9 patients did not have angiography at 1 year for diverse reasons). Twenty patients (29.4%) presented CAV in the first year. Patients with elevated LpA levels had more frequency of CAV at 1 year [11/16 (68.8%) vs 9/43 (17.3%); p&amp;lt;0,001]. LpA levels in patients with CAV was higher (62.5+-58.8 vs 23.9+29.8; p&amp;lt;0,001) (figure 1B). LDLc and Total cholesterol were significantly lower in patients with CAV at 1 year in this population. In univariate analysis, smoker donors were associated with CAV development (60.0% vs 33.3%; p 0.042). We did not find differences in other recipient or donor cardiovascular risk factors, rejection episodes or CMV infection in the first year. Conclusion Elevated LpA levels (≥50 mg/dl) are frequent in HT patients (20%) and in our cohort, were associated with CAV at 1-year post-HT. Further studies are needed to verify these results and study the relationship with the development of other cardiovascular events in HT patients.Table 1Figure 1

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.

Therapeutic potential role of vitamin C in prevention and control of heart transplant rejection and cardiac allograft vasculopathy. A need for consideration

AbstractThe burden of cardiovascular diseases is rising rapidly globally. Heart transplant is one of the most last resort medical option for patients with heart failure. Unfortunately, this surgical intervention is associated with several serious complications including heart transplant rejection (HTR) and Cardiac Allograft Vasculopathy (CAV) which can manifest just within few years' posttransplant. These complications affect significantly the prognosis and quality of life among postheart transplant patients. Several medications including immunosuppressant, antibiotics, antihypertensive, and statins have been used during posttransplant care so as to address such complications. Unfortunately, most of those drugs are expensive and pose a number of serious side effects to the patients enough to compromise patients' quality of life too. Several studies on Vitamin C are therapeutically suggestive that it can be used during postheart transplant care with more cost‐effective benefits with less and minimized side effects compared to the current drugs in place. It should be considered pharmacologically that Vitamin C has a great potential role clinically in prevention and control of HTR and CAV development. On the light of such findings as described above, we recommend more studies especially clinical trials and molecular studies to determine whether Vitamin C can be repositioned to replace or to be used along the current drug regimens used in postheart transplant care for prevention and control of HTR and CAV.

Elevated Lipoprotein A Levels and Development of Moderate or Severe Cardiac Allograft Vasculopathy in Patients with Heart Transplants

Cardiac allograft vasculopathy (CAV) is a high-incident complication of heart transplant (HT) and is the leading cause of death beyond the first post-HT year. Traditional risk factors have been related to CAV development. Elevated lipoprotein (a) (Lp[a]) is an independent, genetic, and causal risk factor for cardiovascular disease; nonetheless, its association with the development or worsening of CAV in HT has not been firmly established. An observational nested case-control study including HT recipients under follow-up in a tertiary center. Lipoprotein (a) levels were determined at the time of inclusion. We considered elevated Lp(a) ≥30 mg/dL. We evaluated the association between Lp(a) levels and the presence and severity of CAV (The International Society For Heart And Lung Transplantation [ISHLT] Cardiac Allograft Vasculopathy Grading Scheme), dividing the sample between No or Mild CAV (0-1) and Moderate-Severe CAV (2-3). Routine coronary angiographies were performed the first year after the transplant and were subsequently symptom-driven. One hundred fifty patients with HTs were included, with a mean follow-up of 110 ± 77 months. Patients with CAV 2 to 3 presented higher median Lp(a) levels (17 vs 86 mg/dL, P=0.001). Elevated Lp(a) level was an independent risk factor for developing CAV 2 to 3 (odds ratio 8.57 [95% CI 2.82-26.04]; P < .001). Patients with Lp(a) ≥30 mg also showed an earlier onset compared with those with Lp(a) <30 mg/dL. Our study suggests that Lp(a) may play a role in the development of CAV. Lipoprotein (a) ≥30 mg/dL defines a subgroup of high-risk patients with HTs as portends to earlier onset and more severe CAV. Lipoprotein (a) determination should be a standard-of-care test in patients with HTs.

Transplant Vasculopathy Versus Native Atherosclerosis: Similarities and Differences.

