Heart Rhythm

Statin Use And Postoperative Atrial Fibrillation After Major Noncardiac Surgery

2011-09-09

Background: Although statin lipid-lowering medications likely reduce perioperative ischemic complications, few data exist to describe statins' effects on risk for and outcomes of atrial fibrillation following noncardiac surgery. Objective: To examine the association between treatment with statin medications and clinically significant postoperative atrial fibrillation (POAF) following major noncardiac surgery. Methods: A retrospective cohort study of patients aged 18 years or older who underwent major noncardiac surgery between January 1, 2008, and December 31, 2008. Cases of clinically significant POAF were selected by using a combination of International Classification of Diseases-9 codes and clinical variables. We defined statin users as those whose pharmacy data included a charge for a statin drug on the day of surgery, the day after surgery, or both. Results: Of 370,447 patients, 10,957 (3.0%) developed clinically significant POAF; overall, 79,871 (21.6%) received a perioperative statin. Patients receiving statins were generally older (68.8 vs 61.1 years; P <.001) and more likely to be receiving a beta-blocker (50.3% vs 21.6%; P < .001). Statin use was associated with a lower unadjusted rate of POAF (2.6% vs 3.0%; P < .001). After adjustment for patient risk factors and surgery type, odds for POAF remained significantly lower among statin-treated patients (adjusted odds ratio = 0.79; 95% confidence interval = 0.71–0.87; P < .001). Statin use was not associated with differences in cost, length of stay, or mortality among patients who developed POAF. Conclusion: Treatment with statin agents appears to be associated with a lower risk for clinically significant POAF following major noncardiac surgery.

Expanding the role of statins in postoperative atrial fibrillation

George Thomas, Bruce B. Lerman — 2011-09-28

Atrial fibrillation (AF) is a growing public health problem, predicted to impact as many as 15 million people by 2050. In addition to its well-known associated risks in an outpatient population, isolated perioperative AF (POAF) following cardiac surgery also contributes to increased mortality, increased length of hospital stay, and increased health-care costs. Various strategies to reduce POAF in cardiac surgery patients have been shown to be effective in reducing POAF and health-care costs.

Atorvastatin for prevention of atrial fibrillation recurrence following pulmonary vein isolation: A double-blind, placebo-controlled, randomized trial

2011-09-14

Background: It is known that statins are effective in preventing atrial fibrillation (AF) in patients undergoing cardiac surgery. Objective: The purpose of this study was to evaluate the efficacy of statins in preventing AF recurrence following left atrial ablation. Methods: One hundred twenty-five patients who had no statin indication undergoing catheter ablation due to drug-refractory paroxysmal (n = 90) or persistent (n = 35) AF were randomized in a prospective, double-blind, placebo-controlled trial to receive 80 mg atorvastatin (n = 62) or placebo (n = 63) for 3 months. The primary endpoint was freedom from symptomatic AF at 3 months. Secondary endpoints included freedom from any atrial arrhythmia recurrence irrespective of symptoms, quality of life (QoL), and reduction in C-reactive protein (CRP). Results: At 3 months, 95% of patients in the atorvastatin group were free of symptomatic AF compared with 93.5% in the placebo group (P = .75). Similarly, 85% of patients treated in the atorvastatin group remained free of any recurrent atrial arrhythmia vs 88% of patients in the placebo group (P = .37). Mean CRP levels decreased in the atorvastatin group (mean change −0.75 ± 3, P = .02) and increased in the placebo group (mean change 2.1 ± 19.9, P = .48). Mean QoL score improved significantly in both groups (mean change 13.14 ± 18.2 in the atorvastatin group and 11.10 ± 17.7 in the placebo group, P = .53). Conclusion: In patients with no standard indication for statin therapy, treatment with atorvastatin 80 mg/day following AF ablation does not decrease the risk of AF recurrence in the first 3 months and should not be routinely administered to prevent periprocedural arrhythmias.

Neutral effects of statins to prevent atrial fibrillation recurrences after catheter ablation of atrial fibrillation: Should we bury upstream therapy for secondary prevention of atrial fibrillation?

Andreas Goette — 2011-10-14

Statins have been introduced to inhibit the main enzyme of cholesterol synthesis 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA-reductase) to lower low-density lipoprotein cholesterol levels. In addition, anti-inflammatory (pleiotropic) effects at the vascular endothelium have been appreciated to reduce inflammatory responses in the vessel wall. Thereby, statins have become a cornerstone of therapy in patients with coronary artery disease.

Is there a relationship between complex fractionated atrial electrograms recorded during atrial fibrillation and sinus rhythm fractionation?

2011-09-26

Background: Ablation of persistent atrial fibrillation (AF) may require adjunctive methods of substrate modification. Both ablation-targeting complex fractionated atrial electrograms (CFAEs) recorded during AF and fractionated electrograms recorded during sinus rhythm (sinus rhythm fractionation [SRF]) have been described. However, the relationship of CFAEs with SRF is unclear. Methods: Twenty patients (age 62 ± 9 years, 13 males) with persistent AF and 9 control subjects without organic heart disease or AF (age 36 ± 6 years, 4 males) underwent detailed CFAE and SRF left atrial electroanatomic maps. The overlap in left atrial regions with CFAEs and SRF was compared in the AF population, and the distribution of SRF was compared among patients with AF and normal controls. Propagation maps were analyzed to identify the activation patterns associated with SR fractionation. Results: SRF (338 ± 150 points) and CFAE (418 ± 135 points) regions comprised 29% ± 14% and 25% ± 15% of the left atrial surface area, respectively. There was no significant correlation between SRF and CFAE maps (r = .2; P = NS). On comparing patients with AF and controls, no significant difference was found in the distribution of SRF between groups (P = .74). Regions of SRF overlapped areas of wave-front collision 75% ± 13% of the time. Conclusions: (1) There is little overlap between regions of CFAEs during AF and regions of SRF measured in the time domain or the frequency domain, (2) the majority of SRF appears to occur in regions with wave-front collision, (3) the distribution of SRF is similar in patients with AF and normal controls, suggesting that this may not have an important role in AF maintenance and may not be a suitable ablation target.

