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Typical atherosclerosis vs. allograft vasculopathy. (From Avery and colleagues. [163] Reprinted with permission) 

Typical atherosclerosis vs. allograft vasculopathy. (From Avery and colleagues. [163] Reprinted with permission) 

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Cardiac allograft vasculopathy remains a major challenge to long-term survival after heart transplantation. Endothelial injury and dysfunction, as a result of multifactorial immunologic and nonimmunologic insults in the donor and the recipient, are prevalent early after transplant and may be precursors to overt cardiac allograft vasculopathy. Curre...

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... transplantation has emerged as the definitive treatment for patients with end-stage heart failure in the USA. Short-term survival after cardiac transplantation has improved significantly as a result of improved immunosup- pressive therapy, monitoring techniques, and surgical strategies. In contrast, long-term survival has not improved as dramatically. A key barrier to the longevity of heart transplant recipients is the persistent prevalence of long- term complications such as malignancy and cardiac allograft vasculopathy (CAV) — a specific form of coronary artery disease prevalent in heart transplant recipients [1]. CAV is characterized by early, diffuse intimal proliferation, ultimately resulting in the development of luminal stenosis and small vessel occlusion. The condition is highly prevalent as early as one year after transplant; CAV causes ap- proximately 10 – 15 % of deaths between years1 and 3 after transplant, and contributes to potentially more deaths which are the result of graft dysfunction [2 – 5]. CAV tends to develop silently — the first clinical manifestation may be progressive heart failure, ventricular arrhythmias, or sudden cardiac death. Unlike native atherosclerotic disease, however, CAV appears to develop more rapidly and is predominantly characterized by diffuse intimal proliferation (Fig. 1) [6]. The distinction between the two entities has been well summarized by Rhamani and colleagues. Similar to native coronary disease and other inflammatory states, the development of the CAV lesion is preceded by endothelial dysfunction. Thus, early identification of endothelial dysfunction in heart transplant recipients could provide a target for the development of preventive strategies and ultimately, prolonga- tion of survival. The following sections describe mechanisms of endothelial dysfunction in CAV and potential therapeutic interventions. The endothelium plays a critical role in sensing changes in hemodynamic forces and blood-borne signals. It responds to these stimuli by releasing vasoactive substances that regulate vascular tone. A critical balance between endothelium- derived relaxing and contracting factors is required to main- tain vascular homeostasis. When this balance is disrupted, the vasculature is predisposed to vasoconstriction, leukocyte ad- herence, platelet activation, mitogenesis, pro-oxidation, thrombosis, impaired coagulation, vascular inflammation, and, in the heart transplant recipient, CAV. Nitric oxide (NO), a key mediator of vascular tone, is often depleted as a result of oxidative stress [7 – 10]. In patients with a transplanted heart, the endothelium is the first immunogenic biological interface encountered by the immune system, providing the milieu for a sustained local vascular response [11]. Recipient immune response to the donor endothelium may determine allograft adaptation and/or vascular rejection, although the mechanisms for ei- ther pathway as consequences of a response to activated endothelium are poorly understood. In heart transplant recipients, the endothelium appears to be both a target and a participant in the development of pathological and physiological processes. In 1962, Medawar hypothesized that replacement of the donor endothelium by recipient endothelial cells occurs in response to endothelial injury and contributes to adaptation of the allograft [12]. A commonly held theory is that CAV development begins as a “ response to injury, ” similar to native coronary artery disease: endothelial dysfunction and intimal hyperplasia develop as a result of vascular remodeling in response to repetitive transplant-related endothelial injury [13]. The consequent vascular remodeling and smooth muscle cell proliferation are potentiated by inflammatory cytokines, growth factors, and chemotactic factors produced by activated endothelial cells. Mononuclear cells are recruited and produce inflammatory cytokines, resulting in the activation of smooth muscle cells and their migration from the media to the intima. Activated smooth muscle cells proliferate and secrete cytokines, which potentiate proliferation and subsequent matrix deposition and luminal narrowing. The traditional theory has been that donor smooth muscle cells migrate from the media; however, more recent findings suggest that recipient-derived cells may be involved. The precise interactions between the host and the donor endothelium as they relate to the development of CAV and/ or graft adaptation are unclear. However, integral to the “ response to injury ” theory of accommodation is the concept that recipient cells are integrated into the endothelium and into the vasculopathy lesion and are involved in the response and repair process. Although the data are conflicting and debate continues, a significant body of evidence supports the concept of partial re-endothelialization by recipient-derived cells, possibly as a response to immune-mediated vascular injury [14 – 16]. Several human and animal studies have demonstrated the presence of recipient-derived endothelial precursors and smooth muscle cells within the transplanted heart and within the CAV neointimal and atherosclerotic lesion. The magnitude of chimerism — that is, the coexistence of both donor and recipient endothelial cells — varies greatly by study [17 – 21]. Replacement of endothelium with recipient-derived cells has been demonstrated in kidney transplant recipients and appears to be associated with both vascular and interstitial rejection [22, 23]. Endothelial chimerism appears to occur in heart transplant recipients at high levels within the first month after transplantation and remains stable thereafter [14, 18]. Using gender mismatched heart transplant recipients, Simper and colleagues [19] demonstrated the presence of recipient endothelial cells within the transplant atherosclerotic lesion in humans. In contrast, Atkinson and colleagues [24] found these cells to be of donor origin. Others have demonstrated chimerism of other cells (lymphocytes, macrophages, and mast cells) but not vascular smooth muscle cells, the predominant cells within the atherosclerotic plaque in CAV [25]. In summary, although re-endothelialization by recipient-derived cells appears to occur after heart transplantation, the true extent and significance of this ...

