INTRODUCTION —
Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. The major limitations to survival in the early posttransplant period (first year) are nonspecific graft failure, multiorgan failure, acute rejection, and infection [1]. Beyond the first year, cardiac allograft vasculopathy (CAV; also called transplant coronary artery disease or cardiac transplant vasculopathy) is among the top three causes of death [2]. (See "Heart transplantation in adults: Prognosis", section on 'Causes of death'.)
The pathogenesis, risk factors, surveillance, and diagnosis of CAV will be reviewed here.
The prevention and treatment of this disease are discussed separately. (See "Heart transplantation: Prevention and treatment of cardiac allograft vasculopathy".)
PATHOLOGY —
CAV is a disease that diffusely affects the allograft coronary arteries and is characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries (figure 1) and concentric medial disease in the microvasculature [3-8]. Coronary angioscopy has demonstrated heterogeneous intimal lesions [9]. CAV is also associated with intracoronary mural and occlusive thrombi, which can cause acute myocardial infarction [10,11].
The development of CAV involves both the cellular and humoral arms of the immune system. Immunologic mechanisms that result in the initiation and maintenance of cellular rejection correlate with the development of CAV. These factors include human leukocyte antigen mismatching, T cell activation, endothelial cell activation, and altered cytokine expression. Investigations suggest that donor-specific antibodies and antibody-mediated rejection are also major contributors to CAV [12].
Transplant recipients also frequently develop proximal coronary artery disease. However, these lesions more closely resemble traditional atherosclerosis pathologically and probably evolve from preexisting disease in the donor heart that is accelerated by the plethora of cardiac risk factors after transplantation [5].
EPIDEMIOLOGY
Prevalence — The prevalence of CAV at 1, 5, and 10 years after transplantation was 8, 29, and 47 percent, respectively [13]. Another study reported a five-year prevalence of 23 percent [14]. The prevalence of severe disease may be lower. In an older study, there was angiographic evidence of CAV in 42 percent of patients at five years after transplantation; however, only 7 percent of these patients had severe disease [15].
Progression — CAV is generally thought to be a slowly progressive disease, though some patients exhibit rapid progression (image 1) [3,16-19]. Serial intravascular (intracoronary) ultrasound testing has shown that most of the intimal thickening occurs during the first year after transplantation [20].
Immunologic risk factors — Immunologic factors have the strongest association with the incidence of CAV and include:
●HLA mismatch and antibody-mediated rejection – Several studies have shown that human leukocyte antigen (HLA) mismatching increases the risk of CAV [3,4]. Development of de novo donor-specific anti-HLA Class I or II antibodies after transplant has been associated with CAV [21]. For example, cardiac transplant recipients who developed anti-HLA antibodies had a lower four-year survival rate than those who did not develop such antibodies (38 versus 90 percent) [22]. Whether specific HLA subtypes increase the risk of CAV is not well-defined [23-25].
Humoral activation, resulting in the production of anti-HLA and antiendothelial antibodies [22,26-29], enhances the development of CAV, and is associated with acute antibody-mediated rejection (also called humoral or vascular rejection) [26,28-31]. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)
●Acute cellular rejection – The number of episodes of moderate to severe cellular rejection appears to correlate with the development of CAV [3,32-35]. In addition, a summary of overall rejection, the total rejection score, has also been associated with CAV [36]. This observation is consistent with animal data that suggest that the immunogenicity of the graft is probably the most important stimulus to the development of vasculopathy [37]. However, some studies have not supported a relationship between severe forms of cellular rejection (eg, grade ≥2R) and vasculopathy [38].
Nonimmunologic factors — Nonimmunologic factors also contribute to the development of CAV and include:
●Recipient and donor age and sex – Age and sex in both the donor and recipient are predictors of CAV:
•Among donor characteristics, older age and male sex are associated with a higher risk of CAV [35,39,40]. In a study of 489 one-year heart transplant survivors who underwent 1435 coronary angiograms, the relative risk for CAV was 1.26 for every 10 years of donor age [35].
•Among recipient characteristics, younger age is associated with a higher risk of CAV [23,35,41].
