Characteristics of cardiac allograft vasculopathy compared to traditional coronary atherosclerosis in the native heart.
Cardiac allograft vasculopathy (CAV) represents the most common cause of late graft failure and limits the long-term success of heart transplantation. It is the most common cause of death, in addition to malignancy, in patients who survive the first year after transplant (Taylor et al., 2006). CAV is a diffuse, accelerated form of coronary artery disease in the transplanted heart. Despite improvements in immunotherapy, the incidence of angiographically detected CAV has not changed appreciably over the past two decades. CAV is associated with a relentless course after heart transplantation and immunological and non-immunological interventions have only partially modified its natural history. Treatment of CAV is limited, highlighting the importance of preventive therapies. Re-transplantation for advanced disease is the only definitive therapy, but is limited to select patients. In this chapter, we will review the epidemiology, natural history, clinical manifestations, screening and diagnostic strategies for CAV while emphasizing current treatment strategies designed to prevent or slow the progression of this disease.
CAV was first described in 1970 as a diffuse, obliterative, accelerated form of arteriosclerosis (Bieber et al., 1970). Pathologically, CAV is distinctly different from traditional coronary atherosclerosis (Table 1). It is characterized by diffuse, concentric intimal smooth muscle hyperplasia involving the entire circumference and length of the vessel, and deposition of neointima in the major epicardial vessels and microvasculature, which progressively obstructs the affected vessel lumen (Figure 1). CAV is further distinguished microscopically as having intense cellular proliferation, composed mainly of smooth muscle cells and inflammatory infiltrates (monocytes and lymphocytes). Specific populations of lymphocytes co-localized with CAV lesions include recipient CD4+ T cells, thus suggesting a role for major histocompatibility complex (MHC) II antigen recognition and processing in the development of CAV. Populations of macrophages and CD8+ T cells have also been localized in CAV lesions, whereas recipient B-cells are rare.
The endomyocardial biopsy has limited sensitivity in the recognition of vasculopathy because it samples only the smallest of intramyocardial arteries and arterioles, which often do not show histologic features of CAV. Reported histologic changes seen in the small arteries in endomyocardial biopsies include concentric intimal thickening with or without foamy macrophages, subendothelial accumulation of lymphocytes, and perivascular fibrosis (Pardo et al., 1997). Evidence of myocardial ischemia, such as myocytolysis, frank coagulation necrosis, and healing ischemic lesions as well as interstitial, perivascular, and replacement fibrosis can be seen (Neish et al., 1992). Identification of myocardial injury should raise the suspicion of CAV as the cause of graft dysfunction. The absence of these findings, however, does not necessarily rule out the presence of CAV.
The development of CAV represents a complex interaction between acute and chronic immune activation via an allo-immune pathway and alloantigen-independent non-immune mechanisms that ultimately lead to inflammation and endothelial injury, the precursor to CAV. (Figure 2). Immunologic events appear to be most important, since CAV develops in the donor’s coronary arteries but not the recipient’s vasculature. The donor coronary artery endothelial cells express major histocompatibility complex (MHC) class I and class II antigens, and thus appear to be primary targets of the cell-mediated and humoral immune responses. These antigens are thought to be recognized by recipient CD8+ and CD4+ T cells and these activated lymphocytes secrete cytokines (interleukins, interferons, and tumor necrosis factors), which promote proliferation and further activation of allo-reactive T cells, monocytes, and macrophages. Macrophages are then recruited to the intima where they elaborate cytokines (IL-1, IL-6, tumor necrosis factor TNF alpha) and growth factors [platelet derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), transforming growth factor-alpha (TGF-alpha), TGF-beta-1], leading to smooth muscle cell proliferation and synthesis of extracellular matrix (Libby P & Tanaka H, 1994).
T cell activation also stimulates the expression of adhesion molecules, [intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin] thereby “activating” endothelial cells, enabling recruitment of proinflammatory cells from the vasculature and the initiation of the immune response and subsequent development of CAV. (Briscoe et al., 1995)
|Pathologic characteristic||CAV||Native CAD|
|Lesion morphology||Diffuse, concentric (variable)||Focal, proximal, eccentric|
|Vessels involved||Intramyocardial, epicardial branches||Epicardial, spares intramyocardial branches|
|Collateral vessels||Minimal||Often extensive|
|Initial Lesion||Smooth muscle proliferation||Fatty streaks|
|Internal Elastic Lamina||Intact||Disrupted|
|T-cell location||Subendothelial||Edge of plaque|
Non –immune mechanisms implicated in the development of CAV include inflammatory injury due to recipient hypertension, dyslipidemia, diabetes and insulin resistance,and obesity, in addition to ischemia-reperfusion injury during organ procurement. Endothelial cell dysfunction resulting from inflammatory injury predisposes to thrombosis, vasoconstriction, and vascular smooth muscle cell proliferation. Reperfusion injury increases expression of endothelin 1, which is associated with post-transplant ischemic fibrosis and subsequent development of arteriopathy, in addition to generating free radicals that promote the expression of such inflammatory adhesion molecules and subsequent leukocyte recruitment (Ferri et al., 2002). More research is needed in the field of organ preservation, possibly targeting specific cellular processes to minimize reperfusion injury. Endothelial injury and dysfunction, regardless of the mechanism, seems to be the key inciting event and the common pathway for the development of CAV.
4. Risk factors
Many risk factors for the development of CAV have been identified and can be broadly divided into donor-specific factors, recipient-specific factors and donor-recipient factors, with the latter being predominantly immune mediated (Table 1).
4.1. Donor factors
Donor factors include a history of hypertension, diabetes, male sex, and history of tobacco use. Older donor hearts confer a higher risk of CAV development compared to younger donor hearts, and this risk appears most significant with donors older than 50 years (Al-Khaldi et al., 2006, Nagji et al., 2010).
