Increases in dietary phosphate levels can augment atrial arrhythmias

Atrial fibrillation (AF) is a rapid, irregular supraventricular tachycardia, which is now the most commonly occurring cardiac arrhythmia worldwide.1 The incidence of AF and its clinical impact, including stroke, heart failure, and other morbidities are increasing, in part due to the aging of populations worldwide.2, 3 In spite of expanded efforts to identify the basic underlying mechanisms in animal models,4 and improve clinical detection, diagnoses and treatment modalities, significant knowledge gaps remain concerning how AF is initiated and maintained.2, 3 An interesting, significant manuscript in this volume of Acta Physiologica5 provides important new information concerning the intracellular signaling pathways through which a high phosphate diet, administered to healthy adult mice, can result in remodeling of the atria of these hearts, while also producing an increased tendency for the myocardium to exhibit AF-like high-frequency firing. In this study,5 either sham (control) or nephrectomized adult mice (a model of chronic kidney disease) were fed high phosphate diets for 10 weeks, and resulting increases in plasma levels of phosphate were measured. Animals were then sacrificed to allow the two main constituents of the atrial myocardium (myocytes and fibroblasts) to be isolated, maintained in short-term culture, and then analyzed using rigorous biochemical, molecular, and bioinformatics-based methods. Based on the resulting extensive and informative datasets, the authors conclude that even when phosphate levels are increased by as little as 1 mM (from normal, approximately 2.5 mM, to approximately 3.5 mM, see Table 1) specific intracellular signaling pathways involving STAT3/NF-κB were activated and consistent signs of mitochondrial stress and associated redox imbalance6 were observed. Additional insights were obtained using a cell line (HL-1), that mimics many of the properties of atrial myocytes. Specifically, alterations in the levels of proteins that are involved in contraction and intracellular calcium release provided the basis for the conclusion that a primary driver of the phosphate-induced effects in mouse atria is mitochondrial impairment, manifested in part as increased redox production and associated oxidative stress in both myocytes and fibroblasts. Furthermore, and importantly, the authors experimentally manipulated the signaling complex7 denoted “the inflammasome” and obtained results that further supported key functional roles for intracellular and paracrine inflammatory mediators. These experiments also identified alterations in ryanodine receptor-mediated intercellular calcium release in settings designed to mimic some of the known features of sterile inflammation leading to some types of AF.8 As these findings are assimilated and put in context it is worthwhile to consider that AF is an electrophysiological disturbance; and that in atrial tissue the myocytes and fibroblasts communicate both electrotonically and by paracrine mechanisms.1-4 In this regard, the Huang group9 and others have published electrophysiological and molecular data based on studies of adult mouse atria and ventricles. Their findings constitute strong evidence for ryanodine receptor-mediated changes in intracellular calcium and related alterations in the sodium current which triggers the action potential.10 They report that when intracellular calcium increases, the size of the sodium current decreases, and this results in slowed conduction and an increased latency or delay prior to action potential firing. In combination, these changes augment AF in both experimental animals and in humans as judged by monophasic action potential recordings and clinical mapping analyses.11 It is also known that reactive oxygen species such as hydrogen peroxide can have proarrhythmic effects by altering (slowing) the time course of inactivation of the sodium current.12 The resulting “late sodium current” reduces the repolarization reserve13 of the action potential and can also destabilize the resting potential of both atrial and ventricular myocytes.14 The finding of Yeh et al.,5 that increased plasma levels of phosphate can activate migration of atrial fibroblasts, suggests that these cells exhibit the well-known transition to the myofibroblast phenotype. Myofibroblasts, functioning as part of the atrial substrate or syncytium, tend to depolarize atrial myocytes15. Associated increases in their release cytokines2, 3 can then promote AF. Detailed consideration of the implications of the Yeh et al.,5 findings also suggest the need for further studies aimed at strengthening the translational significance of these findings. Additional assessment of the functional effects of increases in plasma phosphate levels on the clinical paradigm of AF will require data obtained from a large animal model that has a resting heart rate similar to that of humans (approximately 60 bpm as opposed to the approximately 600 bpm of the adult mouse). Perhaps more importantly “high phosphate” will need to be defined more clearly. Note that in Table 1 of this study,5 normal plasma phosphate levels are approx. 2.5 mM and high phosphate is about 3.5 mM. Nonetheless, the majority of the Yet et al., data compare functional effects of phosphate levels that are increased from 1 to 2 mM. This distinction is important, since until recently the phosphate receptor in question had not been identified.16 In summary, the Yeh et al., group5 have contributed importantly to present understanding of key aspects of the cell signaling and biochemistry that underlies the pathophysiology of atrial arrhythmias in the adult mouse. Their findings also add to, and compliment, ongoing projects based on computational analyses of intracellular signaling pathways that can alter fibroblast and myocyte phenotypes.17 These datasets, used in conjunction with key components of clinical descriptors and biomarkers are likely to be able to support new initiatives that use machine learning and artificial intelligence18 approaches to identify patient-specific regions of the atria that can promote or sustain AF. None.

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