●Hyperlipidemia – Lipid abnormalities are associated with the presence and severity of CAV [42-44]. Heart transplant recipients who receive statins have a lower risk of CAV [45]. Support for a direct role of hypercholesterolemia comes from a study in mice in which hypercholesterolemia increased the rates of neointima formation and vascular occlusion by a mechanism that depends upon smooth muscle cell accumulation [46]. (See "Heart transplantation: Prevention and treatment of cardiac allograft vasculopathy", section on 'Statins'.)
●Cytomegalovirus infection – Cytomegalovirus infection is associated with a higher incidence of CAV [47,48]. One or more of the following mechanisms may contribute:
•A direct endothelial assault, which results in the enhancement of vascular adhesiveness, activation of the coagulation cascade, and elaboration of cytokines.
•Adverse vascular remodeling with greater net lumen loss [49].
•Stimulation of cellular immune responses in the vasculature [50], perhaps via induced expression of major histocompatibility complex antigens on the endothelial cells [51].
●Hyperglycemia – Both impaired glycemic control and insulin resistance may play a role in the pathogenesis of CAV. As an example, an association has been noted between an elevated glycated hemoglobin concentration and the incidence and severity of CAV [52]. In a series of 66 patients with metabolic syndrome, high serum insulin or glucose concentrations were associated with a significantly lower likelihood of freedom from CAV (57 versus 82 percent in patients with normal values) and with reduced survival [53]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
In 98 consecutive heart transplant recipients, high C-reactive protein (CRP) and insulin resistance (defined as triglyceride to high-density lipoprotein ratio >3.0), were significantly associated with CAV identified by angiography. The combination of increased CRP and insulin resistance was synergistic and associated with a fourfold increased risk in developing CAV [54]. (See 'Other tests' below.)
●Donor or recipient history of coronary artery disease – Coronary artery disease in either the donor [39] or recipient [23,32] is associated with the risk of CAV. In one report, CAV at three years after transplantation was more common in hearts from donors with angiographic coronary disease and from older donors [53]. Although older donor age is one of the strongest predictors for CAV, donor age did not affect recipient survival or freedom from ischemic events at a mean follow-up of 3.8 years.
●Mechanism of donor death – Traumatic brain death (eg, gunshot wound, head trauma) and intracerebral hemorrhage in the donor are associated with an increased risk of late CAV and reduced survival in the recipient in some [55,56] but not all studies [40]. Systemic activation of matrix metalloproteinase (MMP)-2 and MMP-9 is associated with intracerebral hemorrhage and may contribute to progression of hemorrhagic stroke [56]. Although activation occurs before the heart is removed from such donors, endomyocardial biopsies obtained in the recipient at one week after transplantation show a marked increase in expression of both MMP-2 and MMP-9 [56].
●Early left ventricular dysfunction – In a review of 117 patients, multivariate analysis showed that mean lumen diameter loss at one year was inversely related to early left ventricular dysfunction as defined by fractional shortening on echocardiography performed within the first week after transplantation [40]. It was speculated that myocardial injury associated with brain death in the donor, myocardial preservation, and ischemia-reperfusion injury might lead to injury to coronary endothelium as well as the myocardium.
●Rare or uncertain factors – A number of other factors may importantly contribute to an increased risk of CAV and include [23,41]:
•Recipient obesity [41].
•Angiotensin converting enzyme (ACE) polymorphism may be associated with the development of CAV [57,58]. In a series of 80 heart transplant recipients, the DD genotype in the donors but not the recipients was associated with the development CAV [57]. This observation suggests the importance of tissue rather than circulating ACE. (See "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'ACE gene polymorphism'.)
•Longer graft ischemia time (the time between heart explant from the donor and implantation in the recipient) and the development of fibrosis [59].
•Increases in elastase activity [60], thrombospondin-1 (a matrix glycoprotein that inhibits angiogenesis and facilitates the smooth muscle proliferation that is characteristic of CAV) [61], and the expression of tissue factor and the vitronectin receptor [62].
•Hepatitis C virus seropositivity in the donor [63].
•Possibly hyperhomocysteinemia [64,65].
•Angiogenesis within the intima [66].
•Higher von Willebrand factor levels [67].
