Y . Yamada et al .: J Extra Corpor Technol 2023 , 55 , 23 – 29 27
Figure
1 . A hypothetical model illustrating the Ca
2 + signaling pathways implicated in POAF . Cytosolic Ca
2 + handling abnormalities in atrial myocytes have been suggested to play an important role in the initiation and maintenance of atrial fibrillation . ( A ) Fakuade et al . reported that
reuptake into the SR is a major contributor to impaired preoperative atrial contractile function and the pre-existing arrhythmogenic substrate in patients developing POAF . Therefore , modulation of SERCA activity may represent a novel mechanistic target to prevent the development of POAF . ( B ) With higher dosing ratios of protamine-to-heparin , the residual protamine may activate RyR2 dose-dependently , followed by RyR2-mediated Ca
2 + leak , resulting in increased cytosolic Ca
2 + and POAF . Therefore , dosing ratios of protamine-to-heparin may be an important determinant in the development of POAF in addition to reduced SERCA-mediated Ca
2 + reuptake into the SR described in Figure 1A . POAF , postoperative atrial fibrillation ; SR , sarcoplasmic reticulum ; SERCA , sarcoplasmic reticulum calcium ATPase ( sarcoplasmic reticulum calcium pump ).
mechanism that contributes both to the impaired pre-existing atrial contractile function as an independent risk factor of POAF and to the arrhythmogenic substrate , which predisposes patients to the development of POAF [ 5 ]. Based on the clinical results , we propose a hypothetical model of protamine-related POAF in Figure 1B . In the case of higher dosing ratios of protamine-toheparin , the residual protamine may activate RyR2 dosedependently , followed by RyR2-mediated Ca 2 + leak , resulting in increased cytosolic Ca 2 + and POAF . In the current retrospective study , POAF developed both in 5 of 57 patients ( 33.3 %) in the dosing ratio of protamine-to-heparin = 1.0 and 10 out of 35 patients ( 66.7 %) in the higher dosing ratios of protamineto-heparin ( Table 2 ). Statistical analysis showed that POAF was associated with higher dosing ratios of protamine-toheparin > 1.0 up to 1.7 and was statistically significant ( odds ratio = 3.890 , 95 % CI = 1.130 – 13.300 , p-value = 0.031 ). POAF development in the dosing ratio of protamine-to-heparin = 1.0 may suggest that residual protamine has some adverse effect on inducing POAF . If this is the case , a lower protamine-toheparin ratio ( less than protamine-to-heparin = 1.0 ) may be used to prevent POAF , as discussed above [ 19 ]. Further studies are needed to elucidate this issue .
Limitations
The study has some limitations . First , this small study is a retrospective analysis of an integrated database from a secondary medical center in the Iga district , Mie , Japan . Second , AF was identified by diagnostic code , electrocardiogram , and medical history , not by a long-term recorder , some patients with AF might be underdiagnosed . Furthermore , although potential arrhythmogenic mechanisms for POAF development may be associated with higher dosing ratios of protamine-to-heparin as shown in this study , there may be additional factors predisposing to the development of POAF , including genetic , type of surgery , autonomic nervous system , inflammation , and preexisting fibrosis .
Conclusion
In conclusion , our results provide evidence that higher dosing ratios of protamine-to-heparin may increase the incidence of POAF . In this regard , STS / SCA / AmSECT and EACTS / EACTA clinical guidelines on anticoagulation during cardiopulmonary bypass are useful in clinical practice .