Cellular damage, platelet activation, and inflammatory response after pulmonary vein isolation: A randomized study comparing radiofrequency ablation with cryoablation

2011-09-14

Background: Experimental data suggest that use of cryoablation in pulmonary vein isolation (PVI) is associated with less cell damage and less thrombus formation compared to radiofrequency (RF) energy. Objective: The purpose of this study was to test the hypothesis that cryoablation significantly reduces markers of cell damage, platelet activation, and inflammation in patients undergoing PVI for treatment of atrial fibrillation (AF). Methods: Sixty patients with symptomatic drug-resistant AF (age 56 ± 9 years, 48 males, 38 with paroxysmal AF) were randomly assigned to undergo PVI using either an open irrigated-tip RF catheter or a cryoballoon. Markers of cell damage (high-sensitive troponin T [hs-TnT], microparticles), platelet activation (platelet reactivity by aggregometry, expression of platelet surface proteins P-selectin and activated glycoprotein [GP] IIb/IIIa), and inflammatory response (high-sensitive C-reactive protein [hs-CRP]) were determined before and up to 48 hours after the procedure. Results: PVI resulted in a significant rise in hs-TnT, microparticles, markers of platelet activation, and hs-CRP over time, with distinct temporal patterns for each parameter. However, after Bonferroni correction for repeated measurements, no significant differences were noted in these parameters between patients treated with cryoablation or RF energy. Procedural time was significantly shorter in patients treated with cryoballoon (177 ± 30 minutes vs 200 ± 46 minutes, P = .03), with no differences in fluoroscopic time, periprocedural complications, or success rate. Conclusion: Cryoablation and RF energy result in a comparable rise of markers of cell damage, platelet activation and inflammatory response. The data do not support the concept of an improved safety profile for cryoablation in PVI.

Thromboembolic risk of the hot- and cold-catheter ablation for atrial fibrillation

Chung-Wah Siu, Hung-Fat Tse — 2011-10-05

In the last decade, catheter ablation procedures aimed at the electrical isolation of arrhythmogenic pulmonary veins (PVs) and/or modification of left atrial substrate have evolved as an important therapeutic option for patients with atrial fibrillation (AF). While conceptually attractive and technical feasible with promising clinical efficacy, these catheter ablation procedures, mainly with radiofrequency energy, are limited by the risk of major complications, including PV stenosis, atrioesophageal fistula, and thromboembolism. Tissue heating with radiofrequency energy can potentially lead to endocardial disruption, charring, PV stenosis, platelet activation, and thrombus formation. As a result, other alternative energy sources such as cryoablation, microwave, and laser have been developed with the aim to reduce these complications. Among these alternative energy sources, cryoablation appears to have the best safety profile. Prior experimental studies have demonstrated that cryoablation creates minimal endocardial disruption with the reservation of underlying tissue architecture, reduce platelet and clotting activation, and is associated with a lower risk of thrombus formation as well as atrioesophageal fistula compared with radiofrequency energy.

Cardiac rhythm devices in the pediatric population: Utilization and complications

2011-09-09

Background: Cardiac rhythm devices are important in the management of pediatric patients with rhythm abnormalities, although factors driving utilization are poorly understood. Objective: This study sought to evaluate utilization trends, complication rates, and cost associated with device implantation in the pediatric population. Methods: Device implantation was analyzed using the Kids' Inpatient Database from 1997 to 2006. The type of device implantation, patient demographics, hospital characteristics, acute in-hospital complications, cost, and length of stay (LOS) were analyzed. χ2 tests were used to test association between categorical variables, and logistic regression analysis was performed to evaluate risk factors associated with complications. Results: There were 5788 hospitalizations with device implantations. Although there was a significant increase in defibrillator implantation, there was no significant increase in the number of pacemaker implantations over this time period. Patient- and device-related complications were relatively common in all device cohorts (pacemaker 11.2%, 7.2%; defibrillator 5.9%, 11.5%; and biventricular device 19.4%, 26.7%). Type of complication was dependent on device type. Increased risk of complication was evident in the pacemaker cohort, patients with congenital heart disease, cardiomyopathy, previous cardiac arrest, and other heart operations. Patient-related complications increased cost and LOS regardless of patient or procedural characteristics. Device implantation in patients <5 years old was associated with increased LOS and cost but was not associated with increased risk of complication. Conclusion: Device utilization in pediatrics is increasing due to escalating defibrillator implantation and biventricular pacing. Cost and LOS are significantly increased by patient complications. Reduction in these complications would improve patient care and lower medical costs.

Orbits and implants: Trends in indications, utilization, and complications in pediatric device therapy

Joel A. Kirsh — 2011-09-26

“I don't pretend we have all the answers. But the questions are certainly worth thinking about.”—Sir Arthur Charles Clarke, 1917–2008 Almost 50 years ago, Arthur C. Clarke, one of the “big three” (with Isaac Asimov and Robert Heinlein) authors of 20th-century science fiction, wrote 2001: A Space Odyssey, expecting that by the time the film's title date arrived, many of the developments described in the script would come to pass. Clarke had good reason to be optimistic about his predictions—in 1945, while working as a Radar Specialist in the Royal Air Force, he suggested that satellites in orbit over the equator could relay telephone, telegraph, and television signals around the world. As Clarke wrote 2001 in the mid-1960s, television coverage of the 1964 Tokyo Summer Olympic Games was relayed across the Pacific Ocean for the first time. Clarke originally proposed that 3 geostationary satellites, 120° apart, could provide “all possible services” over the entire globe, but did not anticipate that by the year 2001, there would be hundreds of such satellites, due to increased demand for communication bandwidth, and new indications such as navigational and military uses.