CLINICAL MANIFESTATIONS
Symptoms and signs — Common presentations of CAV include symptoms of heart failure, myocardial ischemia, arrhythmias, or sudden death. However, the symptoms of CAV, especially those caused by ischemia, often present in an atypical manner or are masked due to complete or partial denervation of the allograft [68-71].
The clinical manifestations of these syndromes are discussed separately:
●(See "Heart failure: Clinical manifestations and diagnosis in adults".)
●(See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
●(See "Overview of the acute management of tachyarrhythmias" and "Sinus node dysfunction: Clinical manifestations and diagnosis".)
Electrocardiogram — In the absence of grossly abnormal electrocardiographic (ECG) findings (eg, atrial fibrillation, heart block, ST-segment elevation) that suggest underlying ischemia or arrhythmia, there are no specific signs of CAV on ECG.
APPROACH TO EVALUATION
Suspected CAV — In general, patients who are not known to have CAV or who could have worsening CAV and present with allograft dysfunction without a clear cause should undergo specific testing for CAV. The clinical suspicion for CAV may be increased in the presence of risk factors for CAV or reduced in patients with other explanations for graft dysfunction. However, since CAV is highly prevalent, and the presence of other causes of graft injury (acute cellular or antibody-mediated rejection) does not exclude the presence of CAV, specific testing for CAV is often required despite the findings from other tests. The approach to testing for suspected CAV consists of the following:
●Initial testing – Initial testing for patients with suspected CAV typically includes troponin and B-type natriuretic peptide assays, ECG, chest radiography, and echocardiography. However, these tests are used to identify the severity of cardiac dysfunction (eg, pulmonary edema) and causes of cardiac dysfunction in such patients and cannot confirm the diagnosis of CAV, which requires dedicated imaging.
●Specific testing for CAV – In patients with signs of graft dysfunction (eg, heart failure, arrhythmias) or ischemia (eg, reduced systolic function) in whom CAV remains on the differential diagnosis, invasive coronary angiography is typically the test of choice for reliably excluding or confirming the presence of CAV. If invasive coronary arteriography does not confirm the presence of CAV and the suspicion for CAV is high, intravascular ultrasound (IVUS) or optical coherence tomography (OCT) can be performed to increase the likelihood of detecting CAV. (See 'Preferred tests' below.)
In patients with mild symptoms that are not clearly caused by graft dysfunction, it is reasonable to perform a noninvasive stress imaging test. (See 'Preferred tests' below.)
Surveillance in asymptomatic patients — In patients without signs or symptoms of CAV, the optimal timing and test for surveillance is uncertain. We test for CAV at the first anniversary of transplantation and then every two years or more thereafter. However, shorter intervals are also reasonable. For example, some centers test for CAV within 30 days of transplantation and as frequently as yearly thereafter.
The optimal test for surveillance is not well-defined but typically includes stress or anatomic imaging. In the absence of significant kidney dysfunction, invasive coronary angiography with or without IVUS is a reasonable test to choose. In patients with significant kidney dysfunction that increases the risk of nephrotoxicity with dye exposure or who prefer a noninvasive approach to surveillance, noninvasive testing with nuclear or echocardiographic imaging are reasonable approaches to surveillance. Among these modalities, nuclear imaging has greater sensitivity but results in radiation exposure.
In patients who choose a noninvasive imaging approach and who have a test result that suggests inducible ischemia or novel infarction (eg, ischemia, infarction), the next step in management is typically invasive coronary angiography.
There are no reliable biomarkers for the detection of asymptomatic CAV. (See 'Other tests' below.)
The International Society for Heart and Lung Transplantation suggests an approach of surveillance at the first year anniversary of transplantation and every one to two years thereafter [72].
The approach to surveillance for CAV is based on our experience, the frequently asymptomatic nature of CAV, and the notion that earlier detection may improve outcomes in individual patients. In patients in whom CAV is detected, the diagnosis may alter the immunosuppressive regimen, frequency of clinical follow-up, and prognosis. In general, CAV is difficult to prevent and treat, which limits the utility of surveillance testing. There are no prospective trials to suggest that surveillance results in reduced mortality and morbidity in this population. Further details on specific prevention and treatment options for CAV are discussed separately. (See "Heart transplantation: Prevention and treatment of cardiac allograft vasculopathy".)
