Intestinal expression profiles and hepatic expression of LEAP2, ghrelin and their common receptor, GHSR, in humans.

Liver-expressed antimicrobial peptide 2 (LEAP2) and ghrelin have reciprocal effects on their common receptor, the growth hormone secretagogue receptor (GHSR). Ghrelin is considered a gastric hormone and LEAP2 a liver-derived hormone and both have been proposed to be involved in the pathophysiology of obesity and type 2 diabetes (T2D). We investigated the mRNA expression of LEAP2, ghrelin and GHSR along the intestinal tract of individuals with and without TD2, and in the liver of men with and without obesity. Mucosal biopsies retrieved with 30-cm intervals throughout the small intestine and from 7 well-defined locations along the large intestine from 12 individuals with T2D and 12 healthy controls together with liver biopsies from 15 men with obesity and 15 lean men were subjected to bulk transcriptomics analysis. Both in individuals with and without T2D, mRNA expression of LEAP2 increased through the small intestine until dropping at the ileocecal valve, with little LEAP2 mRNA expression in the large intestine. Pronounced LEAP2 expression was observed in the liver of men with and without obesity. Robust ghrelin mRNA expression was observed in the duodenum of individuals with and without T2D, gradually decreasing along the small intestine with little expression in the large intestine. Ghrelin mRNA expression was not detected in the liver biopsies, and GHSR mRNA expression was not. In conclusion, we provide unique mRNA expression profiles of LEAP2, ghrelin and GHSR along the human intestinal tract showing no T2D-associated changes, and in the liver showing no differences between men with and without obesity.

Association between catheter ablation of atrial fibrillation and mortality or stroke.

OBJECTIVE: Catheter ablation of atrial fibrillation effectively reduces symptomatic burden. However, its long-term effect on mortality and stroke is unclear. We investigated if patients with atrial fibrillation who undergo catheter ablation have lower risk for all-cause mortality or stroke than patients who are managed medically. METHODS: We retrospectively included 5628 consecutive patients who underwent first-time catheter ablation for atrial fibrillation between 2008 and 2018 at three major Swedish electrophysiology units. Control individuals with an atrial fibrillation diagnosis but without previous stroke were selected from the Swedish National Patient Register, resulting in a control group of 48 676 patients. Propensity score matching was performed to produce two cohorts of equal size (n=3955) with similar baseline characteristics. The primary endpoint was a composite of all-cause mortality or stroke. RESULTS: Patients who underwent catheter ablation were healthier (mean CHA2DS2-VASc score 1.4±1.4 vs 1.6±1.5, p<0.001), had a higher median income (288 vs 212 1000 Swedish krona [KSEK]/year, p<0.001) and had more frequently received university education (45.1% vs 28.9%, p<0.001). Mean follow-up was 4.5±2.8 years. After propensity score matching, catheter ablation was associated with lower risk for the combined primary endpoint (HR 0.58, 95% CI 0.48 to 0.69). The result was mainly driven by a decrease in all-cause mortality (HR 0.51, 95% CI 0.41 to 0.63), with stroke reduction showing a trend in favour of catheter ablation (HR 0.75, 95% CI 0.53 to 1.07). CONCLUSIONS: Catheter ablation of atrial fibrillation was associated with a reduction in the primary endpoint of all-cause mortality or stroke. This result was driven by a marked reduction in all-cause mortality.

[Pulsed Field Ablation shows promise - Experiences from the first 100 patients in Sweden]. / Pulsfältablation verkar lovande ­ står vi inför ett paradigmskifte?

Pulmonary vein isolation (PVI) of symptomatic atrial fibrillation is an effective method of maintaining sinus rhythm. Radiofrequency ablation and cryotechnology have been used for this purpose for many years. One disadvantage of these methods is the risk of serious complications such as pulmonary vein stenosis, phrenic nerve palsy and atrio-oesophageal fistula. Pulsed Field Ablation (PFA) is a promising ablation modality for treatment of atrial fibrillation. This technique employs a train of high amplitude electrical pulses with short duration that ablate myocardium with minimal effect on surrounding tissues. 100 patients underwent PFA at the Capio Arrhythmia Center Stockholm. All pulmonary veins could be identified successfully and isolation could be achieved without difficulty. No serious complication during ablation and observation time after the procedure occurred. Our experience with PFA shows that PVI with this technique in symptomatic atrial fibrillation is a safe and effective method.