Feasibility of postmortem device acquisition for potential reuse in underserved nations

2011-09-26

Objectives: The purpose of the present study was to examine the feasibility and efficacy of a program to acquire devices with adequate battery life from crematories and funeral homes for potential reutilization in underserved nations. Background: There exists a great health-care disparity between the industrialized world and underserved nations—specifically in the frequency of pacemaker implantation. Methods: Flyers were mailed to all 1057 members of the Michigan Funeral Directors Association providing information to download a consent-for-explant form and request a postage-paid envelope from www.myheartyourheart.org in order to send explanted devices. Donated devices from funeral homes and crematories nationwide were also collected from World Medical Relief. Adequate battery life was defined as ≥75% or ≥4 years of estimated longevity. Results: A total of 3176 devices (65% pacemakers, 21% implantable cardioverter-defibrillators [ICDs], 12% biventricular ICDs, and 3% biventricular pacemakers) were donated to the reutilization program. Five hundred fifty devices (21%; 95% confidence interval [CI] 19.4–22.6%) were found to have an acceptable battery life for reutilization. Among these devices, 313 were pacemakers (17.9%; 95% CI 16.1–19.8%), 118 were ICDs (17.9%; 95% CI 15.1–21.1%), 112 were biventricular ICDs (30.3%; 95% CI 25.6–35.2%), and 7 were biventricular pacemakers (17.3%; 95% CI 16.0–18.7%). Conclusions: Approximately 21% of donated devices and 30% of donated biventricular ICDs possess an adequate battery life for potential reuse. Device donations from funeral homes and crematories appear to be a potential resource for device reutilization for those in need in underserved nations.

You shouldn’t take it with you: Postmortem device reuse

William J. Groh — 2011-12-26

Antiarrhythmia devices—pacemakers and implantable cardioverter-defibrillators (ICDs)—are expensive scarce world resources that are available to the majority of the population in the economic “haves” countries but rarely to those without means in the economic “have-nots” countries. Impoverished or developing nations implant what devices they can primarily for life-threatening atrioventricular block, often only in younger patients. ICDs, for any indications, are beyond their scope of practice for all but the richest minority. Generators, leads, and the technical knowledge to implant devices are often obtained through humanitarian assistance, for example, the Pacemaker Banks established under the direction of the philanthropic organization Heartbeat International. Physicians trained and working in first-world countries with ties to the developing nations assist in pacemaker implantation and follow-up. Generators are often donated by manufacturers to the humanitarian organizations, typically outright or at a markedly reduced cost. New devices approaching end of shelf life are commonly used. Despite these programs, available data show that pacemaker implant rates in developing countries are a fraction of that in first-world countries. Although difficult to quantify, there is certainly significant morbidity and mortality associated with limited access to pacemakers. One clear bottleneck is the limited supply of new pacemaker generators.

Celivarone in patients with an implantable cardioverter-defibrillator: Adjunctive therapy for the reduction of ventricular arrhythmia-triggered implantable cardioverter-defibrillator interventions

2011-10-05

Background: Implantable cardioverter-defibrillators (ICDs) remain the treatment of choice for the prevention of life-threatening arrhythmias. However, many patients with ICDs require additional antiarrhythmic therapy to reduce the morbidity associated with recurrent arrhythmia-triggered ICD interventions. Objective: Our study aimed to evaluate the safety and efficacy of celivarone in reducing these interventions. Methods: A total of 153 eligible ICD recipients were randomized to receive either placebo or celivarone 100 or 300 mg once daily for 6 months. The primary end point was the prevention of arrhythmia-triggered ICD therapies. Results: Fewer ventricular tachycardia and ventricular fibrillation episodes were observed in the 300-mg celivarone group than in the placebo group, with a relative risk reduction of 46%, which was not statistically significant. The analysis of all-cause shocks showed a trend toward a decreased number of events in the celivarone 300-mg group. A post hoc analysis of the primary end point in a subgroup of patients in the celivarone 300-mg group, who had received ICD therapy within 1 month of randomization, showed a significant benefit (P = .032). Celivarone was not associated with an increased risk of torsades de pointes, thyroid dysfunction, or pulmonary events. More heart failure events were reported in the celivarone groups than in the placebo group, but the difference was not statistically significant. Conclusion: Celivarone tends to reduce ventricular tachycardia–/ventricular fibrillation–triggered ICD therapies. This effect was not statistically significant. There was a trend toward greater efficacy in the 300-mg group, especially in patients undergoing ICD therapy within 30 days prior to randomization. Overall, celivarone was well tolerated.

Distinguishing “benign” from “malignant early repolarization”: The value of the ST-segment morphology

2011-09-12

Background: Means for distinguishing the very common “benign early repolarization” from the very rare but malignant form are needed. Recently, the presence of early repolarization with “horizontal ST segment” was found to predict arrhythmic death during long-term follow-up in a large population study. We therefore speculated that the combination of “J waves with horizontal ST segment” would correlate with a history of idiopathic ventricular fibrillation (VF) better than the mere presence of J waves. Objectives: To determine whether the morphology of the ST segment adds diagnostic value to the mere presence of J waves in a case–control series of idiopathic VF. Methods: We reanalyzed our case–control study showing that the presence of J waves strongly correlates with a history of idiopathic VF among 45 patients with this disorder, 124 controls matched for age and gender (“matched-control” group), and 121 young athletes. This time we focused only on those patients with J waves and graded their ST-segment morphology as either “horizontal” or “ascending” according to predefined criteria. Results: The presence of J waves was associated with a history of idiopathic VF with an odds ratio of 4.0 (95% confidence intervals = 2.0–7.9), but having both J waves and horizontal ST segment yielded an odds ratio of 13.8 (95% confidence intervals = 5.1–37.2) for having idiopathic VF. Conclusions: We report, for the first time, that the combination of J waves with horizontal/descending ST segment improved our ability to distinguish patients with idiopathic VF from controls matched by gender and age.

Early repolarization patterns: The good, the bad, and the ugly?

Mark G. Hoogendijk, Mark Potse, Ruben Coronel — 2011-09-26

The innocence of the electrocardiographic (ECG) pattern of early repolarization (ER) has been challenged by the recent association of the ER pattern in inferolateral leads with idiopathic ventricular fibrillation (VF). Until then, the ER pattern was considered a benign finding occurring in the absence of heart disease and especially in athletes. As the ER pattern in inferolateral leads is a common finding, occurring in approximately 5% of apparently healthy individuals, the question arises whether these individuals are at increased risk of cardiac arrest and whether further risk stratification can be performed to identify patients eligible for primary prevention.

Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization

2011-09-12

Background: J waves are the hallmark of both inferolateral early repolarization (ER) and Brugada syndrome. While ajmaline, a class 1a antiarrhythmic drug, accentuates the J wave in Brugada syndrome, its effect on ER is unreported. Objective: To describe the effect of ajmaline on the electrocardiogram in ER. Methods: We analyzed electrocardiograms before and after the administration of intravenous ajmaline (1 mg/kg) in 31 patients with ER, 21 patients with Brugada type 1 electrocardiogram (Br), and 22 controls. ER was defined as J-point elevation of ≥1 mm with QRS slurring or notching in ≥2 inferolateral leads (I, aVL, II, III, aVF, V4–V6). Results: Ajmaline decreased mean J-wave amplitude in the ER group from 0.2 ± 0.15 mV at baseline to 0.08 ± 0.09 mV (P < .001). The QRS width prolonged significantly in all 3 groups, but the prolongation was significantly less in the ER group (+21 ms) than in the Br group (+36 ms; P < .001) or controls (+28 ms; P = .010). Decrease in mean inferolateral R-wave amplitude was similar in all the groups (ER group −0.14 mV; Br group −0.11 mV; controls −0.13 mV; P = ns), but mean inferolateral S-wave amplitude increased significantly less in the ER group (ER group +0.14 mV; Br group +16 mV; controls +0.20 mV; P < .001). Conclusions: Ajmaline significantly decreases the J-wave amplitude in ER and prolongs the QRS width significantly less than in patients with Br. This indicates a different pathogenesis for both disorders. The altered terminal QRS vector probably is responsible for the decrease in the J-wave amplitude in ER, although a specific effect of ajmaline on J waves cannot be excluded.

Drug challenge with sodium-channel blockade: Improving phenotypic characterization of early repolarization

Leonard Ilkhanoff, Bradley P. Knight — 2011-10-03

“Early repolarization” (ER), first described by Shipley and Halloran in 1936 as ST-segment elevation in the absence of coronary artery disease, generally has been considered a benign electrocardiographic (ECG) finding. Early studies in the general population reported a prevalence of 6% to 24% and found an association between ER and certain characteristics such as younger age, male sex, and black race. ER did not seem to confer an increased risk of mortality in these early studies. Recently, however, there has been renewed interest in ER based on reports by Haissaguerre et al and Tikkanen et al, suggesting that ER may be associated with a predisposition for malignant arrhythmias and sudden cardiac death, especially in young individuals without structural heart disease.

Clinical impact of the number of extrastimuli in programmed electrical stimulation in patients with Brugada type 1 electrocardiogram

2011-09-21

Background: Use of programmed electrical stimulation (PES) for risk stratification of Brugada syndrome (BrS) is controversial. Objective: To elucidate the role of the number of extrastimuli during PES in patients with BrS. Methods: Consecutive 108 patients with type 1 electrocardiogram (104 men, mean age 46 ± 12 years; 26 with ventricular fibrillation [VF], 40 with syncope, and 42 asymptomatic) underwent PES with a maximum of 3 extrastimuli from the right ventricular apex and the right ventricular outflow tract. Ventricular arrhythmia (VA) was defined as VF or nonsustained polymorphic ventricular tachycardia >15 beats. Patients with VA induced by a single extrastimulus or double extrastimuli were assigned to group SD (Single/Double), by triple extrastimuli to group T (Triple), and the remaining patients to group N. Results: VA was induced in 81 patients (VF in 71 and polymorphic ventricular tachycardia in 10), in 4 by a single extrastimulus, in 41 by double extrastimuli, and in 36 by triple extrastimuli. During 79 ± 48 months of follow-up, 24 patients had VF events. Although the overall inducibility of VA was not associated with an increased risk of VF (log-rank P = .78), group SD had worse prognosis than did group T (P = .004). Kaplan–Meier analysis in patients without prior VF also showed that group SD had poorer outcome than did group T and group N (P = .001). Positive and negative predictive values of VA induction with up to 2 extrastimuli were, respectively, 36% and 87%, better than those with up to 3 (23% and 81%, respectively). Conclusions: The number of extrastimuli that induced VA served as a prognostic indicator for patients with Brugada type 1 electrocardiogram. Single extrastimulus or double extrastimuli were adequate for PES of patients with BrS.

Vagal activity modulates spontaneous augmentation of J-wave elevation in patients with idiopathic ventricular fibrillation

2011-09-21

Background: Although J-wave elevation in the inferolateral leads could be related to idiopathic ventricular fibrillation (IVF), little is known about the pathophysiologic characteristics of J-wave elevation in patients with IVF. Objective: This study aimed to determine the relationship between augmentation of J-wave elevation and changes in RR interval or autonomic nervous activities in patients with IVF. Methods: Eight patients with IVF and 22 controls with J-wave elevation (≥0.1 mV) in lead V5 were studied. The J-wave amplitude was automatically measured in lead CM5 of a digital Holter electrocardiogram, and the J–RR relationship was determined. Based on the analysis of heart rate variability, the relationship between the J-wave amplitude and the natural logarithm of high-frequency (HF) components (J–ln HF relationship) or the ratio of low frequency (LF) components to HF components (J–LF/HF relationship) was also determined. Results: The J–RR slope (mm/s) was greater in patients with IVF than in controls (3.5 ± 0.7 vs 2.4 ± 0.8; P <.01), as was J-wave amplitude (mm) at an RR interval of 1.2 seconds (2.8 ± 0.9 vs 2.0 ± 0.6; P <.05). The J-wave amplitude was correlated positively with ln HF and negatively with LF/HF, and the slopes of both J–ln HF and J–LF/HF regression lines were greater in patients with IVF than in controls. During an entire 24-hour period, there was no difference between the 2 groups in either HF or LF/HF. Nine of the total 11 episodes (82%) of spontaneous ventricular fibrillation occurred between 18:00 and 6:00. Conclusions: In patients with IVF as compared with control subjects, J-wave elevation was more strongly augmented during bradycardia and was associated with an increase in vagal activity. This could be related to the occurrence of ventricular fibrillation predominantly at night in patients with IVF.

