Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis
- Heart Failure, Pulmonary HTN and Mechanical Circulatory Support Program, Heart Failure CARE Center, 1120 South Utica Avenue, Tulsa, OK 74104, USA.
- Co-Medical Director for Heart Failure Institute Services, Integris Baptist Medical Center, 3400 NW Expressway, Bldg C, suite 300 Oklahoma City, OK 73112, USA
Received: August 31, 2017 | Accepted: December 17, 2017 | Published: January 14, 2018
OBM Transplantation 2018, Volume 2, Issue 1 doi:10.21926/obm.transplant.1801007
Academic Editor: Nandini Nair
Recommended citation: Munagala M, Phancao A. Cardiac Allograft Vasculopathy: A Review of Risk Factors and Pathogenesis. OBM Transplantation 2018;2(1):007; doi:10.21926/obm.transplant.1801007.
© 2018 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Cardiac transplant is a widely accepted therapy for select patients with end stage cardiovascular disease. Short-term survival following heart transplantation has improved with the evolution of transplant immunology & immunosuppressive therapy, advances in organ preservation & surgical techniques, as well as diagnosis & management of acute rejection. Despite achieving significant strides in short term survival, the challenges of long-term survival remain unresolved. Chronic rejection, cardiac allograft vasculopathy (CAV), malignancy and renal insufficiency hinder the long-term survival and are direct contributors to graft dysfunction and graft failure [1,2,3,4,5]. CAV remains one of the major causes of mortality and morbidity following the first year of cardiac transplantation [1,2]. The International Society of Heart lung Transplantation registry reported 8% of incidence of CAV at one year following heart transplant and 29% and 48% at 5 and 10 years following the transplant respectively .
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 . This results in diffuse concentric hypertrophy of the vessel wall and microvascular occlusion leading to pathologic remodeling of the transplant heart vasculature . It affects epicardial, intramural arteries, and veins and causes diffuse luminal narrowing which could lead to myocardial infarction (MI) and graft dysfunction . CAV can be indolent or may lead to clinical sequelae such as MI, decreased exercise capacity, heart failure, arrhythmia, and sudden cardiac death [12,13,14]. Clinical presentation is usually delayed as patients usually do not experience angina due to denervated status of the transplant heart and can have silent MI. It is imperative that surveillance angiography with Intravascular ultrasound (IVUS) is used to detect early CAV as sudden cardiac death, ventricular arrhythmias or heart failure could be the first clinical presentation in these patients [15,16].
Definition and Diagnosis
CAV is a morphologically and clinically heterogeneous disease with significant phenotypic variation in angiographic manifestation and clinical presentation . Routine angiographic surveillance is commonly performed in heart transplant recipients by many institutions across the United States. Varying angiographic descriptions are noted in the literature. Gao et al, described angiographic CAV based on type of lesion as Type A, B1, B2 and C lesions . Costanzo et al, classified CAV into normal, mild, moderate and severe categories . There was no uniform definition or description until International Society of Heart and Lung Transplant (ISHLT) formulated the definition and nomenclature for CAV (Table 1). ISHLT issued a consensus statement in 2010 stating that coronary angiography in conjunction with assessment of cardiac allograft function is likely to detect CAV with high degree of confidence .
Table 1 ISHLT recommendations for CAV nomenclature
Degree of vasculopathy
No detectable lesions by angiography
Left main (LM) coronary artery < 50%
Primary vessel < 70%
Secondary vessel or branch stenosis < 70%
including diffuse narrowing
No Allograft dysfunction
LM < 50%
Single primary vessel > 70%
Isolated branch stenosis > 70% involving 2 vessel systems
No Allograft dysfunction
LM > 50%
Two or more primary vessels > 70% stenosis
isolated branch stenosis > 70% in all 3 systems
ISHLT CAV1 or CAV2 with allograft dysfunction
Allograft dysfunction or Restrictive physiology
Modified and adapted with permission – Mehra et al .
A Primary Vessel is defined as the proximal and middle 1/3rd of the left anterior descending artery (LAD), the left circumflex (LCx), the ramus and the dominant or co-dominant right coronary artery (RCA) with the posterior descending (PDA) and posterolateral branches (PLB). A Secondary Branch Vessel is defined as the distal 1/3rd of the primary vessels or any segment within a large septal perforator, diagonals and obtuse marginal branches or any portion of a non-dominant RCA. Allograft dysfunction is described as left ventricular ejection fraction (LVEF) of 45% or less and is usually associated with regional wall motion abnormalities. Restrictive cardiac allograft physiology is described to be symptomatic heart failure with restrictive hemodynamic parameters as described below: Right atrial (RA) pressure > 12 mmHg, pulmonary capillary wedge pressure (PCWP) > 25 mmHg and cardiac index < 2.1 liters/minute/m2; Or with following echocardiographic features: E /A velocity ratio > 2 in adults and a E/A ratio of > 1.5 in children; Shortened isovolumetric relaxation time denoted to be < 60 msec.
Despite pathological differences, CAV and traditional coronary artery disease (CAD) do share some similarities and have some common contributing factors (Table 2) [10,21,22,23]. Immunologic factors play a major role in the development of graft coronary artery disease (GCAD) or CAV, while metabolic and genetic factors play a dominant role in the development of traditional CAD. CAV is primarily a disease of intima and is characterized by diffuse intimal hyperplasia and fibrosis. The characteristic lesions that are seen in CAV are also noted in other solid organ transplants such as kidney, liver, and lung [24,25,26]. CAV is not a homogenous disease and lesions may vary morphologically ranging from lipid-rich atherosclerotic plaques to fibrointimal proliferation of the allograft vasculature [10,17,21,22]. The atherosclerotic lesions seen in the allografts can be either donor derived lesions or de novo lesions developed after transplantation. Traditional CAD is usually characterized by focal eccentric hypertrophy and formation of fibrofatty plaques with disruption of the elastic lamina [21,25,27]. In contrast, in CAV, histologically the elastic lamina is primarily intact, and narrowing of the vasculature is circumferential rather than eccentric [10,27,28,29,30,31]. Fibrofatty plaques could be seen in cardiac allografts, however, characteristic lesion of CAV is fibrointimal hyperplasia of the vessel wall leading to insidious narrowing of the vasculature of the allograft [10,27,28,29,30,31]. While CAD typically takes several years to develop and propagate to clinically significant disease, CAV is rapidly progressive and may become clinically significant in weeks to months [10,32,33].
Table 2 Clinical and histopathological features of CAV vs. CAD
Can present with heart failure or SCD
Angina or Anginal equivalent
Diffuse vessel narrowing leads to characteristic angiographic appearance described as “distal pruning”
Predominantly a focal proximal disease
Internal elastic lamina
Uncommon (may be seen in the advanced stage)
Immunobiology and Pathogenesis of Coronary Allograft Vasculopathy
CAV is an accelerated form of coronary vascular disease seen in the heart transplant recipients characterized by neo-intimal hyperplasia and fibrosis of graft vasculature and microvascular occlusion while sparing the recipient’s native vasculature [27,28,29,30,31,32,33,34]. Immune mediated factors play a dominant role in the initiation and propagation of CAV [35,36,37]. This is supported by the observation that distinct atheromatous disease of graft involves the coronary vasculature and extends to the graft aorta sparing the recipient aorta beyond the suture line. Other evidence of the role of immune mediated mechanisms is demonstrated by a lower incidence of CAV in combined organ transplants, such as heart-lung and heart-kidney recipients, when compared to isolated cardiac transplant recipients. It is suggested that in these combined heart-lung and heart-kidney transplants, the lung and renal system become the primary regions of interface between recipient and host immune systems; hence, graft coronary vasculature is relatively less affected [26,38,39]. Immunologic mechanisms that regulate CAV are complex and heterogeneous and involve cellular and humoral aspects of adaptive and innate immune response pathways [7,9,19,35,36,37,40,41,42].
