Explore the vast range of titles available.

Life-long stable heart function requires a critical balance of intracellular Ca[sup.2+]. Several ion channels and pumps cooperate in a complex machinery that controls the influx, release, and efflux of Ca[sup.2+]. Probably one of the most interesting and most complex players of this crosstalk is the Na[sup.+]/Ca[sup.2+] exchanger, which represents the main Ca[sup.2+] efflux mechanism; however, under some circumstances, it can also bring Ca[sup.2+] into the cell. Therefore, the inhibition of the Na[sup.+]/Ca[sup.2+] exchanger has emerged as one of the most promising possible pharmacological targets to increase Ca[sup.2+] levels, to decrease arrhythmogenic depolarizations, and to reduce excessive Ca[sup.2+] influx. In line with this, as a response to increasing demand, several more or less selective Na[sup.+]/Ca[sup.2+] exchanger inhibitor compounds have been developed. In the past 20 years, several results have been published regarding the effect of Na[sup.+]/Ca[sup.2+] exchanger inhibition under various circumstances, e.g., species, inhibitor compounds, and experimental conditions; however, the results are often controversial. Does selective Na[sup.+]/Ca[sup.2+] exchanger inhibition have any future in clinical pharmacological practice? In this review, the experimental results of Na[sup.+]/Ca[sup.2+] exchanger inhibition are summarized focusing on the data obtained by novel highly selective inhibitors.

During drug development, candidate compounds are extensively tested for proarrhythmic risk and in particular risk of Torsade de Pointes (TdP), as indicated by prolongation of the QT interval. Drugs that inhibit the rapid delayed rectifier K+ current (IKr) can prolong the action potential duration (APD) and thereby the QT interval, and so are routinely rejected. However, simultaneous inhibition of the L-type Ca2+ current (ICaL) can mitigate the effect of IKr inhibition, so that including both effects can improve test specificity. Mathematical models of the action potential (AP) can be used to predict the APD prolongation resulting from a given level of IKr and ICaL inhibition, but for use in safety-testing their predictive capabilities should first be carefully verified. We present the first systematic comparison between experimental drug-induced APD and predictions by AP models. New experimental data were obtained ex vivo for APD response to IKr and/or ICaL inhibition by applying 9 compounds at different concentrations to adult human ventricular trabeculae at physiological temperature. Compounds with similar effects on IKr and ICaL exhibited less APD prolongation compared to selective IKr inhibitors. We then integrated in vitro IC50 patch-clamp data for IKr and ICaL inhibition by the tested compounds into simulations with AP models. Models were assessed against the ex vivo data on their ability to recapitulate drug-induced APD changes observed experimentally. None of the tested AP models reproduced the APD changes observed experimentally across all combinations and degrees of IKr and/or ICaL inhibition: they matched the data either for selective IKr inhibitors or for compounds with comparable effects on IKr and ICaL. This work introduces a new benchmarking framework to assess the predictivity of current and future AP models for APD response to IKr and/or ICaL inhibition. This is an essential primary step towards an in silico framework that integrates in vitro data for translational clinical cardiac safety.

Atrial fibrosis is a hallmark of atrial cardiomyopathy and plays a pivotal role in the pathogenesis of atrial fibrillation (AF), contributing to its onset and progression. The mechanisms underlying atrial fibrosis are multifaceted, involving stretch-induced fibroblast activation, oxidative stress, inflammation, and coagulation pathways. Variations in fibrosis types—reactive and replacement fibrosis—are influenced by patient-specific factors such as age, sex, and comorbidities, complicating therapeutic approaches. The heterogeneity of fibrosis leads to distinct electrophysiological abnormalities that promote AF via reentrant activity and enhanced automaticity mechanisms. Despite advancements in imaging, such as late gadolinium enhancement CMR and electroanatomical mapping, challenges in accurately quantifying fibrosis persist. Emerging therapeutic strategies include antifibrotic agents targeting the renin–angiotensin–aldosterone system, novel pathways like TGF-β signaling, and cardio-metabolic drugs like SGLT2 inhibitors and GLP-1 receptor agonists. Innovative interventions, including microRNA modulation and lipid nanoparticle-based therapies, show promise but require validation. Knowledge gaps remain in correlating clinical outcomes with fibrosis patterns and optimizing diagnostic tools. Future research should focus on precise phenotyping, integrating advanced imaging with molecular biomarkers, and conducting robust trials to evaluate antifibrotic therapies’ efficacy in reducing AF burden and related complications.