The slowest, the worst: Demonstrating the evidence

Philippe Maury, Frederic Sacher — 2011-10-05

In the current issue of HeartRhythm, Mizumaki and colleagues demonstrate that J-wave amplitude was independently modulated by both heart rate and vagal activity in normal subjects and in patients with idiopathic ventricular fibrillation (VF) and early repolarization (ER). By using ambulatory recordings, they demonstrated in a very simple manner a significant increase in J-wave amplitude when the heart rate slowed or during increased levels of vagal activity, both phenomena summating to culminate at night. Interestingly, heart rate variability parameters otherwise did not differ between patients and controls. Owing to the sometimes observed increase in J-wave amplitude immediately prior to the onset of VF and knowing the mainly nocturnal or resting occurrence of VF in patients with the malignant form of ER, it seems therefore tempting to link these findings to the electrophysiological background underlying ER or even to a new factor for risk stratification in patients with ER.

High-density epicardial mapping of the pulmonary vein–left atrial junction in humans: Insights into mechanisms of pulmonary vein arrhythmogenesis

2011-09-09

Background: The pulmonary veins (PVs) and the PV–LA (left atrium) junction are established sources of triggers initiating atrial fibrillation. In addition, they have been implicated in the maintenance of arrhythmia. Objective: To undertake high-density electrophysiological characterization of the right superior PV–LA junction in humans. Methods: Mapping was performed in 18 patients without a history of atrial fibrillation undergoing cardiac surgery. A high-density epicardial plaque was positioned at the anterior right superior pulmonary vein covering 3 regions: LA, PV–LA junction, and the PV. Isochronal maps were created during (1) sinus rhythm (SR); (2) LA pacing (LA-Pace); (3) PV pacing (PV-Pace); (4) LA programmed electrical stimulation (LA-PES); and (5) PV programmed electrical stimulation (PV-PES). Regional differences in conduction slowing/conduction block (CS/CB) and the prevalence of fractionated signals (FS) and double potentials (DPs) were assessed. Results: A region of isochronal crowding representing CS/CB developed at the PV–LA junction in 84% of the maps. Three distinct activation patterns were seen. Pattern 1: Uniform SR activation without CS/CB. LA-Pace and PES caused 1 to 2 lines of isochronal crowding (CS/CB) at the PV–LA junction. Pattern 2: CS/CB occurred at the PV–LA junction in SR. LA/PV-Pace and LA/PV-PES caused an increase in CS/CB at the PV–LA junction with widely split DPs and FS. Pattern 3: A single incomplete line of CS at the PV–LA junction in SR. With LA/PV pacing and LA/PV-PES, multiple lines (≥3) of CS/CB developed at the PV–LA junction with evidence of circuitous activation and a marked increase in DPs and FS. Conclusion: High-density epicardial mapping of the right superior pulmonary vein demonstrates marked functional conduction delay and circuitous activation patterns at the PV–LA junction, creating the substrate for reentry.

Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go–related gene mutant

2011-09-09

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapy–dependent modulation of atrial electrophysiology may provide a more specific alternative to pharmacological and ablative treatment strategies. Objective: We hypothesized that genetic inactivation of atrial repolarizing ether-a-go-go–related gene (ERG) K+ currents using a dominant-negative mutant would provide rhythm control in AF. Methods: Ten domestic swine underwent pacemaker implantation and were subjected to atrial burst pacing to induce persistent AF. Animals were then randomized to receive either AdCERG-G627S to suppress ERG/IKr currents or green fluorescent protein (AdGFP) as control. Adenoviruses were applied using a novel hybrid technique combining atrial virus injection and epicardial electroporation to increase transgene expression. Results: In pigs treated with AdCERG-G627S, the onset of persistent AF was prevented (n = 2) or significantly delayed compared with AdGFP controls (12 ± 2.1 vs. 6.2 ± 1.3 days; P < .001) during 14-day follow-up. Effective refractory periods were prolonged in the AdCERG-G627S group compared with AdGFP animals (221.5 ± 4.7 ms vs. 197.0 ± 4.7 ms; P < .006). Impairment of left ventricular ejection fraction (LVEF) during AF was prevented by AdCERG-G627S application (LVEFCERG-G627S = 62.1% ± 4.0% vs. LVEFGFP = 30.3% ± 9.1%; P < .001). Conclusion: Inhibition of ERG function using atrial AdCERG-G627S gene transfer suppresses or delays the onset of persistent AF by prolongation of atrial refractoriness in a porcine model. Targeted gene therapy represents an alternative to pharmacological or ablative treatment of AF.

Genetic treatment of heart rhythm disorders—where do we stand?

Pieter G. Postema, Hanno L. Tan — 2011-09-19

Groundbreaking discoveries on genetic loci that underlie arrhythmia syndromes, which commenced in the early 1990s, have immensely increased our understanding of these syndromes. These discoveries also rigorously changed daily clinical practice for cardiologists who were faced with the enquiries of presymptomatic family members of symptomatic individuals who were known with an arrhythmia syndrome. Now it has become possible to screen the genome for the risk of arrhythmias or even sudden death and, understandingly, this took a flight. Still, the holy grail of genetic discoveries in disease is in its therapeutic applicability and that promise is indeed coming our way. For example, in Duchenne muscular dystrophy, the increasing knowledge of the diseased locus has recently led to therapeutic gene therapy in a relatively small number of patients in whom the diseased exon was selectively bypassed. For arrhythmia syndromes, we are still in a preclinical phase, but efforts to find curative options by means of genetic therapy are growing. Currently, genetic therapy for atrial fibrillation and bradycardia/conduction disease seems to dominate the field, but ventricular arrhythmias in ischemic conditions are also thoroughly investigated (for a recent review, see, eg, Boink and Rosen). The first in-human studies into the use of gene therapy in heart failure are even underway. In this issue of HeartRhythm, Soucek and colleagues from Heidelberg, Germany, present to us their preclinical work on genetic therapy for atrial fibrillation. Delay of atrial repolarization is considered one approach to genetic therapy for atrial fibrillation, as continuing propagation or reentry of fibrillation waves can be impeded by prolonging the atrial effective refractory period (ERP). The main currents responsible for the atrial ERP are 4 outward potassium currents: IKr, IKur, IKs, and IK1. In their study, Soucek et al focused on suppressing the IKr current by means of introducing an engineered gene that encodes an IKr-suppressing (dominant-negative) protein into the atria of pigs with the use of an adenovirus vector. Their aim was to prevent the development of persistent atrial fibrillation by prolonging atrial ERP.

