Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

AIMS: Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF. METHODS AND RESULTS: We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02). CONCLUSION: Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA. CLINICAL TRIAL REGISTRATION: ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.

The effect of head-up tilt upon markers of heart rate variability in patients with atrial fibrillation.

BACKGROUND: Heart rate variability (HRV) analysis is uncommonly undertaken in patients with atrial fibrillation (AF) due to an assumption that ventricular response is random. We sought to determine the effects of head-up tilt (HUT), a stimulus known to elicit an autonomic response, on HRV in patients with AF; we contrasted the findings with those of patients in sinus rhythm (SR). METHODS: Consecutive, clinically indicated tilt tests were examined for 207 patients: 176 in SR, 31 in AF. Patients in AF were compared to an age-matched SR cohort (n = 69). Five minute windows immediately before and after tilting were analyzed using time-domain, frequency-domain and nonlinear HRV parameters. Continuous, noninvasive assessment of blood pressure, heart rate and stroke volume were available in the majority of patients. RESULTS: There were significant differences at baseline in all HRV parameters between AF and age matched SR. HUT produced significant hemodynamic changes, regardless of cardiac rhythm. Coincident with these hemodynamic changes, patients in AF had a significant increase in median [quartile 1, 2] DFA-α2 (+0.14 [-0.03, 0.32], p < .005) and a decrease in sample entropy (-0.17 [-0.50, -0.01], p < .005). CONCLUSION: In the SR cohort, increasing age was associated with fewer HRV changes on tilting. Patients with AF had blunted HRV responses to tilting, mirroring those seen in an age matched SR group. It is feasible to measure HRV in patients with AF and the changes observed on HUT are comparable to those seen in patients in sinus rhythm.

Ivabradine in treatment of sinus tachycardia mediated vasovagal syncope.

AIMS: Ivabradine, an I(f) current blocker, has shown promising results in treatment of postural orthostatic tachycardia syndrome (POTS). There is a subgroup of vasovagal syncope (VVS) patients, who demonstrate sinus tachycardia before collapse on tilt testing mimicking some features of POTS. These patients may also respond to ivabradine therapy. University Hospital Syncope Clinic where ivabradine was prescribed in a prospective fashion on humanitarian grounds between October 2008 and December 2011. METHODS AND RESULTS: Twenty-five patients of mean age 33±years presenting syncope in all and palpitation in 23, duration 9±years underwent tilt testing with reproduction of usual symptoms including tachycardia preceding collapse. Ivabradine was prescribed in doses of 5-20 mg/day, mean 10.7 mg, as once or twice daily medication. The response to treatment was classified as deterioration in none, no change in 5, improvement in 10, and symptoms abolished in 8 patients. Side effects were minimal; one patient required discontinuation. CONCLUSION: In this pilot study of ivabradine, in patients with VVS, of patients who demonstrated sinus tachycardia before collapse on tilt, 72% reported a marked benefit or complete resolution of symptoms. The drug was well tolerated. A randomized controlled trial against placebo is justified.

Long-term clinical outcomes and cost-effectiveness of catheter vs thoracoscopic surgical ablation in long-standing persistent atrial fibrillation using continuous cardiac monitoring: CASA-AF randomized controlled trial.

BACKGROUND: Long-term clinical outcomes of catheter ablation (CA) compared to thoracoscopic surgical ablation (SA) to treat patients with long-standing persistent atrial fibrillation (LSPAF) are not known. OBJECTIVE: The purpose of this study was to compare the long-term (36-month) clinical efficacy, quality of life, and cost-effectiveness of SA and CA in LSPAF. METHODS: Participants were followed up for 3 years using implantable loop recorders and questionnaires to assess the change in quality of life. Intention-to-treat analyses were used to report the findings. RESULTS: Of the 115 patients with LSPAF treated, 104 (90.4%) completed 36-month follow-up [CA: n = 57 (95%); SA: n = 47 (85%)]. After a single procedure without antiarrhythmic drugs, 7 patients (12%) in the CA arm and 5 (11%) in the SA arm [hazard ratio 1.22; 95% confidence interval (CI) 0.81-1.83; P = .41] were free from atrial fibrillation/tachycardia (AF/AT) ≥30 seconds at 36 months. Thirty-three patients (58%) in the CA arm and 26 (55%) in the SA arm (hazard ratio 1.04; 95% CI 0.57-1.88; P = .91) had their AF/AT burden reduced by ≥75%. The overall impact on health-related quality of life was similar, with mean quality-adjusted life year estimates of 2.45 (95% CI 2.31-2.59) for CA and 2.32 (95% CI 2.13-2.52) for SA. Estimated costs were higher for SA (mean £24,682; 95% CI £21,746-£27,618) than for CA (mean £18,002; 95% CI £15,422-£20,581). CONCLUSION: In symptomatic LSPAF, CA and SA were equally effective at achieving arrhythmia outcomes (freedom from AF/AT ≥30 seconds and ≥75% burden reduction) after a single procedure without antiarrhythmic drugs. However, SA is significantly more costly than CA. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04280042.

