[Catheter ablation of cardiac arrhythmias : Forms of energy and biophysical principles]. / Katheterablation von Herzrhythmusstörungen : Energieformen und biophysikalische Grundlagen.

Catheter ablation of cardiac arrhythmias has evolved over the years and has become a cornerstone in the modern treatment of various supraventricular and ventricular arrhythmias. The goal of ablation is to permanently damage myocardium that is critically involved in the individual arrhythmia mechanism. Different catheters and forms of energy are available. Radiofrequency (RF) ablation is most common. Application of an alternating current at the catheter tip induces heating of tissue and, thus, leads to ablation of a targeted arrhythmogenic substrate. High temperatures (>70 °C at the catheter tip and >95 °C within the tissue) bear the risk of coagulum formation and steam pops and should be avoided, which limits power application. The evolution of irrigated RF ablation catheters enables the transfer of more power to the tissue and thereby increases the dimensions of the lesions. Cryoablation represents a valuable alternative. Cooling of tissue to -80 °C causes the intra- and extracellular formation of ice crystals, finally resulting in a dense circumscribed scar. The cryomapping procedure grants improved surveillance of the safety of ablation. Cryoenergy is very popular for pulmonary vein isolation (PVI) using the cryoballoon. In addition to the laser balloon that is established for PVI, ultrasound, microwaves, and stereotactic irradiation complete the arsenal.

Treatment with mononuclear cell populations improves post-infarction cardiac function but does not reduce arrhythmia susceptibility.

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.

Severe abnormal Heart Rate Turbulence Onset is associated with deterioration of liver cirrhosis.

BACKGROUND: In patients with liver cirrhosis, cardiac dysfunction is frequent and is associated with increased morbidity and mortality. Cardiac dysfunction in cirrhosis seems to be linked to autonomic dysfunction. This study investigates the role of autonomic dysfunction assessed by Heart Rate Turbulence (HRT) analyses in patients with liver cirrhosis. METHODS AND PATIENTS: Inclusion criteria was (1) diagnosis of cirrhosis by clinical, imaging or biopsy and (2) evaluation by standard 12-lead-ECG and 24h holter monitoring and (3) at least 3 premature ventricular contractions. The exclusion criterion was presence of cardiac diseases, independent of liver cirrhosis. Biochemical parameters were analysed using standard methods. HRT was assessed using Turbulence onset (TO) and slope (TS). The endpoint was deterioration of liver cirrhosis defined as increased MELD and readmission for complications of liver cirrhosis. RESULTS: Out of 122 cirrhotic patients, 82 patients (63% male) with median Child score of 6 (range 5-12) and median MELD score of 10 (range 6-32) were included. Increasing Child score, INR and decreasing albumin were correlated with TO. In addition, decompensated patients with ascites showed more abnormal TO and TS. During the observation period, patients with more abnormal TO showed significantly higher rate of rising MELD Score at 6 months (p = 0.03). Nevertheless, at least in our collective HRT-parameters were not independent predictors of deterioration of cirrhosis. CONCLUSION: Parameters of HRT are closely associated with deterioration of cirrhosis and might be helpful in its prediction.

High rate of persistent iatrogenic atrial septal defect after single transseptal puncture for cryoballoon pulmonary vein isolation.

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.

Optogenetic termination of atrial fibrillation in mice.

Aims: The primary goal in the treatment of symptomatic atrial fibrillation/flutter (AF) is to restore sinus rhythm by cardioversion. Electrical shocks are highly effective, but have to be applied under analgo-sedation and can further harm the heart. In order to develop a novel pain-free and less harmful approach, we explored herein the optogenetic cardioversion by light-induced depolarization. Methods and results: Hearts from mice expressing Channelrhodopsin-2 (ChR2) and the AF-promoting loss-of-function Connexin 40 Ala96Ser mutation were explanted and perfused with low K+ Tyrode's solution and an atrial KATP-channel activator. This new protocol shortened atrial refractoriness as well as slowed atrial conduction and thereby enabled the induction of sustained AF. AF episodes could be terminated by epicardial illumination of the atria with focussed blue light (470 nm, 0.4 mW/mm2) with an efficacy of ∼97% (n = 17 hearts). In > 80% of cases, light directly terminated the AF episode with onset of illumination. Because similar illumination intensity was able to locally inhibit atrial activity, we propose that a light-induced block of electrical activity is responsible for reliable AF termination. The success rate was strongly depending on the illuminated area, applied light intensity and duration of illumination. Importantly, we were also able to demonstrate optogenetic termination of AF in vivo, using epicardial illumination through the open chest (n = 3 hearts). To point towards a translational potential, we systemically injected an adeno-associated virus to express ChR2 in wild type hearts. After 6-8 months, we found robust ChR2 expression in the atria, enabling light-mediated AF termination in six of seven mice tested. Conclusion: We provide the first evidence for optogenetic termination of atrial tachyarrhythmia in intact hearts from transgenic as well as wild type mice ex and in vivo. Thus, this report could lay the foundation for the development of implantable devices for pain-free termination of AF.

Outcome in patients with left common pulmonary vein after cryoablation with second-generation cryoballoon.

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.

Laserballoon and Cryoballoon Pulmonary Vein Isolation in Persistent and Longstanding Persistent Atrial Fibrillation.

