Reconnection Rate and Long-Term Outcome with Adenosine Provocation During Cryoballoon Ablation for Pulmonary Vein Isolation.

BACKGROUND: Adenosine can unmask dormant conduction during pulmonary vein isolation (PVI) for atrial fibrillation (AF). Studies of adenosine use in radiofrequency PVI show high reconnection rates and conflicting results for long-term success, however there is limited data with cryoballoon ablation (CBA). METHODS: A prospectively maintained database of patients undergoing first CBA at a single institution was analyzed. Adenosine use was at the discretion of the primary operator. Additional freezes were delivered for reconnected veins until dormant conduction was eliminated. The primary endpoint, time to AF recurrence defined as any episode < 30 seconds after a 3-month blanking period, was assessed by Kaplan-Meier analysis. RESULTS: From 2011 to 2015, 406 patients underwent CBA, 361 of whom had > 3 months follow-up. The mean age was 61.7 years, 69% were male, and the prevalence of paroxysmal AF was 79% with no significant difference between those that did and did not receive adenosine (77% vs 86%, respectively, p = 0.23). Adenosine testing was performed in 78 patients (21.6%) with a mean dose of 10.6 mg/vein. Of the 306 veins evaluated, 17 (6%) demonstrated dormant conduction. Over a median 14.4 months follow-up, there was no significant difference in freedom from AF with adenosine use (p= 0.86). CONCLUSIONS: Dormant conduction with adenosine is uncommon following CBA and its use does not improve long-term success rates.

Current and Emerging Uses of Insertable Cardiac Monitors: Evaluation of Syncope and Monitoring for Atrial Fibrillation.

Insertable cardiac monitors (ICMs) have provided clinicians with a superb tool for assessing infrequent or potentially asymptomatic arrhythmias. ICMs have shown their usefulness in the evaluation of unexplained syncope, providing high diagnostic yields in a cost-effective manner. While unexplained syncope continues to be the most common reason for their use, ICMs are increasingly being used for the monitoring of atrial fibrillation (AF). Recent trials have demonstrated that a substantial proportion of patients with cryptogenic stroke have AF detected only by the prolonged monitoring provided by ICMs. A particularly promising and emerging use for ICMs is in the management of anticoagulation in patients with known paroxysmal AF. The introduction in recent years of ICMs with automatic AF detection algorithms and continuous remote monitoring in combination with novel oral anticoagulants have opened the door for targeted anticoagulation guided by remote monitoring, a strategy that has recently shown promise in pilot studies of this technique. While further research is needed before official recommendations can be given, this use of ICMs opens exciting new possibilities for personalized medicine that could potentially reduce bleeding risk and improve quality of life in patients with atrial fibrillation.

The Safety of Cardiac and Thoracic Magnetic Resonance Imaging in Patients with Cardiac Implantable Electronic Devices.

RATIONALE AND OBJECTIVES: Studies reporting the safety of magnetic resonance imaging (MRI) in patients with a cardiac implantable electronic device (CIED) have mostly excluded examinations with the device in the magnet isocenter. The purpose of this study was to describe the safety of cardiac and thoracic spine MRI in patients with a CIED. MATERIALS AND METHODS: The medical records of patients with a CIED who underwent a cardiac or thoracic spine MRI between January 2011 and December 2014 were reviewed. Devices were interrogated before and after imaging with reprogramming to asynchronous pacing in pacemaker-dependent patients. The clinical interpretability of the MRI and peak and average specific absorption rates (SARs, W/kg) achieved were determined. RESULTS: Fifty-eight patients underwent 51 cardiac and 11 thoracic spine MRI exams. Twenty-nine patients had a pacemaker and 29 had an implantable cardioverter defibrillator. Seventeen percent (n = 10) were pacemaker dependent. Fifty-one patients (89%) had non-MRI-conditional devices. There were no clinically significant changes in atrial and ventricular sensing, impedance, and threshold measurements. There were no episodes of device mode changes, arrhythmias, therapies delivered, electrical reset, or battery depletion. One study was prematurely discontinued due to a patient complaint of chest pain of which the etiology was not determined. Across all examinations, the average peak SAR was 2.0 ± 0.85 W/kg with an average SAR of 0.35 ± 0.37 W/kg. Artifact significantly limiting the clinical interpretation of the study was present in 33% of cardiac MRI studies. CONCLUSIONS: When a comprehensive CIED magnetic resonance safety protocol is followed, the risk of performing 1.5-T magnetic resonance studies with the device in the magnet isocenter, including in patients who are pacemaker dependent, is low.

Modulation of Cardiac Potassium Current by Neural Tone and Ischemia.

