FDG-PET is a Superior Tool in the Diagnosis and Management of Cardiac Sarcoidosis

Editor's Note: This is Part Two article of a two-part Expert Analysis. Click here for Part One.

Cardiac sarcoidosis is a manifestation of systemic sarcoid disease that leads to significant morbidity and mortality. The prevalence of clinically evident cardiac involvement is ~5%, though this may be an underestimation given the difficulties of diagnosing cardiac sarcoidosis.1,2 The autopsy data suggest that cardiac involvement is 20-25%. Current diagnostic criteria are based on the modified Japanese Ministry of Health and Welfare (JMHW) guidelines published in 2006 and the Heart Rhythm Society (HRS) consensus statement published in 2014.3,4 Both involve either a histological demonstration of cardiac sarcoidosis on endomyocardial biopsy or integration of relevant clinical and imaging features (Figure 1).3 As a result, advanced imaging modalities such as cardiac magnetic resonance (CMR) and 18F-flurodeoxyglycose (FDG) positron emission tomography (PET) have emerged as important tools to improve the diagnostic certainty and management of cardiac sarcoidosis. Although both modalities have unique strengths, FDG-PET has a growing evidence base that suggests it is an excellent tool for early diagnosis, prognostication, and follow-up of patients with cardiac sarcoidosis. The pre-imaging preparation required for FDG-PET consists of high fat/no carbohydrate diet for 18-24 hours, plus unfractionated heparin intravenously (10-50IU/kg) 15 minutes prior to FDG injection. The scans are obtained 90 minutes after FDG injection.

Figure 1: Guidelines for Diagnosis of Cardiac Sarcoidosis Based on the 2006 Revised Guidelines of the Japanese Society of Sarcoidosis and Other Granulomatous Disorders and the 2014 HRS Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated With Cardiac Sarcoidosis1,4

Figure 1
Figure 1

Both FDG-PET and CMR offer improved diagnostic accuracy in the evaluation of suspected cardiac sarcoidosis. The sensitivity and specificity of FDG-PET as an initial diagnostic tool for cardiac sarcoidosis was evaluated in a recent meta-analysis of 164 patients with systemic sarcoidosis and found to be 89 and 78% respectively, using the JMHW guidelines as the gold standard.5 However, several studies have shown that imaging identified myocardial involvement in significantly more patients than the standard clinical evaluations based on JMHW guidelines.6 Only one small study has compared FDG-PET directly with CMR and found that PET may have a higher sensitivity than CMR (88 vs. 77%), though the difference was not significant given the small study population.7 In general, FDG-PET has a higher sensitivity, and CMR may have a slightly higher specificity in the diagnosis of cardiac sarcoidosis.3 This pattern in testing efficacy likely reflects the different pathology identified by the two modalities. The foundation of CMR diagnosis is based on the presence of mid-wall and subepicardial late gadolinium enhancement (LGE), which identifies fibrosis. In most cases, fibrosis represents more advanced disease. In contrast, FDG-PET identifies areas of pathologic glucose uptake and inflammation. This is accomplished through a combination of myocardial perfusion imaging using 13N-Ammonia or 82Rubidium and inflammation imaging using FDG. Resulting image interpretation captures a wider spectrum of disease classifying findings into four categories:

  1. Normal: normal perfusion and normal FDG uptake
  2. Early disease: no or mild perfusion defect with increased corresponding FDG uptake
  3. Progressive disease: moderate perfusion defect with increased corresponding FDG uptake
  4. Fibrous disease: severe perfusion defect with minimal or no FDG uptake (Figure 2)8,9

The ability of FDG-PET to characterize inflammation and different stages of myocardial injury results in potentially identifying cardiac sarcoidosis earlier and theoretically improving the sensitivity of the test at the expense of some specificity. As a diagnostic test, the higher sensitivity of FDG-PET is important in capturing earlier disease, which may improve responsiveness to immunosuppressive therapy.9 Of note, fluid-sensitive T2-weighted CMR imaging and T2 mapping strategies have been suggested as a potential correlate to FDG uptake by characterizing myocardial edema with minimal to no LGE in patients with cardiac sarcoidosis. However, this technique has not been well-validated in the diagnostic evaluation of cardiac sarcoidosis and, as such, is not included in the JMHW or HRS criteria.10,11

Figure 2: Classification of Cardiac PET Perfusion/Metabolism Image Patterns and Correlation With Disease Stage in Cardiac Sarcoidosis