Although the precise mechanism of CAV is not completely elucidated, a complex interplay of a wide array of immunologic and non-immunologic factors related to both donor and recipient result in the pathogenesis of CAV. The primary event in the pathogenesis of CAV is thought to be subclinical endothelial injury of the graft vasculature followed by exaggerated immune response and impaired repair mechanism [2,43,44,45,46,47,48,49,50,51]. The endothelium serves as the barrier between the transplanted heart and circulating host immune cells. Endothelial dysfunction induces leukocyte adhesion, thrombus formation, vascular smooth cell proliferation, and impaired vasomotor tone and vascular homeostasis [46,47,48,49,50,51,52]. Endothelial injury and dysfunction leads to imbalance between endothelial derived relaxing factors (EDRFs) and endothelium-derived constricting factors (EDCFs). EDCFs promote inflammation and contribute to the development of atherosclerosis by attenuating the action of EDRFs [2,8,27,29,45,46,47,48,49,50,51,52,53].
The initial endothelial injury might result from ischemia-reperfusion injury or from host immune response to the cardiac allograft leading to activation of endothelium . Any immunologic or non-immunologic triggered injury to the endothelium generates immune response after allo-recognition of foreign major histocompatibility complex (MHC) molecules expressed on the graft endothelium [54,55,56]. Subsequently, the graft vascular wall becomes the target of immune response inducing the remodeling of the allograft vasculature . The immune response is interceded by either direct, indirect, or semi-direct pathways and results in activation of T lymphocytes, induction of cytokine secretion, formation of donor specific antibodies (DSAs) [44,58]. This further bolsters the endothelial activation. Activation of endothelium leads to increased expression of MHC class II antigens and upregulation of adhesion molecules such as inter cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VACM-1) . These adhesion molecules facilitate the adhesion of leukocytes to activated vascular endothelium and also promote mononuclear cell infiltration. Expression of VCAM-1 on intimal and medial smooth muscle cells has been observed in patients with allograft vasculopathy. ICAM-I and VCAM-I may also serve as co-stimulatory signals T cell stimulation during antigen presentation. Various immunoregulatory molecules in conjunction with chemoattractants stimulate the migration of lymphocytes, granulocytes, and monocytes to the intima of the graft vasculature [52,60]. Immune response is further propagated by recruitment of macrophages and other pro-inflammatory cells on to the vessel wall. Activated macrophages elaborate cytokine production and growth factor secretion [9,60,61]. Intercellular communication and coordination between infiltrating cells, adhesion molecules, endothelium, and various components of the extracellular matrix are required for successful recruitment and transmigration of leukocytes. This is followed by altered permeability, smooth muscle cell proliferation and migration along with synthesis and deposition of extracellular matrix . This eventually leads to the characteristic vasculopathic changes of CAV i.e., fibromuscular proliferation of neointima.
Antibody mediated rejection (AMR) or vascular rejection is associated with anti HLA and anti-endothelial antibody formation and has been linked to pathogenesis of CAV [6,62,63,64]. Anti HLA antibodies can exert effects on allograft through complement dependent and independent pathways. High levels of circulating anti-HLA antibodies are associated with poor intermediate and long term survival. Presence of anti-endothelial antibodies is a strong determinant of CAV progression [6,58,62,63,64,65,66,67,68]. Presence of non-HLA antibodies against cardiac myosin and vimentin has also been associated with pathogenesis of CAV. The role of MHC-class-1-chain-related-A (MICA) antibodies in pathogenesis of CAV is imperfectly understood. However, increase in MICA expression is noted on the graft endothelial cells in patients with CAV .
Damaged endothelial surface can instigate platelet adhesion and aggregation and may serve as a nidus for thrombus formation. Platelets are integral players of inflammation and have been shown to regulate vascular permeability, leukocyte infiltration, hemostasis and thrombosis [67,69]. Simpler et al, noted attenuation of circulating endothelial progenitor cells (EPCs) and increased number of endothelial cells derived from recipient’s extracardiac progenitor cells in the coronary vasculature of the transplant recipients. Recipient derived extracardiac progenitor cells engage in endothelial cell repair and are capable of regenerating endothelium of the graft vessel leading to chimerism. Endothelium of allograft vasculature demonstrates a high degree of chimerism and this may contribute to the progression of CAV [70,71]. Although immunologic mechanisms play a central role in pathogenesis of CAV, vasculopathy seen in cardiac allograft is a result of cumulative vascular injury induced by immune dependent and independent insults. Non-immunologic mechanisms that underlie the pathogenesis of CAV may become self-sustaining later in the disease process and could carry out the progression independently.
Risk Factors of CAV
Several risk factors have been implicated in the development of CAV. They are broadly categorized into immunologic risk factors and non-immunologic risk factors related to donor and recipient. Non-immunologic risk factors are primarily metabolic or otherwise described as traditional risk factors that play an important role in atherosclerotic vascular disease . In addition, donor related factors such as donor mode of brain death, age of the donor and ischemic injury at the time of procurement play important roles in the development of CAV. Table 3 summarizes the risk factors for CAV.
Table 3 Risk factors for CAV
Immunologic risk factors have a major role in the genesis and progression of vasculopathic lesions of cardiac allograft. It had long been regarded as a form of chronic rejection until the concept of “response to injury” gained momentum . MHC molecules are central targets of alloimmune response in solid organ transplant. The degree of (HLA) mismatch is a major factor in the development of CAV and correlates with its severity . HLA-DR locus mismatch seems to carry more burden than HLA-A or HLA-B mismatch. Presence of DSA is a predisposing factor for the CAV development and has been reported to be an independent risk factor [74,75]. Autoimmunity confers risk to the development of AMR and CAV. Antibodies against non-HLA antigens have gained attention in the pathogenesis of AMR and CAV [75,76,77]. Antibodies against cardiac self-antigens such as cardiac myosin and vimentin (cytoskeleton protein) are found to be associated with development of AMR and CAV and are considered to be independent risk factor for CAV [66,67,68]. Clinical studies have demonstrated a significant correlation between HLA mismatch, presence of DSA [44,58] and increased anti-MICA levels to AMR and CAV in heart transplant recipients .
Cytomegalovirus (CMV) infection is another risk factor that is postulated to be associated with early CAV development. CMV infection is thought to mediate the effect by triggering the immune response rather than as a consequence of infection. Even a subclinical CMV infection or low-grade viremia can elicit immune response and could lead to rejection or CAV development [78,79,80]. CMV infection cause endothelial dysfunction by promoting local inflammation and increasing the secretion of vascular adhesion molecules, altering the expression of MHC molecules on endothelial surface and impairing the nitric oxide production .
Both humoral and cellular rejections of transplanted heart contribute to the development of graft vasculopathy. The number and duration of acute rejection episodes is an independent risk factor associated with CAV development and progression. Although direct pathway of allorecognition plays a major role in the early rejection, chronic rejection is primarily driven by indirect pathway of allorecognition. Development of donor specific HLA antibodies has been associated with chronic rejection. Both acute cellular rejection (ACR) and AMR have been inferred in the pathogenesis of allograft vasculopathy [76,77,78,79,80,81,82,83,84,85]. Higher incidence of CAV is noted in heart transplant recipients with history of AMR than recipients without the history [76,77,84]. Heart transplant recipients who have experienced AMR are reported to have higher incidence of CAV [76,77,84]. In addition, AMR is associated with early onset of CAV. Number and severity of AMR episodes have been shown to have direct correlation with increased cardiovascular mortality.
Nonimmunologic Risk Factors
Various non-immunologic risk factors contribute to the development of CAV in heart transplant recipients. Several of these non-immunologic risk factors are the same conventional risk factors that contribute to the pathogenesis of atherosclerotic lesions. Hyperlipidemia, hypertension, diabetes mellitus, metabolic syndrome, smoking, and obesity are some significant non-immunologic risk factors that predispose cardiac transplant recipients to CAV [2,9,10,43,50,61,72]. Although these risk factors are not specific for transplant, there is increased occurrence of these risk factors in recipients of solid organ transplant. Immunosuppressive agents used in the management of heart transplant patients are known to cause or worsen pre-existing metabolic disorders.
