Surgical ablation of long-standing persistent atrial fibrillation: 1-year outcomes from the CArdioSurgEry Atrial Fibrillation (CASE-AF) registry.

OBJECTIVES: The CArdioSurgEry Atrial Fibrillation (CASE-AF) registry is a prospective, multicentre study for collecting and analysing real-world data of surgical atrial fibrillation (AF) treatment. This study aimed to evaluate outcomes of surgery for long-standing persistent AF at 1 year. METHODS: In total, 17 centres consecutively include all eligible patients with continuous AF lasting for ≥1 year. Exclusion criteria are missing informed consent or age <18 years. For patient-reported outcomes measures, the European Heart Rhythm Association score was used. No presence of AF (based on ECG findings including Holter ECG and/or implanted devices), no re-ablation, no further cardioversion and no rehospitalization due to AF after a 3-month blanking period defined no AF recurrence at 1 year. RESULTS: From January 2017 to January 2020, a total of 1115 patients were enrolled in CASE-AF. Of them, 202 patients (mean age 69.7 ± 7.8 years, 27.2% female) underwent surgical ablation of long-standing persistent AF (study cohort), mostly accompanied by left atrial appendage closure (n = 180 [89%], resection n = 75 [42%]) and predominantly performed as concomitant (n = 174 [86%]) and left atrial only procedure (n = 144 [71%]). Early mortality (30 days) was 2.0% and morbidity was low. At follow-up (median 14.4 months, interquartile range, 12.7-17.6 months, 100% complete), 106 patients (56%) had no AF recurrence and 93% of them were asymptomatic. AF recurrence was accompanied by AF-related rehospitalization (n = 12, P = 0.003), direct current shock cardioversion (n = 23, P < 0.001), AF ablation (n = 7, P = 0.003) and stroke (n = 3, P = 0.059). Multivariable analysis identified cryoablation, predominantly performed endocardially including additional left atrial (74%) and biatrial (42%) lesions, as a significant factor for freedom from AF recurrence (odds ratio 2.7, 95% confidence interval 1.07-6.79, P = 0.035). CONCLUSIONS: According to CASE-AF, surgical ablation of long-standing persistent AF is most effective when concomitantly performed using endocardial cryoablation. Ongoing follow-up allows further elucidation of efficacious treatment strategies.

Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. METHODS AND RESULTS: We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12 months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12 months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P < 0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12 months (P = 0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P = 0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n = 6, 20%) and 3 years (n = 10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600 pg/mL, or estimated glomerular filtration rate (eGFR) <30 mL/min at baseline. NYHA class and eGFR were independent predictors of mortality. CONCLUSIONS: Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established.

Laser lead extraction in octo- and nonagenarians. A subgroup analysis from the GALLERY registry.

INTRODUCTION: In an aging population with cardiac implantable electronic devices, an increasing number of octo- and even nonagenarians present for lead extraction procedures. Those patients are considered at increased risk for surgical procedures including lead extraction. Here, we investigated safety and efficacy of transvenous lead extraction in a large patient cohort of octo- and nonagenarians. METHODS AND RESULTS: A subgroup analysis of all patients aged ≥80 years (n = 499) in the German Laser Lead Extraction Registry (GALLERY) was performed. Outcomes were compared to the nonoctogenarians from the registry. Primary extraction method was Laser lead extraction, with additional use of mechanical rotational sheaths or femoral snares, if necessary. An analysis of patient- and device characteristics, as well as an assessment of predictors for adverse events via multivariate analyses was conducted. Mean patients age was 84.3 ± 3.7 years in the octogenarians group and 64.1 ± 12.4 years in the nonoctogenarians group. The median lead dwell time was 118.0 months (78; 167) and 92.0 months [60; 133], p < .001 in the octogenarians and nonoctogenarians group, respectively. Clinical procedural success rate was achieved in 97.6% of the cases in octogenarians and 97.9% in nonoctogenarians (p = .70). Overall complication rate was 4.4% in octogenarians and 4.3% in nonoctogenarians (0.91). In octogenarians procedure-related mortality was 0.8% and all-cause in-hospital mortality was 5.4%, while in nonoctogenarians, procedure related and all-cause in-hospital mortality were 0.5% and 3.1%, respectively. A body mass index (BMI) <20 kg/m2 , was the only statistically significant predictor for procedure-related complications in octogenarians, while systemic infection, BMI ≤20 kg/m2 , procedural complications and chronic kidney disease were predictors for in-hospital mortality. CONCLUSIONS: Laser lead extraction in octo- and nonagenarians is safe and effective. BMI ≤20 kg/m2 was the only statistically significant predictor for procedural complications. According to our data, advanced age should not be considered as contraindication for laser lead extraction.

