Ivabradine for controlling heart rate in permanent atrial fibrillation: A translational clinical trial.

BACKGROUND: Pharmacological options for rate control in atrial fibrillation are scarce. Ivabradine was postulated to reduce the ventricular rate in this setting. OBJECTIVES: The objectives of this study were to evaluate the mechanism of inhibition of atrioventricular conduction produced by ivabradine and to determine its efficacy and safety in atrial fibrillation. METHODS: The effects of ivabradine on atrioventricular node and ventricular cells were studied by in vitro whole-cell patch-clamp experiments and mathematical simulation of human action potentials. In parallel, a multicenter, randomized, open-label, phase III clinical trial compared ivabradine with digoxin for uncontrolled permanent atrial fibrillation despite ß-blocker or calcium channel blocker treatment. RESULTS: Ivabradine 1 µM inhibited "funny" current and rapidly activating delayed rectifier potassium channel current by 28.9% and 22.8%, respectively (P < .05). The sodium channel current and L-type calcium channel current were reduced only at 10 µM. Ivabradine slowed the firing frequency of a modeled human atrioventricular node action potential by 10.6% and induced a minimal prolongation of ventricular action potential. Thirty-five (51.5%) patients were randomized to ivabradine and 33 (49.5%) to digoxin. The mean daytime heart rate decreased by 11.6 beats/min (-11.5%) in the ivabradine arm (P = .02) vs 19.6 (-20.6%) in the digoxin arm (P < .001), although the noninferiority margin of efficacy was not met (Z = -1.95; P = .97). The primary safety end point occurred in 3 patients (8.6%) on ivabradine and in 8 (24.2%) on digoxin (P = .10). CONCLUSION: Ivabradine produced a moderate rate reduction in patients with permanent atrial fibrillation. The inhibition of funny current in the atrioventricular node seems to be the main mechanism responsible for this reduction. Compared with digoxin, ivabradine was less effective, was better tolerated, and had a similar rate of serious adverse events.

Stabilization of unstable reentrant atrial tachycardias via fractionated continuous electrical activity ablation (CHAOS study).

BACKGROUND: Unstable reentrant atrial tachycardias (ATs) (i.e., those with frequent circuit modification or conversion to atrial fibrillation) are challenging to ablate. We tested a strategy to achieve arrhythmia stabilization into mappable stable ATs based on the detection and ablation of rotors. METHODS: All consecutive patients from May 2017 to December 2019 were included. Mapping was performed using conventional high-density mapping catheters (IntellaMap ORION, PentaRay NAV, or Advisor HD Grid). Rotors were subjectively identified as fractionated continuous (or quasi-continuous) electrograms on 1-2 adjacent bipoles, without dedicated software. In patients without detectable rotors, sites with spatiotemporal dispersion (i.e., all the cycle length comprised within the mapping catheter) plus non-continuous fractionation on single bipoles were targeted. Ablation success was defined as conversion to a stable AT or sinus rhythm. RESULTS: Ninety-seven patients with reentrant ATs were ablated. Of these, 18 (18.6%) presented unstable circuits. Thirteen (72%) patients had detectable rotors (median 2 [1-3] rotors per patient); focal ablation was successful in 12 (92%). In the other 5 patients, 17 sites with spatiotemporal dispersion were identified and targeted. Globally, and excluding 1 patient with spontaneous AT stabilization, ablation success was achieved in 16/17 patients (94.1%). One-year freedom from atrial arrhythmias was similar between patients with unstable and stable ATs (66.7% vs. 65.8%, p = 0.946). CONCLUSIONS: Most unstable reentrant ATs show detectable rotors, identified as sites with single-bipole fractionated quasi-continuous signals, or spatiotemporal dispersion plus non-continuous fractionation. Ablation of these sites is highly effective to stabilize the AT or convert it into sinus rhythm.

Automatic identification of areas with low-voltage fragmented electrograms for the detection of the critical isthmus of atypical atrial flutters.

