Screen-detected atrial fibrillation predicts mortality in elderly subjects.

AIMS: Current guidelines recommend opportunistic screening for atrial fibrillation (AF) but the prognosis of individuals is unclear. The aim of this investigation is to determine prevalence and 1-year outcome of individuals with screen-detected AF. METHODS AND RESULTS: We performed a prospective, pharmacy-based single time point AF screening study in 7107 elderly citizens (≥65 years) using a hand-held, single-lead electrocardiogram (ECG) device. Prevalence of AF was assessed, and data on all-cause death and hospitalization for cardiovascular (CV) causes were collected over a median follow-up of 401 (372; 435) days. Mean age of participants was 74 ± 5.9 years, with 58% (N = 4130) of female sex. Automated heart rhythm analyses identified AF in 432 (6.1%) participants, with newly diagnosed AF in 3.6% of all subjects. During follow-up, 62 participants (0.9%) died and 390 (6.0%) were hospitalized for CV causes. Total mortality was 2.3% in participants with a screen-detected AF and 0.8% in subjects with a normal ECG [hazard ratio (HR) 2.94; 95% confidence interval (CI) 1.49-5.78; P = 0.002]; hospitalization for CV causes occurred in 10.6% and 5.5%, respectively (HR 2.08; 95% CI 1.52-2.84; P < 0.001). Compared with subjects without a history of AF at baseline and a normal ECG, participants with newly diagnosed or known AF had a significantly higher mortality risk with HRs of 2.64 (95% CI 1.05-6.66; P = 0.04) and 2.68 (95% CI 1.44-4.97; P = 0.002), respectively. After multivariable adjustment, screen-detected AF remained a significant predictor of death or hospitalization for CV causes. CONCLUSION: Pharmacy-based, automated AF screening in elderly citizens identified subjects with unknown AF and an excess mortality risk over the next year.

Safety and acute efficacy of cryoballoon ablation for atrial fibrillation at community hospitals.

AIMS: Pulmonary vein isolation (PVI) using cryoballoon ablation (CBA) is an established procedure for treating symptomatic paroxysmal and persistent atrial fibrillation (AF). The safety and efficacy of PVI performed at community hospitals are unknown. We aimed to determine the safety and acute efficacy of PVI using CBA performed at community hospitals with limited annual case numbers. METHODS AND RESULTS: This registry study included 1004 consecutive patients who had PVI performed for symptomatic paroxysmal (n = 563) or persistent AF (n = 441) from January 2019 to September 2020 at 20 hospitals. Each hospital performed fewer than 100 CBA-PVI procedures/year according to local standards. Procedural data, efficacy, and complication rates were determined. The mean number of CBA procedures performed/year at each centre was 59 ± 25. The average procedure time was 90.1 ± 31.6 min and the average fluoroscopy time was 19.2 ± 11.4 min. Isolation of all pulmonary veins was documented in 97.9% of patients. The most frequent reason for not achieving complete isolation was development of phrenic nerve palsy. No hospital deaths were observed. Two patients (0.2%) suffered a clinical stroke. Pericardial effusion occurred in six patients (0.6%), two of whom (0.2%) required pericardial drainage. Vascular complications occurred in 24 patients (2.4%), two of whom (0.2%) required vascular surgery. Phrenic nerve palsy occurred in 48 patients (4.8%) and persisted up to hospital discharge in six patients (0.6%). CONCLUSION: Pulmonary vein isolation procedures for paroxysmal or persistent AF using CBA can be performed at community hospitals with high acute efficacy and low complication rates.

Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator: A Randomized Clinical Trial.

