Ceruloplasmin dysfunction: a key factor in the pathophysiology of atrial fibrillation?


  • J. Y. Jeremy,

    Corresponding author
    1. NIHR Bristol Biomedical Research Unit, Bristol Heart Institute, University of Bristol, Bristol, UK
    • Correspondence: Jamie Y. Jeremy, Department of Cardiac Surgery, Bristol Heart Institute, BS6 8HW Bristol, UK.

      (fax: +44 117 342 3145; e-mail: j.y.jeremy@bris.ac.uk).

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  • N. Shukla

    1. NIHR Bristol Biomedical Research Unit, Bristol Heart Institute, University of Bristol, Bristol, UK
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Atrial fibrillation (AF), the most common of cardiac arrhythmias, affects more than 7 million Americans and Europeans accounting for one-third of hospitalizations for arrhythmias [1-3]. Quality of life is profoundly affected by AF which elicits chronic fatigue and debilitating pain. Moreover, AF doubles the risk of heart failure and that of stroke fivefold. In the USA and Europe alone, AF is therefore responsible for at least 200 000 deaths and costs in excess of $50 billion. Risk factors for AF include ischaemic heart disease, hypertension, heart failure and metabolic disease [1-3]. AF is therefore expected to more than double in the next 40 years and has been described as an epidemic of the 21st century [1-3].

Although the aetiology of AF is complex and not fully understood, a study published in this issue of JIM demonstrates that a single nucleotide polymorphism (SNP) located in the ceruloplasmin (CP) – gene promoter was strongly associated with AF [4]. Notably, adjustments for plasma levels of CP did not eliminate the significant association, indicating that CP dysfunction rather than absolute levels may be responsible for the association [4]. In a previous study by the same group, it was found that of five plasma indices of inflammation [fibrinogen, haptoglobin, CP, α (1)-antitrypsin and orosomucoid] and two complement factors, only CP was significantly associated with incidence of AF after adjustment for confounding factors [5]. The mechanisms underlying the pathogenic role of CP in AF are unknown and are therefore considered in this guest editorial.

Ceruloplasmin, a circulating protective protein, contains 95% of the copper in blood and has been ascribed with several diverse functions, the most well-established being ferroxidase activity [6]. CP oxidizes intracellular ferrous iron at the cell surface and delivers ferric iron to extracellular transferrin [6]. Dysfunction of CP therefore results in an accumulation of iron in tissues. AF is associated with iron overload (thalassaemia) in man [7] and iron overload in mice results in AF due to an effect on calcium channels [8]. In patients with aceruloplasminaemia [9] and in the CP knockout mouse [10], iron accumulates in the brain which indicates causality in Alzheimer's and Parkinson's disease. Cardiac dysfunction has not been reported in these scenarios which may be due simply to the fact that it was not looked for. However, AF is independently associated with dementia and AF renders dementia patients at high risk of death [11] indicating that CP dysfunction may be a common denominator in both AF and dementia.

Overproduction of reactive oxygen species (ROS) is associated with both AF [12] and CP pathogenicity [6]. ROS, such as superoxide and hydrogen peroxide, are generated by free iron (via Fenton and Haber Weiss-type reactions) and inducible enzymes such as xanthine and NADPH oxidases [6]. Antioxidant systems such as superoxide dismutase, catalase and glutathione are overwhelmed, so that tissues and cells are exposed to excess ROS levels [13, 14]. ROS then elicit effects that include apoptosis, oxidation of functional lipids and activation of pathogenic genes [13, 14]. ROS exert disruptive effects on cardiac electrophysiology that can lead to arrhythmias [15].

Reactive oxygen species also damage the structural integrity of CP such that the copper moieties bound to CP are dissociated [6]. This has two consequences: (i) CP is rendered dysfunctional and therefore promotes the accumulation of iron as outlined above, and (ii) unbound or free copper elicits pathogenic effects in its own right that are similar to that of free iron (apoptosis, cell toxicity, promotion of cell replication, oxidative stress, pathogenic gene activation) [6]. Due to its reactive nature, free copper is carefully controlled intracellularly by chaperone proteins [6]. Intracellular ROS (e.g. initially triggered by free iron) may also compromise copper (and iron) homeostasis within cells through a self-perpetuating cascade [6].