A decade of catheter ablation of cardiac arrhythmias in Sweden: ablation practices and outcomes.

AIMS: Catheter ablation is considered the treatment of choice for many tachyarrhythmias, but convincing 'real-world' data on efficacy and safety are lacking. Using Swedish national registry data, the ablation spectrum, procedural characteristics, as well as ablation efficacy and reported adverse events are reported. METHODS AND RESULTS: Consecutive patients (≥18 years of age) undergoing catheter ablation in Sweden between 01 January 2006 and 31 December 2015 were included in the study. Follow-up (repeat ablation and vital status) was collected through 31 December 2016. A total of 26 642 patients (57 ± 15 years, 62% men), undergoing a total of 34 428 ablation procedures were included in the study. In total, 4034 accessory pathway/Wolff-Parkinson-White syndrome (12%), 7358 AV-nodal re-entrant tachycardia (21%), 1813 atrial tachycardia (5.2%), 5481 typical atrial flutter (16%), 11 916 atrial fibrillation (AF, 35%), 2415 AV-nodal (7.0%), 581 premature ventricular contraction (PVC, 1.7%), and 964 ventricular tachycardia (VT) ablations (2.8%) were performed. Median follow-up time was 4.7 years (interquartile range 2.7-7.0). The spectrum of treated arrhythmias changed over time, with a gradual increase in AF, VT, and PVC ablation (P < 0.001). Decreasing procedural times and utilization of fluoroscopy with time, were seen for all arrhythmia types. The rates of repeat ablation differed between ablation types, with the highest repeat ablation seen in AF (41% within 3 years). The rate of reported adverse events was low (n = 595, 1.7%). Death in the immediate period following ablation was rare (n = 116, 0.34%). CONCLUSION: Catheter ablations have shifted towards more complex procedures over the past decade. Fluoroscopy time has markedly decreased and the efficacy of catheter ablation seems to improve for AF.

The impact of supraventricular ectopic complexes in different age groups and risk of recurrent atrial fibrillation after antiarrhythmic medication or catheter ablation.

INTRODUCTION: Supraventricular ectopic complexes (SVEC) are known risk factors of recurrent atrial fibrillation (AF). However, the impact of SVEC in different age groups is unknown. We aimed to investigate the risk of AF recurrence with higher SVEC burden in patients ±57years, respectively, after treatment with antiarrhythmic medication (AAD) or catheter ablation (CA). METHODS: In total, 260 patients with LVEF >40% and age ≤70 years were randomized to AAD (N=132) or CA (N=128) as first-line treatment for paroxysmal AF. All patients underwent 7-day Holter monitoring at baseline, and after 3, 6, 12, 18 and 24months and were categorized according to median age ±57years. We used multivariate Cox regression analyses and we defined high SVEC burden at 3months of follow-up as the upper 75th percentile >195SVEC/day. AF recurrence was defined as AF ≥1min, AF-related cardioversion or hospitalization. RESULTS: Age >57years were significantly associated with higher AF recurrence rate after CA (58% vs 36%, p=0.02). After CA, we observed a higher SVEC burden during follow-up in patients >57years which was not observed in the younger age group treated with CA (p=0.006). High SVEC burden at 3months after CA was associated with AF recurrence in older patients but not in younger patients (>57years: HR 3.4 [1.4-7.9], p=0.005). We did not find any age-related differences after AAD. CONCLUSION: We found that younger and older patients respond differently to CA and that SVEC burden was only associated with AF recurrence in older patients.

Higher burden of supraventricular ectopic complexes early after catheter ablation for atrial fibrillation is associated with increased risk of recurrent atrial fibrillation.