BACKGROUND: Atrial arrhythmias are common in patients with implantable cardioverter-defibrillator (ICD). External shocks and internal cardioversion through commanded ICD shock for electrical cardioversion are used for rhythm-control. However, there is a paucity of data on efficacy of external versus internal cardioversion and on the risk of lead and device malfunction. We hypothesized that external cardioversion is noninferior to internal cardioversion for safety, and superior for successful restoration of sinus rhythm. METHODS: Consecutive patients with ICD undergoing elective cardioversion for atrial arrhythmias at 13 centers were randomized in 1:1 fashion to either internal or external cardioversion. The primary safety end point was a composite of surrogate events of lead or device malfunction. Conversion of atrial arrhythmia to sinus rhythm was the primary efficacy end point. Myocardial damage was studied by measuring troponin release in both groups. RESULTS: N=230 patients were randomized. Shock efficacy was 93% in the external cardioversion group and 65% in the internal cardioversion group (P<0.001). Clinically relevant adverse events caused by external or internal cardioversion were not observed. Three cases of pre-existing silent lead malfunction were unmasked by internal shock, resulting in lead failure. Troponin release did not differ between groups. CONCLUSIONS: This is the first randomized trial on external vs internal cardioversion in patients with ICDs. External cardioversion was superior for the restoration of sinus rhythm. The unmasking of silent lead malfunction in the internal cardioversion group suggests that an internal shock attempt may be reasonable in selected ICD patients presenting for electrical cardioversion. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03247738.

Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes.

BACKGROUND: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. METHODS: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. RESULTS: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post-IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). CONCLUSION: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated.

Depression, psychological distress, and quality of life in patients with cardioverter defibrillator with or without cardiac resynchronization therapy.

Congestive heart failure is frequent and leads to reduced exercise capacity, reduced quality of life (QoL), and depression in many patients. Cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillators (ICD) offer therapeutic options and may have an impact on QoL and depression. This study was performed to evaluate physical and mental health in patients undergoing ICD or combined CRT/ICD-implantation (CRT-D). Echocardiography, spiroergometry, and psychometric questionnaires [Beck Depression Inventory, General World Health Organization Five Well-being Index (WHO-5), Brief Symptom Inventory and 36-item Short Form (SF-36)] were obtained in 39 patients (ICD: 17, CRT-D: 22) at baseline and 6-month follow-up (FU) after device implantation. CRT-D patients had a higher NYHA class and broader left bundle branch block than ICD patients at baseline. At FU, ejection fraction (EF), peak oxygen uptake, and NYHA class improved significantly in CRT-D patients but remained unchanged in ICD patients. Patients with CRT-D implantation showed higher levels of depressive symptoms, psychological distress, and impairment in QoL at baseline and FU compared to ICD patients. These impairments remained mostly unchanged in all patients after 6 months. Overall, these findings imply that there is a need for careful assessment and treatment of psychological distress and depression in ICD and CRT-D patients in the course of device implantation as psychological burden seems to persist irrespective of physical improvement.

Chronic electrical neuronal stimulation increases cardiac parasympathetic tone by eliciting neurotrophic effects.

RATIONALE: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off. OBJECTIVE: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. METHODS AND RESULTS: In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, ß-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. CONCLUSIONS: HFES of cardiac neurons in vivo and in vitro causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3-mediated acetylcholine upregulation. This knowledge may contribute to develop HFES techniques to augment cardiac parasympathetic tone.

Functional and topographic concordance of right atrial neural structures inducing sinus tachycardia.

Cardiorespiratory autonomic control is in tight interaction with an intracardiac neural network modulating sinus node function. To gain novel mechanistical insights and to investigate possible novel targets concerning the treatment of inadequate sinus tachycardia, we aimed to characterize functionally and topographically the right atrial neural network modulating sinus node function. In 16 sheep 3-dimensional electro-anatomical mapping of the right atrium was performed. In five animals additionally magnetically steered remote navigation was used. Selective stimulation of nerve fibers was conducted by applying high frequency (200 Hz) electrical impulses within the atrial refractory period. Histological analysis of whole heart preparations by acetylcholinesterase staining was performed and compared to the acquired neuroanatomical mapping.We found that neural stimulation in the cranial part of the right atrium, within a perimeter around the sinus node area, elicited predominantly shortening of the sinus cycle length of -20.3 ± 10.1 % (n = 80, P < 0.05). Along the course of the crista terminalis atrial premature beats (n = 117) and atrial fibrillation (n = 123) could be induced. Catheter stability was excellent during remote catheter navigation. Histological work-up (n = 4) was in accord with the distribution of neurostimulation sites. Ganglions were mainly innervated by the dorsal right-atrial subplexus, with substantial additional input from the ventral right atrial subplexus. In conclusion, our findings suggest a functional and topographic concordance of right atrial neural structures inducing sinus tachycardia. This might open up new avenues in the treatment of heart rate related disorders.