Transvenous lead extraction of implantable cardioverter-defibrillators: A comprehensive outcome-and risk factor analysis.

BACKGROUND: Device complications, such as infection or lead dysfunction necessitating transvenous lead extraction (TLE) are continuously rising amongst patients with transvenous implantable-cardioverter-defibrillator (ICD). OBJECTIVES: Aim of this study was to characterize the procedural outcome and risk-factors of patients with indwelling 1- and 2-chamber ICD undergoing TLE. METHODS: We conducted a subgroup analysis of all ICD patients in the GALLERY (GermAn Laser Lead Extraction RegistrY) database. Predictors for procedural failure and all-cause mortality were assessed. RESULTS: We identified 842 patients with an ICD undergoing TLE with the mean age of 62.8 ± 13.8 years. A total number of 1610 leads were treated with lead dysfunction (48.5%) as leading indication for extraction, followed by device-related infection (45.4%). Lead-per-patient ratio was 1.91 ± 0.88 and 60.0% of patients had dual-coil defibrillator leads. Additional extraction tools, such as mechanical rotating dilator sheaths and snares were utilized in 6.5% of cases. Overall procedural complications occurred in 4.3% with 2.0% major complications and a procedure-related mortality of 0.8%. Clinical success rate was 97.9%. All-cause in-hospital mortality was 3.4%, with sepsis being the leading cause for mortality. Multivariate analysis revealed lead-age ≥10 years (OR:5.82, 95%CI:2.1-16.6; p = .001) as independent predictor for procedural failure. Systemic infection (OR:9.57, 95%CI:2.2-42.4; p < .001) and procedural complications (OR:8.0, 95%CI:2.8-23.3; p < .001) were identified as risk factors for all-cause mortality. CONCLUSIONS: TLE is safe and efficacious in patients with 1- and 2-chamber ICD. Although lead dysfunction is the leading indication for extraction, systemic device-related infection is the main driver of all-cause mortality for ICD patients undergoing TLE.

Safety and Efficacy of Excimer Laser Powered Lead Extractions in Obese Patients: A GALLERY Subgroup Analysis.

BACKGROUND: The incidence of cardiac implantable electronic device (CIED)-related complications, as well as the prevalence of obesity, is rising worldwide. Transvenous laser lead extraction (LLE) has grown into a crucial therapeutic option for patients with CIED-related complications but the impact of obesity on LLE is not well understood. METHODS AND RESULTS: All patients (n = 2524) from the GermAn Laser Lead Extraction RegistrY (GALLERY) were stratified into five groups according to their body mass index (BMI, <18.5; 18.5-24.9; 25-29.9; 30-34.9; ≥35 kg/m2). Patients with a BMI ≥ 35.0 kg/m2 had the highest prevalence of arterial hypertension (84.2%, p < 0.001), chronic kidney disease (36.8%, p = 0.020) and diabetes mellitus (51.1%, p < 0.001). The rates for procedural minor (p = 0.684) and major complications (p = 0.498), as well as procedural success (p = 0.437), procedure-related (p = 0.533) and all-cause mortality (p = 0.333) were not different between groups. In obese patients (BMI ≥ 30 kg/m2), lead age ≥10 years was identified as a predictor of procedural failure (OR: 2.99; 95% CI: 1.06-8.45; p = 0.038). Lead age ≥10 years (OR: 3.25; 95% CI: 1,31-8.10; p = 0.011) and abandoned leads (OR: 3.08; 95% CI: 1.03-9.22; p = 0.044) were predictors of procedural complications, while patient age ≥75 years seemed protective (OR: 0.27; 95% CI: 0.08-0.93; p = 0.039). Systemic infection was the only predictor for all-cause mortality (OR: 17.68; 95% CI: 4.03-77.49; p < 0.001). CONCLUSIONS: LLE in obese patients is as safe and effective as in other weight classes, if performed in experienced high-volume centers. Systemic infection remains the main cause of in-hospital mortality in obese patients.

Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age.

AIMS: The incidence of atrial fibrillation (AF) increases with age. Women have a lower risk. Little is known on the impact of age, sex and clinical variables on action potentials (AP) recorded in right atrial tissue obtained during open heart surgery from patients in sinus rhythm (SR) and in longstanding AF. We here investigated whether age or sex have an impact on the shape of AP recorded in vitro from right atrial tissue. METHODS: We performed multivariable analysis of individual AP data from trabeculae obtained during heart surgery of patients in SR (n = 320) or in longstanding AF (n = 201). AP were recorded by sharp microelectrodes at 37 °C at 1 Hz. Impact of clinical variables were modeled using a multivariable mixed model regression. RESULTS: In SR, AP duration at 90% repolarization (APD90) increased with age. Lower ejection fraction and higher body mass index were associated with smaller action potential amplitude (APA) and maximum upstroke velocity (Vmax). The use of beta-blockers was associated with larger APD90. In tissues from women, resting membrane potential was less negative and APA as well as Vmax were smaller. Besides shorter APD20 in elderly patients, effects of age and sex on atrial AP were lost in AF. CONCLUSION: The higher probability to develop AF at advanced age cannot be explained by a shortening in APD90. Less negative RMP and lower upstroke velocity might contribute to lower incidence of AF in women, which may be of clinical relevance.

Transvenous lead extraction in patients with systemic cardiac device-related infection-Procedural outcome and risk prediction: A GALLERY subgroup analysis.

BACKGROUND: Transvenous lead extraction (TLE) has evolved as one of the most crucial treatment options for patients with cardiac device-related systemic infection (CDRSI). OBJECTIVE: The aim of this study was to characterize the procedural outcome and risk factors of patients with CDRSI undergoing TLE. METHODS: A subgroup analysis of patients with CDRSI of the GALLERY (GermAn Laser Lead Extraction RegistrY) database was performed. Predictors for complications, procedural failure, and all-cause mortality were evaluated. RESULTS: A total of 722 patients (28.6%) in the GALLERY had "systemic infection" as extraction indication. Patients with CDRSI were older (70.1 ± 12.2 years vs 67.3 ± 14.3 years; P < .001) and had more comorbidities than patients with local infections or noninfectious extraction indications. There were no differences in complete procedural success (90.6% vs 91.7%; P = .328) or major complications (2.5% vs 1.9%; P = .416) but increased procedure-related (1.4% vs 0.3%; P = .003) and all-cause in-hospital mortality (11.1% vs 0.6%; P < .001) for patients with CDRSI. Multivariate analyses revealed lead age ≥10 years as a predictor for procedural complications (odds ratio [OR] 3.23; 95% confidence interval [CI] 1.58-6.60; P = .001). Lead age ≥10 years (OR 2.57; 95% CI 1.03-6.46; P = .04) was also a predictor for procedural failure. We identified left ventricular ejection fraction <30% (OR 1.70; 95% CI 1.00-2.99; P = .049), age ≥75 years (OR 2.1; 95% CI 1.27-3.48; P = .004), chronic kidney disease (OR 1.92; 95% CI 1.17-3.14; P = .01), and overall procedural complications (OR 5.15; 95% CI 2.44-10.84; P < .001) as predictors for all-cause mortality. CONCLUSION: Patients with CDRSI undergoing TLE demonstrate an increased rate of all-cause in-hospital, as well as procedure-related mortality, despite having comparable procedural success rates. Given these data, it seems paramount to develop preventive strategies to detect and treat CDRSI in its earliest stages.

