Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy

INTRODUCTION — Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. The major limitations to survival in the early post-transplant period (first six months) are nonspecific graft 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. (See "Heart transplantation in adults: Prognosis", section on 'Causes of death'.)

Ischemic consequences of CAV include graft failure, arrhythmias, and sudden death. CAV may cause myocardial infarction, but because of cardiac denervation, it only rarely causes angina pectoris.

The epidemiology, approach, and outcomes of the diagnosis of transplant vasculopathy will be reviewed here. The pathogenesis, risk factors for, prevention, and treatment of transplant vasculopathy are discussed separately. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors" and "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

DEFINITIONS AND TERMINOLOGY — The prevalence and prognosis of CAV after cardiac transplantation vary considerably depending on how vasculopathy is defined and which method is used to detect it. Some studies have defined CAV as coronary artery stenosis ranging from 30 to 70 percent by coronary angiography. Other studies have diagnosed CAV using the much more sensitive technique of intravascular ultrasound.

To resolve the problem of disparate definitions of CAV, guidelines for terminology related to CAV were published by the International Society for Heart and Lung Transplantation in 2010 [2]. A grading system based on conventional invasive coronary angiographic findings and graft function (evaluated by echocardiography or invasive hemodynamic data) was established (table 1).

EPIDEMIOLOGY — In the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry report on data from more than 135,000 heart transplant recipients, the overall prevalence of CAV in survivors at 1, 5, and 10 years after transplantation was 8, 29, and 47 percent, respectively [1]. The incidence of CAV has decreased slightly, but significantly, over time [3], and the importance of CAV as cause of death late after transplantation has decreased over the last decade [1]. In the ISHLT registry, important predictors of development of CAV were older donor age, a donor history of hypertension, younger recipient age, greater numbers of HLA-DR mismatches, and recipient pretransplant diagnosis of ischemic heart disease.

Additional data come from an analysis of donor factors predicting CAV in 39,704 heart transplant recipients from the United Network for Organ Sharing (UNOS) [3]. The prevalence of CAV at five years was somewhat lower than in the ISHLT registry at 23 percent. In the UNOS population, donor factors including older age, a history of hypertension, male sex, being a White person, tobacco use, diabetes, and weight ≥85 kg predicted early development of vasculopathy.

However, the studies mentioned above do not address the severity of CAV. The frequency of clinically important disease was examined in a multicenter analysis of CAV performed by the Cardiac Transplant Research Database, which evaluated 4637 angiograms in 2609 patients transplanted between 1990 and 1995 [4]. At five years, some angiographic evidence of coronary disease was present in 42 percent of patients. However, only 7 percent had severe coronary disease, which was defined as left main coronary artery stenosis >70 percent, stenosis of two or more primary coronary arteries >70 percent, or branch stenosis in all three systems >70 percent.

CAV typically progresses slowly. However, patients occasionally progress rapidly and unpredictably [5-9]. In a matter of months, the angiographic picture can change from a relatively benign appearance to a diffuse, occlusive pattern (image 1). Such rapid progression can be associated with the occurrence of late antibody-mediated rejection (see "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'). A lower incidence of CAV (22 percent) has been observed in patients who survive more than 10 years, suggesting that late onset CAV is infrequent [10], although this conclusion is controversial.

CLINICAL MANIFESTATIONS

Symptoms and signs — Early detection of CAV is challenging because symptoms of myocardial ischemia secondary to CAV are typically absent or atypical due to afferent and efferent allograft denervation [11]. Although there is evidence for reinnervation in some patients by five years after transplantation, the degree of reinnervation is generally incomplete [12,13]. As a result, patients with CAV seldom experience classic angina pectoris. Premonitory symptoms associated with exertion such as chest pain, dyspnea, diaphoresis, gastrointestinal distress, presyncope, or syncope are often missing or atypical, so symptoms do not provide a reliable warning of disease [14]. This was illustrated by a study of 22 cardiac transplant recipients with 25 acute myocardial infarctions at a mean of 3.9 years after transplantation [14]. The most common symptoms were weakness (16), dyspnea (11), and palpitations (eight); only two patients had chest pain, three patients had arm pain, and three patients had no symptoms.

Since early symptoms may be subtle or absent, symptoms and signs of progressive heart failure due to allograft dysfunction, silent myocardial infarction detected on testing (as discussed below), or sudden death are common initial clinical presentations of CAV. CAV may also present with asymptomatic changes in allograft function detected on routine imaging studies (eg, echocardiography) or right heart catheterization.