Aims: Early identification of patients who could benefit from early re-intervention after catheter ablation is highly warranted. Our aim was to investigate the association between post-procedural burden of supraventricular ectopic complexes (SVEC) and the risk of long-term atrial fibrillation (AF) recurrence. Methods and results: A total of 125 patients undergoing catheter ablation for AF were included. Patients underwent 7-day Holter recordings immediately post-procedural. The number of SVEC in post-procedural Holter recordings was categorized into quartiles: 0-72, 73-212, 213-782 and ≥ 783 SVEC/day. Long-term AF recurrence was defined as a combined endpoint of AF ≥ 1 min during follow-up Holter recordings, cardioversion or hospitalization for AF after a 3-month blanking period and within 24 months of follow-up. High post-procedural supraventricular ectopy burden was associated with an increased risk of long-term AF recurrence in a dose-dependent manner (≥ 783 SVEC: HR 4.6 [1.9-11.5], P < 0.001) irrespective of AF recurrence during the blanking period or other risk factors. In patients with early AF recurrence < 90 days after catheter ablation ectopy burden was also highly predictive of long-term AF recurrence (SVEC ≥ 213: HR 3.0 [1.3-6.7], P = 0.007). Correspondingly, patients with early AF recurrence but low ectopy burden remained at low risk of long-term AF recurrence after the blanking period. Conclusion: Our results indicate that post-procedural ectopy burden is highly associated with long-term AF recurrence and could be a potent risk marker for selection of patients for early re-ablation. Development of future ablation risk stratification and strategies should include focus on post-procedural ectopy burden.

Antiarrhythmic medication is superior to catheter ablation in suppressing supraventricular ectopic complexes in patients with atrial fibrillation.

BACKGROUND: Supraventricular ectopic complexes (SVEC) originating in the pulmonary veins are known triggers of atrial fibrillation (AF) which led to the development of pulmonary vein isolation for AF. However, the long-term prevalence of SVEC after catheter ablation (CA) as compared to antiarrhythmic medication (AAD) is unknown. Our aims were to compare the prevalence of SVEC after AAD and CA and to estimate the association between baseline SVEC burden and AF burden during 24months of follow-up. METHODS: Patients with paroxysmal AF (N=260) enrolled in the MANTRA PAF trial were treated with AAD (N=132) or CA (N=128). At baseline and 3, 6, 12, 18 and 24months follow-up patients underwent 7-day Holter monitoring to assess SVEC and AF burden. We compared SVEC burden between treatments with Wilcoxon sum rank test. RESULTS: Patients treated with AAD had significantly lower daily SVEC burden during follow-up as compared to CA (AAD: 19 [6-58] versus CA: 39 [14-125], p=0.003). SVEC burden increased post-procedurally followed by a decrease after CA whereas after AAD SVEC burden decreased and stabilized after 3months of follow-up. Patients with low SVEC burden had low AF burden after both treatments albeit this was more pronounced after CA at 24months of follow-up. CONCLUSION: AAD was superior to CA in suppressing SVEC burden after treatment of paroxysmal AF. After CA SVEC burden increased immediately post-procedural followed by a decrease whereas after AAD an early decrease was observed. Lower SVEC burden was highly associated with lower AF burden during follow-up especially after CA.

Long-term efficacy of catheter ablation as first-line therapy for paroxysmal atrial fibrillation: 5-year outcome in a randomised clinical trial.

OBJECTIVE: The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial compared radiofrequency catheter ablation (RFA) with antiarrhythmic drug therapy (AAD) as first-line treatment for paroxysmal atrial fibrillation (AF). Endpoint of ablation was elimination of electrical activity inside pulmonary veins. We present the results of the 5-year follow-up. METHODS: This pre-specified 5-year follow-up included assessment of any AF and symptomatic AF burden by one 7-day Holter recording and quality of life (QoL) assessment, using SF-36 questionnaire physical and mental component scores. Analysis was intention-to-treat. Imputation was used to compensate for missing Holter data. RESULTS: 245 of 294 patients (83%) randomised to RFA (n=125) or AAD (n=120) attended the 5-year follow-up, 227 with Holter recording. Use of class I or III AAD was more frequent in AAD group (N=61 vs 13, p<0.001). More patients in the RFA group were free from AF (126/146 (86%) vs 105/148 (71%), p=0.001, relative risk (RR) 0.82; 95% CI 0.73 to 0.93) and symptomatic AF (137/146 (94%) vs 126/148 (85%), p=0.015, χ2 test, RR 0.91; 95% CI 0.84 to 0.98) in 7-day Holter recording. AF burden was significantly lower in the RFA group (any AF: p=0.003; symptomatic AF: p=0.02). QoL scores did not differ between randomisation groups. QoL scores remained improved from baseline (both components p<0.001), and did not differ from 2-year scores. CONCLUSIONS: At 5 years, the occurrence and burden of any AF and symptomatic AF were significantly lower in the RFA group than in the AAD group. Improved QoL scores observed after 2 years persisted after 5 years without between-group differences. TRIAL REGISTRATION NUMBER: NCT00133211; Results.