A prospective cluster trial to increase antibiotic prescription quality in seven non-ICU wards.

Aim: To evaluate general shortcomings and faculty-specific pitfalls as well as to improve antibiotic prescription quality (ABQ) in non-ICU wards, we performed a prospective cluster trial. Methods: An infectious-disease (ID) consulting service performed a prospective investigation consisting of three 12-week phases with point prevalence evaluation conducted once per week (=36 evaluations in total) at seven non-ICU wards, followed by assessment of sustainability (weeks 37-48). Baseline evaluation (phase 1) defined multifaceted interventions by identifying the main shortcomings. Then, to distinguish intervention from time effects, the interventions were performed in four wards, and the 3 remaining wards served as controls; after assessing effects (phase 2), the same interventions were performed in the remaining wards to test the generalizability of the interventions (phase 3). The prolonged responses after all interventions were then analyzed in phase 4. ABQ was evaluated by at least two ID specialists who assessed the indication for therapy, the adherence to the hospital guidelines for empirical therapy, and the overall antibiotic prescription quality. Results: In phase 1, 406 of 659 (62%) patients cases were adequately treated with antibiotics; the main reason for inappropriate prescription was the lack of an indication (107/253; 42%). The antibiotic prescription quality (ABQ) significantly increased, reaching 86% in all wards after the focused interventions (502/584; nDf=3, ddf=1,697, F=6.9, p=0.0001). In phase 2 the effect was only seen in wards that already participated in interventions (248/347; 71%). No improvement was seen in wards that received interventions only after phase 2 (189/295; 64%). A given indication significantly increased from about 80% to more than 90% (p<.0001). No carryover effects were observed. Discussion: ABQ can be improved significantly by intervention bundles with apparent sustainable effects.

Twelve-month efficacy of second-generation cryoballoon ablation for atrial fibrillation performed at community hospitals: results of the German register on cryoballoon ablation in local hospitals (regional).

BACKGROUND: The 12-month follow-up (F/U) efficacy of CBA PVI performed at community hospitals for treatment of symptomatic paroxysmal and persistent atrial fibrillation (AF) is unknown. This study determined the 12-month efficacy of pulmonary vein isolation (PVI) using cryoballoon ablation (CBA) performed at community hospitals with limited annual case numbers. METHODS: This registry study included 983 consecutive patients (pts) from 19 hospitals, each with an annual procedural volume of < 100 PVI procedures/year. Pts underwent CBA PVI for paroxysmal AF (n = 520), persistent AF (n = 423), or redo PVI (n = 40). The primary endpoint was frequency of documented recurrent AF, the occurrence of atrial flutter or tachycardia following a 90-day period after the index ablation and up to 12 months. The frequency of repeat ablation was determined. RESULTS: Isolation of all PVs was documented in 98% of pts at the end of the procedure. Twelve-month F/U data could be obtained in 916 pts. A 24-h ECG registration was performed in 641 pts (70.0%); in 107 pts (16.7%) of them, recurrent AF was documented. The primary endpoint was met in 193 F/U pts (21.1%). It occurred in 80/486 F/U pts with paroxysmal AF (16.4%), and in 107/390 F/U pts with persistent AF (27.4%). Redo PVI was performed in 71 pts (7.8%), and atrial flutter ablation was performed in 12 pts (1.4%). CONCLUSIONS: CBA PVI for paroxysmal or persistent AF can be performed at community hospitals with adequate rates of 12-month symptom freedom and arrhythmia recurrence. The study was registered at the German register of clinical studies (DRKS00016504).

Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation.