Figure 2

Prognosis in cardiac sarcoidosis is poorly defined and based largely on metrics such as left ventricular ejection fraction (LVEF) and symptoms (i.e., conduction disturbances/arrhythmias, congestive heart failure, and sudden cardiac death).8 Findings suggestive of cardiac sarcoidosis on CMR and FDG-PET have strong prognostic implications. LGE in a study of 155 patients with systemic sarcoidosis evaluated with CMR predicted a 32-fold increase in hazard for cardiac complications including sudden death, implantable cardioverter-defibrillator (ICD) discharge, and ventricular arrhythmias.12 The largest prospective study using FDG-PET in cardiac sarcoid of 118 patients demonstrated that the presence of a perfusion and metabolism (i.e., FDG) abnormality was associated with a hazard ratio of 3.9 in predicting sudden cardiac death or ventricular tachycardia.8 These studies have led to increased use of ICD prophylaxis in patients with abnormal CMR or FDG-PET imaging, though it is clear that more refined risk stratification is needed. One significant advantage of FDG-PET compared with CMR is the ability to quantify degree of myocardial inflammation using standardized uptake values. This form of quantitation takes into account the decay corrected uptake of FDG tracer in the myocardium divided by the dose of FDG adjusted to body weight.2 Currently, there is no uniform method of quantitation, and sample approaches include the measurement of mean left ventricular standardized uptake value, maximum standardized uptake value, standardized uptake value volume, and FDG volume-intensity.13-16 A retrospective study by Ahmadian et al. in 2014 evaluating 31 patients with known or suspected cardiac sarcoidosis demonstrated that measures of FDG volume-intensity were the only predictor of arrhythmia and congestive heart failure in a multivariate model.13 A separate retrospective review of 27 patients with known cardiac sarcoidosis found that those with atrioventricular block had lower mean left ventricular standardized uptake value and maximum standardized uptake value than those patients with ventricular tachycardia.14 The quantitative analysis of inflammation in FDG-PET for myocardial sarcoidosis is still in its early stages, but these small studies reveal the potential of FDG quantitation in refining the prognosis of patients with cardiac sarcoidosis beyond a binary "positive" or "negative."

Quantification of myocardial FDG uptake in sarcoidosis is the foundation for the most important advantage of FDG-PET over CMR in cardiac sarcoidosis imaging: the ability to assess response to therapy over time (Figure 3).9,17 There are no randomized clinical trials evaluating the efficacy of high-dose glucocorticoids in cardiac sarcoidosis. However, retrospective studies suggest that steroid therapy is associated with improved outcomes related to LVEF and death. Current follow-up of patients on corticosteroid therapy typically includes annual Holter monitoring and transthoracic echocardiography to evaluate for changes in ejection fraction or arrhythmia burden. However, these methods are less sensitive for detecting clinical changes than the use of advanced imaging modalities to assess response to treatment. Osborne et al. performed a prospective evaluation of 23 patients with cardiac sarcoidosis followed over a median of 2 years, the majority of whom were treated with corticosteroids (91%), angiotensin-converting enzyme/ angiotensin-receptor blocker (78%), and beta-blockers (83%). All patients had at least two PET exams at different time points, during which FDG uptake was measured using maximum standardized uptake value and standardized uptake value volume. The authors identified a significant inverse relationship between LVEF and standardized uptake value measurements. Additionally, non-responders to therapy (identified by changes in FDG uptake) had a significant decrease in LVEF compared with responders who demonstrated an increase in LVEF.15 These data again highlight the potential prognostic importance of FDG quantification through its relationship with LVEF. However, more importantly, it offers a method to monitor patients during therapy to identify responders and non-responders early on and decide who may benefit from intensification versus tapering of therapy.

Figure 3: Qualitative and Quantitative Changes in FDG Uptake in the Anterior and Lateral Walls in a Patient With Cardiac Sarcoidosis Pre- and Post-Immunosuppression Therapy

Figure 3

Finally, from a purely technical perspective, the applicability of CMR imaging in patients with cardiac sarcoidosis, especially in follow-up, is limited by the presence of non-CMR-compatible cardiac devices such as permanent pacemakers and ICDs. FDG-PET also offers an opportunity to perform concomitant whole-body FDG imaging to identify patients who may have extracardiac sarcoidosis.1 PET can be safely performed in patients with intracardiac devices and advanced renal dysfunction.