Pre- and postoperative atrial fibrillation in CABG patients have similar prognostic impact.

OBJECTIVES: To study pre- and postoperative atrial fibrillation and its long-term effects in a cohort of aortocoronary bypass surgery patients. DESIGN: Altogether 615 patients undergoing aortocoronary bypass graft surgery in 1999-2000 were studied. Forty-four (7%) had preoperative atrial fibrillation. Postoperative atrial fibrillation occurred in 165/615 patients (27%) while 406/615 patients (66%) had no atrial fibrillation. After a median follow-up of 15 years, symptoms and medication in survivors were recorded, and cause of death in the deceased was obtained. RESULTS: Death due to cerebral ischaemia was most common in the pre- and postoperative atrial fibrillation groups (7% and 5%, respectively, v. 2% among those without atrial fibrillation, p = .038), as were death due to heart failure (18% and 14%, v. 7%, p = .007) and sudden death (9% and 5%, v. 2%, p = .029). The presence of pre- or postoperative atrial fibrillation was an independent risk factor for late mortality (hazard ratios 1.47 (1.02-2.12) and 1.28 (1.01-1.63), respectively). CONCLUSIONS: Patients with pre- or postoperative atrial fibrillation undergoing aortocoronary bypass surgery have increased long-term mortality and risk of cerebral ischemic and cardiovascular death compared with patients in sinus rhythm.

Total endoscopic ablation of patients with long-standing persistent atrial fibrillation: a randomized controlled study.

OBJECTIVES: Total endoscopic ablation of atrial fibrillation is an alternative to catheter ablation, but its clinical role needs further evaluation. The aim of this study was to compare total endoscopic ablation with rate control in patients with long-standing persistent atrial fibrillation and to examine the effect of endoscopic ablation on heart rhythm, symptoms, physical working capacity and myocardial function during 1 year of follow-up. METHODS: In a prospective controlled study, 36 patients aged >50 years with symptomatic long-standing persistent atrial fibrillation were randomized to either total endoscopic ablation (n = 17, after two drop-outs before ablation n = 15) or rate control therapy (n = 19). In the ablation group, a box lesion encircling the pulmonary veins was performed, using temperature-controlled radiofrequency energy. Loop recorders were implanted in all patients. Echocardiography and quality-of-life assessment were performed at 6 and 12 months, and physical working capacity assessment at 6 months. RESULTS: There was no mortality or thromboembolic event. In the control group, all patients were in permanent atrial fibrillation during 12 months of follow-up. In the ablation group, the proportion of patients in sinus rhythm without antiarrhythmic drugs was 12/15 (80%) at 12 months. The median freedom of atrial fibrillation at 3-12 months was 95% in the ablation group and the proportion of patients with an atrial fibrillation burden of <5% at 3-12 months was 8/15 (53%). The left ventricular ejection fraction increased during follow-up in the ablation group compared with the control group (from 53.7 ± 8.6 to 58.8 ± 6.5%, P = 0.003), combined with a reduction in the left atrial area (from 29.2 ± 5.5 to 27.2 ± 6.3 cm(2), P = 0.002). The physical working capacity increased in the ablation group compared with the control group (from 94 ± 21.4 to 102.9 ± 14.4%, P = 0.011). The subjective physical and mental capacity scale also improved during follow-up in the ablation group, but not in the control group (P = 0.003 and 0.018, respectively). CONCLUSIONS: Total endoscopic ablation in patients with long-standing persistent atrial fibrillation significantly reduced atrial fibrillation burden 12 months after intervention compared with controls. The left ventricular function, physical working capacity and subjective physical and mental health were improved. These results need to be confirmed in larger randomized trials. CLINICALTRIALSGOV IDENTIFIER: NCT00940056.

Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries.

