Fluid status telemedicine alerts for heart failure: a randomized controlled trial.

AIMS: Hospital admissions are frequently preceded by increased pulmonary congestion in heart failure (HF) patients. This study evaluated whether early automated fluid status alert notification via telemedicine improves outcome in HF patients. METHODS AND RESULTS: Patients recently implanted with an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy were eligible if one of three conditions was met: prior HF hospitalization, recent diuretic treatment, or recent brain natriuretic peptide increase. Eligible patients were randomized (1:1) to have fluid status alerts automatically transmitted as inaudible text message alerts to the responsible physician or to receive standard care (no alerts). In the intervention arm, following a telemedicine alert, a protocol-specified algorithm with remote review of device data and telephone contact was prescribed to assess symptoms and initiate treatment. The primary endpoint was a composite of all-cause death and cardiovascular hospitalization. We followed 1002 patients for an average of 1.9 years. The primary endpoint occurred in 227 patients (45.0%) in the intervention arm and 239 patients (48.1%) in the control arm [hazard ratio, HR, 0.87; 95% confidence interval (CI), 0.72-1.04; P = 0.13]. There were 59 (11.7%) deaths in the intervention arm and 63 (12.7%) in the control arm (HR, 0.89; 95% CI, 0.62-1.28; P = 0.52). Twenty-four per cent of alerts were not transmitted and 30% were followed by a medical intervention. CONCLUSION: Among ICD patients with advanced HF, fluid status telemedicine alerts did not significantly improve outcomes. Adherence to treatment protocols by physicians and patients might be challenge for further developments in the telemedicine field.

The authentic worker's well-being and performance: the relationship between authenticity at work, well-being, and work outcomes.

Previous research on authenticity has mainly focused on trait conceptualizations of authenticity (e.g., Wood et al., 2008), whereas in specific environments (e.g., at work) state conceptualizations of authenticity (cf. Van den Bosch & Taris, 2013) are at least as relevant. For example, working conditions are subject to change, and this could well have consequences for employees' perceived level of authenticity at work. The current study employs a work-specific, state-like conceptualization of authenticity to investigate the relations between authenticity at work, well-being, and work outcomes. A series of ten separate hierarchical regression analyses using data from 685 participants indicated that after controlling for selected work characteristics and demographic variables, authenticity at work accounted for on average 11% of the variance of various wellbeing and work outcomes. Of the three subscales of authenticity at work (i.e., authentic living, self-alienation, and accepting influence), self-alienation was the strongest predictor of outcomes, followed by authentic living and accepting external influence, respectively. These findings are discussed in the light of their practical and theoretical implications.

Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial.

BACKGROUND: Antiarrhythmic drugs prolong the atrial action potential and refractory period, and thereby prevent recurrent atrial fibrillation after cardioversion. The atrial action potential normalises after 2-4 weeks of sinus rhythm, suggesting that antiarrhythmic drugs might not be needed beyond that period. Therefore, we investigated whether short-term antiarrhythmic drug treatment after cardioversion is non-inferior to long-term treatment. METHODS: We enrolled patients in a prospective, randomised, open-label, blinded endpoint assessment trial between May 4, 2007, and March 12, 2010, at 44 centres in Germany. Eligible patients were adults with persistent atrial fibrillation undergoing planned cardioversion. After successful cardioversion, patients were randomly assigned in permuted blocks of six per centre to: no antiarrhythmic drug treatment (control); treatment with flecainide (200-300 mg per day) for 4 weeks (short-term treatment); or flecainide for 6 months (long-term treatment). The primary endpoint was time to persistent atrial fibrillation or death. Patients and clinicians were unmasked to group assignment and treatment. The primary outcome was assessed in a core laboratory, members of which were masked to treatment group. Patients were monitored for 6 months by daily telemetric electrocardiograph (ECG) and centrally adjudicated Holter ECG recordings whenever atrial fibrillation was noted in two consecutive ECGs. Analyses were per protocol. This trial is registered, number ISRCTN62728742. FINDINGS: After assay sensitivity was established with 4-week follow-up data from 242 patients showing that flecainide was superior to no treatment (Kaplan-Meier survival 70·2%vs 52·5%; p=0·0160), the trial continued to compare short-term versus long-term treatment. The primary outcome occurred in 120 (46%) of 261 patients receiving short-term treatment and in 103 (39%) of 263 patients receiving long-term treatment (event-free survival 48·4% [95% CI 41·9-55·0] vs 56·4% [49·1-63·6]; Kaplan-Meier estimate of difference 7·9% [-1·9 to 17·7]; p=0·2081 for non-inferiority; margin prespecified at 12%). In a post-hoc landmark analysis of patients who had not reached the primary endpoint in the first month, long-term treatment was superior to short-term treatment (Kaplan-Meier estimate of difference 14·3% [5·1-23·6]; hazard ratio 0·31 [0·18-0·56]; p=0·0001). INTERPRETATION: Short-term antiarrhythmic drug treatment after cardioversion is less effective than is long-term treatment, but can prevent most recurrences of atrial fibrillation. FUNDING: The German Federal Ministry of Education and Research, Deutsche Forschungsgemeinschaft, 3M Medica, and MEDA Pharmaceuticals.