Thus, if outcomes are to be improved by early diagnosis, CAV must be detected by screening studies rather than by waiting for the onset of symptoms.

Test findings

Electrocardiogram — As noted above, CAV may present with silent myocardial infarction detected on electrocardiogram or cardiac imaging (eg, regional wall motion abnormalities on echocardiogram). However, the electrocardiogram is usually of limited value in assessing myocardial ischemia in cardiac transplant recipients given the high prevalence of electrocardiographic abnormalities in this population, including Q waves, ST elevation or depression, and T wave inversions [15].

Cardiac imaging — The use of coronary angiography, intravascular ultrasound, and stress testing in diagnosis of CAV is described below. (See 'Approach to diagnosis' below.)

The use of echocardiography and other cardiac imaging in evaluation of patients with CAV is described below. (See 'Evaluation after diagnosis of CAV' below.)

DIAGNOSIS AND EVALUATION

Approach to diagnosis — CAV may be diagnosed as a result of routine screening or when evaluating a change in clinical status, such as the development of allograft dysfunction not explained by rejection.

●Surveillance − All heart transplant recipients should have routine screening for CAV since interventions may improve prognosis. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

•During the first five years following cardiac transplantation, the following screening is recommended:

-For cardiac transplant recipients with preserved kidney function (eg, estimated glomerular filtration rate [eGFR] ≥30 to 40 mL/min/1.73 m²), surveillance for CAV is performed by coronary angiography every one to two years.

-For cardiac transplant recipients with significant kidney disease (eg, eGFR <30 to 40 mL/min/1.73 m²), we suggest annual dobutamine stress echocardiography as a means of reducing exposure to the risk of contrast nephropathy associated with invasive coronary angiography. (See 'Stress testing' below.)

•After the first five years, the following is recommended:

-For low-risk cardiac transplant recipients (ie, those with normal coronary angiography at five years), we suggest annual dobutamine stress echocardiography or another noninvasive screening modality, such as myocardial rubidium positron emission tomography (PET) imaging or computed tomography (CT) coronary angiography.

-For cardiac transplant recipients with evidence of CAV on coronary angiography, annual surveillance with coronary angiography should be continued if renal function permits.

•A patient with an abnormal stress test (dobutamine stress echocardiogram or stress radionuclide myocardial perfusion imaging) should undergo evaluation with invasive coronary angiography, renal function permitting.

●Change in clinical status − In addition, coronary angiography to detect CAV is indicated in cardiac transplant recipients presenting with a change in clinical status, such as development of graft (left ventricular) dysfunction not explained by acute rejection. Coronary angiography is also indicated in cardiac transplant recipients presenting with symptoms suggesting angina, although such symptoms are infrequent due to cardiac denervation.

Intravascular ultrasound (IVUS) is suggested when angiographic findings seem insufficient to explain graft dysfunction or anginal symptoms. Due to the concentric nature of the stenoses associated with transplant vasculopathy, coronary angiography can severely underestimate the presence and burden of this process. IVUS and coronary flow reserve (CFR) measurements overcome this limitation of routine coronary angiography. (See 'Intravascular ultrasound' below and 'Coronary flow reserve' below.)

Coronary angiography — As advocated in the 2010 International Society for Heart and Lung Transplantation (ISHLT) consensus statement, invasive coronary angiography is the standard method for surveillance and monitoring of transplant vasculopathy [2,16] and is used in most transplant centers, though it lacks sensitivity for early stage CAV [17]. Baseline coronary angiography is commonly performed a few weeks after transplantation, unless the donor underwent catheterization as part of the evaluation of the suitability of the organ, and at most centers it is performed annually or biannually starting at one year postoperatively. Noninvasive studies have not proven to be sufficiently sensitive to replace coronary angiography in the early years after cardiac transplantation, although they may serve a useful adjunctive role in detecting myocardial ischemia [18].

Coronary angiography enables identification of coronary luminal narrowing and lesion type, as well as assessment of the rate of contrast filling of the coronary arteries. A standardized description of lesion type was developed and subsequently adopted generally (figure 1) [19]. The description is useful for communicating angiography results in heart transplant recipients, but the classification has not been shown to be of prognostic value. The rate of contrast filling of the coronary arteries provides an important clue for detecting small vessel and distal disease, although methods to quantitate filling rate are somewhat subjective. (See 'TIMI frame count' below.)

