Association of adipocytokines serum levels with left atrial thrombus formation in atrial fibrillation patients on oral anticoagulation (Alert) - A cross-sectional study.

BACKGROUND AND AIMS: Oral anticoagulation is effective for stroke prevention in atrial fibrillation (AF). However, strokes may still occur in high-risk individuals. We conducted a prospective trial to assess the association between adipocytokine serum levels and surrogate parameters for thromboembolic events. METHODS AND RESULTS: In this cross-sectional multicenter trial, we enrolled 189 patients with AF who were on oral anticoagulation. The primary endpoint was defined as either the presence of spontaneous echo contrast (SEC), a left atrial appendage (LAA), or a left atrial (LA) thrombus on transesophageal echocardiography. We investigated the association of adipocytokine serum levels with the combined endpoint using logistic regression analysis. Forty-eight individuals (25%) were assigned to group 1 (G1) due to the occurrence of at least one of the components of the combined endpoint (41 [21.7%] SEC, 3 [1.6%] LA thrombus, 13 [6.9%] LAA thrombus), whereas the remaining patients formed group 2 (G2). The BMI, logarithmized (loge) leptin (G1: 2.0 ± 1.3 µg/ml, G2: 2.0 ± 1.1 µg/ml, p = 0.746) and visfatin serum levels (G1: 3.4 ± 0.3 ng/ml, G2: 3.4 ± 0.5 ng/ml, p = 0.900) did not significantly differ between the groups. Conversely, logarithmized adiponectin (G1: 3.3 ± 0.6 ng/ml, G2: 3.1 ± 0.7 ng/ml, p = 0.036) and resistin levels (G1: 1.8 ± 0.5 ng/ml, G2: 1.6 ± 0.5 ng/ml, p = 0.009) were higher in patients with the primary endpoint. Multivariate logistic regression analysis using a score that combined the individual adiponectin and resistin values in each patient corroborated this association. CONCLUSIONS: Our results suggest that adiponectin and resistin may act as potential biomarkers to identify individuals with AF who are at high thromboembolic risk.

Baroreceptor stimulation in a patient with preexisting subcutaneous implantable cardioverter defibrillator.

BACKGROUND: Many patients with severe heart failure (HF) have an indication for baroreflex activation therapy (BAT) and an implantable cardioverter-defibrillator (ICD). Concerns about device-device interactions were addressed in a study with small sample size that concluded combined BAT and ICD therapy is safe. There are no published data, however, concerning device-device interactions between BAT and a subcutaneous ICD (S-ICD). Since BAT frequently interferes with surface electrocardiogram recordings, there are doubts about compatibility of BAT and S-ICD devices. CASE DESCRIPTION: A 54-year-old male patient with dilated cardiomyopathy and severely reduced left ventricular ejection fraction received an S-ICD after recurrent systemic infections due to a diabetic foot syndrome, ultimately associated with infective endocarditis. Since medical HF therapy could not be further optimized and the patient presented with persistent cardiac decompensations, he was evaluated for BAT. Preoperatively, the barostim was epicutaneously placed on the patient's thorax with conductive gel in order to evaluate a possible interference with the S-ICD. Positioning of the barostim in loco typico did not affect the S-ICD's sensing in any vector. Only positioning of the carotis sinus lead directly upon the S-ICD lead, which is beyond clinical relevance, lead to missensing. Subsequently, BAT was implanted with successful perioperative testing of the S-ICD: there was accurate detection of ventricular fibrillation and immediate termination via first shock delivery under maximum barostim output. CONCLUSIONS: To our knowledge, there are no other reports in which a barostim was safely implanted in a patient with a preexisting S-ICD. Until data with large patient numbers are available, individual perioperative testing is highly recommended.

Safety of the Wearable Cardioverter Defibrillator (WCD) in Patients with Implanted Pacemakers.