Impedance-based remote monitoring in patients with heart failure and concomitant chronic kidney disease.

AIMS: Remote monitoring (RM) of thoracic impedance represents an early marker of pulmonary congestion in heart failure (HF). Chronic kidney disease (CKD) may promote fluid overload in HF patients. We investigated whether concomitant CKD affected the efficacy of impedance-based RM in the OptiLink HF trial. METHODS AND RESULTS: Among HF patients included in the OptiLink HF trial, time to the first cardiovascular hospitalization and all-cause death according to the presence of concomitant CKD was analysed. CKD was defined as GFR < 60 mL/min/1.73 m2 at enrolment. Of the 1002 patients included in OptiLink HF, 326 patients (33%) had HF with concomitant CKD. The presence of CKD increased transmission of telemedical alerts (median of 2 (1-5) vs. 1 (0-3); P = 0.012). Appropriate contacting after alert transmission was equally low in patients with and without CKD (57% vs. 59%, P = 0.593). The risk of the primary endpoint was higher in patients with CKD compared with patients without CKD (hazard ratio (HR), 1.62 [95% confidence interval (CI), 1.16-2.28]; P = 0.005). Impedance-based RM independently reduced primary events in HF patients with preserved renal function, but not in those with CKD (HR 0.68 [95% CI, 0.52-0.89]; P = 0.006). CONCLUSIONS: The presence of CKD in HF patients led to a higher number of telemedical alert transmissions and increased the risk of the primary endpoint. Inappropriate handling of alert transmission was commonly observed in patients with chronic HF and CKD. Guidance of HF management by impedance-based RM significantly decreased primary event rates in patients without CKD, but not in patients with CKD.

[Autonomic nervous system and reflex syncope]. / Autonomes Nervensystem und Reflexsynkope.

This review discusses important aspects of pathophysiology, diagnosis and therapy of reflex syncope. The autonomic nervous system plays a crucial role in the origin of this frequently observed form of syncope. In most cases, reflex syncopes occur under specific circumstances. Thus, a detailed history is essential. Besides a physical exam und a normal 12-lead ECG, dedicated tests like tilt-table-testing, carotid massage and the implantation of a loop recorder often assist in making the correct diagnosis. The basis of therapy for all patients is reassurance about the benign course of the disease as well as education about adequate measures. Pharmacotherapy is reserved to a minority of patients. In older patients with repeat or severe syncopes and documented asystoles, pacemaker therapy is a valuable option.

[Patient with a defibrillator for cardiac resynchronization therapy (CRT-D) and progressive symptoms of heart failure]. / Patientin mit einem Defibrillator zur kardialen Resynchronisationstherapie und zunehmender Herzinsuffizienzsymptomatik.

A 73-year-old woman with advanced heart failure experienced a deterioration of symptoms and left ventricular function despite treatment with cardiac resynchronization therapy (CRT). The cause was diagnosed by 12-lead ECG and corrected by reprogramming, which led to an improvement in symptoms and echocardiography.

Differences in management of telemedicine alerts on weekdays and public holidays: Results from the OptiLink heart failure trial.