Donor mode of death has also been shown to have associations with the development of CAV. Explosive modes of brain death, including gunshot wound to the head, accidental head trauma, or a rapidly progressive intracranial hemorrhage have also been associated with development of CAV after transplantation (Mehra et al., 2004a). It has been demonstrated that rapid brain death induces a calcium overflow injury that affects conduction tissue, coronary artery smooth muscle, and myocardial cells (Cohen et al., 2007, Novitzky et al., 1988). There is also a generalized activation of macrophage-associated cytokines, an up-regulation of immunoregulatory and adhesion cell molecules with subsequent endothelial inflammation and dysfunction, in addition to increased levels of circulating catecholamines, all of which may negatively impact the graft response after heart transplantation (Segel et al., 2002, Takada et al., 1998).
The role of transmitted native vessel atherosclerosis is controversial and conflicting. Studies utilizing serial coronary artery intravascular ultrasound (IVUS) found donor lesions did not significantly change after transplantation (Jimenez et al., 2001). However a maximal intimal thickness 0.5mm at baseline (1 month post transplant) was one of the strongest predictors of plaque progression at one year in another study (Yamasaki et al., 2011). In another observational study, donor lesions (defined by intimal thickness > 0.5mm by IVUS at 1 month post transplant) did not have a greater increase in intimal thickness compared to other sites without donor lesions, however the incidence of angiographically apparent CAV up to three years after transplant was higher in patients with donor transmitted lesions with no apparent effect on 3 year mortality (Li H et al., 2006).
Hepatitis C infection (HCV) in donor hearts increases recipient mortality with mortality rates in one study of 16.9% at 1 year, 41.8% at 5 years, and 50.6% at 10 years, compared to recipients of hepatitis C negative donors who had 8.2%, 18.5%, and 24.3% mortality, respectively (Gasink et al., 2006). Recipients with HCV-positive donor hearts were more likely to die secondary to CAV. Other studies also note higher rates of CAV in recipients of HCV + donor hearts, possibly related to HCV viremia in a significant proportion of these recipients; the exact mechanism however, is not completely understood (Haji et al., 2004). Hepatitis B seropositivity (HBV) has been correlated with increased rates of CAV. In one observational study, HBV seropositivity, defined as either the donor or recipient being hepatitis B core antibody positive, was associated with higher rates of CAV at 1 year compared to cases where neither the donor nor recipient were HBV seropositive (Haji SA et al., 2006).
4.2. Recipient factors
Recipient factors that are associated with the development of CAV include male sex, pre-transplant ischemic heart disease, and higher body mass index (Costanzo et al., 1998, Taylor et al., 2007). Traditional cardiac risk factors in the recipient including hypertension, diabetes, dyslipidemia and smoking also increase the risk of developing CAV (Sanchez et al., 2008). Importantly, hypertension, dyslipidemia and diabetes are commonly induced post transplant as side effects of immunosuppressant therapy with calcineurin inhibitors and steroids. The prevalence of hypertension increases after transplant from 74.4% at one year to 98.5% at 10 years (Taylor et al., 2007). The incidence of diabetes after heart transplant ranges from 15% to 20% (Martinez-Dolz et al., 2005).
4.3. Donor-recipient factors
Donor-recipient factors that increase risk of CAV include episodes of high-grade cellular rejection during the first year after transplantation, HLA-DR mismatches, antibody mediated rejection (including asymptomatic AMR), and cytomegalovirus (CMV) infection. The total cellular rejection score at six months increases the risk of CAV by almost threefold (Raichlin et al., 2009). The total cellular rejection score is assigned based on ISHLT grading as 0R = 0, 1R = 1, 2R = 2, 3R = 3, and normalized by dividing the cumulative scores for the total number of biopsies taken during the 6 month intervals. Antibody-mediated rejection increases the incidence of CAV by 10% at one year and by 36% at five years (Michaels et al., 2003). Asymptomatic AMR, defined as histologic evidence of AMR, including endothelial swelling, interstitial hemorrhage, interstitial edema and neutrophil infiltration and/or immunoperoxidase staining showing CD-68 positive macrophages within capillary cells and C4d complement coating the walls of the myocardial capillaries, in patients without symptoms or any evidence of graft dysfunction, increases the risk of developing CAV compared to those with no AMR (We et al., 2009).
CMV disease appears to increase the risk of early-onset CAV –an effect that may be mediated via immune mechanisms rather than a direct consequence of the infective organism (Weill et al., 2001). CMV infection in endothelial cells, such as those lining the donor coronary arteries, leads to a local proinflammatory state and subsequent increased production of vascular cell adhesion molecule (VCAM)-1, alterations in cell surface MHC I and II molecules, and an increase in proinflammatory cytokines and growth factors. This causes endothelial cell/smooth muscle cell proliferation and narrowing of the vessel lumen. CMV may also cause endothelial dysfunction leading to CAV by impairing the nitric oxide synthase pathway. (Hosenpud et al., 2003, Koskinen 1993, Van Dorp et al., 1989). Nitric oxide prevents vascular inflammation and lesion formation in the vessel wall by inhibiting platelet and leukocyte adherence and by suppressing vascular smooth muscle cell proliferation. CMV infection of the endothelium increases expression of endothelial surface adhesion molecules and promotes mononuclear adhesion, activation, and transendothelial migration within the vasculature. In addition, CMV is a stimulus of plasma ADMA (asymmetric dimethylarginine) accumulation, the endogenous inhibitor of nitric oxide synthase. (Weis M et al., 2004)
|Age ("/50 years), Sex (male) and Mode of Death
History of hypertension, diabetes, smoking
? Donor Transmitted Atherosclerosis
Hepatitis B & C infection
Age ("/40 years), Sex (male)
Hypertension, dyslipidemia, obesity, smoking
|Donor – Recipient Interaction
Rejection (cellular and antibody mediated)
5. Clinical manifestations
Early CAV is clinically silent, and ischemia is usually not evident until the disease is far advanced. Patients are most often diagnosed by routine angiographic surveillance or loss of allograft function by surveillance imaging with negative rejection studies. Clinically, patients present with heart failure symptoms and are found to either have new onset systolic or diastolic dysfunction in the absence of acute cellular or antibody mediated rejection, or may present with ventricular arrhythmias and sudden cardiac death. Patients rarely present with chest pain, due to de-innervation of the cardiac allograft at the time of transplantation. However, 25-40% of patients develop some degree of re-innervation post transplant, manifest primarily by return of heart rate response and less often, ischemic chest pain (De Marco et al., 1995).
