Raphael Martins

Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada Syndrome A Multicenter Study

Background— Implantable cardioverter-defibrillator indications in Brugada syndrome remain controversial, especially in asymptomatic patients. Previous outcome data are limited by relatively small numbers of patients or short follow-up durations. We report the outcome of patients with Brugada syndrome implanted with an implantable cardioverter-defibrillator in a large multicenter registry. Methods and Results— A total of 378 patients (310 male; age, 46±13 years) with a type 1 Brugada ECG pattern implanted with an implantable cardioverter-defibrillator (31 for aborted sudden cardiac arrest, 181 for syncope, and 166 asymptomatic) were included. Fifteen patients (4%) were lost to follow-up. During a mean follow-up of 77±42 months, 7 patients (2%) died (1 as a result of an inappropriate shock), and 46 patients (12%) had appropriate device therapy (5±5 shocks per patient). Appropriate device therapy rates at 10 years were 48% for patients whose implantable cardioverter-defibrillator indication was aborted sudden cardiac arrest, 19% for those whose indication was syncope, and 12% for the patients who were asymptomatic at implantation. At 10 years, rates of inappropriate shock and lead failure were 37% and 29%, respectively. Inappropriate shock occurred in 91 patients (24%; 4±4 shocks per patient) because of lead failure (n=38), supraventricular tachycardia (n=20), T-wave oversensing (n=14), or sinus tachycardia (n=12). Importantly, introduction of remote monitoring, programming a high single ventricular fibrillation zone (>210–220 bpm), and a long detection time were associated with a reduced risk of inappropriate shock. Conclusions— Appropriate therapies are more prevalent in symptomatic Brugada syndrome patients but are not insignificant in asymptomatic patients (1%/y). Optimal implantable cardioverter-defibrillator programming and follow-up dramatically reduce inappropriate shock. However, lead failure remains a major problem in this population.

Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada Syndrome

Background— Brugada syndrome is an arrhythmogenic disease characterized by an increased risk of sudden cardiac death (SCD) by ventricular fibrillation. At present, an implantable cardioverter-defibrillator (ICD) is the recommended therapy in high-risk patients. This multicenter study reports the outcome of a large series of patients implanted with an ICD for Brugada syndrome. Methods and Results— All patients (n=220, 46±12 years, 183 male) with a type 1 Brugada ECG pattern implanted with an ICD in 14 centers between 1993 and 2005 were investigated. ICD indication was based on resuscitated SCD (18 patients, 8%), syncope (88 patients, 40%), or positive electrophysiological study in asymptomatic patients (99 patients, 45%). The remaining 15 patients received an ICD because of a family history of SCD or nonsustained ventricular arrhythmia. During a mean follow-up of 38±27 months, no patient died and 18 patients (8%) had appropriate device therapy (10±15 shocks/patient, 26±33 months after implantation). The complication rate was 28%, including inappropriate shocks, which occurred in 45 patients (20%, 4±3 shocks/patient, 21±20 months after implantation). The reasons for inappropriate therapy were lead failure (19 patients), T-wave oversensing (10 patients), sinus tachycardia (10 patients), and supraventricular tachycardia (9 patients). Among implantation parameters, high defibrillation threshold, high pacing threshold, and low R-wave amplitude occurred, respectively, in 12%, 27%, and 15% of cases. Conclusion— In this large Brugada syndrome population, a low incidence of arrhythmic events was found, with an annual event rate of 2.6% during a follow-up of >3 years, in addition to a significant risk of device-related complications (8.9%/year). Inappropriate shocks were 2.5 times more frequent than appropriate ones.

Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada SyndromeClinical Perspective: A Multicenter Study–Part 2

Background— Implantable cardioverter-defibrillator indications in Brugada syndrome remain controversial, especially in asymptomatic patients. Previous outcome data are limited by relatively small numbers of patients or short follow-up durations. We report the outcome of patients with Brugada syndrome implanted with an implantable cardioverter-defibrillator in a large multicenter registry. Methods and Results— A total of 378 patients (310 male; age, 46±13 years) with a type 1 Brugada ECG pattern implanted with an implantable cardioverter-defibrillator (31 for aborted sudden cardiac arrest, 181 for syncope, and 166 asymptomatic) were included. Fifteen patients (4%) were lost to follow-up. During a mean follow-up of 77±42 months, 7 patients (2%) died (1 as a result of an inappropriate shock), and 46 patients (12%) had appropriate device therapy (5±5 shocks per patient). Appropriate device therapy rates at 10 years were 48% for patients whose implantable cardioverter-defibrillator indication was aborted sudden cardiac arrest, 19% for those whose indication was syncope, and 12% for the patients who were asymptomatic at implantation. At 10 years, rates of inappropriate shock and lead failure were 37% and 29%, respectively. Inappropriate shock occurred in 91 patients (24%; 4±4 shocks per patient) because of lead failure (n=38), supraventricular tachycardia (n=20), T-wave oversensing (n=14), or sinus tachycardia (n=12). Importantly, introduction of remote monitoring, programming a high single ventricular fibrillation zone (>210–220 bpm), and a long detection time were associated with a reduced risk of inappropriate shock. Conclusions— Appropriate therapies are more prevalent in symptomatic Brugada syndrome patients but are not insignificant in asymptomatic patients (1%/y). Optimal implantable cardioverter-defibrillator programming and follow-up dramatically reduce inappropriate shock. However, lead failure remains a major problem in this population.

