Clinical Need: Current Assessment and Supportive Data

Sarcoidosis is a multisystem inflammatory disease of unknown etiology that affects young men and women, typically before the age of 50 years.¹ The incidence of sarcoidosis varies based on a variety of factors including race, gender, and geography with incidence ranging from 0.73 per 100,000 in Japanese males,² 10 per 100,000 age- and gender-adjusted in a predominantly white cohort in the United States¹ and 71 per 100,000 in African American females.³

Cardiac sarcoidosis (CS) has been reported to involve approximately 2%-5% of patients with systemic sarcoidosis.¹ It can also be the only manifestation of sarcoidosis. The clinical presentation is nonspecific and includes sudden cardiac death, ventricular arrhythmias, progressive heart failure, and conduction disturbances. Despite its low reported prevalence, CS accounts for 13%-25% of sarcoidosis-related deaths.⁴

Current diagnostic criteria for CS include the Japanese Ministry of Health and Welfare (JMWH) criteria⁵ and the Heart Rhythm Society Consensus (HRS).⁶ The gold standard for CS is endomyocardial biopsy, which has a low diagnostic yield owing to heterogeneous and patchy involvement of the myocardium. 2-Deoxy-2-[F-18]Fluoro-D-glucose (¹⁸F-FDG) PET-CT is the best advanced imaging tool to evaluate myocardial inflammation in patients with suspected CS. It has a reported sensitivity of up to 85%-100% with more variable specificity of 39%-100%.^7–10 The low specificity is likely due in part to using the JMHW criteria as a gold standard and the difficulty of a definitive diagnosis.

In the HRS guidelines,⁶ clinical diagnosis of CS is probable if there is histological proof of extra CS and one or more advanced imaging findings of CS or unexplained decreased systolic function or arrhythmias when other causes have been reasonably excluded (Table 12-1).

Given the rarity of overt diagnosis of this disease, most of the available literature comes from small observational or retrospective studies and large prospective randomized trials are challenging. Much of the guidance for CS is based on consensus statements from major medical societies. Recent statements are the Joint SNMMI-ASNC Expert Consensus Document on the Role of PET/CT in Cardiac Sarcoid Detection and Therapy Monitoring¹¹ and a joint procedural position statement on imaging in CS from the European Association of Nuclear Medicine, the European Association of Cardiovascular Imaging, and the American Society of Nuclear Cardiology.¹²

The joint SNMMI-ASNC expert consensus document details specific scenarios where cardiac PET/CT may be helpful and these include: patients with histologic evidence of extra CS and abnormal screening of CS; unexplained, new onset of significant conduction system disease; idiopathic SVT and proven CS to follow response to treatment.¹¹ (Table 12-2 is reproduced with permission from SNMMI-ASNC expert consensus document.)

Perfusion defects and mismatch between perfusion and ¹⁸F-FDG images can result from coronary artery disease. Hence, prior to performing ¹⁸F-FDG PET/CT for sarcoidosis, significant coronary artery disease (CAD) must be excluded using noninvasive ischemia testing with radionuclide imaging, echocardiography, or cardiac magnetic resonance imaging or coronary angiography with CT or catheterization.

Assessment of Risk and Therapies: Timing, Indications

Immunosuppressive therapy and implantable cardiac devices (ICD) along with standard heart failure therapy are the mainstays of treatment for CS. Current indications for immunosuppressive therapy include: LV systolic dysfunction, ventricular arrhythmias, evidence of inflammation on ¹⁸F-FDG-PET, conduction defects, late gadolinium enhancement (LGE), or CMR or right ventricular dysfunction in the absence of pulmonary hypertension.¹³ ICD is indicated if LVEF remains <35% after immunosuppressive therapy (Class I) or if LGE is present in patients with LVEF 35%-49% after immunosuppression (Class IIb).⁶

