Effects of Ionizing Radiation on Cardiac Implantable Electronic Devices (CIEDs) in Patients with Esophageal Cancer Undergoing Radiotherapy: A Pilot Study.

(1) Background: The prevalence of cancer patients relying on cardiac implantable electronic device (CIED) is steadily rising. The aim of this study was to evaluate RT-related malfunctions of CIEDs. (2) Methods: We retrospectively analyze sixteen patients with esophageal cancer who were treated with radiotherapy between 2012 and 2022 at the University Hospital Heidelberg. All patients underwent systemic evaluation including pre-therapeutic cardiological examinations of the CIED functionality and after every single irradiation. (3) Results: Sixteen patients, predominantly male (14) with a mean age of 77 (range: 56-85) years were enrolled. All patients received 28 fractions of radiotherapy with a cumulative total dose 58.8 Gy. The mean maximum dose at the CIEDs was 1.8 Gy. Following radiotherapy and during the one-year post-radiation follow-up period, there were no registered events associated with the treatment in this evaluation. (4) Conclusion: The study did not observe any severe CIED malfunctions following each radiation fraction or after completion of RT. Strict selection of photon energy and alignment with manufacturer-recommended dose limits appear to be important. Our study showed no major differences in the measured values of the pacing threshold, sensing threshold and lead impedance after RT.

[Acceptance of telemetric care for patients with sICD safety advice : Qualitative interview study in cardiological health services research]. / Akzeptanz einer telemetrischen Versorgung bei Patienten mit sICD-Sicherheitshinweis : Qualitative Interviewstudie der kardiologischen Versorgungsforschung.

BACKGROUND: Telemonitoring is used to monitor implantable cardioverter defibrillators (ICDs). Despite the scientifically proven effectiveness and safety of telemetric care, studies show that the offer is not used and accepted by all patients. OBJECTIVES: The aim of this study is to investigate the attitudes of ICD patients towards telemonitoring, including which aspects influence attitudes and decision-making. METHODS: Data were collected using semi-structured, guideline-based individual interviews. A total of 14 patients with a subcutaneous ICD (sICD) and both primary and secondary prophylactic indications were recruited. Data analysis followed a content-structuring qualitative approach. RESULTS: Patients with telemonitoring perceived a high benefit with low concerns about digital technology, while the opposite was observed for patients without telemonitoring. The patients' previous medical experience has a crucial impact on the acceptance of telemonitoring. All age groups reported the technical implementation and practical handling of telemonitoring to be simple and uncomplicated. CONCLUSION: The results suggest that the primary and secondary prophylactic indication for ICD implantation have an influence on the attitude towards telemonitoring and, thus, on acceptance. Further qualitative research regarding user acceptance of telemonitoring of other ICD systems is needed.

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP2 binding.

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.

Cryoballoon pulmonary vein isolation-mediated rise of sinus rate in patients with paroxysmal atrial fibrillation.

BACKGROUND: Modulation of the cardiac autonomic nervous system by pulmonary vein isolation (PVI) influences the sinoatrial nodal rate. Little is known about the causes, maintenance and prognostic value of this phenomenon. We set out to explore the effects of cryoballoon PVI (cryo-PVI) on sinus rate and its significance for clinical outcome. METHODS AND RESULTS: We evaluated 110 patients with paroxysmal atrial fibrillation (AF), who underwent PVI using a second-generation 28 mm cryoballoon by pre-, peri- and postprocedural heart rate acquisition and analysis of clinical outcome. Ninety-one patients could be included in postinterventional follow-up, indicating that cryo-PVI resulted in a significant rise of sinus rate by 16.5% (+ 9.8 ± 0.9 beats/min, p < 0.001) 1 day post procedure compared to preprocedural acquisition. This effect was more pronounced in patients with initial sinus bradycardia (< 60 beats/min.) compared to patients with faster heart rate. Increase of rate was primarily driven by ablation of the right superior pulmonary vein and for a subset of patients, in whom this could be assessed, persisted ≥ 1 year after the procedure. AF recurrence was neither predicted by the magnitude of the initial rate, nor by the extent of rate change, but postprocedural sinus bradycardia was associated with higher recurrence of AF in the year post PVI. CONCLUSIONS: Cryo-PVI causes a significant rise of sinus rate that is more pronounced in subjects with previous sinus bradycardia. Patient follow-up indicates persistence of this effect and suggests an increased risk of AF recurrence in patients with postprocedural bradycardia.

