Association Between Inflammation, Incident Heart Failure, and Heart Failure Subtypes in Patients With Rheumatoid Arthritis

Abstract

Objective: In rheumatoid arthritis (RA), there are limited data on risk factors for the clinical heart failure (HF) subtypes of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This study examined the association between inflammation and incident HF subtypes in RA. Because inflammation changes over time with disease activity, we hypothesized that the effect of inflammation may be stronger at the 5-year follow-up than at the standard 10-year follow-up from general population studies of cardiovascular risk.

Methods: We studied an electronic health record (EHR)-based RA cohort with data pre- and post-RA incidence. We applied a validated approach to identify HF and extract ejection fraction to classify HFrEF and HFpEF. Follow-up started from the RA incidence date (index date) to the earliest occurrence of incident HF, death, last EHR encounter, or 10 years. Baseline inflammation was assessed using erythrocyte sedimentation rate or C-reactive protein values. Covariates included demographic characteristics, established HF risk factors, and RA-related factors. We tested the association between baseline inflammation with incident HF and its subtypes using Cox proportional hazards models.

Results: We studied 9,087 patients with RA; 8.2% developed HF during 10 years of follow-up. Elevated inflammation was associated with increased risk for HF at both 5- and 10-year follow-ups (hazard ratio [HR] 1.66, 95% confidence interval [95% CI] 1.12-2.46 and HR 1.46, 95% CI 1.13-1.90, respectively), which is also seen for HFpEF at 5 years (HR 1.72, 95% CI 1.09-2.70) and 10 years (HR 1.45, 95% CI 1.07-1.94). HFrEF was not associated with inflammation for either follow-up time.

Conclusion: Elevated inflammation early in RA diagnosis was associated with HF; this association was driven by HFpEF and not HFrEF, suggesting a window of opportunity for prevention of HFpEF in RA.

Figure 1.

Study design for incident heart failure (HF) in rheumatoid arthritis (RA) patients. A. index date. B. date of HF diagnosis, or death, or date of last encounter in EHR, or end of follow up window (5 vs. 10 years).

Figure 2.

Kaplan-Meier analysis of any HF outcome stratified by presence or absence of elevated inflammatory level. (A) Survival probability free of any HF outcome. (B) Survival probability free of HFrEF or HFpEF outcome. HF: heart failure; HFrEF: HF with reduced ejection fraction; HFpEF: HF with preserved ejection fraction *For clarity, curve for missing inflammation not shown here but available in supplemental figure S2.

Figure 3.

Hazard ratios for multivariable Cox proportional hazards models for incident HF outcomes when followed to 5- and 10-years post-RA diagnosis in incident RA subjects in primary analysis using dichotomized inflammation level. (a) Any HF outcome. (b) HF with reduced ejection fraction. (c) HF with preserved ejection fraction RA diagnosis decade was also included in the model but not shown in this figure (similar effect sizes). CAD: coronary artery disease; CCI: Charlson Comorbidity Index; CKD: chronic kidney disease; HF: heart failure (HFrEF: HF with reduced ejection fraction, HFpEF: HF with preserved ejection fraction); RA: rheumatoid arthritis; TNFi: Tumor necrosis factor-α inhibitor

Figure 4.

Hazard ratios for multivariable Cox proportional hazards models for incident HF outcomes when followed to 5- and 10-years post-RA diagnosis in incident RA subjects in secondary analysis using inflammation tertiles. (a) Any HF outcome. (b) HF with reduced ejection fraction. (c) HF with preserved ejection fraction RA diagnosis decade was also included in the model but not shown in this figure (similar effect sizes). CAD: coronary artery disease; CCI: Charlson Comorbidity Index; CKD: chronic kidney disease; HF: heart failure (HFrEF: HF with reduced ejection fraction, HFpEF: HF with preserved ejection fraction); RA: rheumatoid arthritis; TNFi: Tumor necrosis factor-α inhibitor