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Heart transplantation (HTx) has become standard treatment for selected patients with end-stage heart failure. Improvements in immunosuppressant, donor procurement, surgical techniques, and post-HTx care have resulted in a substantial decrease in acute allograft rejection, which had previously significantly limited survival of HTx recipients. Howeve...

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... In contrast, long-term survival has a key barrier-the persistent prevalence of long-term complications such as malignancy and cardiac allograft vasculopathy (CAV). Patients, however, are also exposed to other traditional risk factors for native heart failure, such as hypertension, diabetes, coronary atherosclerosis, pericardial disease, and cardiac drug toxicity [1,2]. The most frequent posttransplant complications, such as rejection (either acute cellular-ACR or antibody-mediated-AMR), chronic graft dysfunction (CGD), and CAV, remain without a molecular-genetic explanation. ...
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Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.
... One of the most important conditions limiting the long-term survival of heart transplant is cardiac allograft vasculopathy (CAV), which is a distinct form of coronary disease [73,74]. The condition may initiate early during the first year after transplantation [75,76], and due to transplant denervation, progress silently to ventricular arrhythmias and heart failure. ...
... In CAV, the site of injury is the whole arterial vasculature of the transplant starting from the larger coronary arteries, and extending to the microvasculature. The re-endothelialization of tunica intima after injury may result in chimeric presence of donor-and recipient derived cells [73,[88][89][90][91][92][93]. The origin of the recipient-derived neointimal cells has been suggested to derive either from the bone-marrow, the circulating progenitor cells, or from the vascular bed. ...
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The median survival of patients with heart transplants is relatively limited, implying one of the most relevant questions in the field—how to expand the lifespan of a heart allograft? Despite optimal transplantation conditions, we do not anticipate a rise in long-term patient survival in near future. In order to develop novel strategies for patient monitoring and specific therapies, it is critical to understand the underlying pathological mechanisms at cellular and molecular levels. These events are driven by innate immune response and allorecognition driven inflammation, which controls both tissue damage and repair in a spatiotemporal context. In addition to immune cells, also structural cells of the heart participate in this process. Novel single cell methods have opened new avenues for understanding the dynamics driving the events leading to allograft failure. Here, we review current knowledge on the cellular composition of a normal heart, and cellular mechanisms of ischemia-reperfusion injury (IRI), acute rejection and cardiac allograft vasculopathy (CAV) in the transplanted hearts. We highlight gaps in current knowledge and suggest future directions, in order to improve cellular and molecular understanding of failing heart allografts.
... ICA also does not provide any functional assessment of the coronary vasculature or evaluation This article is part of the Topical Collection on Cardiac PET, CT, and MRI of the coronary microvasculature. This is particularly relevant given that microvascular involvement and endothelial dysfunction have been proposed to be the earliest manifestations of CAV [13][14][15][16]. Importantly, there are substantial procedural risks associated with repeated ICA, especially with intravascular imaging. ...
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... 5 In fact, coronary endothelial dysfunction in heart transplant patients has also been shown to precede CAV and future adverse cardiovascular events. 6,7 However, the invasive nature of coronary endothelial function assessment limits its widespread use as routine follow-up procedure in heart transplant recipients. Reactive hyperaemia peripheral arterial tonometry (RH-PAT) is an FDA approved, less operator-dependent non-invasive method to assess peripheral endothelial dysfunction (PED) by measuring changes in digital pulse waveforms during reactive hyperaemia. ...
