Multi-Modality Imaging Evaluation of Cardiac Sarcoidosis

Guest Bloggers: 
Krishna K. Patel MD, MSc1
Saint Luke's Mid America Heart Institute,
Kansas City, MO 
Niti R. Aggarwal, MD2
Mayo Clinic, Rochester, MN1

Sarcoidosis is an inflammatory disorder of non-caseating granulomas, involving any organ. Cardiac involvement is common, and often presents with non-specific symptoms but can be potentially lethal due to increased risk of sudden cardiac death. 
Clinical features of cardiac involvement include heart block, ventricular arrhythmias, and left ventricular dysfunction. Cardiac involvement can occur alone or with extra cardiac involvement. Diagnosis of cardiac sarcoidosis (CS) can often be challenging with no clear diagnostic gold standard. Sensitivity of endomyocardial biopsy is low, around 25%, mainly due to patchy nature of disease along with technical factors.1 Diagnosis of CS currently relies mainly on clinical criteria published by Japanese Ministry of Health and Heart Rhythm Society, both of which require a proven histologic or clinical diagnosis of extra-cardiac sarcoidosis along with clinical criteria mentioned above and/or imaging evidence of CS by cardiac magnetic resonance imaging (CMR) or F-18- Flouro dexoy glucose positron emission tomography (FDG PET).2,3 While a positive cardiac Gallium-67 scan is also one of the imaging criteria for diagnosis, it has poor sensitivity and has been replaced by FDG PET. However, diagnosis of isolated cardiac sarcoidosis using these diagnostic criteria or with endomyocardial biopsy can be challenging.
Among the advanced imaging modalities that are currently available for CS, both  CMR and myocardial F-18 FDG PET or PET/CT imaging play a central role and are complementary to each other in helping with diagnosis and management of CS (Figure 1).3,4 On CMR, CS can be identified by late gadolinium enhancement (LGE) in a sub-epicardial or mid-wall pattern, which is often multifocal, involving septal segments and/or right ventricular free wall,5 with or without evidence of acute edema and or left ventricular segmental dysfunction (Figure 2, 3). Absence of LGE on a high quality diagnostic CMR exam has excellent negative predictive value in CS both from a diagnostic and prognostic perspective.6,7 In a study of 321 patients with biopsy proven CS, CMR had a sensitivity of 97% and a specificity of 99% to diagnose CS.6 In a meta-analysis of 7 studies including 694 patients with CS, LGE on CMR was present in 29%, there was a <1% risk of adverse cardiac events, and no ventricular arrhythmia events in absence of LGE.7 These characteristics make CMR a good screening test to diagnose CS in patients with a high clinical suspicion. LGE burden on CMR can also help identify CS patients without severe decline in ejection fraction where ICD placement is recommended for primary prevention of sudden cardiac death.8 Some limitations of CMR for diagnosis and management of CS should be kept in mind. CCMR offers limited ability to differentiate chronic fibrotic scar from active inflamed myocardium. Newer techniques like T1 mapping hold significant promise to detect myocardial inflammation that may respond to immunosuppressive therapy. Furthermore, CMR may not be able differentiate well between CS and other infiltrative or inflammatory diseases that lead to myocardial scar. Gadolinium based contrast should be used with caution in patients with renal dysfunction. In patients with implantable cardiac devices, CMR is often contraindicated due to concern for damaging the device. Even when images can safely be obtained significant artifact may compromise the diagnostic quality and diagnostic confidence of CMR to diagnose CS.
F-18 FDG PET imaging mitigates some of these limitations of CMR for patients with CS. It is widely available, and can help differentiate and identify the burden for active inflammation from chronic burnt out disease in patients with CS. If performed well, it provides diagnostic quality images in patients with implantable cardiac devices or severe renal dysfunction, and also allows whole body imaging which can help identify foci of extra-cardiac sarcoidosis. Figure 4 demonstrates a whole body FDG PET-image with FDG avid cardiac, hilar and mediastinal lymph nodes.  On cardiac FDG PET imaging a perfusion-metabolic mismatch pattern seen as focal FDG uptake in area of a perfusion defect and occasionally in the setting of normal perfusion suggests inflammatory CS (Figure 2). In contrast, a FDG PET image with a perfusion defect without corresponding increase in FDG uptake suggests chronic scar tissue (Figure 5).  