The cardiac action potential is generated by intricate flows of ions across myocyte cell membranes in a coordinated fashion to control myocardial contraction and the heart rhythm. Modulation of the flow of these ions in response to a variety of stimuli results in changes to the action potential. Abnormal or altered ion currents can result in cardiac arrhythmias. Abnormalities of autonomic regulation of potassium current play a role in the genesis of cardiac arrhythmias, and alterations in acetylcholine-activated potassium channels may play a key role in atrial fibrillation. Ischemia is another important modulator of cardiac cellular electrophysiology.

Appropriate Implantable Defibrillator Therapy in Adults With Hypertrophic Cardiomyopathy.

INTRODUCTION: Implantable cardioverter-defibrillators (ICDs) are effective at terminating the ventricular arrhythmias that cause sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). However, identifying patients at risk for SCD remains an ongoing challenge. METHODS AND RESULTS: We retrospectively studied all adult patients with HCM treated with ICDs at our referral center from 2000 to 2013 to determine the risk factor profile, rates of appropriate ICD therapy, and complications associated with ICD implantation and discharge. Over a mean follow-up period of 5.2 ± 4.5 years, ICDs provided appropriate therapy to 25 of 135 patients (2.6%/year for primary prevention, 9.8%/year for secondary prevention). Established risk factors for SCD were equally prevalent among patients who received appropriate therapy and those who did not. There were similar rates of appropriate therapy for primary prevention patients with each risk factor. Patients with multiple risk factors had similar rates of appropriate therapy to patients with a single risk factor. Patients who underwent implantation at a younger age were more likely to experience appropriate therapy. Inappropriate therapy occurred in 27 of 135 patients (20%). CONCLUSIONS: These data indicate that the rate of appropriate ICD therapy for primary prevention in a contemporary adult HCM population is lower than previously reported. The frequency of appropriate therapy was equally modest regardless of the nature and number of risk factors that led to ICD implantation, and patients with multiple risk factors for SCD did not have an increased rate of appropriate therapy.

Real-world performance of an enhanced atrial fibrillation detection algorithm in an insertable cardiac monitor.

BACKGROUND: Insertable cardiac monitors (ICMs) are used for long-term ECG monitoring. The Reveal LINQ ICM has an improved atrial fibrillation (AF) detection algorithm. OBJECTIVE: The purpose of this study was to investigate the algorithm's real-world performance in patients with syncope, cryptogenic stroke, and known AF. METHODS: Consecutive patients with implanted ICM and AF detection parameters automatically set and maintained depending on the indication for monitoring were included. A single reviewer annotated all stored episodes after ICM implant. A second reviewer annotated a random sample of 10% of all detected AF episodes. The episode detection positive predictive value as well as true and false detection rates were determined for AF episodes of different durations. RESULTS: The study enrolled 3759 patients (1604 [43%] with syncope, 1049 [28%] with known AF, 1106 [29%] with cryptogenic stroke). Overall, 20,659 AF episodes were detected in 1020 patients. The gross episode detection positive predictive value was 84%, 73%, and 26% for all episodes (≥2 minutes) and improved to 97%, 95%, and 91% for detected AF episodes ≥1 hour in the syncope, known-AF, and cryptogenic stroke patient cohorts, respectively. The true (and false) detection rate was 0.23 (0.05), 3.8 (1.4), and 0.23 (0.65) per patient-month of monitoring for the syncope, known-AF, and cryptogenic stroke patient cohorts, respectively. Limiting ECG storage to the longest detected AF episode significantly reduced the burden of episode adjudication without significantly compromising the identification of patients with true AF. CONCLUSION: The performance of LINQ ICM is dependent on the AF incidence rate in the population being monitored, the programmed sensitivity of AF algorithm, and the duration of detected AF episodes.

Constitutive Expression of a Dominant-Negative TGF-ß Type II Receptor in the Posterior Left Atrium Leads to Beneficial Remodeling of Atrial Fibrillation Substrate.

RATIONALE: Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure. Transforming growth factor-ß (TGF-ß) signaling is thought to be intricately involved in creation of atrial fibrosis. OBJECTIVE: We hypothesized that gene-based expression of dominant-negative type II TGF-ß receptor (TGF-ß-RII-DN) in the posterior left atrium in a canine heart failure model will sufficiently attenuate fibrosis-induced changes in atrial conduction and restitution to decrease AF. Because AF electrograms are thought to reflect AF substrate, we further hypothesized that TGF-ß-RII-DN would lead to increased fractionation and decreased organization of AF electrograms. METHODS AND RESULTS: Twenty-one dogs underwent injection+electroporation in the posterior left atrium of plasmid expressing a dominant-negative TGF-ß type II receptor (pUBc-TGFß-DN-RII; n=9) or control vector (pUBc-LacZ; n=12), followed by 3 to 4 weeks of right ventricular tachypacing (240 bpm). Compared with controls, dogs treated with pUBC-TGFß-DN-RII demonstrated an attenuated increase in conduction inhomogeneity, flattening of restitution slope and decreased duration of induced AF, with AF electrograms being more fractionated and less organized in pUBc-TGFß-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, p-SMAD2/3 and p-ERK1/2. CONCLUSIONS: Targeted gene-based reduction of TGF-ß signaling in the posterior left atrium-with resulting decrease in replacement fibrosis-led to beneficial remodeling of both conduction and restitution characteristics of the posterior left atrium, translating into a decrease in AF and increased complexity of AF electrograms. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

