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Introduction: Cardiac resynchronization therapy combined with an implantable cardioverter defibrillator (CRT-D) is widely applied in heart failure patients. Sufficient data on arrhythmia and defibrillator therapies during long-term follow-up of more than 4 years are lacking and data on mortality are conflicting. We aimed to characterize the occurrence of ventricular arrhythmia, respective defibrillator therapies and mortality for several years following CRT-D implantation or upgrade., Material and Methods: Eighty-eight patients with ischemic (ICM) or non-ischemic dilated cardiomyopathy (DCM) and at least one CRT-D replacement were included in this study and analyzed for incidence of non-sustained ventricular tachycardia (NSVT), defibrillator shocks, anti-tachycardia pacing (ATP) and mortality., Results: ICM was the underlying disease in 59%, DCM in 41% of patients. During a mean follow-up of 76.4 ±24.8 months the incidence of appropriate defibrillator therapies (shock or ATP) was 46.6% and was elevated in ICM compared to DCM patients (57.7% vs. 30.6%, respectively; p = 0.017). Kaplan-Meier analysis revealed significantly higher ICD therapy-free survival rates in DCM patients ( p = 0.031). Left ventricular ejection fraction, NSVT per year and ICM (vs. DCM) were independent predictors of device intervention. The ICM patients showed increased mortality compared to DCM patients, with cumulative all-cause mortality at 9 years of follow-up of 45.4% and 10.6%, respectively. Chronic renal failure, peripheral artery disease and chronic obstructive pulmonary disease were independent predictors of mortality., Conclusions: The clinical course of patients with ICM and DCM treated with CRT-D differs significantly during long-term follow-up, with increased mortality and incidence of ICD therapies in ICM patients., Competing Interests: The authors declare no conflict of interest.

Background: Clinical and experimental data give evidence that transplantation of stem and progenitor cells in myocardial infarction could be beneficial, although the underlying mechanism has remained elusive. Ventricular tachyarrhythmia is the most frequent and potentially lethal complication of myocardial infarction, but the impact of mono nuclear cells on the incidence of ventricular arrhythmia is still not clear., Objective: We aimed to characterize the influence of splenic mononuclear cell populations on ventricular arrhythmia after myocardial infarction., Methods: We assessed electrical vulnerability in vivo in mice with left ventricular cryoinfarction 14 days after injury and intramyocardial injection of specific subpopulations of mononuclear cells (MNCs) (CD11b-positive cells, Sca-1-positive cells, early endothelial progenitor cells (eEPCs)). As positive control group we used embryonic cardiomyocytes (eCMs). Epicardial mapping was performed for analysing conduction velocities in the border zone. Left ventricular function was quantified by echocardiography and left heart catheterization., Results: In vivo pacing protocols induced ventricular tachycardia (VT) in 30% of non-infarcted mice. In contrast, monomorphic or polymorphic VT could be evoked in 94% of infarcted and vehicle-injected mice (p<0.01). Only transplantation of eCMs prevented post-infarction VT and improved conduction velocities in the border zone in accordance to increased expression of connexin 43. Cryoinfarction resulted in a broad aggravation of left ventricular function. All transplanted cell types augmented left ventricular function to a similar extent., Conclusions: Transplantation of different MNC populations after myocardial infarction improves left ventricular function similar to effects of eCMs. Prevention of inducible ventricular arrhythmia is only seen after transplantation of eCMs., Competing Interests: The authors have declared that no competing interests exist.

