Interleukin-6 plasma levels predict mortality and heart failure events in cardiac transthyretin amyloidosis

Abstract

Abstract Background Low-grade systemic inflammation is a key component in the pathophysiology of heart failure (HF). In particular, the pleiotropic effects of interleukin-6 (IL-6) signaling are of interest as circulating IL-6 levels are associated with mortality in HF patients. Purpose The purpose of this study was to investigate whether IL-6 plasma levels predict mortality and HF events in patients with cardiac transthyretin amyloidosis (ATTR-CM). Methods This was an analysis of a prospective single-center cohort study comprising 98 ATTR-CM patients. The endpoint was defined as a composite of all-cause mortality and worsening HF events. HF events included HF related hospitalizations and urgent outpatient clinic visits with concomitant intravenous diuretic treatment. Follow-up data were collected using central medical records. Kaplan-Meier estimates and Cox regression analyses were calculated to assess the association between IL-6 and the composite endpoint. Moreover, receiver operator characteristics (ROC) analysis was performed to evaluate the predictive accuracy of IL-6 for the composite endpoint. Results Median age was 79 years (76-81), 86 patients (88%) were male, and 46 patients (47%) received the transthyretin (TTR) stabilizer tafamidis at baseline. Median NT-proBNP levels were 2813 pg/ml (1365-4856), mean estimated glomerular filtration rate (eGFR) was 57.9±17.6 ml/min/1.73m², and median urine protein to creatinine ratio (UPCR) was 122.0 mg/g (89.8-204.5). Median IL-6 plasma levels were 4.9 pg/ml (3.0-9.4). During a median observation period of 21.2 months (11.4-32.4), 27 patiens (28%) reached the composite endpoint. IL-6 levels were associated with the composite endpoint (hazard ratio = 1.028, 95% confidence interval = 1.004 to 1.051; p = 0.012). The association was independent of age, TTR stabilizing medication, log-transformed and eGFR-adjusted NT-proBNP levels, as well as UPCR. The area under the ROC curve for IL-6 was 0.70 (95% confidence interval = 0.59 to 0.81; p = 0.003). The optimal cutoff value was 5.3 pg/ml, as determined by Youden’s index, with a sensitivity of 70% and specificity of 66%. Kaplan-Meier estimates demonstrated a mean survival time of 1030 days (95% confidence interval = 911 to 1150) for the study population. A statistically significant difference between the survival rates of ATTR-CM patients with IL-6 levels ≥5.3 pg/ml and those with IL-6 levels below the threshold was indicated by the log-rank test (p = 0.002). Conclusion Circulating levels of IL-6 independently predicted adverse outcomes in patients with ATTR-CM. IL-6 plasma levels may be useful for identifying a high-risk ATTR-CM subpopulation.Tablewith baseline characteristicsFigurewith Kaplan-Meier estimates