Preferred tests — The approach to testing depends on the clinical scenario, as discussed above. (See 'Suspected CAV' above and 'Surveillance in asymptomatic patients' above.)
Features of the tests typically used for surveillance or evaluation of suspected CAV include:
●Invasive coronary angiography – Coronary angiography can identify coronary luminal narrowing of the epicardial vessels and decreased flow indicative of macro- or microvascular stenosis. However, it is less sensitive than IVUS due to its inability to reliably identify small changes in vessel diameter (figure 1) [38,73]. In addition, the invasive nature of the procedure and the need for radiocontrast limit its use as an annual or biannual surveillance test. The staging of CAV based on the degree of stenosis, location of stenosis, and severity of graft dysfunction has prognostic value, and another system for the standardized description of single lesions is available (figure 2) [74,75].
●Intravascular ultrasound – The advantage of IVUS is its ability to detect early changes in the vessel wall indicative of CAV and its ability to differentiate between CAV and donor atherosclerosis. The disadvantages of IVUS include its invasive nature and the need for radiocontrast. Since IVUS requires coronary angiography, the routine use of IVUS is limited by its invasive nature and the need for radiocontrast. IVUS requires the placement of an intracoronary ultrasound catheter by an experienced cardiologist and has the additional risks of coronary artery perforation and dissection (1.6 percent in one series) [76]. In addition, the experience required and cost of IVUS limit its broader use.
Since CAV is frequently diffuse and circumferential, IVUS has the ability to detect CAV that other tests lack (image 2) [38,73,77]. Abnormalities detected by IVUS are predictive of cardiac events and death as illustrated by the following:
•In an early study, the presence of severe intimal thickening (>0.5 mm) detected by IVUS predicted subsequent adverse cardiac events, which often occurred in patients with normal coronary angiograms [73].
•In a multicenter study of 125 patients, the change in maximal intimal thickness (MIT) from baseline to one year was compared at several matched sites in the same coronary artery [78]. An increase in MIT of ≥0.5 mm was present in 24 patients (19 percent). At five-year follow-up, these 24 patients had more frequent death or graft loss (20.8 versus 5.9 percent in those with an MIT increase <0.5 mm); nonfatal major adverse cardiac events, death, or graft loss (45.8 versus 16.8 percent); and newly occurring angiographic luminal irregularities (65.2 versus 32.6 percent).
•Similar findings were noted in a series of 143 patients in which MIT on IVUS was measured at baseline and one year; rapidly progressive vasculopathy was again defined as an increase in MIT of ≥0.5 mm [38]. Rapid progression by IVUS was noted in 54 patients (37 percent) at one year after transplant. At 5.9-year follow-up, patients with rapid progression at one year had significantly higher rates of mortality (26 versus 11 percent in those with an MIT increase of less than 0.5 mm), the combined endpoint of death or myocardial infarction (51 versus 16 percent), and angiographic disease (22 and 2 percent).
●Stress imaging – Among the tests for noninvasive evaluation of CAV, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have the highest diagnostic accuracy, while dobutamine stress echocardiography (DSE) has lower diagnostic accuracy.
•Stress perfusion imaging – Nuclear perfusion imaging with pharmacologic or exercise stress perfusion imaging with SPECT has reasonable sensitivity for the diagnosis of CAV but requires radiation exposure. Compared with treadmill exercise stress, the use of a vasodilator (eg, regadenoson) as the stressor is more likely to result in a diagnostic study; patients with heart transplantation often have lower-than-average fitness due to a multitude of factors that include cardiac denervation.
In two studies that compared SPECT with coronary angiography, the sensitivity ranged between 63 and 90 percent [79,80]. SPECT also has prognostic value [81].
•Positron emission tomography – PET perfusion is another method for evaluation of CAV that requires an exercise or pharmacologic stress and radiation exposure. Among tests for CAV, it has the unique ability to quantify regional myocardial blood flow. The high cost of PET scanning limits its broader use.
