Nickel hypersensitivity as the cause of atrial fibrillation after patent foramen ovale closure: fact or myth?

This commentary refers to ‘Long-term risk of atrial fibrillation or flutter after transcatheter patent foramen ovale closure: a nationwide Danish study’, by C.V. Skibsted et al., https://doi.org/10.1093/eurheartj/ehad305. We read with great interest the paper by Skibsted et al.1 regarding the long-term risk of atrial fibrillation or flutter (AF) after transcatheter patent foramen ovale (PFO) closure. The authors are to be congratulated for conducting a large-scale prospective study, which revealed that patients who had undergone PFO closure had an increased risk of developing AF within the first 3 months, but not thereafter up to 5 years, compared with PFO patients without closure and a matched comparison cohort. Nevertheless, the arrhythmogenic mechanisms following transcatheter PFO closure remain unanswered. While the authors suggest that topical irritation or inflammation of the atrial septum after device placement could be a possible mechanism, the potential role of nickel hypersensitivity as a causative factor of arrhythmogenesis should also be discussed. Nickel has been widely recognized as the predominant contact allergen worldwide, affecting ∼20% of the population. Nevertheless, our understanding of how nickel behaves when exposed to the systemic bloodstream remains limited. Theoretically, nickel hypersensitivity could lead to localized and systemic inflammation, even beyond the skin, potentially triggering arrhythmogenesis through a mechanism we have previously proposed.2 Several reports have linked nickel hypersensitivity with adverse clinical events after nickel-containing devices implantation.3 The frame of PFO occluders is composed of a nickel–titanium alloy, resulting in a release of nickel into the bloodstream until complete endothelialization of the device, a process typically taking 1–3 months. It is hypothesized that nickel-induced inflammation may have arrhythmogenic potential.4 Interestingly, the peak incidence of AF coincided with nickel release into the bloodstream and higher levels of nickel in the blood. Importantly, the incidence of AF decreased after the initial 3-month period and became comparable with that of PFO patients without closure and a matched comparison cohort. This reduction could be attributed to device endothelialization and the subsequent elimination of nickel release. Preliminary results from our study assessing adverse events, including AF, following PFO closure in patients with and without nickel hypersensitivity, have shown a numerical trend, suggesting a higher incidence of events in allergic patients.5 Although PFO closure remains a safe intervention, it is important not to under-estimate the incidence of AF within the first 3 months. Understanding the underlying mechanisms is crucial for effective prevention and optimal management of AF, and the potential role of nickel hypersensitivity should be considered. Further research, such as the INSPIRE trial (Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder; NCT04713683), has the potential to provide valuable insights into this controversial issue and to answer if it is myth or reality. All authors declare no conflict of interest for this contribution.