Cardiac Monitoring for Atrial Fibrillation in Cryptogenic Stroke.

Despite an extensive initial evaluation, the cause of up to a third of ischemic strokes remains undetermined. The detection of atrial fibrillation (AF) in these patients with cryptogenic stroke is critical as the diagnosis of AF would warrant anticoagulation to reduce the risk of recurrent stroke. Observational studies and prospective randomized controlled trials have shown that a substantial proportion of patients with cryptogenic stroke have AF detected by post-stroke cardiac monitoring with higher AF detection rates observed with longer monitoring periods.

Targeted Anticoagulation for Atrial Fibrillation Guided by Continuous Rhythm Assessment With an Insertable Cardiac Monitor: The Rhythm Evaluation for Anticoagulation With Continuous Monitoring (REACT.COM) Pilot Study.

INTRODUCTION: Chronic anticoagulation is recommended for patients with AF and additional stroke risk factors, even during long periods of sinus rhythm. Continuous rhythm assessment with an insertable cardiac monitor (ICM) and use of rapid onset novel oral anticoagulants (NOACs) allow for targeted anticoagulation only around an AF episode, potentially reducing bleeding complications without compromising stroke risk. METHODS: This multicenter, single-arm study enrolled patients on NOAC with nonpermanent AF and CHADS2 score 1 or 2. After a 60-day run-in with no AF episodes ≥ 1 hour, NOACs were discontinued but reinitiated for 30 days following any AF episode ≥ 1 hour diagnosed through daily ICM transmissions. Major endpoints included time on NOAC, stroke, and bleeding. RESULTS: Among 59 enrollees, 75% were male, age 67 ± 8 years, 76% paroxysmal AF, 69% had prior AF ablation, and mean CHADS2 score 1.3 ± 0.5. Over 466 ± 131 mean days of follow-up there were 24,004 ICM transmissions with a compliance rate of 98.7%. A total of 35 AF episodes ≥ 1 hour occurred in 18 (31%) patients, resulting in a total time on NOAC of 1,472 days. This represents a 94% reduction in the time on NOAC compared to chronic anticoagulation. There were three traumatic bleeds (all on aspirin), three potential transient ischemic attacks (all on aspirin with CHADS2 score of 1), and no strokes or deaths. CONCLUSIONS: A targeted strategy of ICM-guided intermittent NOAC administration is feasible. A large-scale trial is necessary to evaluate the safety of this approach.

Management of device-detected atrial high-rate episodes.

Atrial tachyarrhythmias are common in patients with cardiac implantable electronic devices (CIEDs) with atrial leads. These atrial tachyarrhythmias are detected as atrial high-rate episodes (AHREs) by the CIED. AHREs may be brief, infrequent, and asymptomatic, and may be detected before clinical arrhythmia is apparent. These subclinical device-detected AHREs are associated with an increased stroke risk, similar to, but to a lesser degree than, clinically apparent atrial fibrillation detected by routine methods. Whether a specific duration of AHREs is needed before the risk of stroke increases and whether treatment with anticoagulation for subclinical device-detected AHREs reduces stroke risk is unclear.

The Reveal LINQ insertable cardiac monitor.

Insertable cardiac monitors (ICMs) are leadless subcutaneous devices that continuously monitor the heart rhythm and record events over a timeframe measured in years, allowing for the diagnosis of infrequent rhythm abnormalities that can be the cause of palpitations, syncope and stroke. To date, ICMs have primarily been used in the work-up and management of syncope; however, their use in other areas of rhythm evaluation, particularly atrial fibrillation monitoring, is increasing. The Reveal LINQ™ is the smallest and most versatile ICM available and represents a dramatic leap forward in ICM technology that has the potential to transform patient care in a number of circumstances. Device miniaturization, simplified implant procedure and enhanced automation vastly increase physician and patient acceptance. The next 5 years can be expected to bring a greatly increased use of ICMs for disease diagnosis and management in a variety of clinical settings.

The Impact of Early Detection of Atrial Fibrillation on Stroke Outcomes.