6. Epidemiology and natural history
CAV is detectable by coronary angiography in approximately 10% of heart transplant recipients within the first year, in 32% - 50% by 5 years, and in an even greater number of recipients when detected by intravascular ultrasound (Pflugfelder et al., 1993). Once mild disease is identified angiographically, the likelihood of progression to severe CAV within 5 years is approximately 19% (Costanzo et al., 1998). Lack of development of CAV at 1 year post-transplant identifies a group who are likely to remain free of clinical events through 6 years of follow up (Luyt et al., 2003). In patients with at least 1 focal stenosis 40%, survival was 67% at 1 year, 44% at 2 years, and 17% at 5 years. With 3 vessels involved, survival was 13% at 2 years (Keogl et al., 1992). The overall likelihood of death or re-transplantation as a result of CAV is approximately 50% for severe CAV (Costanzo
Graft function is an important component in evaluating severity of CAV. Patients with CAV and LV dysfunction have significantly lower 5-year survival compared with CAV patients without LV dysfunction (60% vs. 90%) (Stork et al., 2006). Patients with restrictive cardiac physiology [E to A velocity ratio >2, shortened isovolumetric relaxation time (<60msec), shortened deceleration time (≤150ms), or restrictive hemodynamics (right atrial pressure >12mmHg, pulmonary capillary wedge pressure >25mmHg, cardiac index <2.0)] in the presence of preserved LV systolic function and CAV also have a lower 5-year survival than heart transplant patients without restrictive physiology (Itagaki et al., 2007).
Coronary angiography and assessment of cardiac allograft function remains the cornerstone for diagnosis of CAV. Anatomic abnormalities characteristic of CAV include gradual, distal, diffuse, concentric tapering (“distal pruning”) of the major epicardial arteries with obliteration of the small branching vessels. Discrete epicardial stenoses are less likely (Figure 3). As early CAV is asymptomatic, routine screening with annual coronary angiography (with or without intravascular ultrasound) is standard practice among the majority of transplant centers in the first 3-5 years post transplant. After this time period, there are different practice patterns for assessment of CAV, depending on individuals’ risk factor profile for CAV, graft function, renal function, and clinical status. As CAV is a concentric process, early disease may be overlooked if prior angiograms are not compared. For this reason, baseline angiography is usually performed 4-6 weeks post transplant.
In 2010, the ISHLT working group proposed standardized nomenclature for CAV (Table 3) (Mehra et al., 2010). This system defined CAV as not significant, mild, moderate, and severe based on angiographic appearance. Angiography is a very useful test for detecting lesions
located in epicardial arteries and the main branches, however the main limitation of angiography is low sensitivity, especially in those mild cases in which an apparently normal examination can underestimate the presence of CAV. This is primarily due the vascular remodeling that occurs early in the disease in which there is no compromise in luminal diameter (Nissen 2001). Repeated angiography is recommended for the follow-up of patients with moderate lesions or for patients with symptoms leading to the suspicion of CAV.
Intra-vascular ultrasound (IVUS) at coronary angiography has been evaluated as an adjunctive modality for assessing and diagnosing early CAV. Angiography depicts only a 2-dimensional silhouette of the lumen whereas IVUS allows a reproducible view of both actual lumen diameter, as well as the appearance and thickness of the intima and media. As the intima begins to thicken, the vessel area enlarges as a compensatory mechanism to preserve luminal area. Therefore, ‘angiographically normal’ coronary arteries may in fact have significant CAV.
IVUS parameters include intimal thickness, intimal index, and change in maximal intimal thickness at a reference point, total atheroma volume, and percentage of atheroma volume. IVUS can detect occult disease in angiographically normal sites and has emerged as the optimal diagnostic tool for early detection. CAV is considered present when the intimal thickness is >0.3mm (Rickenbacher et al., 1995). The presence of moderate to severe intimal thickening by IVUS is predictive of the future development of angiographically apparent CAV. IVUS-detected maximal intimal thickness (MIT) greater than 0.3mm at 1 year is associated with a 4-year actuarial survival of 73% versus 96% among those with less than 0.3mm of intimal thickening (Rickenbacher et al., 1995). A change in MIT of 0.5mm at a specific site in the coronary tree within the first year after transplant predicts outcomes at 5 years related to the development of angiographic CAV, mortality and myocardial infarction (Kobashigawa et al., 2005; Tuzcu et al., 2005). Death or graft loss occurred in 21% versus 6%, non-fatal major adverse events or death/graft loss in 46% versus 17% and angiographically apparent disease in 65% versus 33% in those with a change in MIT 0.5mm between baseline and 1-year (Kobashigawa et al., 2005) versus those with a lesser degree of intimal thickening. With >0.6mm intimal thickening, patients are 10 times more likely to experience a cardiac event and for those who developed cardiac events, 62% of patients had ‘normal’ angiograms (Mehra
In patients with stable graft function and no history of CAV, most centers alternate coronary angiography with dobutamine stress echocardiography after 3-5 years; reserving invasive catheterization to every other year. The sensitivity and specificity of dobutamine stress echocardiography compared with coronary angiography and IVUS for detecting CAV is approximately 80% and 88% respectively (Derumeaux et al., 1995, Spes et al., 1999). A normal DSE incorporating M-mode measurement of wall thickening predicts an uneventful clinical course (Spes et al., 1999).