BACKGROUND: Electric stimulation of mediastinal sympathetic cardiac nerves increases cardiac contractility but is not selective for the left ventricle because it elicits sinus tachycardia and enhanced atrioventricular conduction. The aim of this study was to identify sympathetic neural structures inside the heart that selectively control left ventricular inotropy and can be accessed by transvenous catheter stimulation. METHODS AND RESULTS: In 20 sheep, high-frequency stimulation (200 Hz) during the myocardial refractory period with electrode catheters inside the coronary sinus evoked a systolic left ventricular pressure increase from 97+/-20 to 138+/-32 mm Hg (P<0.001) without changes in sinus rate or PR time. Likewise, the rate of systolic pressure development (1143+/-334 versus 1725+/-632 mm Hg/s; P=0.004) and rate of diastolic relaxation (531+/-128 versus 888+/-331 mm Hg/s; P=0.001) increased. The slope of the end-systolic pressure-volume relationship increased (2.3+/-0.8 versus 3.1+/-0.6 mm Hg/mL; P=0.04), as did cardiac output (3.5+/-0.8 versus 4.4+/-0.8 L/min; P<0.001). Systemic vascular resistance and right ventricular pressure remained unchanged. There was a sigmoid dose-response curve. Ultrasound analysis revealed an increase in circumferential and radial strain in all left ventricular segments that was significant for the posterior, lateral, and anterior segments. Pressure effects were maintained for at least 4 hours of continued high-frequency stimulation and abolished by beta1-receptor blockade. Histology showed distinct adrenergic nerve bundles at the high-frequency stimulation site. CONCLUSIONS: Cardiac nerve fibers that innervate the left ventricle are amenable to transvenous electric catheter stimulation. This may permit direct interference with and modulation of the sympathetic tone of the left ventricle.

Irregular electrical activation of intrinsic cardiac adrenergic cells increases catecholamine-synthesizing enzymes.

BACKGROUND: Recently, increased cardiac norepinephrine levels were observed in patients who were exposed to irregular stimulation during electrophysiological testing. The molecular mechanisms remain unclear. Intrinsic cardiac adrenergic (ICA) cells are present in mammalian hearts and contain catecholamine-synthesizing enzymes sufficient to produce biologically active norepinephrine levels. Thus, we aimed to investigate the expression of catecholamine-synthesizing enzymes by ICA cells exposed to irregular pacing. METHODS: Co-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48h (standard deviation (SD)=5%, 25% and 50% of mean cycle length) at a constant rate of 5Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels. RESULTS: First, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5Hz significantly increased the expression of TH and DBH enzyme synthesis. Pharmacological approaches have shown that both metoprolol and losartan reversed the irregular pacing induced DBH increase, whereas the expression of TH was only blocked by metoprolol in a significant manner. Blockade of the endothelin-A receptor by BQ123 or the calcineurin-NFAT pathway by cyclosporine-A, 11R-VIVIT or FK506 revealed a potential role of both cascades in irregular pacing induced catecholamine-synthesizing enzyme expression. CONCLUSIONS: ICA cells respond to irregular electrical activation with an increase in catecholamine-synthesizing enzymes. Drugs commonly used in clinical routine significantly influence the expression of TH and DBH by ICA cells via different signaling routes.

Electrical remodelling in cardiac resynchronization therapy: decrease in intrinsic QRS duration.

INTRODUCTION: Cardiac resynchronization therapy (CRT) provides a therapeutic option for patients with congestive heart failure (CHF) and left bundle-branch block. Structural myocardial remodelling due to CRT has been described extensively. We hypothesized that CRT might also induce electrical remodelling, thus decreasing the intrinsic QRS duration. METHODS: In 38 patients with CHF (ejection fraction (EF): 26 +/- 7%) a CRT device was implanted. 18 patients suffered from ischaemic cardiomyopathy (ICM) and 20 from dilated cardiomyopathy (DCM). Echocardiography and 12-lead ECGs without pacing were obtained prior to implantation and after 6 and 12 months. Patients were classified as responders in case of an increase in EF > or = 25% in combination with an increase in NYHA class > or = 1. Variance analysis was performed to determine the impact of response or underlying heart disease (ICM/DCM) on the extent of change in QRS duration (delta QRS duration). RESULTS: The EF increased to 36 +/- 10% (P < 0.0001) after 6 months and 40 +/- 12% (P < 0.0001) after 12 months of CRT. Intrinsic QRS duration decreased from 171 +/- 18 ms before CRT to 164 +/- 23 ms (P = 0.027) after 6 months and 161 +/- 25 ms (P = 0.002) after 12 months of CRT. 22 patients (58%) were classified as responders. Whereas a significant decrease in intrinsic QRS duration was observed in responders, only a slight decrease was seen in non-responders. However, two-factorial variance analyses did not show a significant influence of response or underlying heart disease (ICM/DCM) on delta QRS duration (P = 0.7). CONCLUSION: CRT results in an electrical remodelling with a reduction of the intrinsic QRS duration.