While the optimal timing for repeat ¹⁸F-FDG -PET/CT is not known, current recommendations are to repeat it 4–6 months after initiation of immunosuppression.¹² Observational studies have shown decreased intensity and extent of ¹⁸F-FDG uptake correlating with improved LVEF following initiation of treatment,¹⁴ suggesting that ¹⁸F-FDG-PET/CT may help guide the duration of treatment. In one longitudinal study of 23 patients who had serial ¹⁸F-FDG PET-CT scans for CS, a quantitative decrease in intensity and extent of ¹⁸F-FDG uptake correlated with improvement in ejection fraction, suggesting a role for ¹⁸F-FDG PET-CT in guiding immunosuppressive therapy¹⁴ (Figure 12-1). Both visual and quantitative evaluation using standardized uptake value (SUV) and volume of inflamed myocardium based on an SUV threshold is recommended to increase detection of partial response, which may not be apparent with qualitative/visual analysis. Prospective randomized clinical trials are needed to further assess the role of imaging in guiding immunosuppressive therapy.

With regard to prognosis, focal uptake in the right ventricle, abnormal myocardial perfusion, abnormal myocardial ¹⁸F-FDG uptake, or both (Figure 12-2) and reduced ejection fraction have been found to correlate with worse survival free of ventricular tachycardia and death.^14,15 Furthermore, recent studies suggest that quantitative measures of extent and severity of perfusion and ¹⁸F-FDG metabolic mismatch as well as the coefficient of variation of ¹⁸F-FDG uptake provides incremental prognostic value in CS.¹⁶

Patient Preparation

The key aspect of patient preparation for ¹⁸F-FDG PET-CT for CS assessment is suppression of physiological myocardial glucose metabolism. This can be done through several approaches, all of which share a common goal of shifting myocardial metabolism from glucose to fatty acid use. Current SNMMI/ASNC/SCCT guidelines recommend a high-fat, zero-carbohydrate diet for 12–24 hours, followed by fasting for 12–18 hours and optional IV unfractionated heparin (single dose of 50 IU/kg) 15 minutes prior to radiotracer injection.¹⁷

The best approach remains somewhat controversial. One meta-analysis showed that the diagnostic odds ratio of ¹⁸F-FDG PET-CT was affected by fasting time and heparin administration but not with a high-fat low-carbohydrate diet¹⁸ whereas other studies have shown that fasting alone is inferior to a high-fat low-carbohydrate diet.¹⁹ Also, the appropriate amount of fat or carbohydrate intake has not been standardized. Some suggest more than 35 g of fat and less than 5 g of carbohydrates for at least two meals.^20,21 A high-fat beverage given right before administration of ¹⁸F-FDG, in addition to the diet, has not been shown to have an added benefit.^22–24 There have also been studies showing longer duration of high-fat, high-protein, very low carbohydrate diet of up to 72 hours, can increase diagnostic accuracy of the scan.²⁵

For vegetarians, eggs are an option. Oil and butter can also be used for people on a vegan diet or for those who cannot eat solid foods. For diabetic patients, those on insulin should continue the basal rate and avoid rapid acting insulin if possible. Patients with diabetes on oral hypoglycemic agents, should avoid these medications while fasting and on the day of the exam.

As with standard ¹⁸F-FDG PET-CT for other indications, preparation includes avoiding strenuous activity for at least 24 hours. Despite adequate preparation, the rate of incomplete or unsuccessful myocardial suppression has been reported to be 20%.²¹

How to Perform the Procedure

¹⁸F-FDG PET-CT is performed in conjunction with rest myocardial perfusion imaging. Ideally, obstructive CAD should be ruled out prior to performing sarcoid protocol ¹⁸F-FDG scan. If stress testing with imaging is necessary to exclude CAD, it is preferably performed a day prior to ¹⁸F-FDG PET-CT. Myocardial perfusion imaging should ideally be performed with PET ⁸²Rubidium PET or ¹³N-ammonia PET using standard protocols. However, if PET is not available, ^99mTc-SPECT is an acceptable alternative. This is followed by injection of 5-15 mCi of ¹⁸F-FDG for either 3D or 2D PET, respectively. Recommended uptake time is 90 minutes (minimum 60 minutes), during which there should be no food intake or exercise. Dedicated cardiac PET-CT is then performed followed by limited PET-CT of at least the thorax and upper abdomen to assess for extra cardiac sarcoid involvement. If available, hybrid PET/CT is preferable to dedicated PET, because the CT obtained for attenuation correction (AC) enables better localization of ¹⁸F-FDG uptake to the myocardium versus lung or mediastinal lymph nodes. If PET-CT is not available, PET-only imaging is an alternative. Images are processed and reviewed with standard cardiac displays (short axis, horizontal and vertical long axis) and standard nuclear medicine display for PET/CT. Cardiac images are normalized to the maximum counts per pixel of the respective data set.

Value of Cardiac MRI (CMR)

CMR has an upfront role in diagnosis and is the first line of imaging in patients with suspected CS. Focal myocardial hyperenhancement on delayed contrast enhanced images (LGE) is the most common finding in CS with initial reported sensitivity of 100% and specificity of 78%.²⁶ LGE on CMR showed similarly high diagnostic accuracy (sensitivity 96.9%, specificity 100%) and risk stratification for major adverse cardiac events (cardiac death, heart failure hospitalization, ventricular tachyarrhythmia, or cardiac transplantation) in another study.²⁷ Furthermore, a recent meta-analysis, including 694 patients from 7 studies, showed that LGE increases the risk of ventricular tachyarrhythmia and cardiovascular death.²⁸ However, LGE does not distinguish between myocardial fibrosis and active inflammation. Because disease-modifying therapy is directed by the presence, extent, and severity of myocardial inflammation, following a CMR suspicious for sarcoidosis, ¹⁸F-FDG PET-CT can be performed for evaluation of active inflammation.¹² In a subset of patients who either have non-MR-compatible implanted devices or are unable to obtain a CMR for other reasons, ¹⁸F-FDG PET-CT then becomes the initial imaging test to aid in diagnosis.²⁸

Combining the high spatial resolution of MRI with the high sensitivity of ¹⁸F-FDG PET for inflammation could improve diagnostic accuracy with the use of hybrid PET/MRI imaging. This can potentially show both the extent of scarring and active inflammation. There are a few case reports in the literature that demonstrate the added value of ¹⁸F-FDG PET/MR imaging.²⁹

Following diagnosis of cardiac sarcoid and initiation of immunosuppressive therapy, ¹⁸F-FDG PET-CT is the recommended test for assessment of treatment response (Figure 12-3).

Interpretation and Reporting of Cardiac Sarcoid and Amyloid Studies with Case Examples

¹⁸F-FDG is a nonspecific marker of myocardial glucose uptake. In inflammation, infection, and malignancy the high glycolytic activity of inflamed cells as well as glucose utilization of activated macrophages and cancer cells leads to increased uptake of ¹⁸F-FDG. Notably, patients with sarcoidosis are at increased risk of hematological and solid malignancy, making it even more challenging to interpret ¹⁸F-FDG uptake solely as inflammation in these cases.

Interpretation of the perfusion and ¹⁸F-FDG images involves: (1) assessment of resting myocardial perfusion, (2) assessment of quality of the ¹⁸F-FDG PET/CT for interpretation, (3) assessment of cardiac and extra cardiac ¹⁸F-FDG uptake, (4) correlation with myocardial perfusion data, and (5) comparison with prior ¹⁸F-FDG scan or CMR or echocardiography findings, if available, for assessment of treatment response.

Assessment of resting myocardial perfusion: This is the same as for standard myocardial perfusion imaging. Evaluate for the size, location, and severity of perfusion defects. If gated acquisition was performed, assess for wall motion abnormalities.

Assessment of quality of ¹⁸F-FDG PET/CT for interpretation: It is critical to determine whether myocardial ¹⁸F-FDG uptake was adequately suppressed. In general, diffuse ¹⁸F-FDG uptake throughout the myocardium usually means suppression was inadequate, as discussed in the next section. It is important to remember that suppression can also be incomplete, particularly if the area of ¹⁸F-FDG uptake does not have a matching perfusion defect or LGE on CMR. If clinical suspicion remains high, repeating the ¹⁸F-FDG PET study can be considered with rigorous adherence to the diet and perhaps a longer fasting period.

Assessment of cardiac ¹⁸F-FDG uptake: Uptake within the myocardium from CS is a marker of active inflammation and appears patchy and does not follow a vascular territory. It is important to note that absence of ¹⁸F-FDG uptake does not exclude fibrosis from CS, only that there is no active inflammation.