Dyslipidemia is a frequently observed metabolic abnormality in heart transplant recipients and prevalence is reported to be 60-80% in this population . Hyperlipidemia is a commonly associated clinical condition in patients with atherosclerotic heart disease and is associated with poor outcomes. Numerous studies have shown the impact of dyslipidemia in pathogenesis and progression of CAV [86,87,88]. Immunosuppressive agents that are used in routine post-transplant care are known to cause or worsen pre-existing lipid abnormalities. Elevated plasma levels of triglycerides (TGs), low density lipoprotein cholesterol (LDL-C) levels and low levels of high density lipoprotein (HDL) levels are the common lipid abnormalities seen in the heart transplant recipients [43,50,61,72,88,89]. Lipid metabolism in heart transplant recipients is influenced by various factors including choice of immunosuppressive regimen, genetic predisposition, pre-existing lipid abnormalities, age of the transplant recipient, and presence of other co-morbidities such as diabetes mellitus, obesity, chronic kidney disease (CKD), and proteinuria . Steroid administration after heart transplantation and ischemic heart disease prior to transplant are both significant factors associated with post-transplant lipid abnormalities. Commonly used immunosuppressive agents in the post-transplant care such as corticosteroids, calcineurin inhibitors (CNIs) , proliferating signal inhibitors (PSIs)/mammalian target of rapamycin (mTOR) inhibitors [92,93] and antiproliferative agents may influence lipid metabolism in heart transplant recipients. Although several immunosuppressive agents are known to cause dyslipidemia, mTOR inhibitors and PSIs are associated with profound adverse lipid profiles. Despite causing significant lipid abnormalities, PSI agents have been shown to reduce the progression of CAV.
Hyperlipidemia in heart transplant recipients is usually treated with a 3-hydroxy-3-methyl-glutarylCoA (HMG-CoA) reductase inhibitor (i.e. statin). Therapeutic targets of cholesterol levels are poorly defined in heart transplant population. Nonetheless, efficacy and therapeutic benefit of statins in heart transplant recipients is established unequivocally [94,95,96,97,98,99,100]. In addition to their lipid lowering effects, statins exert their potential beneficial effects by their pleiotropic effects . There are no definitive guidelines to guide therapy in transplant population. American College of Cardiology and American Heart Association (ACC/AHA) guidelines for hyperlipidemia management are extrapolated to these patients. It is also essential to address the secondary causes of lipid abnormalities such as hypo or hyperthyroidism, chronic liver disease, CKD, nephritic syndrome and diabetes. When adjustments are made to immunosuppressive regimen, close monitoring of lipid profile is recommended.
Hypertension is a commonly seen clinical condition in cardiac transplant recipients with a prevalence of 71% of cardiac transplant recipients having hypertension within a year of transplant and 91% within 5 years of transplant . Although there is high prevalence of hypertension in cardiac transplant recipients, less than 50% of the patients achieve target blood pressure goals. Post-transplant hypertension plays a significant role in the onset of angiographic CAV. Hypertension in cardiac transplant recipients is multifactorial and various mechanisms are implicated in the genesis of hypertension [102,103,104,105,106,107]. The pathogenesis of hypertension in heart transplant recipients is multifactorial and complex. The denervated status of cardiac allograft results in impaired regulation of Renin-Angiotensin-Aldosterone System (RAAS) . Corticosteroids and CNIs are the cornerstone of immunosuppressive therapy in heart transplant recipients [108,109,110]. These immunosuppressive agents used in routine post cardiac transplant care have deleterious effects on blood pressure [104,109,110,111]. Introduction of CNIs shifted the paradigm of solid organ transplant. Although there is improved survival and reduced burden of rejection with CNI use, increased incidence of post-transplant hypertension is observed since the introduction of CNI therapy . CNIs are known to cause hypertension in post-transplant patients by inducing endothelial dysfunction and imbalance between vasodilator and vasoconstrictive substances. Salt sensitivity and sympathetic hypertone also contributes to post transplant hypertension [106,107,108]. Diagnosis of hypertension prior to the transplant and advanced age are also predictive of future development of hypertension.
Obtaining a comprehensive medical history including the review of co-existing medical conditions such as renal insufficiency, thyroid or other endocrine disorders, and review of medications including concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or erythropoiesis stimulating agents (ESAs) is essential in the management of hypertension in heart transplant population. Hypertension after heart transplant is preferentially treated with calcium channel blockers and angiotensin converting enzyme inhibitors (ACEIs) [91,105,113,114,115,116]. ACEIs can potentially achieve fluid homeostasis in heart transplant recipients, especially those receiving CNIs [105,113,114,115]. There are no defined guidelines for blood pressure management in heart transplant recipients. However, Kidney Disease Improving Global Outcome (KDIGO) guidelines defined for renal transplant patients can be extrapolated to heart transplant recipients . Abnormal diurnal variations of blood pressures are noted in heart transplant recipients. Ambulatory blood pressure monitoring is advocated to facilitate the diagnosis of hypertension in post cardiac transplant patients .
Diabetes mellitus is one of the most frequent co-morbidities noted in cardiac transplant recipients. Diabetes is a well-known conventional risk factor for atherosclerotic vascular disease and is associated with poor cardiovascular outcome [119,120]. Diabetes mellitus and insulin resistance are frequently encountered metabolic complications in recipients of heart transplantation . Heart transplant recipients may have pre-existing diabetes mellitus or may develop new onset diabetes mellitus after the heart transplant (NODAT) [119,121]. Approximately 23% of heart transplant recipients develop post-transplant diabetes within one year of heart transplantation . Several risk factors are identified to be the predisposing elements for the development of NODAT [122,123,124]. They are delineated below:
a). Blood glucose of >5.6 mmol/liter prior to the transplant 
b). Family history of diabetes
c). Pre-transplant over weight 
e). Administration of immunosuppressive agents (CNIs and Corticosteroids) 
f). Asymptomatic CMV infection 
Immunosuppressive agents vary significantly in their potential to cause diabetes or worsen pre-existing diabetes [121,127]. Although both CNIs and corticosteroids are significantly diabetogenic, the greatest risk of NODAT development is associated with the use of steroids [128,129,130]. Tacrolimus has been reported to be more diabetogenic than cyclosporine .
Heart transplant recipients with diabetes showed comparable rates of long term survival when compared with patients without diabetes [130,132,133,134,135,136]. There was no significant difference in the incidence of infection or CAV. Studies have demonstrated either no significant difference or slightly low incidence of rejection in transplant patients with diabetes when compared with non-diabetic transplant patients. Some studies have shown higher incidence of infection in diabetic cardiac transplant patients compared to nondiabetic patients . Discrepancies in the results of these studies are attributed to the limitations including defining criteria for the diagnosis of diabetes, therapeutic regimen used for the management of diabetes, target glycemic control and presence of any associated micro or macrovascular complications of diabetes [131,137,138]. Further studies are required to define the therapeutic targets and impact of glycemic control on development and prognosis of CAV.
Other Non-Immunologic Risk Factors
There are other non-immunologic risk factors that are known to contribute to the development if CAV. CKD, obesity and smoking have demonstrated risk association with development of CAV [2,9,10,43,50,61,72,138]. Smoking causes endothelial dysfunction and is an important risk factor in the pathogenesis of both CAV and traditional CAD. CKD is a known risk factor for the progression of atherosclerotic vascular disease [10,139,140]. There is a high prevalence of hypertension and other metabolic abnormalities in patients with renal dysfunction. CNIs affect the glomerular filtration and are identified as nephrotoxic agents . Ischemic etiology of end stage heart disease prior to transplantation has been associated with increased risk of CAV. Advanced age of recipient offers a lower risk association with future development of CAV.