Chronic augmentation of the parasympathetic tone to the atrioventricular node: a nonthoracotomy neurostimulation technique for ventricular rate control during atrial fibrillation.

INTRODUCTION: The right inferior ganglionated plexus (RIGP) selectively innervates the atrioventricular node. Temporary electrical stimulation of this plexus reduces the ventricular rate during atrial fibrillation (AF). We sought to assess the feasibility of chronic parasympathetic stimulation for ventricular rate control during AF with a nonthoracotomy intracardiac neurostimulation approach. METHODS AND RESULTS: In 9 mongrel dogs, the small endocardial area inside the right atrium, which overlies the RIGP, was identified by 20 Hz stimulation over a guiding catheter with integrated electrodes. Once identified, an active-fixation lead was implanted. The lead was connected to a subcutaneous neurostimulator. An additional dual-chamber pacemaker was implanted for AF induction by rapid atrial pacing and ventricular rate monitoring. Continuous neurostimulation was delivered for 1-2 years to decrease the ventricular rate during AF to a range of 100-140 bpm. Implantation of a neurostimulation lead was achieved within 37 +/- 12 min. The latency of the negative dromotropic response after on/offset or modulation of neurostimulation was <1 s. Continuous neurostimulation was effective and well tolerated during a 1-2 year follow-up with a stimulation voltage <5 V. The neurostimulation effect displayed a chronaxie-rheobase behavior (chronaxie time of 0.07 +/- 0.02 ms for a 50% decrease of the ventricular rate during AF). CONCLUSION: Chronic parasympathetic stimulation can be achieved via a cardiac neurostimulator. The approach is safe, effective, and well tolerated in the long term. The atrioventricular nodal selectivity and the opportunity to adjust the negative dromotropic effect within seconds may represent an advantage over pharmacological rate control.

Registration of coronary venous anatomy to the site of the latest mechanical contraction.

OBJECTIVE: Cardiac resynchronization therapy (CRT) provides a therapeutic option for patients with congestive heart failure (CHF). There is evidence that the optimal pacing site (OIS) is vicinal to the region of the latest contraction (RLC). However, the RLC is not identified routinely to guide lead implantation to the coronary venous system (CVS). The aim of this study was: (i) to develop a software over-imposing CVS-anatomy on parametric images of left ventricular dyssynchrony in a 3D-format obtained from computed tomography (CT) and cardiac magnetic resonance imaging (MRI); and (ii) to apply this 3D-software for analysing the possible correlation between functional/ clinical improvement and the distance between final implantation site (FIS) and RLC. METHODS AND RESULTS: In 20 CHF-patients (11 men, 65.6 +/- 6.8 y, ejection fraction (EF): 27.5 +/- 6.1%) CRT-leads were implanted; follow-up included echocardiographic and exercise evaluation. The OIS and the FIS were noted on 3D-registrations and the distances OIS-RLC and FIS-RLC measured.The target vessel was reached in 14 cases. NYHA class and EF improved significantly with a low rate of non-responders of 3 (15%) (EF) and 4 (20%) (NYHA). Image registration was possible in all patients. Post-process 3D-analysis revealed no correlation between the distance FIS-RLC and functional or echocardiographic improvements.There was a trend towards a shorter distance FIS-RLC in patients classified as responders (EF). NYHA class improved significantly better in patients with target vessel implantation. CONCLUSIONS: Registration of CT/MRI-images enables efforts to reach the RLC by preoperative identification of corresponding veins. Larger randomized trials must define the definite therapeutic benefit.

Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway.