Studies suggest that PET estimation of myocardial flow reserve is associated with CAV severity and correlated with cardiovascular events after heart transplantation. A prospective study that evaluated the use of rubidium-82 PET early after transplantation to screen for CAV using IVUS as the gold-standard found a modest area under the receiver operating characteristic curve of 0.74 (95% CI 0.61-0.86) for PET measures (eg, stress myocardial blood flow) [82]. PET imaging also has prognostic value, including measurements from single studies and from serial studies [83-87].
•Dobutamine stress echocardiography – DSE is a reasonable noninvasive test for CAV surveillance in patients in whom minimizing exposure to radiation is a priority. Relative to other tests for CAV, it has lower sensitivity. Compared with treadmill exercise stress, the use of dobutamine as the stressor is more likely to result in a diagnostic study; patients with heart transplantation often have lower-than-average fitness due to a multitude of factors that include cardiac denervation. In patients with an abnormal DSE, the next step in management is typically invasive coronary angiography.
While many centers perform surveillance with DSE to reduce the exposure to radiation required with SPECT or PET imaging, the sensitivity of DSE for CAV is relatively low compared with other forms of imaging. In a meta-analysis of studies that included 749 patients, the pooled sensitivity of DSE to detect CAV identified by coronary angiography with or without IVUS was 60 percent (95% CI 33-82 percent), the specificity was 86 percent (95% CI 74-93 percent), and the area under the receiver operating characteristic curve was 0.73 (95% CI 0.72-0.75) [88]. In a study that compared DSE with a gold-standard of IVUS for the diagnosis of CAV, the sensitivity of DSE was 47 percent [89]. In the largest study in the meta-analysis (n = 497 transplant recipients), DSE had a sensitivity of 7 percent and specificity of 98 percent [90].
Other tests — Tests that are not commonly used for testing for CAV include:
●Coronary computed tomographic angiography (CCTA) – CCTA is not routinely used for surveillance of CAV and has a limited role in the assessment of known CAV. CCTA requires iodinated contrast, radiation exposure, and a relatively low heart rate that limits its use in patients with heart transplantation. Guidelines do not recommend CCTA as a standard noninvasive tool for routine monitoring of allograft vasculopathy [72].
The available data suggest that CCTA has reasonable diagnostic accuracy, though few patients have been studied. A meta-analysis reported that sensitivity and specificity of 64-slice CCTA (n = 241 patients) using coronary angiography as a gold standard were 97 and 92 percent, respectively [91]. The use of CT-derived estimates of myocardial perfusion improved the detection of CAV compared with CCTA without perfusion estimates [92].
●Cardiovascular magnetic resonance imaging – The diagnostic value of cardiovascular magnetic resonance (CMR) imaging to detect CAV remains uncertain. CMR abnormalities that may correlate with CAV include depressed myocardial perfusion reserve, late gadolinium enhancement (for detection of myocardial scar or coronary vessel wall), or T1 mapping [93-96].
●Biomarkers – Multiple biomarkers measured in peripheral blood have been evaluated as screening tools for allograft vasculopathy, but none reliably detect CAV. In particular, donor-derived cell-free deoxyribonucleic acid (DNA), which is used to identify acute cellular and antibody-mediated rejection, is not an accurate test for the identification of CAV [97,98]. Elevated levels of von Willebrand factor can be used to detect CAV, but are not routinely used in clinical practice [67].
C-reactive protein, N-terminal pro-B-type natriuretic peptide, and troponin assays do not reliably detect the presence of CAV [99].
●Coronary flow reserve (CFR) – CFR is not routinely used in cardiac transplant recipients to detect CAV, although CFR may provide additional information about the severity of transplant vasculopathy [100,101]. (See "Clinical use of coronary artery pressure flow measurements".)
●Optical coherence tomography – OCT may supplement or replace IVUS in some patients, especially if differentiation between donor-transmitted disease and transplant vasculopathy is important [102-104].
●Endomyocardial biopsy (EMB) – Identification of CAV on EMB is not a reliable method for detection of CAV; the microvasculature is rarely seen on EMB (picture 1) [8,105-107]. However, in patients with evidence of CAV on EMB samples, testing for CAV with angiography or imaging is reasonable. (See 'Preferred tests' above.)