A standardized education protocol significantly reduces traumatic injuries and syncope recurrence: an observational study in 316 patients with vasovagal syncope.

AIMS: The aim of this study was to assess the role of a non-pharmacological approach on the frequency of traumatic injuries and syncope recurrence in patients with vasovagal syncope and normal hearts. We report the experience in our syncope centre with a standardized education and teaching protocol for patients with vasovagal syncope. The treatment of vasovagal syncope is often complex and discouraging. Besides medical options, behaviour modification is a main component of therapy but has no statistical evidence to support its use. METHODS AND RESULTS: Between January 1999 and September 2006, we prospectively enrolled all patients with vasovagal syncope. The patients were counselled about the benign nature of their disease. Specific recommendations were made according to a standardized education protocol established at our syncope centre. A pre-/post-study was conducted to investigate the effectiveness of our approach on syncope recurrence and frequency of injury as the study endpoints. Complete follow-up data were available from 85% of the study population (316 of 371) after a mean time of 710 ± 286 days (mean age 50 years; standard deviation ± 18 years, 160 female). Eighty-seven patients (27.5%) had a syncope recurrence with 22 suffering an injury during syncope. During the follow-up period, the syncope burden per month was significantly reduced from 0.35 ± 0.03 at initial presentation to 0.08 ± 0.02 (P< 0.001). The frequency of traumatic syncope was significantly lower at the time of recurrence compared with the initial presentation (25 vs. 42%; McNemar's test P= 0.02). CONCLUSION: A standardized education protocol significantly reduces traumatic injuries and syncope recurrence in patients with vasovagal syncope.

Persistence of pulmonary vein isolation after robotic remote-navigated ablation for atrial fibrillation and its relation to clinical outcome.

AIMS: A robotic navigation system (RNS, Hansen™) has been developed as an alternative method of performing ablation for atrial fibrillation (AF). Despite the growing application of RNS-guided pulmonary vein isolation (PVI), its consequences and mechanisms of subsequent AF recurrences are unknown. We investigated the acute procedural success and persistence of PVI over time after robotic PVI and its relation to clinical outcome. METHODS AND RESULTS: Sixty-four patients (60.7 ± 9.8 years, 53 male) with paroxysmal AF underwent robotic circumferential PVI with 3-dimensional left atrial reconstruction (NavX™). A voluntary repeat invasive electrophysiological study was performed 3 months after ablation irrespective of clinical course. Robotic PVI was successful in all patients without complication (fluoroscopy time: 23.5 [12-34], procedure time: 180 [150-225] minutes). Fluoroscopy time demonstrated a gradual decline but was significantly reduced after the 30th patient following the introduction of additional navigation software (34 [29-45] vs 12 [9-17] minutes; P < 0.001). A repeat study at 3 months was performed in 63% of patients and revealed electrical conduction recovery in 43% of all PVs. Restudied patients without AF recurrence (n = 28) showed a significantly lower number of recovered PVs (1 (0-2) vs 2 (2-3); P = 0.006) and a longer LA-PV conduction delay than patients with AF recurrences (n = 12). Persistent block of all PVs was associated with freedom from AF in all patients. At 3 months, 67% of patients were free of AF, while reablation of recovered PVs led to an overall freedom from AF in 81% of patients after 1 year. CONCLUSION: Robotic PVI for PAF is safe, effective, and requires limited fluoroscopy while yielding comparable success rates to conventional ablation approaches with PV reconduction as a common phenomenon associated with AF recurrences.

Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease.