A heightened sympathetic tone accelerates the development of lethal arrhythmias after myocardial infarction (MI) and the progression of heart failure (HF). Cardiomyocytes control their local neural milieu by expression of nerve growth factor (NGF), which triggers sympathetic neural growth (sympathetic nerve sprouting: SNS). The molecular mechanisms that regulate NGF expression are largely unknown. During HF or MI the myocytes are exposed to increased mechanical load and adrenergic stimulation. Both stimuli induce myocyte hypertrophy. The angiotensin-II-calcineurin-NFAT (nuclear factor of activated t-cells) pathway is a well characterized signaling cascade in the pathogenesis of myocyte hypertrophy. The present study aims to investigate the molecular mechanisms by which mechanical stretch and/or alpha-1-adrenergic stimulation affect NGF expression in neonatal rat ventricular myocytes. Both stimuli resulted in a down-regulation of NGF gene and protein expression. Angiotensin-II type 1 receptor blockade with losartan blunted the stretch-induced NGF down-regulation. Specific calcineurin inhibition with cyclosporine A and FK506 or NFAT inhibition with 11R-VIVIT reversed the stretch or alpha-1-adrenergic induced decrease of NGF. Calcineurin over-expression increased NFAT-DNA binding activity and decreased NGF expression. The magnitude of NGF decrease was sufficient to reduce neurite outgrowth of cultured sympathetic neurons. In conclusion, mechanical stretch and alpha-1-adrenergic stimulation contribute to a decrease of cardiomyocyte NGF expression via the calcineurin-NFAT pathway. To evaluate if the calcineurin-NFAT is critically involved in the pathogenesis of SNS further in-vivo studies in models of HF and MI are required. Nevertheless, the calcineurin-NFAT pathway may provide promising starting points for new pharmacological strategies to prevent SNS in the heart.

The angiotensin-calcineurin-NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes.

AIM: During atrial fibrillation, arterial hypertension and systolic or diastolic heart failure, atrial myocytes are exposed to increased baseline stretch. Atrial stretch has been shown to induce cellular hypertrophy and extracellular matrix remodeling (ECM) via angiotensin-II dependent pathways and the matrix metalloproteinases system (MMPs). We hypothesized that atrial myocytes exposed to static stretch may increase their ECM remodeling activity via up-regulation of MMP-2/-9. We then tested the hypothesis that the membrane bound angiotensin-II type 1 (AT1) receptor and the intracellular calcineurin (Cn)-NFAT signaling pathway are potential mediators of stretch-induced MMP alterations, since Cn-NFAT is one important contributor to myocyte hypertrophy. METHODS AND RESULTS: Neonatal rat atrial myocytes (NRAM) were cultured under conditions of static stretch by 21%. The differential effects of selective AT1 receptor blockade by losartan, Cn blockade by Cyclosporine-A (CsA) or NFAT inhibition by 11R-VIVIT (VIV), were analyzed. Stretch resulted in a significant up-regulation of active-MMP-2/-9 protein amount (active-MMP-2 ng/microg: control 8.95 +/- 0.64 vs. stretch 13.11 +/- 0.74 / active-MMP-9 ng/microg: control 1.45 +/- 0.18 vs. stretch 1.94 +/- 0.21, all n = 5) and enzyme activity (MMP-2 in %: control 1 +/- 0.0 vs. stretch 1.87 +/- 0.25, n = 7) associated with a significant increase of the membrane-type-1-MMP (MT1-MMP) protein expression (MT1-MMP in %: control 1 +/- 0.0 vs. stretch 2.17 +/- 0.21, n = 8). These observations were accompanied by an activation of the Cn-NFAT pathway (Cn-activity in nmol PO(4) release/20 microg protein/30 min: control 0.37 +/- 0.08 vs. stretch 0.65 +/- 0.09, n = 3 / NFATc1-DNA binding activity in %: control 1 +/- 0.0 vs. stretch 1.53 +/- 0.17, n = 3). Losartan, CsA or VIV abolished stretch-induced alterations in MMP-2/-9 and MT1-MMP expression and enzyme activity by normalizing the Cn-activity and the DNA binding activity of NFATc1. CONCLUSION: Our results present new insights in molecular mechanisms of ECM remodeling activity of atrial myocytes exposed to static stretch. The AT1-Cn-NFAT pathway is a potential mediator of MMP activation.

