Insights of Inflammatory Heart Involvement in Cardiac Sarcoidosis – A Systemic Review

Sarcoidosis is a systemic inflammatory disease, and cardiac involvement is the most frequent cause of death from this condition [1]. While the majority of cases with systemic sarcoidosis show a self-limiting process that only affects the lung and the lymph nodes, cardiac involvement always requires high-dose immunosuppressive therapy [2]. About 5% of cases show symptomatic cardiac sarcoidosis (CS), but autopsy studies suggest that in up to 25% there is a silent cardiac involvement with unknown significance [3, 4].

Myocarditis is defined by an immigration of immune cells and activation of different cytokines, leading to myocyte necrosis and apoptosis as well as fibrosis of the surrounding interstitium [5‐7]. Most frequently, myocarditis is triggered by viral infection with cardiotropic agents, which either directly induce myocyte death or effect a cytokine-mediated activation of the immune system [7, 8]. Moreover, systemic inflammatory diseases like sarcoidosis or rheumatological diseases (e.g. systemic lupus erythematosus, systemic sclerosis, and myositis) frequently involve the myocardium and provoke myocardial inflammation and remodeling processes [7‐10]. The hallmark of CS is the formation of noncaseating granuloma and an overlap of acute, potentially reversible inflammation and irreversible fibrotic remodeling, which result in heart failure, arrhythmia, and sudden cardiac death [2, 11].

The multifarious origins of myocardial inflammation emphasize the importance of both detecting active inflammation and differentiating its etiology. However, a single, noninvasive imaging modality to differentiate these entities is still not available. In this review we focus on the importance of multimodal imaging to diagnose sarcoidosis. We provide information on the identification of active and chronic inflammation and illuminate the current state of the art for monitoring CS during medical therapy.

Sarcoidosis can affect almost every organ and has a different clinical presentation, from asymptomatic incidental findings to sudden cardiac death. The diagnosis of isolated CS can be challenging because of the unspecific clinical presentation [12]. As of today some diagnostic recommendations still require histological confirmation [13, 14]. However, the focal character of the disease results in a high sampling error, so that CS could be missed without adding other diagnostic modalities [12, 15]. Therefore, the Japanese Circulation Society (JCS) guidelines and the Heart Rhythm Society (HRS) consensus paper raised the importance of noninvasive imaging tools like cardiac magnetic resonance (CMR) and 18-fluorodeoxyglucose (¹⁸FDG) positron-emission tomography-computed tomography (PET-CT) [13, 14]. According to the HRS guidelines, however, a definite diagnosis of CS is only possible with extracardiac histopathological proof of noncaseating granuloma [13].

T1 and T2 mapping are excellent methods of tissue characterization as they provide both diagnostic and prognostic information [36‐38]. While native T1 time is sensitive to fibrosis and water, T2 time is an indicator of myocardial edema [36, 39‐42]. An excellent review article by Haaf et al. summarizes the influence of different histological changes in acute myocarditis and in cases of storage diseases on the T1 time. Almost any change in myocardial architecture leads to a prolongation of T1 time. Even deposits of glycosphingolipids and iron in Fabry disease and hemochromatosis result in shortened T1 time [37]. T1 and T2 times are early indictors of heart disease and can be increased before functional limitations of the ventricle or focal fibrosis become evident [36, 43]. Elevated T1 and T2 relaxation time in patients with known extracardiac sarcoidosis also seem to predict an early cardiac involvement [44••, 45‐47]. In 53 biopsy-confirmed CS patients Puntman et al. found higher T1 and T2 times in addition to structural and functional changes compared with healthy controls and irrespective of symptoms, time since diagnosis, and age [44••]. Even in the absence of LGE and preserved EF patients with sarcoidosis show higher T1 values than healthy controls [48]. Both studies conclude that T1 mapping is the best parameter to differentiate between normal and diseased myocardium [44••, 48]. We recently found that the quantification of regional extracellular volume (ECV) by a combination of pre- and post-contrast T1 mapping and the hematocrit can distinguish CS from other inflammatory cardiomyopathy [49]. In 33 LGE- and PET-positive patients ECV was more specific than regional or global native T1 and T2 mapping alone. Further, in our cohort EMB did not yield any histological evidence of CS [49]. Nevertheless, the effect of fibrosis or myocardial edema on the T1 prolongation cannot be discriminated.

