Biomarkers of inflammation predict HF hospitalization and adverse outcomes in AF

Biomarkers of Inflammation and Risk of Hospitalization for Heart Failure in Patients With Atrial Fibrillation

Literature - Benz AP, Aeschbacher S, Krisai P, et al. - J Am Heart Assoc. 2021;10:e019168. doi: 10.1161/JAHA.120.019168.

Introduction and methods

HF and AF conditions often occur concomitantly, which predisposes patients to poor outcomes [1,2]. The event rates for HF hospitalization in patients with AF have remained high and unchanged over the last 2 decades [3,4]. In fact, HF accounts for a substantial amount of deaths in adequately coagulated AF patients [5]. In addition, established therapies for patients with HF, such as beta-blockers, may be less effective in patients with AF and HF [6]. So identifying potentially modifiable risk factors for HF hospitalization in patients with AF to improve clinical outcomes in these patients is necessary.

Biomarkers of inflammation have been associated with atherothrombotic events in multiple patient populations and with HF hospitalization in patients with a prior MI [8-12]. Whether poor outcomes in patients with AF, in whom pathophysiologic patterns are mostly unrelated to atherosclerosis and ischemia, can be predicted by these biomarkers has not been investigated.

This prospective study used a combined data set of patients with established AF who were included in the BEAT-AF and Swiss-AF multicenter cohort studies between January 2010 and August 2017. AF patients with any acute illness or hospitalization for all-causes were enrolled at least 4 weeks after the acute episode or after hospital discharge. The prespecified primary outcome was hospitalization for HF, defined as an unplanned hospital visit with at least one overnight stay due to signs of HF. The secondary prespecified outcomes were all-cause mortality, CV death, a composite endpoint of ischemic stroke, MI, or CV death, and a composite endpoint of ischemic stroke or systemic embolism. Baseline plasma levels of hs-CRP and IL-6 were assessed (median hs-CRP: 1.64 mg/L [IQR: 0.81-3.69 mg/dL]) and median IL-6: 3.42 pg/mL [IQR: 2.14-5.60 pg/mL). Patients (n=3784) were stratified according to an inflammation score ranging from 0 to 4 (1 point for each biomarker between the 50th and 75th percentile and 2 points for each biomarker above the 75th percentile). Median (IQR) follow-up was 4 years (2.9-5.1 years).

Main results

  • There were 447 patients (11.8%) with at least one hospitalization for HF, which corresponded to an overall incidence rate of 3.04 per 100 person-years. The incidence rate across inflammation score categories increased from 1.34 (score 0) to 7.31 (score 4) per 100-person-years.
  • 1 SD increase in IL-6 or hs-CRP was significantly associated with increased hospitalization due to HF (aHR 1.48, 95% CI: 1.35-1.62, P<0.001 for log-transformed IL-6 and aHR 1.22 95% CI: 1.11-1.34, P<0.001 for log-transformed hsCRP).
  • There was a non-linear relationship for log-transformed IL-6 levels and HF hospitalization, suggesting less steep increases in risk at higher IL-6 levels (β=-0.086, SE=0.031, P=0.006).
  • Increase in inflammation score per 1-point was associated with higher risk of HF hospitalization after multivariable adjustment (score of 4 vs. score of 0: aHR: 2.43, 95%CI: 1.80-3.30, P for trend<0.001).
  • After multivariable adjustment, IL-6 and hs-CRP were significantly associated with the secondary outcomes all-cause mortality, CV death, and the composite endpoint ischemic stroke, MI, or CV death (all P<0.001). Only hs-CRP was associated with the composite endpoint ischemic stroke or systemic embolism (P=0.04).
  • Also, inflammation score was associated with all-cause mortality, CV death, and the composite outcome ischemic stroke, MI, or CV death (all P for trends<0.001) and ischemic stroke or systemic embolism (P for trend=0.03).
  • Hs-CRP and IL-6 were both stronger associated with HF hospitalization in patients without a history of HF (both biomarkers P interactions=0.04) or coronary artery disease (both biomarker P interactions=0.001).

Conclusion

This combined cohort study showed that elevated levels of IL-6 and hs-CRP were associated with increased HF hospitalization and other adverse outcomes in patients with AF. The risk for HF hospitalization increased with increasing inflammation scores for IL-6 and hs-CRP.

The authors further stated that RCTs need to determine whether treatment targeted at inflammation improve clinical outcomes in patients with AF.

References

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2. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA. 2011;305:2080–2087.

3. Healey JS, Oldgren J, Ezekowitz M, et al. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet. 2016;388:1161–1169.

4. Miyasaka Y, Barnes ME, Gersh BJ, et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: a community-based study over two decades. Eur Heart J. 2006;27:936–941.

5. Marijon E, Le Heuzey J-Y, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation. 2013;128:2192–2201.

6. Kotecha D, Holmes J, Krum H, et al. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet. 2014;384:2235–2243.

7. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018;378:417–427.

8. Sabatine MS, Morrow DA, Jablonski KA, et al. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007;115:1528–1536.

9. Ridker PM, MacFadyen JG, Glynn RJ, et al. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Eur Heart J. 2020;14:2952–2961.

10. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–1772.

11. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–843.

12. Everett BM, Cornel JH, Lainscak M, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139:1289–1299.

Find this article online at J Am Heart Assoc

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