Hyperhomocysteinemia [141,142,143,144,145,146,147] and high C-Reactive protein (CRP) [148,149,150,151,152] levels are few of the novel risk factors that have been reported to contribute to the pathogenesis of the CAV. High levels of homocysteine can reduce the endothelial nitric oxide production and cause endothelial dysfunction [144,146]. Hyperhomocysteinemia is associated with adverse cardiovascular outcomes. Although high levels of homocysteine are associated with development of CAV, efficacy of homocysteine lowering therapy has not proven to be beneficial . CRP is an inflammatory marker and is known to induce smooth muscle cell proliferation by upregulating smooth muscle cell angiotensin I receptors and migration of smooth cells [148,149,150,151,152]. There has been a strong association between cardiovascular events and plasma CRP levels. High plasma CRP levels are associated with poor cardiovascular outcomes both in general and cardiac transplant recipients. However, further studies are warranted to define if there is a causal relationship between CRP elevation and CAV.
Several donor factors including donor older age, male sex, and donor history of tobacco use confers increased risk of CAV [72,141,153,154,155]. Mode of brain death, and ischemic, and thermal injury to cardiac allograft also play an important role in the development of CAV. Donor age is an independent predictor of development of CAV in the allograft recipient [153,154,155]. Analysis by McGriffin et al., revealed that hearts obtained from donors aged above 35 posed a future risk of CAV development . Various studies have demonstrated conflicting results on the impact of native vessel atherosclerosis of the donor heart in the development of CAV [156,157,158,159,160]. Maximal intimal thickness greater than 0.5 millimeters at one month after transplant is a strong independent predictor of mortality at one year [157,158,160]. Hepatitis B and C seropositive status of the donor is noted to be associated with higher rates of CAV in the heart transplant recipients [161,162].
Mode of Brain Death
Cause and mechanism of brain death of the donor influence the cardiac function of the heart transplant recipients. Physiologic, metabolic, and neurohormonal alterations triggered by explosive nature of brain death adversely influence the cardiac hemodynamics and function. An explosive mode of brain death such as gunshot wound to the head or fatal intracranial hemorrhage leads to rapid progression of brain death. This promotes cytokine production, catecholamine surge, and evokes significant inflammatory response and endothelialitis [163,164,165,166]. Increased levels of circulating catecholamines stimulate the production of several pro-inflammatory cytokines, adhesion molecules, hormones, and inflammatory cells that are known to cause myocardial dysfunction. Explosive mode of brain death is considered to be an independent risk factor for both short and long term survival of cardiac allograft [163,164]. Prudence is warranted in evaluating such donors; especially if additional risk factors are present. Nevertheless, there is significant scarcity of donor organs, therefore declining the organ based on mode of brain death may not be a viable solution. Further evidence is needed to see if hemodynamic management of brain dead donors could change this risk.
Ischemia and reperfusion injury causes denuding injury to endothelium and plays significant role in pathogenesis of CAV [167,168,169,170,171,172]. Graft ischemia and subsequent perfusion causes reperfusion injury. Reperfusion injury results in free radical production and these free radicals scavenge endothelium-derived nitric oxide (NO) and induce endothelial activation and dysfunction . Solution used for cardioplegia at the time of procurement, quality of preservation and degree of thermal injury are some of the factors that influence the reperfusion injury. Cold ischemic time and total ischemic time influence the degree of the thermal injury encountered by the cardiac allograft. Perioperative ischemia at the time of transplant is associated with endothelial injury and stimulates matrix metalloproteinase production [169,172]. Activation of matrix metalloproteinase system is associated with increased fibrosis and myocardial remodeling.
Long-term graft function and long-term success of cardiac transplantation is limited by CAV. Although significant progress has been made in the understanding of donor and recipient physiology, operative technique, transplant immunology and immunosuppressive pharmacology, CAV remains the Achilles heel of cardiac transplantation. Endothelial damage induced by various noxious stimuli followed by exaggerated repair response appears to be the inciting event in the pathogenesis of CAV. CAV is a multifactorial disease induced and propagated by ischemia-reperfusion injury, alloimmune responses to the allograft, de-novo autoimmunity to self-antigens, and classical risk factors. Repetitive denuding and non-denuding insults to endothelium leads to subendothelial cellular deposition, myointimal hyperplasia and vascular remodeling. Evolving understanding of various risk factors that influence endothelial cell modulation, smooth muscle cell proliferation and inflammation, may provide new insights into preventative strategies. Management of CAV is challenging, and therapeutic options are limited. Current strategies focus on aggressive modification of risk factors, institution of statins, adjustment of immunosuppressive regimen, and treatment of established vascular lesions. The future lies in developing the targeted approaches to prevent endothelial injury, early detection and development of immunomodulatory therapies to promote graft tolerance. There is an increased interest in developing and advancing organ preservation techniques, cytoprotective strategies of procured organs and perfusion technologies to reduce the ischemic time, thermal and reperfusion injury of the allograft.
The authors have declared that no competing interests exist.
- Lund LH, Edwards LB, Dipchand AI, Goldfarb S, Kucheryavaya AY, Levvey BJ, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report—2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:1158-1169. [CrossRef]
- Colvin‐Adams M, Agnihotri A. Cardiac allograft vasculopathy: current knowledge and future direction. Clin Transplant. 2011;25:175-184. [CrossRef]
- Young JB. Perspectives on cardiac allograft vasculopathy. Curr Atheroscler Rep. 2000;2:259-271. [CrossRef]
- Weis M. Cardiac allograft vasculopathy: Prevention and treatment options. Transplant Proc. 2002;34:1847-1849. [CrossRef]
- Bacal F, Veiga VC, Fiorelli AI, Bellotti G, Bocchi EA, Stolf NAG, et al. Analysis of the risk factors for allograft vasculopathy in asymptomatic patients after cardiac transplantation. Arq Bras Cardiol. 2000;75:421-428. [CrossRef]
- Nath DS, Basha HI, Mohanakumar T. Anti-human leukocyte antigen antibody induced autoimmunity: role in chronic rejection. Curr Opin Organ Transplant. 2010;15:16-20. [CrossRef]
- Weiss MJ, Madsen JC, Rosengard BR, Allan JS. Mechanisms of chronic rejection in cardiothoracic transplantation. Front Biosci. 2008;13:2980. [CrossRef]
- Colvin-Adams M, Harcourt N, Duprez D. Endothelial dysfunction and cardiac allograft vasculopathy. J Cardiovasc Transl Res. 2013;6:263-277. [CrossRef]
- Vassalli G, Gallino A, Weis M, Von Scheidt W, Kappenberger L, Von Segesser L, et al. Alloimmunity and nonimmunologic risk factors in cardiac allograft vasculopathy. Eur Heart J. 2003;24:1180-1188. [CrossRef]
- Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res. 2006;99:801-815. [CrossRef]
- Vecchiati A, Tellatin S, Angelini A, Iliceto S, Tona F. Coronary microvasculopathy in heart transplantation: consequences and therapeutic implications. World J Transplant. 2014;4:93-101. [CrossRef]
- Aranda Jr JM, Hill J. Cardiac transplant vasculopathy. CHEST J. 2000;118:1792-1800. [CrossRef]
- Marzoa-Rivas R, Perez-Alvarez L, Paniagua-Martin MJ, Ricoy-Martinez E, Flores-Ríos X, Rodriguez-Fernandez JA, et al. Sudden cardiac death of two heart transplant patients with correctly functioning implantable cardioverter defibrillators. J Heart Lung Transplant. 2009;28:412-414. [CrossRef]
- Chantranuwat C, Blakey JD, Kobashigawa JA, Moriguchi JD, Laks H, Vassilakis ME, et al. Sudden, unexpected death in cardiac transplant recipients: an autopsy study. J Heart Lung Transplant. 2004;23:683-689. [CrossRef]
- Johnson TH, McDonald K, Nakhleh R, McGinn AL, Wilson RF, Olivari MT, et al. Allograft vasculopathy and death in a cardiac transplant patient with angiographically normal coronary arteries. Catheter Cardiovasc Interv. 1991;24:37-40. [CrossRef]
- St Goar F, Pinto FJ, Alderman EL, Valantine HA, Schroeder JS, Gao S, et al. Intracoronary ultrasound in cardiac transplant recipients. In vivo evidence of“ angiographically silent” intimal thickening. Circulation. 1992;85:979-987. [CrossRef]
- Lu W-h, Palatnik K, Fishbein GA, Lai C, Levi DS, Perens G, et al. Diverse morphologic manifestations of cardiac allograft vasculopathy: a pathologic study of 64 allograft hearts. J Heart Lung Transplant. 2011;30:1044-1050. [CrossRef]
- Gao S-Z, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol. 1988;12:334-340. [CrossRef]
- Costanzo M, Naftel D, Pritzker M, Heilman 3rd J, Boehmer J, Brozena S, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant. 1998;17:744-753.
- Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, et al. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy—2010. J Heart Lung Transplant. 2010;29:717-727. [CrossRef]
- Billingham ME. Histopathology of graft coronary disease. J Heart Lung Transplant. 1992;11:S38-S44.
- Johnson D, Gao SZ, Schroeder J, DeCampli W, Billingham M. The spectrum of coronary artery pathologic findings in human cardiac allografts. J Heart Lung Transplant. 1989;8:349-359.
- Yeung AC, Davis SF, Hauptman PJ, Kobashigawa JA, Miller LW, Valantine HA, et al. Incidence and progression of transplant coronary artery disease over 1 year: results of a multicenter trial with use of intravascular ultrasound. J Heart Lung Transplant. 1995;14:S215-S220.
- Libby P, Swanson S, Tanaka H, Murray A, Schoen F, Pober J. Immunopathology of coronary arteriosclerosis in transplanted hearts. J Heart Lung Transplant. 1992;11:S5-S6.
- Billingham ME. Pathology of graft vascular disease after heart and heart-lung transplantation and its relationship to obliterative bronchiolitis. Transplant Proc.1995;27:2013-2016.
- Radio S, Wood S, Wilson J, Lin H, Winters G, McManus B. Allograft vascular disease: comparison of heart and other grafted organs. Transplant Proc. 1996;28:496-499.
- Tsutsui H, Schoenhagen P, Ziada KM, Crowe TD, Klingensmith JD, Vince DG, et al. Early constriction or expansion of the external elastic membrane area determines the late remodeling response and cumulative lumen loss in transplant vasculopathy: an intravascular ultrasound study with 4-year follow-up. J Heart Lung Transplant. 2003;22:519-525. [CrossRef]
- Johnson DE, Alderman EL, Schroeder JS, Gao S-Z, Hunt S, DeCampli WM, et al. Transplant coronary artery disease: histopathologic correlations with angiographic morphology. J Am Coll Cardiol. 1991;17:449-457. [CrossRef]
- Clausell N, Butany J, Molossi S, Lonn E, Gladstone P, Rabinovitch M, et al. Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries. J Am Coll Cardiol. 1995;26:110-119. [CrossRef]
- Wong C-K, Ganz P, Miller L, Kobashigawa J, Schwarzkopf A, von Kaeper HV, et al. Role of vascular remodeling in the pathogenesis of early transplant coronary artery disease: a multicenter prospective intravascular ultrasound study. J Heart Lung Transplant. 2001;20:385-392. [CrossRef]
- Kobashigawa J, Wener L, Johnson J, Currier JW, Yeatman L, Cassem J, et al. Longitudinal study of vascular remodeling in coronary arteries after heart transplantation. J Heart Lung Transplant. 2000;19:546-550. [CrossRef]
- Kapadia SR, Nissen SE, Ziada KM, Guetta V, Crowe TD, Hobbs RE, et al. Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis. Circulation. 1998;98:2672-2678. [CrossRef]
- König A, Kilian E, Sohn H-Y, Rieber J, Schiele TM, Siebert U, et al. Assessment and characterization of time-related differences in plaque composition by intravascular ultrasound–derived radiofrequency analysis in heart transplant recipients. J Heart Lung Transplant. 2008;27:302-309. [CrossRef]
- Frigerio M, Garascia A, Roubina E, Distefano G, Orrego PS, Colombo P, et al. Cardiac allograft vasculopathy: differences in de novo and maintenance heart transplant recipients. Transplantation. 2006;82:S5-S12. [CrossRef]
- Shimizu A, Colvin RB. Pathological features of antibody-mediated rejection. Current Drug Targets-Cardiovascular & Hematological Disorders. 2005;5:199-214. [CrossRef]
- Angaswamy N, Tiriveedhi V, Sarma NJ, Subramanian V, Klein C, Wellen J, et al. Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection. Hum Immunol. 2013;74:1478-1485. [CrossRef]
- Pober JS, Jane-Wit D, Qin L, Tellides G. Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy. Arterioscler Thromb Vasc Biol. 2014;34:1609-1614. [CrossRef]
- Stegall MD, Park W, Larson T, Gloor J, Cornell LD, Sethi S, et al. The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant. 2011;11:698-707. [CrossRef]
- Guihaire J, Mercier O, Flécher E, Aymami M, Fattal S, Chabanne C, et al. Comparison of cardiac allograft vasculopathy in heart and heart–lung transplantations: A 15-year retrospective study. J Heart Lung Transplant. 2014;33:636-643. [CrossRef]
- Jansen MA, Otten HG, de Weger RA, Huibers MM. Immunological and fibrotic mechanisms in cardiac allograft vasculopathy. Transplantation. 2015;99:2467-2475. [CrossRef]
- Schmauss D, Weis M. Cardiac allograft vasculopathy. Circulation. 2008;117:2131-2141. [CrossRef]
- Caforio AL, Tona F, Fortina AB, Angelini A, Piaserico S, Gambino A, et al. Immune and nonimmune predictors of cardiac allograft vasculopathy onset and severity: multivariate risk factor analysis and role of immunosuppression. Am J Transplant. 2004;4:962-970. [CrossRef]
- Benatti RD, Taylor DO. Evolving concepts and treatment strategies for cardiac allograft vasculopathy. Curr Treat Options Cardiovasc Med. 2014;16:278. [CrossRef]
- Gohra H, McDonald TO, Verrier ED, Aziz S. Endothelial loss and regeneration in a model of transplant arteriosclerosis. Transplantation. 1995;60:96-102. [CrossRef]
- Ma XL, Weyrich AS, Lefer DJ, Lefer AM. Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium. Circ Res. 1993;72:403-412. [CrossRef]
- Hollenberg SM, Klein LW, Parrillo JE, Scherer M, Burns D, Tamburro P, et al. Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death. Circulation. 2001;104:3091-3096. [CrossRef]
- Kitchens W, Chase C, Uehara S, Cornell LD, Colvin R, Russell P, et al. Macrophage depletion suppresses cardiac allograft vasculopathy in mice. Am J Transplant. 2007;7:2675-2682. [CrossRef]
- Bienvenu K, Granger DN. Molecular determinants of shear rate-dependent leukocyte adhesion in postcapillary venules. Am J Physiol Heart Circ Physiol. 1993;264:H1504-H1508. [CrossRef]
- Davis SF, Yeung AC, Meredith IT, Charbonneau F, Ganz P, Selwyn AP, et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation. 1996;93:457-462. [CrossRef]
- Pinney SP, Mancini D. Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment. Curr Opin Cardiol. 2004;19:170-176. [CrossRef]
- Hollenberg SM, Klein LW, Parrillo JE, Scherer M, Burns D, Tamburro P, et al. Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation. J Heart Lung Transplant. 2004;23:265-271. [CrossRef]
- Smith CW, Entman ML, Lane CL, Beaudet AL, Ty TI, Youker K, et al. Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1. J Clin Invest. 1991;88:1216. [CrossRef]
- Boyle EM, Lille ST, Allaire E, Clowes AW, Verrier ED. Endothelial cell injury in cardiovascular surgery: atherosclerosis. Ann Thorac Surg. 1997;63:885-894. [CrossRef]
- Fischbein MP, Yun J, Laks H, Irie Y, Fishbein MC, Espejo M, et al. CD8+ lymphocytes augment chronic rejection in a MHC class II mismatched model. Transplantation. 2001;71:1146-1153. [CrossRef]
- Szeto WY, Krasinskas AM, Kreisel D, Krupnick AS, Popma SH, Rosengard BR. Depletion of recipient CD4+ but not CD8+ T lymphocytes prevents the development of cardiac allograft vasculopathy1. Transplantation. 2002;73:1116-1122. [CrossRef]
- Rogers NJ, Lechler RI. Allorecognition. Am J Transplant. 2001;1:97-102. [CrossRef]
- Mitchell RN, Libby P. Vascular remodeling in transplant vasculopathy. Circ Res. 2007;100:967-978. [CrossRef]
- Nath DS, Angaswamy N, Basha HI, Phelan D, Moazami N, Ewald GA, et al. Donor-specific antibodies to human leukocyte antigens are associated with and precede antibodies to major histocompatibility complex class I–related chain A in antibody-mediated rejection and cardiac allograft vasculopathy after human cardiac transplantation. Hum Immunol. 2010;71:1191-1196. [CrossRef]
- Zhang X-P, Kelemen SE, Eisen HJ. Quantitative assessment of cell adhesion molecule gene expression in endomyocardial biopsy specimens from cardiac transplant recipients using competitive polymerase chain reaction1. Transplantation. 2000;70:505-513. [CrossRef]
- Choi J, Enis DR, Koh KP, Shiao SL, Pober JS. T lymphocyte–endothelial cell interactions. Annu Rev Immunol. 2004;22:683-709. [CrossRef]
- Seki A, Fishbein MC. Predicting the development of cardiac allograft vasculopathy. Cardiovasc Pathol. 2014;23:253-260. [CrossRef]
- Petrossian GA, Nichols AB, Marboe CC, Sciacca R, Rose EA, Smith CR, et al. Relation between survival and development of coronary artery disease and anti-HLA antibodies after cardiac transplantation. Circulation. 1989;80:III122-III125.