Although coronary angiography is the clinical gold standard for the diagnosis of nontransplant coronary artery disease, it is less sensitive in detecting transplant vasculopathy, as acknowledged in the ISHLT consensus document [2,6,9,20,21]. The lower sensitivity of angiography for CAV is due to the often diffuse, longitudinal, and concentric nature of the disease, as opposed to the focal and eccentric pattern of nontransplant atherosclerosis (figure 2). As a result, many patients who develop clinical events that are presumably due to transplant vasculopathy do not have angiographically significant disease [22,23]. Since transplant vasculopathy is a diffuse process, angiographic diagnosis of CAV is often more difficult than for nontransplant coronary atherosclerotic lesions and interobserver variation of angiographic diagnoses of coronary vasculopathy is large [24]. Angiograms performed to screen for allograft vasculopathy should be reviewed by investigators with particular experience in the field.

Although coronary angiography has relatively low sensitivity for CAV, the presence of angiographic disease has been shown to be prognostically significant. For example, a study of 91 patients found that absence of angiographic coronary disease was a significant predictor of survival without adverse cardiac events at two years [25].

The role of preventive therapy in patients at risk for contrast nephropathy (particularly diabetic patients with renal dysfunction) is discussed separately. (See "Prevention of contrast-associated acute kidney injury related to angiography".)

Intravascular ultrasound — IVUS is suggested when angiographic findings seem insufficient to explain left ventricular dysfunction. IVUS is helpful to confirm the diagnosis of CAV, but its use is limited by technical issues, risk of complications, limited availability of expertise, and cost. IVUS with or without quantitative coronary angiography has been adopted by several cardiac transplant centers as the diagnostic approach of choice [26,27].

In clinical practice (outside of a research setting), IVUS is used mainly in two settings:

●Some centers perform an IVUS exam early after transplantation (typically at the one-year mark) and risk stratify patients based on the findings. Other centers perform IVUS both a few weeks after transplantation and after one year, thus enabling discrimination between donor-transmitted disease and true transplant vasculopathy.

●IVUS is performed in patients with graft failure, when endomyocardial biopsy lacks clear signs of rejection and conventional angiography does not show evidence of CAV. In these cases, demonstration of significant intimal thickening on IVUS is required to confirm a diagnosis of CAV.

Clear consensus on the diagnostic criteria for CAV using IVUS has not been reached, and several measures of changes to the coronary vessel wall (maximal intimal thickness, percent atheroma volume, total atheroma volume) can be obtained by IVUS [2]. However, most apply the criterion used in clinical trials, which is an increase in maximal intimal thickness ≥0.5 mm in the left ascending anterior (LAD) branch from the time of transplantation to one year after transplantation [28]. If the patient is examined later or no baseline exam has been performed, detection of a maximal intimal thickness ≥0.5 mm in LAD would be considered diagnostic of CAV.

In experienced hands, the risk associated with IVUS in transplant recipients is low [29]. This risk of complications with multivessel IVUS has been reported as 1.6 percent [30]. In addition, the exam is time consuming and adds significantly to cost. Consequently, as noted in the ISHLT consensus statement, IVUS is not recommended for routine surveillance outside of clinical trials [2]. In addition to its value in research, IVUS may be of clinical value in identifying the cause of unexplained graft failure (ie, ventricular dysfunction in the absence of rejection) in selected patients with normal coronary arteriography.

Since the intimal and medial layers of the arterial wall have differing acoustic densities, IVUS can distinguish these layers and thereby detect abnormal thickening of the intima. IVUS detects intimal thickening in more than 80 percent of patients as early as one year after transplantation [31-33]. The most rapid rate of intimal thickening occurs in the first year after transplantation, followed by a slower rate of thickening [27]. Since CAV is frequently diffuse and circumferential, many patients with moderate to severe intimal thickening on IVUS, including those who develop clinical events, do not have significant visible disease on coronary angiography (movie 1A-B) [21-23].

In proximal segments of the coronary arteries, the intimal thickening is primarily focal and eccentric, similar to the pattern seen in native coronary artery disease [32,33]. By comparison, intimal thickening in mid and distal segments is more commonly diffuse and circumferential. This suggests at least two etiologies for the vascular lesions: proximal disease that may be donor-transmitted and distal disease that may be the result of acquired immune-mediated vessel injury exacerbated by significant metabolic perturbations that occur after transplant [31,33]. The only possible way to distinguish between donor transmitted disease and de-novo allograft vasculopathy is by performing serial IVUS studies starting with a baseline measurement early postoperatively [34].