AIM: It is unclear if catheter ablation for atrial fibrillation (AF) affects the prognosis or merely is a symptomatic treatment. The aim is to study the association between ablation for AF, ischaemic stroke, and mortality. METHODS AND RESULTS: We identified all 361 913 patients with a diagnosis of AF in the Swedish Patient Register. During a 7-year period, 5176 AF ablations were performed among 4278 individuals. Patients who had undergone catheter ablation were younger (58.7 vs. 74.7 years, P < 0.001) and healthier (mean CHA2DS2-VASc scores 1.5 ± 1.4 vs. 3.6 ± 1.9, P < 0.001) than other patients with AF. Propensity score matching was used to construct two cohorts of equal size (n = 2836) with similar characteristics in 51 dimensions. Mean follow-up was 4.4 ± 2.0 years (minimum 1 year). In the ablated group, 78 patients suffered ischaemic stroke compared with 112 in the non-ablated (annual rates 0.70 vs. 1.0%, P = 0.013). A total of 88 ablated and 184 non-ablated patients died (annual rates 0.77 vs. 1.62%, P < 0.001). After multivariable adjustments, catheter ablation was associated with lower risk of ischaemic stroke [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.51-0.93) and with lower mortality risk (HR 0.50, 95% CI 0.37-0.62). Stroke reduction was most pronounced among patients with CHA2DS2-VASc score ≥2 (HR 0.39, 95% CI 0.19-0.78) and among patients without new cardioversions beyond 6 months after the ablation (HR 0.68, 95% CI 0.48-0.97). CONCLUSION: Ablation may be associated with lower incidence of ischaemic stroke and death in patients with AF. This beneficial finding appears more pronounced in patients with higher thromboembolic risk.

Radiofrequency catheter ablation maintains its efficacy better than antiarrhythmic medication in patients with paroxysmal atrial fibrillation: On-treatment analysis of the randomized controlled MANTRA-PAF trial.

BACKGROUND: The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) is a randomized trial comparing radiofrequency catheter ablation (RFA) to antiarrhythmic drugs (AADs) as first-line treatment of paroxysmal atrial fibrillation (PAF). In order to eliminate the clouding effect of crossover we performed an on-treatment analysis of the data. METHODS AND RESULTS: Patients (n=294) were divided into three groups: those receiving only the assigned therapy (RFA and AAD groups) and those receiving both therapies (crossover group). The primary end points were AF burden in 7-day Holter recordings at 3, 6, 12, 18, and 24 months and cumulative AF burden in all recordings. At 24 months, AF burden was significantly lower in the RFA (n=110) than in the AAD (n=92) and the crossover (n=84) groups (90th percentile 1% vs. 10% vs. 16%, P=0.007), and more patients were free from any AF (89% vs. 73% vs. 74%, P=0.006). In the RFA, AAD and the crossover groups 63%, 59% and 21% (P<0.001) of the patients had no AF episodes in any Holter recording, respectively. Quality of life improved significantly in all groups. There were no differences in serious adverse events between the RFA, AAD and crossover groups (19% vs. 8% vs. 23%) (P=0.10). CONCLUSIONS: In the treatment of antiarrhythmic therapy naïve patients with PAF long-term efficacy of RFA was superior to AAD therapy. Thus, it is reasonable to offer RFA as first-line treatment for highly symptomatic patients who accept the risks of the procedure and are aware of frequent need for reablation(s).

The cost-effectiveness of radiofrequency catheter ablation as first-line treatment for paroxysmal atrial fibrillation: results from a MANTRA-PAF substudy.

AIM: The aim of this prospective substudy was to estimate the cost-effectiveness of treating paroxysmal atrial fibrillation (AF) with radiofrequency catheter ablation (RFA) compared with antiarrhythmic drugs (AADs) as first-line treatment. METHODS AND RESULTS: A decision-analytic Markov model, based on MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) study data, was developed to study long-term effects and costs of RFA compared with AADs as first-line treatment. Positive clinical effects were found in the overall population, a gain of an average 0.06 quality-adjusted life years (QALYs) to an incremental cost of €3033, resulting in an incremental cost-effectiveness ratio of €50 570/QALY. However, the result of the subgroup analyses showed that RFA was less costly and more effective in younger patients. This implied an incremental cost-effectiveness ratio of €3434/QALY in ≤50-year-old patients respectively €108 937/QALY in >50-year-old patients. CONCLUSION: Radiofrequency catheter ablation as first-line treatment is a cost-effective strategy for younger patients with paroxysmal AF. However, the cost-effectiveness of using RFA as first-line therapy in older patients is uncertain, and in most of these AADs should be attempted before RFA (MANTRA-PAF ClinicalTrials.gov number; NCT00133211).

