Risk Stratification for Sudden Cardiac Death in Sarcoidosis

Mohammad Sahebjalal MBBS MRCP,
Specialist Registrar in Cardiology WSHFT
Western Sussex Hospitals NHS Foundation Trust

Mark A Tanner MD MRCP
Consultant Cardiologist and Honorary Senior Clinical Lecturer
Western Sussex Hospitals NHS Foundation Trust & National Heart & Lung Institute, London

Abstract

Sarcoidosis is a multi-system disease of unknown aetiology characterised by the presence of non-caseating granuloma. Symptomatic cardiac involvement occurs in about 5% of patients with systemic sarcoidosis and is associated with heart failure, conduction abnormalities and sudden cardiac death. Sudden death due to ventricular arrhythmia remains a leading cause of death in this population and in this editorial we review the evidence for risk stratification in patients with cardiac sarcoidosis.

Introduction

Sarcoidosis is a multi-system granulomatous disease of unknown aetiology. Systemic sarcoidosis affects the respiratory system or mediastinal lymph nodes in more than 90% of cases, but any organ can be involved [1].  Studies have suggested that symptomatic cardiac involvement occurs in about 5% of patients with systemic sarcoidosis although other data indicate that many patients with systemic sarcoidosis have asymptomatic cardiac involvement [2-5].

Sarcoidosis is a worldwide disease, with a prevalence of 4.7-64 in 100,000. The reported prevalence and incidence varies widely and is strongly influenced by race, gender and geographical location [1,6].

Cardiac Sarcoidosis

Cardiac manifestations range from asymptomatic conduction abnormalities to sudden arrhythmic death, depending upon the location, stage, and extent of the granulomatous process. Ventricular arrhythmias are most likely related to a macro-reentrant circuit surrounding an area of granulomatous scar [2, 7-13]. Additionally, triggered and abnormal automaticity have also been described in relation to the acute inflammatory process [14,15].

Prognosis in Cardiac Sarcoidosis
Sarcoid patients with cardiac involvement have an increased mortality compared to those without, and cardiac complications account for the majority of deaths in sarcoidosis [10,16]. In cardiac sarcoidosis (CS) sudden cardiac deaths are estimated to account for between 27% and 67% of deaths. An estimated 25%-73% are secondary to progressive heart failure [12,13,17].

Predicting Sudden Cardiac Death
Left Ventricular function
In a systematic review of mortality data in CS, Yazaki et al  reported a 5-year survival rate of 89% in patients with a left ventricular ejection fraction of greater that 50% [12]. In this study, they assessed 12 clinical variables as possible predictors of mortality of which severity of left ventricular dysfunction was one the most important independent predictors of mortality.  Similarly, Chiu et al found that all patients with normal left ventricular function were alive at 10 years whereas the survival rate was just 19% (at 10 years) in patients with severe LV dysfunction [12-19].

Further insights into arrhythmic risk as related to LV function have been gained from reports of Implantable Cardioverter Defibrillator (ICD) therapies in the CS population.
  
Compared to general ICD cohorts studies have reported a relatively high frequency of ICD therapies in the CS population [18]. Three studies have reported that a lower LVEF is associated with appropriate ICD therapy [22-24]. Schuller et al performed a cohort study of patients with ICDs and found that 32% of patients with LVEF < 55%, received appropriate therapy. Arrhythmic events also occur in CS patients with relatively mild LV impairment. Betensky et al showed that 41% of patients with appropriate therapy had an LVEF>35% [23]. Conversely, Schuller et al, showed that in their primary prevention cohort, no patient with normal LV and RV function received an appropriate therapy.

Programmed Electrical Stimulation
The role of programmed electrical stimulation (PES) in CS risk stratification was examined by Mehta et al [24]. This population had biopsy confirmed extra-cardiac sarcoidosis with evidence of CS based on imaging (CMR or PET) but did not have arrhythmic symptoms.  76 patients with CS underwent PES with eight patients having inducible arrhythmia. Over a 5 year follow up the event rate was 75% in PES positive group (2 patients died and 4 had appropriate ICD shocks for ventricular tachycardia (VT)) and 1.5% in the PES negative group. There were no cardiac deaths, symptomatic ventricular arrhythmia, or ICD implants in the PES negative group.   