Postcardiac injury syndrome after cardiac implantable electronic device implantation.

BACKGROUND: Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. MATERIAL AND METHODS: All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. RESULTS: We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p < 0.001 in RA lead implantation). Dyspnea, chest pain, dry cough, and fever were the most frequently reported symptoms in patients with PCIS. Pericardial and pleura effusion as well as elevated C­reactive protein (CRP), increased erythrocyte sedimentation rate (ESR), and leukocytosis were the most common findings. CONCLUSION: To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.

Novel approach to discriminate left bundle branch block from nonspecific intraventricular conduction delay using pacing-induced functional left bundle branch block.

PURPOSE: Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061-1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol. METHODS: Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n = 20), wide QRS of right bundle branch block (RBBB) morphology (n = 14), and wide QRS of LBBB morphology (n = 25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation. RESULTS: In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43 ± 0.013 (n = 20) and 0.41 ± 0.026 (n = 14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43 ± 0.022, n = 7) and a group with delayed left ventricular activation (0.75 ± 0.016, n = 18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of "true LBBB" and another group of "apparent LBBB"/nonspecific intraventricular conduction delay (NICD) could be generated. CONCLUSIONS: We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.

Fully digital data processing during cardiovascular implantable electronic device follow-up in a high-volume tertiary center.

BACKGROUND: Increasing numbers of patients with cardiovascular implantable electronic devices (CIEDs) and limited follow-up capacities highlight unmet challenges in clinical electrophysiology. Integrated software (MediConnect®) enabling fully digital processing of device interrogation data has been commercially developed to facilitate follow-up visits. We sought to assess feasibility of fully digital data processing (FDDP) during ambulatory device follow-up in a high-volume tertiary hospital to provide guidance for future users of FDDP software. METHODS: A total of 391 patients (mean age, 70 years) presenting to the outpatient department for routine device follow-up were analyzed (pacemaker, 44%; implantable cardioverter defibrillator, 39%; cardiac resynchronization therapy device, 16%). RESULTS: Quality of data transfer and follow-up duration were compared between digital (n = 265) and manual processing of device data (n = 126). Digital data import was successful, complete and correct in 82% of cases when early software versions were used. When using the most recent software version the rate of successful digital data import increased to 100%. Software-based import of interrogation data was complete and without failure in 97% of cases. The mean duration of a follow-up visit did not differ between the two groups (digital 18.7 min vs. manual data transfer 18.2 min). CONCLUSIONS: FDDP software was successfully implemented into the ambulatory follow-up of patients with implanted pacemakers and defibrillators. Digital data import into electronic patient management software was feasible and supported the physician's workflow. The total duration of follow-up visits comprising technical device interrogation and clinical actions was not affected in the present tertiary center outpatient cohort.

