P-wave detection performance of the BioMonitor III, Confirm Rx and Reveal Linq implantable loop recorders.

INTRODUCTION: Rhythm interpretation of EGMs recorded by implantable loop recorders (ILRs) is facilitated in cases when p-waves are visible. The three most commonly used ILRs (BioMonitor III, Confirm RX and Reveal Linq) vary in size, electrode placement and filter algorithms. Therefore, p-wave visibility and amplitude on EGM may vary according to the implanted device. MATERIAL AND METHODS: Consecutive patients were included after ILR implantation. P-wave visibility and amplitude were evaluated in sinus rhythm on 30-s EGMs with standard resolution (25 mm/mV for Biotronik and St. Jude, 30 mm/mV for Medtronic) and after maximum magnification. Additionally, baseline characteristics and p-wave amplitude in lead II on the surface-ECG were documented. RESULTS: 148 patients with either BioMonitor III (n = 48), Confirm Rx (n = 51) or Reveal Linq (n = 49) ILRs were included. With standard resolution, p-waves were visible in 40 patients (83%) implanted with BioMonitor III, 36 patients (71%) with Confirm Rx and in 35 patients (71%) with Reveal Linq ILRs (p = 0.267). After maximum magnification, p-waves could not be identified in 6 patients with Confirm Rx ILR (12%) and 1 patient in both BioMonitor III and Reveal Linq ILR (2%; p = 0.051). The Biomonitor III showed higher p-wave amplitudes compared to the Confirm Rx (0.050 mV (0.040-0.070) vs. 0.030 mV (0.020-0.040); p < 0.001) and the Reveal Linq ILR (0.050 mV (0.040-0.070) vs. 0.030 mV (0.020-0.040); p < 0.001). CONCLUSION: P-wave amplitudes were higher in patients with Biomonitor III. This did not lead to higher p-wave visibility compared to the Confirm RX ILR or the Reveal Linq ILR.

Atrial standstill in sinus node disease due to extensive atrial fibrosis: impact on dual chamber pacemaker implantation.

AIMS: Atrial standstill is characterized by the absence of atrial activity. We report about a series of cases, in which conventional atrial pacemaker lead implantation in patients with symptomatic sinus node disease failed due to lack of excitable right atrial tissue, thus, prompting the diagnosis of atrial standstill. We hypothesized that mapping of the atria with subsequent identification of myocardium still amenable to atrial pacing would allow dual chamber pacemaker implantation. METHODS AND RESULTS: In four patients, atrial lead implantation failed. In these patients, spontaneous or fibrillatory electrical activity was absent but the atria could not be captured despite high stimulation voltages at conventional atrial sites. We suspected partial or complete atrial standstill and subsequently confirmed this hypothesis by conventional (n = 1) or electroanatomical mapping (n = 3). Areas of fibrotic tissue were present in all patients as identified by lack of spontaneous electrical activity and inability of local electrical capture via the mapping catheter. Surviving atrial tissue, which could be electrically captured with subsequent conduction of activity to the atrioventricular (AV) node, was present in three patients. Successful targeted atrial lead implantation at these sites was achieved in all these patients. Isolated sinus node activity without conduction to the atria was found in one patient. CONCLUSION: Partial atrial standstill may be present and prevent atrial lead implantation in patients with sinus node disease. In these patients, recognition of partial atrial standstill and identification of surviving muscular islets with connection to the AV node by mapping studies may still allow synchronous AV sequential pacing.

Electromagnetic interference with implantable cardioverter-defibrillators at power frequency: an in vivo study.

BACKGROUND: The number of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death is continuing to increase. Given the technological complexity of ICDs, it is of critical importance to identify and control possible harmful electromagnetic interferences between various sources of electromagnetic fields and ICDs in daily life and occupational environments. METHODS AND RESULTS: Interference thresholds of 110 ICD patients (1-, 2-, and 3-chamber ICDs) were evaluated in a specifically developed test site. Patients were exposed to single and combined electric and magnetic 50-Hz fields with strengths of up to 30 kV·m⁻¹ and 2.55 mT. Tests were conducted considering worst-case conditions, including maximum sensitivity of the device or full inspiration. With devices being programmed to nominal sensitivity, ICDs remained unaffected in 91 patients (83%). Five of 110 devices (5%) showed transient loss of accurate right ventricular sensing, whereas 14 of 31 (45%) of the 2- and 3-chamber devices displayed impaired right atrial sensing. No interference was detected in 71 patients (65%) within the tested limits with programming to maximum sensitivity, whereas 20 of 110 subjects (18%) exhibited right ventricular disturbances and 19 of 31 (61%) subjects exhibited right atrial disturbances. CONCLUSIONS: Extremely low-frequency daily-life electromagnetic fields do not disturb sensing capabilities of ICDs. However, strong 50-Hz electromagnetic fields, present in certain occupational environments, may cause inappropriate sensing, potentially leading to false detection of atrial/ventricular arrhythmic events. When the right atrial/right ventricular interferences are compared, the atrial lead is more susceptible to electromagnetic fields. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/ct2/show/NCT01626261. Unique identifier: NCT01626261.