Arrhythmia formation in subclinical (“silent”) long QT syndrome requires multiple insults: Quantitative mechanistic study using the KCNQ1 mutation Q357R as example

Thomas O'Hara, Yoram Rudy — 2011-09-26

Background: In subclinical or silent long QT syndrome, the QT interval is normal under basal conditions. The hypothesis that insults to the repolarization reserve may cause arrhythmias in silent mutation carriers but not in noncarriers has been proposed as a general principle, yet crucial aspects remain descriptive, lacking quantification. Objective: To utilize accurate mathematical models of the human action potential and β-adrenergic stimulation to quantitatively investigate arrhythmia-formation mechanisms peculiar to silent long QT syndrome, using mutation Q357R in KCNQ1 (α subunit of slow-delayed rectifier IKs) as a paradigm. Methods: Markov models were formulated to account for altered IKs kinetics in Q357R compared with wild type and introduced into a detailed model of the human ventricular myocyte action potential. Results: Dominant negative loss of IKs available reserve accurately represents Q357R. Action potential prolongation with mutant IKs was minimal, reproducing the silent phenotype. Partial block of rapid delayed rectifier current (IKr) was needed in addition to fast pacing and isoproterenol application to cause early afterdepolarizations (EADs) in epicardial cells with mutant IKs, but this did not produce EADs in wild type. Reduced channel expression at the membrane, not IKs kinetic differences, caused EADs in the silent mutant. With mutant IKs, isoproterenol plus partial IKr block resulted in dramatic QT prolongation in the pseudo-electrocardiogram and EADs formed without IKr block in mid-myocardial cells during simulated exercise onset. Conclusion: Multiple severe insults are needed to evince an arrhythmic phenotype in silent mutation Q357R. Reduced membrane IKs expression, not kinetic changes, underlies the arrhythmic phenotype.

Silent mutation in long QT syndrome: Pathogenicity prediction by computer simulation

Zahurul A. Bhuiyan — 2011-10-13

Congenital long QT syndrome (LQTS) is an inherited cardiac disorder characterized by prolongation of the QT interval on the surface electrocardiogram. Patients with LQTS are predisposed to ventricular tachyarrhythmias, torsade de pointes, leading to recurrent syncope and sudden cardiac death. The estimated frequency of this disorder is 1 in 2000. Currently, hundreds of mutations in 13 different genes have been described as causal to LQTS pathology, but mutations in KCNQ1, KCNH2, and SCN5A genes comprise 70% of all the mutations. Among all the LQTS causal genes, KCNQ1 is by far the predominant mutation-harboring gene.

Congenital type 1 long QT syndrome unmasked by a highly caffeinated energy drink

Keith A. Dufendach, Justin M. Horner, Bryan C. Cannon, Michael J. Ackerman — 2011-10-13

Long QT syndrome (LQTS) is an uncommon genetic disease that affects approximately 1 in 2500 people and can present with syncope, cardiogenic seizures, and/or sudden cardiac death. This cardiac channelopathy stems from delayed cardiac repolarization that is characterized by a prolonged QT interval on a 12-lead electrocardiogram (ECG). The patient's LQTS substrate can deteriorate into its trademark arrhythmia of torsades de pointes.

Efficacy and safety of atrial fibrillation ablation with phased radiofrequency energy and multielectrode catheters

2011-09-09

Focal radiofrequency (RF) ablation guided by 3-dimesnional (3D) mapping systems has shown considerable success in treating paroxysmal and persistent atrial fibrillation (AF). Unfortunately, the procedure remains complex, time-consuming, and highly dependent on operator competency. Multielectrode catheters were developed to address technical difficulties. The pulmonary vein (PV) ablation catheter (PVAC, Medtronic Ablation Frontiers, Carlsbad, CA) is a 9F deflectable circular multielectrode catheter that enables mapping and circumferential PV ablation. For persistent AF, 2 additional catheters, that is, the multiarray septal catheter (MASC) and the multiarray ablation catheter (MAAC), were developed to facilitate left atrial mapping and substrate modification. The accompanying GENius multichannel, duty-cycled RF generator (Medtronic Ablation Frontiers) enables the delivery of energy in a unipolar or bipolar configuration to all electrodes simultaneously or individually. During an RF application, energy delivery to individual electrodes is temperature controlled by a software algorithm that modulates power to reach the user-defined target temperature (maximum 8 W per electrode with the PVAC in a 4:1 power setting or 10 W in all other settings). Our objective was to systematically review the current knowledge with regard to the efficacy and safety of AF ablation with the PVAC ± MASC and MAAC.

Introduction of new atrial fibrillation ablation technology into clinical practice: The cart before the horse?

Jonathan M. Kalman, Prashanthan Sanders — 2011-09-28

Over the past decade, point-by-point ablation using irrigated radiofrequency (RF) ablation has become the apparent gold standard for pulmonary vein (PV) isolation. An enormous body of observational and prospective randomized data attests to its acute efficacy, safety, and long-term success in preventing atrial fibrillation (AF) with a dramatic impact on the quality of life of patients with symptomatic paroxysmal AF. However, even with 3D mapping, the procedure requires significant technical expertise, with, at times, lengthy procedure and fluoroscopy duration. In an attempt to simplify the procedure (and to perhaps further improve on safety), a variety of “one-shot” technologies for circumferential isolation of the PVs have been developed. Such an approach has the seductive theoretical advantages of being faster, requiring less technical skill, and hence having a shorter learning curve. In addition, sophisticated 3D mapping systems are not required, further simplifying the procedure. Cryoballoon ablation is the most advanced of these technologies and now well established in clinical practice. However, neither the promise of shorter procedure and fluoroscopy times nor the goal of improved efficacy and safety has as yet been definitively realized. Other technologies such as the high-intensity focused ultrasound balloon have been discarded for reasons of either safety or efficacy. Others are in varying stages of development. Given the marked variability in left atrial and PV anatomy, there remains doubt as to whether a “one-size-fits-all” approach will ultimately be feasible.