Computed tomographic angiography, although useful in detecting traditional atherosclerosis, has limitations in heart transplant recipients. The major drawbacks with the routine use of 16 or 64 slice multidetector CT in this population include the high heart rate of most heart transplant recipients (due to cardiac vagal denervation) that may compromise imaging quality, contrast-induced nephropathy and radiation. However, compared with
|ISHLT CAV0 (not significant)||No detectable angiographic lesion|
|ISHLT CAV1 (Mild)||Angiographic left main (LM) <50%, or primary vessel with maximum lesion of <70%, or any branch stenosis <70% (including diffuse narrowing) without allograft dysfunction|
|ISHLT CAV2 (Moderate)||Angiographic LM <50%; a single primary vessel 70% stenosis, or isolated branch stenosis 70% in branches of 2 systems, without allograft dysfunction|
|ISHLT CAV3 (Severe)||Angiographic LM 50%, or 2 primary vessels 70% stenosis, or isolated branch stenosis 70% in all 3 systems; or ISHLT CAV 1 or 2 with allograft dysfunction (defined as LVEF ≤ 45%, usually in the presence of regional wall motion abnormalities) or evidence of significant restrictive physiology (which is common but not specific)|
IVUS, the sensitivity, specificity, positive and negative predictive values for the detection of CAV by dual source CT were 85%, 84%, 76%, and 91% respectively (Schepis et al., 2009). Magnetic resonance coronary angiography, at present, shows limited sensitivity for detecting CAV and positron emission tomography (PET) has not yet been well studied (Muehling et al., 2003).
Serum biomarkers provide important clues to molecular and structural changes within the transplanted heart. The role of inflammation has been demonstrated by the elaboration of inflammatory cytokines in patients with CAV. Elevated CRP levels have been shown to be associated with increased risk of developing CAV, suggesting a link between systemic and local inflammation within the coronary artery of the transplanted heart (Arora et al., 2010, Raichlin et al., 2007). However, it is not clear if CRP is merely a marker or if it is involved in CAV pathogenesis. Persistently elevated troponin I levels after heart transplantation are associated with an increased risk of development of CAV (Labarrere et al., 2000). Elevated BNP has also been correlated with the development of CAV (Mehra et al., 2004b). BNP may be useful in combination with angiographic findings in predicting outcomes, with 50% of patients with high BNP levels and angiographic CAV experiencing cardiac death (Tsutsui et al., 2001). Biomarkers may hold predictive correlation, but are not used routinely for the evaluation of CAV.
8. Prevention and treatment
Therapeutic options in CAV can be thought of in terms of prevention and treatment. Medical therapy aims to slow, halt, or even reverse the intimal proliferation, concentric luminal loss and arterial obliteration that characterize CAV. Preventive therapy targets traditional cardiac risk factors (diabetes mellitus, hyperlipidemia and hypertension) and aggressive treatment of rejection episodes. Rapidly progressive CAV within the first year after heart transplant strongly predicts all-cause mortality, myocardial infarction, and the subsequent development of angiographically severe CAV. Accordingly, prophylactic strategies must be implicated very early to induce significant improvement in long-term prognosis.
Statins have been associated with reduced progression of CAV, and routine administration of statins to all patients after transplant has clearly reduced the mortality and progression of the disease (Wenke et al., 2003). A meta-analysis based on the published results of three randomized clinical trials determined that the use of statins decreased 1-year mortality following heart transplantation from 17.1% to 5.4% (Mehra
There are small studies that suggest calcium channel blockers, such as diltiazem, are effective in slowing the progression of CAV (Schroeder et al., 1993). ACE inhibitors have been associated with plaque regression and improved survival for established CAV, however pre-emptive therapy with ACE inhibitors has unknown preventative effects (Bae et al., 2006). Currently, there is little definitive evidence to suggest that calcium channel blockers or ACE inhibitors are effective in reducing the incidence or slowing the progression of CAV.
Diabetes is common in cardiac transplant recipients and most heart transplant patients are markedly insulin resistant and demonstrate many of the features of compensatory hyperinsulinemia, including the atherogenic and proinflammatory profile of the metabolic syndrome (Potena L & Valantine H, 2007). Patients with high plasma glucose or insulin concentrations after oral glucose intake have greater intimal thickness and are less likely to be free of CAV and have significantly lower survival during 5 years of follow up than patients with low glucose and insulin levels (Valantine et al., 2001). Specific therapies shown to be effective in correcting insulin resistance, such as the thiazolidinediones, offer potential new therapeutic targets for CAV prevention, however the clinical studies are lacking.
Owing to the diffuse nature of vasculopathy, conventional therapeutic approaches including percutaneous coronary intervention and coronary artery bypass grafting are optional only late in the course and are not always successful or even feasible.
Immunosuppression continues to represent the principal means of pharmacologic prophylaxis against and treatment of allograft vasculopathy, with the development and introduction of the proliferation signal inhibitors (PSI) sirolimus and everolimus representing the greatest advance achieved to-date in this field. PSI’s are powerful immunosuppressant drugs that inhibit cellular proliferation and have shown the ability to reduce, and even reverse, coronary intimal growth in established CAV and reduce the incidence of CAV in
In a prospective multi-center randomized double blind control trial, patients who received everolimus, cyclosporine and steroids versus azathioprine, cyclosporine and steroids had a significant reduction in the incidence of CAV at 12 months (35.7% versus 52.8%), fewer grade 3A cellular rejections (21.3% versus 30.6%) and CMV infection (12% versus 41.4%) (Eisen et al., 2003). Similar results were found with sirolimus (Keogh et al., 2004). The long-term results of both studies demonstrate a trend toward a lower incidence of severe vasculopathy in the group that is maintained on PSI with patients treated with everolimus having significantly lower rates of major cardiovascular events related to CAV compared to patients treated with azathioprine (7.9% vs. 13.6%) (Eisen et al., 2006, Keogh et al., 2007).
The available data suggest the efficacy of PSIs in reducing the incidence of CAV; however, up to 30-40% of patients in the clinical trials had to discontinue the PSI during the first year because of poor tolerability. Complications and side effects include bacterial and viral infections (17-30%), oral ulcerations, pericardial effusions (up to 25%) and pleural effusions (15-40%), hematologic abnormalities including anemia and thrombocytopenia, impaired wound healing, acne, and pedal edema. Adverse events may be related to the dosing regimen (high vs. low dose) and timing (immediately post transplant vs. delayed introduction). A recent study with lower serum concentrations of everolimus (3-8ng/mL) report a lower drop-out rate of 15% (Lehmukuhl et al., 2009). At this time, it remains unclear whether patients should be transitioned to a PSI-based immunosuppressant regimen once sternal healing has occurred.
