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.

Gender differences in patients with atrial fibrillation.

AIMS: We aimed to compare gender differences with respect to presentation of consecutive ambulatory patients with atrial fibrillation (AF), management of their disease, and outcomes. METHODS: Post-hoc analysis of an observational (non-interventional) study performed by 616 office- and hospital-based cardiologists in Germany. Consecutive (mainly ambulatory) patients with Electrocardiography (ECG) -confirmed AF and available data from baseline (BL) and two follow-up visits at 6 and 12 months were assessed. RESULTS: A total of 2,742 patients (62.8% males, mean age 67.5 years; 37.2% women, mean age 71.2 years) were analysed. Women had more frequently paroxysmal and less frequently permanent AF. Quality of life scores were slightly worse in women compared to men, for all types of AF. For class III anti-arrhythmic drugs at baseline (more frequent in men), and for digitalis (less frequent in men at BL and 1 year) statistically significant differences were noted. Oral anti-coagulation (OAC) without anti-platelet drugs was given in 67.9% at BL and in 62.7% at 1 year (no differences between genders). During follow-up, drug conversions in men/women were reported in 12.3%/14.9% (p=0.054), and electrical conversions in 14.6%/11.7% (p=0.03). Hospitalisations occurred in 25.9% and strokes in 3.5%. Patients with higher CHA2DS2-VASc scores had increased stroke rates (0, 1 and ≥2 points: 0.0, 1.5 and 3.9%, respectively; with no significant gender differences). CONCLUSION: In everyday management of patients with AF, there were no differences in treatment and major outcomes, in particular stroke, between women and men. This finding is opposed to earlier studies reporting OAC undertreatment of women and higher stroke rates.

Atrial reverse remodeling: restitution of early tachycardia-induced alterations of atrial ion currents after termination of rapid atrial pacing in rabbits.

BACKGROUND AND PURPOSE: Studies report on the reversal of electrophysiological parameters altered by atrial tachycardia after cessation of the latter. However, there is no data concerning reversal of tachycardia-induced alterations of ion currents. Reverse remodeling of atrial ion currents (I(Ca,L), I(to), I(sus)) was studied in our rabbit model of tachycardia-induced electrical remodeling. METHODS: Three groups each with four animals were built. Rapid atrial pacing (600/min) for 5 days was applied in all groups. Thereafter, different time intervals (5, 10, 20 days) were awaited before the patch clamp experiments. RESULTS: Similar to I(to) remodeling in our model, within 20 days after cessation of atrial tachycardia, time course of I(to) reverse remodeling was also U-shaped. In contrast, there was no significant recovery of I(Ca,L) which was initially reduced by rapid atrial pacing. CONCLUSION: Relevance of a missing recovery of I(Ca,L) is likely as this current is closely linked with intracellular calcium handling.

Atrial fibrillation management, outcomes and predictors of stable disease in daily practice: prospective non-interventional study.

BACKGROUND: We aimed to describe the current management of patients with atrial fibrillation (AF) by cardiologists, and to identify predicting factors for a stable disease course. METHODS: 2753 consecutive patients with ECG-confirmed AF in the previous 12 months were documented in a 1-year observational (non-interventional) study from 616 centers. Stable disease was defined as having neither AF related intervention nor change in antiarrhythmic therapy in the previous 12 months. Stepwise selection of parameters for multivariate regression was used to identify factors for stable AF. RESULTS: At baseline, paroxysmal AF was reported in 33.5%, persistent in 26.7%, and permanent in 39.7%; rate control alone was the prevailing antiarrhythmic strategy (64.2%). Drugs for thromboembolic prevention were administered in 93.8%, with a clear predominance of oral anticoagulants (OAC), alone or in combination with antiplatelet drugs. Electrical or pharmacological conversions were reported in 23.6%. A total of 96 (3.5%) patients in the total cohort experienced stroke, 72 patients (2.6%) TIA, and 24 (0.9%) arterial embolism. 26% were hospitalized during follow-up (0.4 events per patient), and 9.4% developed incident heart failure (42% prevalence at follow-up). The rate of stable patients was 43.4%. In the multivariate model male gender, history of stroke, and permanent (vs. persistent) AF were associated with stable disease. Conversely, the factors chronic heart failure, impaired left ventricular function, rhythm-control (vs. other), OAC and antiplatelet therapy were significantly correlated with unstable disease. CONCLUSIONS: The relatively low proportion of stable patients and in particular, the high hospitalization and stroke rate indicate difficulties in everyday management of patients with AF.