Cardiac allograft vasculopathy (CAV) is one of the leading causes of graft failure and death after heart transplantation. Alloimmune-dependent and -independent factors trigger the pathogenesis of CAV through activation of the recipients' (and to a lesser extent donor-derived) immune system. Early diagnosis of CAV is complicated by the lack of clinical symptoms for ischemia in the denervated heart, by the impact of early functional coronary alterations, by the insensitivity of coronary angiography, and by the involvement of small intramyocardial vessels. CAV in general is a panarterial disease confined to the allograft and characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries and concentric medial disease in the microvasculature. Plaque composition in CAV may include early fibrous and fibrofatty tissue and late atheromatous calcification. In contrast, native coronary atherosclerosis usually develops over decades, is focal, noncircumferential, and typically diminishes proximal parts of the epicardial vessels. The rapid and early development of CAV has an adverse prognostic impact, and current prevention and treatment strategies are of limited efficacy compared with established strategies in native atherosclerosis. Following acute coronary syndromes, patients after heart transplantation were more likely to have accompanying cardiogenic shock and higher mortality compared with acute coronary syndromes patients with native hearts.

Early Assessment of Cardiac Allograft Vasculopathy Risk Among Recipients of Hepatitis C Virus-infected Donors in the Current Era

BackgroundTransplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre–direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test–positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear. Methods and ResultsWe performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT– donors. Additionally, in a subsample of 149 patients (including 55 in the NAT+ cohort and 94 in the NAT– cohort) who had serial adjunctive intravascular ultrasound examination performed, we compared development of rapidly progressive CAV, defined as an increase in maximal intimal thickening of ≥0.5 mm in matched vessel segments during the first year post-transplant. In an unadjusted analysis, recipients of HCV NAT+ hearts had reduced survival free of CAV ≥1 over the first year after heart transplant compared with recipients of HCV NAT– hearts. After adjustment for known CAV risk factors, however, there was no significant difference between cohorts in the likelihood of the primary outcome, nor was there a difference in development of rapidly progressive CAV. ConclusionsThese findings support larger, longer-term follow-up studies to better elucidate CAV outcomes in recipients of HCV NAT+ hearts and to inform post-transplant management strategies.

Heart transplantation and anti-HLA antibodY: myocardial dysfunction and prognosis - HeartLAy study.

The presence of anti-human leucocyte antigen (HLA) antibodies has been implicated in a higher incidence of complications as well as mortality rate in heart transplantation. The aim of the study was to identify through non-invasive parameters early signs of myocardial dysfunction in the presence of anti-HLA antibodies but without evidence of antibody-mediated rejection (AMR) and its possible prognostic impact. A total of 113 heart-transplanted patients without acute cellular rejection (ACR) and AMR or cardiac allograft vasculopathy (CAV) were prospectively enrolled and divided into two groups ['HLA+' (50 patients) and 'HLA-' (63 patients)], based on the presence of anti-HLA antibodies. Each patient was followed for 2years after the enrolment, recording episodes of AMR, ACR, CAV, and mortality. Clinical characteristics were similar between the two groups. Among laboratory data, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin values were significantly higher in the presence of anti-HLA antibodies (P<0.001 and P=0.003, respectively). The echocardiographic parameters that showed a statistically significant difference between the two groups were deceleration time of E wave (DecT E, P<0.001), left ventricular global longitudinal strain (P<0.001), tricuspid annular plane systolic excursion (P=0.011), tricuspid S' wave (P=0.002), and free wall right ventricular longitudinal strain (fwRVLS, P=0.027), whereas left atrial strain did not differ significantly (P=0.408). Univariate analysis showed that anti-HLA antibodies were associated with the development of CAV at both 1 and 2year follow-up [odds ratio (OR) 11.90, 95% confidence interval (CI) 1.43-90.79, P=0.022 and OR 3.37, 95% CI 1.78-9.67, P=0.024, respectively]. Bivariate analysis demonstrated that both fwRVLS and DecT E were predictors of CAV development independently from HLA status. The presence of circulating anti-HLA antibodies is correlated with a mild cardiac dysfunction, even in the absence of AMR, and CAV development. Interestingly, reduced values of DecT E and fwRVLS were predictors of future development of CAV, independently from anti-HLA antibody.