In relation to the pharmacologic treatment of established CAV, aggressive control of traditional cardiac risk factors is important; however, the PSIs represent the most important advance. Studies in which patients with established CAV were switched to a PSI from MMF or azathioprine demonstrated a significant reduction in CAV-related adverse events (5% vs. 25%) including death, percutaneous coronary intervention (PCI), myocardial infarction, or angiographic progression of the disease 2 years following the transition and a reduction in plaque size compared to progression (Mancini et al., 2003; Segovia et al., 2004). Larger studies are needed to corroborate these initial findings; however, it is generally accepted practice that patients with established CAV are transitioned to PSI.
The treatment of established CAV represents a clinical challenge. Non-pharmacologic treatment includes PCI, coronary artery bypass grafting (CABG), and retransplantation. Percutaneous and surgical revascularization is limited by the diffuse coronary involvement, the infrequency of focal lesions with suitable distal targets, and the high mortality rates with surgical intervention (up to 30-40%) (Musci et al., 1998, Patel et al., 1997). PCI is associated with excellent short-term results, however is associated with high restenosis rates. With the advent of drug eluting stents, preliminary studies suggest much lower restenosis rates. (Lee et al., 2008). PCI remains a palliative therapy, as CAV is a diffuse and progressive disease process. It may be appropriate to perform PCI in patients with discrete focal lesions with abnormal graft function or evidence of stress-induced functional significance by stress imaging. Retransplantation is the only definitive therapy for CAV; however, survival is lower than after primary heart transplant and the probability of CAV in the retransplanted heart is higher than in de novo transplants (up to 50% at 3 years) (Musci et al., 1998, Srivastava et al., 2000). Re-transplantation is reserved for highly selected patients with CAV.
The development of CAV has been described as the Achilles heel of cardiac transplantation. The increased mortality observed in the years after the diagnosis of CAV reflects that fact that, at present, the management of these patients represents a clinical challenge. Diagnosis is heavily reliant on invasive testing and early diagnosis and preventive strategies are crucial, but remain ineffective in many cases. Statins, antihypertensive drugs, and anti-CMV agents have all demonstrated a modest beneficial reduction in CAV; however, the proliferation signal inhibitors represent the best prevention and treatment options available at this time. Current research focuses on identification of novel agents that are effective in preventing the development and progression of CAV, and non-invasive techniques for CAV diagnosis.
Al-Khaldi A. Oyer P. E. Robbins R. C. 2006Outcome analysis of donor gender in heart transplantation. , 25 4(February 2006), 461 468, 1053-2498
Arora S. Gunther A. Wennerblom B. Uelan T. Andreassen A. K. Gude E. Endresen K. Geiran O. Wilhelmsen N. Andersen R. Aukrust P. Gullestad L. 2010 Systemic Markers of inflammation are associated with cardiac allograft vasculopathy and an increased intimal inflammatory component. , 10 6(June 2010), 1428 1436, 1600-6135
Bae J. H. Rihal C. S. Edwards B. S. Kushwaha S. S. Mathew V. Prasad A. Holmes D. R. Jr Lerman A. 2006 Association of angiotensin-converting enzyme inhibitors and serum lipids with plaque regression in cardiac allograft vasculopathy., 82 8(October 2006), 1108 1111, 0041-1337
Bieber C. P. Stinson E. B. Shumway N. E. Payne R. Kosek J. 1970 Cardiac transplantation in man. VII. Cardiac allograft vasculopathy. , 41 5(January 1970), 753 772, 0009-7322
Briscoe D. M. Yeung A. C. Schoen F. J. Allred E. N. Stavrakis G. Ganz P. Cotran R. S. Pober J. S. Schoen E. L. 1995Predictive value of inducible endothelial cell adhesion molecule expression for acute rejection of human cardiac allografts. , 59 2(January 1995), 204 211, 0041-1337
Cohen O. De La Zerda D. J. Beygui R. Hekmat D. Laks H. 2007 Donor brain death mechanisms and outcomes after heart transplantation. , 39 10(December 2007), 2964 2969, 0041-1345
Costanzo M. R. Naftel D. C. Pritzker M. R. Hellman J. K. Boehmer J. P. Brozena S. C. Dec W. G. Ventura H. O. Kirklin J. K. Bourge R. C. Miller L. W. 1998Heart transplant coronary artery disease detected by coronary angiography: a multi-institutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. The Journal of Heart and Lung Transplantation, 17 8(August 1998), 744 753, 1053-2498
De Marco T. Dae M. Yuen-Green M. Kumar S. Sudhir K. Keith F. Amidon T. Rifkin C. Klinski C. Lau D. Botvinick E. Chatterjee K. 1995 Iodine-123 metaiodobenzylguanidine scintigraphic assessment of the transplanted human heart: evidence for late reinnervation., 25 4(March 1995), 927 931, 0735-1097
Derumeaux G. Redonnet M. Mouton-Schleifer D. Bessou J. P. Cribier A. Saoudi N. Koning R. Soyer R. Letac B. Research VACOMED Group 1995 Dobutamine stress echocardiography in orthotopic heart transplant recipients. , 25 7(June 1995), 1665 1672, 0735-1097
Eisen H. J. Tuzcu E. M. Dorent R. Kobashigawa J. Mancini D. Valantine-von Kaeppler. H. A. Starling R. C. Sorensen K. Hummel M. Lind J. M. Abeywickrama K. H. Bernhardt P. 2003 Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients., 349 9(August 2003), 847 858, 0028-4793
Eisen H. Yang X. 2006 The impact of proliferation signal inhibitors on the healthcare burden of major adverse cardiac events following heart transplantation. , 82 8SUPPL, (October 2006), S13 S18, 0041-1337
Ferri C. Properzi G. Tomassoni G. Santucci A. Desideri G. Giuliani A. E. Cook D. J. Mc Carthy P. Young J. B. Yamani M. H. 2002 Patterns of myocardial endothelin-1 expression and outcome after cardiac transplantation., 105 15(April 2002), 1768 1771, 0009-7322
Gasink L. B. Blumberg E. A. Localio A. R. Desai S. S. Israni A. K. Lautenbach E. 2006 Hepatitis C virus seropositivity in organ donors and survival in heart transplant recipients. 296 15(October 2006), 1843 1850, 0098-7484
Haji S. A. Avery R. K. Yamani M. H. Tuzcu E. M. Crowe T. D. Cook D. J. Mawhorter S. D. Hobbs R. Young J. B. Smedira N. Starling R. C. 2006 Donor or recipient hepatitis B seropositivity is associated with allograft vasculopathy. , 25 3(March 2006), 294 297, 1053-2498
Haji S. A. Starling R. C. Avery R. K. Mawhorter S. Tuzcu E. M. Schoenhagen P. Cook D. J. Ratliff N. B. Mc Carthy P. M. Young J. B. Yamani M. H. 2004 Donor hepatitis-C seropositivity is an independent risk factor for the development of accelerated coronary vasculopathy and predicts outcome after cardiac transplantation. , 23 3(March 2004), 277 283, 1053-2498
Hollenberg M. Klein L. W. Parrillo J. E. Scherer M. Burns D. Tamburro P. Oberoi M. Johson M. R. Costanzo M. R. 2001 Coronary endothelial dysfunction after heart transplantation predicts allograft vasculopathy and cardiac death., 104 25(2001), 3091 3096, 0009-7322
Hosenpud J. D. Streblow D. N. Kreklywich C. Yin Q. De La Melena V. T. Corless C. L. Smith P. A. Brakebill C. Cook J. W. Vink C. Bruggeman C. A. Nelson J. A. Orloff S. L. 2003Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplant. 77 3(February 2003), 2182 2194, 0002-2538X.