Dominant Frequency Increase Rate Predicts Transition from Paroxysmal to Long-Term Persistent Atrial Fibrillation

Background— Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results— Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. Conclusions— In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Long-Term Frequency Gradients During Persistent Atrial Fibrillation in Sheep Are Associated With Stable Sources in the Left Atrium

Background— Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF), and left atrial (LA)-to-right atrial (RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in vivo the time course in atrial DF values from paroxysmal to persistent AF in sheep and testing the hypothesis that an LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results— AF was induced using RA tachypacing (n=8). Electrograms were obtained weekly from an RA lead and an implantable loop recorder implanted near the LA. DFs were determined for 5-second-long electrograms (QRST subtracted) during AF in vivo and in ex vivo optical mapping. Underlying structural changes were compared with weight-matched controls (n=4). After the first AF episode, DF increased gradually during a 2-week period (7±0.21 to 9.92±0.31 Hz; n=6; P<0.05). During 9 to 24 weeks of AF, the DF values on the implantable loop recorder were higher than the RA (10.6±0.08 versus 9.3±0.1 Hz, respectively; n=7; P<0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz; P<0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA. Persistent AF sheep showed significant enlargement of the posterior LA compared with controls. Conclusions— In the sheep, transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in vivo together with enlargement of the posterior LA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

Shear stress triggers insertion of voltage-gated potassium channels from intracellular compartments in atrial myocytes

Significance The heart is continuously subjected to mechanical forces. The atria in particular are susceptible to changes in the mechanical environment due to their unique position as “pressure sensors.” Here, we show that increased shear stress induces the recruitment of potassium channels from intracellular storage pools to the plasma membrane, via signaling pathways that link the extracellular matrix to the cytoskeleton. This process is altered in myocytes experiencing chronically increased mechanical stress. The incorporation of channels into the membrane causes changes in the electrical activity of the myocyte and may be an important way for cells to adapt to increased mechanical forces. Atrial myocytes are continuously exposed to mechanical forces including shear stress. However, in atrial myocytes, the effects of shear stress are poorly understood, particularly with respect to its effect on ion channel function. Here, we report that shear stress activated a large outward current from rat atrial myocytes, with a parallel decrease in action potential duration. The main ion channel underlying the increase in current was found to be Kv1.5, the recruitment of which could be directly observed by total internal reflection fluorescence microscopy, in response to shear stress. The effect was primarily attributable to recruitment of intracellular pools of Kv1.5 to the sarcolemma, as the response was prevented by the SNARE protein inhibitor N-ethylmaleimide and the calcium chelator BAPTA. The process required integrin signaling through focal adhesion kinase and relied on an intact microtubule system. Furthermore, in a rat model of chronic hemodynamic overload, myocytes showed an increase in basal current despite a decrease in Kv1.5 protein expression, with a reduced response to shear stress. Additionally, integrin beta1d expression and focal adhesion kinase activation were increased in this model. This data suggests that, under conditions of chronically increased mechanical stress, the integrin signaling pathway is overactivated, leading to increased functional Kv1.5 at the membrane and reducing the capacity of cells to further respond to mechanical challenge. Thus, pools of Kv1.5 may comprise an inducible reservoir that can facilitate the repolarization of the atrium under conditions of excessive mechanical stress.

Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes

Summary Atrial fibrillation (AF) usually starts as paroxysmal but can evolve relentlessly to the persistent and permanent forms. However, the mechanisms governing such a transition are unknown. The authors show that intracardiac serum levels of galectin (Gal)-3 are greater in patients with persistent than paroxysmal AF and that Gal-3 independently predicts atrial tachyarrhythmia recurrences after a single ablation procedure. Using a sheep model of persistent AF the authors further demonstrate that upstream therapy targeting Gal-3 diminishes both electrical remodeling and fibrosis by impairing transforming growth factor beta–mediated signaling and reducing myofibroblast activation. Accordingly, Gal-3 inhibition therapy increases the probability of AF termination and reduces the overall burden of AF. Therefore the authors postulate that Gal-3 inhibition is a potential new upstream therapy to prevent AF progression.

