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The inwardly rectifying potassium current of the cardiomyocyte (IK1) is the main determinant of the resting potential. Ion channels Kir2.1, Kir2.2, and Kir2.3 form tetramers and are the molecular correlate of macroscopic IK1 current. Verapamil is an antiarrhythmic drug used to suppress atrial and ventricular arrhythmias. Its primary mechanism of action is via blocking calcium channels. In addition, it has been demonstrated to block IK1 current and the Kir2.1 subunit. Its effect on other subunits that contribute to IK1 current has not been studied to date. We therefore analyzed the effect of verapamil on the Kir channels 2.1, 2.2, and 2.3 in the Xenopus oocyte expression system. Kir2.1, Kir2.2, and Kir2.3 channels were heterologously expressed in Xenopus oocytes. Respective currents were measured with the voltage clamp technique and the effect of verapamil on the current was measured. At a concentration of 300 µM, verapamil inhibited Kir2.1 channels by 41.36% ± 2.7 of the initial current, Kir2.2 channels by 16.51 ± 3.6%, and Kir2.3 by 69.98 ± 4.2%. As a verapamil effect on kir2.3 was a previously unknown finding, we analyzed this effect further. At wash in with 300 µM verapamil, the maximal effect was seen within 20 min of the infusion. After washing out with control solution, there was only a partial current recovery. The current reduction from verapamil was the same at − 120 mV (73.2 ± 3.7%), − 40 mV (85.5 ± 6.5%), and 0 mV (61.5 ± 10.6%) implying no voltage dependency of the block. Using site directed mutations in putative binding sites, we demonstrated a decrease of effect with pore mutant E291A and absence of verapamil effect for D251A. With mutant I214L, which shows a stronger affinity for PIP2 binding, we observed a normalized current reduction to 61.9 ± 0.06% of the control current, which was significantly less pronounced compared to wild type channels. Verapamil blocks Kir2.1, Kir2.2, and Kir2.3 subunits. In Kir2.3, blockade is dependent on sites E291 and D251 and interferes with activation of the channel via PIP2. Interference with these sites and with PIP2 binding has also been described for other Kir channels blocking drugs. As Kir2.3 is preferentially expressed in atrium, a selective Kir2.3 blocking agent would constitute an interesting antiarrhythmic concept.

Introduction Remote patient monitoring (RPM) of heart failure patients has the potential to reduce healthcare resource use and costs, but current evidence has been inconclusive. This study aims assess the impact of RPM of heart failure patients with an implantable cardioverter defibrillator on medical resource use, direct medical costs, quality-adjusted life years (QALYs), and travel time of patients, and to estimate its commercial headroom in the Netherlands and Germany. Methods Data from the REMOTE-CIED randomized controlled trial were used to calculate differences in length of hospital stay, outpatient clinic visits, telephone consults, emergency room visits, and travel time between patients on in-clinic follow-up and RPM in the Netherlands, Germany, and France. Incremental cardiac-related healthcare costs and QALYs were calculated and used to calculate the commercial headroom of RPM in the Netherlands and Germany. The impact of imputation, parameter, and case-mix uncertainty on these outcomes was explored using probabilistic analysis. Results Length of hospitalization, number of unscheduled admissions, and number of outpatient visits were lower in the remote monitoring group in all three countries. Number of hospital admissions was higher, and number of calls was lower in the Netherlands and Germany but not in France. Costs were lower in both the Netherlands (−€1041, 95% confidence interval (CI): −€3308, €1005) and Germany (−€2865, 95% CI: −€7619, €1105), while incremental effectiveness differed: −0.003 (95% CI: −0.114, 0.107) QALY in the Netherlands and +0.086 (95% CI: −0.083, 0.256) in Germany. Commercial headroom was estimated at €881 (95% CI: −€5430, €7208) in the Netherlands and €5005 (95% CI: −€1339, €11,960) in Germany. Discussion RPM was found to result in reduced medical resource use and travel time. Whether it is cost saving or cost effective strongly depends on the costs of remote monitoring. Trial registration number and trial register ClinicalTrials.gov: NCT01691586.

Aims Remote patient monitoring (RPM) systems offer a promising alternative to conventional In-Clinic check-ups, hereby reducing unnecessary clinic visits. Especially with the rise of the COVID-19 pandemic, this reduction is of paramount importance. Regarding the association between RPM and clinical outcomes, findings of previous studies have been inconsistent. The aim of this study is to elucidate the effect of partly substituting In-Clinic visits by RPM on clinical outcomes in implantable cardioverter-defibrillator (ICD) patients. Methods and results The study included 595 heart failure patients (LVEF ≤35%; NYHA Class II/III) implanted with an ICD compatible with the Boston Scientific LATITUDE™ system. Participants were randomized to RPM plus an annual In-Clinic visit or 3–6 months In-Clinic check-ups alone. The investigated endpoints after 2 years of follow-up included a composite of all-cause mortality and cardiac hospitalization, mortality and cardiac hospitalization as independent endpoints and ICD therapy. The incidence of mortality and hospitalization did not differ significantly as independent, nor as composite endpoint between the RPM and In-Clinic group (all Ps, Graphical Abstract Graphical Abstract