Abnormalities detected by IVUS are predictive of cardiac events and death as illustrated by the following observations:

●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 [23].

●IVUS evidence of progression of CAV during the first year after transplantation is a predictor of adverse events as illustrated by the following studies:

•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 [28]. 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 [22]. 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 end point of death or myocardial infarction (51 versus 16 percent), as well as angiographic disease (22 and 2 percent).

These observations confirm the utility of IVUS assessment of CAV and as a prognostic indicator in cardiac transplant recipients. IVUS has been used as a surrogate end point in clinical trials of new immunosuppressive and other agents known to affect intimal proliferation.

Stress testing — Stress testing (predominantly dobutamine stress echocardiography) is used to screen cardiac transplant recipients with significant kidney disease (eg, eGFR <30 to 40 mL/min/1.73 m²) at risk for developing contrast nephropathy with coronary angiography. In addition, selected low-risk patients (ie, those with normal angiography and/or IVUS at five years) are followed noninvasively by stress testing (predominantly dobutamine stress echocardiography) in some programs. If the noninvasive evaluation is abnormal, patients require evaluation by invasive coronary angiography.

Dobutamine stress echocardiography is a well-validated noninvasive technique correlating with prognosis in cardiac transplant recipients [35-37]. Conventional electrocardiogram (ECG) stress testing is of little value in heart transplant recipients, since resting ECG abnormalities are frequently present. The value of dobutamine stress echocardiography (DSE) was illustrated in a study of 109 transplant recipients in whom yearly DSE was performed at the time of angiography and IVUS [37]. Index DSE (2D and M-mode) had a sensitivity of 85 percent and a specificity of 85 percent for CAV, using combined angiography and IVUS as the gold standard. Furthermore, there were no events in the patients with negative 2D and M-mode dobutamine stress studies, suggesting an excellent negative predictive value. Consequently, DSE has gained popularity and is a recommended screening procedure for CAV. However, subsequent studies found that DSE has limited diagnostic value for CAV (eg, 7 percent sensitivity, 82 percent positive predictive value, and 41 percent negative value for any CAV in a study of 497 transplant recipients [38]), and it has become evident that DSE results must be interpreted with caution [17,38].

Dobutamine stress testing appears to be generally safe in cardiac transplant recipients [39], although responses to stress may be altered. The presence of cardiac sensory denervation in heart transplants can affect the symptoms associated with ischemia, the occurrence of arrhythmia, and the potential for hypotension associated with dobutamine. Patients suspected of having severe transplant vasculopathy should likely be referred directly for coronary angiography. Coronary arteriography should be performed promptly in patients with symptoms suggestive of transplant vasculopathy, even if dobutamine stress echocardiogram results are normal.

For patients who have nondiagnostic echocardiographic images, stress radionuclide myocardial perfusion imaging (eg, single photon emission computed tomography scintigraphy [SPECT], PET) is an alternative approach to screening for allograft vasculopathy [40-44]. The potential role of other noninvasive approaches, such as CT, is discussed below. (See 'Investigational diagnostic methods' below.)

Evaluation after diagnosis of CAV — Once CAV is diagnosed, monitoring of graft function using echocardiography is indicated, and annual angiogram should be performed to evaluate if lesions amenable to percutaneous coronary intervention have developed or if the disease has progressed to a state where retransplantation might be considered. (See "Heart transplantation in adults: Indications and contraindications", section on 'Indications for retransplantation'.)

Investigational diagnostic methods — Given the limitations of coronary angiography (including limited sensitivity and risk of complications associated with its invasive nature and need for exogenous contrast agent), other diagnostic methods have been evaluated to improve the diagnosis and evaluation of CAV.

Investigational invasive approaches

Coronary flow reserve — While CFR (measured as fractional flow reserve) is used to determine whether treatment is indicated for an isolated coronary stenoses in transplant vasculopathy, as in native coronary disease, CFR is not used routinely in cardiac transplant recipients. An intracoronary wire tipped with a Doppler ultrasound transducer can measure the velocity of coronary artery blood flow as well as CFR, which is the increase in coronary blood flow in response to a vasodilator such as adenosine. Measurement of coronary artery flow reserve may provide additional information about the presence and severity of transplant vasculopathy [45]. Patients with vasculopathy are more likely to have reduced coronary artery flow reserve compared with those without evidence of vasculopathy [46]. (See "Clinical use of coronary artery pressure flow measurements".)