New devices in heart failure: an European Heart Rhythm Association report: developed by the European Heart Rhythm Association; endorsed by the Heart Failure Association.

Several new devices for the treatment of heart failure (HF) patients have been introduced and are increasingly used in clinical practice or are under clinical evaluation in either observational and/or randomized clinical trials. These devices include cardiac contractility modulation, spinal cord stimulation, carotid sinus nerve stimulation, cervical vagal stimulation, intracardiac atrioventricular nodal vagal stimulation, and implantable hemodynamic monitoring devices. This task force believes that an overview on these technologies is important. Special focus is given to patients with HF New York Heart Association Classes III and IV and narrow QRS complex, who represent the largest group in HF compared with patients with wide QRS complex. An overview on potential device options in addition to optimal medical therapy will be helpful for all physicians treating HF patients.

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.

The reliability and accuracy of a noncontact electrocardiograph system for screening purposes.

BACKGROUND: Electrocardiography (ECG) requires the application of electrodes to the skin and often necessitates undressing. Capacitively coupled electrodes embedded in a normal chair would be a rational alternative for ECG screening. We evaluated the reliability and accuracy of ECG electrodes imbedded in a chair cushion. METHODS: Two independent clinicians compared ECG recordings obtained using skin electrodes with recordings obtained using capacitively coupled electrodes that were embedded in a chair cushion in an anesthesiology premedication room, a cardiology outpatient ward, and a cardiology day ward. We analyzed the data to compare the sensitivity and specificity for the diagnosis of cardiac arrhythmias. RESULTS: ECG recordings were obtained from 107 patients. Heart rate was accurately measured using the capacitively coupled electrodes, but motion artifacts made the identification of P and T waves unreliable. Signal quality was poor for patients with low body weight, patients wearing clothing containing mixed fibers, and patients wearing sweaty shirts. CONCLUSIONS: Heart rate was accurately measured, and some cardiac arrhythmias were correctly diagnosed using capacitive ECG electrodes. Capacitive electrodes embedded into an examination chair are a promising tool for preoperative screening. Improved artifact reduction algorithms are needed before capacitive electrodes will replace skin electrodes.

Poor sleep quality is associated with depressive symptoms in patients with heart disease.

BACKGROUND: Depression in cardiac patients has gained importance due to increased mortality. Although sleep disturbances are a core symptom of depression, the prevalence and patterns of sleep disturbances in heart disease have hardly been examined regarding depression. PURPOSE: This cross-sectional study aims to examine sleep disturbances and depressive symptoms in consecutively admitted cardiac patients and depressed patients. METHODS: Two hundred four inpatients (113 male, 91 female) were examined: 94 cardiac inpatients (mean age 49.3 ± 14.3 years) with different heart diseases and 110 psychiatric inpatients (mean age 41.6 ± 13.0 years) with depressive disorders (DP). A depressive episode according to International Classification of Diseases (ICD)-10 was also diagnosed in 14 of the cardiac patients (DCP). The Pittsburgh Sleep Quality Index (PSQI) and the Beck Depression Inventory (BDI) were used to assess subjective sleep quality and severity of depressive symptoms. RESULTS: Poor sleep quality (PSQI > 5) was reported in all comorbid DCP (PSQI 12.00 ± 3.53, BDI 17.86 ± 4.28), in 60% of the 80 non-DCP (PSQI 5.59 ± 3.73, BDI 4.47 ± 3.07), and in 86.4% of the DP (PSQI 11.76 ± 4.77, BDI 27.11 ± 10.54). The cardiac inpatients showed a significant correlation between increased depressive symptoms and the PSQI components subjective sleep quality (r = 0.40) and daytime dysfunction (r = 0.34). Both sleep components were significant predictors of self-rated depression (R² = 0.404). CONCLUSIONS: Most cardiac patients experience poor sleep quality. Self-reported sleep disturbances in heart disease could serve as predictors of clinical or subclinical comorbid depression outside of a psychiatric setting in cardiology and other fields, and such patients should be referred to consultation-liaison psychiatry or polysomnography where sleep disorders like sleep apnea are suspected.

