Elevated interleukin-6 levels are associated with impaired outcome in cardiac transthyretin amyloidosis

Abstract

BACKGROUND Elevated interleukin (IL)-6-levels have been described in familial variant transthyretin amyloidosis (ATTRv) associated polyneuropathy and heart failure. However, IL-6 in cardiac ATTR amyloidosis (ATTR-CM) and its prognostic value have not been investigated yet. AIM We aim to study the correlation between IL-6 levels with clinical presentation (Gillmore-class) and outcome [heart transplantation or death (htx/death)], or the combined endpoint of cardiac decompensation or htx/death in ATTR-CM. METHODS IL-6 levels of 106 ATTR-CM patients [54 wild-type ATTRwt, 52 ATTRv-CM], 15 asymptomatic carriers of ATTR mutations (aATTRv-CM) and 27 healthy donors were quantified using Luminex technology. Statistical analysis was performed using parametric survival regression models. RESULTS We found that IL-6 levels from wild-type ATTR patients were significantly elevated compared to healthy controls, while aATTRv-CM carriers and ATTRv-CM patients did not show a significant difference. IL-6 levels showed significantly higher values in increasing Gillmore classes. Univariate analyses revealed association of low IL-6 levels with cardiac decompensation and htx/death [odds ratio: 0.26 (0.09-0.72), P = 0.01] and htx/death [odds ratio: 0.15 (0.04-0.58), P = 0.006]. However, in the multivariate model, no significant improvement of risk prediction was seen for IL-6, while established prognostic factors were significantly associated with outcome. CONCLUSION Raised IL-6 levels correlate with clinical presentation and are associated with worse outcome in ATTR-CM but do not improve stratification in addition to established risk factors.

Histologic Diagnosis of Coronary Amyloidosis Using Percutaneous Transluminal Directional Atherectomy

“…However, a reasonable speculation is that amyloid depositions might have accelerated arteriosclerosis through amyloid-triggered inflammation— taking into account a study demonstrating that plasma levels of proinflammatory interleukin-6 were elevated in patients with ATTR-CA, and clinical evidence showing that IL-6 independently predicts future cardiovascular events. 6 A case report has been made of ATTR amyloid accumulation in eccentric intimal thickening of a saphenous vein graft harvested for coronary artery bypass grafting surgery. 7 This observation reinforces our hypothesis that amyloid toxicity plays a role in the development of vascular disease, including arteriosclerosis and vasculopathy.…”

Transthyretin deposition alters cardiomyocyte sarcomeric architecture, calcium transients, and contractile force

“…Cardiac amyloidosis is accompanied by fibrosis and wall stiffness, which may be partially explained by the finding that cardiac fibroblasts cultured on deposited TTR fibrils had increased proliferation and migration rates (Dittloff et al, 2021). Additionally, patients with TTR amyloidosis have increased inflammatory profiles that correlate with disease progression (Azevedo et al, 2019; Hein, Knoll, et al, 2021), which was also seen in fibroblast culture (Dittloff et al, 2021). Note that the primary myocyte cultures used here also contain fibroblasts, so upregulation of the inflammatory genes was to be expected (see Figures for pathway analysis of RNA‐seq data).…”