TIMI frame count — This technique is used frequently by angiographers as a visual screen for CAV. The TIMI frame count, which is the number of cine frames required for dye to reach standardized distal coronary landmarks during coronary angiography, is a simple and reproducible method for identifying a decrease in rate of coronary blood flow on routine angiograms. Worsening microvascular function signified by increasing TIMI frame count may or may not correlate with progression of epicardial disease. In a study of 42 cardiac transplant recipients followed for five years, an increase in the TIMI frame count was observed in those who developed angiographic evidence of transplant atherosclerosis [47]. On the other hand, a later study of 52 patients followed for a mean of 4.3 years found no correlation between TIMI frame count and progression of CAV by IVUS [48]. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction", section on 'Primary failure'.)

The TIMI frame count appears to also have prognostic value. Increasing global TIMI frame count (the mean TIMI frame count for the three coronary arteries) from baseline to one year was associated with increased mortality rate during mean 4.3-year follow-up [48]. The potential prognostic value of CFR in transplant recipients remains to be determined.

Optical coherence tomography — Optical coherence tomography (OCT) may supplement or replace IVUS in some patients, especially if differentiation between donor-transmitted disease and transplant vasculopathy is important [49]. A greater understanding of CAV has emerged from studies using OCT angiography, allowing for high-resolution evaluation of the coronary artery wall structure and composition. It appears to be particularly well suited to detect very early CAV and to evaluate plaque stability in these patients. More research is needed before a definite role for OCT in cardiac transplantation can be defined [50,51].

Endomyocardial biopsy — Many patients with evidence of CAV in the epicardial coronary arteries also have significant alterations in the microvasculature in routine endomyocardial biopsies obtained as part of allograft rejection surveillance (picture 1) [52-54]. Identification of microvascular CAV is not relied on in routine clinical practice but gives supplementary information when evaluating patients for CAV, especially those with new graft dysfunction or arrhythmia. In these patients, an endomyocardial biopsy is obtained to detect acute cellular rejection, and hence information on CAV as a possible cause (when acute cellular rejection is ruled out) can be obtained "for free" using the biopsy specimen. However, the sensitivity of a histopathologic diagnosis of allograft vasculopathy using angiography or IVUS as a gold standard is low, probably because of the low probability of biopsies containing microvasculature.

When documented, microvasculopathy may have prognostic importance. In a report from a single-center study, stenosis of the coronary microvasculature was evaluated on histologic examination of routine post-transplant endomyocardial biopsy specimens [55]. In biopsies harvested from 873 patients during the first post-transplantation year, stenotic microvasculopathy was detected in 43 percent of biopsies and was predominantly due to medial disease. Stenotic microvasculopathy was associated with reduced overall survival (10.9 versus 13.4 years) and decreased freedom from fatal cardiac events (96 versus 99 percent, 87 versus 97 percent, and 76 versus 90 percent at 1, 5, and 10 years, respectively).

In this study, the occurrence of microvasculopathy was independent of the existence of epicardial transplant vasculopathy. However, patients with microvasculopathy detected at 271 to 365 days post-transplantation were at increased risk of later developing stenotic three-vessel epicardial disease (odds ratio 3.28). It has been postulated that microvasculopathy may represent a sensitive marker for the risk of developing transplant vasculopathy, and thus is a potential surrogate end point in future prevention trials [55]. Further study is needed to define the potential prognostic value of microvasculopathy and the potential role of microvasculopathy detection in disease management has not been defined.

Investigational noninvasive approaches

CT coronary angiography — Use of multislice CT coronary angiography (CCTA) to potentially replace invasive cardiac catheterization is an area of active investigation. CCTA is an attractive potential screening tool because it allows for direct visualization of the coronary arteries with less associated patient discomfort, risk, and cost than conventional angiography. It is used in patients with preserved renal function but in whom conventional angiography is considered high risk, for instance due to peripheral vascular disease, and who are poor candidates for stress echocardiography, for instance because of low image quality. Guidelines do not recommend CCTA as a standard noninvasive tool for routine monitoring allograft vasculopathy, but with technical developments improving image quality and reducing radiation and dye requirements, CCTA will likely be used in selected patients in the future.