In summary, FDG-PET is an excellent diagnostic modality for the evaluation and management of cardiac sarcoidosis. A criticism of FDG-PET is its decreased specificity in some studies compared with CMR. These studies, all over 3 years old, may underestimate the specificity of FDG-PET given a growing experience identifying non-specific variations of FDG uptake (i.e., in the lateral wall in the absence of a perfusion defect) that represent normal myocardium.8,3 In addition, disease activity can be quantified with FDG-PET using standardized uptake value measurements, which cannot be performed with CMR. Larger, prospective studies are needed to evaluate the utility of these quantitative methods in the prognosis and follow-up of patients with cardiac sarcoidosis. However, recent initial data suggest that there is significant applicability for quantitative analysis to refine cardiac risk and monitor clinical course during treatment. CMR remains very important in the work-up of cardiomyopathy and provides unique adjunct information, including biventricular function, wall thickness, and regional wall motion, that cannot be obtained with FDG-PET. CMR (myocardial damage) and FDG-PET (inflammation) findings are complimentary because they identify different pathological processes. CMR methods such as fluid-sensitive T2 imaging may provide earlier, reversible evidence of myocardial sarcoidosis activity and provide a measure for future clinical follow-up; however, these methods are not well-studied to date in the cardiac sarcoidosis population. As such, in patients with suspicion of cardiac sarcoidosis or with known cardiac sarcoidosis, FDG-PET may be a reasonable test for initial diagnosis, prognostication, and follow-up.

References

  1. Blankstein R, Waller AH. Evaluation of Known or Suspected Cardiac Sarcoidosis. Circ Cardiovasc Imaging 2016;9:e000867.
  2. Hulten E, Aslam S, Osborne M, Abbasi S, Bittencourt MS, Blankstein R. Cardiac sarcoidosis-state of the art review. Cardiovasc Diagn Ther 2016;6:50-63.
  3. Aggarwal NR, Snipelisky D, Young PM, Gersh BJ, Cooper LT, Chareonthaitawee P. Advances in imaging for diagnosis and management of cardiac sarcoidosis. Eur Heart J Cardiovasc Imaging 2015;16:949-58.
  4. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305-23.
  5. Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012;53:241-8.
  6. Patel MR, Cawley PJ, Heitner JF, et al. Detection of myocardial damage in patients with sarcoidosis. Circulation 2009;120:1969-77.
  7. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18f-fluoro-2-deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008;35:933-41.
  8. Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014;63:329-36.
  9. Skali H, Schulman AR, Dorbala S. 18F-FDG PET/CT for the assessment of myocardial sarcoidosis. Curr Cardiol Rep 2013;15:352.
  10. Amano Y, Tachi M, Tani H, Mizuno K, Kobayashi Y, Kumita S. T2-weighted cardiac magnetic resonance imaging of edema in myocardial diseases. Scientific World Journal 2012;2012:194069.
  11. Crouser ED, Ono C, Tran T, He X, Raman SV. Improved detection of cardiac sarcoidosis using magnetic resonance with myocardial T2 mapping. Am J Respir Crit Care Med 2014;189:109-12.
  12. Greulich S, Deluigi CC, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging 2013;6:501-11.
  13. Ahmadian A, Brogan A, Berman J, et al. Quantitative interpretation of FDG PET/CT with myocardial perfusion imaging increases diagnostic information in the evaluation of cardiac sarcoidosis. J Nucl Cardiol 2014;21:925-39.
  14. Mc Ardle BA, Birnie DH, Klein R, et al. Is there an association between clinical presentation and the location and extent of myocardial involvement of cardiac sarcoidosis as assessed by 18F- fluorodoexyglucose positron emission tomography? Circ Cardiovasc Imaging 2013;6:617-26.
  15. Osborne MT, Hulten EA, Singh A, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014;21:166-74.
  16. Waller AH, Blankstein R. Quantifying myocardial inflammation using F18-fluorodeoxyglucose positron emission tomography in cardiac sarcoidosis. J Nucl Cardiol 2014;21:940-3.
  17. Cabrera R, Ananthasubramaniam K. Diagnosis, therapeutic response assessment, and detection of disease recurrence in cardiac sarcoidosis: Integral role of cardiac PET. J Nucl Cardiol 2016;23:850-3.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Atrioventricular Block, Cardiomyopathies, Defibrillators, Implantable, Diagnostic Tests, Routine, Echocardiography, Electrocardiography, Ambulatory, Gadolinium, Glucocorticoids, Heart Failure, Magnetic Resonance Spectroscopy, Myocardial Perfusion Imaging, Myocardium, Positron-Emission Tomography, Sarcoidosis, Stroke Volume, Tachycardia, Ventricular, Diagnostic Imaging


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