INTRODUCTION: Critical isthmuses of atypical atrial flutters (AAFLs) are usually located at slow conduction areas that exhibit fractionated electrograms. We tested a novel software, intended for integration with a commercially available navigation system, that automatically detects fractionated electrograms, to identify the critical isthmus in patients with AAFL ablation. METHODS AND RESULTS: All available patients were analyzed; 27 patients with 33 AAFLs were included. The PentaRay NAV catheter (Biosense Webster) was used for mapping. The novel software was retrospectively applied; fractionated points with duration ≥80 ms and bipolar voltage between 0.05 and 0.5 mV were highlighted on the surface of maps. In 10 randomly chosen AAFLs, an expert electrophysiologist evaluated the positive predictive value of the algorithm to detect true fractionation: 74.4%. We tested the capacity of the software to identify areas of fractionation (defined as clusters of ≥3 adjacent points with fractionation) at the critical isthmus of the AAFLs (defined using conventional mapping criteria). An area of fractionation was identified at the critical isthmus in 30 cases (91%). Globally, 144 areas of fractionation (median number per AAFL 4 [3-6]) were identified. Duration of the fractionation or the surface of the areas was not different between areas at critical isthmuses and the rest. Setting the fractionation score filter of the software in nine provided best performance. CONCLUSIONS: The novel software detected areas of fractionation at the critical isthmus in most AAFLs, which may help identify the critical isthmus in clinical practice.

High-density mapping with fragmentation analysis in patients with reentrant atrial tachycardias (MAP-FLURHY study).

PURPOSE: Reentrant atrial tachycardias (ATs) use areas of slow conduction that can be visualized as fragmented electrograms. We aimed to test an ablation strategy based on the identification and ablation of spots with fragmented electrograms in reentrant ATs, using Rhythmia navigation system. METHODS: All consecutive patients from June 2016 to June 2019 were included. The IntellaMap ORION Catheter was used to detect sites with fragmentation, arbitrarily defined as fragmented electrograms > 70 ms. Entrainment was used to check if these areas belonged to the AT circuit. Ablation targeted the longest fragmented electrogram within the circuit: focal ablation for microreentries and lines for macroreentries. Ablation success was defined from each AT as conversion to sinus rhythm or another AT. RESULTS: Twenty-seven consecutive patients with 44 mappable ATs were included. All ATs showed sites with fragmented electrograms (104 sites; 2.4 sites per AT); 43/44 ATs had fragmented electrograms within the circuit, which were the target of ablation. Ablation success: 34/36 ATs (94%); success could not be assessed in 8 circuits, in 6 due to mechanical conversion to sinus rhythm at the target fragmented site. Fragmented electrograms within the AT circuits were longer than electrograms outside the circuits (110 ± 30 vs 90 ± 15 ms, p < 0.001). A fragmentation duration > 100 ms/ > 40% of the AT cycle length predicted to be a successful site for ablation with 72.3%/73.8% specificity, respectively. Sixty-two percent of the patients were free from atrial arrhythmias at 1 year. CONCLUSIONS: Most ATs had detectable fragmented electrograms within the circuit, which could be the target of ablation with high efficacy.

Heart failure hospitalization reduction and cost savings achieved by improved delivery of effective biventricular pacing: economic implications of the OLE study under the US setting.

Background: The hOLter for Efficacy analysis (OLE) study demonstrated that current device pacing diagnostics overestimate the amount of cardiac resynchronization therapy (CRT) pacing that effectively stimulates the cardiac tissue. Sub-optimal pacing increases mortality, hospitalizations, and associated health-care costs. We sought to estimate the expected number of hospital admissions due to heart failure (HF) and its respective financial impact in patients with maximized effective pacing versus conventional pacing. Methods: A Markov model was developed to project HF hospitalizations and quantify the costs that could be avoided if pacing was maximally effective. OLE data were used to inform the prevalence of ineffective pacing among CRT patients and and average loss of pacing by causes. Adaptive CRT trial data quantified the reduction in underlying hospitalization risk by increasing effective pacing delivered. Survival was informed by a meta-analysis of 5 randomized clinical trials. Costs were analyzed from a US payer perspective. Results: Projected average hospitalizations totaled 4.58 over a lifetime horizon for CRT patients with conventional pacing. Maximizing effective pacing delivery was projected to avoid 1.83 HF admissions/patient over the lifetime. This equates to a savings of 40% (US$22,802) compared with conventional pacing from the Medicare perspective. In a sensitivity analysis, CRT with effective pacing was projected to provide cost savings in all scenarios. Conclusions: Maximized effective pacing leads to a lower number of HF hospitalizations, thus allowing significant cost offsets in the US setting.

