There has been a worldwide increase in implantation of cardiovascular devices, including cardiac implantable electronic devices (CIED), valve prostheses, left ventricular assist devices (LVAD), and vascular grafts. CIEDs, including pacemakers and implantable cardioverter defibrillators (ICDs) are the major devices installed. Almost one-half of the world’s cardiac device installation is performed in the United States.¹ Infection is a major complication after device installation, and, unfortunately, the increasing number of cardiac device procedures is exceeded by an even higher rate of increasing cases of device infection, mainly because of older age of the new device recipients with longer hospital stays and multiple comorbidities.^2,3 Approximately 20%-30% of patients with CIED require device extraction and reinstallation, mainly due to infection,⁴ which is a major societal and medical burden. Infection of a foreign body device is also associated with a high risk of mortality. It has been reported that 12-week all-cause mortality was 35% in patients with a confirmed cardiac device infection, especially for those with methicillin-resistant S. aureus infection.⁵ One-year mortality was reported as high as 17% in endovascular infection patients even after device removal.⁶ Thus, early and accurate diagnosis of cardiac device infection is critical for prompt clinical decision making, such as intravenous antibiotics alone or device removal in a timely manner before significant damage occurs. Diagnosis of cardiac device infection remains a challenge for current diagnostic radiology tools. For example, CT or MRI suffers from metal artifacts and findings are nonspecific for infection. Transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) is limited to identification of intracardiac infection, and not useful for extracardiac source of infection. Although radiolabeled autologous white blood cell (WBC) scintigraphy has been used for infection evaluation, its sensitivity for device infection is variable.^7,8 Thus, a scan with high sensitivity and accuracy is needed to facilitate the prompt and accurate diagnosis of cardiac device infection.

¹⁸F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a functional imaging tool that targets the body’s glucose utilization. Clinically it is mainly used for cancer staging, restaging, and posttreatment effect evaluation, as malignant cells have increased glucose uptake. On the other hand, preexisting inflammatory cells (macrophages, neutrophils, and lymphocytes) at an infection site also overexpress glucose transporters and could accumulate FDG. Bacteria at the infection site also rely on glucose as an energy source. FDG uptake in both inflammatory cells and bacteria at an infection site can then be detected by PET with high sensitivity. Compared to radiolabeled WBC scintigraphy, FDG PET/CT has the advantages of high spatial resolution with superior tomographic images, short procedure time (less than 2 hours, compared to 24 hours with WBC scan), less labor-intensive and lower radiation exposure. Prospectively conducted studies have shown that FDG PET/CT has a better accuracy in detecting infection for patients with joint prostheses than the WBC scan.^9,10 Although most of the published results regarding the role of FDG PET/CT for cardiac device infection are from retrospective studies, case reports, or even incidental findings without a well-designed multicenter prospective study, current data in the literature support the application of FDG PET/CT for earlier detection of cardiac device infection, particularly for complicated and difficult cases, before morphological changes occur.¹¹ An additional benefit of FDG PET/CT is its ability to identify other sites of infection given the whole body scan nature, which could be the original source of infection. Noninfectious inflammation remains a challenge for the FDG PET/CT to image infection and could be a false positive source, but it can be potentially differentiated from true infection by careful evaluation of imaging patterns, and clinical history, such as timing of device implant.

This chapter discusses the roles of FDG PET/CT in diagnosing infection of four major cardiac devices: CIED, valve prosthesis, LVAD, and vascular graft.

Although the heart preferentially utilizes fatty acid as its energy source, based on the nutritional supply, it can also use other substrates such as glucose, ketones, or amino acids. With the current FDG PET/CT imaging protocol for cancer evaluation, it is common for the heart to accumulate FDG uptake after a simple 4-hour fasting. This may not be a major issue for cancer imaging as it is rare to have cardiac primary or metastatic malignancy, but would definitely hinder evaluation of cardiac device infection, for example, lead vegetation or valve prosthesis infection, leading to a false positive study. Thus, it is critical to suppress physiological myocardial FDG uptake when performing PET/CT for cardiac device infection. In addition, cardiac and respiratory motion can also affect visualization of FDG uptake, particularly in a small infected lesion, such as vegetation. Currently, there is no standardized imaging protocol for cardiac device infection diagnosis with FDG PET/CT. As a general rule, the following procedures work well in the authors’ clinical practice. It is highly recommended that a standardized protocol be used once it is published.