To determine the pre-procedural value of different fibrotic biomarkers and comprehensive cardiac magnetic resonance (CMR) for the prediction of poor response to ablation therapy in patients with atrial fibrillation (AF). Left atrial (LA) late gadolinium enhancement (LGE) and native LA T1 relaxation times were assessed using CMR. Plasma levels of relaxin, myeloperoxidase and serum levels of matrix metalloproteinase (MMP)-mediated cardiac specific titin fragmentation and MMP-mediated type IV collagen degradation were obtained. Poor outcome was defined by the recurrence of AF during 1-year follow-up. 61 patients were included in final analysis. Twenty (32.8%) patients had recurrence of AF. Patients with a recurrence of AF had a higher percentage of LA LGE (26.7 ± 12.5% vs. 17.0 ± 7.7%; P < 0.001), higher LA T1 relaxation times (856.7 ± 112.2 ms vs. 746.8 ± 91.0 ms; P < 0.001) and higher plasma levels of relaxin (0.69 ± 1.34 pg/ml vs. 0.37 ± 0.88 pg/ml; P = 0.035). In the multivariate Cox regression analysis, poor ablation outcome was best predicted by advanced LGE stage (hazard ratio (HR):5.487; P = 0.001) and T1 relaxation times (HR:1.007; P = 0.001). Pre-procedural CMR is a valuable tool for prediction of poor response to catheter ablation therapy in patients with AF. It offers various imaging techniques for outcome prediction and might be valuable for a better patient selection prior to ablation therapy.

Purpose: Congenital atrial septal defect (ASD) is associated with increased morbidity, whereas little is known about the rate of spontaneous closure, associated clinical and echocardiographic parameters, or complications of iatrogenic atrial septal defect (iASD) beyond 1 year of follow-up. Persistent iASD after transseptal puncture for PVI has been described in up to 38% of small cohorts of patients in short-term follow-up after transseptal puncture. We sought to investigate the course of iASD after single transseptal puncture for first pulmonary vein isolation (PVI) with cryoballoon, along with possible risk factors for persistent iASD., Methods: After a first PVI with cryoballoon, 102 patients (64 ± 10 years, 64% male) underwent long-term clinical follow-up and comprehensive transthoracic and transesophageal echocardiographic study., Results: Prevalence of iASD after PVI was 37% after 2.9 (1.6-4.9) years. No clinical complications or deterioration of echocardiographic parameters were associated with iASD. Lower left atrial appendage flow velocity was associated with higher risk of persistence of iASD (3.5% for every 1 cm/s decrease, p = 0.002)., Conclusions: Despite a high rate of iASD after cryoballoon PVI in long-term follow-up, this was not associated with increased clinical complications. Lower LAA velocity was associated with higher risk of persistent iASD. Repeated routine echocardiographic follow-up may not be necessary in these patients.

Background: Pulmonary vein isolation (PVI) has become a widely accepted therapy in patients suffering from symptomatic atrial fibrillation (AF)., Hypothesis: AF-free survival differs in patients with left common pulmonary vein (LCPV) after PVI with second-generation cryoballoon., Methods: We included patients scheduled for first PVI for paroxysmal or persistent AF. Symptomatic and/or documented arrhythmia episodes (>30 seconds) were defined as AF recurrence, excluding a 3-month blanking period., Results: We observed a LCPV in 37 of 270 consecutive patients (13.7%). Analyses were performed in a 1:1 propensity score matched cohort of 68 patients. During a median follow-up of 77.0 weeks, 37 patients (54.4%) had recurrent AF. The prevalence of LCPV was numerically higher in patients with AF recurrence (62.2% vs 35.5%, P  =  0.051) and Kaplan-Meier analysis showed lower AF-free survival in patients with existence of a LCPV (P  =  0.028). At 1-year follow-up, 70.6% of patients without versus 55.1% of patients with LCPV were free of AF. Multivariate Cox regression analysis revealed presence of a LCPV (hazard ratio [HR]: 2.996), chronic heart failure (HR: 3.423), and mitral regurgitation > I° (HR: 2.571) as predictors of AF recurrence., Conclusion: Patients with LCPV had significantly reduced AF-free survival after ablation with the second-generation cryoballoon, despite similar acutely successful PVIs., (© 2017 Wiley Periodicals, Inc.)