A summary of study results thus far is provided in a table (table 2) [56-65]. The reported sensitivity of CCTA for CAV has improved with improving CT technology, ranging from 85 to 100 percent at the patient level in various studies. A meta-analysis reported that sensitivity and specificity of 64-slice CCTA (n = 241 patients) using coronary angiography as a gold standard was 97 and 92 percent, respectively [66]. Detection of distal and small vessel disease using CCTA remains an issue to some extent. In addition, a proportion of patients have been excluded from the studies because of poor image quality, tachycardia, or renal insufficiency. While most studies have reported a high negative-predictive value, the relation of CCTA findings to long-term prognosis is unclear.

Although multislice CCTA is noninvasive, it adds to the burden of radiation already imposed on heart transplant recipients by repeated biopsies requiring fluoroscopy. CCTA also requires use of significantly greater amounts of iodine containing dye than conventional angiography, thus increasing the risk of nephrotoxicity.

Current guidelines do not recommend CCTA as a standard noninvasive tool for routine monitoring of allograft vasculopathy, but as technical developments improve image quality and reduce radiation and dye requirements, CCTA may become the screening method of choice. (See "Cardiac imaging with computed tomography and magnetic resonance in the adult".)

Cardiovascular magnetic resonance — The diagnostic value of cardiovascular magnetic resonance (CMR) to detect CAV is under investigation but is not used in clinical practice. CMR abnormalities that may correlate with CAV include depressed myocardial perfusion reserve and late gadolinium enhancement (for detection of myocardial scar or coronary vessel wall) [67-69].

Positron emission tomography — This method is gaining greater popularity due to its noninvasive nature and is used in patients who are poor candidates for stress echocardiography due to intolerance of dobutamine or poor acoustic windows and in patients with renal dysfunction making modalities requiring dye less attractive. The diagnostic and prognostic value of PET in patients at risk for CAV is under investigation. The prognostic value of PET was illustrated by a single study of 140 cardiac transplant recipients undergoing dipyridamole rubidium-82 PET [70]. PET abnormalities were predictors of adverse events (including death, acute coronary syndrome, and heart failure hospitalization). Studies have confirmed that rubidium-82 PET estimation of myocardial flow reserve is associated with CAV severity and correlated with cardiovascular events after heart transplantation, supporting clinical use in patients in whom invasive angiography is not desirable [71,72].

Biomarkers — Multiple biomarkers measured in peripheral blood have been evaluated as screening tools for allograft vasculopathy, but none are relied on for use in clinical practice. Markers such as C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and von Willebrand factor (vWF) are each predictive of all-cause death [73,74]. Although neither CRP nor NT-proBNP were predictive of CAV, patients with high levels of both had elevated risk of CAV [73]. Elevated levels of vWF also predict CAV [74]. Further study is needed to define the potential role of these markers for identifying CAV.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis in patients with graft dysfunction (which may be initially manifest as low ejection fraction, arrhythmias, or heart failure symptoms) developing weeks to years after transplantation includes CAV, acute cellular or humoral rejection, and nonspecific graft dysfunction. Time from transplantation determines the likelihood of rejection or CAV being responsible for graft dysfunction, with CAV more common later after transplantation. A diagnosis of rejection is typically made by endomyocardial biopsy. (See "Heart transplantation in adults: Graft dysfunction".)

As noted above, CAV is typically diagnosed by coronary angiography. In cardiac transplant patients with evidence of disease on coronary angiography, the differential diagnosis of CAV includes atherosclerotic coronary artery disease (CAD). CAD is typically focal and eccentric and is associated with late calcification while CAV is typically diffuse and circumferential, although focal eccentric lesions can occur. Some patients have both CAV and CAD, and pre-existing CAD lesions may be remodeled by allograft immune responses [75]. Coronary artery spasm may mimic angiographic diffuse vessel narrowing caused by CAV and can lead to an erroneous diagnosis of CAV. If spasm is suspected, 200 microgram intracoronary nitroglycerin will usually resolve it. (See 'Coronary angiography' above.)

