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

Sarcoidosis is an inflammatory disorder characterized by the formation of noncaseating granulomas. Its etiology is unknown, and any organ may be affected, although cardiac involvement is associated with worse prognosis.¹ Appropriately diagnosing and treating cardiac sarcoidosis remains an important goal because cardiac involvement may occur in up to 25% of patients with sarcoidosis, the large majority of whom may not clinically manifest cardiac symptoms.² Yet accurately diagnosing cardiac sarcoidosis remains challenging due to limitations of available clinical criteria and the low yield of endomyocardial biopsy.³ As a result, there is growing interest in the use of noninvasive advanced imaging techniques, such as cardiac magnetic resonance (CMR) and ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET), to evaluate patients with suspected or known cardiac sarcoidosis. This viewpoint will summarize the evidence in support of using CMR for the evaluation of cardiac sarcoidosis.

A major limitation in the evaluation of cardiac sarcoidosis is that no gold standard clinical diagnostic criteria exist. The primary clinical manifestations of cardiac sarcoidosis most frequently include conduction abnormalities and arrhythmias and less frequently include congestive heart failure and sudden death.^3,4 Left ventricular ejection fraction (LVEF) is an important clinical predictor of mortality in patients with cardiac sarcoidosis, but even those with preserved LVEF may be at risk.⁵ The key pathologic feature of cardiac sarcoidosis (presence of noncaseating epithelioid granulomas) is associated with successive histological stages of edema, inflammation, and fibrosis leading to scarring, but the disease is usually patchy and multifocal.^6,7 Thus, although a positive endomyocardial biopsy is definitive for diagnosing cardiac sarcoidosis, the sensitivity of this technique is limited (to approximately 30%)⁸ and may not justify the added procedural risk. In this setting, clinical guidelines for diagnosing cardiac sarcoidosis,^9,10 which have largely relied on histological diagnosis from myocardial tissue, have been less useful. More recently, expert consensus guidelines¹¹ incorporated the histological diagnosis of extracardiac sarcoidosis for diagnosing probable cardiac sarcoidosis (>50% likelihood) in the presence of suspicious clinical findings with no reasonable alternative explanation, but this overlooks the possibility of diagnosing isolated cardiac sarcoidosis, which is an increasingly recognized entity that may account for up to 25% of patients with cardiac sarcoidosis.¹² So despite best efforts, there remains significant uncertainty in current diagnostic and treatment algorithms for cardiac sarcoidosis.

CMR provides a noninvasive and multidimensional assessment of the heart for evaluation of cardiac sarcoidosis by allowing for the detection of myocardial scar, edema, perfusion defects, and abnormal biventricular function. Although CMR can detect suggestive morphological abnormalities including ventricular wall thinning, the primary method of detecting cardiac sarcoidosis by CMR relies on identifying the presence of late gadolinium enhancement (LGE) in typical patterns along the ventricular wall.¹³ Gadolinium, an extracellular contrast agent, demonstrates slow washout from areas of fibrosis (and inflammation¹⁴) relative to normal myocardium, which allows for its visualization on delayed images on CMR. The excellent in-plane spatial resolution of CMR allows for LGE visualization of subcentimeter lesions, as well as the distinction between subepicardium, midmyocardium, and subendocardium involvement. Although various patterns of LGE may be seen in patients with cardiac sarcoidosis, findings are usually patchy and multifocal, with sparing of the subendocardium, which is more often associated with infarct from ischemic heart disease. Typical LGE patterns in patients with cardiac sarcoidosis include subepicardial and midwall LGE along the basal septum, sometimes with extension into the right ventricular insertion points as well as the inferolateral wall. Nonetheless, no specific pattern of LGE on CMR is diagnostic for cardiac sarcoidosis. The presence of LGE in a non-infarct pattern may also be associated with fibrosis from prior myocarditis or idiopathic cardiomyopathy; rarely, cardiac sarcoidosis may mimic an infarct pattern.^4,5 Besides LGE, there is growing interest in the addition of T2 mapping to CMR to identify areas of reversible myocardial tissue pathology (i.e., edema and inflammation) to enhance detection of active cardiac sarcoidosis, identify increased risk of ventricular arrhythmias, and potentially help guide adequacy of immune-suppression therapy.¹⁵

Despite this, it can be problematic to compare the utility of CMR and FDG-PET for the evaluation of patients with suspected cardiac sarcoidosis because few high-quality comparative data exist, and, as already discussed, a gold standard comparator is lacking. Importantly, CMR and FDG-PET evaluate different pathological processes, namely fibrosis via LGE in the former and inflammation via labeled-glucose uptake of activated macrophage in the latter, and neither technique is specific for fibrosis or inflammation caused by cardiac sarcoidosis. As such, these different advanced imaging tests may provide complementary information for the appropriately selected patient in whom clinical suspicion for cardiac sarcoidosis warrants further evaluation (Figure 1).^3,16 A commonly cited study⁷ comparing the diagnostic accuracy of CMR and FDG-PET for diagnosis of suspected cardiac sarcoidosis reported that both techniques provided high sensitivity (>75%) for detection of cardiac sarcoidosis (albeit as determined using the insensitive Japanese Ministry of Health and Welfare criteria) but was underpowered to detect differences between these techniques. Thus, to date, the true diagnostic accuracy of these modalities as compared with each other remains unclear.