- Suciu-FocA N, Reed E, Marboe C, Harris P, Xi YP, Yu-Kai S, et al. The role of anti-HLA antibodies in heart transplantation. Transplantation. 1991;51:716-724. [CrossRef]
- Nath DS, Basha HI, Tiriveedhi V, Alur C, Phelan D, Ewald GA, et al. Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy. J Heart Lung Transplant. 2010;29:1277-1285. [CrossRef]
- BALDWIN III WM, Pruitt SK, Brauer RB, Daha MR, Sanfilippo F. Complement in organ transplantation contributions to inflammation, injury, and rejection. Transplantation. 1995;59:797-808. [CrossRef]
- Nath DS, Angaswamy N, Basha HI, Phelan D, Moazami N, Ewald GA, et al. Donor specific antibodies to HLA are associated with and precede antibodies to MICA in antibody mediated rejection and cardiac allograft vasculopathy following human cardiac transplantation. Hum Immunol. 2010;71:1191-1196. [CrossRef]
- Leong H, Mahesh B, Day J, Smith J, McCormack A, Ghimire G, et al. Vimentin autoantibodies induce platelet activation and formation of platelet-leukocyte conjugates via platelet-activating factor. J leukoc Biol. 2008;83:263-271. [CrossRef]
- Rolls HK, Kishimoto K, Dong VM, Illigens BM, Sho M, Sayegh MH, et al. T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection1. Transplantation. 2002;74:1053-1057. [CrossRef]
- Modjeski KL, Morrell CN. Small cells, big effects: the role of platelets in transplant vasculopathy. J Thromb Thrombolysis. 2014;37:17-23. [CrossRef]
- Simper D, Wang S, Deb A, Holmes D, McGregor C, Frantz R, et al. Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of noncardiac origin are enriched in transplant atherosclerosis. Circulation. 2003;108:143-149. [CrossRef]
- Lagaaij EL, Cramer-Knijnenburg GF, van Kemenade FJ, van Es LA, Bruijn JA, van Krieken JH. Endothelial cell chimerism after renal transplantation and vascular rejection. The Lancet. 2001;357:33-37. [CrossRef]
- Valantine H. Cardiac allograft vasculopathy after heart transplantation: risk factors and management. J Heart Lung Transplant. 2004;23:S187-S193. [CrossRef]
- Andrade CF, Waddell TK, Keshavjee S, Liu M. Innate immunity and organ transplantation: the potential role of toll‐like receptors. Am J Transplant. 2005;5:969-975. [CrossRef]
- Costanzo-Nordin M. Cardiac allograft vasculopathy: relationship with acute cellular rejection and histocompatibility. J Heart Lung Transplant. 1992;11:S90-S103.
- Kerman RH, Kimball P, Scheinen S, Radovancevic B, Van Buren CT, Kahan BD, et al. The relationship among donor-recipient HLA mismatches, rejection, and death from coronary artery disease in cardiac transplant recipients1. Transplantation. 1994;57:884-888. [CrossRef]
- Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant. 2003;22:58-69. [CrossRef]
- Rose ML, Smith JD. Clinical relevance of complement-fixing antibodies in cardiac transplantation. Hum Immunol. 2009;70:605-609. [CrossRef]
- Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. Jama. 1989;261:3561-3566. [CrossRef]
- Weis M, Kledal TN, Lin KY, Panchal SN, Gao S, Valantine HA, et al. Cytomegalovirus infection impairs the nitric oxide synthase pathway. Circulation. 2004;109:500-505. [CrossRef]
- Streblow DN, Kreklywich C, Yin Q, De La Melena V, Corless CL, Smith PA, et al. Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplants. J Virol. 2003;77:2182-2194. [CrossRef]
- Costello JP, Mohanakumar T, Nath DS. Mechanisms of chronic cardiac allograft rejection. Tex Heart Inst J. 2013;40:395-399.
- Yamani MH, Yousufuddin M, Starling RC, Tuzcu M, Ratliff NB, Cook DJ, et al. Does acute cellular rejection correlate with cardiac allograft vasculopathy? J Heart Lung Transplant. 2004;23:272-276. [CrossRef]
- Hosenpud JD, Everett JP, Morris TE, Mauck KA, Shipley GD, Wagner CR. Cardiac allograft vasculopathy. Association with cell-mediated but not humoral alloimmunity to donor-specific vascular endothelium. Circulation. 1995;92:205-211. [CrossRef]
- Salomon RN, Hughes C, Schoen F, Payne D, Pober J, Libby P. Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol. 1991;138:791-798.
- Loupy A, Cazes A, Guillemain R, Amrein C, Hedjoudje A, Tible M, et al. Very late heart transplant rejection is associated with microvascular injury, complement deposition and progression to cardiac allograft vasculopathy. Am J Transplant. 2011;11:1478-1487. [CrossRef]
- Esper E, Glagov S, Karp RB, Simonsen KK, Filer SR, Scanu AM, et al. Role of hypercholesterolemia in accelerated transplant coronary vasculopathy: results of surgical therapy with partial ileal bypass in rabbits undergoing heterotopic heart transplantation. J Heart Lung Transplant. 1997;16:420-435.