Itagaki B. K. Kobashigawa J. A. Wu G. W. Patel J. K. Kawano M. A. Kittleson M. M. Fishbein M. C. 2007Widespread fibrosis of myocardial and adjacent tissues causing restrictive cardiac physiology in patients needing re-do heart transplant. Proceedings of the International Society of Heart and Lung Transplantation, San Francisco, April 2007.
Jimenez J. Kapadia S. R. Yamani M. H. Platt L. Hobbs R. E. Rincon G. Botts-Silverman C. Starling R. Young J. B. Nissen S. E. Tuzcu M. 2001 Cellular rejection and rate of progression of transplant vasculopathy: A 3-year serial intravascular ultrasound study. , 20 4(April 2001), 393 398, 1053-2498
Kapadia S. R. Ziada K. M. L’Allier P. L. Crowe T. D. Rincon G. Hobbs R. E. Bott-Silverman C. Young J. B. Nissen S. E. Tuzcu E. M. 2000Intravascular ultrasound imaging after cardiac transplantation: advantage of multivessel imaging. 19 2(February 2000), 167 172, 1053-2498
Keogh A. Richardson M. Ruygrok P. Spratt P. Galbraith A. O’Driscoll G. Macdonald P. Esmore D. Muller D. Faddy S. 2004 Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial., 110 17(October 2004), 2694 2700, 0009-7322
Keogh A. Richardson M. Ruygrok P. Macdonald P. Schneider L. O’Driscoll G. Galbraith A. 2007Sirolimus vs. azathioprine from the time of heart transplantation: 65 month follow-up for vascular (MACE) and malignant events. San Francisco, April 2007.
Keogl A. M. Valantine H. A. Hunt S. A. Schroeder J. Mc Intosh N. Oyer P. Stinson E. 1992Impact of proximal or midvessel discrete coronary artery stenosis on survival after heart transplanation. , 11(1992), 892 901.
Kobashigawa J. A. Tobis J. M. Starling R. C. Tuzcu E. M. Smith A. L. Valantine H. A. Yeung A. C. Mehra M. R. Anzai H. Oeser B. T. Abeywickrama K. H. Murphy J. Cretin N. 2005 Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years., 45 9(May 2005), 1532 1537, 0735-1097
Koskinen P. K. 1993The association of the induction of vascular cell adhesion molecule-1 with cytomegalovirus antigenemia in human heart allografts. Transplantation, 56 5(November 1993), 1103 1108, 0041-1337
Labarrere C.A Nelson D. R. Cox C. J. Pitts D. Kirlin P. Halbrook H. 2000 Cardiac-specific troponin I levels and risk of coronary artery disease and graft failure following heart transplantation. 284 4(July 2000), 457 464, 0098-7484
Lee M. S. Kobashigawa J. Tobis J. 2008 Comparison of percutaneous coronary intervention with bare metal and drug eluting stents for cardiac allograft vasculopathy. 1 6(December 2008), 710 715, 1936-87982282
Lehmukuhl H. Arizon J. Vigano M. Almenar L. Gerosa G. Maccherini M. Varnous S. Musumeci F. Hexham J. Mange K. Livi U. 2009Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients. 88 1(July 2009), 115 122, 0041-1337
Li H. Tanaka K. Anzai H. Oeser B. Lai D. Kobashigawa J. A. Tobis J. M. 2006 Influence of pre-existing donor atherosclerosis on the development of cardiac allograft vasculopathy and outcomes in heart transplant recipients. , 47 12(June 2006), 2470 2476, 0735-1097
Libby P. Tanaka H. 1994 The pathogenesis of coronary arteriosclerosis (“chronic rejection”) in transplanted hearts., 3 2June 1994), 313 318, 0902-0063
Luyt C. E. Drobinski G. Dorent R. Ghossoub J. Collet J. Choussat R. Dalby M. Thomas D. Gandjbakhch I. 2003 Prognosis of moderate coronary artery lesions in heart transplant patients. , 22 2(February 2003), 130 136, 1053-2498
Mancini D. Pinney S. Burkhoff D. La Manca J. Itescu S. Burke E. Edwards N. Oz M. Marks A. 2003 Use of rapamycin slows progression of cardiac transplantation vasculopathy., 108 1(July 2003), 48 53, 0009-7322
Martinez-Dolz L. Almenar L. Martinez-Ortiz L. Arnau M. A. Chamorro C. Moro J. Osa A. Rueda J. Garcia C. Palencia M. 2005 Predictive factors for development of diabetes mellitus post-heart transplant., 37 9(November 2005), 4064 4066, 0041-1345
Mehra M. R. Crespo-Leiro M. G. Dipchand A. Ensminger S. M. Hiemann N. E. Kobashigawa J. A. Madsen J. Parameshwar J. Starling R. C. Uber P. A. 2010International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy- 2010. , 29 7(July 2010), 717 727, 1053-2498
Mehra M. R. Raval N. Y. 2004cMetaanalysis of statins and survival in de novo cardiac transplantation. Transplantation Proceedings, 36 5(June 2004), 1539 1541, 0041-1345
Mehra M. R. Uber P. A. Potluri S. Ventura H. O. Scott R. L. Park M. H. 2004b Usefulness of an elevated B-type natriuretic peptide to predict allograft failure, cardiac allograft vasculopathy, and survival after heart transplantation., 94 4(August 2004), 454 458, 0002-9149
Mehra M. R. Uber P. A. Ventura H. O. Scott R. L. Park M. H. 2004aThe impact of mode of donor brain death on cardiac allograft vasculopathy. Journal of the American College of Cardiology, 43 5(March 2004), 806 810, 0735-1097