The impact of asbestos exposure in Swedish construction workers.

OBJECTIVE: To study the occurrence of pleural mesothelioma as a measure of the impact on health from asbestos exposure in the construction industry. METHODS: The occurrence of pleural mesothelioma in different occupations, time periods and birth cohorts was studied in a cohort of construction workers. They were prospectively followed after they had participated in health examinations between 1971 and 1993. The analysis was restricted to men and in total 367,568 men was included in the analysis. RESULTS: In total there were 419 cases of pleural mesotheliomas between 1972 and 2009. As expected the age adjusted incidence was high in insulation workers and plumbers (39 and 16 cases per 100,000 person-years, respectively). However, only 21% of the pleural mesotheliomas occurred in those occupational groups. Occupational groups with many cases of pleural mesothelioma were concrete workers (N = 56), wood workers (N = 55), painters (N = 32), electricians (N = 48), and foremen (N = 37). The highest risk was in birth cohorts born between 1935 and 1945. Between 1995 and 2009 around one-third of all male cases in the country occurred in this birth cohort. The risk seemed to decrease considerably in men born after 1955. CONCLUSION: In Sweden a considerable proportion of pleural mesotheliomas occur among construction workers; and not only in jobs traditionally associated with asbestos exposure such as insulators and plumbers but also among electricians, for example. The results shows that asbestos exposure occurs in many occupational groups, indicating that safe handling of asbestos is a very difficult or even impossible task in the construction industry.

The predictive value of C-reactive protein on recurrence of atrial fibrillation after cardioversion with or without treatment with atorvastatin.

BACKGROUND: The aim of this study was to investigate whether high-sensitivity C-reactive protein (hsCRP) levels prior to cardioversion (CV) predict recurrence of atrial fibrillation (AF) in patients randomized to treatment with either atorvastatin or placebo 30 and 180 days after CV. METHODS: This was a prespecified substudy of 128 patients with persistent AF randomized to treatment with atorvastatin 80 mg/day or placebo, initiated 14 days before CV, and continued 30 days after CV. HsCRP levels were measured at randomization, at the time of CV, and 2 days and 30 days after CV. RESULTS: In univariate analysis of those who were in sinus rhythm 2h after CV, hsCRP did not significantly (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.99-1.25) predict recurrence of AF at 30 days. However, after adjusting for treatment with atorvastatin, hsCRP predicted the recurrence of AF (OR 1.14, 95% CI 1.01-1.27). In a multivariate logistic regression analysis with gender, age, body mass index (BMI), smoking, cholesterol, and treatment with atorvastatin as covariates, the association was still significant (OR 1.14, 95% CI 1.01-1.29). Six months after CV, hsCRP at randomization predicted recurrence of AF in both univariate analysis (OR 1.30, 95% CI 1.06-1.60) and in multivariate logistic regression analysis (OR 1.33, 95% CI 1.06-1.67). CONCLUSION: HsCRP was associated with AF recurrence one and six months after successful CV of persistent AF. However, the association at one month was significant only after adjusting for atorvastatin treatment.

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.

BACKGROUND: There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. METHODS: We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis. RESULTS: There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation. CONCLUSIONS: In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.).

Markers of fibrinolysis as predictors for maintenance of sinus rhythm after electrical cardioversion.

INTRODUCTION: Inflammation, endothelial dysfunction and metabolic pathways provide possible links between the inflammatory and hypofibrinolytic states in atrial fibrillation. Our aim was to explore the role of mass concentrations of PAI-1 and tPA, activities of PAI-1 and tPA as predictors of recurrence of atrial fibrillation adjusted for CRP. MATERIALS AND METHODS: The study included 129 patients with persistent atrial fibrillation. Laboratory analyses were performed including PAI-1 activity, PAI-1 mass, tPA activity, tPA mass and CRP in baseline. Patients were then randomized to atorvastatin (40 mg, two tablets once daily) or placebo, initiated at least 14 days before the elective cardioversion. Further samples and follow-up were made at day 2 and 30 days after cardioversion. RESULTS: In univariate logistic regression no fibrinolytic variable was significantly correlated with rhythm in day 30. In multivariate analysis lower PAI-1 mass was significantly associated with sinus rhythm in all models including fibrinolytic variables, CRP, metabolic components, age, hypertension and smoking. After adding treatment allocation to the fully adjusted model, PAI-1 mass remained significantly associated with sinus rhythm both at day 2 and 30 (OR 0.98; 95% CI 0.95-1.00). CONCLUSIONS: No fibrinolytic component alone was found to be a predictor of recurrence of atrial fibrillation. In multivariate models lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP, markers of the metabolic syndrome and treatment with atorvastatin. Our findings suggest a patophysiological link between AF and PAI-1 mass but the relation to inflammation remains unclear.