Energy Dissipation in Resynchronization Therapy: Impact of Atrioventricular Delay.

BACKGROUND: Optimal atrioventricular delay (AVD) achieves maximum cardiac output in patients undergoing cardiac resynchronization therapy (CRT). Nonoptimal AVD decreases left ventricular (LV) end-diastolic volume and causes loss of flow momentum prior to LV ejection. OBJECTIVE: We investigated the potential role of energy dissipation (ED) in these changes in cardiac output through the study of intraventricular flow. We hypothesized that short and long AVD increases ED when compared with optimal AVD by altering the physiologic flow mechanics that preserve kinetic energy in the LV. METHODS: Forty-four patients under CRT underwent echocardiographic LV flow analysis under optimal, short, and long AVD. LV ED and vortical flow in the inflow-outflow tract were studied during the end-diastolic and early systolic period, and paired comparisons were obtained between optimal and nonoptimal values. RESULTS: ED in the left ventricle was minimal in optimal AVD and significantly increased with nonoptimal values (79.1 ± 27.5 J/m·sec in optimal AVD vs 96.5 ± 34.7 J/m·sec in short AVD; n = 18, P = .006; 123.3 ± 67.6 J/m·sec in optimal AVD vs 292.4 ± 202.5 J/m·sec in long AVD; P < .001). Increase in ED occurred due to inadequate flow redirection toward the outflow tract in short AVD and due to both turbulence and prolonged ineffective flow rotation in long AVD. CONCLUSIONS: Optimal AVD in resynchronization therapy favors physiological vortex flow patterns in the left ventricle during the end-diastolic and early systolic period. These patterns are altered when nonoptimal values are programmed, increasing ED.

Contact force-sensing catheters: performance in an ex vivo porcine heart model.

PURPOSE: Contact force (CF) catheters are useful to address proper contact during ablation. However, interactions between the ablation process, or its associated irrigation flow changes, with the CF sensing may translate into unexpected CF value fluctuations. We aimed to test for unintentional CF value variations during radiofrequency applications at a fixed applied force, with two commercially available catheters (TactiCath™ and SmartTouch™), and to evaluate its theoretical clinical significance by correlating CF-derived automatic ablation algorithms (force-time integral and lesion index) and actual lesion size at two standard CF values. METHODS: Four series of 20 perpendicular epicardial ablations (20 W, 60 s, 17 ml/min) were performed on porcine left ventricle submerged in 37 °C saline. Catheters were mechanically fixed at a constant position and evaluated at 10 and 20 g. CF values were digitally analysed before each application changing irrigation rate (2-17-30 ml/min), and during ablation. Finally, lesions were quantified. RESULTS: Increasing irrigation before ablation led to a slight but significant CF decrease. During ablation, CF showed a reproducible pattern: fast initial decrease, subsequent increase until higher-than-initial values and final plateau phase (CF variation up to 69% at 10 g). CF variability was significantly higher at 10 g and using TactiCath™. There were no major differences in lesion size between catheters at the same initial CF. CF only correlated mildly to lesion measures, and automatic algorithms globally failed to predict lesion size. CONCLUSIONS: CF measured values spontaneously vary during ablation following a predictable pattern (initial decrease, subsequent increase and final plateau). This is especially remarkable applying lower CF.

Device pacing diagnostics overestimate effective cardiac resynchronization therapy pacing results of the hOLter for Efficacy analysis of CRT (OLÉ CRT) study.