BACKGROUND: The wearable cardioverter defibrillator (WCD) is an important approach for better risk stratification, applied to patients considered to be at high risk of sudden arrhythmic death. Patients with implanted pacemakers may also become candidates for use of the WCD. However, there is a potential risk that pacemaker signals may mislead the WCD detection algorithm and cause inappropriate WCD shock delivery. The aim of the study was to test the impact of different types of pacing, various right ventricular (RV) lead positions, and pacing modes for potential misleading of the WCD detection algorithm. METHODS: Sixty patients with implanted pacemakers received the WCD for a short time and each pacing mode (AAI, VVI, and DDD) was tested for at least 30 seconds in unipolar and bipolar pacing configuration. In case of triggering the WCD detection algorithm and starting the sequence of arrhythmia alarms, shock delivery was prevented by pushing of the response buttons. RESULTS: In six of 60 patients (10%), continuous unipolar pacing in DDD mode triggered the WCD detection algorithm. In no patient, triggering occurred with bipolar DDD pacing, unipolar and bipolar AAI, and VVI pacing. Triggering was independent of pacing amplitude, RV pacing lead position, and pulse generator implantation site. CONCLUSION: Unipolar DDD pacing bears a high risk of false triggering of the WCD detection algorithm. Other types of unipolar pacing and all bipolar pacing modes do not seem to mislead the WCD detection algorithm. Therefore, patients with no reprogrammable unipolar DDD pacing should not become candidates for the WCD.

Applicability of a Novel Formula (Bogossian formula) for Evaluation of the QT-Interval in Heart Failure and Left Bundle Branch Block Due to Right Ventricular Pacing.

BACKGROUND: The presence of left bundle branch block (LBBB) due to right ventricular pacing represents a particular challenge in properly measuring the QTc interval. In 2014, a new formula for the evaluation of QT interval in patients with LBBB was reported. METHODS: 145 patients with implantable cardioverter defibrillator were included in this prospective multicenter observational study. Inclusion criteria were: no permanent right ventricular stimulation, an intrinsic QRS interval of <120 ms, and reduced left ventricular function. 12-lead electrocardiogram recordings during intrinsic rhythm and during right ventricular threshold testing were performed. After LBBB correction using the reported Bogossian formula, the QTc interval was evaluated with Bazett's formula. The corrected QTc interval was compared in each patient with the QTc interval during intrinsic rhythm. All measurements were performed by an experienced electrophysiologist and a trainee who worked independently and in a blinded manner. RESULTS: 74 patients (65 ± 13 years; male n = 42) with apical and 71 patients (68 ± 11 years; male n = 42) with nonapical right ventricular pacing were included in this study. The mean left ventricular ejection fraction was 40 ± 13%. The QTc interval was determined to be 461 ± 34 ms (modified by Bogossian's formula) in paced and 436 ± 34 ms in intrinsic rhythm. The QTc interval was overestimated by ΔQTc of 25 ± 21 ms (mean deviation 5.7%) when using the Bogossian formula. CONCLUSION: The novel Bogossian formula seems to be a reliable tool for QTc interval evaluation in patients with heart failure and right ventricular pacing. However, a slight overestimation of the QT-interval must be respected.

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.

Safety and Performance of the Subcutaneous Implantable Cardioverter Defibrillator Detection Algorithm INSIGHTTM in Pacemaker Patients.

BACKGROUND: The use of the S-ICD is limited by its inability to provide backup pacing. Combined use of the S-ICD with a pacemaker may be a good choice in certain situations, yet current experience concerning the compatibility is limited. The goal of this study was to determine the safety and efficacy of the S-ICD in patients with a pacemaker. METHODS: A total of 74 consecutive patients with a bipolar pacemaker were prospectively enrolled. First, surface rhythm strips were recorded in all possible pacemaker stimulation modes, to screen for T-wave oversensing (TWOS). Second, a S-ICD functional dummy was placed epicutaneously on the patient in the typical implant position. The same standardized pacing protocol was used as mentioned above, and every stimulation mode was recorded via S-ECG in all vectors. RESULTS: In 16 patients (21.6%), programmed stimulation would have led to VT/VF detection. Triggered episodes were due to counting of the pacing spike(s), QRS complex, premature ventricular contractions, and/or additional TWOS. Three cases triggered in the bipolar stimulation mode. Oversensing was associated with lung emphysema and a reduced QRS amplitude in the S-ECG. CONCLUSION: The combination of an S-ICD and a pacemaker may lead to inadequate shock delivery due to oversensing, even under programmed bipolar stimulation. Oversensing cannot be sufficiently predicted by the screening tool in pacemaker patients. Testing with an epicutaneous S-ICD dummy in all vectors and stimulation settings is recommended in patients with pre-existing pacemakers.

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.

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.

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.

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.

Tilt testing and what you should know about it - Experience with 835 consecutive patients with syncope of unknown origin.