Mehra M. R. Ventura H. O. Stapleton D. D. Smart F. W. Collins T. C. Ramee S. R. 1995Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. The Journal of Heart and Lung Transplantation, 14 4(July-August 1995), 632 639, 1053-2498
Michaels P. J. Espejo M. L. Kobashigawa J. Alejos J. C. Burch C. Takemoto S. Reed E. F. Fishbein M. C. 2003 Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. , 22 1(January 2003), 58 69, 1053-2498
Muehling O. M. Wilke N. M. Panse P. Jerosch-Herold M. Wilson B. V. Wilson R. F. Miller L. W. 2003 Reduced myocardial perfusion reserve and transmural perfusion gradient in heart transplant arteriopathy assessed by magnetic resonance imaging., 42 6(September 2003), 1054 1060, 0735-1097
Musci M. Loebe M. Wellnhofer E. Meyer R. Pasic M. Hummel M. Bocksch W. Grauhan O. Weng Y. Hetzer R. 1998 Coronary angioplasty, bypass surgery, and retransplantation in cardiac transplant patients with graft coronary artery disease. , 46 5(October 1998), 268 274, 0171-6425
Nagji A. S. Hranjec T. Swenson B. R. Kern J. A. Bergin J. D. Jones D. R. Kron I. L. Lau C. L. Ailawadi G. 2010 Donor age is associated with chronic allograft vasculopathy after adult heart transplantation: implications for donor allocation. 90 1(July 2010), 168 175, 0003-4975
Neish A. S. Loh E. Schoen F. J. 1992 Myocardial changes in cardiac transplant-associated coronary arteriosclerosis: potential for timely diagnosis., 19 3(March 1992), 586 592, 0735-1097
Nissen S. 2001 Coronary angiography and intravascular ultrasound., 87 4A(February 2001), 15A 20A, 0002-9149
Novitzky D. Rose A. G. Cooper D. K. 1988 Injury of myocardial conduction tissue and coronary artery smooth muscle following brain death in the baboon., 45 5(May 1988), 964 966, 0041-1337
Pardo Mindan. F. J. Panizo A. Lozano M. D. Herreros J. Mejia S. 1997 Role of endomyocardial biopsy in the diagnosis of chronic rejection in human heart transplantation., 11 5(October 1997), 426 431, 0902-0063
Patel V. S. Radovancevic B. Springer W. Frazier O. H. Massin E. Benrey J. Kadipasaoglu K. Cooley D. A. 2007 Revascularization procedures in patients with transplant coronary artery disease. , 11 5(May 1997), 895 901, 1010-7940
Pflugfelder P. W. Boughner D. R. Rudas L. Kostuk W. J. 1993 Enhanced detection of cardiac allograft arterial disease with intracoronary ultrasonographic imaging., 125 6(June 1993), 1583 1591, 0002-8703
Potena L. Valantine H. 2007Cardiac allograft vasculopathy and insulin resistance- hope for new therapeutic targets. , 36 4(December 2007), 965 981, 0889-8529
Raichlin E. Edwards B. S. Kremers W. K. Clavell A. L. Rodeheffer R. J. Frantz R. P. Pereira N. L. Daly R. C. Mc Gregor C. G. Lerman A. Kushwaha S. S. 2009 Acute cellular rejection and the subsequent development of allograft vasculopathy after cardiac transplantation. , 28 4(April 2009), 320 327, 1053-2498
Raichlin E. R. Mc Connell J. P. Lerman A. Kremers W. K. Edwards B. S. Kushwaha S. S. Clavell A. L. Rodeheffer R. J. Frantz R. P. 2007 Systemic inflammation and metabolic syndrome in cardiac allograft vasculopathy. , 26 8(August 2007), 826 833, 1053-2498
Rickenbacher P. R. Pinto F. J. Lewis N. P. Hunt S. A. Alderman E. L. Schroeder J. S. Stinson E. B. Brown B. W. Valantine H. A. 1995Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation, 92 12(December 1995), 3445 3452, 0009-7322
Sanchez Lazaro. I. J. Bonet L. A. Lopez J. M. Lacuesta E. S. Martinez-Dolz L. Ramon-Llin J. A. Lalaguna L. A. Perez O. C. Martinez V. O. Fuentes F. B. Sanz A. S. 2008 Influence of traditional cardiovascular risk factors in the recipient on the development of cardiac allograft vasculopathy after heart transplantation., 40 9(November 2008), 3056 3057, 0041-1345
Schepis T. Achenbach S. Weyand M. Raum P. Marwan M. Pflederer T. Daniel W. B. Tandler R. Kondruweit M. Ropers D. 2009 Comparison of dual source computed tomography versus intravascular ultrasound for evaluation of coronary arteries at least one year after cardiac transplantation. 104 10(November 2009), 1351 1356, 0002-9149
Schoreder J. S. Gao S. Z. Alderman E. L. Hunt S. A. Johnstone I. Boothroyd D. B. Wiederhold V. Stinson E. B. 1993A preliminary study of diltiazem in the prevention of coronary artery disease in heart-transplant recipients. , 328 3(January 1993), 164 170, 0028-4793
Segel L. D. Von Haag. D. W. Zhang J. Follette D. M. 2002 Selective overexpression of inflammatory molecules in hearts from brain-dead rats. 21 7July 2002), 804 811, 1053-2498
Segovia J. Aloinso-Pulpon L. Ortiz P. Jimenez-Mazuecos J. Alfonso F. Escaned J. Hernandez-Antolin R. Macaya C. 2004 Rapastat: evaluation of the role of oral sirolimus in the treatment of established graft vessel disease. A prospective, randomized intravascular ultrasound study. Transplantation, San Francisco, April 2004.