Long QT syndrome type 1 with affected I[sub.Ks] is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target I[sub.Ks] as antiarrhythmics. We examined the antiarrhythmic effect of I[sub.Ks] channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). I[sub.Ks] channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

The incidence of recurrent ventricular arrhythmias is increasing these days. Ventricular electrical storm can be of three types as follows: monomorphic ventricular tachycardia (VT), polymorphic VT, and ventricular fibrillation. The mechanism of ventricular storm is complex, and its management is quite a challenge for the clinicians due to its life-threatening consequences. We report a case of ventricular storm in whom all the conventional methods for the management of arrhythmias were ineffective, and the case is managed effectively with thoracic epidural anesthesia (TEA). A 60-year-old male patient was admitted to recurrent ventricular arrhythmias. He received defibrillator shocks and other antiarrhythmic drugs, but he was not responding to the treatment. We managed to revert the ventricular arrhythmias to the sinus rhythm with TEA. Ventricular storm is a challenging complication, which can be managed effectively with timely diagnosis and effective management.

Dofetilide is an effective antiarrhythmic medication for rhythm control in atrial fibrillation, but carries a significant risk of pro-arrhythmia and requires meticulous dosing and monitoring. The cornerstone of this monitoring, measurement of the QT/QTc interval, is an imperfect surrogate for plasma concentration, efficacy, and risk of pro-arrhythmic potential. The aim of our study was to test the application of a deep learning approach (using a convolutional neural network) to assess morphological changes on the surface ECG (beyond the QT interval) in relation to dofetilide plasma concentrations. We obtained publically available serial ECGs and plasma drug concentrations from 42 healthy subjects who received dofetilide or placebo in a placebo-controlled cross-over randomized controlled clinical trial. Three replicate 10-s ECGs were extracted at predefined time-points with simultaneous measurement of dofetilide plasma concentration We developed a deep learning algorithm to predict dofetilide plasma concentration in 30 subjects and then tested the model in the remaining 12 subjects. We compared the deep leaning approach to a linear model based only on QTc. Fourty two healthy subjects (21 females, 21 males) were studied with a mean age of 26.9 ± 5.5 years. A linear model of the QTc correlated reasonably well with dofetilide drug levels (r = 0.64). The best correlation to dofetilide level was achieved with the deep learning model (r = 0.85). This proof of concept study suggests that artificial intelligence (deep learning/neural network) applied to the surface ECG is superior to analysis of the QT interval alone in predicting plasma dofetilide concentration.

This editorial summarizes the 22 scientific papers published in the Special Issue “Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment” of the International Journal of Molecular Sciences [...]

Background Availability of portable and home‐based electrocardiography (ECG) is an important medical innovation, which has a potential to transform medical care. We performed this review to understand the current state of out‐of‐hospital portable ECG technologies with respect to their scope, ease of use, data transmission capabilities, and diagnostic accuracy. Methods We conducted PubMed and Internet searches for “handheld” or “wearable” or “patch” electrocardiography devices to enlist available technologies. We also searched PubMed with names of individual devices to obtain additional citations. We classified available devices as a “single limb lead ECG recording devices” and chest‐lead “ECG recording devices.” If a device used more than three electrodes, it was defined as a conventional electrocardiography or Holter machine and was excluded from this review. Results We identified a total of 15 devices. Overall, only six of these devices (five single lead and one chest lead) featured in published medical literature as identified from PubMed search. A total of 13 citations were available for the single limb lead ECG recording devices and 6 citations for the chest‐lead ECG recording devices. Conclusions Despite the increase in number of such devices, published biomedical literature regarding their diagnostic accuracy, reproducibility, or utility is scant.

Heart failure (HF) is a life-threatening disorder and is treated by drug therapies and surgical interventions such as heart transplantation and left ventricular assist device (LVAD). However, these treatments can lack effectiveness in the long term and are associated with issues such as donor shortage in heart transplantation, and infection, stroke, or gastrointestinal bleeding in LVADs. Therefore, alternative therapeutic strategies are still needed. In this respect, stem cell therapy has been introduced for the treatment of HF and numerous preclinical and clinical studies are employing a range of stem cell varieties. These stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have been shown to improve cardiac function and attenuate left ventricular remodeling. IPSCs, which have a capacity for unlimited proliferation and differentiation into cardiomyocytes, are a promising cell source for myocardial regeneration therapy. In this review, we discuss the following topics: (1) what are iPSCs; (2) the limitations and solutions for the translation of iPSC-CMs practically; and (3) the current therapeutic clinical trials.