BACKGROUND: Renal insufficiency in patients with ischemic heart disease and acquired heart failure is associated with higher mortality and morbidity. We studied the prevalence of renal dysfunction in adult patients with congenital heart disease (ACHD) and its relation to outcome. METHODS AND RESULTS: A total of 1102 adult patients with congenital heart disease (age 36.0+/-14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (> or =90 mL . min(-1) . 1.73 m(-2)), mildly impaired GFR (60 to 89 mL . min(-1) . 1.73 m(-2)), and moderately/severely impaired GFR (<60 mL . min(-1) . 1.73 m(-2)). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL . min(-1) . 1.73 m(-2), P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score-weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR). CONCLUSIONS: Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Robotically assisted ablation produces more rapid and greater signal attenuation than manual ablation.

INTRODUCTION: Robotic remote catheter ablation potentially provides improved catheter-tip stability, which should improve the efficiency of radiofrequency energy delivery. Percentage reduction in electrogram peak-to-peak voltage has been used as a measure of effectiveness of ablation. We tested the hypothesis that improved catheter-tip stability of robotic ablation can diminish signals to a greater degree than manual ablation. METHODS: In vivo NavX maps of 7 pig atria were constructed. Separate lines of ablation were performed robotically and manually, recording pre- and postablation peak-to-peak voltages at 10, 20, 30, and 60 seconds and calculating signal amplitude reduction. Catheter ablation settings were constant (25W, 50 degrees , 17 mL/min, 20-30 g catheter tip pressure). The pigs were sacrificed and ablation lesions correlated with NavX maps. RESULTS: Robotic ablation reduced signal amplitude to a greater degree than manual ablation (49 +/- 2.6% vs 29 +/- 4.5% signal reduction after 1 minute [P = 0.0002]). The mean energy delivered (223 +/- 184 J vs 231 +/- 190 J, P = 0.42), power (19 +/- 3.5 W vs 19 +/- 4 W, P = 0.84), and duration of ablation (15 +/- 9 seconds vs 15 +/- 9 seconds, P = 0.89) was the same for manual and robotic. The mean peak catheter-tip temperature was higher for robotic (45 +/- 5 degrees C vs 42 +/- 3 degrees C [P < 0.0001]). The incidence of >50% signal reduction was greater for robotic (37%) than manual (21%) ablation (P = 0.0001). CONCLUSION: Robotically assisted ablation appears to be more effective than manual ablation at signal amplitude reduction, therefore may be expected to produce improved clinical outcomes.

A fortuitous syncope. The pitfalls of integrated bipolar defibrillator leads.

Myopotential oversensing in implantable defibrillators causing inhibition of pacing and inappropriate therapies is well described. Current literature is dominated by reports of diaphragmatic muscle as the source of such far-field oversensing. Those reporting pectoral muscle sources were invariably due to unipolar sensing circuits, incorrect DF-1 connections or inappropriate programming. We report an interesting case of pectoral muscle myopotential oversensing causing inhibition of bradycardia pacing leading to presyncope and syncope.

Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival.

BACKGROUND: Limited data exist with which to stratify risk in adult congenital heart disease (ACHD). An increased ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production (V(E)/V(CO2) slope), is an established predictor of impaired survival in acquired heart disease. We sought to establish the distribution, relation to cyanosis, and prognostic value of the V(E)/V(CO2) slope across a wide spectrum of ACHD patients. METHODS AND RESULTS: Five hundred sixty ACHD patients of varying diagnoses and 50 healthy controls underwent cardiopulmonary exercise testing at a single laboratory between 2001 and 2004. Patient age was 33.2 +/- 12.9 years (mean +/- SD). Peak oxygen consumption was 23.5 +/- 9.0 mL.kg(-1).min(-1).V(E)/V(CO2) slope for all patients was 36.3 +/-15.3. The slope was raised in all ACHD groups compared with controls and was 73% higher in cyanotic patients. Cyanosis, with or without pulmonary arterial hypertension, was the strongest predictor of abnormal V(E)/V(CO2) slope. The V(E)/V(CO2) slope was the most powerful univariate predictor of mortality in the noncyanotic group and the only independent predictor of mortality among exercise parameters on multivariate analysis. In cyanotic patients, no parameter was predictive of death. CONCLUSIONS: Ventilatory response to exercise is abnormal across the spectrum of ACHD. Cyanosis is a powerful stimulus for such exaggerated ventilatory patterns irrespective of the presence of pulmonary arterial hypertension. Increased V(E)/V(CO2) slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Mechanism of cardiac output gain from cardiac resynchronization therapy in patients with coronary artery disease or idiopathic dilated cardiomyopathy.