BACKGROUND: A high percentage of biventricular (BiV) or left ventricular (LV) pacing in cardiac resynchronization therapy (CRT) devices has been associated with superior clinical outcomes. However, the percent ventricular (%V) pacing reported by CRT devices simply indicates the number of paces the device has delivered and not the proportion of pacing that has captured the LV effectively. OBJECTIVE: The purpose of this study was to determine whether a beat-by-beat evaluation of effective pacing would provide a more accurate evaluation of CRT delivery. METHODS: An automatic electrogram (EGM)-based algorithm that classifies each LV pace as effective or ineffective based on detection of QS/QS-r morphology on the unipolar LV EGM during pacing was developed and validated. LV EGMs that were recorded by 24-hour Holter from 57 CRT patients were postprocessed. The percent effective CRT (%e-CRT) pacing was calculated by dividing the time spent in e-CRT pacing by the total time of the recording. RESULTS: In this CRT cohort, the average %V pacing (94.8% ± 8%) significantly overestimated the %e-CRT pacing (87.5% ± 23%; P <.001). A significant minority of subjects (18%) had a discrepancy of at least 3 percentage points between %V pacing and %e-CRT pacing (mean 39% ± 41%). CONCLUSION: Current device pacing diagnostics overestimate the amount of CRT pacing actually delivered. The new algorithm quantifies ineffective CRT pacing, which enables clinicians to identify patients with this issue and to address the reasons behind suboptimal CRT delivery.

An Automatic Algorithm Based on Morphological Stability During Fast Ventricular Arrhythmias Predicts Successful Antitachycardia Pacing in ICD Patients: A Multicenter Study.

BACKGROUND: Different types of ventricular arrhythmias (monomorphic ventricular tachycardia [VT], polymorphic VT, or ventricular fibrillation) can be detected by implantable cardiac defibrillators (ICDs) in fast VT zone. The efficacy of antitachycardia pacing (ATP) depends on the type of the treated arrhythmia. We hypothesized that an automatic algorithm based on morphological affinity of ICD far-field electrograms during tachycardia can predict ATP success and the need of shock. METHODS: The algorithm was evaluated on ventricular arrhythmias recorded in CareLink ICD remote monitoring system (Medtronic Inc., Minneapolis, MN, USA). Patients were selected if first ATP programmed was a burst of eight pulses at 88% coupling interval and if a far-field electrogram was available. The algorithm calculated a stability coefficient (SC) for all their stored ATP-treated fast ventricular arrhythmia (VA) episodes (LC 200-300 ms), analyzing the morphology homogeneity of the last eight recorded far-field electrograms before ventricular arrhythmias detection. RESULTS: Inclusion criteria were fulfilled by 717 patients from 29 centers. Three hundred and twenty fast VA were recorded in 103 patients. A higher SC was observed in episodes terminated with the first-ATP (0.78 [0.72-0.84] vs 0.74 [0.60-0.84]; P = 0.006). These differences were especially marked among the 62 episodes of very fast VA (CL ≤250 ms) (0.77 [0.74-0.85] vs 0.64 [0.51-0.8]; P = 0.006). In the multivariate analysis, a SC > 70% was independently associated with a higher likelihood of first-ATP success (odds ratio [OR] = 2.5; [95% confidence interval (CI) = 1.4-4.5], P = 0.001) and a lower need of shock (OR = 0.37; [95% CI = 0.2-0.7], P = 0.002). CONCLUSION: This automatic algorithm (stability coefficient) shows that ATP therapy response can be predicted in fast ventricular arrhythmias through morphology evaluation.

Wireless Ultrasound-Guided Axillary Vein Cannulation for the Implantation of Cardiovascular Implantable Electric Devices.

