Academic literature on the topic 'Anti-arrhythmic strategy'

Atrial fibrillation (AF) remains a difficult management problem. The restoration and maintenance of sinus rhythm—rhythm control therapy—can markedly improve symptoms and haemodynamics for patients who have paroxysmal or persistent AF, but some patients fare well with rate control alone. Sinus rhythm can be achieved with anti-arrhythmic drugs or electrical cardioversion, but the maintenance of sinus rhythm without recurrence is more challenging. Catheter ablation of the AF triggers is more effective than anti-arrhythmic drugs at maintaining sinus rhythm. Whilst pulmonary vein isolation is an effective strategy, other ablation targets are being evaluated to improve sinus rhythm maintenance, especially in patients with chronic forms of AF. Previously extensive ablation strategies have been used for patients with persistent AF, but a recent trial has shown that pulmonary vein isolation without additional ablation lesions is associated with outcomes similar to those of more extensive ablation. This has led to an increase in catheter-based technology to achieve durable pulmonary vein isolation. Furthermore, a combination of anti-arrhythmic drugs and catheter ablation seems useful to improve the effectiveness of rhythm control therapy. Two large ongoing trials evaluate whether a modern rhythm control therapy can improve prognosis in patients with AF.

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.

Atrial fibrillation is an epidemic in Asia that is increasingly prevalent. Apart from stroke risk stratification and management of anticoagulation, physicians managing this group of patients also need to determine an optimal strategy in terms of rate or rhythm control. With new techniques of catheter ablation to maintain patients in sinus rhythm, patients with atrial fibrillation now have more options for treatment, on top of pharmacological methods. This paper aims to review the current evidence for rate and rhythm control in both general patients and subgroups of interest commonly encountered in clinical practices such as obesity, heart failure and thyroid disease. Key words: Ablation, Anti-arrhythmic drugs, Stroke

Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

Arrhythmogenic cardiomyopathy (ACM) is an inheritable heart muscle disease characterised pathologically by fibrofatty myocardial replacement and clinically by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Although, in its original description, the disease was believed to predominantly involve the right ventricle, biventricular and left-dominant variants, in which the myocardial lesions affect in parallel or even mostly the left ventricle, are nowadays commonly observed. The clinical management of these patients has two main purposes: the prevention of SCD and the control of arrhythmic and heart failure (HF) events. An implantable cardioverter defibrillator (ICD) is the only proven lifesaving treatment, despite significant morbidity because of device-related complications and inappropriate shocks. Selection of patients who can benefit the most from ICD therapy is one of the most challenging issues in clinical practice. Risk stratification in ACM patients is mostly based on arrhythmic burden and ventricular dysfunction severity, although other clinical features resulting from electrocardiogram and imaging modalities such as cardiac magnetic resonance may have a role. Medical therapy is crucial for treatment of VAs and the prevention of negative ventricular remodelling. In this regard, the efficacy of novel anti-HF molecules and drugs acting on the inflammatory pathway in patients with ACM is, to date, unknown. Catheter ablation represents an effective strategy to treat ventricular tachycardia relapses and recurrent ICD shocks. The present review will address the current strategies for prevention of SCD and treatment of VAs and HF in patients with ACM.

Background: Atrial fibrillation (AF) increases the risk of dementia. Whether the pharmacological rhythm control of AF can reduce the risk of dementia compared to the rate control strategy remains unclear. We hypothesize that the rhythm control strategy is better than the rate control strategy in preventing dementia. Methods: AF patients aged ≥65 years were identified from the Taiwan National Health Insurance Database. Patients receiving anti-arrhythmic drugs at a cumulative defined daily dose (cDDD) of >30 within the first year of enrollment constituted the rhythm control group. Patients who used rate control medications for a cDDD of >30 constituted the rate control group. A multivariate Cox hazards regression model was used to determine the hazard ratio (HR) for dementia. Results: A total of 3382 AF patients (698 in the rhythm control group; 2684 in the rate control group) were analyzed. During a 4.86 ± 3.38 year follow-up period, 414 dementia events occurred. The rhythm control group had a lower rate of dementia than the rate control group (adjust HR: 0.75, p = 0.031). The rhythm control strategy reduced the risk of dementia particularly in those receiving aspirin (p = 0.03). Conclusions: In patients with AF, pharmacological rhythm control was associated with a lower risk of dementia than rate control over a long-term follow-up period, particularly in patients receiving aspirin treatment.

