Cardiac Sarcoidosis: Epidemiology, Characteristics, and Outcome Over 25 Years in a Nationwide Study

Background

This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. Systemic sarcoidosis is considered to be involving the heart in the minority of cases but sometimes the disease may be confined to the heart. The clinical manifestations vary from asymptomatic to heart failure, AV conduction block and sudden death. Because data on diagnosis, prognosis and treatment of this rare condition are based on case series and selected populations disease management constitutes a challenge. The authors collected data on all cases of histologically confirmed CS in Finland over the last 25 years focusing on the epidemiology, characteristics, and long-term outcome of CS.

Methods

Cases of CS from years 1988-2012 were identified from the discharge, pathology, and device registries of the member institutions of Myocardial Inflammatory Diseases in Finland (MIDFIN) Study Group and from 17 central hospitals covering all of  Finland. Data were collected on patient demographics, symptoms, clinical manifestations, imaging and laboratory studies as well as invasive procedures, details of treatment and the occurrence of adverse cardiac events. The inclusion criteria  were sarcoidosis histology in extracardiac tissue or endomyocardial biopsy combined with clinical manifestations indicative of a myocardial disease and compatible abnormalities on imaging (echo-Doppler or CMR or FDG-PET). The histological diagnosis of sarcoidosis required the presence of non-necrotizing epithelioid cell granulomas with isolated giant cells and the absence of both myocardial necrosis and more than solitary eosinophils.

Changes in LVEF over the first year of steroid therapy were analyzed with the paired Student t test. Survival curves were plotted according to Kaplan–Meier method. Cardiac death, a composite of cardiac death and transplantation (whichever came first), and a composite of cardiac death+transplantation+aborted sudden cardiac death were defined as end points. The analyses were made in the total population and after the exclusion of  cases diagnosed only at transplantation or autopsy (n=8).

Results

110 cases were included (51±9, 27-69 yr., 65% females). There was a marked increase (x20) in the rate of CS diagnosis over time. Fifty five (50%) were diagnosed on cardiac biopsy, 47 on extracardiac biopsy and 6/2 in the explanted heart/autopsy, respectively. CS was confined to the heart in 65%, i.e. isolated CS. The median time from the first cardiac manifestation to diagnosis was 9.0 months (range, 0.3–168).  The initial cardiac manifestation was AV block in 44%, VT/VF in 33% and heart failure in 18%. On ECG 45% had advanced AV block, 37% had RBBB and 21% - LBBB. Left ventricular systolic dysfunction was found in 59% and delayed gadolinium enhancement on CMR was found in 83%; these were more common in isolated CS. Abnormal myocardial uptake of FDG was found in ~70%. Elevated serum ACE, lysozyme  and hypercalciuria were found in ~50% and these were relatively uncommon in individuals with isolated CS.

Steroids were given to 102/110 and other immunosuppressors (mostly azathioprime) to 62. Steroids went uninterrupted in 48, were given intermittently in 54 but had to be discontinued in 4 patients. ICD was impanted in 59% and permanent pacemaker in another 29%.

On median follow up of 79 (12-303) months, 10 experienced a cardiac death (9 sudden) and 11 underwent heart transplantation. Another 11 had ventricular fibrillation  as their first cardiac event: either aborted sudden death (n=8) or an appropriate ICD shock for VF (n=3). Six died from non-cardiac causes.

An appropriate ICD treatment for VT was delivered in n=15 but that was not included in the end-point analysis.

Isolated CS, reduced LVEF, congestive heart failure at presentation and higher NYHA class were associated with adverse prognosis. A year of steroid therapy did not lead to an improvement of LVEF in the entire cohort but was beneficial for those with severely impaired LV function (28+4 to 34+8%, p<0.005). Recovery of AV conduction occurred in 20% of those who received a pacer for AV block.

Discussion and Conclusion

The authors point to the marked increase in the diagnosis of CS with contemporary diagnostic modalities and a remarkably favorable 91% transplant-free cardiac survival in patients who received an immunosuppressive and appropriate device therapy. The 2012 prevalence of clinically manifest CS in Finland was 22 patients per 1 million adult population. According to the latest data, 5.3 new cases of CS per 1 million adults are diagnosed and need treatment each year. The true prevalence of cardiac sarcoidosis may still be underestimated because the diagnostic modalities (biopsy, FDG-PET and CMR with gadolinium) are not routinely used for cardiac evaluation, in particular in mildly symptomatic patients. Isolated CS is associated with particularly adverse prognosis because of advanced disease due to a delay in diagnosis and a high prevalence of malignant arrhythmia on presentation.

The authors summerize that the majority of clinically isolated CS is characterized by female preponderance, a more severe LV involvement, less frequent elevation of laboratory markers. The 10 year probability of transplant free cardiac survival was 83% and 91% in those receiving immunosuppressive therapy. Heart failure, LVEF <35% and isolated CS type predicted impaired event-free outcome. 

Comment

Cardiac involvement is a major cause of mortality in sarcoidosis. In the past many have been diagnosed on autopsy suggesting that sudden death is a common cause of mortality in CS. Others have been diagnosed in an explanted heart. The real prevalence of CS, of cardiac involvement in cases of systemic sarcoidosis and the presence of extracardiac involvement among those diagnosed as isolated CS varied between series and depends on various inclusion bias as well as the stringency of diagnostic criteria. Isolated CS  requires demonstration of typical histological findings in myocardial tissue (1). Because of various problems of this technique including low sensitivity (20-30%) this crucial diagnosis may be missed. Kandolin et al adopted a protocol to collect up to 12 biopsy samples under echo guidance (2). Of 72 patients with unexplained AV block they diagnosed CS in 14 (19%) and 9 of those had isolated CS (3).

Biomarkers and markers of systemic inflammation are also less useful in isolated CS.  There appears to be a role for high sensitivity troponins and BNP in diagnosis and activity monitoring in CS but their value requires further validation (1).

The JSSOG adopted the following algorithm to diagnose CS in the presence of extracardiac disease. Two major or 1 major + 2 minor of both clinical and imaging criteria are required:

It is important to note that many patients with extracardiac sarcoidosis have an asympthomatic cardiac involvement while other have a minor involvement which does not satisfy the above criteria. For example, in the study by Nagao et al (4) of 274 patients diagnosed with extracardiac sarcoidosis 10 had cardiac involvement at baseline evaluation and another 37 developed it in the course of the first year of follow up. Among the remaining 227 with no cardiac manifestations, 25% still had ECG abnormalities and those were associated a markedly increased event rate (23.8 vs 1.5 per 1000 person*years).

The algorythm for diagnosing isolated CS requires high index of suspicion, ruling out coronary artery disease, other forms of myocarditis and then searching for systemic granulomatuous disease (1). While  endomyocardial biopsy remains a gold standard, certain imaging results (such as interventricular septal wall thinning to less than 4 mm) are highly specific to cardiac sarcoidosis.

CS is an indication for immunosuppressive therapy although the threshold for initiating therapy for minor cardiac abnormalities is not established. Most experts start with Prednisone 40 mg/day and attempt to taper down to 10 mg/day and below within 6 months. There is no concensus how to use immunomodulators for steroid sparing and whether/when to discontinue completely the steroids. There are no established guidelines  how to monitor the disease activity in the heart during tapering and discontinuation of therapy (5). The paper of the month (6) does not specify if there were differences in outcome between patients who were on permanent steroids compared to those who discontinued. While many are entusiastic about primary prevention ICD in patients with CS (54% of the patients reported in the paper of the month received an ICD, most for primary prevention), there is no concensus on this topic. Noteworthy, while 20 subjects from 102 had a Sudden Death event, only 3 of 59 with ICD had a discharge for VF during a rather lengthy follow up (6). Other 15 had a therapy for VT which was (correctly) disregarded as an endpoint. It remains to be found out to what extent the risk of arrhythmia is reduced by immunosuppressive therapy and in which subgroups.

 ICDs are not without risk in subjects receving immunosuppresion and are associated with increased prevalence of inappropriate shocks due to atrial arrhythmia in CS (5).  There is a consensus on impanting a device in CS with LVEF ≤ 35% despite optimal medical therapy. Some recommend to use a DDD ICD once an indication for pacing is present although in such individuals an electrophysiological study may help with decision making.  Inducible VT in CS often responds well to radiofrequency ablation, what may sometimes be used to avoid device implantation. Finally, a wearable defibrillator (VEST) may be used as a bridge to decision in those cases where immunosuppression is given to improve LV function or then the long term of an ablation procedure needs to be accertained.