PROGNOSIS — Advancing CAV ultimately results in heart failure and death due to ventricular dysfunction or arrhythmias. In some patients, sudden death may be the first symptom of CAV. Sudden death in transplant recipients with CAV can occur even in patients who have functioning implantable defibrillators in place, and mechanisms other than ventricular arrhythmias may be responsible for sudden cardiac death in this population, most likely rapidly-developing pump failure with electromechanical dissociation [76]. There is a paucity of data on the risk of developing graft failure and ventricular arrhythmias in patients with angiographic evidence of CAV.

Angiographically significant CAV is associated with a high mortality rate [4,77], and the degree of CAV, as assessed by the ISHLT grading system (table 1), is correlated with graft survival [78]. In the above cited Cardiac Transplant Research Database study of 2609 patients transplanted between 1990 and 1995, death or retransplantation due to coronary disease occurred at five years in 7 percent overall, but occurred in two-thirds of those with severe coronary disease (defined as left main stenosis >70 percent, two or more primary vessels stenoses >70 percent, or branch stenoses >70 percent in all three systems). In an older report of 54 patients with at least 40 percent stenosis in one or more coronary arteries, overall survival was 67, 44, and 17 percent at one, two, and five years [77]. Survival varied with disease severity, being worst in patients with three-vessel disease (13 percent at two years).

The 2014 International Society for Heart and Lung Transplantation (ISHLT) Registry report noted that allograft CAV and late graft failure (likely due to CAV) were responsible for 32 percent of all deaths five years after transplantation [1]. This proportion remained fairly constant when mortality rates were assessed at 5 to 10 and >10 years after transplant. There appears to have been some improvement over time in the prognosis of patients with CAV. In the 2014 ISHLT report, a significant improvement was seen in survival of patients with CAV when comparing patients who were transplanted between 1994 and 2002 with those transplanted between 2003 and 2012 [79]. (See "Heart transplantation in adults: Prognosis", section on 'Causes of death'.)

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SUMMARY AND RECOMMENDATIONS

●Surveillance for CAV after transplant – Serial monitoring for the detection of cardiac allograft vasculopathy (CAV) is recommended, since CAV limits long-term survival in cardiac transplant recipients and because medical and interventional therapies may be effective. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)

•Within five years of transplantation – During the first five years following cardiac transplantation, the following is recommended:

-For cardiac transplant recipients with preserved kidney function (eg, estimated glomerular filtration rate [eGFR] ≥30 to 40 mL/min/1.73 m²), we recommend routine annual invasive coronary angiography. (See 'Coronary angiography' above.)

-For cardiac transplant recipients with significant kidney disease (eg, eGFR <30 to 40 mL/min/1.73 m²), we suggest annual dobutamine stress echocardiography (early or late after transplantation) as a means of reducing exposure to the risk of contrast nephropathy associated with invasive coronary angiography. (See 'Stress testing' above.)

•After the first five years of transplantation – After the first five years, the following is recommended:

-For low-risk cardiac transplant recipients (ie, those with normal coronary angiography at five years), we suggest annual dobutamine stress echocardiography or another noninvasive screening test after the first five years of invasive monitoring. (See 'Stress testing' above.)

-For patients with evidence of CAV on coronary angiography, annual surveillance with coronary angiography should be continued if renal function permits.

●Testing for suspected CAV – The following tests are used to evaluate patients with cardiac allograft dysfunction:

•Coronary angiography – For patients with cardiac allograft dysfunction that is not explained by transplant rejection, we suggest invasive coronary angiography. Invasive coronary arteriography should be performed promptly in patients with symptoms suggestive of transplant vasculopathy, even if dobutamine stress echocardiogram or other noninvasive work-up is negative. (See 'Coronary angiography' above.)

Intravascular ultrasound or coronary flow reserve measurements are suggested when angiographic findings seem insufficient to explain left ventricular dysfunction or anginal symptoms. (See 'Coronary flow reserve' above and 'Intravascular ultrasound' above.)

Due to the concentric nature of the stenoses associated with transplant vasculopathy, coronary angiography can severely underestimate the presence and burden of this process. Intravascular ultrasound overcomes this limitation of routine coronary angiography. (See 'Intravascular ultrasound' above.)

●Cardiovascular computed tomography – Use of multislice computed tomography coronary angiography to potentially replace invasive cardiac catheterization in evaluating CAV is an area of active investigation. (See 'CT coronary angiography' above.)

●Endomyocardial biopsy – The clinical utility of screening endomyocardial biopsy specimens for microvasculopathy has not yet been defined. (See 'Endomyocardial biopsy' above.)