BACKGROUND: In the OptiLink heart failure study, timely and appropriate reactions to telemedicine alerts improved clinical outcomes in heart failure patients. This analysis investigates the relation between the weekday of alert transmission and the subsequent patient contact. METHODS: In patients enrolled in the intervention arm of the OptiLink heart failure study (n = 505, age 66.1 ± 10.1, 77.2% male, left-ventricular ejection fraction 26.7% ± 6.1%), fluid index threshold crossing alerts were analysed according to the weekday of the transmission. Transmissions on Mondays-Thursdays were categorized as TD1, Fridays-Sundays as well as public holidays as TD2. RESULTS: Of 1365 transmitted alerts, 867 (63.5%) were categorized as TD1 and 498 (36.5%) as TD2. Same day telephone contacts were more frequent in TD1 (46.2%) than in TD2 (18.3%; p < 0.001). Accordingly, the median time to contact was significantly longer in TD2 compared with TD1 (2(1-3) vs 0(0-1) days; p < 0.001). Rates of no telephone contact were no different between the groups (12.1% vs 12.4%; p = 0.866). Although signs of worsening heart failure were prevalent in 32.4% in TD1 versus 32.1% in TD2 (p = 0.996), initiation of a pharmacological intervention occurred more likely in TD1 compared with TD2 (27.9% vs 22.9%; p = 0.041). No differences existed concerning hospitalization for heart failure within 30 days after alert transmission (3.9% vs 3.4%; p = 0.636). CONCLUSION: Alert transmissions during weekends and public holidays were less likely associated with timely patient contacts and initiation of pharmacological interventions than during the week. Telemedical centres providing 24/7 remote monitoring service and specific education programmes for physicians might help to optimize patient care.

Hospitalizations for heart failure: still major differences between East and West Germany 30 years after reunification.

AIMS: Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences. METHODS AND RESULTS: We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF-related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF-related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; -29%), while the total number of HF-related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in-hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population). CONCLUSIONS: Heart failure remains the most common cause of hospitalization and in-hospital death throughout Germany. The increase in HF-related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.

[Structural requirements and prerequisites for outpatient implantation of defibrillators, devices for cardiac resynchronization and event recorders]. / Strukturmerkmale und Voraussetzungen zur ambulanten Implantation von implantierbaren Defibrillatoren, Geräten zur kardialen Resynchronisation und Ereignisrekordern.

The possibility of outpatient implantation of defibrillators, devices for cardiac resynchronization, and event recorders (collectively called cardiac implantable electronic devices, CIEDs) is becoming increasingly important. In Germany, only a few options for outpatient implantation are currently realized. Furthermore, there is a lack of uniform, recognized, and binding quality criteria. This article provides insight into the current contract constellations for outpatient surgery and defines a first, holistic quality concept for outpatient implantations of CIEDs. The present works aims to initiate a discourse in the specialist society in order to define a coordinated, binding quality concept. Then, this should serve as the basis for future outpatient implantation services, enabling comparability and to contribute long-term evidence.

Remote Monitoring With Appropriate Reaction to Alerts Was Associated With Improved Outcomes in Chronic Heart Failure: Results From the OptiLink HF Study.

BACKGROUND: Impedance-based remote monitoring (RM) failed to reduce clinical events in the OptiLink heart failure (HF) trial. However, rates of alert-driven interventions triggered by intrathoracic fluid index threshold crossings (FTC) were low indicating physicians' inappropriate reactions to alerts. METHODS: We separated appropriate from inappropriate contacts to FTC transmissions in the OptiLink HF trial (Optimization of Heart Failure Management Using OptiVol™ Fluid Status Monitoring and CareLink™). Appropriate contacts had to meet the following criteria: (1) initial telephone contact within 2 working days after FTC transmission, (2) follow-up contacts according to study protocol, and (3) medical intervention initiated after FTC due to cardiac decompensation. We compared time to cardiovascular death or HF hospitalization between RM patients contacted appropriately or inappropriately and patients with usual care. RESULTS: In the RM group, at least one FTC alert was transmitted in 356 patients (70.5%; n=505). Of note, only 55.5% (n=758) of all transmitted FTCs (n=1365) were followed by an appropriate contact. While 113 patients (31.7%; n=356) have been contacted appropriately after every FTC, in 243 patients (68.3%; n=356) at least one FTC was not responded by an appropriate contact. Compared with usual care, RM with appropriate contacts to FTC alerts independently reduced the risk of the primary end point (hazard ratio, 0.61 [95% CI, 0.39-0.95]; P=0.027). CONCLUSIONS: RM appropriate reactions to FTC alerts are associated with significantly improved clinical outcomes in patients with advanced HF and implantable cardioverter-defibrillators.