- Pethig K, Klauss V, Heublein B, Mudra H, Westphal A, Weber C, et al. Progression of cardiac allograft vascular disease as assessed by serial intravascular ultrasound: correlation to immunological and non-immunological risk factors. Heart. 2000;84:494-498. [CrossRef]
- Kapadia SR, Nissen SE, Ziada KM, Rincon G, Crowe TD, Boparai N, et al. Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study. J Am Coll Cardiol. 2001;38:206-213. [CrossRef]
- Singh N, Jacobs F, Rader DJ, Vanhaecke J, Van Cleemput J, De Geest B. Impaired cholesterol efflux capacity and vasculoprotective function of high-density lipoprotein in heart transplant recipients. J Heart Lung Transplant. 2014;33:499-506. [CrossRef]
- Zawaideh MA, Ghishan FK, Molmenti EP. Regulation of cholesterol homeostasis in solid organ transplantation. Transplantation. 2006;81:316-317. [CrossRef]
- Taylor DO, Barr ML, Radovancevic B, Renlund DG, Mentzer Jr RM, Smart FW, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant. 1999;18:336-345. [CrossRef]
- Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847-858. [CrossRef]
- Keogh A, Richardson M, Ruygrok P, Spratt P, Galbraith A, O’Driscoll G, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years. Circulation. 2004;110:2694-2700. [CrossRef]
- Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333:621-627. [CrossRef]
- Wu AH, Ballantyne CM, Short BC, Torre-Amione G, Young JB, Ventura HO, et al. Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry. Am J Cardiol. 2005;95:367-372. [CrossRef]
- Grigioni F, Carigi S, Potena L, Fabbri F, Russo A, Musuraca A, et al. Long-term safety and effectiveness of statins for heart transplant recipients in routine clinical practice. Transplant Proc. 2006;38:1507-1510. [CrossRef]
- Holdaas H, Fellström B, Cole E, Nyberg G, Olsson AG, Pedersen T, et al. Long‐term cardiac outcomes in renal transplant recipients receiving fluvastatin: the alert extension study. Am J Transplant. 2005;5:2929-2936. [CrossRef]
- Mahle WT, Vincent RN, Berg AM, Kanter KR. Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant. 2005;24:63-66. [CrossRef]
- Wenke K, Meiser B, Thiery J, Reichart B. Impact of simvastatin therapy after heart transplantation. Herz. 2005;30:431-432. [CrossRef]
- Lindenfeld J, Miller GG, Shakar SF, Zolty R, Lowes BD, Wolfel EE, et al. Drug therapy in the heart transplant recipient. Circulation. 2004;110:3858-3865. [CrossRef]
- Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation. 2003;108:2113-2120. [CrossRef]
- Frohlich ED, Ventura HO, Ochsner JL. Arterial hypertension after orthotopic cardiac transplantation. J Am Coll Cardiol. 1990;15:1102-1103. [CrossRef]
- Murali S, Uretsky BF, Reddy PS, Griffith BP, Hardesty RL, Trento A. Hemodynamic abnormalities following cardiac transplantation: relationship to hypertension and survival. Am Heart J. 1989;118:334-341. [CrossRef]
- Radovancevic B, Poindexter S, Poindexter S, Birovljev S, Velebit V, McAllister H, et al. Risk factors for development of accelerated coronary artery disease in cardiac transplant recipients. Eur J Cardiothorac Surg. 1990;4:309-313. [CrossRef]
- Braith RW, Mills RM, Wilcox CS, Davis GL, Hill JA, Wood CE. High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients. J Am Coll Cardiol. 2003;41:426-432. [CrossRef]
- Braith RW, Mills Jr RM, Wilcox CS, Convertino VA, Davis GL, Limacher MC, et al. Fluid homeostasis after heart transplantation: the role of cardiac denervation. J Heart Lung Transplant. 1996;15:872-880.
- Ciarka A, Najem B, Cuylits N, Leeman M, Xhaet O, Narkiewicz K, et al. Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients. Hypertension. 2005;45:894-900. [CrossRef]
- Ventura HO, Lavie C, Messerli F, Valentino V, Smart F, Stapleton D, et al. Cardiovascular adaptation to cyclosporine-induced hypertension. J Hum Hypertens. 1994;8:233-237.
- Hoorn EJ, Walsh SB, McCormick JA, Fürstenberg A, Yang C-L, Roeschel T, et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat Med. 2011;17:1304-1309. [CrossRef]
- Ventura HO, Milani RV, Lavie CJ, Smart FW, Stapleton DD, Toups TS, et al. Cyclosporine-induced hypertension. Efficacy of omega-3 fatty acids in patients after cardiac transplantation. Circulation. 1993;88:II281-II285.
- Klauss V, König A, Spes C, Meiser B, Rieber J, Siebert U, et al. Cyclosporine versus tacrolimus (FK 506) for prevention of cardiac allograft vasculopathy. Am J Cardiol. 2000;85:266-269. [CrossRef]
- Grimm M, Rinaldi M, Yonan N, Arpesella G, Arizón Del Prado J, Pulpón L, et al. Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients—a large European trial. Am J Transplant. 2006;6:1387-1397. [CrossRef]
- Mehra MR, Ventura HO, Smart FW, Collins TJ, Ramee SR, Stapleton DD. An intravascular ultrasound study of the influence of angiotensin-converting enzyme inhibitors and calcium entry blockers on the development of cardiac allograft vasculopathy. Am J Cardiol. 1995;75:853-854. [CrossRef]
- Bae J-H, Rihal CS, Edwards BS, Kushwaha SS, Mathew V, Prasad A, et al. Association of angiotensin-converting enzyme inhibitors and serum lipids with plaque regression in cardiac allograft vasculopathy. Transplantation. 2006;82:1108-1111. [CrossRef]
- Erinc K, Yamani MH, Starling RC, Crowe T, Hobbs R, Bott-Silverman C, et al. The effect of combined Angiotensin-converting enzyme inhibition and calcium antagonism on allograft coronary vasculopathy validated by intravascular ultrasound. J Heart Lung Transplant. 2005;24:1033-1038. [CrossRef]
- Schroeder JS, Gao S-Z, Alderman EL, Hunt SA, Johnstone I, Boothroyd DB, et al. A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. N Engl J Med. 1993;328:164-170. [CrossRef]
- Levin A, Stevens PE, Bilous RW, Coresh J, De Francisco AL, De Jong PE, et al. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150.
- Ramesh Prasad G. Ambulatory blood pressure monitoring in solid organ transplantation. Clin Transplant. 2012;26:185-191. [CrossRef]
- Kemna MS, Valantine HA, Hunt SA, Schroeder JS, Chen YI, Reaven GM. Metabolic risk factors for atherosclerosis in heart transplant recipients. Am Heart J. 1994;128:68-72. [CrossRef]
- Hoang K, Chen Y-DI, Reaven G, Zhang L, Ross H, Billingham M, et al. Diabetes and dyslipidemia. Circulation. 1998;97:2160-2168. [CrossRef]
- Klingenberg R, Gleissner C, Koch A, Schnabel PA, Sack F-U, Zimmermann R, et al. Impact of pre-operative diabetes mellitus upon early and late survival after heart transplantation: a possible era effect. J Heart Lung Transplant. 2005;24:1239-1246. [CrossRef]
- Depczynski B, Daly B, Campbell L, Chisholm D, Keogh A. Predicting the occurrence of diabetes mellitus in recipients of heart transplants. Diabetic Med. 2000;17:15-19. [CrossRef]
- Hathout EH, Chinnock RE, Johnston JK, Fitts JA, Razzouk AJ, Mace JW, et al. Pediatric Post‐Transplant Diabetes: Data From a Large Cohort of Pediatric Heart‐Transplant Recipients. Am J Transplant. 2003;3:994-998. [CrossRef]
- Kahn J, Rehak P, Schweiger M, Wasler A, Wascher T, Tscheliessnigg K, et al. The impact of overweight on the development of diabetes after heart transplantation. Clin Transplant. 2006;20:62-66. [CrossRef]
- Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta‐analysis. Am J Transplant. 2004;4:583-595. [CrossRef]
- Hjelmesaeth J, Sagedal S, Hartmann A, Rollag H, Egeland T, Hagen M, et al. Asymptomatic cytomegalovirus infection is associated with increased risk of new-onset diabetes mellitus and impaired insulin release after renal transplantation. Diabetologia. 2004;47:1550-1556. [CrossRef]
- Kato T, Chan MC, Gao S-Z, Schroeder JS, Yokota M, Murohara T, et al. Glucose intolerance, as reflected by hemoglobin a 1c level, is associated with the incidence and severity of transplant coronary artery disease. J Am Coll Cardiol. 2004;43:1034-1041. [CrossRef]
- Räkel A, Karelis A. New-onset diabetes after transplantation: risk factors and clinical impact. Diabetes Metab. 2011;37:1-14. [CrossRef]
- Rhenman M, Rhenman B, Icenogle T, Christensen R, Copeland J. Diabetes and heart transplantation. J Heart Transplant. 1987;7:356-358.
- Badellino M, Cavarocchi N, Narins B, Jessup M, Alpern J, McClurken J, et al., editors. Cardiac transplantation in diabetic patients. Transplant Proc. 1990;22:2384-2388.
