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Cardiac involvement in sarcoidosis is related to lethal arrhythmias and is considered a serious condition. Because steroid therapy is an effective treatment, early diagnosis of cardiac sarcoidosis (CS) is of paramount importance in respect to improving prognosis. However, the diagnostic yield of histologic examination by endomyocardial biopsy (EMB) in CS is usually low. We report the case of isolated CS histopathologically proven by electroanatomical voltage mapping (EVM)-guided EMB combined with cardiac magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). A 53-year-old man presented with general fatigue. Electrocardiography showed intermittent complete atrioventricular block and echocardiography showed reduced cardiac function. CMR showed late gadolinium enhancement (LGE) in the areas of myocardium with suspected sarcoidosis. Next, we performed an EVM-guided EMB and found a non-caseating epithelioid granuloma in the right ventricular septum, which showed low voltage on EVM and LGE on CMR. FDG-PET showed accumulation in the same cardiac region. This case shows that EVM-guided EMB combined with diagnostic imaging can be a valuable approach in cases of suspected isolated CS.
<Learning objective: To reduce inflammation and prevent ventricular remodeling by early corticosteroid treatment, detecting cardiac sarcoidosis (CS)-affected regions is important. Cardiac magnetic resonance imaging and positron emission tomography help detect such regions. However, histopathological diagnosis of CS by endomyocardial biopsy (EMB) is usually difficult. The present case suggests that electroanatomical voltage mapping-guided EMB combined with diagnostic imaging improves detection of CS-affected regions.>
Sarcoidosis is a multisystem non-caseating granulomatous disease of unknown etiology. The rates of cardiac involvement in sarcoidosis have been reported to be higher in patients from Japan than in those from Europe and the USA [
]. Cardiac involvement in patients with sarcoidosis affects cardiac function and causes ventricular failure, disrupts the cardiac conduction system, and leads to advanced atrioventricular (AV) block, malignant ventricular tachycardia (VT), and sudden cardiac death. Therefore, early diagnosis and treatment of this progressive and potentially severe condition are critically important.
The detection rates of non-caseating epithelioid granulomas by endomyocardial biopsy (EMB) in patients with cardiac sarcoidosis (CS) have been reported to be only 20% [
]. Therefore, the histopathological diagnosis is not easy especially in patients with isolated CS.
Diagnostic imaging methods such as cardiac magnetic resonance imaging (CMR) and positron emission tomography (PET) have been advancing rapidly. In patients with CS, a scar or intense inflammation can expand the extracellular space and causes a slower washout of gadolinium, resulting in areas of late gadolinium enhancement (LGE). PET with 18F-fluorodeoxyglucose (FDG) is also useful in detecting infection and inflammation foci in patients with cardiomyopathy. Both CMR and FDG-PET are effective in assessing the extent and degree of disease in sarcoidosis [
]. There have been no reports of histopathological diagnosis by EVM-guided EMB combined with diagnostic imaging in patients with suspected isolated CS.
In the current report, we present a case of CS diagnosed by EVM-guided EMB of an affected cardiac area with abnormal electrical activity, selectively combined with CMR and PET imaging.
A 53-year-old man was referred to our department because of aggravating dyspnea for several months, enlargement of the cardiac silhouette on chest radiograph, reduced cardiac function on echocardiography [left ventricular ejection fraction (LVEF) of 38%], and intermittent complete atrioventricular block (cAVB) on electrocardiography. He reported dyspnea and fatigue during work and AV block was detected on a medical examination earlier in the year.
At the first physical examination, his blood pressure was 116/72 mmHg. There were no rales and murmurs on auscultation, and no edema was noted on the extremities. He was diagnosed as having New York Heart Association (NYHA) functional class II, and his B-type natriuretic peptide (BNP) level was 98.5 pg/mL. His angiotensin-converting enzyme level was 10.3 IU/L (8.3–21.4 IU/L), and lysozyme level was 5.0 μg/mL (5.0–10.2 μg/mL). Thoracic computed tomography (CT) scan showed no hilar lymphadenopathy. Echocardiography showed low LVEF (35%), and thinning of the basal septum. His CMR showed a significantly increased signal intensity of LGE in the anteroseptal area and entire circumference of the area of basal and lateral wall (Fig. 1). Despite negative Ga-67 imaging, CS was suspected based on the significantly hyperintense epicardial LGE signal on CMR. Cardiac catheterization showed a left ventricular aneurysm and no significant coronary stenosis. Myocardial tissue samples were taken from the right ventricular (RV) apex during the first catheterization, but the biopsy failed to capture a non-caseating epithelioid granuloma.
The patient met the major criteria for a diagnosis of CS, according to the revised Japanese Ministry of Health, Labour and Welfare guidelines for the diagnosis of CS [
]: cAVB, thinning of the septum, and reduced LVEF. Apart from the heart, no other areas of suspected sarcoidosis were detected in the other organs. Histopathological analysis of the affected cardiac region was necessary for a diagnosis of isolated CS.
