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.

Aging-related mitochondrial dysfunction facilitates the occurrence of serious arrhythmia after myocardial infarction.

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.

Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.

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-1ß 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.

A real world wearable cardioverter defibrillator experience - Very high appropriate shock rate in ischemic cardiomyopathy patients at a European single-center.

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.

AMP-activated protein kinase α1-sensitive activation of AP-1 in cardiomyocytes.

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampkα2 to the Ampkα1 was observed. The present study explored possible isoform specific effects of Ampkα1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampkα1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampkα1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampkα1 increased the phosphorylation of Pkcζ. Constitutively active Ampkα1 further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkcζ silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampkα1 and Pkcζ, but not of Ampkα2. In wild-type mice, angiotensin-II infusion increased cardiac Ampkα1 and cardiac Pkcζ protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampkα1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampkα1 and Pkcζ abundance as well as c-Fos, Il6 and Ncx1 mRNA expression, effects again blunted in Ampkα1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampkα1 increased Pkcζ protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampkα1 promotes myocardial AP-1 activation in a Pkcζ-dependent manner and thus contributes to cardiac stress signaling.

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.

AMP-activated protein kinase α1 regulates cardiac gap junction protein connexin 43 and electrical remodeling following pressure overload.

BACKGROUND/AIMS: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. METHODS: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by "transverse aortic constriction" (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. RESULTS: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1(-/-) mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1(-/-) mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK(WT) and constitutively active AMPK(γR70Q), but not by catalytically inactive AMPK(αK45R). CONCLUSION: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.

Association of Heart Rate Turbulence With Arrhythmia Susceptibility and Heart Disease in Mice.

INTRODUCTION: Recent studies have demonstrated the feasibility of measuring heart rate turbulence (HRT) as a marker of baroreflex function in healthy mice. The aim of this investigation was to measure HRT in a mouse model with induced structural heart defects and to determine if there were threshold values of HRT for inducible ventricular tachycardias (VTs). METHODS AND RESULTS: HRT was measured during electrophysiological investigations 2 weeks after transverse aortic constriction (TAC, n = 13) or myocardial cryoinfarction (MCI, n = 14). Sham-operated mice served as controls (n = 8 for TAC controls and n = 9 for MCI controls). Mice with heart disease lacked an early acceleration (turbulence onset [TO]) in heart rate after extrastimulus pacing (heart disease: 0.39% [0.19%-0.59%] vs. all controls: -0.04% [-0.25-0.19%]; P < 0.01). At a cutoff value of >0.25%, TO could be used to classify mice with induced heart disease with a sensitivity of 64.0% and specificity of 88.2% (P < 0.01) but did not identify mice at higher risk of induced VTs. Animals that were susceptible to VTs (n = 8) had lower values for turbulence slope (TS) compared with noninducible mice (6.2 milliseconds/beat [3.1-9.5 milliseconds/beat] vs. 10.1 milliseconds/beat [7.2-14.2 milliseconds/beat]; P = 0.03). TS <7.8 milliseconds/beat identified mice with inducible VTs with a sensitivity of 75.0% and specificity of 75.8% (P = 0.02). CONCLUSION: Measurement of HRT is feasible in mouse models with induced structural heart disease. More abnormal values for TO were found in the presence of structural heart disease but did not predict susceptibility to VTs. Decreased TS was associated with VTs induced by programmed stimulation.

The toxic effect of R350P mutant desmin in striated muscle of man and mouse.

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.

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.

Induced and spontaneous heart rate turbulence in mice: influence of coupling interval.

AIMS: Heart rate turbulence (HRT) is a prognostic parameter for risk stratification in patients suffering from coronary artery disease. The aims of this study were to demonstrate the feasibility of quantifying HRT in mice, both in long-term electrocardiograms (ECGs) as well as after extrastimulus pacing, and to analyse its characteristics. METHODS AND RESULTS: We performed long-term ECG recordings using implanted telemetric chips and electrophysiological (EP) investigations, using transvenously inserted EP catheters, in healthy mice. Heart rate turbulence was calculated using the established turbulence onset (TO) and slope (TS) algorithm. After spontaneous ventricular premature complexes (VPCs), we found a negative TO (-2.2 ± 7.5%) and positive TS (15.5 ± 18.3 ms/RR interval). Electrophysiological investigations revealed positive values for TO (0.6 ± 1.1%) and TS (6.5 ± 2.9 ms/RR interval) after extrastimulus pacing maneuvers. The shortening of the extrastimuli coupling intervals delivered during EP investigations significantly influenced TO (r = 0.57; P = 0.01): shorter coupling intervals provoked more positive TO values. CONCLUSION: Mice display both spontaneous and induced HRT. In terms of TO, VPCs generated by extrastimulus pacing are significantly dependent on the coupling interval. Determining HRT in mice is feasible and provides insight into basic mechanisms of blood pressure regulation, which is realized by the baroreflex.