Background: The peptide hormone relaxin-2 (RLX) exerts beneficial effects during myocardial ischemia, but functional data on lower-dose RLX in myocardial infarction (MI) is lacking. Therefore, we investigated the impact of 75μg/kg/d RLX treatment on electrical vulnerability and left ventricular function in a mouse model of MI., Methods and Results: Standardized cryoinfarction of the left anterior ventricular wall was performed in mice. A two week treatment period with vehicle or RLX via subcutaneously implanted osmotic minipumps was started immediately after MI. The relaxin receptor RXFP1 was expressed on ventricular/atrial cardiomyocytes, myofibroblasts, macrophages and endothelial but not vascular smooth muscle cells of small coronary vessels. RLX treatment resulted in a significant reduction of ventricular tachycardia inducibility (vehicle: 91%, RLX: 18%, p<0.0001) and increased epicardial conduction velocity in the left ventricle and borderzone. Furthermore, left ventricular function following MI was improved in RLX treated mice (left ventricular ejection fraction; vehicle: 41.1±1.9%, RLX: 50.5±3.5%, p=0.04). Interestingly, scar formation was attenuated by RLX with decreased transcript expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were upregulated in hearts of vehicle treated animals compared to mice without MI. Application of RLX attenuated this inflammatory response. In addition, macrophage infiltration was reduced in the borderzone of RLX treated mice., Conclusion: Treatment with lower-dose RLX in mice prevents post-infarction ventricular tachycardia due to attenuation of scar formation and cardiac inflammation. Therefore, RLX could be evaluated as new therapeutic option in the treatment of MI., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: During aging a mosaic of normal cells and cells with mitochondrial deficiency develops in various tissues including the heart. Whether this contributes to higher susceptibility for arrhythmia following myocardial infarction (MI) is unknown., Methods and Results: Myocardial cryoinfarction was performed in 12-month-old transgenic mice with accelerated accumulation of deletions in mitochondrial DNA. Occurrence and pathogenesis of arrhythmia was investigated after two weeks. Holter-ECG recordings revealed higher rates of premature ventricular complexes (incidence > 10/24 h: 100% vs. 20%; p = 0.048) and more severe spontaneous arrhythmia during stress test in mutant mice with MI as compared to control mice with MI. Mice with mitochondrial dysfunction exhibited longer spontaneous AV-blocks (467 ± 26 ms vs. 377 ± 24 ms; p = 0.013), an increased probability for induction of ventricular tachycardia during in vivo electrophysiological investigation (22% vs. 9%; p = 0.044), and a reduced conduction velocity in the infarct borderzone (38.5 ± 0.5 cm/s vs. 55.3 ± 0.9 cm/s; p = 0.001). Furthermore, mutant mice exhibited a significant reduction of the phospho-Cx43/Cx43 ratio in right (0.59 ± 0.04 vs. 0.85 ± 0.01; p = 0.027) and left ventricular myocardium (0.72 ± 0.01 vs. 0.86 ± 0.02; p = 0.023)., Conclusions: Aging-related cardiac mosaic respiratory chain dysfunction facilitates the occurrence of spontaneous and inducible cardiac arrhythmia after myocardial infarction and is associated with slowing of electrical impulse propagation in the infarct borderzone., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Generalized tonic-clonic seizures (GTCS) frequently lead to emergency inpatient referrals. Laboratory blood values are routinely performed on admission to detect underlying causes and metabolic or cardiac complications. Our goal was to assess the nature and frequency of complications occurring in association with GTCS., Methods: We retrospectively extracted data from emergency protocols and discharge letters of adult patients admitted to the Department of Epileptology between 01/2010 and 06/2015. Inclusion criteria were diagnosis of GTCS and admission via emergency services. Exclusion criteria were status epilepticus prior to admission to hospital and non-generalized seizures., Results: A total of 223 patients (of 986 screened cases) were included. Overall, 1.8% required intubation while 1.3% had less severe respiratory problems. In 5.6% of patients, a transient hypoxemia was measured. Hypertensive urgencies affected 7.8% of the patients, sinus tachycardia occurred in 41.2%. Troponin I (cTNI) was determined in 75 patients and was increased in 12% of these cases. Occurrence of elevated cTNI levels was significantly correlated with patient's age. Four patients were diagnosed with NSTEMI and one patient with STEMI. Creatine kinase (CK) was increased in 59.4% of the patients, with <5-fold increases in 47%, <10-fold in 5.8% and >10-fold increases in 4.3%. Rhabdomyolysis with an >50 fold increase in CK was detected in 1.9% of patients. Prolonged disturbances of consciousness affected 5% of cases while agitation, delirium, and psychotic episodes occurred in 6.3%. Minor traumatic injuries affected 45.7% of patients., Conclusions: Troponin elevations in association with GTCS are one of the more common complications after emergency admissions especially in older patients. In our selected patient population, serious complications such as intracranial hemorrhage, myocardial infarction and acute renal failure occurred in <1% of GTCS only.