The mechanisms underlying cardiac resynchronization therapy have consistently been studied at rest and remain ill defined. Peak stress total isovolumic time (t-IVT) is a major determinant of cardiac output (CO) in chronic heart failure. In this study, pharmacologic stress was used to assess the effects of atrioventricular (AV) delay shortening and ventricular resynchronization elements of cardiac resynchronization therapy. Thirty patients undergoing cardiac resynchronization therapy were studied <6 months after implantation. t-IVT and CO were measured during native activation (left bundle branch block), AV delay shortening (right ventricular dual-chamber pacing), and full resynchronization (atrio-biventricular pacing). Full resynchronization shortened peak stress t-IVT by 9.4 +/- 6.2 s/min (p <0.001) and increased peak stress CO by 0.9 +/- 0.4 L/min (p <0.001), with the effects in individual patients showing a large correlation (r = -0.64, p <0.001). In contrast, simple AV delay shortening did not shorten peak stress t-IVT nor increase peak stress CO, nor was CO at rest affected by full resynchronization or AV delay shortening. Of all measurements during native activation, the best predictor of gain in peak stress CO from full resynchronization was peak stress t-IVT (r = 0.75, p <0.001), with every 5 s/min increment in peak stress t-IVT during native activation predicting a 6% gain in peak stress CO. No conventional measures during native activation at rest or during stress (including QRS duration, the Tei index, tissue Doppler intraventricular delay, and t-IVT at rest) added significant additional information. In conclusion, only during stress does resynchronization consistently increase CO. Second, little of this increment in CO is achieved by AV delay shortening alone. Third, under native activation, long t-IVT during peak stress is the single best predictor of resynchronization-mediated increment in peak stress CO.

Life-years gained from defibrillator implantation: markedly nonlinear increase during 3 years of follow-up and its implications.

BACKGROUND: Although treatment benefit in randomized controlled trials of defibrillators is often summarized by the numbers of lives saved (absolute risk difference), this may not be a good representation of what matters most to patients, namely, the amount of life they should expect to gain from implantation. The estimate of gain in life-years may depend on duration of follow-up. In this study, we examine this dependency. METHODS AND RESULTS: We estimated, from published data of 8 landmark defibrillator trials, the cumulative benefit in life-years gained at time points from 3 months to 3 years. Because the trial populations, clinical status, and prognosis varied widely between studies, we expressed for each study the benefit at each time point as the proportion of benefit at 3 years. The average dependency of the benefit on duration of follow-up was then calculated. We found that the number of life-years gained from 1 device implantation increases with length of follow-up considered. Importantly, this increase is markedly nonlinear. Within the 3-year span addressable, the benefit rises with the square of time (gain infinity t(1.94), R2=0.998, P<0.001). CONCLUSIONS: Measurable benefit from a defibrillator to patients' life spans (life-years gained) is dramatically dependent on the time window over which the benefit is assessed. Because the effort of implantation is front loaded, yet benefit grows with time, the choice of an early time point artificially reduces apparent benefit and artificially increases the apparent number needed to treat to prevent an event. These are useful considerations for the formulation of treatment policy (and even for planning of the follow-up phase of clinical trials).

Chronic heart failure patients with restrictive LV filling pattern have significantly less benefit from cardiac resynchronization therapy than patients with late LV filling pattern.

BACKGROUND: Cardiac resynchronization fails to improve symptoms in up to one third of patients meeting criteria for this treatment, for reasons which are unclear. Indeed, the very mechanism of benefit from resynchronization is controversial. Resynchronization may work by improving ventricular filling: we tested the hypothesis that benefit from resynchronization depends on filling pattern. METHODS AND RESULTS: We assessed symptoms (NYHA class) and LV filling of 40 patients with chronic heart failure and prolonged QRS who underwent resynchronization. Fifteen had restrictive filling pattern (E velocity>or=1.0 m/s, E/A ratio>1 and E wave deceleration time

Cardiac resynchronisation may reduce all-cause mortality: meta-analysis of preliminary COMPANION data with CONTAK-CD, InSync ICD, MIRACLE and MUSTIC.