L-type voltage-dependent calcium (Ca2+) channels (CaV1.2) initiate cardiac excitation-contraction coupling producing a rapid Ca2+ current (peak ICa,L) that triggers Ca2+ release from the intracellular stores, and a persistent current (late ICa,L) that flows towards the end of the action potential (AP). Peak and late ICa,L shape the plateau phase of the AP, counterbalancing potassium currents. An exaggerated activation of the late ICa,L during AP repolarization can cause transient membrane potential depolarizations called Early Afterdepolarizations (EADs), that can trigger lethal arrhythmias. Therefore, CaV1.2 channels represent a highly promising therapeutic target to abolish EADs. Current anti-arrhythmic drugs that operate on CaV channels (Class IV antiarrhythmics) reduce peak ICa,L, causing a negative inotropic effect. Based on the discovery that a small reduction of the late ICa,L can potently suppress EAD occurrence, we hypothesized that drugs selectively targeting this late component should efficiently suppress EADs preserving contractility. To test this hypothesis, we used roscovitine, a purine analog that reduces the late (non-inactivating) ICa,L over “peak”, accelerating the voltage-dependent inactivation of CaV1.2 channels. We proved that decrease of late ICa,L by roscovitine, verified both in native and cloned CaV1.2 channels, abolished EADs in rabbit ventricular myocytes preserving contraction efficiency. Moreover, this reduction suppressed and prevented EAD-mediated ventricular fibrillation in rabbit and rat hearts. In both isolated myocyte and heart experiments, the effect was independent from the mechanism chosen to induce EADs (hypokalemia and/or oxidative stress). These results suggest that 1) limiting anomalous Ca2+ channels action during the plateau phase is an effective and safe antiarrhythmic strategy and that 2) roscovitine can be considered as a potential pilot compound for a new class of antiarrhythmics that likely would not compromise heart contractility. Cav1.2 channels derive their voltage dependence properties from the structural asset of the α1 pore-forming subunit which comprises 4 positively charged modules, called voltage-sensing domains (VSD I-IV), that undergo a conformational change upon membrane depolarization, opening the channel. The voltage-dependent properties of these four VSDs are modulated by several auxiliary subunits (such as α2δ and β) interacting with the α1 subunit. Specifically, α2δ subunit, by remodelling the voltage-dependent properties of 3 out of 4 cardiac VSDs, allows CaV1.2 channels to operate at physiological membrane potentials producing the typical fast-activating current. Interestingly, the same auxiliary subunit produces opposite effects on the close relative CaV1.1 channels which regulate the excitation-contraction coupling in the skeletal muscle. Here, the α2δ subunit slows down CaV1.1 activation kinetics and leaves almost unperturbed the voltage-dependent activation of the pore. The molecular mechanism by which the α2δ subunit differently modulates CaV1.1 channels compared to CaV1.2 isoform is still unknown. To gain a mechanistic insight, we expressed in Xenopus oocytes CaV1.1 channels (α1S and the auxiliary subunit β1a) with or without α2δ. Using the voltage clamp fluorometry technique, we tracked the voltage-dependent conformational rearrangement of each VSD in conducting channels to derive pore and VSD voltage-dependent relationships. Analogously to CaV1.2, each CaV1.1 VSD had unique biophysical properties that might reveal different functional roles. The presence of α2δ remodelled only VSD I voltage-dependent properties, shifting its activation ~ 20 mV to more negative membrane potentials, may accounting for the ~ 10 mV-hyperpolarizing shift of pore opening observed with the accessory subunit. As opposite to CaV1.2, α2δ slowed down CaV1.1 activation kinetics and accelerated the rate of channel closure, contributing to reduce Ca2+ influx during depolarization.