Influence of dexamethasone on atrial ion currents and their early ionic tachycardia-induced electrical remodeling in rabbits.

BACKGROUND: Certain evidence points to a role of inflammation in AF pathophysiology. Thus, antiinflammatory treatment of AF is discussed. Effects of a dexamethasone treatment (7 days) on atrial ion currents (I(Ca,L), I(to), I(sus)) and their tachycardia-induced remodeling were studied in a rabbit model. METHODS: 6 groups of 4 animals each were built. Rapid atrial pacing (600 min) was performed for 24 and 120 hours with/ without dexamethasone treatment. Ion currents were measured using whole cell patch clamp method. RESULTS: Rapid atrial pacing reduced (I(Ca,L), I(to) was decreased after 24 hours but almost returned to control values after 120 hours. When dexamethasone-treated animals also underwent atrial tachypacing, pacing-induced reduction of I(Ca,L) was still observed after 24 hours and was even augmented after 120 hours compared to untreated but tachypaced animals. I(to) was not influenced by dexamethasone alone. In dexamethasone-treated animals, reduction of I(to) was not observed after 24 hours but occurred after 120 hours of atrial tachypacing. I(sus) was neither influenced by rapid atrial pacing nor by dexamethasone. Biophysical properties of all currents were affected neither by rapid atrial pacing nor by dexamethasone. CONCLUSION: Dexamethasone influenced tachycardia-induced alterations of atrial I(to). Our experiments give evidence that - amongst other anti-inflammatory action - impact of dexamethasone on ion currents and their tachycardia-induced alterations might also play a role in treatment/prevention of AF with steroids.

Intensified ambulatory cardiology care: effects on mortality and hospitalisation-a comparative observational study.

Since 2010, an intensified ambulatory cardiology care programme has been implemented in southern Germany. To improve patient management, the structure of cardiac disease management was improved, guideline-recommended care was supported, new ambulatory medical services and a morbidity-adapted reimbursement system were set up. Our aim was to determine the effects of this programme on the mortality and hospitalisation of enrolled patients with cardiac disorders. We conducted a comparative observational study in 2015 and 2016, based on insurance claims data. Overall, 13,404 enrolled patients with chronic heart failure (CHF) and 19,537 with coronary artery disease (CAD) were compared, respectively, to 8,776 and 16,696 patients that were receiving usual ambulatory cardiology care. Compared to the control group, patients enrolled in the programme had lower mortality (Hazard Ratio: 0.84; 95% CI: 0.77-0.91) and fewer all-cause hospitalisations (Rate Ratio: 0.94; 95% CI: 0.90-0.97). CHF-related hospitalisations in patients with CHF were also reduced (Rate Ratio: 0.76; 95% CI: 0.69-0.84). CAD patients showed a similar reduction in mortality rates (Hazard Ratio: 0.81; 95% CI: 0.76-0.88) and all-cause hospitalisation (Rate Ratio: 0.94; 95% CI: 0.91-0.97), but there was no effect on CAD-related hospitalisation. We conclude that intensified ambulatory care reduced mortality and hospitalisation in cardiology patients.

Alcohol-induced electrical remodeling: effects of sustained short-term ethanol infusion on ion currents in rabbit atrium.