- Kobashigawa J, Miller L, Russell S, Ewald G, Zucker M, Goldberg L, et al. Tacrolimus with mycophenolate mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in cardiac transplant patients: 1‐year report. Am J Transplant. 2006;6:1377-1386. [CrossRef]
- Ladowski J, Kormos R, Uretsky B, Griffith B, Armitage J, Hardesty R. Heart transplantation in diabetic recipients. Transplantation. 1990;49:303-305. [CrossRef]
- Faglia E, Favales F, Mazzola E, Pizzi G, De R, Mangiavacchi M, et al. Heart transplantation in mildly diabetic patients. Diabetes. 1990;39:740-746. [CrossRef]
- Munoz E, Lonquist J, Radovancevic B, Baldwin R, Ford S, Duncan J, et al. Long-term results in diabetic patients undergoing heart transplantation. J Heart Lung Transplant. 1992;11:943-949.
- Aleksic I, Czer L, Freimark D, Dalichau H, Takkenberg J, Blanche C, et al. Heart transplantation in patients with diabetic end-organ damage before transplantation. Thorac Cardiovasc Surg. 1996;44:282-288. [CrossRef]
- Lang CC, Beniaminovitz A, Edwards N, Mancini DM. Morbidity and mortality in diabetic patients following cardiac transplantation. J Heart Lung Transplant. 2003;22:244-249. [CrossRef]
- Wilkinson A, Davidson J, Dotta F, Home PD, Keown P, Kiberd B, et al. Guidelines for the treatment and management of new‐onset diabetes after transplantation. Clin Transplant. 2005;19:291-298. [CrossRef]
- Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48:319-327.
- Wali RK, Henrich WL. Chronic kidney disease: a risk factor for cardiovascular disease. Cardiol Clin. 2005;23:343-362. [CrossRef]
- London GM, Marchais SJ, Guérin AP, Métivier F. Impairment of arterial function in chronic renal disease: prognostic impact and therapeutic approach. Nephrol Dial Transplant. 2002;17:13-15. [CrossRef]
- Sipahi I, Starling RC. Cardiac allograft vasculopathy: an update. Heart Fail Clin. 2007;3:87-95. [CrossRef]
- Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050. [CrossRef]
- Doshi SN, Goodfellow J, Lewis MJ, McDowell IF. Homocysteine and endothelial function. Elsevier Sci. 1999.
- Zhang X, Li H, Jin H, Ebin Z, Brodsky S, Goligorsky MS. Effects of homocysteine on endothelial nitric oxide production. Am J Physiol Renal Physiol. 2000;279:F671-F678. [CrossRef]
- Ambrosi P, Garçon D, Riberi A, Habib G, Barlatier A, Kreitmann B, et al. Association of mild hyperhomocysteinemia with cardiac graft vascular disease. Atherosclerosis. 1998;138:347-350. [CrossRef]
- Chambers JC, Ueland PM, Wright M, Doré CJ, Refsum H, Kooner JS. Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects. Circ Res. 2001;89:187-192. [CrossRef]
- Gupta A, Moustapha A, Jacobsen DW, Goormastic M, Tuzcu EM, Hobbs R, et al. High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients. Transplantation. 1998;65:544-550. [CrossRef]
- Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165-2168. [CrossRef]
- Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106:1439-1441. [CrossRef]
- Hognestad A, Endresen K, Wergeland R, Stokke O, Geiran O, Holm T, et al. Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients. J Am Coll Cardiol. 2003;42:477-482. [CrossRef]
- Wang C-H, Li S-H, Weisel RD, Fedak PW, Dumont AS, Szmitko P, et al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation. 2003;107:1783-1790. [CrossRef]
- Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, et al. C-reactive protein in the arterial intima. Arterioscler Thromb Vasc Biol. 2000;20:2094-2099. [CrossRef]
- McGiffin DC, Savunen T, Kirklin JK, Naftel DC, Bourge RC, Paine TD, et al. Cardiac transplant coronary artery disease: a multivariable analysis of pretransplantation risk factors for disease development and morbid events. J Thorac Cardiovasc Surg. 1995;109:1081-1089. [CrossRef]
- Al-Khaldi A, Oyer PE, Robbins RC. Outcome analysis of donor gender in heart transplantation. J Heart Lung Transplant. 2006;25:461-468. [CrossRef]
- Nagji AS, Hranjec T, Swenson BR, Kern JA, Bergin JD, Jones DR, et al. Donor age is associated with chronic allograft vasculopathy after adult heart transplantation: implications for donor allocation. Ann Thorac Surg. 2010;90:168-175. [CrossRef]
- Kobashigawa JA, Tobis JM, Starling RC, Tuzcu EM, Smith AL, Valantine HA, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients. J Am Coll Cardiol. 2005;45:1532-1537. [CrossRef]
- Tuzcu EM, Kapadia SR, Sachar R, Ziada KM, Crowe TD, Feng J, et al. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J Am Coll Cardiol. 2005;45:1538-1542. [CrossRef]
- Yamasaki M, Sakurai R, Hirohata A, Honda Y, Bonneau HN, Luikart H, et al. Impact of donor-transmitted atherosclerosis on early cardiac allograft vasculopathy: new findings by three-dimensional intravascular ultrasound analysis. Transplantation. 2011;91:1406-1411. [CrossRef]
- Li H, Tanaka K, Anzai H, Oeser B, Lai D, Kobashigawa JA, et al. Influence of pre-existing donor atherosclerosis on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients. J Am Coll Cardiol. 2006;47:2470-2476. [CrossRef]
- Mehra MR, Ventura HO, Chambers R, Collins TJ, Ramee SR, Kates MA, et al. Predictive model to assess risk for cardiac allograft vasculopathy: an intravascular ultrasound study. J Am Coll Cardiol. 1995;26:1537-1544. [CrossRef]
- Gasink LB, Blumberg EA, Localio AR, Desai SS, Israni AK, Lautenbach E. Hepatitis C virus seropositivity in organ donors and survival in heart transplant recipients. Jama. 2006;296:1843-1850. [CrossRef]
- Haji SA, Avery RK, Yamani MH, Tuzcu EM, Crowe TD, Cook DJ, et al. Donor or recipient hepatitis B seropositivity is associated with allograft vasculopathy. J Heart Lung Transplant. 2006;25:294-297. [CrossRef]
- Cohen O, De La Zerda D, Beygui R, Hekmat D, Laks H. Donor brain death mechanisms and outcomes after heart transplantation. Transplant Proc.2007;39:2964-2969. [CrossRef]
- Yamani MH, Starling RC, Cook DJ, Tuzcu EM, Abdo A, Paul P, et al. Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient. Circulation. 2003;108:1724-1728. [CrossRef]
- Yamani MH, Cook DJ, Tuzcu EM, Abdo A, Paul P, Ratliff NB, et al. Systemic up‐regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage. Am J Transplant. 2004;4:1097-1102. [CrossRef]
- Mehra M. Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. Am J Transplant. 2006;6:1248-1256. [CrossRef]
- Day JD, Rayburn BK, Gaudin PB, Baldwin W, Lowenstein CJ, Kasper EK, et al. Cardiac allograft vasculopathy: the central pathogenetic role of ischemia-induced endothelial cell injury. J Heart Lung Transplant. 1995;14:S142-S149.
- Jordan JE, Montalto MC, Stahl GL. Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury. Circulation. 2001;104:1413-1418. [CrossRef]
- Collard CD, Väkevä A, Morrissey MA, Agah A, Rollins SA, Reenstra WR, et al. Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol. 2000;156:1549-1556. [CrossRef]
- Wang E, Nie Y, Zhao Q, Wang W, Huang J, Liao Z, et al. Circulating miRNAs reflect early myocardial injury and recovery after heart transplantation. J Cardiothorac Surg. 2013;8:165. [CrossRef]
- Zhou L, Zang G, Zhang G, Wang H, Zhang X, Johnston N, et al. MicroRNA and mRNA signatures in ischemia reperfusion injury in heart transplantation. PLos One. 2013;8:e79805. [CrossRef]
- Massberg S, Enders G, de Melo Matos FC, Tomic LID, Leiderer R, Eisenmenger S, et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood. 1999;94:3829-3838.[Blood]