Presentation of atrial fibrillation and its management by cardiologists in the ambulatory and hospital setting: MOVE cross-sectional study.

OBJECTIVE: The aim of the study was to collect comprehensive data on atrial fibrillation (AF) in ambulatory and hospital-based management in Germany. METHODS: Consecutive patients with ECG-confirmed AF in the previous 12 months were documented in a non-interventional study in 638 physician offices (78.0%) or hospitals (12.7%). RESULTS: Of the 3354 patients (mean age 68.9 ± 10.1 years; CHADS(2) score 1.9 ± 1.3), a total of 1136 (33.9%) had paroxysmal, 899 (26.8%) persistent, 1295 (38.6%) permanent and 24 (0.7%) unspecified AF. In the 12 months prior to documentation, pharmacological conversion was attempted in 18.2%, electric cardioversion in 17.5%, the combination of both in 31.2%, and catheter ablation of AF in 5.5%. Only 41.4% of patients met the definition of stable disease (having neither AF related intervention nor change in antiarrhythmic therapy in the previous 12 months). As treatment strategy, physicians stated rate control in 64%, rhythm control in 8%, and both in 19% (not reported: 8%). Patients received antiarrhythmic drugs of class IA in 1.3%, IC in 13.8%, II in 78.1%, III in 17.9%, IV in 9.7% and digitalis in 26.7%. Drugs for thromboembolic prevention (oral anticoagulants and/or antithrombotics) were administered in 81.5%. Hospitalisations for AF or associated diseases in the previous 12 months were reported in 34.2%. Possible limitations include the open, observational design, selection of physicians with particular interest in the field and selection of patients (i.e. underrepresentation of critically ill individuals). CONCLUSIONS: While treatment rates with regards to the prevention of thromboembolic events were among the highest reported to date, the low proportion of stable patients and in particular, the high hospitalisation rate hint at difficulties in the management of patients with AF in clinical practice.

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.

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.

Inhibition of the renin-angiotensin system: effects on tachycardia-induced early electrical remodelling in rabbit atrium.

INTRODUCTION: Tachycardia-induced atrial remodelling (as an equivalent to atrial fibrillation) can be influenced by the renin-angiotensin system. Effects of a seven-day enalapril pre-treatment (EPT, 0.16 mg/kg body weight subcutaneously every 24 h) on ionic currents underlying tachycardia-induced early electrical remodelling after 24 h rapid atrial pacing (RAP, 600 beats/min) in rabbit atrium were studied. MATERIALS AND METHODS: Animals were divided into four groups (n=4 each): control; paced only; enalapril only; and enalapril and paced, respectively. Using patch-clamp technique in whole-cell mode, current densities were measured in isolated atrial myocytes. RESULTS: EPT nearly doubled L-type calcium current (ICa,L, -7.7+/-0.6 pA/pF [control] vs. f -12.3+/-1.2 pA/pF [enalapril only]). RAP reduced ICa,L to -3.6+/-0.7 pA/pF (paced only). Also after EPT, RAP led to a significant downregulation of ICa,L by 39% (-7.5+/-1.3 pA/pF [paced and enalapril]). RAP decreased transient outward potassium current (Ito, -45%, 51.5+/-3.9 pA/pF [control] vs. 28.5+/-4.5 pA/pF [paced only]). EPT did not alter Ito (44.2+/-8.1 pA/pF [enalapril only]). However, RAP did not affect Ito in enalapril-treated animals and averaged 50.4+/-9.8 pA/pF (paced and enalapril). CONCLUSIONS: In summary, EPT has several effects on ion channels in rabbit atrium: 1) EPT increases ICa,L current density, but cannot prevent its downregulation due to RAP; 2) EPT has no influence on Ito current density, but can prevent its downregulation due to RAP. Although changes of single ion channels must be interpreted in context of the complex atrial electrophysiology as a whole, our results provide a possible explanation of the in vivo observation that angiotensin-converting enzyme inhibition is mainly beneficial on the early electrical remodelling due to the atrial fibrillation-equivalent RAP.

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.

Long-term experience with subcutaneous ICD leads: a comparison among three different types of subcutaneous leads.