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Aims: Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non-heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation. Methods and results: We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index < 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re-transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3 /mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow-up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high-density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03). Conclusions: Peripheral endothelial dysfunction is associated with increased plaque progression and adverse long-term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.
... CAV, a progressive and diffuse process involving both the epicardial coronary arteries and the microcirculation remains the major cause of late mortality in heart transplant recipients. Unlike native atherosclerotic disease, it develops more rapidly and is predominantly characterized by a diffuse intimal proliferation [11]. Although the ISHLT classification is a standard method of assessing CAV severity and has been described as an accurate predictor of long-term outcomes after heart transplant [12], the visual angiographic evaluation exhibits high variability particularly in CAV where the disease is diffuse [13]. ...
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Background: Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography (COR) which has several limitations. Recently, vessel fractional flow reserve (vFFR) derived from COR has emerged as a diagnostic computational tool to quantify the functional severity of coronary artery disease. Purpose: The present study assessed the usefulness of vFFR to detect CAV in HTx recipients. Methods: In HTx patients referred for annual check-up, undergoing surveillance COR, the extent of CAV was graded according to the criteria proposed by the international society of heart and lung transplantation (ISHLT). In addition, three-dimensional coronary geometries were constructed from COR to calculate pressure losses using vFFR. Results: In 65 HTx patients with a mean age of 53.7 ± 10.1 years, 8.5 years (IQR 1.90, 15.2) years after HTx, a total number of 173 vessels (59 LAD, 61 LCX, and 53 RCA) were analyzed. The mean vFFR was 0.84 ± 0.15 and median was 0.88 (IQR 0.79, 0.94). A vFFR ≤ 0.80 was present in 24 patients (48 vessels). HTx patients with a history of ischemic cardiomyopathy (ICMP) had numerically lower vFFR as compared to those with non-ICMP (0.70 ± 0.22 vs. 0.79 ± 0.13, p = 0.06). The use of vFFR reclassified 31.9% of patients compared to the anatomical ISHLT criteria. Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 8 patients (34.8%). Conclusion: The impairment in epicardial conductance assessed by vFFR in a subgroup of patients without CAV according to standard ISHLT criteria suggests the presence of a diffuse vasculopathy undetectable by conventional angiography. Therefore, we speculate that vFFR may be useful in risk stratification after HTx.
... To fully understand the benefits of statin therapy after HT, more comprehensive mechanistic evaluations of CAV are necessary, including assessments of coronary vascular dysfunction, a precursor to anatomic changes to the coronary vasculature. [21][22][23][24] Additionally, further studies are necessary to determine the extent to which statins act through LDL-C-lowering or through immunomodulatory mechanisms. 6,[25][26][27] In a recent study, pre-operative treatment of cardiac donors with simvastatin significantly reduced recipient plasma inflammatory cytokine levels post-operatively, altered myocardial gene transcript signatures, and reduced treated episodes of haemodynamically significant rejection. ...
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... This, in turn, leads to early allograft failure and later cardiac allograft vasculopathy. 30,31 Longer follow-up in the current clinical DCD studies will determine if these allografts demonstrate higher rates of coronary vasculopathy. ...
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Background: There has been an increased interest in donation after circulatory death (DCD) to expand donor pool for cardiac transplantation. Normothermic regional perfusion (NRP) allows in situ assessment of DCD hearts, allowing only acceptable organs to be procured. We sought to determine if extended cold storage was possible for DCD hearts following NRP and to compare hearts stored using standard cold storage with a novel cardioprotective solution designed for room temperature storage. Methods and results: Donor pigs underwent hypoxic cardiac arrest (DCD) followed by 15 minutes of warm ischemia and resuscitation on NRP. They were then randomly assigned to static storage with histidine-tryptophan-ketoglutarate (HTK) at 4°C (HTK group, n=5) or SOM-TRN-001 at 21°C (SOM group, n=5). Conventional beating-heart donations were used as controls (n=4). Fourteen transplants were successfully performed. HTK hearts showed initial dysfunction following reperfusion; however, they demonstrated significant recovery up to 3 hours post-transplant. No significant differences were seen between HTK and control hearts post-transplantation (cardiac index: control 49.5±6% and HTK 48.5±5% of baseline). SOM improved myocardial preservation; hearts showed stable contractility after transplantation (cardiac index: 113.0±43% of NRP function) and improved diastolic function compared with HTK. Preservation in SOM also significantly reduced proinflammatory cytokine production and release following transplantation and partially prevented endothelial dysfunction. Conclusions: DCD hearts stored using a standard preservation solution demonstrated comparable post-transplantation myocardial function to standard controls. Thus, short periods of cold storage following successful NRP and documented adequate function is an acceptable strategy for DCD hearts. Preservation in SOM at room temperature is feasible and can improve cardiac recovery by minimizing endothelial dysfunction and tissue injury.