The funny current has a major pacemaking role in the sinus node

Dario DiFrancesco, Denis Noble — 2011-09-19

The ability to produce rhythmic, spontaneous contractions is a primary function of the heart, and it has intrigued generations of cardiac physiologists in the search for the underlying processes. Spontaneous electrical activity was recorded intracellularly from cardiac tissue by Silvio Weidmann since the mid-1950s. In the early 1960s, the first numerical reconstruction of cardiac activity showed that the cardiac action potential could be interpreted on the basis of specific kinetic properties of identified ionic currents and this opened the way to investigation of the contribution of cellular mechanisms to action potential generation in cardiac cells by numerical modeling.

The funny current in the context of the coupled-clock pacemaker cell system

Victor A. Maltsev, Edward G. Lakatta — 2011-09-19

It has been now widely documented in many laboratories in many species (review) that local Ca2+ releases (LCRs), generated by the sarcoplasmic reticulum (SR) via spontaneous ryanodine receptor (RyR) activation, emerge during early diastolic depolarization (DD), grow in magnitude during the DD, and peak during late DD, forming an LCR ensemble Ca2+ signal, that is, late diastolic Ca2+ elevation (A–C). LCRs nearly instantaneously generate inward Na+/Ca2+exchange (NCX) current fluctuations that depolarize the surface membrane, prompting the rapid action potential (AP) upstroke (D). The SR has been referred to as an intracellular “Ca2+ clock” because LCRs are roughly periodic. The delay between the AP-triggered global cytosolic Ca2+ transient and LCR that emerges during DD is the LCR period (A). Variations in the sinoatrial nodal cell (SANC) AP cycle length are predicted by variations in the LCR period (vide infra).

The role of gap junctions in the arrhythmias of ischemia and infarction

Andrew L. Wit, Nicholas S. Peters — 2011-09-21

Gap junction remodeling (changes in function, quantity, and location) likely contributes to arrhythmias in ischemia and infarction by altering conduction, refractoriness, and automaticity, therefore offering a novel target for antiarrhythmic therapy. However, this approach has many complexities and challenges.

Entrainment versus resetting of a long RP tachycardia: What is the diagnosis?

Reginald T. Ho, David L. Fischman — 2010-11-25

A 71-year-old man with a history of chronic obstructive pulmonary disease presented for electrophysiological study because of recurrent hospitalizations due to a long-RP-interval narrow complex tachycardia refractory to verapamil therapy. His 12-lead electrocardiogram and echocardiogram were normal. Baseline atrio-His and His-ventricular intervals measured 56 ms and 41 ms, respectively. During programmed atrial extrastimulation, dual atrioventricular (AV) node physiology was not observed. Retrograde conduction was midline (earliest at the anteroseptum) and confirmed to be over the fast pathway (FP) of the AV node by para-Hisian pacing at multiple cycle lengths. Tachycardia was easily and reproducibly induced from both the ventricle and the atrium (). The response of tachycardia to entrainment from the ventricle and diastolic ventricular premature depolarizations (VPDs) are shown in , respectively. Based on these observations, what is the mechanism of tachycardia?

Retrograde placement of a defibrillator lead through the pulmonary valve

Tobias Reichlin, Christian Sticherling, Jean-Luc Crevoisier, Stefan Osswald — 2010-11-10

We report the placement of an implantable cardioverter-defibrillator (ICD) lead using a retrograde access to the right ventricle via the pulmonary artery and the pulmonary valve in a patient with previous surgery including cavopulmonary anastomosis (modified bidirectional Glenn shunt). A 55-year-old woman was admitted because of monomorphic ventricular tachycardia associated with presyncope. At the age of 48 years, she had suffered an extensive inferoposterior myocardial infarction involving the right ventricle. Despite percutaneous coronary revascularization, the patient developed severe right heart failure accompanied by severe tricuspid valve regurgitation. At the age of 49 years, surgical reconstruction of the tricuspid valve using a Carpentier ring was performed and the patient received a bypass graft to the right coronary artery. In addition, the superior vena cava (SVC) was disconnected from the right atrium and anastomosed to the right pulmonary artery (modified bidirectional Glenn shunt) to unload the failing right ventricle. At current presentation, echocardiography demonstrated a left ventricular ejection fraction of 40% with an inferior aneurysm and a severely impaired right ventricular function with a severe tricuspid valve regurgitation as well as a mild pulmonary valve regurgitation. An ICD was placed for secondary prevention. Because of the previous disconnection of the SVC from the right atrium and the subsequent anastomosis to the right pulmonary artery, the right ventricular lead could not be placed through the SVC and the right atrium. Epicardial lead placement was considered but rejected because of the risk to harm the bypass graft. Accordingly, a retrograde access to the right ventricle via SVC, pulmonary artery, and pulmonary valve was chosen for lead placement (). Defibrillation testing was successful at 21 J. Echocardiography 2 weeks after implantation showed no increase in the preexisting pulmonary valve regurgitation.

EP News: Basic and Translational

Peng-Sheng Chen — 2011-12-26

During the American Heart Association Annual Meeting, Rizzo et al (Circulation 2011:124:A13059) reported pathological characteristics of stellate ganglia resected from 5 long QT syndrome (LQTS) and 5 catecholaminergic polymorphic ventricular tachycardia (CPVT) patients. Control stellate ganglia were obtained from 4 accidently deceased patients. Sections were immunostained with antibodies against various lymphocyte markers. The authors found that stellate ganglia of all 10 LQTS/CVPT patients had mild but distinct inflammatory infiltrates composed of T-lymphocytes and macrophages. These cells were diffusely spread, but also clustered in small foci or even inside ganglion cells. These findings are interpreted as T cell-mediated ganglionitis. The authors conclude that a low grade cytotoxic T cells-mediated ganglionitis occurs in stellate ganglia of all 10 severely symptomatic LQTS/CVPT patients. Cytotoxicity towards ganglion cells may boost adrenergic activity, and thus electrical instability in these patients who are genetically predisposed to arrhythmias.

