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Cardiac oxidative stress: a potential tool for risk stratification in cardiac sarcoidosis

Sarcoidosis is a progressive disease of unclear aetiology with most evidence supporting an aberrant immune response to an unidentified antigen(s) in genetically predisposed individuals. Clinical cardiac manifestations occur in 5% of patients with systemic sarcoidosis. Subclinical cardiac involvement has been described in 20%–25% of patients in autopsy studies with further validation from cardiovascular MRI studies. Cardiac sarcoidosis (CS) is characterised by inflammatory noncaseating myocardial granulomas and myocardial fibrosis. Importantly, this condition is associated with various cardiac manifestations, ranging from heart failure to conduction defects, ventricular arrhythmias and sudden cardiac death (SCD). Recent registry findings of 351 patients in the MIDFIN registry from Ekström et al suggest that up to 14% of patients with CS had a presenting manifestation of SCD. Furthermore, of all the deaths recorded in this registry, 64% (n=54/84) were unexpected SCD and cardiac involvement detected at autopsy. The emerging data on the association of ventricular arrhythmias with myocardial scar in patients with CS, diagnosed by cardiac MRI, have led to its incorporation into the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guidelines for primary prevention of SCD. As a result, a large proportion of patients diagnosed with CS now fulfil class I or IIa criteria for implantable cardioverter defibrillator (ICD) implantation. A recent metaanalysis of 19 studies found crude rates of SCD/aborted SCD are high in primary prevention (23%) and secondary prevention (58%) of patients with CS. In this condition that is already challenging to diagnose and detect, the risk of SCD is high, and an appropriate selection of patients for appropriate ICD therapy is crucial. Despite this, over the years, risk stratification for SCD and selection of patients appropriate for primary prevention of SCD have proven challenging, particularly in the absence of overt cardiac symptoms. The rarity of this condition further complicates this, making prospective cohort studies with large sample sizes uncommon and challenging to execute. Myocardial scarring and also active inflammation have been implicated in the development of fatal ventricular arrhythmias. Electrophysiological study, cardiac MRI and positron emission tomography (PET) imaging provide critical information on the inducibility of ventricular arrhythmias, myocardial scarring and active inflammation, respectively, and are associated with increased risk of sudden death and major adverse cardiac events. The absence of late gadolinium enhancement (LGE) on cardiac MRI predicts not only low risk of ventricular arrhythmias but also futility of electrophysiology study in such patients with suspected or ‘possible’ CS and normal cardiac MRI. 6 The current guidelines recommend a stepwise approach using these prognostic tools to determine if ICD implantation is appropriate. Interestingly, a recent evaluation of the 2017 AHA/ACC/HRS guidelines by Takenaka et al found that of the 188 consecutive patients diagnosed with CS clinically, 179 patients (95%) fit either class I (n=82) or class IIa (n=97) indications for an ICD. Of these, the annualised event rate (AER) was 4.93% in class I indication patients and 2.06% in class IIa indication patients. A study by Kazmirczak et al demonstrated similar findings with an AER of 2.38% for patients with CS and left ventricular ejection fraction (LVEF) >35% and any LGE. This event rate is higher than the threshold of calculated 6% SCD risk over 5 years in patients with hypertrophic cardiomyopathy for recommending primary prophylaxis ICD. LGE burden >5.7% was shown to improve risk stratification in CS, consistent with other studies. ACE, soluble interleukin2 receptor and troponin have been investigated for their role in diagnosing and managing sarcoidosis but are not ready for clinical use. Urinary 8hydroxy2’deoxyguanosine (8OHdG) similarly shows promise and is a specific, accurate and established biomarker for cellular oxidative stress, measured by a simple urine sample economically and efficiently by ELISA. This surrogate marker for oxidative stress has already been shown to correlate with activity on PET scan, oxidative stress on myocardial biopsy and a history of ventricular tachycardia in patients with CS. Interestingly, this correlation appears to remain unchanged even in the context of active pulmonary sarcoidosis, indicating that this biomarker is not influenced significantly by systemic extraCS. Resultantly, this noninvasive test may prove promising for prognostic stratification and subsequent management of patients with CS. In this context, this journal issue presents a prospective study by Yoshitomi et al on the utility and prognostic stratification of patients with CS (article reference). Having previously shown the promising use of urinary 8OHdG in CS, this research group sought to prospectively enrol and followup 61 patients with CS who had active inflammation on PET scan. As urinary 8OHdG can be elevated in patients with heart failure, New York Heart Association III and IV patients were excluded to prevent confounding results. During a median followup of 46 months, 12 patients experienced sustained ventricular tachycardia and three experienced SCD. After adjusting for baseline factors, quantitative urinary 8OHdG was associated with a 1.118fold increased risk of these composite outcomes per ng/ mg·Cr. Similarly, the presence of ventricular aneurysm at baseline was associated with a 4.180fold increased risk of SCD at followup. Notably, the authors found an optimal cutoff value of 14.9 ng/mg·Cr for urinary 8OHdG measurements. Active inflammation on PET scan with urinary 8OHdG lower than 14.9 ng/mg·Cr was associated with 0.6 event/100 patientyears, whereas those with higher values experienced 12.3 events/100 patientyears. Despite these promising findings, there is a significant limitation in the number of patients that underwent cardiac MRI (n=33, 54%) or electrophysiology study (n=16, 26%). This led to underpowering of these important prognostic markers for multivariate analysis. In addition, the exclusion of PET negative patients makes it difficult to contextualise the prognostic power of this biomarker in comparison to current gold standard tools. The same limitation holds true for the ventricular School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia Royal Adelaide Hospital, Adelaide, South Australia, Australia Department of Cardiology, Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia