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Smoking is a major public health issue and the leading preventable cause of illness and death worldwide. It is known to contribute to the development of cardiac arrhythmias, including atrial fibrillation (AF). The addictive component of cigarettes and e-cigarettes, nicotine, is believed to have proarrhythmic effects. A recent study suggests that chronic nicotine exposure may reduce sympathetic innervation in the heart, potentially contributing to ventricular arrhythmogenesis in smokers. Additionally, smoking has been associated with an increased risk of AF, and nicotine may have direct effects on the atria. The study also found that chronic nicotine exposure increases susceptibility to alternans of action potential duration and calcium transient amplitude, which are risk factors for AF. The protective effect of acute sympathetic nerve stimulation against alternans was lost with chronic nicotine exposure. The article highlights the need for further research on the effects of nicotine on atrial sympathetic innervation and fibrosis, as well as efforts to reduce smoking and its impact on health. [Extracted from the article]

The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF. [ABSTRACT FROM AUTHOR]

The purpose of this article is to review the basis of arrhythmogenesis, the functional and clinical role of the late Na current, and its therapeutic inhibition. Under pathological conditions such as ischemia and heart failure this current is abnormally enhanced and influences cellular electrophysiology as a proarrhythmic substrate in myocardial pathology. Ranolazine the only approved late Na current blocker has been demonstrated to produce antiarrhythmic effects in the atria and the ventricle. We summarize recent experimental and clinical studies of ranolazine and other experimental late Na current blockers and discuss the significance of the available data. [ABSTRACT FROM AUTHOR]

Aims: Enhanced cardiac late Na-current (late INa) and increased sarcoplasmic reticulum (SR) Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late INa and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and Results: In murine atrial CMs SR-Ca2+-leak was increased by the late INa enhancer ATX-II. An inhibition of Ca2+/calmodulin-dependent protein-kinase II (AIP), Protein kinase A (H89), or late INa (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was neither detected when the Na+/Ca2+-exchanger was inhibited (KBR) nor in CaMKIIdc-knockout mice. FRET-measurements revealed increased cAMP-levels upon ATX-II stimulation, which could be prevented by inhibition of adenylylcyclase 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA-activation via an adenylylcyclase-dependent increase of cAMP-levels. Western blots showed late INa-dependent hyperphosphorylation of CaMKII- as well as PKA target-sites at RyR2 (-S2815, -S2809) and PLB (-Thr17, -S16). Enhancement of late INa did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late INa activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased whereas PKA-inhibition reduced Ca2+ transient amplitude and load and slowed Ca2+-elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late INa, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion: Late INa exerts distinct effects on Ca2+-homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late INa represents a potential approach to attenuate CaMKII-activation and decrease SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA-system further increases the antiarrhythmic potential of late INa-inhibition. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF. [ABSTRACT FROM AUTHOR]