Enhanced oxidative stress and presence of ventricular aneurysm for risk prediction in cardiac sarcoidosis

Abstract

Objective: Sudden cardiac death (SCD) is the major cause of death in cardiac sarcoidosis (CS). We aimed to identify the prognostic markers for sustained ventricular tachycardia (sVT) and SCD in patients with CS.

Methods: We performed a prospective observational cohort study for patients with CS diagnosed according to the Japanese or Heart Rhythm Society guidelines between June 2008 and March 2020 in our hospital. The primary endpoint was a composite of the first sVT and SCD. The levels of urinary 8-hydroxy-2'-deoxyguanosine (U-8-OHdG), a marker of oxidative DNA damage that reflects the inflammatory activity of CS, other biomarkers, and indices of cardiac function and renal function were measured on admission.

Results: Eighty-nine consecutive patients with CS were enrolled; 28 patients with no abnormal ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) accumulation in the heart were excluded and 61 patients with abnormal ¹⁸F-FDG accumulation were followed up for a median of 46 months (IQR: 20-84). During the follow-up period, 15 of 61 patients showed sVT (n=12) or SCD (n=3). A Cox proportional hazard model showed that U-8-OHdG concentration and presence of ventricular aneurysm (VA) were independent predictors of first sVT/SCD. The cut-off U-8-OHdG concentration for predicting first sVT/SCD was 14.9 ng/mg·Cr. Patients with U-8-OHdG concentration ≥14.9 ng/mg·Cr and VA showed a significantly increased risk of sVT/SCD.

Conclusions: U-8-OHdG and presence of VA were powerful predictors of first sVT/SCD in patients with CS, facilitating the stratification of cardiac events and providing relevant information about the substrates of ventricular tachycardia.

Keywords: biomarkers; cardiomyopathies; tachycardia; ventricular.

Figure 1

Study design. (A) 8-OHdG as a marker of DNA oxidative damage. Enhanced production of ROS may occur in cardiomyocytes during the active phase of CS, leading to DNA oxidisation (from 2’-deoxyguanosine (blue rod) to 8-OHdG (blue rod with red star)) in the nuclei DNA and mitochondrial DNA, with subsequent excretion of 8-OHdG, in urine via blood. The concentration of 8-OHdG can be measured by ELISA method using an anti-8-OHdG antibody (N45.1). The normal range of U-8-OHdG concentration is defined as <10 ng/mg·Cr, as taken from a previous study. (B) Study protocol. (C) Study flow chart. The 89 patients with CS were divided according to the presence of ¹⁸F-FDG accumulation in the heart into the following groups: active CS (n=61) and non-active CS (n=28). Patients with active CS were further divided into the sVT/SCD event (+) group (n=15) and the sVT/SCD event (−) group (n=46). ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; BNP, B-type natriuretic peptide; CRP, C reactive protein; CS, cardiac sarcoidosis; eGFR, estimated glomerular filtration rate; HF, heart failure; IL-6, interleukin 6; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PET, positron emission tomography; ROC, receiver operating characteristic; ROS, reactive oxygen species; SCD, sudden cardiac death; SUVmax, maximum standardised uptake value; sVT, sustained ventricular tachycardia; TNF-α, tumour necrosis factor; TnT, troponin T.

Figure 2

ROC analysis for predicting sustained ventricular tachycardia/sudden cardiac death. ROC method was performed to analyse time-to-event data at 1, 2, 3, 4 and 5 years and at the final observation point. Each of the maximal cut-off value, sensitivity and specificity was calculated by the Youden’s index method. The results are shown in each ROC curve. Harrell’s c-statistic was calculated as 0.77. Finally, the cut-off value for U-8-OHdG was decided at 14.9 ng/mg·Cr by the Youden’s index method. At (A) 1 year, (B) 2 years, (C) 3 years, (D) 4 years, (E) 5 years and (F) at the final observation period. AUC, area under the curve; ROC, receiver operating characteristic; U-8-OHdG, urinary 8-hydroxy-2′-deoxyguanosine.

Figure 3

Survival analyses for patients with active CS divided into two groups based on the cut-off value for U-8-OHdG. The primary outcome was a composite of sVT/SCD in our cohort. Cumulative event-free survival rates of a composite (A), sVT (B), SCD (C) and a composite of sVT/SCD excluding patients with a history of VT (D) were estimated using the Kaplan-Meier method. CS, cardiac sarcoidosis; SCD, sudden cardiac death; sVT, sustained ventricular tachycardia; U-8-OHdG, urinary 8-hydroxy-2′-deoxyguanosine; VT, ventricular tachycardia.

Figure 4

Survival analyses for patients with CS divided into two groups based on the presence of VA. The primary outcome was a composite of sVT/SCD in our cohort. The cumulative event-free survival rates of a composite (A), sVT (B), SCD (C) and a composite of sVT/SCD excluding patients with a history of VT (D) were estimated using the Kaplan-Meier method. CS, cardiac sarcoidosis; SCD, sudden cardiac death; sVT, sustained ventricular tachycardia; VA, ventricular aneurysm; VT, ventricular tachycardia.

Figure 5

Risk stratification based on U-8-OHdG and VA. Patients showing U-8-OHdG concentration ≥14.9 ng/mg·Cr and presence of VA had a significantly highest risk of sVT/SCD (log-rank, p<0.001 vs patients with neither, events per 100 patient-year, 31.0). SCD, sudden cardiac death; sVT, sustained ventricular tachycardia; U-8-OHdG, urinary 8-hydroxy-2′-deoxyguanosine; VA, ventricular aneurysm; VT, ventricular tachycardia.