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, CHA2 DS2 -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.

Anti-atherosclerotic effects of serelaxin in apolipoprotein E-deficient mice.

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.

Fluoroscopy of spontaneous breathing is more sensitive than phrenic nerve stimulation for detection of right phrenic nerve injury during cryoballoon ablation of atrial fibrillation.

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.

Left atrial pressure as predictor for recurrence of atrial fibrillation after pulmonary vein isolation.

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.

Interleukin-6 is the strongest predictor of 30-day mortality in patients with cardiogenic shock due to myocardial infarction.

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.

Left phrenic nerve injury during cryoballoon ablation of the left superior pulmonary vein.

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.

Atrioesophageal fistula after cryoballoon pulmonary vein isolation.

The risk of atrioesophageal fistula after cryoballoon pulmonary vein isolation is thought to be much lower than after radiofrequency ablation, seeing that no data exist on this complication so far. We report for the first time on the occurrence of an atrioesophageal fistula 4 weeks after cryoballoon ablation at the site of the left inferior pulmonary vein. We suggest that even when using cryothermal ablation technique, an imaging modality to assess the proximity of esophagus and left atrium should be routinely performed to avoid this fatal complication.

Prevalence of asymptomatic upper extremity venous obstruction in 302 patients undergoing first implantation of cardioverter defibrillator.

BACKGROUND: Little is known about the prevalence of upper extremity vein obstruction or anomalies in patients before first implantation of implantable cardioverter defibrillator (ICD). It remains unclear in which patients contrast venography is warranted before implantation procedure. METHODS: Results of clinical data and contrast venography of 302 consecutive patients scheduled for first ICD implantation were analyzed. RESULTS: Prevalence of upper vein obstruction was 6.6% (20/302 patients) in a typical patient population undergoing first ICD implantation. Age, left ventricular ejection fraction, underlying heart disease, prior open-heart surgery, or cardiopulmonary resuscitation were not predictors of obstruction. Patients with previous cardiac pacemaker implantation had a higher rate of obstruction, though this was not statistically significant (20% vs 15.7%, P = 0.54). Persistent left vena cava was found in 0.7%. CONCLUSION: There is no clinical parameter sufficient enough to predict upper extremity venous obstruction. Contrast venography may be considered in patients with previous pacemaker placement but should not be a routine diagnostic tool in unselected patients prior to first ICD-implantation procedure.

Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: a case-control study.

INTRODUCTION: Ablation of pulmonary veins (PV) is an established therapeutic option for patients with symptomatic drug-refractory paroxysmal atrial fibrillation (AF). Radiofrequency (RF) is currently the most widespread energy source for PV ablation. Cryothermal energy applied with a cryoballoon technique as an alternative has recently evolved. METHODS AND RESULTS: In a case-control setting, we compared 20 patients with paroxysmal AF who underwent their first PV ablation with the cryoballoon technique to 20 matched patients with conventional RF ablation. In the case of persistent electrical potentials after cryoballoon ablation, it was combined with ablation with a conventional cryocatheter. All patients performed daily event recording for 3 months after ablation procedure. Ablation parameters and success rate after 3 and 6 months were compared. In the cryoballoon group, the overall success rate was 55% (50% in the cryoballoon only group [14 patients] and 66% in the combination group [6 patients]), as opposed to the RF group with 45%. AF episode burden was lower after cryoballoon ablation. There was no significant difference between cryoballoon and RF ablation regarding procedure parameters. In the cryoballoon group, 3 phrenic nerve palsies occurred using the 23 mm balloon that resolved spontaneously. CONCLUSION: PV ablation with the cryoballoon technique is feasible and seems to have a similar success rate in comparison to RF ablation. Procedure- and fluoroscopy duration are not longer than in conventional RF ablation.

The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans.

Oculodentodigital dysplasia (ODDD) is a dominant negatively inherited disorder with variable but characteristic anomalies of the fingers and toes, eyes, face and teeth, which are caused by mutations in the connexin 43 (Cx43) gene. All mutations analyzed so far have a negative influence on the conductance through gap junctional channels and hemichannels, as well as trafficking of Cx43 protein in transfected cells. In this study, we inserted the human Cx43G138R point mutation into the mouse Cx43 gene and generated mice conditionally expressing this mutation. All ODDD phenotypic manifestations observed in humans, including syndactyly and enamel hypoplasia as well as craniofacial, bone and heart anomalies, were also observed with significant penetrance in Cx43G138R mice. When this mutation was specifically expressed in cardiomyocytes, characteristic alterations in the electrocardiogram and spontaneous arrhythmias were recorded. In vitro studies with Cx43G138R-expressing cells revealed loss of the Cx43 P2 phosphorylation state, which was also absent in the mutated hearts. This loss has previously been associated with gap junctional dysfunction and increased cellular ATP release. The Cx43G138R mutated mice show significantly increased arrhythmogeneity ex vivo in Langendorff experiments with explanted hearts and in vivo in particular under hypoxic conditions. Our results suggest that the increased activity of ATP-releasing channels in Cx43G138R mutated cardiomyocytes may further reduce the already decreased gap junctional communication and thus aggravate arrhythmogenesis in the mouse mutant.