A randomized invasive cardiac electrophysiology study of the combined ion channel blocker AZD1305 in patients after catheter ablation of atrial flutter.

BACKGROUND: This study assessed the cardiac electrophysiological and hemodynamic effects of an intravenous infusion of the combined ion channel blocker AZD1305. METHODS: After successful ablation of atrial flutter, patients were randomized to receive placebo (n = 12) or AZD1305 (n = 38) in 4 ascending dose groups. Electrophysiological and hemodynamic measurements were performed before and commencing 20 minutes after start of infusion. RESULTS: Left atrial effective refractory period increased dose and the primary outcome measure increased dose and plasma concentration dependently, with a mean increase of 55 milliseconds in dose group 3. There was a corresponding increase in right atrial effective refractory period of 84 milliseconds. The right ventricular effective refractory period and the paced QT interval also increased dose and concentration dependently, by 59 and 70 milliseconds, respectively, in dose group 3. There were indications of moderate increases of atrial, atrioventricular nodal, and ventricular conduction times. No consistent changes in intracardiac pressures were observed, but there was a small transient decrease in systolic blood pressure. Adverse events were consistent with the study population and procedure, and there were no signs of proarrhythmia despite marked delay in ventricular repolarization in some individuals. CONCLUSIONS: AZD1305 shows electrophysiological characteristics indicative of potential antiarrhythmic efficacy in atrial fibrillation.

Effects of AZD0837, a novel direct thrombin inhibitor, on the electrophysiological properties of the human heart: a randomized, double-blind, parallel-group, placebo-controlled study.

BACKGROUND: AZD0837 is an investigational oral anticoagulant that is bioconverted to its active form, AR-H067637, a selective direct thrombin inhibitor. OBJECTIVES: The objectives of the present study were to investigate if there are any clinically relevant adverse effects of intravenous AZD0837 on cardiac conduction, refractoriness and repolarization, and to study its safety and tolerability. METHODS: In this randomized, double-blind, parallel-group, placebo-controlled study (study code D1250C00026), invasive electrophysiological measurements were performed twice in 30 subjects with a history of, or ongoing, atrial flutter, starting 30 minutes after successful ablation of atrial flutter and then 60 minutes after start of an intravenous infusion of AZD0837. Pre-study warfarin therapy was not an exclusion criterion. The stimulation protocol was performed mainly at 500 and 400 ms drive cycle length. A 12-lead ECG was also recorded before and during AZD0837 infusion. Plasma concentrations of AZD0837 and its metabolites were obtained at predefined timepoints. RESULTS: Measurements were made at baseline and during stable plasma concentrations of the prodrug AZD0837 (mean +/- standard deviation 7.96 +/- 2.38 micromol/L, approximate target of 10 micromol/L), the intermediate metabolite AR-H69927 (1.26 +/- 0.39 micromol/L, target 1-2 micromol/L) and the active direct thrombin inhibitor AR-H067637 (0.35 +/- 0.14 micromol/L, target 0.5-1.0 micromol/L). There were no clinically relevant effects on cardiac conduction (QRS duration, PR interval, His bundle electrogram, Wenckebach point), refractoriness (atrial, atrioventricular and ventricular effective refractory periods) or repolarization (QT, QT interval corrected for heart rate using Fridericia's formula, QRS onset to the top of the T wave [QT(top)], QRS onset to the end of the T wave [QT(end)] or QT(top) - QT(end)). CONCLUSIONS: AZD0837 was well tolerated, and had no clinically relevant effects on cardiac electrophysiology of the target population, either in subjects previously treated with warfarin or in those without previous treatment.