Figure 1¹⁶

What about for very early-stage disease, which may precede detectable LGE by CMR? Although it is conceivable that diagnosis of cardiac sarcoidosis in this scenario may be facilitated by FDG-PET (albeit without a corresponding perfusion defect), it is important to note that of the available data linking imaging findings to clinical outcomes, LGE emerges as a very sensitive marker of prognosis. In a relatively large study¹⁷ of 155 patients with systemic sarcoidosis who underwent CMR for evaluation of suspected cardiac sarcoidosis, the presence of LGE emerged as the strongest independent risk factor (above LVEF and end-diastolic volume) for death and aborted sudden cardiac death, with a very high negative predictive value for adverse outcomes, including arrhythmic events. The extent of myocardial LGE is also an important prognostic marker. A recent study showed that patients with cardiac sarcoidosis with large-extent LGE (≥20% of left ventricular mass) had higher risk of cardiac mortality and hospitalization for heart failure and life-threatening arrhythmias and were less likely to demonstrate functional left ventricle recovery following steroid therapy.¹⁸

Furthermore, the prognostic value of abnormal FDG appears to be strongest in the presence of a concurrent resting myocardial perfusion defect,¹⁹ which would correspond to the presence of scar visible as LGE on CMR. This may reflect that the diagnostic accuracy for FDG-PET depends in large part on the appropriate suppression of physiologic glucose utilization by normal myocardium, as facilitated by patient compliance with a high fat/very low carbohydrate diet.²⁰ Indeed, an important advantage of CMR may be a substantially lower number of nondiagnostic scans relative to FDG-PET. Although certain technical issues, including gating and motion artifacts,²¹ as well as patient-specific problems (i.e., ability to breath-hold), can affect the diagnostic quality of CMR and, uncommonly, render a study nondiagnostic, this contrasts with the much higher nondiagnostic rate of FDG-PET due to incomplete FDG suppression, which has led to the recommendation that centers continuously review the quality of achieved suppression for all FDG-PET cardiac studies to maintain a level sufficient for diagnostic evaluation in at least 80% of studies.²⁰

Additional benefits of CMR relative to FDG-PET include the following:

1. No patient exposure to ionizing radiation (a limited whole body PET/computed tomography from skull-base through mid-thighs is associated with a total effective dose of approximately 14.0 mSv),²² with low risk from gadolinium contrast in patients with GFR >30 ml/min
2. No need for specialized patient preparation requiring adherence to complex diet (of multiple high fat/very low carbohydrate meals followed by fasting with or without administration of intravenous unfractionated heparin)²⁰
3. The ability to identify alternative cardiomyopathies or infiltrative diseases that may account for the patient's clinical presentation

Although both FDG-PET and CMR can guide location of biopsy, FDG-PET may be useful for monitoring of ongoing inflammation in response to therapy.^23,24 As with CMR, abnormal findings are not necessarily specific for cardiac sarcoidosis and must be interpreted with caution because abnormal myocardial FDG uptake may also occur with myocarditis or hibernating myocardium in the setting of ischemic heart disease. Another advantage of FDG-PET with whole-body imaging is the ability to evaluate metabolically active extracardiac sarcoidosis. Finally, FDG-PET would be preferred in patients with cardiac pacemakers or implantable cardioverter-defibrillator devices and patients with advanced kidney disease because CMR is contraindicated in most patients with the former, and administration of gadolinium is contraindicated in the latter.

In summary, CMR has high diagnostic accuracy and prognostic value for the evaluation of individuals with suspected cardiac sarcoidosis. Absence of myocardial LGE on a diagnostic-quality CMR makes the likelihood of clinically relevant sarcoid heart involvement quite low, even in the presence of known extracardiac sarcoidosis. As such, and consistent with the 2014 Heart Rhythm Society consensus statement,¹¹ Hulten et al. recently proposed the following algorithm (Figure 2) for the use of advanced imaging in the diagnosis and management of cardiac sarcoidosis, recognizing that some patients with cardiac devices or other contraindications, as well as the highly selected patient with normal CMR and a very high clinical suspicion, may need to undergo FDG-PET.⁴ Ultimately, any evaluation must be individualized to the specific patient and local expertise of the center performing the tests. Combined CMR and FDG-PET, which allows for detailed assessment of function and fibrosis (by CMR with LGE) and inflammation (by FDG-PET),^16,25 may also be useful in select cases.

Figure 2⁴

References

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Keywords: Arrhythmias, Cardiac, Cardiomyopathies, Cicatrix, Defibrillators, Implantable, Gadolinium, Granuloma, Heart Failure, Heart Ventricles, Heparin, Kidney Diseases, Magnetic Resonance Spectroscopy, Myocardial Ischemia, Myocarditis, Myocardium, Positron-Emission Tomography, Radiation, Ionizing, Risk Factors, Sarcoidosis, Stroke Volume, Tomography, Diagnostic Imaging

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