It is important to note that PES positivity correlated with the degree of LV dysfunction. Patients with positive PES had a mean baseline LVEF of 36.4% (+/- 4.2%) compared to a mean LVEF of 55.8% +/- 1.5% in the negative PES group. However, it is worth noting that those patients with a reduced ejection fraction and negative PES  (37% of patients) were not at higher risk of events over the follow-up period. This led the authors to conclude that CS patients with a negative PES appear to have a benign course. A positive PES in patients with CS and LVEF >35% may help identify those at risk of ventricular arrhythmia who will benefit from a primary prevention ICD. Applicability to a larger sarcoid population would require a larger study with higher event rates and it remains unclear whether positive PES is more predictive of events than an estimation of LVEF.

Whilst recognizing the data limitations a recent HRS expert consensus document recommended that an electrophysiological study may be considered in CS patients with LVEF >35% to assist in risk stratification [15].

Cardiac MRI
Cardiac magnetic resonance imaging (CMR) is an established tool in the diagnosis of CS (see Figure 1 for example). There is also emerging evidence for the prognostic utility of CMR [27-30]. Patel et al reported on 81 patients with biopsy proven extra-cardiac sarcoidosis who underwent Late Gadolinium Enhancement (LGE) CMR. 26% of patients were identified as having changes consistent with myocardial damage on LGE. The LGE positive patients had a 9-fold higher rate of adverse events and an 11.5-fold higher rate of cardiac death than patients without damage [27].

In another study, 155 patients with CS underwent CMR with LGE. 39 patients had a positive LGE scan out of which 11 patients had sudden cardiac death or ventricular arrhythmia during the follow up period.  In this study the presence of LGE had a Cox hazard ratio of 31.6 for death, aborted sudden cardiac death or appropriate ICD discharge, which was shown to be superior to only LVEF [28].

Cardiac Positron Emission Tomography (PET)
A significant myocardial uptake of 18F-fluorodeoxyglucose (FDG) in sarcoid patients can be used to identify patients with cardiac involvement. The potential to use this technique for prognostic purposes has been explored in a recent study. Blankstein et al reported on 118 patients referred for PET evaluation of suspected CS. The presence of both a perfusion defect and an abnormal FDG uptake (seen in 29% of patients) was associated with death or sustained VT even after adjusting for LVEF [31]. In another small study, patients with CS and VT had significantly more FDG uptake as compared with CS patients with AV block and asymptomatic controls [32].

Thus cardiac PET might be helpful in identifying at risk CS patients but currently there is insufficient data to support a clear role in risk stratification [18].   

Indications for ICD

As a relatively rare condition it follows that there is an absence of randomized trial data to inform the indications for ICD therapy in the CS population. In the recent HRS expert consensus document it was agreed that the recommendation from the general ICD guideline for primary and secondary prevention should also be applied to the CS population [18].

The conventional LVEF threshold for (primary prevention) ICD consideration is ≤35% [20,21]. However, as described earlier there is evidence to suggest that in CS this threshold might not be appropriate. Data from ICD trials show a high rate of appropriate therapies in sarcoid cohorts and importantly it has been observed that even where LV function is mildly suppressed there remains significant rates of ventricular arrhythmia [22-24]. Kron et al reported that most primary (and secondary) prevention patients who received appropriate ICD therapies had an LVEF of above 35%.

Heart Rhythm Society Expert Consensus Recommendations [18]
The observation of increased arrhythmic risk in relatively mild LV dysfunction is reflected in the recent HRS document, lending a class IIb recommendation for consideration of ICD therapy in patients with LVEF 36%–49%  (despite optimal medical therapy).  

Whilst the prognostic significance of LGE on MRI was acknowledged only a minority of the panel voted in favour of including the presence of LGE as a IIb indication for ICD insertion. However, in the group of normal LVEF with LGE the writing group suggested that further risk stratification with PES might be considered.  

Further details of the HRS recommendations are outlined in Table 1.

Conclusions

Sudden arrhythmic death remains a leading cause of mortality in patients with sarcoidosis. Data for risk stratification for sudden cardiac death are limited and LV ejection fraction appears to be the most important predictor. Additional markers of risk might include LGE on CMR and Inducible arrhythmias provoked by PES. Until more robust data is available decisions regarding ICD implantation are likely to be best informed by a multi-disciplinary approach and reference to the recent HRS consensus statement.

Figure 1 Left panel demonstrates CMR LGE in 4 chamber view. Arrows indicate mid-wall septal and lateral wall changes indicative of myocardial fibrosis. Right panel demonstrates basal short axis appearances with fibrotic changes in septal sub-epicardial locations in addition to more extensive fibrosis in the antero-septal wall (top arrow). Images courtesy of Hatef Mansoubi, Western Sussex Hospitals Foundation Trust. 

Table 1- HRS Expert Consensus Recommendations for ICD Implantation in Patients with Cardiac Sarcoidosis [18].

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