Gender-Specific Performance of One- Compared to Two-Catheter Concepts in Transradial Coronary Angiography - Insights From the Randomized UDDC-Radial-Trial.

OBJECTIVES: The present sub-analysis from the randomized UDDC-Radial-Trial sought to compare one-catheter concepts (OCC) with two-catheter concepts (TCC) in different patient subgroups, particularly in those depending on gender and age. BACKGROUND: There is an ongoing debate regarding potential performance differences of OCC compared to TCC for transradial coronary angiography in specific patient subgroups. METHODS: The randomized UDDC-Radial-Trial enrolled a total of 300 patients planed for coronary angiography in a 2:1 ratio to either OCC by Tiger II (n = 100) and BLK (n = 100) or TCC by Judkins (n = 100) catheters. Predefined patient subgroups stratified for age, gender and patient constitution were analyzed with regard to the primary outcome measure of time required for a complete coronary angiography. RESULTS: In male patients time for coronary angiography was significantly shorter in the TCC group compared to the OCC group (510 ± 37 s vs. 615 ± 35 s; p = 0.046). No difference between the catheter concepts was observed in the subset of female patients (525 ± 34 s vs. 583 ± 54 s; p = 0.43). TCC was associated with shorter coronary angiography time in patients aged <71 years compared to OCC (462 ± 23 s vs. 570 ± 38 s; p = 0.018). In patients ≥72 years of age no difference was detected (573 ± 41 s vs. 636 ± 45 s; p = 0.31). Other subgroups showed no relevant differences in angiography time among OCC and TCC. CONCLUSIONS: The present subgroup analysis from the UDDC-radial trial demonstrates the use of OCC in transradial diagnostic angiography to be inferior compared to TCC in terms of angiography time in younger and male patients.

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.

Mechanical stretch of sympathetic neurons induces VEGF expression via a NGF and CNTF signaling pathway.

Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.

Predicting neurally mediated syncope based on pulse arrival time: algorithm development and preliminary results.

BACKGROUND: Neurally mediated syncope (NMS) is a common disorder that is triggered by orthostatic stress. The circulatory adjustments to orthostatic stress occur just prior to a sudden loss of consciousness. NMS prediction would protect patients from falls or accidents. METHODS AND RESULTS: Based on simultaneously recorded heart rate (HR) and pulse wave during 70° head-up tilt (HUT) table testing we investigated a syncope warning system. In 14 patients with a history of suspected NMS we tested 2 algorithms based on HR and/or pulse arrival time (PAT). When the cumulative risk exceeded the threshold, which was calculated during the first 2 minutes following the posture change to upright position, a syncope prediction alarm was triggered. All syncopes (n = 7) were detected more than 16 seconds before the onset of dizziness or unconsciousness by using a prediction alarm based on HR and PAT (syncope prediction algorithm 2). No false alarm was generated in patients with negative HUT (n = 7). Syncope prediction was improved by detecting the slope of HR changes as compared with monitoring PAT changes alone (syncope prediction algorithm 1). The duration between the prediction alarm and the occurrence of syncope was 99 ± 108 seconds. CONCLUSION: Predicting NMS is feasible by monitoring HR and the onset of the pulse wave at the periphery. This approach might improve NMS management.

Sympathetic neurons express and secrete MMP-2 and MT1-MMP to control nerve sprouting via pro-NGF conversion.

Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.

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.

Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA.

Neuronal remodeling with increased sympathetic innervation density has been implicated in the pathogenesis of atrial fibrillation (AF). Recently, increased transcardiac nerve growth factor (NGF) levels were observed in a canine model of AF. Whether atrial myocytes or cardiac sympathetic neurons are the source of neurotrophins, and whether NGF is the main neurotrophic factor contributing to sympathetic nerve sprouting (SNS) in AF still remains unclear. Therefore, neonatal rat atrial myocytes were cultured under conditions of high frequency electrical field stimulation (HFES) to mimic rapid atrial depolarization. Likewise, sympathetic neurons from the superior cervical ganglia of neonatal rats were exposed to HFES to simulate the physiological effect of sympathetic stimulation. Real-time PCR, ELISA and Western blots were performed to analyze the expression pattern of NGF and neurotrophin-3 (NT-3). Baseline NGF and NT-3 content was 3-fold higher in sympathetic neurons than in atrial myocytes (relative NGF protein expression: 1+/-0.0 vs. 0.37+/-0.11, all n=5, p<0.05). HFES of sympathetic neurons induced a frequency dependent NGF and NT-3 gene and protein up-regulation (relative NGF protein expression: 0Hz=1+/-0.0 vs. 5Hz=1.13+/-0.19 vs. 50Hz=1.77+/-0.08, all n=5, 0Hz/5Hz vs. 50Hz p<0.05), with a subsequent increase of growth associated protein 43 (GAP-43) expression and morphological SNS. Moreover, HFES of sympathetic neurons increased the tyrosine kinase A (TrkA) receptor expression. HFES induced neurotrophic effects could be abolished by lidocaine, TrkA blockade or NGF neutralizing antibodies, while NT-3 neutralizing antibodies had no significant effect on SNS. In neonatal rat atrial myocytes, HFES resulted in myocyte hypertrophy accompanied by an increase in NT-3 and a decrease in NGF expression. In summary, this study provides evidence that high-rate electrical stimulation of sympathetic neurons mediates nerve sprouting by an increase in NGF expression that targets the TrkA receptor in an autocrine/paracrine manner.

