Heart Failure in RA: Inflammation Matters

Patients with rheumatoid arthritis (RA) who had high levels of inflammation at baseline were at increased risk for later heart failure, a large cohort study found.

After adjustment for demographics, traditional risk factors for heart failure, and RA disease factors, the hazard ratio for heart failure at 10 years was 1.46 (95% CI 1.13-1.90) among patients with elevated levels of inflammatory markers, said Kathrine P. Liao, MD, of Brigham and Women’s Hospital in Boston, and colleagues.

However, as shown in their study online in Arthritis Care & Research, the risk with elevated inflammation in early RA was observed only for the subset of heart failure patients who had preserved ejection fraction.

As many studies have demonstrated, heart failure is a major cause of morbidity and mortality in RA, but data for the subtypes of heart failure — with preserved ejection fraction versus reduced ejection fraction — have been sparse.

The two subtypes are thought to differ in pathophysiology. The subtype with reduced ejection fraction is believed to result from ischemic factors, whereas with preserved ejection fraction, the primary driver is considered to be inflammation, reflected by the presence of inflammatory mediators such as interleukin 6 and tumor necrosis factor (TNF)-α.

Therefore, to explore the hypothesis that the association with heart failure in RA could be specific to the subtype with preserved ejection fraction, Liao’s group analyzed data from the electronic health records of more than 15,000 RA patients seen at two large academic centers in Boston from 1994 to 2017.

Elevated inflammation at the time of RA diagnosis was defined as an erythrocyte sedimentation rate (ESR) of 20-30 mm/h, and/or a C-reactive protein (CRP) of 8-10 mg/L.

Heart failure with reduced ejection fraction was defined as an ejection fraction of 40% or less, while preserved ejection fraction was 50% or higher. Those whose ejection fraction was 40-50% were classified as mid-range and were not considered a specific subtype.

The analysis included 9,087 RA patients, whose median follow-up was 10.7 years. Three-quarters were women, mean age was 56, and 55% were seropositive. Treatments included corticosteroids in 23.4%, methotrexate in 15%, antimalarials in 9.7%, and TNF inhibitors in 5%.

Median ESR at baseline was 24.7 mm/h, and median CRP was 5.9 mg/L. Patients whose inflammatory markers were elevated typically were older, female, seropositive, and taking corticosteroids. They also more often had cardiovascular comorbidities such as hypertension, coronary artery disease, and diabetes.

The usual time frame for estimating cardiovascular risks in the general population is 10 years, but this study also included 5-year risk to determine whether heart failure onset was earlier in RA patients, the researchers noted.

During 10 years of follow-up, heart failure was diagnosed in 749 patients, for an incidence rate of 11 per 1,000 person-years. The heart failure developed within 5 years of RA diagnosis in 379 patients.

Ejection fraction was reduced in 127 and preserved in 561; the remainder of patients had mid-range ejection fraction.

While overall rates of heart failure were increased at both 5 and 10 years in patients with high inflammation at baseline, a similar pattern was observed only among those with preserved ejection fraction, with HRs of 1.72 (95% CI 1.09-2.70) at 5 years and 1.45 (95% CI 1.07-1.94) at 10 years. Elevated inflammation at baseline was not associated with heart failure among patients with reduced ejection fraction.

In a secondary analysis that considered tertiles of inflammation, higher levels of inflammation were significantly associated with any heart failure at years 5 and 10, and also for the subtype with preserved ejection fraction. Again, however, no association was seen among patients with reduced ejection fraction.

Other factors that influenced heart failure risk included lower risks with seropositivity and the use of methotrexate, and higher risk with coronary artery disease, particularly among patients with reduced ejection fraction. That observation supports the concept that ischemia, rather than inflammation, is central to the pathogenesis of the reduced ejection fraction subtype of heart failure, Liao and co-authors noted.

They said that because high levels of inflammation early in RA were linked with heart failure, there are implications for intervention, in RA and possibly beyond. “Since inflammation is modifiable by RA treatments, these findings suggest an opportunity for mitigating the risk of heart failure, specifically heart failure with preserved ejection fraction risk, early in the RA disease course,” the team wrote.

That a sizeable number of patients developed heart failure by 5 years suggested that evaluations for risk factors for heart failure in RA may need to begin earlier than the usual 10 years, the researchers noted. Moreover, “although this study was conducted in RA patients, the findings [also] may inform the effect of chronic inflammation on heart failure risk in the general population without RA.”

A limitation of the study, the investigators said, was its setting in two tertiary care centers, so the findings may not be entirely generalizable to the larger RA population.