Detection of edema is of particular importance for the identification of active inflammation. This can be achieved in two different ways: as T2 mapping is specifically sensitive to the water content of the tissue, either increased signal intensity is delineated on T2w turbo spin echo sequences, ideally in relation to the signal of skeletal muscle, or the T2 time is measured directly by parametric techniques. T2 can be considered as a physical biomarker: the higher the T2 time, the higher the water content of the tissue [50, 51]. T2 mapping sequences are a quantitative method and have been shown to be superior to T2-weighted turbo spin echo sequences for the detection of inflammation [41]. Spieker et al. found that elevated T2 time is associated with the presence of inflammatory cells in EMB in dilated cardiomyopathy [41]. By adding T2 mapping to the JCS recommendations, the diagnostic accuracy for active CS can be improved [52••]. Although studies addressing T2 mapping as a follow-up parameter during treatment of CS are sparse, the importance of this parameter has been demonstrated for other inflammatory heart diseases [53, 54]. In a small case series of 8 patients, including 6 undergoing immunosuppressive therapy, Crouser et al. showed alterations in the T2 signal during follow-up, which supports the reproducibility of this parameter [55]. Therefore, we recommend both T1 and T2 mapping for diagnostic considerations. Selectively elevated T1 time and normal T2 time indicate fibrotic remodeling, whereas an elevation of both parameters is suggestive of myocardial inflammation.

In summary, CMR provides an opportunity for detailed characterization of tissues of the whole myocardium that overcomes the issue of sampling error of EMB. T1 and T2 mapping are excellent methods for the discrimination of diseased and normal myocardium, the identification of remodeling, and even detection of subtle inflammation. T2 mapping has been identified as a suitable parameter for monitoring progression in many inflammatory diseases such as myocarditis or systemic sclerosis and is therefore an essential component in monitoring immunosuppressive therapy of CS patients. LGE adds insights regarding the underlying process of different cardiomyopathies and adds prognostic information to the diagnostic data. However, there is room for improvements, particularly for device-implanted patients who represent not an inconsiderable proportion. In the future, wideband sequences could overcome the problem of off-resonance artefacts and could make the modality suitable for this particular cohort.

A high glucose metabolism is a hallmark of inflammatory processes and sarcoid granuloma. Macrophages show high metabolic activity and therefore high ¹⁸FDG uptake. ¹⁸FDG PET-CT uses this feature to visualize pathological ¹⁸FDG uptake not just in the heart but in all potentially affected organs and to confirm active myocardial inflammation [56]. To suppress the physiological glucose metabolism in the heart, a fasting period is necessary to improve diagnostic accuracy [57, 58]. Further, coronary artery disease needs to be excluded because ischemia can also result in abnormal ¹⁸FDG uptake. At our center we use a fasting period of 18 h with a last meal that is low in carbohydrates. Before ¹⁸FDG application all patients are prepared with 50 I.E./kg bodyweight heparin to suppress the tracer uptake. In a meta-analysis of 7 studies with 164 patients the accuracy of ¹⁸FDG PET-CT for detecting CS was determined to have a sensitivity of 89% and a specificity of 78% [59]. All ¹⁸FDG PET-CT scans should be interpreted qualitatively and quantitatively by an experienced examiner [60]. Quantitative parameters like the maximum standard uptake value (SUV_max) can improve the assessment of therapy response, but they are not validated for prognostic information [61, 62]. However, qualitative PET-CT findings appear to add a prognostic value. Pathological tracer uptake is associated with a higher risk of VA or death [63].

A combination of CMR and fasting PET-CT scans is a widely used approach to confirm CS and to discriminate an acute from a chronic condition [49, 64]. In a recently published study Greulich et al. highlighted the role of a hybrid method of CMR and ¹⁸FDG PET-CT for the differentiation of active and chronic CS [65••]. In a cohort of 43 patients with histologically confirmed extracardiac sarcoidosis the authors found that a combined approach of CMR mapping method and PET-CT scan can increase the accuracy for diagnosing active CS. They showed that even in the absence of LGE, increased T1 and T2 mapping values can indicate active inflammation that can be confirmed by PET-CT with crucial therapeutic implications [65••]. ¹⁸FDG uptake in the atria can be a predictor of the development of atrial fibrillation during follow-up. In a multimodal approach in 118 CS patients without atrial fibrillation at initial diagnosis, Niemelä et al. found atrial inflammation and atrial enlargement as independent predictors of future atrial fibrillation [66•].

Figure 3 shows a comparison of CMR and PET-CT findings in a young male patient presenting with sudden cardiac death and provides an example of the additive information that can be obtained from multimodal imaging CS of myocardial inflammation.

