Circulating Biomarkers Predictive of Postoperative Atrial Fibrillation

Abstract

Postoperative atrial fibrillation (PoAF), a common complication of cardiac surgery, contributes significantly to morbidity, mortality, and increasing healthcare costs. Despite advances in surgical and medical management, the overall incidence of PoAF has not changed significantly, partly because of the limited understanding of mechanisms underlying acute surgery-related factors, such as myocardial injury, inflammation, sympathetic activation, and oxidative stress, which play an important role in the initiation of PoAF, whereas a preexisting atrial substrate appears to be more important in the maintenance of this dysrhythmia. Thus, in a majority of patients, PoAF becomes a manifestation of an underlying arrhythmogenic substrate that is unmasked after acute surgical stress. As such, the ability to identify which patients have this proarrhythmic substrate and are, therefore, at high risk for developing AF postoperatively, is important for the improved selection for prophylactic interventions, closer monitoring for complications, and establishing the probability of AF in the long term. This review highlights the role of the underlying substrate in promoting PoAF, proposed mechanisms, and the potential role of serum biomarkers to identify patients at risk for PoAF.

FIGURE 1

Incidence of postoperative atrial fibrillation (PoAF) with age and over time. (A) Estimated probability of developing PoAF by age rises slowly in younger patient (<55 years age), but more steeply beyond age 55 years. (B) The overall incidence of new-onset PoAF in 10,390 patients without preexisting atrial arrhythmias undergoing cardiac surgeries (7,284 coronary artery bypass grafting [CABG] only, 887 CABG and valve, 1,399 valve only, 820 other cardiac surgeries), has not changed significantly over the last 20 years. CI indicates confidence interval. (With permission from Shen J, Lall S, Zheng V, et al. The persistent problem of new-onset postoperative atrial fibrillation: a single-institution experience over two decades. J Thorac Cardiovasc Surg. 2011;141:559–570.) ref

FIGURE 2

The underlying substrate increases the risk of postoperative atrial fibrillation (PoAF). (A) Histological differences in interstitial collagen deposition demonstrated by increase in mason trichrome positive areas (blue) within the myocardium (magenta) in a patient who was free of PoAF (sinus rhythm) versus a patient who developed PoAF. Both patients had no prior history of AF and no significant cardiac abnormality by echocardiogram. (B) In patients with no prior history of AF, the percentage of collagen content within the myocardium was significantly higher in those who developed PoAF than those who remained in sinus rhythm. With permission from Mirza M, Strunets A, Holmuhamedov E, et al: A novel histology based classification system to identify patients at risk of postoperative atrial fibrillation. Circ Res 2013;113:A038. Ref

FIGURE 3

Schematic representation of collagen protein secreted as a procollagen molecule and its breakdown peptides that can be measured in circulating blood. (A) Collagen I and III are secreted as a procollagen precursor containing an amino and carboxy terminal propeptide and telopeptides that are released during collagen synthesis and degradation. (B) During injury the released cytokines and profibrotic mediators activate fibroblasts (vimentin positive) to myofibroblasts that express alpha-smooth muscle actin (α-SMA). Myofibroblasts increase production of collagen I and III in the myocardium and trigger a cascade of events that take place during the synthesis and degradation of collagen type I and III molecules. PICP indicates carboxy terminal propeptide of collagen I; PINP, amino terminal propeptide of collagen I; PIIINP, amino terminal propeptide of collagen III; PIIICP, carboxy terminal propeptide of collagen III; CITP, carboxy terminal telopeptide of collagen I; MMP, matrix metalloproteinases; and TIMP, tissue inhibitor of matrix metalloproteinases. In the boxed inset, several micro-RNA (miR) that have been shown to regulate expression of genes involved in extracellular matrix remodeling are summarized. (The fibroblast and myofibroblast figures were isolated from right atrial appendage of a patient undergoing coronary artery bypass grafting).