Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study

Abstract

Background: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk.

Methods and results: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT.

Conclusions: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Keywords: PET; cardiovascular risk; coronary microvascular dysfunction; inflammation; rheumatoid arthritis.

Figure 1. Design of the LiiRA study.

LiiRA indicates Lipids, Inflammation, and Cardiovascular Risk in Rheumatoid Arthritis; PET, positron emission tomography; and TNF, tumor necrosis factor.

Figure 2. Histogram and box plot represent the distribution among myocardial flow reserve (A) and stress myocardial blood flow among patients with rheumatoid arthritis at baseline (B) (n=73) compared with healthy controls (n=22) (myocardial flow reserve 2.65±0.48 versus 3.23±0.94 P=0.01; stress myocardial blood flow: 2.00±0.3 vs 2.15±0.51, P=0.189).

LiiRA indicates Lipids, Inflammation, and Cardiovascular Risk in Rheumatoid Arthritis study; MBF, myocardial blood flow; and RA, rheumatoid arthritis.

Figure 3. Summary of study findings with regards to prevalence of subclinical myocardial injury and coronary microvascular disease and relationship with changes before and after anti‐inflammatory therapy in rheumatoid arthritis.

ASCVD indicates atherosclerotic cardiovascular disease; CMD, coronary microvascular dysfunction; hsCRP, high‐sensitivity C‐reactive protein; hs‐cTnT, high‐sensitivity cardiac troponin T; MFR, myocardial flow reserve; RA, rheumatoid arthritis; and TNFi, tumor necrosis factor inhibitor.