BACKGROUND: Numerous tilt testing protocols with and without a preceding passive phase or the administration of nitrates have already been investigated. However, a truely standardized method for the investigation does not yet exist. METHODS AND RESULTS: A total of 835 consecutive patients who underwent tilt testing between January 2005 and March 2015 were included in this study. Results of a passive tilt test (PTT), a nitrate-stimulated tilt test (NSTT) with a preceding passive phase of 20 min, or an early nitrate-stimulated tilt test (ENSTT) without a preceding passive phase were compared and analyzed retrospectively in 735 patients. In addition, a further 100 consecutive patients were prospectively randomized 1:1 to compare NSTT and ENSTT. In the retrospective analysis, 38% of the patients in the ENSTT group had a positive test response compared with 45% in the NSTT group and only 27% in the PTT group (p = 0.0002). In the prospective study, 34% of the patients had a positive test response in the ENSTT group compared with 42% in the NSTT group (p = 0.537). The mean duration to a positive test response was significantly shorter in the ENSTT group (retrospective and prospective p < 0.001). The nitrate-stimulated groups did not differ significantly with respect to the hemodynamic characteristics of a positive test response (retrospective: p = 0.773; prospective: p = 0.086). CONCLUSION: Due to the rate of positive test response being comparable to other protocols and its significantly shorter test duration, nitrate-stimulated tilt testing without a preceding passive tilt test may be favored for use in a busy clinical practice.

Late deterioration of left ventricular function after right ventricular pacemaker implantation.

OBJECTIVES: Right ventricular (RV) pacing induces a left bundle branch block pattern on ECG and may promote heart failure. Patients with dual chamber pacemakers (DCPs) who present with progressive reduction in left ventricular ejection fraction (LVEF) secondary to RV pacing are candidates for cardiac resynchronization therapy (CRT). This study analyzes whether upgrading DCP to CRT with the additional implantation of a left ventricular (LV) lead improves LV function in patients with reduced LVEF following DCP implantation. METHODS: Twenty-two patients (13 males) implanted with DCPs and a high RV pacing percentage (>90%) were evaluated in term of new-onset heart failure symptoms. The patients were enrolled in this retrospective single-center study after obvious causes for a reduced LVEF were excluded with echocardiography and coronary angiography. In all patients, DCPs were then upgraded to biventricular devices. LVEF was analyzed with a two-sided t-test. QRS duration and brain natriuretic peptide (BNP) levels were analyzed with the unpaired t-test. RESULTS: LVEF declined after DCP implantation from 54±10% to 31±7%, and the mean QRS duration was 161±20 ms during RV pacing. NT-pro BNP levels were elevated (3365±11436 pmol/L). After upgrading to a biventricular device, a biventricular pacing percentage of 98.1±2% was achieved. QRS duration decreased to 108±16 ms and 106±20 ms after 1 and 6 months, respectively. There was a significant increase in LVEF to 38±8% and 41±11% and a decrease in NT-pro BNP levels to 3088±2326 pmol/L and 1860±1838 pmol/L at 1 and 6 months, respectively. CONCLUSION: Upgrading to CRT may be beneficial in patients with DCPs and heart failure induced by a high RV pacing percentage.

[Successful ablation of an atrioventricular nodal reentrant tachycardia ablation 2 years after orthotopic heart transplantation]. / Erfolgreiche Ablation einer AV-Knoten-Reentry-Tachykardie 2 Jahre nach orthotoper Herztransplantation.

We report the case of a 48-year-old woman with an orthotopic heart transplantation. Two years after transplantation, the patient reported intermittent palpitations and dyspnea. The results of the 12-lead electrogram provided suspicion of AV nodal reentrant tachycardia (AVNRT), which was confirmed in the electrophysiological examination. The AVNRT was successfully eliminated without complications by radiofrequency catheter ablation of the slow pathway. The case shows that an AVNRT, even with existing sinus rhythm of the original heart, can also occur on the transplanted heart and ablation is safe and feasible.

Subthreshold High-Frequency Electrical Field Stimulation Induces VEGF Expression in Cardiomyocytes.