To summarize, ¹⁸FDG PET-CT scans are suitable for the identification of active inflammation but provide limited information about chronic irreversible disease status. ¹⁸FDG PET-CT is not able to reliably detect fibrotic remodeling areas whose presence is a significant prognosticator. The preparation of the patient for ¹⁸FDG PET-CT can affect the results and the comparability of the examinations [58], but to date there are no precise recommendations for the best dietary approach to optimize the scans. We recommend a controlled fasting period within an inpatient stay to ensure the suppression of physiological glucose uptake and to avoid false positive results. Furthermore, a lack of ¹⁸FDG-uptake only indicates the absence of active inflammation; it does not rule out chronic fibrotic remodeling in healed CS which is still associated with a relevant increased risk for malignant VA and SCD. Therefore, both methods – PET and CMR – are indispensable for the identification of CS and the assessment of activity status.

CS always requires high-dose immunosuppressive therapy with glucocorticoids and optionally methotrexate or azathioprine as well as standard heart failure therapy [67]. As concerns still exist about the optimal dose and period of immunosuppressive therapy, many centers have their own follow-up regimen, which often makes comparability between studies difficult. CS is often characterized clinically by high-grade AV-block and malignant VA. Therefore, many patients are provided with a pacemaker or defibrillator. The electronic device influences in particular the image quality of CMR or even makes its application impossible. In such cases ¹⁸FDG PET-CT is an important alternative, especially for detecting disease recurrence under therapy [60, 68]. A reduction of ¹⁸FDG uptake seems to be associated with an improvement of EF [69]. The optimal timepoint for imaging follow-up is still a matter of debate, but a period of more than 5 months seems to be enough to reflect medically induced changes [70]. In a cohort of 68 patients Arps et al. investigated imaging parameters for the detection of a relapse [71•]. They found that about 50% of patients suffered disease recurrence, and the initial amount of LGE and isolated CS were relevant predictors.

In our center we use a multimodal approach consisting of clinical parameters, laboratory findings, and imaging modalities. In cases of suspected CS in CMR imaging, a fasting ¹⁸FDG PET-CT scan is always obtained to quantify disease activity status. As a follow-up tool we prefer CMR, if applicable. CMR does not entail exposure to radiation, which makes a serial application feasible. For interpretation of inflammation, we use the development of global and regional T1 and T2 mapping values and the amount of LGE. For the assessment of heart failure, we rely on functional and morphological parameters like EF and end-diastolic and end-systolic volumes. In cases having inconclusive CMR results, or if CMR is inapplicable or leaves any doubt about CS activity status, we add ¹⁸FDG PET-CT for further decision making. The imaging information is always put into context together with all collected parameters, and every case is discussed in an interdisciplinary conference for rare heart diseases before introduction, change, or termination of therapy. Figures 4 and 5 depict two cases in which CMR and ¹⁸FDG PET-CT were used to confirm treatment response.

Serial CMR is a reliable and sensitive tool to monitor the course of inflammation during therapy and avoids radiation exposure. However, in patients with implanted devices ¹⁸FDG PET-CT is indispensable. In serial ¹⁸FDG PET-CT a change of at least 20% in uptake regions and/or SUV_max are the recommended threshold for indicating therapy response [72]_. Alterations of SUV_max in serial measurements do not correlate with prognosis and clinical outcome.

There are still gaps in our knowledge concerning the best therapeutic approach, the optimal corticosteroid dose and therapy period, follow-up imaging settings and period, and indicators for escalating or deescalating immunosuppressive therapy. As a consequence, heart centers use their own strategy, which makes studies difficult to compare and to translate to clinical practice. An expert consensus-based, standardized follow-up approach that includes clinical and imaging parameters should be implemented, and multicenter studies will be necessary to significantly improve the management of the rare but life-threatening disease of CS.

Due to the multifaceted clinical appearance and imaging features of CS, a multimodal approach for diagnosis and follow-up is mandatory. According to the current state of knowledge, a combination of CMR and fasting ¹⁸FDG PET-CT is the favorable method for the diagnosis and identification of active inflammation. T1 and T2 mapping sequences provide a unique opportunity to quantify and track fibrosis and inflammation before any structural changes are observable. In addition, ¹⁸FDG PET-CT detects metabolically active areas, which is a fundamental feature in inflammatory processes. Finally, the evaluation of CS always requires an interdisciplinary approach for best decision making.