Modulated Calcium Homeostasis and Release Events Under Atrial Fibrillation and Its Risk Factors: A Meta-Analysis

Background: Atrial fibrillation (AF) is associated with calcium (Ca²⁺) handling remodeling and increased spontaneous calcium release events (SCaEs). Nevertheless, its exact mechanism remains unclear, resulting in suboptimal primary and secondary preventative strategies. Methods: We searched the PubMed database for studies that investigated the relationship between SCaEs and AF and/or its risk factors. Meta-analysis was used to examine the Ca²⁺ mechanisms involved in the primary and secondary AF preventative groups. Results: We included a total of 74 studies, out of the identified 446 publications from inception (1982) until March 31, 2020. Forty-five were primary and 29 were secondary prevention studies for AF. The main Ca²⁺ release events, calcium transient (standardized mean difference (SMD) = 0.49; I ² = 35%; confidence interval (CI) = 0.33-0.66; p < 0.0001), and spark amplitude (SMD = 0.48; I ² = 0%; CI = -0.98-1.93; p = 0.054) were enhanced in the primary diseased group, while calcium transient frequency was increased in the secondary group. Calcium spark frequency was elevated in both the primary diseased and secondary AF groups. One of the key cardiac currents, the L-type calcium current (I_CaL) was significantly downregulated in primary diseased (SMD = -1.07; I ² = 88%; CI = -1.94 to -0.20; p < 0.0001) and secondary AF groups (SMD = -1.28; I ² = 91%; CI = -2.04 to -0.52; p < 0.0001). Furthermore, the sodium-calcium exchanger (I_NCX) and NCX1 protein expression were significantly enhanced in the primary diseased group, while only NCX1 protein expression was shown to increase in the secondary AF studies. The phosphorylation of the ryanodine receptor at S2808 (pRyR-S2808) was significantly elevated in both the primary and secondary groups. It was increased in the primary diseased and proarrhythmic subgroups (SMD = 0.95; I ² = 64%; CI = 0.12-1.79; p = 0.074) and secondary AF group (SMD = 0.66; I ² = 63%; CI = 0.01-1.31; p < 0.0001). Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) expression was elevated in the primary diseased and proarrhythmic drug subgroups but substantially reduced in the secondary paroxysmal AF subgroup. Conclusions: Our study identified that I_CaL is reduced in both the primary and secondary diseased groups. Furthermore, pRyR-S2808 and NCX1 protein expression are enhanced. The remodeling leads to elevated Ca²⁺ functional activities, such as increased frequencies or amplitude of Ca²⁺ spark and Ca²⁺ transient. The main difference identified between the primary and secondary diseased groups is SERCA expression, which is elevated in the primary diseased group and substantially reduced in the secondary paroxysmal AF subgroup. We believe our study will add new evidence to AF mechanisms and treatment targets.