INTRODUCTION: Ultrasound guidance for vascular cannulation seems safer and more effective than an anatomical landmark approach, though it has not gained widespread support partly due to workflow interference of wired probes. A wireless ultrasound transducer (WUST) may overcome this issue. We report the effectiveness, time consumption, and safety of the first-in-human experience in axillary vein cannulation guided with a novel WUST for the implantation of cardiovascular implantable electric devices (CIEDs). METHODS AND RESULTS: After a one-month training period, we routinely performed WUST-guided puncture to all first implants, prospectively registering data from the first 50 patients. We analyzed the time needed for preparing the WUST and for achieving each vein cannulation, and the rate of unsuccessful or accidental arterial punctures and complications. WUST-guided axillary vein access was successful in 49 out of 50 patients, totaling 86 cannulated veins. Median WUST preparation time was 55 [44-62] seconds and median time needed for each venous cannulation was 56 [36-71] seconds. A total of 84.9% of the veins were cannulated at the first attempt. There were 7 unsuccessful puncture attempts and 1 accidental arterial puncture. No pneumothorax, hemothorax, or nervous injury occurred in the 49 successfully cannulated patients. The unsuccessful one (distal subclavian occlusion) developed a minor local subcutaneous emphysema with no confirmed radiologic pneumothorax, not requiring intervention. During a follow-up of 2.5 ± 1.1 months, a patient developed a pocket infection, with no other significant complications. CONCLUSION: Ultrasound-guided axillary vein cannulation using a wireless transducer for the implantation of CIEDs is a feasible, fast, and safe method.

Impact of previous cardiac surgery on long-term outcome of cavotricuspid isthmus-dependent atrial flutter ablation.

AIMS: The aim of this study was to determine the acute and long-term outcome of radiofrequency catheter ablation (RFCA) for cavotricuspid isthmus-dependent atrial flutter (CTI-AFL) in adults with and without previous cardiac surgery (PCS), and predictors of these outcomes. Structural alterations of the anatomical substrate of the CTI-AFL are observed in post-operative patients, and these may have an impact on the acute success of the ablation and in the long-term. METHODS AND RESULTS: Clinical records of consecutive adults undergoing RFCA of CTI-AFL were analysed. Two main groups were considered: No PCS and PCS patients, who were further subdivided into acquired heart disease (AHD: ischaemic heart disease and valvular/mixed heart disease) and congenital heart disease [CHD: ostium secundum atrial septal defect (OS-ASD) and complex CHD]. Multivariate analysis identified clinical and procedural factors that predicted acute and long-term outcomes. A total of 666 patients (73% men, age 65 ± 12 years) were included: 307 of them with PCS. Ablation was successful in 647 patients (97%), 96% in the PCS group and 98% in the No PCS group (P = 0.13). Regression analysis showed that surgically corrected complex CHD was related to failure of the procedure [odds ratio 5.6; 95% confidence interval (CI) 1.6-18, P = 0.008]. After a follow-up of 45 ± 15 months, recurrences were observed in 90 patients (14%), more frequently in the PCS group: absolute risk of recurrence 18 vs. 10.5%, relative risk 1.71, 95% CI: 1.2-2.5, P = 0.006. Multivariate analysis indicated that the types of PCS [OS-ASD vs. No PCS: hazard ratio (HR) 2.57; 95% CI: 1.1-6.2, P = 0.03 and complex CHD vs. No PCS: HR 2.75; 95% CI: 1.41-5.48, P = 0.004], female gender (HR 1.55; 95% CI: 1.04-2.4, P = 0.048), and severe LV dysfunction (HR 1.36; 95% CI: 1.06-1.67, P = 0.04) were independent predictors of long-term recurrence. CONCLUSION: Radiofrequency catheter ablation of CTI-AFL after surgical correction of AHD and CHD is associated with high acute success rates. The severity of the structural alterations of the underlying heart disease and consequently the type of surgical correction correlates with higher risk for recurrence.

Long-Term Outcome After Ablation of Right Atrial Tachyarrhythmias After the Surgical Repair of Congenital and Acquired Heart Disease.