Background: The wearable cardioverter defibrillator (WCD) has emerged as a valuable tool to protect patients with increased risk of sudden cardiac death (SCD). We sought to characterize WCD patients and to analyze predictors of ventricular arrhythmia (VA) occurrence and WCD shock delivery., Methods and Results: One hundred fourteen patients with WCD use were included in the study. Indications were mainly ischemic cardiomyopathy (ICM; 31.6%), non-ICM (45.6%) and explantation of implantable cardioverter defibrillator due to device infection (11.4%). We observed sustained VA in 9.6% of the study population and 6.1% received an appropriate shock. VA occurred in 16.7% of ICM, 3.8% of non-ICM and 15.4% of patients with device infection., Conclusions: Our data demonstrate a very high rate of sustained VA in patients at risk for SCD during WCD use. ICM patients, including those with recent MI, bore the highest risk., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI)., Methods: Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 μg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps., Results: RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1β were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups., Conclusion: Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy characterized by an acute reduction in left ventricular ejection fraction (LVEF). Sudden deaths during the course of PPCM are reported to be elevated, the underlying mechanisms remains unknown. The aim of the present multi-centre study was to evaluate the arrhythmia burden in a multi-centre approach in patients with PPCM using a wearable cardioverter/defibrillator (WCD)., Methods and Results: Forty-nine patients from 16 German centres with newly diagnosed PPCM and LVEF ≤35% receiving a WCD were included in this retrospective analysis. Mean follow-up was 15 ± 10 months. At diagnosis, mean age was 33 ± 5 years, parity was 2.1 ± 1.6, LVEF was 21 ± 7%, NYHA functional class was 3.4 ± 0.7. Mean wear time was 120 ± 106 days, mean wear time per day was 21.4 ± 3.3 h. Six (12%) patients presented eight ventricular tachyarrhythmias during WCD period: five episodes of VF, two sustained ventricular tachycardia (VT) and one non-sustained VT occurred., Conclusion: This multicentre study underpins the elevated risk for ventricular tachyarrhythmias in patients with newly diagnosed PPCM and reduced LVEF. A WCD should be considered for 3-6 months in these patients to prevent sudden cardiac death from ventricular tachyarrhythmias.

Background: Visually guided laserballoon (LB) ablation has recently been introduced for pulmonary vein (PV) isolation (PVI). We analyzed efficacy and safety results of the newly introduced LB ablation technique in patients with persistent and longstanding persistent atrial fibrillation (AF), and compared this with an established standard method using the cryoballoon (CB)., Methods: A total of 35 patients with symptomatic persistent AF underwent LB ablation and were followed-up for 1 year. Results were compared to 35 patients who underwent CB ablation at the same institution and case matched for age, sex, CHA 2 DS 2 -VASc score, and left atrial volume., Results: Complete isolation of all PVs was achieved in 68.6% in the LB and 97.1% in the CB group (P < 0.01). No significant differences were found for AF-free survival after 12 months in the complete cohort of all patients (LB: 53.3% vs CB: 70.4%; P = n.s.) and after excluding patients without complete PVI (LB: 57.8% vs CB: 72.5%; P = n.s.). LB ablation resulted in longer procedure (158.5 ± 37.9 minutes vs 110.9 ± 26.5 minutes; P < 0.01) and fluoroscopy durations (28.4 ± 11.1 minutes vs 23.5 ± 9.4 minutes; P = 0.04.), and a trend toward more major complications (14.3% vs 2.9%; P = n.s.). Procedure durations and complications declined over time and were level with CB-treated patients when reaching the last quartile of the LB patients., Conclusion: PVI in patients with persistent AF using the LB or the CB resulted in comparable success rates. Initial prolongations in procedure and safety parameters as a result of a learning curve effect for the LB have to be considered before starting to use this technique., (© 2016 Wiley Periodicals, Inc.)

Background and Aims: Serelaxin (SLX) is a recombinant form of human relaxin-2, a naturally occurring peptide that regulates maternal cardiovascular adaptations to pregnancy. It is unclear whether SLX has a therapeutic effect on atherosclerosis. Therefore, we investigated direct vascular effects of SLX in a mouse model of atherosclerosis., Methods: 6-8 week-old female apolipoprotein E-deficient mice were fed a high-fat, cholesterol-rich diet for 6 weeks and additionally received a continuous treatment with vehicle or SLX (0.05 or 0.1 μg/h), during the last 4 weeks, via subcutaneously implanted osmotic mini-pumps. Vascular oxidative stress, vasorelaxation and atherosclerotic plaque development were assessed., Results: Vascular oxidative stress was reduced in SLX-treated mice (vehicle: 322.67 RLU/s, SLX 0.05 μg/h: 119.76 RLU/s (p < 0.001 vs. vehicle), SLX 0.1 μg/h: 109.33 RLU/s (p < 0.001 vs. vehicle; p = 0.967 vs. 0.05 μg/h SLX)). Further SLX improved endothelium-dependent vasodilatation without influencing endothelium-independent vasorelaxation. Atherosclerotic plaque development was significantly reduced by SLX (vehicle: 0.38 ± 0.02 mm(2), 0.05 μg/h SLX: 0.32 ± 0.02 mm(2) (p = 0.047 vs. vehicle), 0.1 μg/h SLX: 0.29 ± 0.02 mm(2) (p = 0.002 vs. vehicle; p = 0.490 vs. 0.05 μg/h SLX)). Neither vascular macrophage, T-cell or neutrophil infiltration, nor collagen/vascular smooth muscle cell content differed between the groups. We observed a significant down-regulation of the angiotensin II type 1a receptor and a decrease in IL-6 and an increase in IL-10 plasma concentrations., Conclusions: Our data demonstrates novel pleiotropic effects of SLX on vascular oxidative stress, endothelial dysfunction and atherosclerotic plaque burden. Therefore, SLX could serve as a new drug for the treatment of atherosclerosis-related diseases., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Myeloperoxidase (MPO), expressed mainly in neutrophils, is an enzyme linked to inflammation and oxidative stress. MPO is an independent prognostic marker in healthy individuals as well as in patients with coronary artery disease. In this present study we analyze the role of MPO in experimental atherogenesis and neointima formation after vascular injury in mice., Methods and Results: 6-8 weeks old apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-cholesterol diet for 8 weeks with concomitant treatment with two different doses (10 μg/mg bw vs. 20 μg/mg bw) of 4-ABAH (MPO inhibitor). Application at lower dosage did not affect oxidative stress, endothelial function and atherosclerotic plaque development. 4-ABAH in higher dosage decreased inflammatory markers and vascular oxidative stress, consecutively improved endothelial function and reduced significantly atherosclerotic plaque development. To assess the role of circulating intracellular MPO, irradiated ApoE(-/-) mice were repopulated with bone marrow-derived cells from MPO(-/-) mice and were fed a high-cholesterol diet for 8 weeks. This MPO deficiency resulted in alleviated inflammation, reduced oxidative stress and improved endothelial function with a significant impact on plaque formation. To understand the possible role of MPO in vascular remodeling, we tested its effects on neointima formation following vascular injury in mice. MPO inhibition by 4-ABAH reduced significantly neointima formation. It was significantly reduced in MPO deficient mice, whereas transfer of spleen-derived neutrophils from WT mice enhanced it., Conclusion: Our data suggests a central role of MPO in the pathogenesis of atherogenesis and prefers pharmacological MPO inhibition as a therapeutic strategy for prevention and therapy of atherosclerosis and restenosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The effectiveness of the wearable cardioverter defibrillator (WCD) therapy in early post-myocardial infarction (MI) patients remains uncertain., Methods: We analyzed the characteristics and outcomes of patients who received a WCD in the early post-MI phase., Results: Twenty-four patients were followed-up for 8 months (range, 4-16 months). Two patients (8.3%) received appropriate shocks. Left ventricular ejection fraction improved after the WCD therapy (P<0.01). Fourteen patients (58%) received an implantable cardioverter defibrillator at the end of the follow-up period., Conclusion: Early post-MI patients at high risk of sudden cardiac death may benefit from WCD therapy.

Introduction: Right phrenic nerve palsy (PNP) is a typical complication of cryoballoon ablation of the right-sided pulmonary veins (PVs). Phrenic nerve function can be monitored by palpating the abdomen during phrenic nerve pacing from the superior vena cava (SVC pacing) or by fluoroscopy of spontaneous breathing. We sought to compare the sensitivity of these 2 techniques during cryoballoon ablation for detection of PNP., Methods and Results: A total of 133 patients undergoing cryoballoon ablation were monitored with both SVC pacing and fluoroscopy of spontaneous breathing during ablation of the right superior PV. PNP occurred in 27/133 patients (20.0%). Most patients (89%) had spontaneous recovery of phrenic nerve function at the end of the procedure or on the following day. Three patients were discharged with persistent PNP. All PNP were detected first by fluoroscopic observation of diaphragm movement during spontaneous breathing, while diaphragm could still be stimulated by SVC pacing. In patients with no recovery until discharge, PNP occurred at a significantly earlier time (86 ± 34 seconds vs. 296 ± 159 seconds, P < 0.001). No recovery occurred in 2/4 patients who were ablated with a 23 mm cryoballoon as opposed to 1/23 patients with a 28 mm cryoballoon (P = 0.049)., Conclusion: Fluoroscopic assessment of diaphragm movement during spontaneous breathing is more sensitive for detection PNP as compared to SVC pacing. PNP as assessed by fluoroscopy is frequent (20.0%) and carries a high rate of recovery (89%) until discharge. Early onset of PNP and use of 23 mm cryoballoon are associated with PNP persisting beyond hospital discharge., (© 2014 Wiley Periodicals, Inc.)

Background: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF., Methods and Results: C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF., Conclusions: The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.

Purpose: Identification of reliable risk factors for recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI) has important implications. Left atrial (LA) pressure is a largely observator-independent parameter that can easily be determined after transseptal puncture. The purpose of this study was to investigate the predictive value of LA pressure for AF recurrence after PVI., Methods: Two hundred five consecutive patients with paroxysmal or persistent AF scheduled for first PVI were included. Baseline clinical data were collected. During PVI, LA pressure was determined invasively after transseptal puncture. PVI was performed with radiofrequency or cryoenergy, and patients were followed for 25 ± 7 months., Results: One hundred five (51 %) patients had AF recurrence. Patients with persistent AF prior to ablation had significantly more recurrences than patients with paroxysmal AF (70.1 vs. 42.0 %, p < 0.001). Mean LA pressure was significantly higher in patients with recurrence of AF (13.4 ± 7.1 vs. 11.0 ± 5.2 mmHg, p = 0.007), as was mean LA volume index (40.1 ± 18.5 vs. 33.0 ± 11.2 mL/m(2), p < 0.001). In the multivariate analysis, mean LA pressure was predictive in patients with normal or mildly enlarged LA, while AF type was not predictive. For each 1-mmHg increase in LA pressure, the risk of AF recurrence increased by 11 % in this subgroup. In patients with moderately or severely enlarged LA, AF type was predictive whereas LA pressure was not., Conclusion: LA pressure, AF type, and LA volume index are independent predictors for recurrence of AF after PVI. LA pressure may be helpful especially in patients with small atria, where AF type is not predictive.

Rationale: The gap junctional protein connexin (Cx) 45 is strongly expressed in the early embryonic myocardium. In the adult hearts of mice and humans, the expression mainly is restricted to the cardiac conduction system. Cx45 plays an essential role for development and function of the embryonic heart because general and cardiomyocyte-directed deficiencies of Cx45 in mice lead to embryonic lethality attributable to morphological and functional cardiovascular defects. The function of Cx45 in the adult mouse has not yet been cleared., Objective: To clarify the function of Cx45 in the adult mouse heart., Methods and Results: To circumvent the embryonic lethality resulting from Cx45 deficiency, mice were generated in which deletion of Cx45 specifically was induced in cardiomyocytes of adult mice. These Cx45-deficient mice were viable but showed a decrease in atrioventricular nodal conductivity. In addition, the Cx30.2 protein that is coexpressed with Cx45 in the cardiac conduction system was posttranscriptionally reduced by 70% in mutant hearts. Furthermore, deletion of both Cx45 and Cx30.2 resulted in viable mice that, however, showed stronger impairment of atrioventricular nodal conduction than the single Cx45-deficient mice., Conclusions: Cx45 is required for optimal impulse propagation in the atrioventricular node and stabilizes the level of the coexpressed Cx30.2 protein in the adult mouse heart. In contrast to the embryo, Cx45 is not essential for the viability of adult mice.

Transcatheter ablation of the pulmonary veins (PVs) has been established as a therapeutic option for patients with symptomatic atrial fibrillation. Cryothermal energy is an alternative energy source that has been developed to overcome some of the disadvantages of radiofrequency ablation. The major complication of the cryoballoon technique seems to be right-sided phrenic nerve injury (PNI) following ablation of the right superior PV. This case report describes a left-sided PNI after cryoballoon ablation of the left superior PV., (©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.)

Introduction: Cardiogenic shock (CS) remains the leading cause of death in patients hospitalized for myocardial infarction (MI). Systemic inflammation with inappropriate vasodilatation is observed in many patients with CS and may contribute to an excess mortality rate. The purpose of this study was to determine the predictive role of serial measurements of Nt-proBNP, interleukin-6 (IL-6), and procalcitonin (PCT) for 30-day mortality in patients with CS due to MI., Methods: The present study is a prospective single-center study including 87 patients with MI complicated by CS treated with acute revascularization and intraaortic balloon counterpulsation (IABP) support. Predictive values of plasma levels at admission (T0), after 24 hours (T1), and after 72 hours (T2) were examined according to 30-day mortality., Results: Significant differences between survivors (n = 59) and nonsurvivors (n = 28) were seen for Nt-proBNP at T0, for IL-6 at T0 and T1, and for PCT at T1 and T2. According to ROC analyses, the highest accuracy predicting 30-day mortality was seen at T0 for IL-6, at T1 for PCT, and at T2 for PCT. In univariate analysis, significant values were found for Nt-proBNP at T1, and for IL-6 and PCT at all points in time. Within the multivariate analysis, age, creatinine, and IL-6 were significant determinants of 30-day mortality, in which IL-6 showed the highest level of significance., Conclusions: In patients with MI complicated by CS, IL-6 represented a reliable independent early prognostic marker of 30-day mortality. PCT revealed a significant value at later points in time, whereas Nt-proBNP seemed to be of lower relevance.

Heat shock proteins (HSPs) are among the most highly conserved and immunogenic proteins shared by microbial agents and mammals. Human (h) HSP60 is upregulated under stress conditions and serves as a target for cross-reactive cytotoxic HSP-serum-antibodies. The present study evaluates the expressions of hHSP60 and its homologue chlamydial (c) HSP60 in advanced human coronary lesions and correlates intimal tissue-bound HSP expressions with circulating HSP-antibodies. Coronary atherectomy specimens retrieved from 100 primary target lesions of patients with unstable angina (UA; n = 40) or stable angina (SA; n = 60) were assessed immunohistochemically for the presence of hHSP60 and cHSP60. In a subgroup (n = 40), blood samples were tested for anti-Chl. pn.-IgG/IgA-titers and anti-HSP65-antibody titers. Coronary plaques revealed immunoreactive hHSP60 in 55% and cHSP60 in 45% of the lesions. Expression of both HSP homologues was significantly (each p < 0.001) higher in UA lesions compared with SA lesions (7.4 vs. 1.2% and 6.0 vs. 1.1%). HSP homologues showed positive correlations both in UA- and SA-lesions (r = 0.41, 0.33; p < 0.05). cHSP60 showed no association with anti-Chl. pn.-IgG/IgA-titers, whereas expressions of both homologues correlated positive with anti-HSP65-Ab titers (r = 0.42, p < 0.05; r = 0.50, p < 0.01). Intimal amounts of HSP60 homologues were associated with increased expressions of C-reactive protein, Toll-like receptor-4 and tissue factor. Human and chlamydial HSP60 colocalize within coronary atheroma, most prevalent in lesions associated with UA. Our data demonstrate a significant correlation between the intimal expressions of HSP60 homologues and serum HSP65 antibodies, thereby suggesting that humoral immune reactions may play an important role in coronary atherosclerosis and plaque instability.

Background: Increasing evidence supports a link between serological evidence of pathogen burden (PB) and the risk for future cardiovascular events. Our study evaluates the intimal presence of 4 pathogens in atheroma, clinically associated with acute coronary syndromes (ACS) and stable angina (SA), and the effect on the expression of intimal C-reactive protein (CRP), tissue factor (TF) and human heat-shock protein 60 (hHSP60)., Methods: Coronary atherectomy specimens retrieved from 60 primary lesions of patients with ACS (n=35) or SA (n=25) were assessed immunohistochemically for the presence of Chlamydia pneumoniae (Cpn), Helicobacter pylori (HP), Cytomegalovirus (CMV) and Epstein–Barr Virus (EBV) and for the expression of CRP, TF, and hHSP60., Results: Analysis revealed eight lesions without, 22 lesions with one, 19 lesions with two, seven lesions with three, and four lesions with four pathogens. Cpn was present in 73%, HP in 31%, CMV in 16%, and EBV in 40%. Mean value of PB in ACS-lesions was significantly increased. Expressions of CRP, TF, and hHSP60 were significantly higher in ACS lesions. The number of infectious pathogens correlated significant with the expressions of CRP, TF, and hHSP60., Conclusions: Our data demonstrate the impact of PB in plaque instability and suggest local proinflammatory, prothrombotic, and proimmunogenic effects., (© 2010 Elsevier Inc. All rights reserved.)

Observational clinical and ex vivo studies have established a strong association between atrial fibrillation and inflammation. However, whether inflammation is the cause or the consequence of atrial fibrillation and which specific inflammatory mediators may increase the atria's susceptibility to fibrillation remain elusive. Here we provide experimental and clinical evidence for the mechanistic involvement of myeloperoxidase (MPO), a heme enzyme abundantly expressed by neutrophils, in the pathophysiology of atrial fibrillation. MPO-deficient mice pretreated with angiotensin II (AngII) to provoke leukocyte activation showed lower atrial tissue abundance of the MPO product 3-chlorotyrosine, reduced activity of matrix metalloproteinases and blunted atrial fibrosis as compared to wild-type mice. Upon right atrial electrophysiological stimulation, MPO-deficient mice were protected from atrial fibrillation, which was reversed when MPO was restored. Humans with atrial fibrillation had higher plasma concentrations of MPO and a larger MPO burden in right atrial tissue as compared to individuals devoid of atrial fibrillation. In the atria, MPO colocalized with markedly increased formation of 3-chlorotyrosine. Our data demonstrate that MPO is a crucial prerequisite for structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation.

Background: Serum C-reactive protein (CRP) is a strong risk predictor of cardiovascular events, and tissue factor (TF) plays a central role in thrombus formation of advanced atherosclerotic plaques. Aim of the present study was to quantify in situ CRP and TF in coronary atherectomy specimens associated with acute coronary syndromes (ACS) or stable angina (SA). In addition, the effect of statin treatment on both intimal determinants was analyzed., Methods and Results: Serial sections from atherectomy probes retrieved from coronary primary target lesions of 42 ACS and 70 SA patients were examined for CRP and TF expression using immunostaining. CRP and TF intimal expression was consistently higher in ACS lesions and a positive correlation between both determinants was detected. In both subgroups intimal staining intensity of CRP but not TF was strongly associated with serum CRP levels. Using angioscopy, complex plaques revealed a higher intimal CRP and TF expression than white/yellow plaques. Both CRP and TF were consistently lower expressed in target lesions of patients with pre-existing statin treatment., Conclusions: CRP and TF expression is markedly increased in plaques derived from patients with ACS as compared to SA patients. Statin treatment appears to reduce vascular expression of CRP and TF.