BACKGROUND: In some patients, above-average alcohol consumption before occurrence of atrial fibrillation (AF) in terms of a "holiday heart syndrome" (HHS) can be determined. There is evidence that long before development of apparent alcohol-induced cardiomyopathy, above-average alcohol consumption generates an arrhythmogenic substrate which abets the onset of AF. Changes of atrial current densities in terms of an electrical remodeling after sustained short-term ethanol infusion in rabbits as a potential part of HHS pathophysiology were examined in this study. METHODS: Rabbits of the ethanol group (EG) received sustained short-term intravenous alcohol infusion for 120 hours (during infusion period, blood alcohol level did not fall below 158 mg/dl), whereas NaCl 0.9% was infused in the placebo group (PG). Using patch clamp technique in whole-cell mode, atrial current densities were measured and compared between both groups. RESULTS: Ethanol infusion did not alter current densities of I(to) [58.7 +/- 5.0 pA/pF (PG, n = 20 cells) vs. 53.9 +/- 5.0 pA/pF (EG, n = 24)], I(sus) [11.3 +/- 1.4 pA/pF (PG, n = 20) vs. 10.2 +/- 1.0 pA/pF (EG, n = 24)], and I(K1) [-1.6 +/- 0.3 pA/pF (PG, n = 17) vs. -2.0 +/- 0.3 pA/pF (EG, n = 22)]. However, alcohol infusion resulted in a remarkable reduction of I(Ca,L) current densities [-28.4 +/- 1.8 pA/pF (PG, n = 20) vs. -15.2 +/- 1.4 pA/pF (EG, n = 22)] and I(Na) [-75.4 +/- 3.6 pA/pF (PG, n = 17) vs. -35.4 +/- 4.4 pA/pF (EG, n = 21)], respectively. CONCLUSION: Sustained short-term ethanol infusion in rabbits alters atrial current densities. HHS might be favored by alcohol-induced atrial electrical remodeling.

Authenticity at Work: A Matter of Fit?

Authenticity at work refers to the extent to which a worker feels in touch with their true self while at work. At first sight this concept seems to overlap with the concept of person-environment (P-E) fit, that is, the degree to which an individual experiences good fit with their work environment. Drawing on a sample of 867 Dutch gifted workers, structural equation modeling was used to investigate (i) whether authenticity at work and P-E fit can be distinguished, and (ii) how authenticity at work and P-E fit were associated with employee well-being. As expected, confirmatory factor analysis revealed that authenticity at work and P-E fit were distinct from each other. Moreover, the mediated effect of authenticity at work was stronger for two negative forms of well-being (burnout and boredom) than for two positive forms of well-being (work engagement and job satisfaction). The theoretical and practical implications of these findings are discussed, especially focusing on the distinction between authenticity and P-E fit.

Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium.

We investigated the effects of a 7-day verapamil pretreatment (VPT, 7.5 mg/kg bodyweight subcutaneously every 12 h) on ionic currents and molecular mechanisms underlying tachycardia-induced early electrical remodeling after 24-h rapid atrial pacing (RAP, 600 bpm) in rabbit atrium. Animals were divided into four groups (n = 6 each group): control (not paced, no verapamil), paced only, verapamil only and verapamil and paced, respectively. VPT doubled ICa,L [7.0 +/- 0.7 pA/pF (control) vs 14.2 +/- 0.6 pA/pF (verapamil only)]. RAP reduced ICa,L by 48% to 3.6 +/- 0.7 pA/pF (paced only). RAP did not affect ICa,L in verapamil-treated animals and averaged 15.3 +/- 0.2 pA/pF (paced and verapamil). RAP resulted in a significant decrease of the expression of the alpha1c subunit (-24.7%) and the beta2A subunit (-13.3%), respectively. VPT led to a similar alteration of subunit expression as RAP ["control" vs "verapamil only", decrease of alpha1c subunit (-25.4%), but no significant change in beta2A subunit expression]. However, after VPT, further diminishment of alpha1c and beta2A subunit expression after rapid atrial pacing was absent. ("verapamil" vs "verapamil and paced", n = 6 both groups). RAP decreased Ito [-45%, 51.5 +/- 3.9 pA/pF (control) vs 26.8 +/- 1.5 pA/pF (paced only)] and was not influenceable by VPT. IK1 was neither affected by RAP nor verapamil pretreatment. Downregulation of alpha1c and beta2A subunit expression and the resulting decay of ICa,L current densities were prevented by verapamil. However, these effects are abolished by multiple other adverse effects of verapamil on atrial electrophysiology.

Influence of verapamil on tachycardia-induced alterations of PP1 and PP2A in rabbit atrium.