Targeting of cardiac autonomic plexus for modulation of intracardiac neural tone.

AIMS: Ventricular rate control is considered as an initial choice of therapy in many patients with atrial fibrillation (AF). We could previously show that electrostimulation of the right inferior ganglionated plexus (RIGP), which supplies the AV node, instantly decreases ventricular rate during AF. This study describes the development of a technique to reliably implant a chronic lead inside the RIGP. METHODS AND RESULTS: In nine mongrel dogs with AF, the RIGP was identified by neuromapping with probatory high-frequency stimulation (20 Hz) over steerable electrode catheters until a significant ventricular rate slowing was achieved. Then an active fixation, permanent pacemaker lead was fixed closed to the mapping catheter left in place as anatomical marker. Initially (n = 4) available guiding catheters and steerable lead stylets were employed to navigate and anchor the lead, which resulted in repetitive screw-in attempts. Therefore, a guiding catheter was developed, which allowed angiography, lead advancement through its lumen, and probatory neurostimulation over its tip. This tool allowed lead delivery within 40 min (n = 5). Neurostimulation via the permanent lead elicited negative dromotropic effects with stimulation frequency, voltage, and impulse duration as determinants of stimulation efficacy. CONCLUSION: Active fixation of a permanent pacing lead inside the RIGP is feasible without thoracotomy. Thereby, ventricular rate control during AF can be achieved with stimulus voltages applied for myocardial electrostimulation.

Initial experience with remote magnetic navigation for left ventricular lead placement.

BACKGROUND: A novel magnetic navigation system allows remote steering of guidewires and catheters. This system may be used for left ventricular lead placement for cardiac resynchronization therapy (CRT). We sought to evaluate the feasibility and safety of magnetic guidewire navigation for CRT procedures. METHODS: 123 consecutive patients underwent CRT implantation/revision procedures (including pacemaker upgrades in n=22 and left ventricular lead placement after dislocation in n=4 patients). Left ventricular lead placement in a coronary sinus side branch was performed either conventionally or using magnetic navigation. The magnetic navigation system (Niobe) consists of two permanent magnets creating a steerable magnetic field. Guidewires with integrated magnets align to the magnetic field and were used for over-the-wire implantation of pacemaker leads in the coronary sinus. Patients were assigned to conventional (n=93) or magnetic (n=30) navigation according to room availability. Venography of the coronary venous system was performed to select a target vessel for lead implantation. RESULTS: Guidewire access to the target vessel was achieved in 100% using magnetic navigation compared to 87% with the conventional approach (P < 0.05). Implantation success rates, total procedure and fluoroscopy times did not differ significantly between groups. No periprocedural death and no intraoperative device dysfunction occurred in either group.The magnetic guidewire ruptured in one patient. CONCLUSION: Left ventricular lead placement using magnetic guidewire navigation to engage the desired coronary sinus side branch can be successfully performed for CRT.

Development of an item bank for the assessment of depression in persons with mental illnesses and physical diseases using Rasch analysis.

OBJECTIVE: The calibration of item banks provides the basis for computerized adaptive testing that ensures high diagnostic precision and minimizes participants' test burden. The present study aimed at developing a new item bank that allows for assessing depression in persons with mental and persons with somatic diseases. METHOD: The sample consisted of 161 participants treated for a depressive syndrome, and 206 participants with somatic illnesses (103 cardiologic, 103 otorhinolaryngologic; overall mean age = 44.1 years, SD =14.0; 44.7% women) to allow for validation of the item bank in both groups. Persons answered a pool of 182 depression items on a 5-point Likert scale. RESULTS: Evaluation of Rasch model fit (infit < 1.3), differential item functioning, dimensionality, local independence, item spread, item and person separation (>2.0), and reliability (>.80) resulted in a bank of 79 items with good psychometric properties. CONCLUSIONS: The bank provides items with a wide range of content coverage and may serve as a sound basis for computerized adaptive testing applications. It might also be useful for researchers who wish to develop new fixed-length scales for the assessment of depression in specific rehabilitation settings.