Landmark trials have demonstrated that biventricular pacing (also called cardiac resynchronisation therapy or CRT) in chronic heart failure due to left ventricular dysfunction improves symptomatic status, exercise capacity and quality of life. Yet critically, all-cause mortality has not been demonstrated to be reduced in any of the four randomised controlled trials with mortality data (CONTAK-CD, InSync implantable-cardioverter defibrillator (ICD), MIRACLE and MUSTIC). With the much larger COMPANION study now terminated, however, the currently available pooled data from all five trials shows a significant reduction in all-cause mortality, odds ratio (OR), 0.74: 95% confidence interval (CI) 0.56-0.97. This may now establish biventricular pacing as a standard therapy for a specific subset of patients with chronic heart failure and LBBB.

Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker).

BACKGROUND: While treatment with either angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) is clearly superior to placebo in the treatment of heart failure patients, controversy still surrounds the effects of ARBs in patients already receiving an ACEi. Even more controversial is the wisdom of administering ARBs in patients already on an ACEi and beta-blocker. METHODS: We present meta-analyses of the available randomised controlled trials to date (October 2003) of angiotensin II receptor antagonists versus placebo in patients with symptomatic chronic heart failure in which both groups received ACEi. The two largest eligible trials were CHARM-Added and Val-HeFT. We examined two endpoints: mortality and a combined endpoint of mortality and morbidity. RESULTS: In the first meta-analysis, covering all patients regardless of beta-blocker use, we found a significant reduction in the combined endpoint (odds ratio [OR]=0.89; 95% confidence interval [CI] 0.81-0.98), but no significant reduction in mortality itself (OR=0.97; CI: 0.87-1.08). In the second meta-analysis, covering patients concomitantly on beta-blockers, we found no significant effect on mortality (OR=1.08; CI: 0.90-1.29) or on the combined endpoint (OR=0.94; CI: 0.82-1.10). In the third meta-analysis, covering patients not on concomitant beta-blockers, there is clear evidence of a reduction in the combined endpoint (OR=0.83; CI: 0.73-0.94), but not on mortality (OR=0.93; CI: 0.81-1.06). CONCLUSION: There is now good evidence for the use of ARBs to prevent events in patients with heart failure on ACEi who are not suitable for beta-blockers.

One swallow does not a summer make: safety and renal denervation.

Renal denervation is increasingly being adopted as a treatment option in patients with resistant hypertension. The long-term safety of this procedure is unknown. Though the procedure interrupts the sympathetic nerves at the renal level, it also has effects on other organ beds, notably the heart and vasculature. These effects have been purported to be clinically beneficial and thus formed a rationale for examining the role of renal denervation in other conditions, including heart failure, arrhythmia, obstructive sleep apnoea and the metabolic syndrome. There is a theoretical concern that attenuating the renal sympathetic nerves might cause orthostatic hypotension or syncope. From the limited data available from hypertension trials, the procedure has not been associated with excessive episodes of syncope and this is supported by mechanistic tilt table data in asymptomatic patients. Ultimately, the safety of this technique will only be established once we have larger phase III/IV studies.

Prognostic role of subsequent atrial tachycardias occurring during ablation of persistent atrial fibrillation: a prospective randomized trial.

BACKGROUND: The role of subsequent atrial tachycardias (AT) in the context of persistent atrial fibrillation (AF) remains undetermined. This study evaluated the prognostic role of subsequent ATs for arrhythmia recurrences after catheter ablation of persistent AF. METHODS AND RESULTS: A total of 110 patients with persistent AF (63±9 years; 22 women; 61 long-lasting persistent AF) underwent pulmonary vein isolation followed by electrogram-guided ablation. After AF terminated to AT, patients were separated by the randomization protocol to receive either direct cardioversion (group A) or further ablation of subsequent ATs to sinus rhythm (group B). After a mean follow-up of 20.1±13.3 months after the first procedure, significantly more group B patients were in sinus rhythm as compared with patients in group A (30 [57%] versus 18 [34%]; P=0.02). Moreover, recurrences of AF were significantly less frequent of group B than in group A patients (10 [19%] versus 26 [49%]; P=0.001). After the last procedure (follow-up, 34.0±6.4 months), significantly more group B patients were free of AF as compared with patients of group A (49 [92%] versus 39 [74%]; P=0.01). The proportion of AT recurrences did not differ between the 2 groups after the first and final procedures. The strongest predictor for an arrhythmia-free survival after a single procedure was randomization to the procedural end point of termination to sinus rhythm by elimination of subsequent ATs (P=0.004). CONCLUSIONS: Catheter ablation of subsequent ATs increases freedom from AF but not AT, suggesting a contributing role of subsequent ATs in the mechanisms of persistent AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01896570.