A major contributory factor for AF is atheromatous coronary artery disease (CAD) and myocardial infarction (MI) [3]. Because iron and copper generate ROS, accumulation of these metals in atheromas has been implicated in the aetiology of CAD and MI [6]. Chelators of both iron and copper inhibit atherosclerosis in APO-E knockout mice [16, 17]. Epidemiology points to an association of CP and copper with CAD and MI [6]. Free copper interacts with thiols, such as homocysteine, to generate ROS which reacts with nitric oxide (NO) to generate peroxynitrite, a highly toxic free radical [18]. Impaired NO formation is firmly associated with CAD [19]. Furthermore, CP, by virtue of its copper moieties, promotes angiogenesis which involves replication of endothelial cells and vascular smooth muscle, illustrating that copper and CP exert a potent impact on endothelial cell biology. Dysfunction of cerebral (micro) vasculature may certainly contribute to dementia and possibly to the central control of cardiac rhythm.

At the blood level, CP plays a number of protective and antioxidant roles. CP maintains plasma nitrite (which act as a substrate pool for NO formation), by catalysing the oxidation of NO to NO+ and subsequent hydration to nitrite [20]. Many studies have shown that CP has antioxidant properties [5]. CP dysfunction elicited either by SNP or by ROS would therefore result in augmented oxidative stress at the blood level.

Atrial fibrillation is also a major complication following coronary artery bypass graft surgery (CABG) [21]. Plasma CP levels are markedly elevated after CABG that persists for 6 weeks and perhaps beyond [22] CABG is associated with an induction of oxidative stress [23]. It is therefore reasonable to propose a causal involvement in CP and oxidative stress in AF associated with CABG.

The therapeutic control of cardiac rhythm is complex as AF is classified as paroxysmal, persistent, long-standing persistent or permanent and the presence of another disease that can render an intervention harmful [3, 24]. AF is treated pharmacologically with anti-arrhythmic drugs such as amiodarone and flecainide, but these have either low efficacy or poor safety profile [3, 24]. Drugs that are more efficacious, atrial specific and less pro-arrhythmic are being actively sought. Patients with AF, due to the risk of stroke, are treated with antithrombotic drugs (aspirin, clopidogrel and warfarin). The risk of bleeding in the elderly patients is problematic, however [3]. Notably, statins, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have proven to be effective in reducing AF [3], which is indicative of the importance of CAD and hypertension in AF.

If CP dysfunction is central to the aetiology of AF, then the development of CP mimetics by the Pharmaceutical Industry, or indeed independent researchers, is an obvious necessity. Iron and copper chelators are also intuitively indicated as a therapeutic strategy. In laboratory models, chelators of iron reduce arrhythmias and ischaemia reperfusion injury [25, 26]. Iron chelators also inhibit platelet activity [27]. Notably, free iron augments fibrin formation in blood [28], and CP and iron status are linked to stroke [29]. However, iron and copper are crucial for enzyme systems that are fundamental to health. Long-term use of chelators may therefore prove to be counter productive. Nevertheless, the exploration of chelators in the context of AF should be pursued. As oxidative stress results in CP dysfunction and therefore AF, then antioxidant therapy aimed at protecting circulating CP is also indicated.

Given the study of Adamsson Eyrd et al. [4], and the evidence presented in this editorial, it is clear that further studies need to be undertaken to explore the role of CP in AF. More clinical studies on SNP of the CP gene in patients with AF are warranted. The functionality of CP should be studied concomitantly by assessing antioxidant roles of CP in blood. Plasma nitrite status, which is affected by CP functionality, may be a valuable marker. Iron status in both blood and tissues as well as cardiac and vascular function should be investigated. As assessing iron accumulation and distribution in the hearts of living patients is not feasible, iron homeostasis could be assessed in blood-borne cells such as monocytes and neutrophils. Post-mortem studies on cardiac tissue banks would be valuable in determining whether iron accumulation (and its location) occurs in AF. Laboratory-based studies on isolated cells and tissues and animal models are of course mandatory for understanding the AF and the CP iron as well as the exploration of interventions. The CP knockout mouse represents a good model for studying the effect of iron overload.

Thus, from the evidence available, it appears that CP dysfunction, rather than its absolute plasma levels, may play a major aetiological role in AF and in turn that CP dysfunction can be due to genetic mutation or oxidative stress. A model of these mechanisms is given in fig. 1. Understanding this association and devising novel interventions may prove not only valuable to the treatment for AF but also to dementia and neurodegenerative diseases, heart failure, stroke, atherosclerosis, MI and vein graft failure. The study of Adamsson Eyrd et al. [4] may therefore prove to be of considerable historic importance.

Figure 1.

Hypothetical model of ceruloplasmin dysfunction and cell pathology.

Conflict of interest statement

No conflicts of interest to declare.