Inhibition of inwardly rectifying Kir2.x channels by the novel anti-cancer agent gambogic acid depends on both pore block and PIP2 interference.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential. Inhibition of the cardiac IK1 current may lead to ventricular arrhythmia due to delayed afterdepolarizations. Compared to Kv2.1, hERG and Kir1.1, a slow, delayed inhibition of Kir2.1 channels by GA in a mammalian cell line was reported before but no data exist in literature concerning action of GA on homomeric Kir2.2 and Kir2.3 and heteromeric Kir2.x channels. Therefore, the aim of this study was to provide comparative data on the effect of GA on homomeric and heteromeric Kir2.x channels. Homomeric and heteromeric Kir2.x channels were heterologously expressed in Xenopus oocytes, and the two-microelectrode voltage-clamp technique was used to record Kir2.x currents. To investigate the mechanism of the channel inhibition by GA, alanine-mutated Kir2.x channels with modifications in the channels pore region or at phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sites were employed. GA caused a slow inhibition of homomeric and heteromeric Kir2.x channels at low micromolar concentrations (with IC50 Kir2.1/2.2 < Kir2.2 < Kir2.2/2.3 < Kir2.3 < Kir2.1 < Kir2.1/2.3). The effect did not reach saturation within 60 min and was not reversible upon washout for 30 min. The inhibition showed no strong voltage dependence. We provide evidence for a combination of direct channel pore blockade and a PIP2-dependent mechanism as a molecular basis for the observed effect. We conclude that Kir2.x channel inhibition by GA may be relevant in patients with pre-existing cardiac disorders such as chronic heart failure or certain rhythm disorders and recommend a close cardiac monitoring for those patients when treated with GA.

Role of plasma membrane-associated AKAPs for the regulation of cardiac IK1 current by protein kinase A.

The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream ß-adrenoreceptors. Patch clamp and voltage clamp experiments were used to record currents and co-immunoprecipitation, and co-localization experiments were performed to show spatial and functional coupling. Activation of PKA inhibited IK1 current in rat cardiomyocytes. This regulation was markedly attenuated by disrupting PKA-binding to AKAPs with the peptide inhibitor AKAP-IS. We observed functional and spatial coupling of the plasma membrane-associated AKAP15 and AKAP79 to Kir2.1 and Kir2.2 channel subunits, but not to Kir2.3 channels. In contrast, AKAPyotiao had no functional effect on the PKA regulation of Kir channels. AKAP15 and AKAP79 co-immunoprecipitated with and co-localized to Kir2.1 and Kir2.2 channel subunits in ventricular cardiomyocytes. In this study, we provide evidence for coupling of cardiac Kir2.1 and Kir2.2 subunits with the plasma membrane-bound AKAPs 15 and 79. Cardiac membrane-associated AKAPs are a functionally essential part of the regulatory cascade determining IK1 current function and may be novel molecular targets for antiarrhythmic therapy downstream from ß-adrenoreceptors.

Efficacy, High Procedural Safety And Rapid Optimization Of Cryoballoon Atrial Fibrillation Ablation In The Hands Of A New Operator.

BACKGROUND: Cryoballoon (CB) ablation is successful in eliminating atrial fibrillation (AF). PURPOSE: The purpose of this study was to assess procedural efficacy and safety of CB ablation performed by a newly trained operator. METHODS: Forty patients with documented paroxysmal AF (58 ± 11 years, 26 male) undergoing CB catheter ablation were prospectively enrolled. RESULTS: Electrical pulmonary vein (PV) isolation was achieved in all patients (156 PVs). The primary end point (PV isolation using CB only) was reached in 31 patients (92% PV isolation, 144/156 PVs). In the remaining 9 patients (12 PVs), additional single point cryofocal ablations were required to achieve isolation of all veins (LSPV, n = 5; LIPV, n = 3; LCPV, n = 2; RSPV, n = 1; RIPV, n = 1). There was no vascular access complication, pericardial effusion/tamponade, stroke/transient ischemic attack, phrenic nerve palsy, acute PV stenosis, or atrioesophageal fistula. The procedure duration decreased with experience by 30% from 155 min during the first 10 procedures to 108 min (final 10 treatments). Similar effects were observed with fluoroscopy time (-57%; from 28 min to 12 min), dose area product (-66%; from 22 Gy x cm2 to 8 Gy x cm2), CB time in the left atrium (-24%; from 99 min to 75 min), and cryoenergy delivery time (-19%; from 83 min to 67 min), when comparing cases #1-10 to cases #30-40. CONCLUSIONS: CB ablation of AF is effective and safe in the hands of a new operator. Procedure and fluoroscopy times decrease with user experience.

Inhibition of Cardiac Kir Current (IK1) by Protein Kinase C Critically Depends on PKCß and Kir2.2.