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy.

Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calcium-regulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2's role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects.

Optimizing fibrosis detection: a comparison of electroanatomical mapping and late enhancement gadolinium magnetic resonance imaging.

BACKGROUND: Fibrotic atrial cardiomyopathy plays an important role in determining the outcome of ablation in patients with atrial fibrillation (AF). Two main methods are being used for the evaluation of fibrosis: voltage-based high-density (HD) electroanatomical mapping (EAM) and late gadolinium enhancement MRI (LGE-MRI). The comparability between both methods in detecting fibrosis has not been systematically investigated. METHODS: LGE-MRIs of the left atrium (LA) were performed in 21 patients. LA-fibrosis was evaluated using a custom-designed software generating a 3D-model of the LA. HD-electroanatomical maps were recorded in each patient. After processing the maps and the MRI models by excluding the mitral valve, pulmonary veins, and the left atrial appendage, the LGE areas were measured and compared to the low voltage areas (LVA) in the HD maps using three different cutoff values of 0.5 mV, 0.7 mV, and 1.0 mV. RESULTS: The analysis revealed significant differences between EAM and LGE-MRI in assessing LA-fibrosis at 0.5-mV (for anterior and posterior walls) and 1.0-mV cutoffs (for anterior and posterior wall and septum). However, no significant differences were found between EAM and LGE-MRI when using a 0.7-mV cutoff for all the investigated areas. CONCLUSIONS: A voltage cutoff of 0.7 mV provided the best correlation between EAM and LGE MRI for detecting left atrial fibrosis. It supports the idea that a 0.5-mV cutoff may underestimate fibrosis, as areas with local signal voltages between 0.6 and 0.8 mV could also show LGE on MRI. Further research is needed to determine the ideal voltage cutoff for detecting left atrial fibrosis.

The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a major cause of stroke. In the mammalian heart the gap junction proteins connexin40 (Cx40) and connexin43 (Cx43) are strongly expressed in the atrial myocardium mediating effective propagation of electrical impulses. Different heterozygous mutations in the coding region for Cx40 were identified in patients with AF. We have generated transgenic Cx40A96S mice harboring one of these mutations, the loss-of-function Cx40A96S mutation, as a model for atrial fibrillation. Cx40A96S mice were characterized by immunochemical and electrophysiological analyses. Significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation were found after induction in Cx40A96S mice. Analyses of the gating properties of Cx40A96S channels in cultured HeLa cells also revealed significantly lower junctional conductance and enhanced sensitivity voltage gating of Cx40A96S in comparison to Cx40 wild-type gap junctions. This is caused by reduced open probabilities of Cx40A96S gap junction channels, while single channel conductance remained the same. Similar to the corresponding patient, heterozygous Cx40A96S mice revealed normal expression levels and localization of the Cx40 protein. We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient.

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.

Superiority of gold versus platinum irrigated tip catheter ablation of the pulmonary veins and the cavotricuspid isthmus: a randomized study comparing tip temperatures and cooling flow requirements.

INTRODUCTION: In order to optimize power delivery into the myocardium during radiofrequency ablation (RFA) without overheating the electrode tip, active cooling of the tip electrode as well as electrode tips made of gold have evolved. Recently, an externally irrigated gold tip electrode ablation catheter has been developed to combine the advantages of these 2 technologies. We sought to investigate the procedural parameters tip temperature, delivered power and cooling flow requirements of the irrigated gold tip catheter in comparison to the conventional irrigated platinum iridium (Pt) tip catheter in pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. METHODS AND RESULTS: Sixty patients referred for first PVI were randomized into ablation with irrigated gold tip catheter versus irrigated Pt tip catheter. Forty-nine patients received ablation of CTI following PVI. Mean and standard deviation from all measurements were calculated for each patient. During RFA of pulmonary veins, mean catheter tip temperature was significantly lower in the gold group (35.4 ± 0.9 °C vs 38.2 ± 0.8 °C, P < 0.001), and total amount of delivered energy was higher (1303.1 ± 81.1 W vs 1223.7 ± 115.6 W, P = 0.004). During CTI ablation, necessary saline flow was almost 2.5-fold lower in the gold group (22.5 ± 5.9 mL/min vs 52.5 ± 9.7 mL/min, P < 0.001), accompanied by significantly lower tip temperature (39.1 ± 0.6 °C vs 40.5 ± 1.4 °C, P < 0.001). CONCLUSION: The irrigated gold tip electrode allows to deliver significantly more energy at a lower electrode tip temperature in RFA of PV and CTI in comparison to the irrigated Pt tip electrode. The required saline flow during CTI ablation is much lower than in Pt.

Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice.

BACKGROUND: Mutations in the human desmin gene (DES) cause autosomal-dominant and -recessive cardiomyopathies, leading to heart failure, arrhythmias, and AV blocks. We analyzed the effects of vascular pressure overload in a patient-mimicking p.R349P desmin knock-in mouse model that harbors the orthologue of the frequent human DES missense mutation p.R350P. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed on heterozygous (HET) DES-p.R349P mice and wild-type (WT) littermates. Echocardiography demonstrated reduced left ventricular ejection fraction in HET-TAC (WT-sham: 69.5 ± 2.9%, HET-sham: 64.5 ± 4.7%, WT-TAC: 63.5 ± 4.9%, HET-TAC: 55.7 ± 5.4%; p<0.01). Cardiac output was significantly reduced in HET-TAC (WT sham: 13088 ± 2385 µl/min, HET sham: 10391 ± 1349µl/min, WT-TAC: 8097 ± 1903µl/min, HET-TAC: 5793 ± 2517µl/min; p<0.01). Incidence and duration of AV blocks as well as the probability to induce ventricular tachycardias was highest in HET-TAC. We observed reduced mtDNA copy numbers in HET-TAC (WT-sham: 12546 ± 406, HET-sham: 13526 ± 781, WT-TAC: 11155 ± 3315, HET-TAC: 8649 ± 1582; p = 0.025), but no mtDNA deletions. The activity of respiratory chain complexes I and IV showed the greatest reductions in HET-TAC. CONCLUSION: Pressure overload in HET mice aggravated the clinical phenotype of cardiomyopathy and resulted in mitochondrial dysfunction. Preventive avoidance of pressure overload/arterial hypertension in desminopathy patients might represent a crucial therapeutic measure.

In vitro comparison of platinum-iridium and gold tip electrodes: lesion depth in 4 mm, 8 mm, and irrigated-tip radiofrequency ablation catheters.

AIMS: We compared a newly developed irrigated gold tip electrode ablation catheter and a gold tip 4 and 8 mm catheter with the corresponding platinum-iridium (Pt) tip catheters in an in vitro setting. METHODS AND RESULTS: In a flow chamber simulating physiological flow conditions, radiofrequency catheter ablation was performed on tissue samples of porcine endomyocardium and liver. Lesion depth, energy and temperature delivery, and popping frequency were determined. Two hundred and fifty-three ablations were conducted. Four and eight millimetre, gold tip electrode catheters produced significantly deeper lesions compared with the Pt tip electrode (liver 4 mm: 4.67 +/- 1.7 vs. 2.9 +/- 1.0 mm, P < 0.0001; endomyocardium 4 mm: 3.88 +/- 1.1 vs. 2.81 +/- 0.7 mm, P < 0.001; liver 8 mm: 3.98 +/- 1.0 vs. 2.03 +/- 1.1 mm, P < 0.001; endomyocardium 8 mm: 4.00 +/- 0.9 vs. 3.39 +/- 0.8 mm, P < 0.001) and correlated with the amount of energy delivery. Popping frequency was significantly higher in gold tip electrodes. In irrigated tip electrodes, there was no difference in the lesion depth comparing gold with Pt (liver: 5.18 +/- 0.7 vs. 5.01 +/- 0.7 mm, P = ns; endomyocardium: 4.89 +/- 0.7 vs. 4.78 +/- 0.8 mm, P = ns). There was a trend towards less popping in the gold tip electrode. CONCLUSION: Both 4 and 8 mm not-irrigated gold tip catheters produced deeper lesions than the corresponding Pt tip catheter. In irrigated tip catheters, gold and Pt tip material did not show differences in the lesion depth.

Increased mortality and ICD therapies in ischemic versus non-ischemic dilated cardiomyopathy patients with cardiac resynchronization having survived until first device replacement.

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.