Chloroquine Terminates Stretch-Induced Atrial Fibrillation More Effectively Than Flecainide in the Sheep Heart

Background—Blockade of inward-rectifier K+ channels by chloroquine terminates reentry in cholinergic atrial fibrillation (AF). However, it is unknown whether inward-rectifier K+ channels and reentry are also important in maintaining stretch-induced AF (SAF). We surmised that reentry underlies SAF, and that abolishing reentry with chloroquine terminates SAF more effectively than traditional Na+-channel blockade by flecainide. Methods and Results—Thirty Langendorff-perfused sheep hearts were exposed to acute and continuous atrial stretch, and mapped optically and electrically. AF dynamics were studied under control and during perfusion of either chloroquine (4 µmol/L, n=7) or flecainide (2–4 µmol/L, n=5). Chloroquine increased rotor core size and decreased reentry frequency from 10.6 ± 0.7 Hz in control to 6.3 ± 0.7 Hz (P<0.005) just before restoring sinus rhythm (7/7). Flecainide had lesser effects on core size and reentry frequency than chloroquine and did not restore sinus rhythm (0/5). Specific IKr blockade by E-4031 (n=7) did not terminate AF when frequency values were >8 Hz. During pacing (n=11), flecainide reversibly reduced conduction velocity (≈30% at cycle length 300, 250, and 200 ms; P<0.05) to a larger extent than chloroquine (11% to 19%; cycle length, 300, 250, and 200 ms; P<0.05). Significant action potential duration prolongation was demonstrable only for chloroquine at cycle length 300 (12%) and cycle length 250 ms (9%) (P<0.05). Conclusions—Chloroquine is more effective than flecainide in terminating SAF in isolated sheep hearts by significantly increasing core size and decreasing reentry frequency. Chloroquine’s effectiveness may be explained by its inward-rectifier K+ channel blockade profile and suggest that reentry is important to maintain acute SAF.

Translational research in atrial fibrillation: a quest for mechanistically based diagnosis and therapy.

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is associated with increased risk of stroke, heart failure, and death.1 However, currently available treatments for AF are less than satisfactory. Many drugs have been tried with limited success.2 However, the demonstration of AF triggers in the atrial sleeves of the pulmonary veins (PVs)3 has led to a significant improvement in therapy. Today, PV isolation by means of radiofrequency (RF) ablation is a gold standard treatment for paroxysmal AF.4 However, the success rate of RF ablation in the more prevalent and highly heterogeneous persistent and long-term persistent AF populations has been disappointing.5 The reasons are probably multifactorial, but undoubtedly incomplete understanding of the mechanism(s) underlying this complex arrhythmia has contributed substantially to such a poor outcome. Increased knowledge of cardiac arrhythmias in general has come from studies aimed at elucidating cardiac impulse formation and propagation at several levels of integration, from computer modeling, through electrophysiological experiments in cells, tissues and the whole animal, and the human patient.6 In clinical electrophysiology (EP), progress has been driven, to a large extent, by available technology designed for the detection of electrical signals on the endocardial and epicardial surfaces of the heart. Although the surface ECG is the obvious first and compulsory starting point in the clinical diagnostic ladder, programmed cardiac stimulation, combined with intracardiac activation mapping, enables electrophysiological characterization and is the cornerstone for successful diagnosis and treatment of most types of arrhythmias.7 In contrast to what happens in most other arrhythmic problems, electrical impulses during AF often are highly irregular, changing in number, direction, and width on a beat-to-beat basis, with significant temporal variations in the timing and morphology of the intracardiac atrial electrograms. Consequently, time-domain analysis of the signals recorded by …

High-resolution endocardial and epicardial optical mapping in a sheep model of stretch-induced atrial fibrillation.

Atrial fibrillation (AF) is a complex cardiac arrhythmia with high morbidity and mortality.(1,2) It is the most common sustained cardiac rhythm disturbance seen in clinical practice and its prevalence is expected to increase in the coming years.(3) Increased intra-atrial pressure and dilatation have been long recognized to lead to AF,(1,4) which highlights the relevance of using animal models and stretch to study AF dynamics. Understanding the mechanisms underlying AF requires visualization of the cardiac electrical waves with high spatial and temporal resolution. While high-temporal resolution can be achieved by conventional electrical mapping traditionally used in human electrophysiological studies, the small number of intra-atrial electrodes that can be used simultaneously limits the spatial resolution and precludes any detailed tracking of the electrical waves during the arrhythmia. The introduction of optical mapping in the early 90s enabled wide-field characterization of fibrillatory activity together with sub-millimeter spatial resolution in animal models(5,6) and led to the identification of rapidly spinning electrical wave patterns (rotors) as the sources of the fibrillatory activity that may occur in the ventricles or the atria.(7-9) Using combined time- and frequency-domain analyses of optical mapping it is possible to demonstrate discrete sites of high frequency periodic activity during AF, along with frequency gradients between left and right atrium. The region with fastest rotors activates at the highest frequency and drives the overall arrhythmia.(10,11) The waves emanating from such rotor interact with either functional or anatomic obstacles in their path, resulting in the phenomenon of fibrillatory conduction.(12) Mapping the endocardial surface of the posterior left atrium (PLA) allows the tracking of AF wave dynamics in the region with the highest rotor frequency. Importantly, the PLA is the region where intracavitary catheter-based ablative procedures are most successful terminating AF in patients,(13) which underscores the relevance of studying AF dynamics from the interior of the left atrium. Here we describe a sheep model of acute stretch-induced AF, which resembles some of the characteristics of human paroxysmal AF. Epicardial mapping on the left atrium is complemented with endocardial mapping of the PLA using a dual-channel rigid borescope c-mounted to a CCD camera, which represents the most direct approach to visualize the patterns of activation in the most relevant region for AF maintenance.