Device-related complications in subcutaneous versus transvenous ICD: a secondary analysis of the PRAETORIAN trial.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is developed to overcome lead-related complications and systemic infections, inherent to transvenous ICD (TV-ICD) therapy. The PRAETORIAN trial demonstrated that the S-ICD is non-inferior to the TV-ICD with regard to the combined primary endpoint of inappropriate shocks and complications. This prespecified secondary analysis evaluates all complications in the PRAETORIAN trial. METHODS AND RESULTS: The PRAETORIAN trial is an international, multicentre, randomized trial in which 849 patients with an indication for ICD therapy were randomized to receive an S- ICD (N = 426) or TV-ICD (N = 423) and followed for a median of 49 months. Endpoints were device-related complications, lead-related complications, systemic infections, and the need for invasive interventions. Thirty-six device-related complications occurred in 31 patients in the S-ICD group of which bleedings were the most frequent. In the TV-ICD group, 49 complications occurred in 44 patients of which lead dysfunction was most frequent (HR: 0.69; P = 0.11). In both groups, half of all complications were within 30 days after implantation. Lead-related complications and systemic infections occurred significantly less in the S-ICD group compared with the TV-ICD group (P < 0.001, P = 0.03, respectively). Significantly more complications required invasive interventions in the TV-ICD group compared with the S-ICD group (8.3% vs. 4.3%, HR: 0.59; P = 0.047). CONCLUSION: This secondary analysis shows that lead-related complications and systemic infections are more prevalent in the TV-ICD group compared with the S-ICD group. In addition, complications in the TV-ICD group were more severe as they required significantly more invasive interventions. This data contributes to shared decision-making in clinical practice.

The GermAn Laser Lead Extraction RegistrY: GALLERY.

AIMS: The GermAn Laser Lead Extraction RegistrY: GALLERY is a retrospective, national multicentre registry, investigating the safety and efficacy of laser lead extraction procedures in Germany. METHODS AND RESULTS: Twenty-four German centres that are performing laser lead extraction have participated in the registry. All patients, treated with a laser lead extraction procedure between January 2013 and March 2017, were consecutively enrolled. Safety and efficacy of laser lead extraction were investigated. A total number of 2524 consecutive patients with 6117 leads were included into the registry. 5499 leads with a median lead dwell time of 96 (62-141) months were treated. The mean number of treated leads per patient was 2.18 ± 1.02. The clinical procedural success rate was 97.86% and the complete lead removal was observed in 94.85%. Additional extraction tools were used in 6.65% of cases. The rate of procedural failure was 2.14% with lead age ≥10 years being its only predictor. The overall complication rate was 4.32%, including 2.06% major and 2.26% minor complications. Procedure-related mortality was 0.55%. Female sex and the presence of abandoned leads were predictors for procedure-related complications. The all-cause in-hospital mortality was 3.56% with systemic infection being the strongest predictor, followed by age ≥75 years and chronic kidney disease. CONCLUSION: In the GALLERY, a high success- and low procedure-related complication rates have been demonstrated. In multivariate analysis, female sex and the presence of abandoned leads were predictors for procedure-related complications, while the presence of systemic infection, age ≥75 years, and chronic kidney disease were independent predictors for all-cause mortality.

Wearable cardioverter defibrillator multicentre experience in a large cardiac surgery cohort at transient risk of sudden cardiac death.

OBJECTIVES: The wearable cardioverter defibrillator (WCD) is an established, safe, effective solution, protecting patients at risk of sudden cardiac death. We specifically investigated WCD use in cardiac surgery patients since data for this patient group are rare. METHODS: Retrospective data analysis in 10 German cardiac surgery centres was performed. Cardiac surgery patients with left ventricular ejection fraction (LVEF) ≤35% or after implantable cardioverter defibrillator (ICD) explantation who received WCD between 2010 and 2020 were assessed using LifeVest Network data. RESULTS: A total of 1168 patients with a median age of 66 years [interquartile range (IQR) 57-73] were enrolled; 87% were male. Clinical indications included coronary artery bypass grafting (43%), valve surgery (16%), combined coronary artery bypass graft/valve surgery (15%), ICD explantation (24%) and miscellaneous (2%). The median wear time of WCD was 23.4 h/day (IQR 21.7-23.8). A total of 106 patients (9.1%) exhibited ventricular tachycardia. A total of 93.2% of episodes occurred within the first 3 months. Eighteen patients (1.5%) received 26 adequate shocks. The inadequate shock rate was low (8 patients, 0.7%). LVEF improved from a median of 28% (IQR 22-32%) before WCD prescription to 35% (IQR 28-42%) during follow-up. Excluding ICD explant patients, 37% of patients received an ICD. CONCLUSIONS: The risk of sudden cardiac death is substantial within the first 3 months after cardiac surgery. Patients were protected effectively by WCD. Due to significant LVEF improvement, the majority did not require ICD implantation after WCD use. Compliance was high despite sternotomy. This multicentre experience confirms existing data regarding effectiveness, safety and compliance. Therefore, WCD should be considered in cardiac surgery patients with severely reduced LVEF.

Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial.

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks. METHODS: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population. RESULTS: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05). CONCLUSIONS: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

Muscarinic type-1 receptors contribute to IK,ACh in human atrial cardiomyocytes and are upregulated in patients with chronic atrial fibrillation.

BACKGROUND: Basal and acetylcholine-gated inward-rectifier K+-currents (IK1 and IK,ACh, respectively) are altered in atrial fibrillation (AF). Gi-protein-coupled muscarinic (M) receptors type-2 are considered the predominant receptors activating IK,ACh. Although a role for Gq-coupled non-M2-receptor subtypes has been suggested, the precise regulation of IK,ACh by multiple M-receptor subtypes in the human atrium is unknown. Here, we investigated M1-receptor-mediated IK,ACh regulation and its remodeling in chronic AF (cAF). METHODS AND RESULTS: M1-receptor mRNA and protein abundance were increased in atrial cardiomyocyte fractions and atrial homogenates from cAF patients, whereas M2-receptor levels were unchanged. The regulation of IK,ACh by M1-receptors was investigated in right-atrial cardiomyocytes using two applications of the M-receptor agonist carbachol (CCh, 2µM), with pharmacological interventions during the second application. CCh application produced a rapid current increase (Peak-IK,ACh), which declined to a quasi-steady-state level (Qss-IK,ACh). In sinus rhythm (Ctl) the selective M1-receptor antagonists pirenzepine (10nM) and muscarinic toxin-7 (MT-7, 10nM) significantly inhibited CCh-activated Peak-IK,ACh, whereas in cAF they significantly reduced both Peak- and Qss-IK,ACh, with no effects on basal inward-rectifier currents in either group. Conversely, the selective M1-receptor agonist McN-A-343 (100µM) induced a current similar to the CCh-activated current in Ctl atrial cardiomyocytes pretreated with pertussis toxin to inhibit M2-receptor-mediated Gi-protein signaling, which was abolished by MT-7. Computational modeling indicated that M1- and M2-receptors redundantly activate IK,ACh to abbreviate APD, albeit with predominant effects of M2-receptors. CONCLUSION: Our data suggest that Gq-coupled M1-receptors also regulate human atrial IK,ACh and that their relative contribution to IK,ACh activation is increased in cAF patients. We provide novel insights about the role of non-M2-receptors in human atrial cardiomyocytes, which may have important implications for understanding AF pathophysiology.

Block of Na(+)/Ca(2+) exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation.

The Na(+)/Ca(2+) exchanger (NCX) plays a major role in myocardial Ca(2+) homoeostasis, but is also considered to contribute to the electrical instability and contractile dysfunction in chronic atrial fibrillation (AF). Here we have investigated the effects of the selective NCX blocker SEA0400 in human right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF in order to obtain electrophysiological evidence for putative antiarrhythmic activity of this new class of drugs. Action potentials were measured in right atrial trabeculae using conventional microelectrodes. Human myocytes were enzymatically isolated. Rat atrial and ventricular cardiomyocytes were used for comparison. Using perforated-patch, NCX was measured as Ni(2+)-sensitive current during ramp pulses. In ruptured-patch experiments, NCX current was activated by changing the extracellular Ca(2+) concentration from 0 to 1mM in Na(+)-free bath solution (100mM Na(+) intracellular, "Hilgemann protocol"). Although SEA0400 was effective in rat cardiomyocytes, 10µM did not influence action potentials and contractility, neither in SR nor AF. SEA0400 (10µM) also failed to affect human atrial NCX current measured with perforated patch. With the "Hilgemann protocol" SEA0400 concentration-dependently suppressed human atrial NCX current, and its amplitude was larger in AF than in SR cardiomyocytes. Our results confirm higher NCX activity in AF than SR. SEA0400 fails to block Ni(2+)-sensitive current in human atrial cells unless unphysiological conditions are used. We speculate that block of NCX with SEA0400 depends on intracellular Na(+) concentration.

