Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca²⁺ homeostasis

Abstract

(21,22,26) has been implicated in the ventricular arrhythmogenic tendency observed in conditions such as sudden cardiac death in heart failure. It has been suggested that the RyR2 phosphorylation observed in failing human hearts dissociates the regulatory protein FKBP12.6 from the RyR2 Ca 2ϩ -release channel, thereby increasing the sensitivity of the channel to cytosolic Ca 2ϩ (22). The resulting leak of sarcoplasmic reticular (SR) Ca 2ϩ could then initiate triggered arrhythmogenesis (9). Furthermore, the consequent reduction in SR Ca 2ϩ content would compromise release of intracellularly stored Ca 2ϩ (16,29), reduce myocyte Ca 2ϩ transients (11, 30), and potentially cause the contractile dysfunction associated with cardiac failure. Recently, mutations in human RyRs have similarly been associated with effort-induced ventricular arrhythmias (31), and studies on mouse RyR2s have attributed these to increases in basal RyR channel activity (13, 36).Caffeine similarly increases open probabilities in RyR2s in isolated myocytes in vitro (35) and induces ventricular arrhythmias in canine and rabbit hearts in vivo (12, 24). The present experiments accordingly sought to correlate the effects of caffeine on propagation of excitation in perfused intact mouse hearts with its effects on Ca 2ϩ homeostasis in isolated myocytes. Use of mouse hearts additionally provided baseline data for a model system for which experimentally useful arrhythmogenic genetic variants are becoming increasingly available (1,4,6,8,17,25,28,36). The proarrhythmic effects of caffeine were confirmed by demonstrating the extent to which a technique of programmed electrical stimulation (PES), adapted from cardiological practice and applied for the first time under these pharmacological conditions to experimental systems, induced ventricular arrhythmogenesis. The findings were compared with results from an adaptation of paced electrogram fractionation analysis (PEFA). This technique has hitherto been employed to detect arrhythmogenic propensities resulting from reentrant electrical activity in clinical proarrhythmic conditions (33, 34) and in murine cardiac models (1).We demonstrated that caffeine exerted marked arrrhythmogenic effects yet did not influence electrogram duration (EGD). This excluded slowed conduction and reentrant electrical activity as their underlying cause. In contrast, the results closely correlated with observed in vitro effects of caffeine in isolated fluo-3-loaded ventricular myocytes imaged using confocal microscopy. Caffeine then increased the frequency of spontaneous Ca 2ϩ -release events, the background cytosolic Ca 2ϩ concentration ([Ca 2ϩ ]) in high extracellular [Ca 2ϩ ] solution, and the amplitude of Ca 2ϩ transients after paced electrical stimulation. These effects in turn were mimicked by the immunosuppressant FK506, which is also thought to increase the open probability of RyR2s (3,14,15,38,39), specifically by dissociating FKBP12.6 from RyR2 in parallel with the consequences of RyR2 hyperphosphorylation by protein...

Pancreatic protease activation by alcohol metabolite depends on Ca 2+ release via acid store IP 3 receptors

“…Therefore, the inhibitory effect of caffeine on IP 3 Rs (41, 42) could be a useful starting point for therapeutic considerations. Unfortunately, other caffeine effects, for example activation of RyRs mediating Ca 2ϩ release from the sarcoplasmic reticulum in the heart, potentially causing serious cardiac arrhythmias (43), limit the usefulness of caffeine itself as a drug for pancreatitis treatment.…”

Ryanodine receptor dysfunction and triggered activity in the heart

“…Recent work suggests that disruption of the RyR complex can lead to arrhythmogenic right ventricular dysplasia type 2 and catecholaminergic and familial polymorphic ventricular tachycardia (5,26,27,43). These lethal disruptions have been linked to genetic defects (13,17,27,37,43), transient pharmacological treatment (caffeine, tacrolimus) (3,4,31), or acquired diseases such as heart failure (49). Using a transgenic FKBP12.6-knockout model, Wehrens et al (45) observed calcium-mediated triggered activity associated with exercise and elevated catecholamine levels (45).…”

Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling

“…In contrast, HNO increases spark frequency without altering individual spark characteristics or adversely impacting Ca 2ϩ stability. The action of HNO on RyR2 is also different from that of caffeine, which increases the frequency of spontaneous Ca 2ϩ -release events (Ca 2ϩ waves), an effect that persists even after discontinuing the drug, 30 leading to a substantial decrease in SR Ca 2ϩ content. The unique action of HNO on RyR2 may relate to its thiophilic chemistry.…”