DIAGNOSIS —
The clinical diagnosis of CAV can be established by invasive coronary angiography or by intravascular ultrasound (IVUS):
Coronary angiography criteria and grades — The clinical diagnosis of CAV via coronary angiography requires evidence of epicardial stenosis or decreased blood flow. Typically, the diagnosis is made quantitatively by assessment of epicardial stenosis severity or qualitatively based on estimates of reduced myocardial blood flow based on procession of afferent and efferent contrast flow during angiography (table 1) or the presence of characteristic lesions (figure 2).
In addition, stages of CAV require angiographic and functional assessment of the cardiac allograft and are defined by the International Society for Heart and Lung Transplantation (ISHLT) as (table 2) [75]:
●ISHLT CAV0 (Not significant) – No detectable angiographic lesion.
●ISHLT CAV1 (Mild) – Angiographic left main (LM) <50 percent, primary vessel with maximum lesion of <70 percent, or any branch stenosis <70 percent (including diffuse narrowing) without allograft dysfunction.
●ISHLT CAV2 (Moderate) – Angiographic LM <50 percent; single primary vessel ≥70 percent, or isolated branch stenosis ≥70 percent in branches of two systems, without allograft dysfunction.
●ISHLT CAV3 (Severe) – Angiographic LM ≥50 percent, two or more primary vessels stenosis ≥70 percent, isolated branch stenosis ≥70 percent in all three systems, ISHLT CAV1 or CAV2 with allograft dysfunction (defined as LVEF ≤45 percent usually in the presence of regional wall motion abnormalities), or evidence of significant restrictive physiology.
In this classification system, "primary vessel" refers to the proximal one-third of a major epicardial artery (eg, left anterior descending artery); "secondary branch vessel" refers to the distal third of any epicardial vessel or to stenosis of a septal, diagonal, or obtuse marginal artery; and "restriction" refers to symptomatic HF with echocardiographic or hemodynamic evidence of high filling pressures.
IVUS criteria — The diagnosis of CAV is established in patients with coronary artery lesions with increased circumferential intimal thickness with either:
●Increase in maximal intimal thickness ≥0.5 mm in an epicardial coronary artery [78]
●Detection of a maximal intimal thickness ≥0.5 mm in an epicardial coronary artery
This definition is based on definitions in trials. The stages of CAV are defined by coronary angiographic findings and allograft function, as noted above. (See 'Coronary angiography criteria and grades' above.)
DIFFERENTIAL DIAGNOSIS —
In patients with tests that support the diagnosis of CAV, graft atherosclerosis is the main entity on the differential diagnosis. Graft atherosclerosis can be differentiated from CAV by its appearance on intravascular ultrasound or optical coherence tomography imaging. (See 'Preferred tests' above and 'Other tests' above.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stress testing and cardiopulmonary exercise testing".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Nuclear heart testing (The Basics)" and "Patient education: Cardiac catheterization (The Basics)" and "Patient education: Heart transplant (The Basics)")
●Beyond the Basics topics (see "Patient education: Heart transplantation (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathology – Cardiac allograft vasculopathy (CAV) is a disease that diffusely affects the allograft coronary arteries and is characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries (figure 1) and concentric medial disease in the microvasculature. (See 'Pathology' above.)
●Epidemiology – CAV is a progressive disease that is present in more than 20 percent of patients within five years of transplantation. (See 'Prevalence' above and 'Progression' above.)
Risk factors for CAV include human leukocyte antigen (HLA) mismatch, frequent episodes of cellular or antibody-mediated rejection, cytomegalovirus, older donor age, donor hearts from males, and mechanism of death. (See 'Immunologic risk factors' above and 'Nonimmunologic factors' above.)
●Clinical manifestations
•Symptoms and signs – Common presentations of CAV include symptoms of heart failure, myocardial ischemia, arrhythmias, or sudden death. However, the symptoms of CAV, especially those caused by ischemia, often present in an atypical manner or are masked due to complete or partial denervation of the allograft. (See 'Symptoms and signs' above.)
•Electrocardiogram – In the absence of grossly abnormal ECG findings (eg, atrial fibrillation, heart block, ST-segment elevation) that suggest underlying ischemia or arrhythmia, there are no specific signs of CAV on ECG. (See 'Electrocardiogram' above.)