Atrial myopathy, atriotomies, and fibrotic scars are the pathophysiological substrate of lines of conduction block, promoting atrial macroreentry. The aim of this study was to determine the acute and long-term outcome of radiofrequency catheter ablation (RFCA) for right atrial tachyarrhythmia (AT) in adults after cardiac surgery for congenital heart disease (CHD) and acquired heart disease (AHD) and predictors of these outcomes. Clinical records of adults after surgery for heart disease undergoing RFCA of right-sided AT were analyzed retrospectively. Multivariate analyses identified clinical and procedural factors predicting acute and long-term outcomes. A total of 372 patients (69% men; age 61 ± 15 years) after surgical repair of CHD (n = 111) or AHD (n = 261) were studied. Cavotricuspid isthmus-dependent atrial flutter (CTI-AFL) was observed in 300 patients and non-CTI-AFL in 72 patients. Ablation was successful in 349 cases (94%). During a mean follow-up of 51 ± 30 months, recurrences were observed in 24.5% of patients. Multivariate analysis showed that non-CTI-AFL (hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.1 to 2.9) and CHD (HR 1.75, 95% CI 1.07 to 2.9) were independent predictors of long-term recurrences. Multivariate analysis showed that female gender (HR 2.29, 95% CI 1.6 to 3.3), surgery for AHD (HR 95% 2.31, 95% CI 1.5 to 3.7), and left atrial dilatation (HR 2.1, 95% CI 1.3 to 3.2) were independent predictors of long-term atrial fibrillation. In conclusion, RFCA of right-sided AT after cardiac surgery is associated with high acute success rates and significant long-term recurrences. Non-CTI-dependent AFL and surgery for CHD are at higher risk of recurrence. Atrial fibrillation is common during follow-up, particularly in patients with AHD and enlarged left atrium.

Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study).

BACKGROUND: Catheter ablation (CA) is a highly effective therapy for the treatment of paroxysmal atrial fibrillation (AF) when compared with antiarrhythmic drug therapy (ADT). No randomized studies have compared the two strategies in persistent AF. The present randomized trial aimed to compare the effectiveness of CA vs. ADT in treating persistent AF. METHODS AND RESULTS: Patients with persistent AF were randomly assigned to CA or ADT (excluding patients with long-standing persistent AF). Primary endpoint at 12-month follow-up was defined as any episode of AF or atrial flutter lasting >24 h that occurred after a 3-month blanking period. Secondary endpoints were any atrial tachyarrhythmia lasting >30 s, hospitalization, and electrical cardioversion. In total, 146 patients were included (aged 55 ± 9 years, 77% male). The ADT group received class Ic (43.8%) or class III drugs (56.3%). In an intention-to-treat analysis, 69 of 98 patients (70.4%) in the CA group and 21 of 48 patients (43.7%) in the ADT group were free of the primary endpoint (P = 0.002), implying an absolute risk difference of 26.6% (95% CI 10.0-43.3) in favour of CA. The proportion of patients free of any recurrence (>30 s) was higher in the CA group than in the ADT group (60.2 vs. 29.2%; P < 0.001) and cardioversion was less frequent (34.7 vs. 50%, respectively; P = 0.018). CONCLUSION: Catheter ablation is superior to medical therapy for the maintenance of sinus rhythm in patients with persistent AF at 12-month follow-up. CLINICAL TRIAL REGISTRATION INFORMATION: NCT00863213 (http://clinicaltrials.gov/ct2/show/NCT00863213).

Non-antiarrhythmic drugs to prevent atrial fibrillation.

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. The majority of patients with AF are still candidates for antiarrhythmic drug treatment, not only for acute reversion to sinus rhythm but also for long-term treatment to prevent recurrences of AF. Currently available antiarrhythmic drugs, however, are unable to provide complete efficacy in all patients, and present problematic risks of proarrhythmia. The progressively increasing prevalence of AF supports the need to develop improved therapeutic approaches for the clinical management of arrhythmia. Accordingly, new treatment techniques aimed at suppressing the origin of the arrhythmogenic foci have been developed in the last decade. However, ablative treatments are only available for selected patients. Because of these factors, and also because primary prevention of AF should be our goal, the introduction of non-antiarrhythmic agents that could prevent both new-onset AF and recurrences of AF may eventually improve patient outcomes and reduce the incidence of this epidemic disease. The potential clinical value of these non-antiarrhythmic options is currently under active investigation. There is now clinical and experimental evidence that many drugs may have beneficial effects in preventing AF through several possible mechanisms. Non-antiarrhythmic drugs, such as ACE inhibitors and angiotensin receptor blockers, HMG-CoA reductase inhibitors (statins), corticosteroids, and N-3 polyunsaturated fatty acids may have a positive effect in patients with AF or in preventing AF in patients at risk.