Early detection of atrial fibrillation (AF) before an AF-related stroke potentially allows for prevention, but the best methods are uncertain. Population screening trials have demonstrated the ability to increase detection in older individuals by systematic screening. The subset of patients with implantable cardiac rhythm management devices are at particular risk. Remote monitoring has substantially reduced the time to detection. Although primary prevention of stroke is a priority, detection in patients with cryptogenic stroke represents another opportunity for therapeutic intervention. Evidence that early detection actually leads to improved stroke outcomes is still being gathered.

Risk of stroke and atrial fibrillation after radiofrequency catheter ablation of typical atrial flutter.

BACKGROUND: Studies suggest that 18%-50% of the patients develop atrial fibrillation (AF) after typical atrial flutter (AFL) ablation. However, little data exist about the incidence of and risk factors for stroke and AF after successful ablation of typical AFL. OBJECTIVES: To determine the risk of stroke and AF after radiofrequency ablation of typical AFL. METHODS: A retrospective review of patients undergoing AFL ablation between 2002 and 2010 was performed to determine the incidence of and risk factors for stroke and AF after successful ablation of typical AFL. RESULTS: The study cohort consisted of 126 patients (age 66 ± 10 years) with a mean follow-up of 40 ± 30 months after ablation. Following successful AFL ablation, AF occurred in 46 patients (37%), with an incidence of 104 cases of documented AF per 1000 person-years after AFL ablation. Twenty patients (16%) developed new AF after AFL ablation. Stroke occurred in 8 patients (6%) during follow-up, with an incidence of 21 strokes per 1000 person-years. Six of the 8 patients (75%) with strokes had documented AF occurrences after AFL ablation. The presence of AF after AFL ablation was the only risk factor associated with the risk for future stroke. CONCLUSIONS: Patients with typical AFL undergoing successful ablation are at an elevated risk for AF and stroke following the procedure. Because postprocedure AF is the only identifiable risk factor for stroke, rigorous monitoring of patients after typical AFL may help identify those patients who are at an increased risk for stroke.

Randomized ablation strategies for the treatment of persistent atrial fibrillation: RASTA study.

BACKGROUND: The single-procedure efficacy of pulmonary vein isolation (PVI) is less than optimal in patients with persistent atrial fibrillation (AF). Adjunctive techniques have been developed to enhance single-procedure efficacy in these patients. We conducted a study to compare 3 ablation strategies in patients with persistent AF. METHODS AND RESULTS: Subjects were randomized as follows: arm 1, PVI + ablation of non-PV triggers identified using a stimulation protocol (standard approach); arm 2, standard approach + empirical ablation at common non-PV AF trigger sites (mitral annulus, fossa ovalis, eustachian ridge, crista terminalis, and superior vena cava); or arm 3, standard approach + ablation of left atrial complex fractionated electrogram sites. Patients were seen at 6 weeks, 6 months, and 1 year; transtelephonic monitoring was performed at each visit. Antiarrhythmic drugs were discontinued at 3 to 6 months. The primary study end point was freedom from atrial arrhythmias off antiarrhythmic drugs at 1 year after a single-ablation procedure. A total of 156 patients (aged 59±9 years; 136 males; AF duration, 47±50 months) participated (arm 1, 55 patients; arm 2, 50 patients; arm 3, 51 patients). Procedural outcomes (procedure, fluoroscopy, and PVI times) were comparable between the 3 arms. More lesions were required to target non-PV trigger sites than a complex fractionated electrogram (33±9 versus 22±9; P<0.001). The primary end point was achieved in 71 patients and was worse in arm 3 (29%) compared with arm 1 (49%; P=0.04) and arm 2 (58%; P=0.004). CONCLUSIONS: These data suggest that additional substrate modification beyond PVI does not improve single-procedure efficacy in patients with persistent AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00379301.

Human papillomavirus vaccines for the prevention and treatment of cervical cancer.

The identification of human papillomavirus (HPV) as a cause of cervical cancer and its precursor lesions indicates that HPV vaccines can potentially be used to prevent or treat cervical cancer and other HPV-associated malignancies. Prophylactic HPV vaccines aim to prevent infection by producing neutralizing antibodies against HPV capsid proteins L1 and L2. However, because HPV-infected basal keratinocytes and HPV-transformed cells generally do not express L1 or L2, therapeutic HPV vaccines are being developed to treat established HPV infections and HPV-associated malignancies by targeting non-structural early viral antigens of HPV, such as E6 and E7 (two viral oncogenic proteins required for the induction and maintenance of malignant cancer). Results from preclinical HPV vaccine studies have led to several HPV vaccine clinical trials. If these prophylactic and therapeutic HPV vaccines prove as successful in patients as they have in animal models, HPV vaccines may have a role in the control of HPV infection and HPV-associated disease.