Impact of myocardial bridging on coronary artery plaque formation and long-term mortality after heart transplantation

ObjectivesThis study aimed to explore the impact of myocardial bridging (MB) on early development of cardiac allograft vasculopathy and long-term graft survival after heart transplantation. BackgroundMB has been reported to be associated with acceleration of proximal plaque development and endothelial dysfunction in native coronary atherosclerosis. However, its clinical significance in heart transplantation remains unclear. MethodsIn 103 heart-transplant recipients, serial (baseline and 1-year post-transplant) volumetric intravascular ultrasound (IVUS) analyses were performed in the first 50 mm of the left anterior descending (LAD) artery. Standard IVUS indices were evaluated in 3 equally divided LAD segments (proximal, middle, and distal segments). MB was defined by IVUS as an echolucent muscular band lying on top of the artery. The primary endpoint was death or re-transplantation, assessed for up to 12.2 years (median follow-up: 4.7 years). ResultsIVUS identified MB in 62% of the study population. At baseline, MB patients had smaller intimal volume in the distal LAD than non-MB patients (p = 0.002). During the first year, vessel volume decreased diffusely irrespective of the presence of MB. Intimal growth diffusely distributed in non-MB patients, whereas MB patients demonstrated significantly augmented intimal formation in the proximal LAD. Kaplan-Meier analysis revealed significantly lower event-free survival in patients with versus without MB (log-rank p = 0.02). In multivariate analysis, the presence of MB was independently associated with late adverse events [hazard ratio 5.1 (1.6–22.2)]. ConclusionMB appears to relate to accelerated proximal intimal growth and reduced long-term survival in heart-transplant recipients.

Role of genetics in the development of cardiac allograft vasculopathy.

The association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options. This prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Typeassays and Fluidigm 48.48 Dynamic ArrayIFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx). During the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p < 0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p < 0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added. Results of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Early aspirin use and the development of cardiac allograft vasculopathy in pediatric heart transplant recipients: A pediatric heart transplant society analysis.

Cardiac allograft vasculopathy (CAV) remains a leading cause of graft loss in pediatric heart transplant (HTx) recipients. Adult literature suggests that aspirin (ASA) use in the early post-HTx period may reduce the risk of CAV. This study aimed to determine the impact of early ASA use on the development of CAV in pediatric HTx recipients. All subjects <17 years of age at time of primary HTx who survived ≥3 years without evidence of CAV were identified for inclusion from the Pediatric Heart Transplant Society database (1996-2019). Early ASA use was defined as ASA started within the first 3 years post-HTx and was classified as continuous or intermittent. Frequency of ASA use was described across centers. Kaplan-Meier method assessed freedom from CAV and overall graft survival. Multiphase parametric hazard analyses and propensity score matched analysis were used to identify independent risk factors. 3,011 patients were included with 387 (13%) receiving continuous ASA, 676 (22%) receiving intermittent ASA, and 1,948 (65%) receiving no ASA. ASA use was highly variable across centers (0%-100%). At baseline patients receiving continuous ASA therapy demonstrated inferior graft survival (p < 0.001) and worse freedom from CAV (p=0.002), but with lower CAV grades (p=0.05). In multiphase parametric hazard modeling continuous ASA use was not independently associated with CAV, but remained associated with inferior graft survival. Propensity-matched sub-analysis between continuous and no ASA groups demonstrated no difference in freedom from CAV or overall graft loss. ASA use varies widely across pediatric HTx centers. Early ASA use did not reduce the risk of CAV or graft loss in pediatric heart transplant recipients.

Increased fibrosis and microvessel disease in allograft endomyocardial biopsies of children with chronic graft failure due to cardiac allograft vasculopathy