In a meta-analysis of 17 studies including 891 patients with suspected CS, visual assessment of FDG uptake (with or without corresponding perfusion defect) had a pooled sensitivity of 84% and pooled specificity of 83%.  Quantitative metrics of FDG uptake can further improve the diagnostic accuracy of FDG PET for CS. In a study of 37 patients with CS compared with 55 controls without CS, Yokoyama et al established an optimal SUVmax threshold of 4 offered a higher sensitivity (97.3%) and higher specificity (83.6%) for diagnosis of CS. FDG PET CT also helps identify candidates at a high risk of ventricular arrhythmias and adverse cardiac events in patients with CS.9,10 In a study of 118 patients with suspected CS, those with a focal perfusion defect and FDG uptake on myocardial FDG PET had a 3.9 times greater hazard of death or VT, even after adjusting for left ventricular ejection fraction (LVEF) and clinical information.10 Summed perfusion scores in segments with a perfusion-metabolism mismatch in F-18 FDG PET CT and variability in SUV as estimated by co-efficient of variation provided incremental prognostic value in 203 patients with suspected CS.9 As FDG PET imaging identifies active inflammatory disease, it can be used to guide immunosuppressive treatment, as well as to serially monitor response to immunosuppression.11 In a study of 23 patients, a significant inverse relationship between the change in SUV max and a change in LVEF was seen, with a predicted increase in LVEF of 7.9% per 10 g/ml decrease in SUVmax.12 Figure 6 shows a suggested algorithm for use of FDG PET results to guide immunosuppressive treatment in patients with CS. While CMR is a good first line screening test to rule out CS for most patients, FDG PET should be considered as a first line test among young patients, especially those with AV block who could have isolated inflammatory disease in the AV node which can be missed on CMR, patients with implantable cardiac devices or severe renal dysfunction where contrast is contraindicated to detect active inflammatory burden of CS and to identify need for immunosuppression and monitor response to therapy.
It is important to be mindful of limitations of FDG PET in CS. A strict dietary preparation with no carbohydrate-high fat diet to suppress physiologic glucose uptake by normal myocardial cells is essential for a diagnostic F-18 FDG PET study. Poor diet preparation should be suspected when diffuse FDG uptake is noted, and scan should be repeated before starting treatment. Poor diet preparation is the most common cause of false positive and/or non-diagnostic PET studies, which have important implications regarding treatment of patients with suspected cardiac sarcoidosis. Lack of standardization in diet preparation instructions, study protocols, hardware and software used for interpretation lead to uncertain reproducibility of FDG PET results. Use of similar diet preparation, injected dose of radio-activity, same protocol and software, as well as use of quantitative metrics of assessment in addition to visual assessment while performing serial FDG PET scans can help decrease variability between scan interpretation.
In conclusion, both CMR and FDG PET-CT play a complementary role in evaluation and treatment of patients with CS.
Figure 1:  Non-invasive approach to initial evaluation of patient with suspected cardiac sarcoidosis. Reproduced from reference 2.

Figure 2: Perfusion and metabolic patterns on FDG PET CT corresponding with cardiac sarcoidosis.

Figure 3: Patient with a cardiac MRI with global hypokinesis, ejection fraction 22%, and presence of transmural delayed myocardial enhancement involving the inferior and inferoseptal segments. Patient had a normal coronary angiogram, and biopsy results consistent with sarcoidosis.
Figure 4:  Whole body FDG PET image with FDG-avid cardiac, mediastinal and hilar lymph nodes

Figure 5: N13- perfusion PET scan with FDG PET metabolism on short-axis images, with decreased perfusion in the basal inferior segment. There is no corresponding increase in myocardial FDG to suggest inflammation. These findings are considered secondary to chronic fibrosis in this patient with longstanding sarcoidosis.

Figure 6: Use of FDG PET imaging to guide immunosuppression. Reproduced from reference 2.
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12.        Osborne MT, Hulten EA, Singh A, et al. Reduction in (1)(8)F-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(1):166-174.