BACKGROUND: Cardiac inwardly rectifying Kir current (IK1) mediates terminal repolarisation and is critical for the stabilization of the diastolic membrane potential. Its predominant molecular basis in mammalian ventricle is heterotetrameric assembly of Kir2.1 and Kir2.2 channel subunits. It has been shown that PKC inhibition of IK1 promotes focal ventricular ectopy. However, the underlying molecular mechanism has not been fully elucidated to date. METHODS AND RESULTS: In the Xenopus oocyte expression system, we observed a pronounced PKC-induced inhibition of Kir2.2 but not Kir2.1 currents. The PKC regulation of Kir2.2 could be reproduced by an activator of conventional PKC isoforms and antagonized by pharmacological inhibition of PKCß. In isolated ventricular cardiomyocytes (rat, mouse), pharmacological activation of conventional PKC isoforms induced a pronounced inhibition of IK1. The PKC effect in rat ventricular cardiomyocytes was markedly attenuated following co-application of a small molecule inhibitor of PKCß. Underlining the critical role of PKCß, the PKC-induced inhibition of IK1 was absent in homozygous PKCß knockout-mice. After heterologous expression of Kir2.1-Kir2.2 concatemers in Xenopus oocytes, heteromeric Kir2.1/Kir2.2 currents were also inhibited following activation of PKC. CONCLUSION: We conclude that inhibition of cardiac IK1 by PKC critically depends on the PKCß isoform and Kir2.2 subunits. This regulation represents a potential novel target for the antiarrhythmic therapy of focal ventricular arrhythmias.

Class III antiarrhythmic drug dronedarone inhibits cardiac inwardly rectifying Kir2.1 channels through binding at residue E224.

Dronedarone is a novel class III antiarrhythmic drug that is widely used in atrial fibrillation. It has been shown in native cardiomyocytes that dronedarone inhibits cardiac inwardly rectifying current IK1 at high concentrations, which may contribute both its antifibrillatory efficacy and its potential proarrhythmic side effects. However, the underlying mechanism has not been studied in further detail to date. In the mammalian heart, heterotetrameric assembly of Kir2.x channels is the molecular basis of IK1 current. Therefore, we studied the effects of dronedarone on wild-type and mutant Kir2.x channels in the Xenopus oocyte expression system. Dronedarone inhibited Kir2.1 currents but had no effect on Kir2.2 or Kir2.3 currents. Onset of block was slow but completely reversible upon washout. Blockade of Kir2.1 channels did not exhibit strong voltage dependence or frequency dependence. In a screening with different Kir2.1 mutants lacking specific binding sites within the cytoplasmic pore region, we found that residue E224 is essential for binding of dronedarone to Kir2.1 channels. In conclusion, direct block of Kir2.1 channel subunits by dronedarone through binding at E224 may underlie its inhibitory effects on cardiac IK1 current.

Inhibition of cardiac Kir2.1-2.3 channels by beta3 adrenoreceptor antagonist SR 59230A.

Kir2.x channels form the molecular basis of cardiac I(K1) current and play a major role in cardiac electrophysiology. However, there is a substantial lack of selective Kir2 antagonists. We found the ß(3)-adrenoceptor antagonist SR59230A to be an inhibitor of Kir2.x channels. Therefore, we characterized the effects of SR59230A on Kir2.x and other relevant cardiac potassium channels. Cloned channels were expressed in the Xenopus oocyte expression system and measured with the double-microelectrode voltage clamp technique. SR59230A inhibited homomeric Kir2.1 channels with an IC(50) of 33µM. Homomeric Kir2.2 and Kir2.3 channels and Kir2.x heteromers were also inhibited by SR59230A with similar potency. In contrast, no relevant inhibitory effects of SR59230A were found in cardiac Kv1.5, Kv4.3 and KvLQT1/minK channels. In hERG channels, SR59230A only induced a weak inhibition at a high concentration. These findings establish SR59230A as a novel inhibitor of Kir2.1-2.3 channels with a favorable profile with respect to additional effects on other cardiac repolarizing potassium channels.