IntroductionChronic graft failure (CGF) is the leading cause of mortality in pediatric heart transplant (PHT) patients and has multifactorial pathogenesis including cardiac allograft vasculopathy (CAV). CGF can present with microvessel disease (MVD) and myocardial fibrosis on endomyocardial biopsies (EMB). We investigated if CGF due to moderate- severe (M-S) CAV has histopathologic MVD and fibrosis prior to or at the time of CAV diagnosis. MethodThis retrospective case-control study included PHT with CGF secondary to M-S CAV. Control patients had no CAV or CGF. EMBs from CAV (3 sets: at 1-year post-transplant 1yrCAV, pre-CAV, and at the time of CAV diagnosis) and non-CAV cohorts were reviewed to grade the fibrosis and quantify MVD. Histopathologic changes were correlated and compared between CAV/non-CAV groups. ResultsEach group had 8 patients. The median age at transplantation and time since transplant were similar between the two groups (P=.71 and P=.91, respectively). Fibrosis grade was 3.0 for CAV cohort compared to 1.0 for control (P= .003) and MVD score was 2.1 in CAV and 0.5 in non-CAV patients (P=.003). Similar degrees of fibrosis and MVD were present even before any evidence of CAV (1yrCAV fibrosis grade 2.5, pre-CAV fibrosis grade 2; 1yrCAV vs CAV P=.75, pre-CAV vs CAV P=.63; 1yrCAV MVD score 2, pre-CAV MVD score 2; 1yrCAV vs CAV P=1, pre-CAV vs CAV P=.91). The degree of MVD correlated with fibrosis (r=0.63, P<.0001) for all EMBs. ConclusionSimultaneous myocardial fibrosis and MVD are noted in CGF secondary to M-S CAV, changes that occur before angiographic CAV. EMBs can reveal significant changes in patients with subsequent development of CAV and may be used to modify the follow-up and treatment for these high-risk patients.

Pancreatitis as a Potential Trigger for Severe Accelerated Cardiac Allograft Vasculopathy Early Post Heart Transplant: A Case Report

We present a case of severe accelerated cardiac allograft vasculopathy (CAV), an infrequent finding usually related to dismal prognosis, in a heart recipient with recurrent episodes of acute pancreatitis. A 38-year-old male was transplanted owing to advanced heart failure related to nonischemic dilated cardiomyopathy. On the fifth day after transplantation, a nonbiliary acute ischemic pancreatitis occurred. Recurrent relapses ensued within the following year requiring hospital readmissions for both supportive and pain management. The patient developed graft dysfunction by the 18th month post-transplant with severe multivessel CAV. A trial of bortezomib and percutaneous coronary interventions with drug-eluting stents at coronary arteries were attempted but the patient died suddenly, before the scheduled staged percutaneous coronary intervention for the coronary total occlusion was performed. The causal mechanisms of aggressive accelerated CAV are unclear, but it is suggested that important inflammatory and/or humoral responses may play a pivotal role in this life-threatening disease pathogenesis. Increased levels of biomarkers have been linked to advanced CAV, as well as pancreatitis pathogenesis, related to cytokine activation with remarkable systemic inflammatory response. Some of those inflammatory mediators have been reported as central in both pancreatitis and CAV, more specifically interleukin-6. A pro-inflammatory state due to recurrent acute pancreatitis early after transplantation may have contributed to severely accelerated CAV development in the presented case. Comprehensive evaluation of risk factors may assist in close surveillance and targeted therapies in the management of this challenging post-heart transplant scenario.

Diltiazem as a cyclosporine A-sparing agent in heart transplantation: Benefits beyond dose reduction.

Diltiazem (DZ) is widely prescribed in transplant recipients because of its drug-drug interactions with calcineurin inhibitors (CNI). However, these interactions have been primarily investigated in renal transplantation, and data regarding the long-term efficacy and safety of DZ in orthotopic heart transplantation (OHT) are still sparse.Our study aimed to elucidate the extent to which the co-prescription of DZ reduces the dose required to maintain adequate blood levels of cyclosporine A (CsA) and the resulting effect on morbidity and mortality in OHT recipients.We performed a retrospective single-center analysis of OHT recipients on a long-term immunosuppressive regimen based on CsA and mycophenolate mofetil (MMF).The study population consisted of 95 adult OHT recipients with a mean follow-up of 15.8 ± 6.7 years. DZ was co-prescribed in 39 subjects (41.1%) and was associated with a 28.6% reduction of the mean CsA daily dose (P < .001). Patients on DZ had less frequent rejection episodes (P = .002), better renal function (P = .009) and a lower rate of end-stage renal disease (P = .008). Additionally, they developed later cardiac allograft vasculopathy (CAV). We observed no prognostic relevance of DZ co-prescription in univariate and multivariate Cox-regression analyses.In addition to reducing the CsA dose required to maintain adequate blood through levels, DZ may have nephroprotective properties in OHT. The co-administration of DZ may decelerate the development of CAV and reduce the frequency of the rejection episodes. However, the beneficial influence on morbidity has no impact on mortality.