Dietary Preparation

The most critical portion of the scan is dietary preparation to completely suppress the physiological myocardial FDG uptake. A high-fat and low-carbohydrate diet has been shown to decrease myocardial FDG uptake.¹² Despite this, a commonly agreed protocol has not been defined in terms of the amount and timing of high-fat, low-carbohydrate diet for cardiac infection imaging. It is generally suggested that patient should start a high-fat and low-carbohydrate diet one day before or at least the prior dinner before the scheduled FDG PET/CT scan. The patient should then fast for at least 4 hours before the injection of FDG. If a scan is scheduled in the late morning or early afternoon, a continued high-fat and low-carbohydrate breakfast would improve the suppression. Although prolonged fasting (18 hours) would generate fatty acids due to the metabolic switch to fat, its effect on myocardial FDG uptake is not complete and consistent.¹³ In addition, long-time fasting is a compliance challenge for some patients.

Heparin

Heparin can increase serum free fatty acid level by inducing lipolysis of lipoprotein particles. Thus, intravenous unfractionated heparin injection before the scan has been used alone or in combination with a high-fat and low-carbohydrate diet preparation to suppress myocardial uptake. However, the effect of heparin on myocardial FDG uptake suppression has not been well established. Further, the optimal dose and timing of heparin injection has not been defined. Heparin is not applied in our own practice.

Imaging Acquisition Time After FDG Injection Shows

For routine cancer evaluation, PET/CT data are acquired 1 hour after FDG injection. Studies on atherosclerosis imaging suggested that delayed acquisitions at 2 or 3 hours after FDG injection increased plaque visualization.¹⁴ It is unknown whether delayed PET imaging would improve infection diagnosis or not, though both target inflammatory macrophages and neutrophils (which is different from cancer imaging). In our practice, imaging acquired at 1 hour after FDG injection shows good results for injection evaluation. An uptake interval of 60 minutes is recommended, but delayed imaging at 90–120 minutes can be considered.

Although most of the cardiac devices are located in the chest, acquiring whole-body PET/CT scan in order to assess extracardiac infection source is highly recommended. The images can be reconstructed and reviewed according to procedure guidelines for oncology PET/CT imaging. The registered PET/CT images can be displayed on a standard workstation in the axial, coronal, and sagittal planes as well as a rotating maximum-intensity projection (MIP) image. It is important that PET images with and without attenuation correction should be reviewed for device infection evaluation, given the attenuation artifact from the metal device. Respiratory motion correction has not been shown significant improvement and is not essential. The interpretation criteria will be incorporated in the following each of the devices.

CIEDs, mainly implantable cardioverter defibrillators and pacemakers, are the most widely used cardiac devices. No matter its type, a CIED consists of a pocket that is usually placed in the upper chest wall subcutaneous region and leads that are placed intravascularly or in the epicardial area of the heart (Figure 13-1). Infection can occur at any part of a CIED with different clinical significances. Infection limited to the superficial soft tissue of a CIED pocket may be treated by local debridement or by antibiotics alone, while infection deep to a pocket or along the leads requires complete extraction of the entire device. Given its tomographic imaging, FDG PET/CT is capable of localizing the site of infection and guiding clinical management.

Performance of FDG PET/CT for CIED Infection

While it appears straightforward to diagnose pocket infection in the presence of severe local chest wall infection signs, such as skin redness or suppuration over the pocket, real clinical cases are more complicated if there are equivocal findings. For those difficult cases, FDG PET/CT can provide incremental information for accurate diagnosis. It has been reported that with device culture after extraction or clinical follow-up as the gold standard, FDG PET/CT has a high sensitivity and specificity for diagnosis of CIED infection, and impact on clinical management.^15,16 FDG PET/CT can clearly distinguish deep pocket infection from superficial soft tissue infection which requires different managements. Figure 13-2 shows a case with deep pocket infection, with a focus of intense FDG uptake beneath the pocket. FDG PET/CT could also detect lead infection along its course, with sensitivity slightly lower than pocket infection.^15,16 Figure 13-3 shows a case with lead infection in the subcutaneous region. In contrast to the pocket and lead infection evaluation, FDG PET/CT may be less sensitive for identifying lead-related vegetation infection, because of the small size and motion of the vegetation during a cardiac cycle. Figure 13-4 shows a focus of uptake corresponding to the tip of lead in the left ventricle, indicating infection, although vegetation is not clearly seen on the CT portion of the PET.

Differentiation of Infection from Inflammation

FDG is a nonspecific tracer and can accumulate in any cells with increased glucose utilization. Thus, it is critical to address the significance of FDG uptake related to noninfectious inflammation, which could create a potential false positive diagnosis. Quantitative measurement of metabolic activity as assessed by standard uptake value (SUV) on PET scan has not been demonstrated reliable for differentiation between inflammation and true infection. There is overlapping of SUV between the two conditions. Visual or semi-quantification (compared to the liver uptake) remains the most reliable way for the differentiation. Infection tends to show focal and intense FDG uptake within or immediately adjacent to the CIED pocket or along the lead, while FDG uptake in inflammatory area is mild, and in a diffuse/homogenous pattern along the entire pocket, rather than limited to a focal area.¹⁷ Clinical history is also helpful, that inflammatory change occurs in recently implanted devices (less than 8 weeks). Figure 13-5 shows a case with postsurgical inflammation without evidence of infection, which demonstrates a different pattern as infection (Figures 13-2 and 13-3).