Therefore, we performed an EVM-guided EMB (Fig. 2A) , performed concomitantly with induction and ablation of VT. In this study, sustained monomorphic VT was induced by RV apex pacing, but that was unmappable. We made a RV voltage map and recognized that the low voltage area from basal to mid lateral and basal to mid septal RV wall (Fig. 2B) was the same region as the increased LGE signal intensity area on CMR, and performed a biopsy of the mid septal RV wall. Selective EMB of the low-voltage areas was performed using a bioptome (Boston Scientific Corp., San Jose, CA, USA) with a 6-Fr long sheath placed into the right femoral vein.
The abnormal FDG accumulation only in the heart suggested isolated CS (Fig. 3A and B ). A fused PET and CT image was reconstructed and significant myocardial FDG uptake was found in the basal septum (Fig. 3C). Histopathologically, isolated CS was diagnosed because of the presence of a non-caseating epithelioid (positive for CD68) granuloma (Fig. 2C).
Following diagnosis, the patient was started on prednisolone 30 mg daily for CS, and carvedilol 2.5 mg and enalapril 2.5 mg daily for heart failure. Because sustained VT was induced by the electrophysiological study, and the patient had intermittent cAVB and reduced cardiac function, he underwent cardiac resynchronization with an implantable cardioverter-defibrillator (CRT-D) for primary prevention of sudden cardiac death. After six months, steroid therapy was gradually tapered to 15 mg daily and echocardiography did not show improvement of cardiac function, although FDG-PET showed a marked decrease in size of the affected area. His cardiac status was NYHA functional class I; plasma BNP level was 51.2 pg/mL, and he had no episodes of ventricular tachyarrhythmia one year after discharge.
Sarcoidosis is a systemic disease with formation of non-caseating epithelioid granulomas in organs such as the lungs, lymph nodes, skin, eyes, heart, and muscles. Sarcoidosis generally has a spontaneous remission; however, complication with cardiac involvement may contribute to poor prognosis [
]. Therefore, CS should be diagnosed before irreversible damage occurs; however, early diagnosis and treatment of isolated CS are difficult because histopathological diagnosis is not easy. According to a report of autopsy cases of sarcoidosis, only 26% were diagnosed with sarcoidosis during their lifetime [
]. In particular, it is difficult to diagnose and treat isolated CS cases in which other organs are not affected. Epithelioid granuloma detection was extremely important in making a histopathological diagnosis in these cases. EVM-guided biopsy of an area of abnormal electrical activity, combined with diagnostic imaging, is useful for histopathological diagnosis of isolated CS with focal involvement.
In our case, a non-caseating epithelioid granuloma was not detected by the first catheter biopsy of the apex of the heart. Therefore, we performed an EVM-guided EMB of the mid septum, which was the site of abnormal electrical activity. We recognized that the low voltage area was the same region as the increased LGE signal intensity area and the inflamed region in the fused PET and CT image. There are some reports indicating that EVM-guided EMB can help in the diagnosis of isolated CS [
]. In cardiomyopathy, histopathological myocardial affection is often only focal. In this case, we could detect a non-caseating epithelioid granuloma in a low-voltage area that was the same as the inflamed region in CMR and PET images. To detect histopathological CS areas, selective EVM-guided EMB of the cardiac areas of abnormal electrical activity, combined with diagnostic imaging techniques, such as CMR and PET, may be useful.
Vasaiwala et al. report that three of the 20 (15%) suspected arrhythmogenic RV cardiomyopathy/dysplasia (ARVC/D) cases were finally diagnosed as CS by myocardial biopsy [
]. The distinction between ARVC/D and CS is sometimes difficult because of an overlap in their clinical presentation and CMR findings, and because all types of ventricular arrhythmias in ARVC mimic those in CS. Ejima et al. reported that EVM-guided EMB allowed a definitive diagnosis of ARVC/D [
]. Because the definitive diagnosis of CS by detection of a non-caseating epithelioid granuloma is important to decide on initiation of early steroid therapy, the EVM-guided EMB may be useful in differentiating CS from other cardiomyopathies.
Imaging techniques developed have contributed to accurate diagnosis of sarcoidosis; however, imaging alone does not lead to a histopathological diagnosis. Ga-67 scintigraphy has been used for detection of inflamed regions in sarcoidosis, but the sensitivity of sarcoid region detection is low. Delayed enhancement on CMR has the advantage of providing a high contrast between normal and abnormal tissue and portends multiple advantages for the detection of cardiac granulomatous infiltration [
]. It is assumed that parts of non-caseating epithelioid granulomas can be detected by an LGE pattern on CMR. Therefore, EVM-guided EMB was performed at the same region as the increased LGE signal intensity area. It has been reported that PET imaging is also useful for detecting sarcomatoid lesions and is an established method for evaluating disease activity [
]. The combination of PET and CT allowed identification of the focal activity of isolated CS in this case.
We reported a case of isolated CS that was diagnosed by EVM-guided EMB of the affected area, combined with CMR and PET imaging. The EVM-guided EMB of the cardiac area with abnormal electrical activity, as detected by an LGE pattern on CMR, is useful for histopathological diagnosis of isolated CS.
Conflicts of interest
The authors declare that there is no conflict of interest.
This work was supported by JSPS KAKENHI Grant Number 15K21388 .