Subthreshold electrical stimulation (SES) has been shown to induce an improvement of angiogenesis in ischemic and nonischemic skeletal muscles, mediated by increased VEGF expression. VEGF plays a key role in physiological and pathological angiogenesis. Cardiomyocytes possess the ability to synthesize and secrete VEGF. Thus, we thought to investigate the effect of SES on VEGF regulation in cultured neonatal rat ventricular myocytes (NRVMs), in the aim to reveal new techniques for therapeutic angiogenesis in ischemic heart disease. Cell cultures of NRVMs were electrically stimulated with field strengths below the myocyte depolarization threshold (0.5 V/cm with 1 ms bipolar impulse duration). Frequencies ranging from 5 Hz up to 25, 50, and 99 Hz were applied over a period of 48 h. The expression of VEGF and its receptor KDR was determined with Western blot and ELISA. To reveal the biological activity of the secreted VEGF amount, cultured human coronary artery endothelial cells (HCAECs) were treated with the cell culture supernatant of NRVMs exposed to SES. A dominant effect of SES was observed at 25 Hz. Within this particular frequency the VEGF protein amount in the cytoplasm as well as in the cell culture supernatant increased significantly. In parallel, the protein expression of the KDR receptor decreased in a significant manner. Moreover, cell culture supernatant of NRVMs exposed to SES augmented the growth of HCAECs. Cardiomyocytes respond to SES with an increase in biologically active VEGF expression that promotes cell proliferation of HCAECs. This mechanism may provide new approaches to develop therapeutic angiogenesis in the ischemic heart.

Increase of ventricular interval during atrial fibrillation by atrioventricular node vagal stimulation: chronic clinical atrioventricular-nodal stimulation download study.

BACKGROUND: Patients with a high ventricular rate during atrial fibrillation (AF) are at increased risk of receiving inappropriate implantable cardioverter defibrillator shocks. The objective was to demonstrate the feasibility of high frequency atrioventricular-nodal stimulation (AVNS) to reduce the ventricular rate during AF to prevent inappropriate implantable cardioverter defibrillator shocks. METHODS AND RESULTS: Patients with a new atrial lead placement as part of a cardiac resynchronization therapy and defibrillator implant and a history of paroxysmal or persistent AF were eligible. If proper atrial lead position was confirmed, AVNS software was uploaded to the cardiac resynchronization therapy device, tested, and optimized. AVNS was delivered via a right atrial pacing lead positioned in the posterior right atrium. Software allowed initiation of high frequency bursts triggered on rapidly conducted AF. Importantly, the efficacy was evaluated during spontaneous AF episodes between 1 and 6 months after implant. Forty-four patients were enrolled in 4 centers. Successful atrial lead placement occurred in 74%. Median implant time of the AVNS lead was 37 minutes. In 26 (81%) patients, manual AVNS tests increased the ventricular interval by >25%. Between 1 and 6 months, automatic AVNS activations occurred in 4 patients with rapidly conducted AF, and in 3 patients, AVNS slowed the ventricular rate out of the implantable cardioverter defibrillator shock zone. No adverse events were associated with the AVNS software. CONCLUSIONS: The present study demonstrated the feasibility of implementation of AVNS in a cardiac resynchronization therapy and defibrillator system. AVNS increased ventricular interval >25% in 81% of patients. AVNS did not influence the safety profile of the cardiac resynchronization therapy and defibrillator system. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Unique Identifier: NCT01095952.

Age-related regional differences in cardiac nerve growth factor expression.

Age has been identified as an independent risk factor for cardiovascular diseases. A shift of the cardiac autonomic nervous system towards an increase in sympathetic tone has been reported in the elderly. Nerve growth factor (NGF) is the main neurotrophic factor that increases the sympathetic activity of the heart. If there is a shift of NGF expression in old compared to young cardiomyocytes and whether there are regional differences in the heart still remain unclear. Therefore, we chose a rat model of different-aged rats (3-4 days = neonatal, 6-8 weeks = young, 20-24 months = old), and isolated cardiomyocytes from the left and the right atrium (LA, RA), as well as from the left and the right ventricle (LV, RV), were used to determine NGF expression on mRNA and protein levels. In neonatal, young, and old rats, NGF amount in LA and RA was significantly lower as compared to LV and RV. In young and old rats, we found significant higher NGF protein levels in LA compared to RA. In addition, both atria showed an increase in NGF expression between age groups neonatal, young, and old. In both ventricles, we observed a significant decrease in NGF expression from neonatal to young rats and a significant increase from young to old rats. The highest NGF amount in LV and RV was observed in neonatal rats. Regarding tyrosine kinase A receptor (TrkA) expression, the main receptor for NGF signaling, both atria showed the largest expression in old rats; while in LV and RV, TrkA was expressed mainly in young rats. These results point to a contribution of nerve growth factors to the change of autonomic tone observed in elderly patients.