Spes C. H. Klauss V. Mudra H. Schnaack S. D. Tammen A. R. Rieber J. Siebert U. Henneke K. H. Uberfuhr P. Reichart B. Theisen K. Angermann C. E. 1999 Diagnostic and prognostic value of serial dobutamine stress echocardiography for noninvasive assessment of cardiac allograft vasculopathy: a comparison with coronary angiography and intravascular ultrasound., 100 5(August 1999), 509 515, 0009-7322
Srivastava R. Keck B. M. Bennett L. E. Hosenpud J. D. 2000 The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung /United Network for Organ Sharing Thoracic Registry., 70 4 606 612, 0041-1337
Stork S. Behr T. Birk M. Uberfuhr P. Klauss V. Spes C. Angermann C. 2006Assessment of cardiac allograft vasculopathy late after heart transplantation: when is coronary angiography necessary? , 25 9(September 2006), 1103 1108, 1053-2498
Takada M. Nadeau K. C. Hancock W. W. Mackenzie H. S. Shaw G. D. Waaga A. M. Chandraker A. Sayegh M. H. Tilney N. L. 1998 Effects of explosive brain death on cytokine activation of peripheral organs in the rat., 65 12(June 1998), 1533 1542, 0041-1337
Taylor D. O. Edwards L. B. Boucek M. M. Trulock E. P. Waltz D. A. Keck B. M. Hertz M. I. 2006Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report- 2006. The Journal of Heart and Lung Transplantation, 25 8(August 2006), 869 879, 1053-2498
Taylor D. O. Edwards L. B. Boucek M. M. Trulock E. P. Aurora P. Christie J. Dobbels F. Rahmel A. O. Keck B. M. Hertz M. I. 2007Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official heart transplant report-2007. 26 8(August 2007), 769 781, 1053-2498
Tona F. Caforio A. Montisci R. Gambino A. Angelini A. Ruscazio M. toscano G. Feltrin F. Ramondo A. Gerosa G. Iliceto S. 2006 Coronary Flow Velocity Pattern and Coronary Flow Reserve by Contrast-Enhanced Transthoracic echocardiography predict long-term outcome in heart transplantation., 114No. I Suppl, (July 2006), I49 I55, 0009-7322
Tsutsui H. Ziada K. M. Schoenhagen P. Iyisoy A. Magyar W. A. Crowe T. D. Klingensmith J. D. Vince D. G. Rincon G. Hobbs R. E. Yamagishi M. Nissen S. E. Tuzcu E. M. 2001 Lumen loss in transplant coronary artery disease is a biphasic process involving early intimal thickening and late constrictive remodeling: results from a 5-year serial intravascular ultrasound study., 104 6 653 657, 0009-7322
Tuzcu E. M. Kapadia S. R. Sachar R. Ziada K. M. Crowe T. D. Feng J. Magyar W. A. Hobbs R. E. Starling R. C. Young J. B. Mc Carthy P. Nissen S. E. 2005 Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation., 45 9(May 2005), 1538 1542, 0735-1097
Valantine H. A. Gao S. Z. Menon S. G. Renlund D. G. Hunt S. A. Oyer P. Stinson E. B. Brown B. W. Merigan T. C. Schroeder J. S. 1999 Impact of prophylactic immediate posttransplant ganciclovir on development of transplant atherosclerosis: A post hoc analysis of a randomized, placebo-controlled study., 100 1(July 1999), 61 66, 0009-7322
Valantine H. Rickenbacker P. Kemna M. Hunt S. Chen Y. Reaven G. Stinson E. 2001 Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease: a prospective study., 103 17(May 2001), 2144 2152, 0009-7322
Van Dorp W. T. Jonges E. Bruggeman C. A. Daha M. R. Van Es L. A. Van Der Woude F. J. 1989 Direct induction of MHC class I, but not class II, expression on endothelial cells by cytomegalovirus infection., 48 3(September 1989), 469 472, 0041-1337
We G. W. Kobashigawa J. A. Fishbein M. C. Patel J. K. Kittleson M. M. Reed E. F. Kiyosaki K. K. Ardehali A. 2009Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. , 28 5(May 2009), 417 422, 1053-2498
Weill D. 2001 Role of cytomegalovirus in cardiac allograft vasculopathy. , 3Supplement 2, (2001), 44 48, 1398-2273
Weis M. Kledal T. N. Lin K. Y. Panchal S. N. Gao S. Z. Valantine H. A. Mocarski E. S. Cooke J. P. 2004 Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis., 109 4(February 2004), 500 505, 0009-7322
Wenke K. Meiser B. Thiery J. Nagel D. von Scheidt. W. Krobot K. Steinbeck G. Seidel D. Reichart B. 2003 Simvastatin initiated early after heart transplantation: 8-year prospective experience., 107 1(January 2003), 93 97, 0009-7322
Yamasaki M. Sakurai R. Hirohata A. Honda Y. Bonneau H. N. Luikart H. Yock P. G. Fitzgerald P. J. Yeung A. C. Valantine H. A. Fearon W. F. 2011 Impact of donor-transmitted atherosclerosis on early cardiac allograft vasculopathy: new findings by three-dimensional intravascular ultrasound analysis. , 91 12(June 2011), 1406 1411, 0041-1337