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.

Resynchronization therapy optimization by intracardiac impedance.

AIMS: For successful cardiac resynchronization therapy (CRT), an optimization of left ventricular (LV) lead position and stimulation timing is required. The feasibility of optimizing LV lead position, atrioventricular delay (AVd), and interventricular delay (VVd) in CRT using intracardiac impedance measurement was evaluated. METHODS AND RESULTS: Heart failure patients (n = 14, NYHA 13×III, 1×II, ejection fraction: 26 ± 6%, QRS: 165 ± 30 ms) were stimulated by AAI and biventricular (DDD-BiV) pacing in turn. Left ventricular lead site, AVd, and VVd were varied. An external pacemaker measured impedance, and a micromanometer catheter measured LV and aortic pressure. Left ventricular dP/dt(max), pulse pressure (PP), stroke volume (SV), end-systolic impedance (ESZ), and stroke impedance (SZ) were determined. Optimization results achieved by maximum increase in PP, SV, SZ, or ESZ were compared with the reference method (dP/dt(max) increase). Left ventricular lead site variation resulted in a mean optimal dP/dt(max) benefit of 18.2%. Lead site selection by SZ/PP/SV showed benefits of 17.4/17.9/17.2%, respectively. Atrioventricular delay optimization increased the optimal benefit to 22.1%, the methods ESZ/PP/SV achieved 20.1/20.8/19.4%. Interventricular delay optimization resulted in a benefit of 19.1/19.4/19.9% (SZ/PP/SV) with an optimum of 21.8%. The achieved benefit did not differ significantly between impedance, SV, and PP methods. A significant correlation between AVd values selected by dP/dt(max) and by the other methods was observed (r = 0.75/0.67/0.60 for ESZ/PP/SV). CONCLUSION: The feasibility of optimizing LV lead site, AVd, and VVd by intracardiac impedance has been demonstrated for CRT patients with a similar performance as using SV and PP. Application of intracardiac impedance for automatic implant-based CRT optimization appears to be within reach.

Intracardiac impedance monitors stroke volume in resynchronization therapy patients.

AIMS: Monitoring of haemodynamic parameters or surrogate parameters of the left ventricle is especially important for patients under cardiac resynchronization therapy (CRT). Intracardiac impedance reflects left ventricular (LV) volume changes well in animal models. Since it is unknown whether this also holds in humans with heart failure (HF), we examined the correlation of LV intracardiac impedance with haemodynamic parameters in CRT patients for different positions of the LV lead. METHODS AND RESULTS: In 14 HF patients with non-ischaemic cardiomyopathy (four female, age 70 +/- 6 years, NYHA 2.9 +/- 0.3, EF 26 +/- 6%), one or two suitable implantation sites for the LV lead were selected. Following atrial, right ventricular, and LV catheter positioning, a micro-manometer catheter was placed in the ascending aorta. Surface ECG, impedance, and aortic pressure were recorded during graded overdrive bi-ventricular pacing in DDD mode. The correlation between impedance and stroke volume (SV) or pulse pressure (PP) changes was compared for different LV lead positions. In total, 20 overdrive pacing tests were performed at six different LV lead positions. Strong correlations were found between stroke impedance (SZ) and SV (R = 0.82 +/- 0.16) as well as between SZ and PP (R = 0.81 +/- 0.16) without significant influence of LV lead position. CONCLUSION: In HF patients, a strong correlation between changes in intracardiac impedance and LV SV was found. Typical LV lead implant positions have been tested and all appear to be suitable for this method of LV volume monitoring.