BACKGROUND: Long-term atrial fibrillation changes in many regulatory and structural processes may result in stabilization of the arrhythmia. There is evidence that decreased amplitude of L-type Ca(2+) current - probably a key mechanism of atrial remodelling -resulting from changes in expression of regulatory proteins is at least jointly responsible. OBJECTIVES: To assess the expressions of protein phosphatases PP1 and PP2A, as well as the effect of verapamil pretreatment (VPT), in the early phases of atrial fibrillation in a rabbit model. METHODS: FOUR GROUPS, EACH CONSISTING OF SIX ANIMALS, WERE STUDIED: 'not paced, no drug' group; 'paced, no drug' group (rapid atrial pacing [RAP] 600 beats/min for 24 h); 'not paced, verapamil' (NPV) group (duration of VPT was seven days, verapamil 7.5 mg/kg was administered every 12 h); and 'paced, verapamil' (PV) group (pacemaker stimulation after VPT). Protein expression was evaluated by Western blot analysis. RESULTS: RAP resulted in an augmented (32%) PP1 expression (not paced, no drug group versus paced, no drug group). The increase in PP1 expression was prevented with VPT (NPV group versus PV group). Expression of PP2A was not influenced by RAP. However, VPT led to an increase of PP2A expression (16%) after RAP (NPV group versus PV group). CONCLUSIONS: Fortified expression of protein phosphatases might be - besides transcriptional downregulation of channel subunits - another important cause of reduced L-type Ca(2+) current after RAP. Blocking L-type Ca(2+) channels with verapamil to prevent tachycardia-induced changes of PP1 expression might be expedient.

[Telemetric follow-up of implantable electronic cardiac devices : Optimisation of care in clinical practice]. / Telemetrische Nachsorge von implantierbaren kardialen Aggregaten : Optimierung der Betreuung in der Praxis.

Remote follow-up of patients with implantable electronic cardiac devices (IECD) is a scientifically well-evaluated and technically mature method. Advantages over conventional follow-up include rapid detection of clinically relevant events (i. e. arrhythmias) and of technical problems. Additionally, telemetric follow-up of IECDs has a high degree of acceptance among both patients as well as health care professionals and carries the potential to reduce health care costs. The implementation of a remote follow-up programme is associated with organisational, infrastructural and legal aspects, which are reviewed.

Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits.

OBJECTIVES: The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP). BACKGROUND: Long-term atrial fibrillation reduces L-type Ca(2+) (I(Ca,L)) and transient outward K(+) (I(to)) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown. METHODS: Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively. RESULTS: L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca(2+) channel beta subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the alpha(1) subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I(to). Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected. CONCLUSIONS: L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

beta3-Adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes.

OBJECTIVES: I(Ks), the slow component of the delayed rectifier potassium current, underlies a strong beta-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I(Ks). Recent work has pointed to an opposing biological effect of beta(1)- and beta(3)-adrenoceptors in the heart. However the role of these subtypes in the regulation of cardiac ion channel function is unknown. METHODS: We investigated the effects of beta(1)- and beta(3)-adrenoceptor modulation on I(Ks) in guinea-pig ventricular myocytes, using patch-clamp techniques. RESULTS: Superfusion with 100 nmol/l isoproterenol increased the step current amplitude by 81.3+/-8.0%. In contrast, after block of beta(1)- (1 micromol/l atenolol) and beta(2)-receptors (1 micromol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3+/-3.5%. The beta(3)-selective agonist BRL37344 significantly reduced the I(Ks) step current at +70 mV in a concentration-dependent manner (IC(50): 5.01 nmol/l). In the presence of bupranolol (beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist), the effect of BRL37344 was markedly attenuated, from 27.3+/-5.6% (100 nmol/l BRL37344 alone) to 4.0+/-1.3% (100 nmol/l BRL37344+1 micromol/l bupranolol). BRL37344 (100 micromol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel. 1 micromol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+7.8%) CONCLUSIONS: We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology.

Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes.

PURPOSE: The chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes. METHODS AND RESULTS: Single atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (I(Ks), I(Kr), in guinea pig, I(to), I(Kur), I(K1) in humans) were recorded at 36 degrees C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of I(Ks) with a half maximal concentration (EC(50)) of 6.8 nmol/l. 10 micromol/l HMR 1556 almost completely inhibited I(Ks) (97.2+/-3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. I(Kr) currents were not affected up to concentrations of 10 micromol/l. HMR 1556 did not inhibit other potassium currents in human atrium: I(to), I(Kur) and the classical inward rectifier potassium current I(K1) were not significantly affected up to concentrations that completely blocked I(Ks) (10 micromol/l). CONCLUSIONS: HMR 1556 is a highly-potent blocker of I(Ks) channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of I(Ks) vs. I(Kr) blockade, the drug's new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.