ICDs provide protection against sudden cardiac death in patients with life-threatening arrhythmias. Nevertheless, efficacy of defibrillation remains an important issue to guarantee the future safety of patients who receive an ICD. There is a significant number of patients who need an additional subcutaneous lead to obtain a defibrillation safety margin of at least 10 J between the maximum output of the ICD and the energy needed for ventricular defibrillation. However, few data exists about the long-term performance of different types of subcutaneous leads. Therefore, the aim of this study was to analyze the long-term experience with three different types of subcutaneous leads. The study included 132 patients (109 men, 23 women; mean age 59.8 years [SD +/- 10.7 years]). All of them received a subcutaneous lead in addition to a single chamber or dual chamber ICD between October 1990 and April 2002. Two patients received a second subcutaneous lead after the first lead had been removed so that a total of 134 subcutaneous leads were evaluated. Inclusion criteria for the implantation of an additional subcutaneous lead were (1) unsuccessful ventricular defibrillation at implant without a subcutaneous lead, (2) insufficient safety margin (< 10 J) between the maximum output of the ICD and the energy needed for ventricular defibrillation, or (3) clinical evaluation of a new subcutaneous lead (Medtronic 13014). There were no significant differences between the three study groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The results of the DFT testing during follow-up (prehospital discharge test and 1 and 3 years) were compared to the baseline value obtained during the implantation procedure. All lead related complications were analyzed. Eighty-two single element subcutaneous array electrodes (SQ-A1), 31 subcutaneous three-finger electrodes (SQ-A3), and 21 subcutaneous patch electrodes (SQ-P) were implanted during the study period. The median follow-up was 1,499 days (25th percentile: 798 days, 75th percentile: 1,976 days) in the SQ-A1 group, 2,209 days (25th percentile: 1,242 days, 75th percentile: 2,710 days) in the SQ-A3 group, and 1,419 days (25th percentile: 787 days, 75th percentile: 2,838 days) in the SQ-P group. None of the three groups had a significant change of the DFT during follow-up compared to baseline. Major complications occurred in six (7.3%) patients in group SQ-A1 and in two (9.5%) patients in group SQ-P. There were no major complications in group SQ-A3. Kaplan-Meier curves analyzing freedom from subcutaneous lead related complications did not show a significant difference between the three study groups (P = 0.16). SQ-A1, SQ-A3, and SQ-P leads provide stable DFTs during long-term follow-up. Major complications are rare. However, a careful follow-up including chest radiographs at regular intervals is needed to detect potentially fatal complications like lead fractures.

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.

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.

Efficacy of metoprolol and sotalol in the prevention of recurrences of sustained ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator.

ICDs provide protection against sudden cardiac death in patients with life-threatening ventricular arrhythmias. Nevertheless, most ICD recipients receive adjunctive antiarrhythmic drug therapy to reduce the number of recurrent episodes and ICD discharges. The aim of the study was to compare the efficacy of metoprolol and d,l-sotalol in preventing VT/VF recurrences in patients with an ICD in a prospective, randomized trial. One hundred patients (83 men, 17 women; mean age 59 years, SD +/- 11 years) were randomized to receive metoprolol or sotalol after implantation of an ICD. There were no significant differences between the two groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The median follow-up was 728 days (25th percentile: 530 days, 75th percentile: 943 days) in the metoprolol group and 727 days (25th percentile: 472 days, 75th percentile: 1,223 days) in the sotalol group (P = 0.52). Thirty-three patients treated with metoprolol and 30 patients receiving sotalol had at least one episode during the follow-up. Event-free survival curves were generated for the two treatment arms using the Kaplan-Meier method and showed no significant difference (P = 0.68). Eight patients treated with metoprolol and six patients treated with sotalol died during follow-up. Total mortality was not significantly different between the two study groups (P = 0.43). Metoprolol is as efficacious as sotalol in preventing VT/VF recurrences in patients with an ICD.

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.

[Remodeling in atrial fibrillation]. / Remodeling bei Vorhofflimmern.

BACKGROUND: Atrial fibrillation is associated with alterations in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. This process was termed electrical remodeling in atrial fibrillation. The underlying cellular and molecular mechanisms have intensively been investigated over the past few years in patients with atrial fibrillation and in different experimental models. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation, are reviewed. CELLULAR AND MOLECULAR MECHANISMS: On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as to changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa,L) and of potassium channels (Ito, IK1, IKACh). The molecular mechanisms of intraatrial conduction slowing are less well understood, changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) have been reported in some studies. A trigger of initiation for electrical remodeling is an overload of the cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. CONCLUSION: These changes in the cellular and molecular milieu importantly determine the clinical course and the efficacy of therapeutical interventions in atrial fibrillation. The clinical relevance and potential new therapeutic approaches are discussed in the last part.