Clinical Significance of FDG PET/CT for CIED Infection

In addition to providing incremental information for accurate diagnosis of CIED infection, FDG PET/CT findings could guide subsequent clinical management of these cases. Despite clinical suspicion of infection, if an FDG PET/CT scan is negative, then the device system can be left in place, without objective signs of disease progression during follow-up.¹⁵ On the other hand, if PET is positive for a deep pocket or lead infection, then the entire system should be extracted. Superficial tissue infection as seen on PET/CT without abnormal uptake in the rest of the pocket and leads can be managed by antibiotics. Overall, studies have shown that FDG PET/CT positive cases correlate well with device extraction culture results. FDG PET/CT negative cases correlate well with clinical follow up without device extraction.^16,17 The results suggest that FDG PET/CT findings can guide the clinical decision making for difficult cases with clinically suspected but not confirmed cardiac device infection.¹⁶

Pitfalls and Mimics

A CIED infection treated with intensive intravenous antibiotics, or a less severe infection may not be definitely detected by FDG PET/CT (false negative). The possible underlying mechanism may include the less migration of WBCs to the infection site due to decreased secretion of cytokines by bacteria after antibiotics. Nevertheless, as mentioned earlier, studies have shown that if FDG PET/CT is negative, then the device can be left in place with good clinical outcome after a course of antibiotics alone without device extraction, even if the diagnosis is a false negative. On the other hand, a false positive diagnosis can be caused by inflammation, which can be differentiated by clinical history, pattern of uptake, and intensity as mentioned earlier. Attenuation correction artifact from the metals can also lead to a false positive diagnosis. Thus, it is important to review FDG PET/CT images on both the attenuation-corrected and nonattenuation-corrected images. Thrombus formation is also a source of false positive diagnosis, which can be morphologically differentiated.

In summary, although evidence regarding FDG PET/CT in the diagnosis of CIED infection is mainly from retrospective studies or prospective studies with a small cohort of patients, data advocate the role of FDG PET/CT in diagnosing CIED infection, particularly for cases with equivocal anatomical imaging findings. Importantly, FDG PET/CT correlates well with clinical outcome, that is, a positive PET correlates well with device extraction culture, while a negative PET correlates well with clinical follow up without extraction. It is essential to standardize the imaging protocol, including patient preparation, data acquisition processes (for example, the time of imaging after FDG injection), and, more importantly, imaging interpretation. Aggressive dietary preparation is always required to suppress the physiological myocardial glucose utilization for better evaluation of intracardiac lead infection, such as vegetation. Noninfectious inflammation is better differentiated by the distribution and pattern of FDG uptake rather than the intensity. A focal uptake favors a true infection while mild diffuse activity along the device or the lead is more likely inflammation.

In addition to hemolysis and thrombosis, infection is a major complication of valve prosthesis implantation. Diagnosis of prosthesis valve endocarditis remains a challenge. If not treated promptly, mortality from endocarditis is high.¹⁸ The final diagnosis of endocarditis is made based on the Duke Endocarditis Service criteria,¹⁹ which are mainly based on blood culture and TEE or TTE findings. Unlike a native valve, a prosthetic valve is more challenging for TEE or TTE to detect vegetation due to acoustic shadowing from the metal ring.²⁰ On the other hand, TEE may prompt a false-positive diagnosis related to thickened valve, nodular valve, or calcifications.¹⁹ The yield of a positive blood culture can be affected by many factors like blood sampling, or antibiotic treatment, and a positive culture result does not necessarily point to the source of infection. Owing to inconclusive blood culture and TEE findings, a high percentage of cases with clinically suspected endocarditis remain unconfirmed by the Duke criteria. Indeed, it has been reported that up to 24% of patients with pathologically proven endocarditis were misclassified as having a possible endocarditis based on the Duke criteria alone.²¹ Modified Duke criteria have been proposed and are the current gold standard for diagnosis of endocarditis.²² It should be noted that the modified Duke criteria were initially established for epidemiological study of endocarditis, classified at the end of the disease. It may not be optimal for early diagnosis of endocarditis in an acute clinical setting. In addition, the criteria have a lower accuracy for prosthetic valve endocarditis than native endocarditis. Thus, it is a plausible goal to develop a new imaging tool to facilitate and supplement the modified Duke criteria for early diagnosis of prosthetic valve endocarditis.