The Harm of Delayed Diagnosis of Arrhythmogenic Cardiac Sarcoidosis

A Case Series

Jarieke C. Hoogendoorn; Maarten K. Ninaber; Sebastiaan R.D. Piers; Marta de Riva; Robert W. Grauss; Frank M. Bogun; Katja Zeppenfeld

Disclosures

Europace. 2020;22(9):1376-138. 

In This Article

Discussion

This study aimed to evaluate the diagnostic- and disease course of patients with arrhythmogenic cardiac sarcoidosis. The main findings can be summarized as follows: (i) cardiac sarcoidosis is an important differential diagnosis in patients referred for VT ablation with a prevalence of 12% among patients with 'idiopathic' non-ischaemic cardiomyopathy, (ii) in 67% of patients, the diagnosis of ACS was delayed, despite typical presentation with VT or AV-block, (iii) in none of the patients with delayed diagnosis 18F-FDG-PET was performed at first presentation, (iv) in 60% of patients with delayed diagnosis, CS was suspected after electroanatomical voltage mapping, (v) delayed diagnosis of ACS had harmful consequences, with irreversible deterioration of cardiac function in 60% and a high mortality (50%).

Cardiac Sarcoidosis as Underlying Aetiology in Patients Presenting With Ventricular Tachycardia

Ventricular arrhythmias are a typical clinical manifestation of CS. Retrospective studies have shown a prevalence of 5–8% among patients with non-ischaemic cardiomyopathy (NICM) referred for ablation of ventricular arrhythmias.[12,13] Interestingly, prospective studies performing 18F-FDG-PET in all patients presenting with monomorphic sustained VT with idiopathic NICM, report a definite diagnosis of CS in up to 17–29% of patients.[14,15] The current study shows a prevalence of 12% in a retrospective idiopathic NICM cohort referred for VT ablation (both left- and right-sided) after exclusion of all other known causes. This is slightly higher than in previous retrospective studies, which can be explained by the comprehensive evaluation of our patients referred for ablation, including genetic testing and detailed EAVM substrate mapping.[16]

Importantly, CS is not only an important differential diagnosis in patients referred for VT ablation, but also in patients presenting with ventricular arrhythmias. In our population, 67% of patients had an early arrhythmogenic presentation, frequently without additional AV conduction abnormalities. This high proportion of patients presenting with VT as initial symptom without previous AV block, can be partly explained by the inclusion criteria. Atrioventricular block is the most frequent cardiac presentation of CS. Of interest, in a Finnish registry including symptomatic CS patients, 33% presented with ventricular arrhythmias (including sudden cardiac death) without additional AV block,[4] suggesting that VT without AV block is not a rare finding. Moreover, in a population more similar to this series, namely a VT ablation population, 74% of patients had a first presentation with ventricular arrhythmias (including premature ventricular complexes (PVCs) and non-sustained VTs])[10]

Strikingly, in the current study, electroanatomical voltage mapping (EAVM) prompted suspicion for CS in 60% of cases with delayed diagnosis. At EAVM, patients with CS seem to have a more patchy and better demarcated scar pattern compared to other aetiologies,[13,17,18] which is in line with autopsy findings.[1] This, together with the high prevalence among patients referred for VT ablation and the frequency of arrhythmias as first presentation, supports the important role of electrophysiologists in diagnosing CS as underlying aetiology.

Arrhythmogenic Cardiac Sarcoidosis is Initially Frequently Misdiagnosed

In our cohort, the diagnosis of CS was significantly delayed in 67% of patients with a median time of 24 months, comparable with previous studies in patients with CS. In patients with 2nd or 3rd degree AV block, 56% of patients had a delay in diagnosis of CS, with a median time to diagnosis of 23 months.[4] In a VT-ablation cohort, a median delay of 24 months has been described.[10]

There are several explanations for this important delay. First, CS is known as the great masquerader, which can mimic other cardiac conditions.[7,8] Second, the diagnostic yield of EMB for showing the gold standard for diagnosis, the typical non-necrotizing granulomas,[5,6] is low (although can be increased by cumulative EMB and mapping-guided biopsy).[3,5] However, in 90% of patients with delayed diagnosis in our population, EMB was not performed at first cardiac presentation because CS was not suspected.

Third, with evolving imaging techniques, diagnosis can also be made with 18F-FDG-PET and/or CMR, but, similarly to biopsy, in none of the studied patients with delayed diagnosis 18F-FDG-PET was performed. This is comparable with a previous report including CS patients presenting with a complete AV-block, where in none of the patients with delayed diagnosis 67Ga Scintigraphy and/or 18F-FDG-PET was performed.[19]

Last, the diagnosis might be confirmed by positive extracardiac histology with cardiac symptoms, but extracardiac symptoms are frequently absent.[3,19] However, despite absence of extracardiac complaints or involvement, it can be worthwhile to perform additional pulmonary diagnostic testing. A mediastinal lymphnode biopsy and/or bronchoalveolar lavage confirmed diagnosis in 84% of patients with suspected CS without extracardiac complaints, regardless of imaging findings.[20]

To conclude, a delay in diagnosing CS is not only due to diagnostic challenges, but can be mainly attributed to the fact that diagnostic tests (such as biopsy and/or 18F-FDG-PET) are not initiated. Therefore, major improvement may be achieved by a comprehensive evaluation of all patients with a VT substrate of unknown aetiology.

Harmful Consequences of Delayed Diagnosis

Interestingly, patients with early diagnosis had a relatively preserved cardiac function when started on treatment and function remained stable. On the contrary, 60% of patients with delayed diagnosis had already a moderately to severely decreased function at the time of diagnosis, which did not improve despite immunosuppressive treatment.

Previously, in patients with CS presenting with complete AV-block, the same trend was observed with a benefit of early diagnosis.[19] Although patient populations are small, corticosteroid therapy seems to maintain cardiac function in patients with preserved function, improve function in patients with mild-moderate dysfunction and does not have effect in patients with severely decreased function.[21] These findings suggest that there may be a tipping point, after which cardiac function is beyond repair.

Hence, delayed diagnosis of ACS is likely to have harmful consequences leading to irreversible cardiac dysfunction, higher morbidity (more VT ablation and heart failure admissions) and higher mortality. Based on our study results, we strongly recommend to perform additional diagnostic tests (LGE-CMR and 18F-FDG-PET) in every patient presenting with VT of unknown aetiology. If the 18F-FDG-PET shows extracardiac FDG-uptake, we aim to obtain extracardiac histological confirmation. If there is no extracardiac FDG-uptake, we have currently introduced mapping-guided biopsy.[22]

Limitations

This is a retrospective case series with a small sample size from a tertiary referral centre. Therefore, the overall prevalence of CS among patients referred for VT ablation might be overestimated. However, the prevalence might also be underestimated, since not all idiopathic NICM patients underwent LGE-CMR, 18F-FDG-PET and/or biopsies and a negative 18F-FDG-PET does not exclude the presence of CS. In addition, the included patients were from a highly selected population (referred for VT ablation) and therefore described results cannot be extrapolated to other cohorts.

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