In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias.

BACKGROUND AND PURPOSE: 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 µM) respectively. EXPERIMENTAL APPROACH: Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. KEY RESULTS: Maximum force responses to 5-HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5-HT in peAF and the inotropic potency of 5-HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5-HT were not decreased in peAF. Responses of ICa,L to 5-HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5-HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. CONCLUSIONS AND IMPLICATIONS: PDE3, but not PDE4, reduced inotropic responses to 5-HT in peAF, independently of lusitropy and ICa,L , but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5-HT to induce arrhythmias by inhibition of PDE3 plus PDE4.

Reduced Incidence of Thromboembolic Events After Surgical Closure of Left Atrial Appendage in Patients With Atrial Fibrillation.

OBJECTIVE: Most of the detected thrombi in patients with atrial fibrillation (AF) can be found in the left atrial appendage (LAA). Interventional LAA closure recently proved to be noninferior to warfarin therapy. Whether these results can be fully translated into surgical LAA closure remains unclear. Corresponding data are still lacking. The present observational study evaluated the impact of surgical LAA closure in patients with AF undergoing cardiac surgery on postoperative thromboembolic events. METHODS: A prospective registry enrolled 398 patients with permanent AF undergoing cardiac surgery. Concomitant procedures were isolated surgical ablation (group I, n = 71), isolated LAA closure (group II, n = 44), and combined surgical ablation and LAA closure (group III, n = 196). The control group consisted of 87 patients without concomitant surgical ablation or LAA closure. One-year follow-up was completed in all patients. End points were thromboembolic events and death from any cause. RESULTS: Clinical baseline characteristics were comparable among the groups. General hospital mortality was 5.5% and likewise differed not significantly. Postoperatively, mean (SD) CHAD2S2-VASc score of 3.5 (1.3) differed not significantly among the groups, indicating comparable thromboembolic risk. Follow-up referred to all hospital survivors (n = 376). Herein, overall incidence of thromboembolic events was 9.8% (n = 37), with an associated mortality of 41.0%. Patients with LAA closure alone or in combination with surgical ablation had a significantly reduced incidence of thromboembolic events (6.6% vs 20.5%, P < 0.01) and consecutively improved survival after 1 year of follow-up (7.0% vs 17.1%, P < 0.01). CONCLUSIONS: Left atrial appendage closure alone or in combination with surgical ablation was associated with a significantly reduced rate of thromboembolic events and consecutively improved survival after 1 year of follow-up.

Late Sodium Current in Human Atrial Cardiomyocytes from Patients in Sinus Rhythm and Atrial Fibrillation.

Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 µM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 µM) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Application of the RIMARC algorithm to a large data set of action potentials and clinical parameters for risk prediction of atrial fibrillation.

Ex vivo recorded action potentials (APs) in human right atrial tissue from patients in sinus rhythm (SR) or atrial fibrillation (AF) display a characteristic spike-and-dome or triangular shape, respectively, but variability is huge within each rhythm group. The aim of our study was to apply the machine-learning algorithm ranking instances by maximizing the area under the ROC curve (RIMARC) to a large data set of 480 APs combined with retrospectively collected general clinical parameters and to test whether the rules learned by the RIMARC algorithm can be used for accurately classifying the preoperative rhythm status. APs were included from 221 SR and 158 AF patients. During a learning phase, the RIMARC algorithm established a ranking order of 62 features by predictive value for SR or AF. The model was then challenged with an additional test set of features from 28 patients in whom rhythm status was blinded. The accuracy of the risk prediction for AF by the model was very good (0.93) when all features were used. Without the seven AP features, accuracy still reached 0.71. In conclusion, we have shown that training the machine-learning algorithm RIMARC with an experimental and clinical data set allows predicting a classification in a test data set with high accuracy. In a clinical setting, this approach may prove useful for finding hypothesis-generating associations between different parameters.