... CAV is multifactorial in origin and is considered to be a form of chronic rejection previously due to the crucial role played by various alloimmune and autoimmune mechanisms in the pathogenesis of CAV [6][7][8]. Although immune mediated factors play a major role, several studies have demonstrated the role of traditional risk factors of coronary artery disease (CAD) in the progression of CAV [8][9][10]. ...
... CAV is multifactorial in origin and is considered to be a form of chronic rejection previously due to the crucial role played by various alloimmune and autoimmune mechanisms in the pathogenesis of CAV [6][7][8]. Although immune mediated factors play a major role, several studies have demonstrated the role of traditional risk factors of coronary artery disease (CAD) in the progression of CAV [8][9][10]. Based on progress gained in this field, CAV is currently viewed as an "impaired response to vascular injury" resulting in altered permeability, migration of smooth muscle cells and fibroproliferation [10]. ...
... Based on progress gained in this field, CAV is currently viewed as an "impaired response to vascular injury" resulting in altered permeability, migration of smooth muscle cells and fibroproliferation [10]. This results in diffuse concentric hypertrophy of the vessel wall and microvascular occlusion leading to pathologic remodeling of the transplant heart vasculature [8]. It affects epicardial, intramural arteries, and veins and causes diffuse luminal narrowing which could lead to myocardial infarction (MI) and graft dysfunction [11]. ...
... However, cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients, continues to be a major cause of mortality during the first year after a heart transplant [6]. Although the pathogenesis of CAV is not been completely understood, many studies show that the development of a CAV lesion is preceded by vascular inflammation, endothelial dysfunction, and vascular smooth muscle cell proliferation [6][7][8][9][10]. Based on these studies, we suggest that transient receptor potential (TRP) channels as cellular sensors for various internal and external stimuli play crucial roles in the pathophysiological processes of vascular inflammation, endothelial dysfunction, and smooth muscle cell proliferation during heart transplantation and may become an effective therapeutic intervention target to attenuate the progression of CAV. ...
... During heart transplantation, recipients with classical risk factors such as hyperlipidemia, hypertension, diabetes, or metabolic syndrome, and transplant-associated risk factors such as ischemia-reperfusion injury, human leukocyte antigen (HLA) mismatching, preservation damage, and cytomegalovirus (CMV) infection are more likely to trigger severe vascular inflammation, endothelial injury and dysfunction, and vascular smooth muscle cell proliferation through multifactorial and complex processes than recipients who do not have these risk factors [6,7,11]. It is still difficult to define all the risk factors associated with the development of CAV and to elucidate the whole pathogenesis; however, vascular inflammation, endothelium injury and dysfunction, and vascular smooth muscle cell proliferation are widely known as the 3 most important processes in the development of CAV [6][7][8][9][10] (Figure 1). All of these 3 key pathophysiological processes are associated with specific cell cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in varying degrees. ...
... During heart transplantation, the injured coronary endothelium can neither effectively sense changes in hemodynamic forces and blood-borne signals nor respond to these stimuli by releasing specific vasoactive substances. The vascular homeostasis balance is disrupted, and the consequent effects on the vasculature are abnormal vasoconstriction, leukocyte adherence, platelet activation, vascular inflammation, and the development of CAV [8,47]. TRP channels, as cellular sensors, not only participate in sensing vascular signals, but also have crucial roles in releasing vasoactive substances. ...
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Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.
... Early posttransplantation endothelial cell injuries initiate potent intragraft inflammatory responses, which subsequently augment adaptive immune responses. Early endothelial injuries have been the precursors to overt atherosclerotic lesions as well as cardiac allograft vasculopathy (37). Classical pathological manifestations of graft rejection rely heavily on the presence of adaptive immune cells (such as T cell infiltrates) that are late players of graft rejection (38). ...
Article
One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, non-invasive and practical diagnostic tools to detect transplant rejection. Early intra-graft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in micro-vascular perfusion (MP) of cardiac transplants using Contrast Enhanced Ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, 92% on days 4, 6, and 8 post-transplantation, respectively) and chronic rejection (33%, 33%, 92% on days 5, 14, and 30 post-transplantation, respectively). Our perfusion studies showed restoration of MP following anti-rejection therapy, highlighting its potential to help monitor efficacy of anti-rejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for non-invasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection. This article is protected by copyright. All rights reserved.