EP News Clinical

N.A. Mark Estes — 2011-12-26

Imazio and colleagues (Circulation 2011 Nov 22; 124(21):2290–2295. Epub 2011 Nov 16 PMID: 22090167) evaluated colchicine (C) for the prevention of post-operative AF (POAF) after cardiac surgery in 336 patients in a multicenter, double-blind, placebo (P) controlled randomized trial. Patients were in sinus rhythm before starting the intervention (P or C 1.0 mg twice daily starting on postoperative day 3 followed by a maintenance dose of 0.5 mg twice daily for 1 month). The primary endpoint was the incidence of POAF at 1 month. Despite well-balanced baseline characteristics, patients on C had a reduced incidence of POAF (12.0% versus 22.0%, respectively; P = 0.021; relative risk reduction, 45%) with a shorter in-hospital stay (9.4 ± 3.7 versus 10.3 ± 4.3 days; P = 0.040). Side effects were similar in the study groups. The authors conclude that C is safe and efficacious in the reduction of POAF.

To the Editor–Ablation of persistent atrial fibrillation

Ratika Parkash, Anthony S.L. Tang — 2011-11-14

Rostock et al confirm the difficulty faced in the ablation of persistent atrial fibrillation (AF) in their study examining the long-term success of catheter ablation in this group of patients, with a single procedure efficacy at 27%. They comment on atrial substrate modification with various approaches to catheter ablation. We believe that the substrate—both electrophysiological and structural—is crucial to address in patients with persistent AF. We found in a meta-analysis of randomized studies of catheter ablation in AF that irrespective of the approach used in persistent AF in addition to pulmonary vein isolation, the results are similar. The most important aspect to catheter ablation in this group is additional ablation beyond pulmonary vein isolation. The other concept that is important, not addressed by Rostock et al, is the relative contribution of ongoing risk factors for AF, including heart failure, hypertension, sleep apnea, and diabetes.

Reply to the Editor—Persistent Atrial Fibrillation

Thomas Rostock, Stephan Willems — 2011-11-14

We thank Drs. Parkash and Tang for their interest in our recent work. The authors outlined that additional substrate ablation beyond the pulmonary veins is required in patients with persistent atrial fibrillation (AF); however, it does result in similar outcomes irrespective to the approach used to target the substrate. This is true when recurrences are not further classified according to arrhythmia mechanism. When arrhythmia recurrences are distinguished between AF and atrial tachycardia (AT), the impact of ablation complexity becomes evident: an increasing extensiveness of substrate ablation is associated with a decrease of AF and increase of AT recurrences. Furthermore, the distinction of the mode of recurrent arrhythmia is of particular importance because recurrence of AT is considered a step forward on the way to sinus rhythm.

Letter to the Editor—Atrial fibrillation: An inflammatory and autoimmune disorder

David O. Schairer, William R. Levis — 2011-11-21

Atrial fibrillation (AF) is an established inflammatory disorder. Autoimmunity has been suggested to play an important role as autoantibodies have been identified in AF. Identification of contactin-2 on His-Purkinje cells by Pallante et al raises the potential of TH17 cells in the pathogenesis of AF. Contactin-2 is an identified target of TH17 in the gray matter of patients with multiple sclerosis and animals with experimental autoimmune encephalomyelitis—both of which are TH1 and TH17 autoimmune disorder. Recently, psoriasis, another TH1-, TH17-, and TH22-mediated disease, has been identified as a risk factor for AF. On the basis of these findings, we propose that AF is a T-cell autoimmune disorder involving cytotoxic TH1, TH17, and possibly TH22 cells acting on His-Purkinje cells. This hypothesis can be tested by using the methods outlined by Derfuss et al. Autoantibodies, inflammation, and fibrosis are known to be associated with AF. The possibility of a TH2 subtype with pathogenic autoantibodies and fibrosis as well as TH1 (interferon gamma) and TH17 (interleukin 17A) subtypes with pathogenic CD8 T cells need to be considered in the pathogenesis of AF. Further study of AF in autoimmune disorders along with exploring an autoimmune hypothesis in idiopathic AF is warranted.

Reply to the Editor—Atrial Fibrillation: An Inflammatory and Autoimmune Disorder

Hon-Chi Lee, Xiao-Li Wang, Kristin T. Huang, Win-Kuang Shen, Mark R. Pittelkow — 2011-11-18

Many factors contribute to the pathogenesis of atrial fibrillation, including electrical, structural, neurohumoral, and inflammatory mechanisms. Our review indicated that various autoantibodies that may play a role in the development and maintenance of atrial fibrillation have been identified. Indeed, mounting evidence demonstrates correlations between diseases with autoimmune mechanisms, including Graves' disease, celiac disease, and psoriasis, and an increased risk of atrial fibrillation. Schairer and Levis suggested that T-cell–mediated autoimmune disorders should be considered in the pathogenesis of atrial fibrillation. Such mechanisms in atrial fibrillation are currently unknown and unexplored. They proposed the intriguing hypothesis that atrial fibrillation is a T-cell autoimmune disorder involving cytotoxic T helper cells acting on His-Purkinje cells, which express contactin-2, a target of TH17 in patients with multiple sclerosis. It is not known whether patients with multiple sclerosis have a higher incidence of atrial fibrillation, but paroxysmal atrial fibrillation associated with attacks of multiple sclerosis has been reported. Most of the His-Purkinje cells are in the ventricles, and Purkinje fibers are implicated in the development of idiopathic ventricular fibrillation. It is thought-provoking that atrial Purkinje cells may similarly precipitate fibrillation in the atria. The recently reported association as well as potential immune-mediated mechanisms leading to atrial fibrillation in psoriasis needs to be validated and further explored. Although TH1–TH17 cells are critical to induce the skin pathology of psoriasis, the potential for disease-linked autoantibody, cytokine, or other autoinflammatory-mediated mechanisms will need to be examined in the subpopulation of patients with psoriasis who develop or are at risk for atrial fibrillation. Proteomic, immune, and molecular screening technologies to identify and characterize these pathogenic mechanisms can be leveraged to enhance the yield in this search. Adoptive transfer studies reported by Derfuss et al may be useful but have limitations to more broadly characterize novel disease pathomechanisms. We fully agree that further studies to investigate atrial fibrillation in autoimmune disorders as well as to delineate autoimmune mechanisms in idiopathic atrial fibrillation are warranted.