●Approach to evaluation
•Suspected CAV – In general, patients who are not known to have CAV or who could have worsening CAV and present with allograft dysfunction without a clear cause should undergo specific testing for CAV. The clinical suspicion for CAV may be increased in the presence of risk factors for CAV or reduced in patients with other explanations for graft dysfunction. However, since CAV is highly prevalent, and the presence of other causes of graft injury (acute cellular or antibody-mediated rejection) does not exclude the presence of CAV, specific testing for CAV is often required despite the findings from other tests. The approach to testing for suspected CAV consists of the following:
-Initial testing – Initial testing for patients with suspected CAV typically includes troponin and B-type natriuretic peptide assays, ECG, chest radiography, and echocardiography. However, these tests are used to identify the severity of cardiac dysfunction (eg, pulmonary edema) and causes of cardiac dysfunction in such patients and cannot confirm the diagnosis of CAV, which requires dedicated imaging.
-Specific testing for CAV – In patients with signs of graft dysfunction (eg, heart failure, arrhythmias) or ischemia (eg, reduced systolic function) in whom CAV remains on the differential diagnosis, invasive coronary angiography is typically the test of choice for reliably excluding or confirming the presence of CAV. If invasive coronary arteriography does not confirm the presence of CAV and the suspicion for CAV is high, intravascular ultrasound (IVUS) or optical coherence tomography (OCT) can be performed to increase the likelihood of detecting CAV. (See 'Preferred tests' above.)
In patients with mild symptoms that are not clearly caused by graft dysfunction, it is reasonable to perform a noninvasive stress imaging test. (See 'Preferred tests' above.)
●Surveillance in asymptomatic patients – In patients without signs or symptoms of CAV, the optimal timing and test for surveillance is uncertain. We test for CAV at the first anniversary of transplantation and then every two years or more thereafter. However, shorter intervals are also reasonable. For example, some centers test for CAV within 30 days of transplantation and as frequently as yearly thereafter.
The optimal test for surveillance is not well-defined but typically includes stress or anatomic imaging. In the absence of significant kidney dysfunction, invasive coronary angiography with or without IVUS is a reasonable test to choose. In patients with significant kidney dysfunction that increases the risk of nephrotoxicity with contrast exposure or who prefer a noninvasive approach to surveillance, noninvasive testing with nuclear or echocardiographic imaging are reasonable approaches to surveillance. Among these modalities, nuclear imaging has greater sensitivity but results in radiation exposure.
In patients who choose a noninvasive imaging approach and who have a test result that suggests inducible ischemia or novel infarction (eg, ischemia, infarction), the next step in management is typically invasive coronary angiography.
●Testing for CAV – The preferred tests for CAV are invasive coronary angiography with or without IVUS, nuclear perfusion scan (eg, single photon emission computed tomography [SPECT] or positron emission tomography [PET]), and dobutamine stress echocardiography (DSE). (See 'Preferred tests' above.)
Tests that are not commonly used to diagnose CAV include coronary computed tomographic angiography (CCTA), cardiovascular magnetic resonance (CMR), OCT, and serum biomarkers. (See 'Other tests' above.)
●Diagnosis – CAV can be diagnosed with coronary angiography or IVUS:
•Coronary angiography – The clinical diagnosis of CAV via coronary angiography requires evidence of epicardial stenosis or decreased blood flow. Typically, the diagnosis is made quantitatively by assessment of epicardial stenosis severity or qualitatively based on estimates of reduced myocardial blood flow based on procession of afferent and efferent contrast flow during angiography (table 1) or the presence of characteristic lesions (figure 2).
In addition, stages of CAV require angiographic and functional assessment of the cardiac allograft and are defined by the International Society for Heart and Lung Transplantation (ISHLT). (See 'Coronary angiography criteria and grades' above.)
•IVUS criteria— The diagnosis of CAV is established in patients with coronary artery lesions with increased circumferential intimal thickness, with either (see 'IVUS criteria' above):
-Increase in maximal intimal thickness ≥0.5 mm in an epicardial coronary artery
-Detection of a maximal intimal thickness ≥0.5 mm in an epicardial coronary artery